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Non-HLA Antibodies May Accelerate Immune Responses After Intestinal and Multivisceral Transplantation.

PubMed

Gerlach, Undine Ariane; Lachmann, Nils; Ranucci, Giuseppina; Sawitzki, Birgit; Schoenemann, Constanze; Pratschke, Johann; Dragun, Duska; Pascher, Andreas

2017-01-01

Non-HLA alloantibodies and autoantibodies are involved in allograft rejection in kidney and heart transplantation. Their role in intestinal transplantation has not yet been described. We examined the development of antiangiotensin II type I receptor antibodies (anti-AT1R) and antiendothelin type A receptor antibodies associated with the clinical course and histopathological findings of intestinal transplantation recipients. Thirty-seven patients underwent intestinal or multivisceral transplantation. Non-HLA antibodies (non-HLAabs) were screened in 29 transplant recipients. Antibody-levels greater than 12 U/L were considered positive and were evaluated retrospectively regarding rejection episodes. Twenty patients developed anti-AT1R and/or antiendothelin type A receptor antibodies (non-HLAabs group), 9 did not (control group). The non-HLAabs group had a higher rate of allograft rejection than controls (80% vs 55%), especially a higher rate of antibody-mediated rejections (55% vs 11%, P < 0.01) with detection of donor-specific anti-HLAabs. All rejection episodes in the non-HLAabs group appeared around the time of positive non-HLAabs detection. Five patients had acute cellular rejections at the time of non-HLAabs development, 4 had viral infections. Our data suggest that antibody-mediated mechanisms targeting antigens beyond HLA may trigger and accelerate immune responses. Given the possibility of pharmacologic targeting of non-HLA receptors, future studies will focus on the explanation of mechanisms how non-HLAabs may enhance rejection and affect long-term allograft survival.
Vγ4 γδ T Cells Provide an Early Source of IL-17A and Accelerate Skin Graft Rejection.

PubMed

Li, Yashu; Huang, Zhenggen; Yan, Rongshuai; Liu, Meixi; Bai, Yang; Liang, Guangping; Zhang, Xiaorong; Hu, Xiaohong; Chen, Jian; Huang, Chibing; Liu, Baoyi; Luo, Gaoxing; Wu, Jun; He, Weifeng

2017-12-01

Activated γδ T cells have been shown to accelerate allograft rejection. However, the precise role of skin-resident γδ T cells and their subsets-Vγ5 (epidermis), Vγ1, and Vγ4 (dermis)-in skin graft rejection have not been identified. Here, using a male to female skin transplantation model, we demonstrated that Vγ4 T cells, rather than Vγ1 or Vγ5 T cells, accelerated skin graft rejection and that IL-17A was essential for Vγ4 T-cell-mediated skin graft rejection. Moreover, we found that Vγ4 T cells were required for early IL-17A production in the transplanted area, both in skin grafts and in the host epidermis around grafts. Additionally, the chemokine (C-C motif) ligand 20-chemokine receptor 6 pathway was essential for recruitment of Vγ4 T cells to the transplantation area, whereas both IL-1β and IL-23 induced IL-17A production from infiltrating cells. Lastly, Vγ4 T-cell-derived IL-17A promoted the accumulation of mature dendritic cells in draining lymph nodes to subsequently regulate αβ T-cell function after skin graft transplantation. Taken together, our data reveal that Vγ4 T cells accelerate skin graft rejection by providing an early source of IL-17A. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
Rat Cytomegalovirus Vaccine Prevents Accelerated Chronic Rejection in CMV‐Naïve Recipients of Infected Donor Allograft Hearts

PubMed Central

Hwee, Y. K.; Kreklywich, C. N.; Andoh, T.; Denton, M.; Smith, P.; Hart, E.; Broekel, R.; Pallett, C.; Rogers, K.; Streblow, A. D.; Chuop, M.; Perry, A.; Slifka, M.; Messaoudi, I.; Orloff, S. L.

2015-01-01

Cytomegalovirus accelerates transplant vascular sclerosis (TVS) and chronic rejection (CR) in solid organ transplants; however, the mechanisms involved are unclear. We determined the efficacy of a CMV vaccine in preventing CMV‐accelerated rat cardiac allograft rejection in naïve recipients of CMV+ donor hearts. F344 donor rats were infected with RCMV 5 days prior to heterotopic cardiac transplantation into CMV‐naïve or H2O2‐inactivated RCMV‐vaccinated Lewis recipients. Recipients of RCMV‐infected donor hearts rejected at POD59, whereas vaccinated recipients exhibited a significantly prolonged time to rejection‐POD97, similar to recipients of uninfected donor hearts (POD108). Although all of the donor hearts were preinfected, the vaccinated recipients had lower graft and PBMC viral loads at POD 7 compared to unvaccinated controls. Adoptive T cell and passive antibody transfers from vaccinated Lewis rats into naïve recipients demonstrate that both T‐cell and B‐cell arms of the adaptive immune response provide protection against CMV‐accelerated rejection. Similar findings were obtained when testing three different adjuvants in passive transfer experiments. We have determined that the timing of the vaccine prior to transplantation and the specific adjuvant play critical roles in mediating anti‐viral responses and promoting graft survival. CMV vaccination prior to transplantation may effectively increase graft survival. PMID:25766876
Micromanaging alloimmunity.

PubMed

Ford, Mandy L

2016-07-01

Increasing evidence indicates that microbes have a large influence on immune function. Previous studies have linked pathogenic microorganisms with decreased allograft tolerance and subsequent rejection. In this issue of the JCI, Lei and colleagues demonstrate that commensal organisms also influence the host response to allograft transplantation. Using murine skin and cardiac transplant models, the authors demonstrate that allograft rejection is accelerated in mice with a normal microbiome compared with germ-free animals and antibiotic-treated mice. The increased graft rejection observed in conventional animals was due to enhanced T cell priming and was mediated through type I IFN. Together, these results suggest that altering a patient's microbial community prior to transplant could improve allograft acceptance.
Adenovirus-mediated HIF-1α gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection

PubMed Central

Jiang, Xinguo; Khan, Mohammad A.; Tian, Wen; Beilke, Joshua; Natarajan, Ramesh; Kosek, Jon; Yoder, Mervin C.; Semenza, Gregg L.; Nicolls, Mark R.

2011-01-01

Chronic rejection, manifested as small airway fibrosis (obliterative bronchiolitis [OB]), is the main obstacle to long-term survival in lung transplantation. Recent studies demonstrate that the airways involved in a lung transplant are relatively hypoxic at baseline and that OB pathogenesis may be linked to ischemia induced by a transient loss of airway microvasculature. Here, we show that HIF-1α mediates airway microvascular repair in a model of orthotopic tracheal transplantation. Grafts with a conditional knockout of Hif1a demonstrated diminished recruitment of recipient-derived Tie2+ angiogenic cells to the allograft, impaired repair of damaged microvasculature, accelerated loss of microvascular perfusion, and hastened denudation of epithelial cells. In contrast, graft HIF-1α overexpression induced via an adenoviral vector prolonged airway microvascular perfusion, preserved epithelial integrity, extended the time window for the graft to be rescued from chronic rejection, and attenuated airway fibrotic remodeling. HIF-1α overexpression induced the expression of proangiogenic factors such as Sdf1, Plgf, and Vegf, and promoted the recruitment of vasoreparative Tie2+ cells. This study demonstrates that a therapy that enhances vascular integrity during acute rejection may promote graft health and prevent chronic rejection. PMID:21606594
Rescue of CD8+ T cell vaccine memory following sublethal γ irradiation.

PubMed

McFarland, Hugh I; Berkson, Julia D; Lee, Jay P; Elkahloun, Abdel G; Mason, Karen P; Rosenberg, Amy S

2015-07-31

Sublethal γ irradiation eliminates CD8+ T cell mediated memory responses. In this work, we explored how these memory responses could be rescued in the aftermath of such exposure. We utilized two models of CD8+ T cell mediated immunity: a mouse model of Listeria monocytogenes (LM) infection in which CD8+ T cells specific for LM expressed antigens (Listeriolysin O, LLO) can be tracked, and a murine skin graft model in which CD8+ T cells mediate rejection across a MHC class I (D(d)) disparity. In the LM immunized mice, LL0 specific CD8+ T memory cells were lost on irradiation, preserved with rapid revaccination with an attenuated strain 1-3 days post-irradiation (PI), and these mice survived a subsequent wild type LM challenge. A genetic "signature of rescue" identified a group of immune-associated mRNA maintained or upregulated following irradiation and rescue. A number of these factors, including IL-36γ, dectin-2 (Clec4n), and mir101c are upregulated rapidly after exposure of mice to sublethal γ radiation alone and are sustained by early, but not later rescue. Such factors will be evaluated as potential therapeutics to replace individual vaccines for global rescue of CD8+ T memory cell responses following sublethal γ irradiation. The skin allograft model mirrored that of the LM model in that the accelerated D(d) skin allograft rejection response was lost in mice exposed to sublethal γ radiation, but infusion of allogeneic D(d) expressing bone marrow cells 1-4 days PI preserved the CD8+ T memory mediated accelerated rejection response, further suggesting that innate immune responses may not always be essential to rescue of CD8+ memory T cells following γ irradiation. Published by Elsevier Ltd.
Inflammation Causes Resistance to Anti-CD20-Mediated B Cell Depletion.

PubMed

Laws, L H; Parker, C E; Cherala, G; Koguchi, Y; Waisman, A; Slifka, M K; Oberbarnscheidt, M H; Obhrai, J S; Yeung, M Y; Riella, L V

2016-11-01

B cells play a central role in antibody-mediated rejection and certain autoimmune diseases. However, B cell-targeted therapy such as anti-CD20 B cell-depleting antibody (aCD20) has yielded mixed results in improving outcomes. In this study, we investigated whether an accelerated B cell reconstitution leading to aCD20 depletion resistance could account for these discrepancies. Using a transplantation model, we found that antigen-independent inflammation, likely through toll-like receptor (TLR) signaling, was sufficient to mitigate B cell depletion. Secondary lymphoid organs had a quicker recovery of B cells when compared to peripheral blood. Inflammation altered the pharmacokinetics (PK) and pharmacodynamics (PD) of aCD20 therapy by shortening drug half-life and accelerating the reconstitution of the peripheral B cell pool by bone marrow-derived B cell precursors. IVIG (intravenous immunoglobulin) coadministration also shortened aCD20 drug half-life and led to accelerated B cell recovery. Repeated aCD20 dosing restored B cell depletion and delayed allograft rejection, especially B cell-dependent, antibody-independent allograft rejection. These data demonstrate the importance of further clinical studies of the PK/PD of monoclonal antibody treatment in inflammatory conditions. The data also highlight the disconnect between B cell depletion on peripheral blood compared to secondary lymphoid organs, the deleterious effect of IVIG when given with aCD20 and the relevance of redosing of aCD20 for effective B cell depletion in alloimmunity. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.
Circulating donor-specific anti-HLA antibodies are a major factor in premature and accelerated allograft fibrosis.

PubMed

Gosset, Clément; Viglietti, Denis; Rabant, Marion; Vérine, Jérôme; Aubert, Olivier; Glotz, Denis; Legendre, Christophe; Taupin, Jean-Luc; Duong Van-Huyen, Jean-Paul; Loupy, Alexandre; Lefaucheur, Carmen

2017-09-01

Addressing the causes of kidney allograft-accelerated aging is an important challenge for improving long-term transplant outcomes. Here we investigated the role of circulating donor-specific anti-HLA antibodies (HLA-DSAs) in the development and the progression of kidney allograft fibrosis with inclusion of traditional risk factors for allograft fibrosis. We prospectively enrolled 1539 consecutive kidney recipients transplanted in two centers and assessed interstitial fibrosis and tubular atrophy (IF/TA) in biopsies performed at one year post-transplantation. The HLA-DSAs and all traditional determinants of IF/TA were recorded at transplantation and within the first year post-transplantation, including histological diagnoses in 2260 "for cause" biopsies. This identified 498 (32%) patients with severe IF/TA (Banff IF/TA grade 2 or more). HLA-DSAs were significantly associated with severe IF/TA (adjusted odds ratio, 1.53; 95% confidence interval 1.16-2.01) after including 37 determinants. HLA-DSAs remained significantly associated with severe IF/TA in patients without antibody-mediated rejection (adjusted odds ratio 1.54; 1.11-2.14). HLA-DSAs were the primary contributor, being involved in 11% of cases, while T cell-mediated rejection, calcineurin-inhibitor toxicity, acute tubular necrosis, pyelonephritis, and BK virus-associated nephropathy were involved in 9%, 8%, 6%, 5%, and 4% of cases, respectively. One hundred fifty-four patients with HLA-DSA-associated severe IF/TA showed significantly increased microvascular inflammation, transplant glomerulopathy, C4d deposition in capillaries, and decreased allograft survival compared to 344 patients with severe IF/TA without HLA-DSAs. Three hundred seventy-eight patients with post-transplant HLA-DSAs exhibited significantly accelerated progression of IF/TA compared to 1161 patients without HLA-DSAs in the biopsies performed at one year post-transplant and beyond. Thus, circulating HLA-DSAs are major determinants of premature and accelerated allograft fibrosis acting independently of traditional risk factors and antibody-mediated rejection. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
Endogenous Memory CD8 T Cells Directly Mediate Cardiac Allograft Rejection

PubMed Central

Su, C. A.; Iida, S.; Abe, T.; Fairchild, R. L.

2014-01-01

Differences in levels of environmentally induced memory T cells that cross-react with donor MHC molecules are postulated to account for the efficacy of allograft tolerance inducing strategies in rodents versus their failure in nonhuman primates and human transplant patients. Strategies to study the impact of donor-reactive memory T cells on allografts in rodents have relied on the pre-transplant induction of memory T cells cross-reactive with donor allogeneic MHC molecules through recipient viral infection, priming directly with donor antigen, or adoptive transfer of donor-antigen primed memory T cells. Each approach accelerates allograft rejection and confers resistance to tolerance induction, but also biases the T cell repertoire to strong donor-reactivity. The ability of endogenous memory T cells within unprimed mice to directly reject an allograft is unknown. Here we show a direct association between increased duration of cold ischemic allograft storage and numbers and enhanced functions of early graft infiltrating endogenous CD8 memory T cells. These T cells directly mediate rejection of allografts subjected to prolonged ischemia and this rejection is resistant to costimulatory blockade. These findings recapitulate the clinically significant impact of endogenous memory T cells with donor reactivity in a mouse transplant model in the absence of prior recipient priming. PMID:24502272
Central memory CD8+ T lymphocytes mediate lung allograft acceptance

PubMed Central

Krupnick, Alexander Sasha; Lin, Xue; Li, Wenjun; Higashikubo, Ryuiji; Zinselmeyer, Bernd H.; Hartzler, Hollyce; Toth, Kelsey; Ritter, Jon H.; Berezin, Mikhail Y.; Wang, Steven T.; Miller, Mark J.; Gelman, Andrew E.; Kreisel, Daniel

2014-01-01

Memory T lymphocytes are commonly viewed as a major barrier for long-term survival of organ allografts and are thought to accelerate rejection responses due to their rapid infiltration into allografts, low threshold for activation, and ability to produce inflammatory mediators. Because memory T cells are usually associated with rejection, preclinical protocols have been developed to target this population in transplant recipients. Here, using a murine model, we found that costimulatory blockade–mediated lung allograft acceptance depended on the rapid infiltration of the graft by central memory CD8+ T cells (CD44hiCD62LhiCCR7+). Chemokine receptor signaling and alloantigen recognition were required for trafficking of these memory T cells to lung allografts. Intravital 2-photon imaging revealed that CCR7 expression on CD8+ T cells was critical for formation of stable synapses with antigen-presenting cells, resulting in IFN-γ production, which induced NO and downregulated alloimmune responses. Thus, we describe a critical role for CD8+ central memory T cells in lung allograft acceptance and highlight the need for tailored approaches for tolerance induction in the lung. PMID:24569377
Issues in solid-organ transplantation in children: translational research from bench to bedside

PubMed Central

Lipshultz, Steven E.; Chandar, Jayanthi J.; Rusconi, Paolo G.; Fornoni, Alessia; Abitbol, Carolyn L.; Burke III, George W.; Zilleruelo, Gaston E.; Pham, Si M.; Perez, Elena E.; Karnik, Ruchika; Hunter, Juanita A.; Dauphin, Danielle D.; Wilkinson, James D.

2014-01-01

In this review, we identify important challenges facing physicians responsible for renal and cardiac transplantation in children based on a review of the contemporary medical literature. Regarding pediatric renal transplantation, we discuss the challenge of antibody-mediated rejection, focusing on both acute and chronic antibody-mediated rejection. We review new diagnostic approaches to antibody-mediated rejection, such as panel-reactive antibodies, donor-specific cross-matching, antibody assays, risk assessment and diagnosis of antibody-mediated rejection, the pathology of antibody-mediated rejection, the issue of ABO incompatibility in renal transplantation, new therapies for antibody-mediated rejection, inhibiting of residual antibodies, the suppression or depletion of B-cells, genetic approaches to treating acute antibody-mediated rejection, and identifying future translational research directions in kidney transplantation in children. Regarding pediatric cardiac transplantation, we discuss the mechanisms of cardiac transplant rejection, including the role of endomyocardial biopsy in detecting graft rejection and the role of biomarkers in detecting cardiac graft rejection, including biomarkers of inflammation, cardiomyocyte injury, or stress. We review cardiac allograft vasculopathy. We also address the role of genetic analyses, including genome-wide association studies, gene expression profiling using entities such as AlloMap®, and adenosine triphosphate release as a measure of immune function using the Cylex® ImmuKnow™ cell function assay. Finally, we identify future translational research directions in heart transplantation in children. PMID:24860861
Rituximab Therapy for Rejection in Pediatric Heart Transplant.

PubMed

Erdogan, Ilkay; Varan, Birgul; Sezgin, Atilla; Pirat, Arash; Zeyneloglu, Pinar

2018-04-01

Humoral rejection is the B-cell-mediated production of immunoglobulin G antibody against the transplanted heart. Antibody-mediated rejection may be resistant to standard immunosuppressive therapy and is associated with high mortality and graft loss. Rituximab can be used to treat antibody-mediated rejection in heart transplant recipients. This retrospective study describes our experience with rituximab treatment in children with heart transplants. We present 7 pediatric patients with antibody-mediated rejection who were treated with plasma exchange and rituximab therapy. Rituximab was given at a dose of 375 mg/m2 by slow infusion in the intensive care unit after 5 days of plasmapheresis, in addition to a conventional regimen consisting of steroids, mycophenolate mofetil, and tacrolimus. The peripheral blood count and sodium, potassium, serum urea nitrogen, creatinine, aspartate aminotransferase, and alanine aminotransferase levels were measured in all patients before and after treatment. Seven patients were treated with plasma exchange and rituximab. We repeated this therapy in 5 patients because of refractoriness or recurrent rejection. After diagnoses of antibody-mediated rejection, 4 patients died within 6 months (mortality rate of 57.1%). We did not observe any adverse effects or complications related to rituximab. Rituximab can be used in humoral rejection after pediatric heart transplant. However, the success of the treatment is controversial, and further study is needed to find an effective treatment for antibody-mediated rejection and steroid-resistant cellular rejection in children.
The Emerging Importance of Non-HLA Autoantibodies in Kidney Transplant Complications.

PubMed

Cardinal, Héloise; Dieudé, Mélanie; Hébert, Marie-Josée

2017-02-01

Antibodies that are specific to organ donor HLA have been involved in the majority of cases of antibody-mediated rejection in solid organ transplant recipients. However, recent data show that production of non-HLA autoantibodies can occur before transplant in the form of natural autoantibodies. In contrast to HLAs, which are constitutively expressed on the cell surface of the allograft endothelium, autoantigens are usually cryptic. Tissue damage associated with ischemia-reperfusion, vascular injury, and/or rejection creates permissive conditions for the expression of cryptic autoantigens, allowing these autoantibodies to bind antigenic targets and further enhance vascular inflammation and renal dysfunction. Antiperlecan/LG3 antibodies and antiangiotensin II type 1 receptor antibodies have been found before transplant in patients with de novo transplants and portend negative long-term outcome in patients with renal transplants. Here, we review mounting evidence suggesting an important role for autoantibodies to cryptic antigens as novel accelerators of kidney dysfunction and acute or chronic allograft rejection. Copyright © 2017 by the American Society of Nephrology.
Phenotypes of antibody-mediated rejection in organ transplants.

PubMed

Mengel, Michael; Husain, Sufia; Hidalgo, Luis; Sis, Banu

2012-06-01

Antibody-mediated hyperacute rejection was the first rejection phenotype observed in human organ transplants. This devastating phenotype was eliminated by reliable crossmatch technologies. Since then, the focus was on T-cell-mediated rejection and de novo donor-specific antibodies were considered an epiphenomenon of cognate T-cell activation. The immune theory was that controlling the T-cell response would entail elimination of antibody-mediated rejection (ABMR). With modern immunosuppressive drugs, T-cell-mediated rejection is essentially treatable. However, this did not prevent ABMR from emerging as a significant phenotype in all types of organ transplants. It became obvious that both rejection types require distinct treatment and thus reliable diagnosis. This is the current challenge. ABMR, depending on stage, grade, time course, organ type or prior treatment, can present with a wide spectrum of phenotypes. This review summarizes the current diagnostic consensus for ABMR, describes unmet needs and challenges in diagnostics, and proposes new approaches for consideration. © 2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation.
Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence.

PubMed

Sellarés, J; de Freitas, D G; Mengel, M; Reeve, J; Einecke, G; Sis, B; Hidalgo, L G; Famulski, K; Matas, A; Halloran, P F

2012-02-01

We prospectively studied kidney transplants that progressed to failure after a biopsy for clinical indications, aiming to assign a cause to every failure. We followed 315 allograft recipients who underwent indication biopsies at 6 days to 32 years posttransplant. Sixty kidneys progressed to failure in the follow-up period (median 31.4 months). Failure was rare after T-cell-mediated rejection and acute kidney injury and common after antibody-mediated rejection or glomerulonephritis. We developed rules for using biopsy diagnoses, HLA antibody and clinical data to explain each failure. Excluding four with missing information, 56 failures were attributed to four causes: rejection 36 (64%), glomerulonephritis 10 (18%), polyoma virus nephropathy 4 (7%) and intercurrent events 6 (11%). Every rejection loss had evidence of antibody-mediated rejection by the time of failure. Among rejection losses, 17 of 36 (47%) had been independently identified as nonadherent by attending clinicians. Nonadherence was more frequent in patients who progressed to failure (32%) versus those who survived (3%). Pure T-cell-mediated rejection, acute kidney injury, drug toxicity and unexplained progressive fibrosis were not causes of loss. This prospective cohort indicates that many actual failures after indication biopsies manifest phenotypic features of antibody-mediated or mixed rejection and also underscores the major role of nonadherence. © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.
Does perceived parental rejection make adolescents sad and mad? The association of perceived parental rejection with adolescent depression and aggression.

PubMed

Hale, William W; Van Der Valk, Inge; Engels, Rutger; Meeus, Wim

2005-06-01

To research the association of perceived parental rejection to adolescent depression and aggression. This study focused on 1329 Dutch junior high and high school students (47.9% males and 52.1% females; age range 10-19 years) that completed depression, aggression and perceived parental rejection questionnaires. The data were analyzed by structural equation modeling that assumed a relationship between perceived parental rejection and adolescent aggression, as mediated by adolescent depression. Perceived parental rejection, mediated through adolescent depression, explains aggressive behaviors of adolescents, as tested by a mediation model. Additionally, the fit of this mediation model is somewhat enhanced when direct paths from perceived parental rejection to aggression are included. Further analysis demonstrates that these effects are also somewhat dependent on the gender and the age of the adolescents, as would be expected in light of previous studies of these cohorts. The study of perceived parental rejection should receive the same attention in the research of the development of both adolescent depression and aggression, as has been the case for adolescent peer rejection.
Explaining the paradoxical rejection-aggression link: the mediating effects of hostile intent attributions, anger, and decreases in state self-esteem on peer rejection-induced aggression in youth.

PubMed

Reijntjes, Albert; Thomaes, Sander; Kamphuis, Jan H; Bushman, Brad J; de Castro, Bram Orobio; Telch, Michael J

2011-07-01

People are strongly motivated to feel accepted by others. Yet when faced with acute peer rejection they often aggress against the very peers they desire acceptance from, which may lead to further rejection. The present experiment tests three potential mediators of aggressive responses to acute peer rejection in the critical developmental stage of early adolescence. Participants (N=185, M(age)=11.5 years) completed personal profiles that were allegedly evaluated online by peers. After receiving negative or neutral peer feedback, participants could aggress against the same peers who had evaluated them. Rejected participants attributed more hostile intent to the peers, were angrier, showed a greater reduction in state self-esteem, and were more aggressive. Mediational analyses showed that hostile intent attributions mediated the acute peer rejection-aggression relationship, whereas increases in anger and decreases in state self-esteem did not. Thus, acute peer rejection evokes hostile intent attributions that, in turn, lead to aggressive reactions. © 2011 by the Society for Personality and Social Psychology, Inc
Rejection Sensitivity Mediates the Relationship between Social Anxiety and Body Dysmorphic Concerns

PubMed Central

Fang, Angela; Asnaani, Anu; Gutner, Cassidy; Cook, Courtney; Wilhelm, Sabine; Hofmann, Stefan G.

2011-01-01

The goal of this study was to examine the role of rejection sensitivity in the relationship between social anxiety and body dysmorphic concerns. To test our hypothesis that rejection sensitivity mediates the link between social anxiety and body dysmorphic concerns, we administered self-report questionnaires to 209 student volunteers. Consistent with our prediction, rejection sensitivity partially mediated the relationship between social anxiety symptoms and body dysmorphic concerns. The implications of the overlap between these constructs are discussed. PMID:21741203
The Mediating Roles of Rejection Sensitivity and Proximal Stress in the Association Between Discrimination and Internalizing Symptoms Among Sexual Minority Women.

PubMed

Dyar, Christina; Feinstein, Brian A; Eaton, Nicholas R; London, Bonita

2018-01-01

The negative impact of discrimination on mental health among lesbian, gay, and bisexual populations has been well documented. However, the possible mediating roles of sexual orientation rejection sensitivity and rejection-based proximal stress in the association between discrimination and internalizing symptoms remain unclear. Rejection-based proximal stress is a subset of proximal stressors that are theorized to arise from concerns about and expectations of sexual orientation-based rejection and discrimination. Drawing on minority stress theory, we tested potential mediating effects using indirect effects structural equation modeling in a sample of 300 sexual minority women. Results indicated that the indirect effect of discrimination on internalizing symptoms (a latent variable indicated by depression and anxiety symptoms) through sexual orientation rejection sensitivity and rejection-based proximal stress (a latent variable indicated by preoccupation with stigma, concealment motivation, and difficulty developing a positive sexual identity) was significant. Additionally, the indirect effects of discrimination on rejection-based proximal stress through sexual orientation rejection sensitivity and of sexual orientation rejection sensitivity on internalizing symptoms through rejection-based proximal stress were also significant. These findings indicate that sexual orientation rejection sensitivity plays an important role in contributing to rejection-based proximal stress and internalizing symptoms among sexual minority women.
Autologous Hematopoietic Stem Cell Transplantation to Prevent Antibody Mediated Rejection After Vascularized Composite Allotransplantation

DTIC Science & Technology

2017-10-01

Award Number: W81XWH-16-1-0664 TITLE: Autologous Hematopoietic Stem Cell Transplantation to Prevent Antibody-Mediated Rejection after...Annual 3. DATES COVERED 15 Sep 2016 – 14 Sep 2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Autologous Hematopoietic Stem Cell Transplantation to...sensitization, autologous hematopoietic stem cell transplantation, antibody mediated rejection, donor specific antibodies 16. SECURITY CLASSIFICATION OF

Peer Rejection and Internalizing Behavior: The Mediating Role of Peer Victimization in Preschool.

PubMed

Metin Aslan, Özge

2018-05-23

The author examined the relationship among peer rejection, peer victimization, and internalizing behaviors. The author hypothesized that physical and relational victimization would have a different indirect effect on the relationship between peer rejection and internalizing behaviors. Participants were 94 preschool children (37 girls; average age 49.97 months) from two university preschools located in the northern part of the United States. The results indicated that internalizing behaviors predicted the mediating variables only regarding relational victimization. Relational victimization indirectly affected the association between peer rejection and internalizing behaviors. The study provides evidence of the mediating effect of victimization behaviors on the relationship among peer rejection, victimization, and internalizing behaviors.
Enhancement of islet engraftment and achievement of long-term islet allograft survival by Toll-like receptor 4 blockade.

PubMed

Giovannoni, Laurianne; Muller, Yannick D; Lacotte, Stéphanie; Parnaud, Géraldine; Borot, Sophie; Meier, Raphaël P H; Lavallard, Vanessa; Bédat, Benoît; Toso, Christian; Daubeuf, Bruno; Elson, Greg; Shang, Limin; Morel, Philippe; Kosco-Vilbois, Marie; Bosco, Domenico; Berney, Thierry

2015-01-01

Toll-like receptors are key players in sterile inflammation phenomena and can link the innate and adaptive immune systems by enhancing graft immunogenicity. They are also considered mediators of types 1 and 2 diabetes development. The aim of the present study was to assess the role of Toll-like receptor-4 (TLR4) in mediating the inflammatory and immune responses to pancreatic islets, thereby promoting inflammatory destruction and immune rejection of islet grafts. Experiments were conducted in murine and human in vitro systems and in vivo murine islet transplant models, using species-specific anti-TLR4 monoclonal antibodies. In vitro, mixed lymphocyte-islet reaction experiments were performed to assess T-cell activation and proliferation. In vivo, both a syngeneic (B6-to-B6) marginal mass islet transplant model to assess the impact of TLR4 blockade on islet engraftment and an allogeneic (DBA1-to-B6) model were used. In vitro TLR4 blockade decreased lipopolysaccharide-mediated β-cell apoptosis and T-cell activation and proliferation against allogeneic islets. In vivo, TLR4 blockade resulted in significantly better syngeneic marginal mass islet engraftment and in indefinite allogeneic islet graft survival. Tolerance was not observed because donor-specific skin graft rechallenge in nonrejecting animals resulted in rejection of both skin and islets, but without accelerated rejection as compared to naive animals. Taken together, our data indicate that TLR4 blockade leads to a significant improvement of syngeneic islet engraftment and of allogeneic islet graft survival. A mechanism of graft accommodation with concurrent inhibition of donor-specific immune memory is likely to be involved.
PRINS Long Noncoding RNA Involved in IP-10-Mediated Allograft Rejection in Rat Kidney Transplant.

PubMed

Zou, X-F; Song, B; Duan, J-H; Hu, Z-D; Cui, Z-L; Yang, T

2018-06-01

Previously, high levels of CXCR3+ T-cell recruitment was demonstrated in the prolonged ischemia-accelerated acute allograft rejection in rat kidney transplant. In the present study, the effect of chemokine IP-10 was investigated and the expression of chemokine-related PRINS (Psoriasis susceptibility-related RNA gene induced by stress) lncRNA determined in the allografts subjected to ischemia. F344-to-Lewis rat kidney transplantation was performed, and renal grafts were stored for 2 hours or 16 hours. Samples were removed at 24 hours and 7 days after operation. Cellular infiltration was determined with the use of immunohistochemistry, and messenger RNA expression was assessed with the use of real-time polymerase chain reaction. The 16-hour-ischemia kidney displayed acute tubule damage and up-regulation of PRINS lncRNA expression. On day 7, IP-10 expression and CD3-positive T cells were increased in allografts compared with control samples, which were inhibited by the IP-10 antibody treatment accompanied by reduced serum creatinine. These observations provide evidence for IP-10 in a regulatory role in cold ischemia-elicited acute allograft rejection and in PRINS lncRNA expression. Our data enhance the understanding of the mechanism underlying between prolonged ischemia and acute rejection. Copyright © 2018 Elsevier Inc. All rights reserved.
Endothelial chimerism and vascular sequestration protect pancreatic islet grafts from antibody-mediated rejection

PubMed Central

Chen, Chien-Chia; Pouliquen, Eric; Broisat, Alexis; Andreata, Francesco; Racapé, Maud; Bruneval, Patrick; Kessler, Laurence; Ahmadi, Mitra; Bacot, Sandrine; Saison-Delaplace, Carole; Marcaud, Marina; Van Huyen, Jean-Paul Duong; Loupy, Alexandre; Villard, Jean; Demuylder-Mischler, Sandrine; Morelon, Emmanuel; Tsai, Meng-Kun; Kolopp-Sarda, Marie-Nathalie; Koenig, Alice; Mathias, Virginie; Ghezzi, Catherine; Dubois, Valerie; Defrance, Thierry

2017-01-01

Humoral rejection is the most common cause of solid organ transplant failure. Here, we evaluated a cohort of 49 patients who were successfully grafted with allogenic islets and determined that the appearance of donor-specific anti-HLA antibodies (DSAs) did not accelerate the rate of islet graft attrition, suggesting resistance to humoral rejection. Murine DSAs bound to allogeneic targets expressed by islet cells and induced their destruction in vitro; however, passive transfer of the same DSAs did not affect islet graft survival in murine models. Live imaging revealed that DSAs were sequestrated in the circulation of the recipients and failed to reach the endocrine cells of grafted islets. We used murine heart transplantation models to confirm that endothelial cells were the only accessible targets for DSAs, which induced the development of typical microvascular lesions in allogeneic transplants. In contrast, the vasculature of DSA-exposed allogeneic islet grafts was devoid of lesions because sprouting of recipient capillaries reestablished blood flow in grafted islets. Thus, we conclude that endothelial chimerism combined with vascular sequestration of DSAs protects islet grafts from humoral rejection. The reduced immunoglobulin concentrations in the interstitial tissue, confirmed in patients, may have important implications for biotherapies such as vaccines and monoclonal antibodies. PMID:29202467
A Developmental Perspective on Peer Rejection, Deviant Peer Affiliation, and Conduct Problems Among Youth.

PubMed

Chen, Diane; Drabick, Deborah A G; Burgers, Darcy E

2015-12-01

Peer rejection and deviant peer affiliation are linked consistently to the development and maintenance of conduct problems. Two proposed models may account for longitudinal relations among these peer processes and conduct problems: the (a) sequential mediation model, in which peer rejection in childhood and deviant peer affiliation in adolescence mediate the link between early externalizing behaviors and more serious adolescent conduct problems; and (b) parallel process model, in which peer rejection and deviant peer affiliation are considered independent processes that operate simultaneously to increment risk for conduct problems. In this review, we evaluate theoretical models and evidence for associations among conduct problems and (a) peer rejection and (b) deviant peer affiliation. We then consider support for the sequential mediation and parallel process models. Next, we propose an integrated model incorporating both the sequential mediation and parallel process models. Future research directions and implications for prevention and intervention efforts are discussed.
A Developmental Perspective on Peer Rejection, Deviant Peer Affiliation, and Conduct Problems among Youth

PubMed Central

Chen, Diane; Drabick, Deborah A. G.; Burgers, Darcy E.

2015-01-01

Peer rejection and deviant peer affiliation are linked consistently to the development and maintenance of conduct problems. Two proposed models may account for longitudinal relations among these peer processes and conduct problems: the (a) sequential mediation model, in which peer rejection in childhood and deviant peer affiliation in adolescence mediate the link between early externalizing behaviors and more serious adolescent conduct problems; and (b) parallel process model, in which peer rejection and deviant peer affiliation are considered independent processes that operate simultaneously to increment risk for conduct problems. In this review, we evaluate theoretical models and evidence for associations among conduct problems and (a) peer rejection and (b) deviant peer affiliation. We then consider support for the sequential mediation and parallel process models. Next, we propose an integrated model incorporating both the sequential mediation and parallel process models. Future research directions and implications for prevention and intervention efforts are discussed. PMID:25410430
Family and community rejection and a Congolese led mediation intervention to reintegrate rejected survivors of sexual violence in Eastern Democratic Republic of Congo.

PubMed

Kohli, Anjalee; Tosha, Maphie; Ramazani, Paul; Safari, Octave; Bachunguye, Richard; Zahiga, Isaya; Iragi, Aline; Glass, Nancy

2013-01-01

Our purpose in this study is to describe the multiple and inter-related health, economic, and social reasons for rejection and to provide an example of a Congolese-led family mediation program to reintegrate survivors into their families. We conducted this study in Eastern Democratic Republic of Congo (DRC) and included two focus group discussions and twenty-seven interviews. Rejection extends beyond physical dislocation to include economic and social aspects. Family mediation is a process requiring knowledge of traditions and norms. Understanding the context of rejection and supporting promising local reintegration efforts will likely improve health, economic, and social outcomes for the survivor, her family, and her community.
Free to be me: The relationship between the true self, rejection sensitivity, and use of online dating sites.

PubMed

Hance, Margaret A; Blackhart, Ginette; Dew, Megan

2018-01-01

Prior research (Blackhart et al., 2014) found that rejection-sensitive individuals are more likely to use online dating sites. The purpose of the current research was to explain the relationship between rejection sensitivity and online dating site usage. Study 1 examined whether true self mediated the relation between rejection sensitivity and online dating. Study 2 sought to replicate the findings of Study 1 and to examine whether self-disclosure moderated the relationship between true self and online dating in the mediation model. Results replicated those found by Blackhart et al. and also found that true self mediated the relationship between rejection sensitivity and online dating site usage. These findings suggest that rejection-sensitive individuals feel they can more easily represent their "true" selves in online environments, such as online dating sites, which partially explains why they are more likely to engage in online dating.
Rituximab-Related Late-Onset Neutropenia in Kidney Transplant Recipients Treated for Antibody-Mediated Acute Rejection.

PubMed

Ahmadi, Fatemeh; Dashti-Khavidaki, Simin; Khatami, Mohammad-Reza; Lessan-Pezeshki, Mahboob; Khalili, Hossein; Khosravi, Malihe

2017-08-01

Kidney transplant is a new area for use of rituximab, which is being used to treat acute antibody-mediated rejection or as an induction agent in ABO- or HLA-incompatible grafts. We report on late-onset neutropenia in rituximab-treated kidney transplant recipients with antibody-mediated rejection. This observational prospective study was performed on kidney transplant recipients with clinically suspicious or biopsy-proven antibody-mediated rejection treated with plasmapheresis plus intravenous immunoglobulin with (cases) or without (controls) rituximab. Compared with none of the controls, 4 of 6 patients (66.7%) in the rituximab-treated group experienced late-onset neutropenia 35 to 93 days after the last dose of rituximab. The course of neutropenia was complicated by endocarditis in 1 patient, resulting in his death just because of a lack of valvular surgery. Increased use of rituximab to treat antibody-mediated rejection among kidney transplant recipients requires attention to its late-onset adverse event, neutropenia. Although asymptomatic in some patients, kidney transplant recipients treated concomitantly with plasmapheresis and mycophenolate mofetil are predisposed to hypogammaglobulinemia, and monitoring of patients for infections is required.
Resilience and rejection sensitivity mediate long-term outcomes of parental divorce.

PubMed

Schaan, Violetta K; Vögele, Claus

2016-11-01

Increasing divorce rates leave more and more children to deal with the separation of their parents. Recent research suggests that children of divorced parents more often experience psychological and physical symptoms than children of non-divorced parents. The processes that mediate the relationship between parental divorce and ill-health, however, are still elusive. This study investigated the mediating role of psychological factors such as resilience and rejection sensitivity on the long-term consequences of parental divorce in young adults. One hundred and ninety-nine participants (mean age 22.3 years) completed an online survey, including measures of mental health, childhood trauma, resilience, and rejection sensitivity. Participants with divorced parents (33 %) reported increased levels of psychological symptoms, childhood trauma, rejection sensitivity, and lower levels of resilience. The association between parental divorce and mental health was fully mediated by resilience, rejection sensitivity, and childhood trauma. The mediation model explained up to 44 % of the total variance in mental health symptoms. Resilience and rejection sensitivity are crucial factors for successful coping with the experience of parental separation. Prevention programs that help to boost children's resilience might help to reduce the long-term effects of parental divorce on their attachment style (e.g., rejection sensitivity), thereby improving their mental health on the long run. Furthermore, the results call for parental awareness and counseling to target and reduce the observed increased level of childhood trauma. Limitations concern the cross-sectional and retrospective design of the study.
Rejection Sensitivity, Jealousy, and the Relationship to Interpersonal Aggression.

PubMed

Murphy, Anna M; Russell, Gemma

2018-07-01

The development and maintenance of interpersonal relationships lead individuals to risk rejection in the pursuit of acceptance. Some individuals are predisposed to experience a hypersensitivity to rejection that is hypothesized to be related to jealous and aggressive reactions within interpersonal relationships. The current study used convenience sampling to recruit 247 young adults to evaluate the relationship between rejection sensitivity, jealousy, and aggression. A mediation model was used to test three hypotheses: Higher scores of rejection sensitivity would be positively correlated to higher scores of aggression (Hypothesis 1); higher scores of rejection sensitivity would be positively correlated to higher scores of jealousy (Hypothesis 2); jealousy would mediate the relationship between rejection sensitivity and aggression (Hypothesis 3). Study results suggest a tendency for individuals with high rejection sensitivity to experience higher levels of jealousy, and subsequently have a greater propensity for aggression, than individuals with low rejection sensitivity. Future research that substantiates a link between hypersensitivity to rejection, jealousy, and aggression may provide an avenue for prevention, education, or intervention in reducing aggression within interpersonal relationships.
Natural killer cells play a critical role in mediating inflammation and graft failure during antibody-mediated rejection of kidney allografts.

PubMed

Kohei, Naoki; Tanaka, Toshiaki; Tanabe, Kazunari; Masumori, Naoya; Dvorina, Nina; Valujskikh, Anna; Baldwin, William M; Fairchild, Robert L

2016-06-01

While the incidence of antibody-mediated kidney graft rejection has increased, the key cellular and molecular participants underlying this graft injury remain unclear. Rejection of kidney allografts in mice lacking the chemokine receptor CCR5 is dependent on production of donor-specific antibody. Here we determine if cells expressing cytotoxic function contributed to antibody-mediated kidney allograft rejection in these recipients. Wild-type C57BL/6, B6.CCR5(-/-), and B6.CD8(-/-)/CCR5(-/-) mice were transplanted with complete MHC-mismatched A/J kidney grafts, and intragraft inflammatory components were followed to rejection. B6.CCR5(-/-) and B6.CD8(-/-)/CCR5(-/-) recipients rejected kidney allografts by day 35, whereas 65% of allografts in wild-type recipients survived past day 80 post-transplant. Rejected allografts in wild-type C57BL/6, B6.CCR5(-/-), and B6.CD8(-/-)/CCR5(-/-) recipients expressed high levels of VCAM-1 and MMP7 mRNA that was associated with high serum titers of donor-specific antibody. High levels of perforin and granzyme B mRNA expression peaked on day 6 post-transplant in allografts in all recipients, but were absent in isografts. Depletion of natural killer cells in B6.CD8(-/-)/CCR5(-/-) recipients reduced this expression to background levels and promoted the long-term survival of 40% of the kidney allografts. Thus, natural killer cells have a role in increased inflammation during antibody-mediated kidney allograft injury and in rejection of the grafts. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
Natural killer cells play a critical role in mediating inflammation and graft failure during antibody-mediated rejection of kidney allografts

PubMed Central

Kohei, Naoki; Tanaka, Toshiaki; Tanabe, Kazunari; Masumori, Naoya; Dvorina, Nina; Valujskikh, Anna; Baldwin, William M.; Fairchild, Robert L.

2016-01-01

While the incidence of antibody-mediated kidney graft rejection has increased, the key cellular and molecular participants underlying this graft injury remain unclear. Rejection of kidney allografts in mice lacking the chemokine receptor CCR5 is dependent on production of donor-specific antibody. Here we determine if cells expressing cytotoxic function contributed to antibody-mediated kidney allograft rejection in these recipients. Wild type C57BL/6, B6.CCR5−/− and B6.CD8−/−/CCR5−/− mice were transplanted with complete MHC mismatched A/J kidney grafts and intra-graft inflammatory components were followed to rejection. B6.CCR5−/− and B6.CD8−/−/CCR5−/− recipients rejected kidney allografts by day 35 whereas 65% of allografts in wild type recipients survived past day 80 post-transplant. Rejected allografts in wild-type C57BL/6, B6.CCR5−/− and B6.CD8−/−/CCR5−/− recipients expressed high levels of VCAM-1 and MMP7 mRNA that was associated with high serum titers of donor-specific antibody. High levels of perforin and granzyme B mRNA expression peaked on day 6 post-transplant in allografts in all recipients, but were absent in isografts. Depletion of natural killer cells in B6.CD8−/−/CCR5−/− recipients reduced this expression to background levels and promoted the long-term survival of 40% of the kidney allografts. Thus, natural killer cells have a role in increased inflammation during antibody-mediated kidney allograft injury and in rejection of the grafts. PMID:27165816
Warm and harsh parenting as mediators of the relation between maternal and adolescent emotion regulation.

PubMed

Sarıtaş, Dilek; Grusec, Joan E; Gençöz, Tülin

2013-12-01

Maternal hostility/rejection and warmth were considered as potential mediators of the relation between mothers' and adolescents' emotion regulation. Participants were first-year high school students living in Ankara, Turkey and their mothers (N = 365). Scales assessing emotion regulation difficulties and maternal hostility/rejection and warmth were administered to both the adolescents and their mothers. Maternal hostility/rejection, but not warmth, mediated the relation between maternal and adolescent emotion regulation. For girls there was, additionally, a direct effect of maternal emotion regulation. The different roles played by parental rejection and parental warmth in the development of adolescents' emotion regulation accord with arguments that socialization occurs in different domains and that rejection and warmth are not aspects of the same domain. Copyright © 2013 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.
Recurrent AA Amyloidosis Combined With Chronic Active Antibody-mediated Rejection After Kidney Transplantation.

PubMed

Yeo, Min-Kyung; Ham, Young Rok; Choi, Song-Yi; Lee, Yong-Moon; Park, Moon Hyang; Suh, Kwang-Sun

2017-07-01

Kidney transplantation for amyloidosis remains a contentious issue. Recurrence of amyloidosis is one of the risks of transplantation. Chronic active antibody-mediated rejection is an important cause of chronic allograft dysfunction. A 47-year-old woman underwent kidney transplantation due to renal AA amyloidosis with unknown etiology. Six years posttransplantation, a kidney biopsy showed AA amyloidosis with chronic active antibody-mediated rejection. Donor-specific antibody class II was positive. The patient underwent intravenous plasmapheresis and treatment with rituximab and colchicine. The relationship between recurrence of amyloidosis and rejection was not obvious. Clinical characteristics of kidney transplantation for AA amyloidosis were subjected to literature review and 315 cases were identified. The incidence of amyloidosis recurrence and acute and chronic rejection rates were 15%, 15%, and 8%, respectively. Five-year patient and graft survival rates were 77% and 82%, respectively. Clinical courses of kidney transplantation in AA amyloidosis were, thus, identified.
HEart trAnsplantation Registry of piTie-Salpetriere University Hospital

ClinicalTrials.gov

2018-01-08

Cardiac Transplant Disorder; Cardiac Death; Heart Failure; Acute Cellular Graft Rejection; Antibody-Mediated Graft Rejection; Cardiac Allograft Vasculopathy; Heart Transplant Rejection; Immune Tolerance
Dissolved organic matter and estrogen interactions regulate estrogen removal in the aqueous environment: A review.

PubMed

Ma, Li; Yates, Scott R

2018-06-03

This review summarizes the characterization and quantification of interactions between dissolved organic matter (DOM) and estrogens as well as the effects of DOM on aquatic estrogen removal. DOM interacts with estrogens via binding or sorption mechanisms like π-π interaction and hydrogen bonding. The binding affinity is evaluated in terms of organic-carbon-normalized sorption coefficient (Log K OC ) which varies with types and composition of DOM. DOM has been suggested to be a more efficient sorbent compared with other matrices, such as suspended particulate matter, sediment and soil; likely associated with its large surface area and concentrated carbon content. As a photosensitizer, DOM enhanced estrogen photodegradation when the concentration of DOM was below a threshold value, and when above, the acceleration effect was not observed. DOM played a dual role in affecting biodegradation of estrogens depending on the recalcitrance of the DOM and the nutrition status of the degraders. DOM also acted as an electron shuttle (redox mediator) mediating the degradation of estrogens. DOM hindered enzyme-catalyzed removal of estrogens while enhanced their transformation during the simultaneous photo-enzymatic process. Membrane rejection of estrogens was pronounced for hydrophobic DOM with high aromaticity and phenolic moiety content. Elimination of estrogens via photolysis, biodegradation, enzymolysis and membrane rejection in the presence of DOM is initiated by sorption, accentuating the role of DOM as a mediator in regulating aquatic estrogen removal. Published by Elsevier B.V.
C4d-negative antibody-mediated rejection with high anti-angiotensin II type I receptor antibodies in absence of donor-specific antibodies.

PubMed

Fuss, Alexander; Hope, Christopher M; Deayton, Susan; Bennett, Greg Donald; Holdsworth, Rhonda; Carroll, Robert P; Coates, P Toby H

2015-07-01

Acute antibody-mediated rejection can occur in absence of circulating donor-specific antibodies. Agonistic antibodies targeting the anti-angiotensin II type 1 receptor (anti-AT1 R) are emerging as important non-human leucocyte antigen (HLA) antibodies. Elevated levels of anti-angiotensin II receptor antibodies were first observed in kidney transplant recipients with malignant hypertension and allograft rejection. They have now been studied in three separate kidney transplant populations and associate to frequency of rejection, severity of rejection and graft failure. We report 11 cases of biopsy-proven, Complement 4 fragment d (C4d)-negative, acute rejection occurring without circulating donor-specific anti-HLA antibodies. In eight cases, anti-angiotensin receptor antibodies were retrospectively examined. The remaining three subjects were identified from our centre's newly instituted routine anti-angiotensin receptor antibody screening. All subjects fulfilled Banff 2013 criteria for antibody-mediated rejection and all responded to anti-rejection therapy, which included plasma exchange and angiotensin receptor blocker therapy. These cases support the routine assessment of anti-AT1 R antibodies in kidney transplant recipients to identify subjects at risk. Further studies will need to determine optimal assessment protocol and the effectiveness of pre-emptive treatment with angiotensin receptor blockers. © 2015 Asian Pacific Society of Nephrology.
Disappearance of T Cell-Mediated Rejection Despite Continued Antibody-Mediated Rejection in Late Kidney Transplant Recipients

PubMed Central

Chang, Jessica; Famulski, Konrad; Hidalgo, Luis G.; Salazar, Israel D.R.; Merino Lopez, Maribel; Matas, Arthur; Picton, Michael; de Freitas, Declan; Bromberg, Jonathan; Serón, Daniel; Sellarés, Joana; Einecke, Gunilla; Reeve, Jeff

2015-01-01

The prevalent renal transplant population presents an opportunity to observe the adaptive changes in the alloimmune response over time, but such studies have been limited by uncertainties in the conventional biopsy diagnosis of T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). To circumvent these limitations, we used microarrays and conventional methods to investigate rejection in 703 unselected biopsies taken 3 days to 35 years post-transplant from North American and European centers. Using conventional methods, we diagnosed rejection in 205 biopsy specimens (28%): 67 pure TCMR, 110 pure ABMR, and 28 mixed (89 designated borderline). Using microarrays, we diagnosed rejection in 228 biopsy specimens (32%): 76 pure TCMR, 124 pure ABMR, and 28 mixed (no borderline). Molecular assessment confirmed most conventional diagnoses (agreement was 90% for TCMR and 83% for ABMR) but revealed some errors, particularly in mixed rejection, and improved prediction of failure. ABMR was strongly associated with increased graft loss, but TCMR was not. ABMR became common in biopsy specimens obtained >1 year post-transplant and continued to appear in all subsequent intervals. TCMR was common early but progressively disappeared over time. In 108 biopsy specimens obtained 10.2–35 years post-transplant, TCMR defined by molecular and conventional features was never observed. We conclude that the main cause of kidney transplant failure is ABMR, which can present even decades after transplantation. In contrast, TCMR disappears by 10 years post-transplant, implying that a state of partial adaptive tolerance emerges over time in the kidney transplant population. PMID:25377077
Borderline Personality Features, Anger, and Intimate Partner Violence: An Experimental Manipulation of Rejection.

PubMed

Armenti, Nicholas A; Babcock, Julia C

2018-04-01

Individuals with borderline personality features may be susceptible to react to situational stressors with negative and interpersonally maladaptive emotionality (e.g., anger) and aggression. The current study attempted to test two moderated mediation models to investigate dispositional risk factors associated with borderline personality features and intimate partner violence (IPV). Results from an experimental rejection induction paradigm were examined using moderated regression to observe contextual reactions to imagined romantic rejection from a current romantic partner among individuals with borderline personality features. An ethnically diverse sample of 218 undergraduates at a large public university in the southwestern United States was recruited. Participants responded to demographic questions and self-report measures, and engaged in an experimental rejection induction paradigm. Borderline personality features was positively associated with rejection sensitivity, physical assault, and psychological aggression. Contrary to initial hypotheses, rejection sensitivity did not serve as a mediator of the relations between borderline personality features and physical assault and psychological aggression. However, trait anger mediated the relation between borderline personality features and psychological aggression. As such, trait anger may be an important explanatory variable in the relation between borderline personality features and psychological aggression specifically. Results of the rejection induction paradigm indicated that, for individuals who were asked to imagine an ambiguous rejection, the relation between borderline personality features and state anger post-rejection was strengthened. For individuals who imagined a critical rejection, there was no significant relation between borderline personality features and state anger post-rejection. Findings suggest that trait anger may be an important dispositional factor in the link between borderline personality features and IPV. In addition, contextual factors, such as ambiguous rejection by an intimate partner, may be especially relevant in activating anger or aggression in individuals with borderline personality features.

Victimization, social anxiety, and body dysmorphic concerns: appearance-based rejection sensitivity as a mediator.

PubMed

Lavell, Cassie H; Zimmer-Gembeck, Melanie J; Farrell, Lara J; Webb, Haley

2014-09-01

Body dysmorphic disorder (BDD) is characterized by extreme preoccupation with perceived deficits in physical appearance, and sufferers experience severe impairment in functioning. Previous research has indicated that individuals with BDD are high in social anxiety, and often report being the victims of appearance-based teasing. However, there is little research into the possible mechanisms that might explain these relationships. The current study examined appearance-based rejection sensitivity as a mediator between perceived appearance-based victimization, social anxiety, and body dysmorphic symptoms in a sample of 237 Australian undergraduate psychology students. Appearance-based rejection sensitivity fully mediated the relationship between appearance-based victimization and body dysmorphic symptoms, and partially mediated the relationship between social anxiety and body dysmorphic symptoms. Findings suggest that individuals high in social anxiety or those who have a history of more appearance-based victimization may have a bias towards interpreting further appearance-based rejection, which may contribute to extreme appearance concerns such as BDD. Copyright © 2014 Elsevier Ltd. All rights reserved.
Revisiting Traditional Risk Factors for Rejection and Graft Loss after Kidney Transplantation

PubMed Central

Dunn, TB; Noreen, H; Gillingham, K; Maurer, D; Ozturk, O. Goruroglu; Pruett, TL; Bray, RA; Gebel, HM; Matas, AJ

2011-01-01

Single antigen bead (SAB) testing permits reassessment of immunologic risk for kidney transplantation. Traditionally, high panel reactive antibody (PRA), retransplant and deceased donor (DD) grafts have been associated with increased risk. We hypothesized that this risk was likely mediated by (unrecognized) donor-specific antibody (DSA). We grouped 587 kidney transplants using clinical history and SAB testing of day of transplant serum as 1) unsensitized; PRA=0 (n= 178), 2) 3rd party sensitized; no DSA (n=363), or 3) donor sensitized; with DSA (n=46), and studied rejection rates, death censored graft survival (DCGS), and risk factors for rejection. Antibody-mediated rejection (AMR) rates were increased with DSA (p<0.0001), but not with PRA in the absence of DSA. Cell-mediated rejection (CMR) rates were increased with DSA (p<0.005); with a trend to increased rates when PRA>0 in the absence of DSA (p=0.08). Multivariate analyses showed risk factors for AMR were DSA, worse HLA matching, and female gender; for CMR: DSA, PRA>0 and worse HLA matching. AMR and CMR were associated with decreased DCGS. The presence of DSA is an important predictor of rejection risk, in contrast to traditional risk factors. Further development of immunosuppressive protocols will be facilitated by stratification of rejection risk by donor sensitization. PMID:21812918
Peer Rejection and Social Information-Processing Factors in the Development of Aggressive Behavior Problems in Children

PubMed Central

Dodge, Kenneth A.; Lansford, Jennifer E.; Burks, Virginia Salzer; Bates, John E.; Pettit, Gregory S.; Fontaine, Reid; Price, Joseph M.

2009-01-01

The relation between social rejection and growth in antisocial behavior was investigated. In Study 1, 259 boys and girls (34% African American) were followed from Grades 1 to 3 (ages 6–8 years) to Grades 5 to 7 (ages 10–12 years). Early peer rejection predicted growth in aggression. In Study 2, 585 boys and girls (16% African American) were followed from kindergarten to Grade 3 (ages 5–8 years), and findings were replicated. Furthermore, early aggression moderated the effect of rejection, such that rejection exacerbated antisocial development only among children initially disposed toward aggression. In Study 3, social information-processing patterns measured in Study 1 were found to mediate partially the effect of early rejection on later aggression. In Study 4, processing patterns measured in Study 2 replicated the mediation effect. Findings are integrated into a recursive model of antisocial development. PMID:12705561
Blood Vessels in Allotransplantation.

PubMed

Abrahimi, P; Liu, R; Pober, J S

2015-07-01

Human vascularized allografts are perfused through blood vessels composed of cells (endothelium, pericytes, and smooth muscle cells) that remain largely of graft origin and are thus subject to host alloimmune responses. Graft vessels must be healthy to maintain homeostatic functions including control of perfusion, maintenance of permselectivity, prevention of thrombosis, and participation in immune surveillance. Vascular cell injury can cause dysfunction that interferes with these processes. Graft vascular cells can be activated by mediators of innate and adaptive immunity to participate in graft inflammation contributing to both ischemia/reperfusion injury and allograft rejection. Different forms of rejection may affect graft vessels in different ways, ranging from thrombosis and neutrophilic inflammation in hyperacute rejection, to endothelialitis/intimal arteritis and fibrinoid necrosis in acute cell-mediated or antibody-mediated rejection, respectively, and to diffuse luminal stenosis in chronic rejection. While some current therapies targeting the host immune system do affect graft vascular cells, direct targeting of the graft vasculature may create new opportunities for preventing allograft injury and loss. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
CD4+CD25+ regulatory T cells suppress allograft rejection mediated by memory CD8+ T cells via a CD30-dependent mechanism.

PubMed

Dai, Zhenhua; Li, Qi; Wang, Yinong; Gao, Ge; Diggs, Lonnette S; Tellides, George; Lakkis, Fadi G

2004-01-01

CD4(+)CD25(+) regulatory T (Treg) cells suppress naive T cell responses, prevent autoimmunity, and delay allograft rejection. It is not known, however, whether Treg cells suppress allograft rejection mediated by memory T cells, as the latter mount faster and stronger immune responses than their naive counterparts. Here we show that antigen-induced, but not naive, Treg cells suppress allograft rejection mediated by memory CD8(+) T cells. Suppression was allospecific, as Treg cells induced by third-party antigens did not delay allograft rejection. In vivo and in vitro analyses revealed that the apoptosis of allospecific memory CD8(+) T cells is significantly increased in the presence of antigen-induced Treg cells, while their proliferation remains unaffected. Importantly, neither suppression of allograft rejection nor enhanced apoptosis of memory CD8(+) T cells was observed when Treg cells lacked CD30 or when CD30 ligand-CD30 interaction was blocked with anti-CD30 ligand Ab. This study therefore provides direct evidence that pathogenic memory T cells are amenable to suppression in an antigen-specific manner and identifies CD30 as a molecule that is critical for the regulation of memory T cell responses.
CD4+CD25+ regulatory T cells suppress allograft rejection mediated by memory CD8+ T cells via a CD30-dependent mechanism

PubMed Central

Dai, Zhenhua; Li, Qi; Wang, Yinong; Gao, Ge; Diggs, Lonnette S.; Tellides, George; Lakkis, Fadi G.

2004-01-01

CD4+CD25+ regulatory T (Treg) cells suppress naive T cell responses, prevent autoimmunity, and delay allograft rejection. It is not known, however, whether Treg cells suppress allograft rejection mediated by memory T cells, as the latter mount faster and stronger immune responses than their naive counterparts. Here we show that antigen-induced, but not naive, Treg cells suppress allograft rejection mediated by memory CD8+ T cells. Suppression was allospecific, as Treg cells induced by third-party antigens did not delay allograft rejection. In vivo and in vitro analyses revealed that the apoptosis of allospecific memory CD8+ T cells is significantly increased in the presence of antigen-induced Treg cells, while their proliferation remains unaffected. Importantly, neither suppression of allograft rejection nor enhanced apoptosis of memory CD8+ T cells was observed when Treg cells lacked CD30 or when CD30 ligand–CD30 interaction was blocked with anti–CD30 ligand Ab. This study therefore provides direct evidence that pathogenic memory T cells are amenable to suppression in an antigen-specific manner and identifies CD30 as a molecule that is critical for the regulation of memory T cell responses. PMID:14722622
Antibody-Mediated Rejection of Single Class I MHC-Disparate Cardiac Allografts

PubMed Central

Hattori, Yusuke; Bucy, R. Pat; Kubota, Yoshinobu; Baldwin, William M.; Fairchild, Robert L.

2012-01-01

Murine CCR5−/− recipients produce high titers of antibody to complete MHC-mismatched heart and renal allografts. To study mechanisms of class I MHC antibody-mediated allograft injury, we tested the rejection of heart allografts transgenically expressing a single class I MHC disparity in wild-type C57BL/6 (H-2b) and B6.CCR5−/− recipients. Donor-specific antibody titers in CCR5−/− recipients were 30-fold higher than in wild-type recipients. B6.Kd allografts survived longer than 60 days in wild-type recipients whereas CCR5−/− recipients rejected all allografts within 14 days. Rejection was accompanied by infiltration of CD8 T cells, neutrophils, and macrophages and C4d deposition in the graft capillaries. B6.Kd allografts were rejected by CD8−/−/CCR5−/−, but not μMT−/−/CCR5−/−, recipients indicating the need for antibody but not CD8 T cells. Grafts retrieved at day 10 from CCR5−/− and CD8−/−/CCR5−/− recipients and from RAG-1−/− allograft recipients injected with anti-Kd antibodies expressed high levels of perforin, myeloperoxidase and CCL5 mRNA. These studies indicate that the continual production of anti-donor class I MHC antibody can mediate allograft rejection, that donor-reactive CD8 T cells synergize with the antibody to contribute to rejection, and that expression of three biomarkers during rejection can occur in the absence of this CD8 T cell activity. PMID:22578247
Comprehending emotional eating in obese youngsters: the role of parental rejection and emotion regulation.

PubMed

Vandewalle, J; Moens, E; Braet, C

2014-04-01

The present study examined the role of emotion regulation in the relation between parental rejection and emotional eating of obese youngsters. Participants were 110 obese youngsters between the ages of 10 and 16 years who were referred to a Belgian treatment centre for obesity. Participants completed questionnaires assessing maternal and paternal rejection, emotion regulation strategies and emotional eating during their intake at the treatment centre. Bootstrapping procedure was used to test if emotion regulation mediated the relationship between maternal and paternal rejection on the one hand and emotional eating of the youngster on the other hand. Results revealed that the use of maladaptive emotion regulation strategies mediated the relation between maternal rejection and emotional eating. Paternal rejection was neither associated with the emotion regulation nor with the emotional eating of the youngster. The findings highlight the importance of assessing the emotional bond between mother and child and the emotion regulation of the youngster in the treatment of pediatric obesity.
Clazakizumab in Highly-HLA Sensitized Patients Awaiting Renal Transplant

ClinicalTrials.gov

2018-05-08

Kidney Failure, Chronic; End-Stage Renal Disease; Transplant Glomerulopathy; Transplant;Failure,Kidney; Kidney Transplant Failure and Rejection; Antibody-mediated Rejection; Kidney Transplant; Complications
Revisiting traditional risk factors for rejection and graft loss after kidney transplantation.

PubMed

Dunn, T B; Noreen, H; Gillingham, K; Maurer, D; Ozturk, O G; Pruett, T L; Bray, R A; Gebel, H M; Matas, A J

2011-10-01

Single-antigen bead (SAB) testing permits reassessment of immunologic risk for kidney transplantation. Traditionally, high panel reactive antibody (PRA), retransplant and deceased donor (DD) grafts have been associated with increased risk. We hypothesized that this risk was likely mediated by (unrecognized) donor-specific antibody (DSA). We grouped 587 kidney transplants using clinical history and single-antigen bead (SAB) testing of day of transplant serum as (1) unsensitized; PRA = 0 (n = 178), (2) third-party sensitized; no DSA (n = 363) or (3) donor sensitized; with DSA (n = 46), and studied rejection rates, death-censored graft survival (DCGS) and risk factors for rejection. Antibody-mediated rejection (AMR) rates were increased with DSA (p < 0.0001), but not with panel reactive antibody (PRA) in the absence of DSA. Cell-mediated rejection (CMR) rates were increased with DSA (p < 0.005); with a trend to increased rates when PRA>0 in the absence of DSA (p = 0.08). Multivariate analyses showed risk factors for AMR were DSA, worse HLA matching, and female gender; for CMR: DSA, PRA>0 and worse HLA matching. AMR and CMR were associated with decreased DCGS. The presence of DSA is an important predictor of rejection risk, in contrast to traditional risk factors. Further development of immunosuppressive protocols will be facilitated by stratification of rejection risk by donor sensitization. ©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.
Immunosuppressive therapies after intestinal transplant modulate the expression of Th1 signature genes during acute cellular rejection. Implications in the search for rejection biomarkers.

PubMed

Zambernardi, Agustina; Chiodetti, Ana; Meier, Dominik; Cabanne, Ana; Nachman, Fabio; Solar, Héctor; Rumbo, Carolina; Gondolesi, Gabriel E; Rumbo, Martin

2014-12-01

Acute cellular rejection (ACR) and infections are leading causes of graft loss and death in intestinal transplant patients. Our aim was to evaluate the impact of maintenance immunosuppressive therapies on the expression of pro-inflammatory mediators in small bowel at ACR diagnosis. We analyzed expression levels of Th1-associated genes, IFNG, CXCL10, and CXCL11 by qPCR in 46 selected graft biopsies unequivocally assigned to mild ACR (n = 14) or normal histopathology and clinical condition (n = 32) from 15 patients receiving two different immunosuppressive (IS) schemes. Double treatment: corticosteroids and tacrolimus (n = 17) and triple treatment: sirolimus or mycophenolate mofetil in addition to the basal therapy (n = 29). IFNG, CXCL10, and CXCL11 were induced during rejection (p < 0.05; p < 0.005, and p < 0.05, respectively). However, when rejection and control groups were classified according to immunosuppressive treatment, in the rejection group, significant differences of IFNG, CXCL10, and CXCL11 expression (p < 0.001; p < 0.005, and 0.01, respectively) were detected, whereas no differences were observed in the control group. Gene expression of Th1 response mediators is higher during ACR. Triple IS group showed significantly lower expression of pro-inflammatory Th1 mediators during mild ACR indicating that use of these markers to monitor rejection can be affected by the IS treatment used. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Testing a mediation framework for the link between perceived discrimination and psychological distress among sexual minority individuals.

PubMed

Liao, Kelly Yu-Hsin; Kashubeck-West, Susan; Weng, Chih-Yuan; Deitz, Cori

2015-04-01

Perceived discrimination is a risk factor for mental health problems among sexual minority individuals. An increasing number of research studies have investigated the mechanisms through which stigma-related stressors such as perceived discrimination are linked with adverse mental health outcomes for sexual minority populations. The integrative mediation framework proposed by Hatzenbuehler (2009) underscores the importance of identifying mediators in the association between stigma-related stressors and mental health outcomes. This study tested 3 mediators--expectations of rejection, anger rumination, and self-compassion--in the perceived discrimination-distress link. Moreover, it examined associations among these mediators. A nationwide sample of 265 sexual minorities responded to an online survey. Structural equation modeling results supported the mediator roles of expectations of rejection, anger rumination, and self-compassion. More specifically, perceived discrimination was associated with expectations of rejection, which, in turn, was associated with increased anger rumination and less self-compassion, resulting in greater psychological distress. The findings suggest several avenues for prevention and intervention with sexual minority individuals. (c) 2015 APA, all rights reserved).
Tobacco smoke exposure in either the donor or recipient before transplantation accelerates cardiac allograft rejection, vascular inflammation, and graft loss.

PubMed

Khanna, Ashwani K; Xu, Jianping; Uber, Patricia A; Burke, Allen P; Baquet, Claudia; Mehra, Mandeep R

2009-11-03

Tobacco exposure in cardiac transplant recipients, before and after transplantation, may increase the risk of cardiac allograft vasculopathy and allograft loss, but no direct evidence for this phenomenon is forthcoming. In this experimental study, we investigated early consequences of tobacco smoke exposure in cardiac transplant donors and recipients with an emphasis on alloinflammatory mediators of graft outcome. Using heterotopic rat cardiac transplantation, we tested the effects of donor or recipient tobacco smoke exposure in 6 groups of animals (rat heterotopic cardiac transplantation) as follows: tobacco-naïve allogeneic rejecting controls (n=6), tobacco-naïve nonrejecting controls (n=3; killed on day 5 to simulate survival times of tobacco-treated animals), isografts (n=3), both donor and recipient rats exposed to tobacco smoke (n=4), only donor rats exposed to tobacco smoke (n=7), and only recipient rats exposed to tobacco smoke (n=6). Polymerase chain reaction studies of tissue and peripheral (systemic) protein expression were performed to evaluate inflammatory (tumor necrosis factor-alpha, interferon-gamma, interleukin-6) and alloimmune (interleukin-1 receptor 2, programmed cell death-1, and stromal cell-derived factor-1) pathways, as was histological analysis of the cardiac allografts. Our experiments reveal that pretransplantation tobacco exposure in donors and/or recipients results in heightened systemic inflammation and increased oxidative stress, reduces posttransplantation cardiac allograft survival by 33% to 57%, and increases intragraft inflammation (tumor necrosis factor-alpha, interferon-gamma, interleukin-6) and alloimmune activation (CD3, interleukin-1 receptor 2, programmed cell death-1, and stromal cell-derived factor-1) with consequent myocardial and vascular destruction. These sentinel findings confirm that tobacco smoke exposure in either donors or recipients leads to accelerated allograft rejection, vascular inflammation, and graft loss. Molecular pathways that intersect as arbiters in this phenomenon include instigation of alloimmune activation associated with tobacco smoke-induced inflammation.
Antibody-mediated rejection in kidney transplantation: a review of pathophysiology, diagnosis, and treatment options.

PubMed

Kim, Miae; Martin, Spencer T; Townsend, Keri R; Gabardi, Steven

2014-07-01

Antibody-mediated rejection (AMR), also known as B-cell-mediated or humoral rejection, is a significant complication after kidney transplantation that carries a poor prognosis. Although fewer than 10% of kidney transplant patients experience AMR, as many as 30% of these patients experience graft loss as a consequence. Although AMR is mediated by antibodies against an allograft and results in histologic changes in allograft vasculature that differ from cellular rejection, it has not been recognized as a separate disease process until recently. With an improved understanding about the importance of the development of antibodies against allografts as well as complement activation, significant advances have occurred in the treatment of AMR. The standard of care for AMR includes plasmapheresis and intravenous immunoglobulin that remove and neutralize antibodies, respectively. Agents targeting B cells (rituximab and alemtuzumab), plasma cells (bortezomib), and the complement system (eculizumab) have also been used successfully to treat AMR in kidney transplant recipients. However, the high cost of these medications, their use for unlabeled indications, and a lack of prospective studies evaluating their efficacy and safety limit the routine use of these agents in the treatment of AMR in kidney transplant recipients. © 2014 Pharmacotherapy Publications, Inc.
Self-Silencing and Rejection Sensitivity in Adolescent Romantic Relationships

ERIC Educational Resources Information Center

Harper, Melinda S.; Dickson, Joseph W.; Welsh, Deborah P.

2006-01-01

This study examined the link between rejection sensitivity, self-silencing behaviors, and depressive symptomatology among adolescent dating couples. Self-silencing was hypothesized to be the process mediating the association between rejection sensitivity and depressive symptoms. Our sample included 211 couples between 14 and 21 who were dating at…
Alloimmunity and Tolerance in Corneal Transplantation.

PubMed

Amouzegar, Afsaneh; Chauhan, Sunil K; Dana, Reza

2016-05-15

Corneal transplantation is one of the most prevalent and successful forms of solid tissue transplantation. Despite favorable outcomes, immune-mediated graft rejection remains the major cause of corneal allograft failure. Although low-risk graft recipients with uninflamed graft beds enjoy a success rate ∼90%, the rejection rates in inflamed graft beds or high-risk recipients often exceed 50%, despite maximal immune suppression. In this review, we discuss the critical facets of corneal alloimmunity, including immune and angiogenic privilege, mechanisms of allosensitization, cellular and molecular mediators of graft rejection, and allotolerance induction. Copyright © 2016 by The American Association of Immunologists, Inc.
Postoperative rebound of antiblood type antibodies and antibody-mediated rejection after ABO-incompatible living-related kidney transplantation.

PubMed

Ishida, Hideki; Kondo, Tsunenori; Shimizu, Tomokazu; Nozaki, Taiji; Tanabe, Kazunari

2015-03-01

The purpose of this study is to examine whether postoperative antiblood type antibody rebound is attributed to kidney allograft rejection in ABO blood type-incompatible (ABO-I) living-related kidney transplantation (KTx). A total of 191 ABO-I recipients who received ABO-I living-related KTx between 2001 and 2013 were divided into two groups: Group 1 consisted of low rebound [(≦1:32), N = 170] and Group 2 consisted of high rebound [(≧1:64), N = 21], according to the levels of the rebounded antiblood type antibodies within 1 year after transplantation. No prophylactic treatment for rejection was administered for elevated antiblood type antibodies, regardless of the levels of the rebounded antibodies. Within 1 year after transplantation, T-cell-mediated rejection was observed in 13 of 170 recipients (13/170, 8%) in Group 1 and in 2 of 21 recipients (2/21, 10%) in Group 2 (Groups 1 vs. 2, P = 0.432). Antibody-mediated rejection was observed in 15 of 170 recipients (15/170, 9%) and 2 of 21 recipients (2/21, 10%) in Groups 1 and 2, respectively (P = 0.898). In this study, we found no correlation between the postoperative antiblood type antibody rebound and the incidence of acute rejection. We concluded that no treatment is necessary for rebounded antiblood type antibodies. © 2014 Steunstichting ESOT.
Anti-IL-17 therapy restricts and reverses late-term corneal allo-rejection

PubMed Central

Yin, Xiao-Tang; Zobell, Stephanie; Jarosz, Jason G.; Stuart, Patrick M.

2015-01-01

Corneal allograft rejection has been described as a Th1-mediated process involving IFN-γ production. However, recent evidence has also implicated IL-17 as being involved during acute corneal allograft responses. Our data supports those that maintain that IL-17 is involved in early acute corneal allograft acceptance. However, we decided to extend these studies to include a later phase of rejection in which there is a peak of IL-17 production that is >15 fold higher than seen during acute rejection that occurs >45 days post-engraftment at the onset of late-term rejection. We demonstrate that neutralizing IL-17A at this time significantly reduced corneal graft rejection. Surprisingly, when corneal grafts that are undergoing this later phase of rejection are treated with anti-IL17A there is a reversal of both opacity and neovascularization. When compared to the early phase of rejection, the cellular infiltrate is significantly less with a greatly reduced presence of Gr-1+ neutrophils with a relative increase in CD4+ T cells and macrophages. We went on to identify that the cells expressing IL-17 were CD4+ IL-17+ T cells and somewhat surprisingly, IL-17+ F4/80+ macrophages within the rejecting corneal allografts. Taken together, these findings describe a distinct late phase of corneal allograft rejection which is likely mediated by Th17 cells and that therapeutic neutralization of IL-17A reverses this rejection. This further suggests that IL-17 might serve as an excellent therapeutic target to reduce this form of corneal allograft rejection. PMID:25754737
Developmental Pathways from Childhood Aggression-Disruptiveness, Chronic Peer Rejection and Deviant Friendships to Early-Adolescent Rule Breaking

PubMed Central

Ettekal, Idean; Ladd, Gary W.

2015-01-01

Childhood aggression-disruptiveness, chronic peer rejection, and deviant friendships were examined as predictors of early-adolescent rule breaking behaviors. Using a sample of 383 children (193 girls and 190 boys) who were followed from ages 6 to 14, peer rejection trajectories were identified and incorporated into a series of alternative models to assess how chronic peer rejection and deviant friendships mediate the association between stable childhood aggression-disruptiveness and early-adolescent rule breaking. There were multiple mediated pathways to rule breaking that included both behavioral and relational risk factors and findings were consistent for boys and girls. Results have implications for better understanding the influence of multiple social processes in the continuity of antisocial behaviors from middle childhood to early adolescence. PMID:25403544
Recollections of parental rejection, self-criticism and depression in suicidality.

PubMed

Campos, Rui C; Besser, Avi; Blatt, Sidney J

2013-01-01

The present study examines whether self-criticism and depressive symptoms mediate the relationship between recollections of parental rejection and suicidality. A community sample of 200 Portuguese adults completed, in counterbalanced order, a socio-demographic questionnaire, the short form of the Inventory for Assessing Memories of Parental Rearing Behaviour (EMBU), the Depressive Experiences Questionnaire (DEQ), the Center for Epidemiologic Studies Depression Scale (CES-D), and reports of any suicide intention and/or ideation and suicide attempts. Structural Equation Modeling (SEM) indicated that recollections of parental rejection are significantly associated with depressive symptoms and suicidality. Recollections of parental rejection are indirectly associated with depressive symptoms and suicidality through self-criticism. The association between self-criticism and suicidality is mediated by depressive symptoms. In addition to a significant direct association between recollections of parental rejection and suicidality, the final model indicated that recollections of parental rejection are significantly associated with self-criticism. That same self-criticism is significantly associated with depressive symptoms which, in turn, are significantly associated with suicidality. Individuals with recollections of parental rejection are at greater risk for suicide ideation and behavior, possibly because such experiences predispose them to intense self-criticism which is a risk factor for depression associated with suicidal ideation and behavior.

Infiltration of Macrophages Correlates with Severity of Allograft Rejection and Outcome in Human Kidney Transplantation.

PubMed

Bergler, Tobias; Jung, Bettina; Bourier, Felix; Kühne, Louisa; Banas, Miriam C; Rümmele, Petra; Wurm, Simone; Banas, Bernhard

2016-01-01

Despite substantial progress in recent years, graft survival beyond the first year still requires improvement. Since modern immunosuppression addresses mainly T-cell activation and proliferation, we studied macrophage infiltration into the allografts of 103 kidney transplant recipients during acute antibody and T-cell mediated rejection. Macrophage infiltration was correlated with both graft function and graft survival until month 36 after transplantation. Macrophage infiltration was significantly elevated in antibody-mediated and T-cell mediated rejection, but not in kidneys with established IFTA. Treatment of rejection with steroids was less successful in patients with more prominent macrophage infiltration into the allografts. Macrophage infiltration was accompanied by increased cell proliferation as well as antigen presentation. With regard to the compartmental distribution severity of T-cell-mediated rejection was correlated to the amount of CD68+ cells especially in the peritubular and perivascular compartment, whereas biopsies with ABMR showed mainly peritubular CD68 infiltration. Furthermore, severity of macrophage infiltration was a valid predictor of resulting creatinine values two weeks as well as two and three years after renal transplantation as illustrated by multivariate analysis. Additionally performed ROC curve analysis showed that magnitude of macrophage infiltration (below vs. above the median) was a valid predictor for the necessity to restart dialysis. Having additionally stratified biopsies in accordance to the magnitude of macrophage infiltration, differential CD68+ cell infiltration was reflected by striking differences in overall graft survival. The differences in acute allograft rejection have not only been reflected by different magnitudes of macrophage infiltration, but also by compartment-specific infiltration pattern and subsequent impact on resulting allograft function as well as need for dialysis initiation. There is a robust relationship between macrophage infiltration, accompanying antigen-presentation and resulting allograft function.
Infiltration of Macrophages Correlates with Severity of Allograft Rejection and Outcome in Human Kidney Transplantation

PubMed Central

Bourier, Felix; Kühne, Louisa; Banas, Miriam C.; Rümmele, Petra; Wurm, Simone; Banas, Bernhard

2016-01-01

Objective Despite substantial progress in recent years, graft survival beyond the first year still requires improvement. Since modern immunosuppression addresses mainly T-cell activation and proliferation, we studied macrophage infiltration into the allografts of 103 kidney transplant recipients during acute antibody and T-cell mediated rejection. Macrophage infiltration was correlated with both graft function and graft survival until month 36 after transplantation. Results Macrophage infiltration was significantly elevated in antibody-mediated and T-cell mediated rejection, but not in kidneys with established IFTA. Treatment of rejection with steroids was less successful in patients with more prominent macrophage infiltration into the allografts. Macrophage infiltration was accompanied by increased cell proliferation as well as antigen presentation. With regard to the compartmental distribution severity of T-cell-mediated rejection was correlated to the amount of CD68+ cells especially in the peritubular and perivascular compartment, whereas biopsies with ABMR showed mainly peritubular CD68 infiltration. Furthermore, severity of macrophage infiltration was a valid predictor of resulting creatinine values two weeks as well as two and three years after renal transplantation as illustrated by multivariate analysis. Additionally performed ROC curve analysis showed that magnitude of macrophage infiltration (below vs. above the median) was a valid predictor for the necessity to restart dialysis. Having additionally stratified biopsies in accordance to the magnitude of macrophage infiltration, differential CD68+ cell infiltration was reflected by striking differences in overall graft survival. Conclusion The differences in acute allograft rejection have not only been reflected by different magnitudes of macrophage infiltration, but also by compartment-specific infiltration pattern and subsequent impact on resulting allograft function as well as need for dialysis initiation. There is a robust relationship between macrophage infiltration, accompanying antigen-presentation and resulting allograft function. PMID:27285579
The roles of trauma exposure, rejection sensitivity, and callous-unemotional traits in the aggressive behavior of justice-involved youth: A moderated mediation model.

PubMed

Mozley, Michaela M; Modrowski, Crosby A; Kerig, Patricia K

2018-05-01

Research has demonstrated an association between childhood trauma exposure and adolescent aggression. This association may be explained by rejection sensitivity, defined as anger, or anxiety in the anticipation of rejection, which can be a consequence of trauma exposure. Callous-unemotional (CU) traits also are associated with trauma exposure and aggressive behavior; however, research has not yet investigated the interactive roles that rejection sensitivity and CU traits play in the relation between trauma exposure and aggression. Therefore, this study sought to investigate the role of rejection sensitivity in the association between trauma exposure and aggression, and whether this indirect effect was moderated by CU traits. Participants included 380 detained youth (98 girls, 282 boys) who completed self-report measures of trauma exposure, angry, and anxious rejection sensitivity, CU traits, and aggression. Results of moderated mediation demonstrated that the relation between trauma exposure and aggression exhibited an indirect effect through angry rejection sensitivity, but only at moderate or high levels of CU traits. This pattern was not found for anxious rejection sensitivity. Results suggest that interventions aimed to decrease aggressive behavior in traumatized adolescents may benefit from considering how youth respond to rejection, as well as whether youth endorse CU traits, as this may help to limit further involvement in the juvenile justice system after release. © 2018 Wiley Periodicals, Inc.
Peer Exclusion and Victimization: Processes That Mediate the Relation Between Peer Group Rejection and Children's Classroom Engagement and Achievement?

ERIC Educational Resources Information Center

Buhs, Eric S.; Ladd, Gary W.; Herald, Sarah L.

2006-01-01

Longitudinal data from a study of kindergarten through 5th graders were used to estimate a structural model in which chronic peer exclusion and chronic peer abuse were hypothesized to mediate the link between children's early peer rejection, later classroom engagement, and achievement. Peer exclusion and abuse were expected to predict changes in 2…
Hostility and Substance Use in Relation to Intimate Partner Violence and Parenting Among Fathers

PubMed Central

Stover, Carla Smith; Kiselica, Andrew

2016-01-01

Intimate partner violence (IPV) is a significant public health and economic problem, which also increases the risks for child maltreatment. One attribute that may contribute to both IPV and poor parenting is hostility. Moreover, the link between hostility and these outcomes may be mediated by substance use, such that more hostile individuals are at greater risk for using drugs and alcohol, leading them to engage in more aggressive and rejecting behavior towards their partners and children. We tested this possibility in sample of 132 fathers. Additionally, we explored whether hostility and substance use had interactive effects on IPV and parenting by examining moderated-mediation models. The results show that substance use mediated the relationship between hostility and all IPV and parenting outcomes. Furthermore, this mediated relationship was moderated by substance use level for parenting outcomes, but not IPV. In the case of parenting, the mediated path from hostility to aggressive and rejecting parenting only occurred for those high in substance use. Limitations and implications for prevention and treatment of IPV and aggressive and rejecting parenting are discussed. PMID:25043704
Emotion Dysregulation Mediates the Relation between Mindfulness and Rejection Sensitivity.

PubMed

Velotti, Patrizia; Garofalo, Carlo; Bizzi, Fabiola

2015-09-01

The role of rejection sensitivity (RS; the tendency to anxiously expect, readily perceive, and overreact to implied or overt interpersonal rejection) in psychopathology has mainly been studied with regard to borderline personality disorder (BPD). In the present study, we first sought to extend previous evidence of heightened RS in a clinical group with psychiatric disorders other than BPD, when compared with a community sample. Then, we tested whether emotion dysregulation and mindfulness were associated with RS in both sample, further hypothesizing that emotion dysregulation would mediate the relation between mindfulness deficits and RS. We adopted a cross-sectional design involving 191 psychiatric patients and 277 community participants (total N=468). All participants completed the Rejection Sensitivity Questionnaire, the Five Facet Mindfulness Questionnaire, and the Difficulties in Emotion Regulation Scale. Our hypotheses were supported, with psychiatric patients reporting greater levels of rejection sensitivity and emotion dysregulation, and lower level of mindfulness. Mindfulness deficits and emotion dysregulation explained a significant amount of variance in RS, in both samples. Finally, bootstrap analyses revealed that mindfulness deficits played an indirect effect on RS through the mediating role of emotion dysregulation. In particular, two different patterns emerged. Among psychiatric patients, an impairment in the ability to assume a non-judgmental stance towards own thoughts and feelings was related to RS through the mediation of limited access to emotion regulation strategies. Conversely, in the community sample, overall emotion dysregulation mediated the effect of lack of attention and awareness for present activities and experience on RS. Longitudinal studies could help in delineating etiological models of RS, and the joint role of deficits in mindfulness and emotion regulation should inform treatment programs.
An integrated view of molecular changes, histopathology and outcomes in kidney transplants.

PubMed

Halloran, P F; de Freitas, D G; Einecke, G; Famulski, K S; Hidalgo, L G; MengeL, M; Reeve, J; Sellares, J; Sis, B

2010-10-01

Data-driven approaches to deteriorating kidney transplants, incorporating histologic, molecular and HLA antibody findings, have created a new understanding of transplant pathology and why transplants fail. Transplant dysfunction is best understood in terms of three elements: diseases, the active injury-repair response and the cumulative burden of injury. Progression to failure is mainly attributable to antibody-mediated rejection, nonadherence and glomerular disease. Antibody-mediated rejection usually develops late due to de novo HLA antibodies, particularly anti-class II, and is often C4d negative. Pure treated T cell-mediated rejection does not predispose to graft loss because it responds well, even with endothelialitis, but it may indicate nonadherence. The cumulative burden of injury results in atrophy-fibrosis (nephron loss), arterial fibrous intimal thickening and arteriolar hyalinosis, but these are not progressive without ongoing disease/injury, and do not explain progression. Calcineurin inhibitor toxicity has been overestimated because burden-of-injury lesions invite this default diagnosis when diseases such as antibody-mediated rejection are missed. Disease/injury triggers a stereotyped active injury-repair response, including de-differentiation, cell cycling and apoptosis. The active injury-repair response is the strongest correlate of organ function and future progression to failure, but should always prompt a search for the initiating injury or disease.
Isolated v-lesion represents a benign phenotype of vascular rejection of the kidney allograft- a retrospective study.

PubMed

Novotny, Marek; Hruba, Petra; Vichova, Petra; Maluskova, Jana; Honsova, Eva; Viklicky, Ondrej; Wohlfahrtova, Mariana

2018-05-31

While the detrimental impact of the humoral acute vascular rejection (AVR) phenotype is recognized, the prognostic significance of isolated v-lesion (IV) remains unclear. In this retrospective single-centre study, AVR was found in 98 out of 1015 patients (9.7%) who had undergone kidney transplantation in 2010-2014, with donor-specific antibodies (DSA) evaluated in all of them. The outcome of four AVR phenotypes was evaluated during median follow-up of 59 months; in 25 patients with IV, 18 with T cell-mediated vascular rejection (TCMRV), 19 with antibody-mediated vascular rejection (AMRV) and 36 with suspected antibody-mediated rejection (sAMRV). AVR was diagnosed mainly by for-cause biopsy (81%) early after transplantation (median 19 POD) and appeared as mild grade intimal arteritis. IV occurred in low sensitized patients after the first transplantation (96%) in the absence of DSA. IV responded satisfactorily to treatment (88%), showed no persistence of rejection in surveillance biopsy, had stable graft function, minimal proteinuria and excellent DCGS (96%). Contrary to that, Kaplan-Meier estimate of 3-year DCGS of AMRV was 66% (log rank=0.0004). Early IV represents a benign phenotype of AVR with a favourable outcome. This study prompts further research to evaluate the nature of IV before considering any change in the classification and management. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Zbtb7a induction in alveolar macrophages is implicated in anti-HLA-mediated lung allograft rejection.

PubMed

Nayak, Deepak K; Zhou, Fangyu; Xu, Min; Huang, Jing; Tsuji, Moriya; Yu, Jinsheng; Hachem, Ramsey; Gelman, Andrew E; Bremner, Ross M; Smith, Michael A; Mohanakumar, Thalachallour

2017-07-12

Chronic rejection significantly limits long-term success of solid organ transplantation. De novo donor-specific antibodies (DSAs) to mismatched donor human leukocyte antigen after human lung transplantation predispose lung grafts to chronic rejection. We sought to delineate mediators and mechanisms of DSA pathogenesis and to define early inflammatory events that trigger chronic rejection in lung transplant recipients and obliterative airway disease, a correlate of human chronic rejection, in mouse. Induction of transcription factor zinc finger and BTB domain containing protein 7a (Zbtb7a) was an early response critical in the DSA-induced chronic rejection. A cohort of human lung transplant recipients who developed DSA and chronic rejection demonstrated greater Zbtb7a expression long before clinical diagnosis of chronic rejection compared to nonrejecting lung transplant recipients with stable pulmonary function. Expression of DSA-induced Zbtb7a was restricted to alveolar macrophages (AMs), and selective disruption of Zbtb7a in AMs resulted in less bronchiolar occlusion, low immune responses to lung-restricted self-antigens, and high protection from chronic rejection in mice. Additionally, in an allogeneic cell transfer protocol, antigen presentation by AMs was Zbtb7a-dependent where AMs deficient in Zbtb7a failed to induce antibody and T cell responses. Collectively, we demonstrate that AMs play an essential role in antibody-induced pathogenesis of chronic rejection by regulating early inflammation and lung-restricted humoral and cellular autoimmunity. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Banff schema for grading pancreas allograft rejection: working proposal by a multi-disciplinary international consensus panel.

PubMed

Drachenberg, C B; Odorico, J; Demetris, A J; Arend, L; Bajema, I M; Bruijn, J A; Cantarovich, D; Cathro, H P; Chapman, J; Dimosthenous, K; Fyfe-Kirschner, B; Gaber, L; Gaber, O; Goldberg, J; Honsová, E; Iskandar, S S; Klassen, D K; Nankivell, B; Papadimitriou, J C; Racusen, L C; Randhawa, P; Reinholt, F P; Renaudin, K; Revelo, P P; Ruiz, P; Torrealba, J R; Vazquez-Martul, E; Voska, L; Stratta, R; Bartlett, S T; Sutherland, D E R

2008-06-01

Accurate diagnosis and grading of rejection and other pathological processes are of paramount importance to guide therapeutic interventions in patients with pancreas allograft dysfunction. A multi-disciplinary panel of pathologists, surgeons and nephrologists was convened for the purpose of developing a consensus document delineating the histopathological features for diagnosis and grading of rejection in pancreas transplant biopsies. Based on the available published data and the collective experience, criteria for the diagnosis of acute cell-mediated allograft rejection (ACMR) were established. Three severity grades (I/mild, II/moderate and III/severe) were defined based on lesions known to be more or less responsive to treatment and associated with better- or worse-graft outcomes, respectively. The features of chronic rejection/graft sclerosis were reassessed, and three histological stages were established. Tentative criteria for the diagnosis of antibody-mediated rejection were also characterized, in anticipation of future studies that ought to provide more information on this process. Criteria for needle core biopsy adequacy and guidelines for pathology reporting were also defined. The availability of a simple, reproducible, clinically relevant and internationally accepted schema for grading rejection should improve the level of diagnostic accuracy and facilitate communication between all parties involved in the care of pancreas transplant recipients.
He loves her, he loves her not: attachment style as a personality antecedent to men's ambivalent sexism.

PubMed

Hart, Joshua; Hung, Jacqueline A; Glick, Peter; Dinero, Rachel E

2012-11-01

The authors present an integrative account of how attachment insecurities relate to sexism. Two studies showed that attachment avoidance predisposes men to endorse hostile but to reject benevolent sexism (BS), whereas attachment anxiety predisposes men toward ambivalent (both hostile and benevolent) sexism. The authors also tested predicted mediators, finding that men's social dominance orientation (a competitive intergroup ideology) mediated the avoidance to hostile sexism link. In addition, romanticism (an idealized interpersonal ideology) mediated attachment insecurity to BS links: (a) Avoidant men tended to reject romanticism (i.e., were cynical about romance) and, in turn, were likely to reject BS, whereas (b) anxious men tended to endorse romanticism (i.e., were idealistic about romance) and, in turn, likely to endorse BS. The authors conclude that men's sexism stems in part from dispositional attachment working models, both directly and through the interpersonal and intergroup ideologies they generate.
Plug-in module acceleration feedback control for fast steering mirror-based beam stabilization systems

NASA Astrophysics Data System (ADS)

Deng, Chao; Ren, Wei; Mao, Yao; Ren, Ge

2017-08-01

A plug-in module acceleration feedback control (Plug-In AFC) strategy based on the disturbance observer (DOB) principle is proposed for charge-coupled device (CCD)-based fast steering mirror (FSM) stabilization systems. In classical FSM tracking systems, dual-loop control (DLC), including velocity feedback and position feedback, is usually utilized to enhance the closed-loop performance. Due to the mechanical resonance of the system and CCD time delay, the closed-loop bandwidth is severely restricted. To solve this problem, cascade acceleration feedback control (AFC), which is a kind of high-precision robust control method, is introduced to strengthen the disturbance rejection property. However, in practical applications, it is difficult to realize an integral algorithm in an acceleration controller to compensate for the quadratic differential contained in the FSM acceleration model, resulting in a challenging controller design and a limited improvement. To optimize the acceleration feedback framework in the FSM system, different from the cascade AFC, the accelerometers are used to construct DOB to compensate for the platform vibrations directly. The acceleration nested loop can be plugged into the velocity loop without changing the system stability, and the controller design is quite simple. A series of comparative experimental results demonstrate that the disturbance rejection property of the CCD-based FSM can be effectively improved by the proposed approach.
Man-Computer Interactive Data Access System (McIDAS). Continued development of McIDAS and operation in the GARP Atlantic tropical experiment

NASA Technical Reports Server (NTRS)

Suomi, V. E.

1975-01-01

The complete output of the Synchronous Meteorological Satellite was recorded on one inch magnetic tape. A quality control subsystem tests cloud track vectors against four sets of criteria: (1) rejection if best match occurs on correlation boundary; (2) rejection if major correlation peak is not distinct and significantly greater than secondary peak; (3) rejection if correlation is not persistent; and (4) rejection if acceleration is too great. A cloud height program determines cloud optical thickness from visible data and computer infrared emissivity. From infrared data and temperature profile, cloud height is determined. A functional description and electronic schematics of equipment are given.
Interferon-γ converts human microvascular pericytes into negative regulators of alloimmunity through induction of indoleamine 2,3-dioxygenase 1

PubMed Central

Liu, Rebecca; Manes, Thomas D.; Qin, Lingfeng; Tietjen, Gregory T.; Broecker, Verena; Fang, Caodi; Xie, Catherine; Chen, Ping-Min; Kirkiles-Smith, Nancy C.; Jane-Wit, Dan; Pober, Jordan S.

2018-01-01

Early acute rejection of human allografts is mediated by circulating alloreactive host effector memory T cells (TEM). TEM infiltration typically occurs across graft postcapillary venules and involves sequential interactions with graft-derived endothelial cells (ECs) and pericytes (PCs). While the role of ECs in allograft rejection has been extensively studied, contributions of PCs to this process are largely unknown. This study aimed to characterize the effects and mechanisms of interactions between human PCs and allogeneic TEM. We report that unstimulated PCs, like ECs, can directly present alloantigen to TEM, but while IFN-γ–activated ECs (γ-ECs) show increased ability to stimulate alloreactive T cells, IFN-γ–activated PCs (γ-PCs) instead suppress TEM proliferation but not cytokine production or signaling. RNA sequencing analysis of PCs, γ-PCs, ECs, and γ-ECs reveal induction of indoleamine 2,3-dioxygenase 1 (IDO1) in γ-PCs to significantly higher levels than in γ-ECs that correlates with tryptophan depletion in vitro. Consistently, shRNA knockdown of IDO1 markedly reduces γ-PC–mediated immunoregulatory effects. Furthermore, human PCs express IDO1 in a skin allograft rejection humanized mouse model and in human renal allografts with acute T cell–mediated rejection. We conclude that immunosuppressive properties of human PCs are not intrinsic but instead result from IFN-γ–induced IDO1-mediated tryptophan depletion. PMID:29515027
Dependency, self-criticism and negative affective responses following imaginary rejection and failure threats: meaning-making processes as moderators or mediators.

PubMed

Besser, Avi; Priel, Beatriz

2011-01-01

This study evaluated the intervening role of meaning-making processes in emotional responses to negative life events based on Blatt's (1974, 2004) formulations concerning the role of personality predispositions in depression. In a pre/post within-subject study design, a community sample of 233 participants reacted to imaginary scenarios of interpersonal rejection and achievement failure. Meaning-making processes relating to threats to self-definition and interpersonal relatedness were examined following the exposure to the scenarios. The results indicated that the personality predisposition of Dependency, but not Self-Criticism predicted higher levels of negative affect following the interpersonal rejection event, independent of baseline levels of negative affect. This effect was mediated by higher levels of negative meaning-making processes related to the effect of the interpersonal rejection scenario on Dependent individuals' senses of interpersonal relatedness and self-worth. In addition, both Self-Criticism and Dependency predicted higher levels of negative affect following the achievement failure event, independent of baseline levels of negative affect. Finally, the effect of Self-Criticism was mediated by higher levels of negative meaning-making processes related to the effect of the achievement failure scenario on self-critical individuals' senses of self-definition.
Self-esteem moderates neuroendocrine and psychological responses to interpersonal rejection.

PubMed

Ford, Máire B; Collins, Nancy L

2010-03-01

In this study, the authors investigated self-esteem as a moderator of psychological and physiological responses to interpersonal rejection and tested an integrative model detailing the mechanisms by which self-esteem may influence cognitive, affective, and physiological responses. Seventy-eight participants experienced an ambiguous interpersonal rejection (or no rejection) from an opposite sex partner in the context of an online dating interaction. Salivary cortisol was assessed at 5 times, and self-reported cognitive and affective responses were assessed. Compared with those with high self-esteem, individuals with low self-esteem responded to rejection by appraising themselves more negatively, making more self-blaming attributions, exhibiting greater cortisol reactivity, and derogating the rejector. Path analysis indicated that the link between low self-esteem and increased cortisol reactivity was mediated by self-blame attributions; cortisol reactivity, in turn, mediated the link between low self-esteem and increased partner derogation. Discussion centers on the role of self-esteem as part of a broader psychobiological system for regulating and responding to social threat and on implications for health outcomes.
Innate NK cells and macrophages recognize and reject allogeneic nonself in vivo via different mechanisms.

PubMed

Liu, Wentao; Xiao, Xiang; Demirci, Gulcin; Madsen, Joren; Li, Xian C

2012-03-15

Both innate and adaptive immune cells are involved in the allograft response. But how the innate immune cells respond to allotransplants remains poorly defined. In the current study, we examined the roles of NK cells and macrophages in recognizing and rejecting allogeneic cells in vivo. We found that in naive mice NK cells are the primary effector cells in the killing of allogeneic cells via "missing self" recognition. However, in alloantigen-presensitized mice, NK cells are dispensable. Instead, macrophages become alloreactive and readily recognize and reject allogeneic nonself. This effect requires help from activated CD4(+) T cells and involves CD40/CD40L engagement, because blocking CD40/CD40L interactions prevents macrophage-mediated rejection of allogeneic cells. Conversely, actively stimulating CD40 triggers macrophage-mediated rejection in the absence of CD4(+) T cells. Importantly, alloantigen-primed and CD4(+) T cell-helped macrophages (licensed macrophages) exhibit potent regulatory function in vivo in an acute graft-versus-host disease model. Together, our data uncover an important role for macrophages in the alloimmune response and may have important clinical implications.
Antibody-Mediated Rejection of the Kidney after Simultaneous Pancreas-Kidney Transplantation

PubMed Central

Pascual, Julio; Samaniego, Milagros D.; Torrealba, José R.; Odorico, Jon S.; Djamali, Arjang; Becker, Yolanda T.; Voss, Barbara; Leverson, Glen E.; Knechtle, Stuart J.; Sollinger, Hans W.; Pirsch, John D.

2008-01-01

The prevalence, risk factors, and outcome of antibody-mediated rejection (AMR) of the kidney after simultaneous pancreas-kidney transplantation are unknown. In 136 simultaneous pancreas-kidney recipients who were followed for an average of 3.1 yr, 21 episodes of AMR of the kidney allograft were identified. Eight episodes occurred early (≤90 d) after transplantation, and 13 occurred later. Histologic evidence of concomitant acute cellular rejection was noted in 12 cases; the other nine had evidence only of humoral rejection. In 13 cases, clinical rejection of the pancreas was diagnosed simultaneously, and two of these were biopsy proven and were positive for C4d immunostaining. Multivariate analysis identified only one significant risk factor: Female patients were three times more likely to experience AMR. Nearly all early episodes resolved with treatment and did not predict graft loss, but multivariate Cox models revealed that late AMR episodes more than tripled the risk for kidney and pancreas graft loss; therefore, new strategies are needed to prevent and to treat late AMR in simultaneous pancreas-kidney transplant recipients. PMID:18235091
Interleukin-12 (IL-12)-driven alloimmune responses in vitro and in vivo: requirement for beta1 subunit of the IL-12 receptor.

PubMed

Piccotti, J R; Li, K; Chan, S Y; Eichwald, E J; Bishop, D K

1999-06-15

Interleukin-12 (IL-12) mediates its biologic activities via binding high-affinity receptors on T and natural killer cells. Although emphasis has been placed on the requirement for IL-12Rbeta2 in IL-12 bioactivity, the role of IL-12Rbeta1 is less well defined. The current study evaluated the effects of exogenous IL-12 on alloantigen-specific immune responses and determined the requirement for IL-12Rbeta1 in IL-12-mediated alloimmunity. The mouse heterotopic cardiac transplant model was employed to evaluate the effects of IL-12 on alloantigen-specific immune responses in vivo. In addition, IFN-gamma production in mixed lymphocyte cultures (MLC) supplemented with IL-12 was measured to assess the effects of IL-12 on Th1 function in vitro. Mice deficient in IL-12Rbeta1 (IL-12Rbeta1-/-) were used to determine the requirement for this receptor component in IL-12-driven alloimmune responses. Addition of IL-12 to MLC consisting of wild-type splenocytes enhanced alloantigen-specific proliferative responses and Th1 development. In contrast, IL-12 did not alter these in vitro immune parameters in IL-12Rbeta1-/- MLC. Treatment of wild-type cardiac allograft recipients with IL-12 resulted in high concentrations of serum interferon-gamma (IFN-gamma) and a 10-fold increase in IFN-gamma production by recipient splenocytes after restimulation in vitro. However, this fulminate Th1 response did not accelerate allograft rejection. Importantly, IL-12 had no effect on serum IFN-gamma or in vivo priming of Thl in IL-12Rbeta1-/- recipients. Finally, administration of IL-12 to WT allograft recipients resulted in a bimodal alloantibody response: antibody production was suppressed at high doses of IL-12, and enhanced at lower doses. IL-12 markedly enhances alloantigen-specific immune function; however, these exaggerated Th1-driven responses do not culminate in accelerated allograft rejection. Further, these data indicate that IL-12Rbeta1 is essential for the enhancement of both in vitro and in vivo alloimmune responses by exogenous IL-12.
Review: The transcripts associated with organ allograft rejection.

PubMed

Halloran, Philip F; Venner, Jeffery M; Madill-Thomsen, Katelynn S; Einecke, Gunilla; Parkes, Michael D; Hidalgo, Luis G; Famulski, Konrad S

2018-04-01

The molecular mechanisms operating in human organ transplant rejection are best inferred from the mRNAs expressed in biopsies because the corresponding proteins often have low expression and short half-lives, while small non-coding RNAs lack specificity. Associations should be characterized in a population that rigorously identifies T cell-mediated (TCMR) and antibody-mediated rejection (ABMR). This is best achieved in kidney transplant biopsies, but the results are generalizable to heart, lung, or liver transplants. Associations can be universal (all rejection), TCMR-selective, or ABMR-selective, with universal being strongest and ABMR-selective weakest. Top universal transcripts are IFNG-inducible (eg, CXCL11 IDO1, WARS) or shared by effector T cells (ETCs) and NK cells (eg, KLRD1, CCL4). TCMR-selective transcripts are expressed in activated ETCs (eg, CTLA4, IFNG), activated (eg, ADAMDEC1), or IFNG-induced macrophages (eg, ANKRD22). ABMR-selective transcripts are expressed in NK cells (eg, FGFBP2, GNLY) and endothelial cells (eg, ROBO4, DARC). Transcript associations are highly reproducible between biopsy sets when the same rejection definitions, case mix, algorithm, and technology are applied, but exact ranks will vary. Previously published rejection-associated transcripts resemble universal and TCMR-selective transcripts due to incomplete representation of ABMR. Rejection-associated transcripts are never completely rejection-specific because they are shared with the stereotyped response-to-injury and innate immunity. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

CD4+ T cell-mediated rejection of MHC class II-positive tumor cells is dependent on antigen secretion and indirect presentation on host APCs.

PubMed

Haabeth, Ole Audun Werner; Fauskanger, Marte; Manzke, Melanie; Lundin, Katrin U; Corthay, Alexandre; Bogen, Bjarne; Tveita, Anders Aune

2018-05-11

Tumor-specific CD4+ T cells have been shown to mediate efficient anti-tumor immune responses against cancer. Such responses can occur through direct binding to MHC class II (MHC II)-expressing tumor cells or indirectly via activation of professional antigen-presenting cells (APC) that take up and present the tumor antigen. We have previously shown that CD4+ T cells reactive against an epitope within the Ig light chain variable region of a murine B cell lymphoma can reject established tumors. Given the presence of MHC II molecules at the surface of lymphoma cells, we investigated whether MHC II-restricted antigen presentation on tumor cells alone was required for rejection. Variants of the A20 B lymphoma cell line that either secreted or intracellularly retained different versions of the tumor-specific antigen revealed that antigen secretion by the MHC II-expressing tumor cells was essential both for the priming and effector phase of CD4+ T cell-driven anti-tumor immune responses. Consistent with this, genetic ablation of MHC II in tumor cells, both in the case of B lymphoma and B16 melanoma, did not preclude rejection of tumors by tumor antigen-specific CD4+ T cells in vivo. These findings demonstrate that MHC class II expression on tumor cells themselves is not required for CD4+ T cell-mediated rejection, and that indirect display on host APC is sufficient for effective tumor elimination. These results support the importance of tumor-infiltrating APC as mediators of tumor cell killing by CD4+ T cells. Copyright ©2018, American Association for Cancer Research.
A hierarchical exact accelerated stochastic simulation algorithm

NASA Astrophysics Data System (ADS)

Orendorff, David; Mjolsness, Eric

2012-12-01

A new algorithm, "HiER-leap" (hierarchical exact reaction-leaping), is derived which improves on the computational properties of the ER-leap algorithm for exact accelerated simulation of stochastic chemical kinetics. Unlike ER-leap, HiER-leap utilizes a hierarchical or divide-and-conquer organization of reaction channels into tightly coupled "blocks" and is thereby able to speed up systems with many reaction channels. Like ER-leap, HiER-leap is based on the use of upper and lower bounds on the reaction propensities to define a rejection sampling algorithm with inexpensive early rejection and acceptance steps. But in HiER-leap, large portions of intra-block sampling may be done in parallel. An accept/reject step is used to synchronize across blocks. This method scales well when many reaction channels are present and has desirable asymptotic properties. The algorithm is exact, parallelizable and achieves a significant speedup over the stochastic simulation algorithm and ER-leap on certain problems. This algorithm offers a potentially important step towards efficient in silico modeling of entire organisms.
Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies.

PubMed

Valenzuela, Nicole M; Reed, Elaine F

2017-06-30

Solid organ transplantation is a curative therapy for hundreds of thousands of patients with end-stage organ failure. However, long-term outcomes have not improved, and nearly half of transplant recipients will lose their allografts by 10 years after transplant. One of the major challenges facing clinical transplantation is antibody-mediated rejection (AMR) caused by anti-donor HLA antibodies. AMR is highly associated with graft loss, but unfortunately there are few efficacious therapies to prevent and reverse AMR. This Review describes the clinical and histological manifestations of AMR, and discusses the immunopathological mechanisms contributing to antibody-mediated allograft injury as well as current and emerging therapies.
Antibody-Mediated Rejection of Human Orthotopic Liver Allografts

PubMed Central

Demetris, A. Jake; Jaffe, Ron; Tzakis, A.; Ramsey, Glenn; Todo, S.; Belle, Steven; Esquivel, Carlos; Shapiro, Ron; Markus, Bernd; Mroczek, Elizabeth; Van Thiel, D. H.; Sysyn, Greg; Gordon, Robert; Makowka, Leonard; Starzl, Tom

1988-01-01

A clinicopathologic analysis of liver transplantation across major ABO blood group barriers was carried out 1) to determine if antibody-mediated (humoral) rejection was a cause of graft failure and if humoral rejection can be identified, 2) to propose criteria for establishing the diagnosis, and 3) to describe the clinical and pathologic features of humoral rejection. A total of 51 (24 primary) ABO-incompatible (ABO-I) liver grafts were transplanted into 49 recipients. There was a 46% graft failure rate during the first 30 days for primary ABO-I grafts compared with an 11% graft failure rate for primary ABO compatible (ABO-C), crossmatch negative, age, sex and priority-matched control patients (P < 0.02). A similarly high early graft failure rate (60%) was seen for nonprimary ABO-I grafts during the first 30 days. Clinically, the patients experienced a relentless rise in serum transaminases, hepatic failure, and coagulopathy during the first weeks after transplant. Pathologic examination of ABO-I grafts that failed early demonstrated widespread areas of geographic hemorrhagic necrosis with diffuse intraorgan coagulation. Prominent arterial deposition of antibody and complement components was demonstrated by immunoflourescent staining. Elution studies confirmed the presence of tissue-bound, donor-specific isoagglutinins within the grafts. No such deposition was seen in control cases. These studies confirm that antibody mediated rejection of the liver occurs and allows for the development of criteria for establishing the diagnosis. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5Figure 6 PMID:3046369
Chronic Antibody-Mediated Rejection in Nonhuman Primate Renal Allografts: Validation of Human Histological and Molecular Phenotypes.

PubMed

Adam, B A; Smith, R N; Rosales, I A; Matsunami, M; Afzali, B; Oura, T; Cosimi, A B; Kawai, T; Colvin, R B; Mengel, M

2017-11-01

Molecular testing represents a promising adjunct for the diagnosis of antibody-mediated rejection (AMR). Here, we apply a novel gene expression platform in sequential formalin-fixed paraffin-embedded samples from nonhuman primate (NHP) renal transplants. We analyzed 34 previously described gene transcripts related to AMR in humans in 197 archival NHP samples, including 102 from recipients that developed chronic AMR, 80 from recipients without AMR, and 15 normal native nephrectomies. Three endothelial genes (VWF, DARC, and CAV1), derived from 10-fold cross-validation receiver operating characteristic curve analysis, demonstrated excellent discrimination between AMR and non-AMR samples (area under the curve = 0.92). This three-gene set correlated with classic features of AMR, including glomerulitis, capillaritis, glomerulopathy, C4d deposition, and DSAs (r = 0.39-0.63, p < 0.001). Principal component analysis confirmed the association between three-gene set expression and AMR and highlighted the ambiguity of v lesions and ptc lesions between AMR and T cell-mediated rejection (TCMR). Elevated three-gene set expression corresponded with the development of immunopathological evidence of rejection and often preceded it. Many recipients demonstrated mixed AMR and TCMR, suggesting that this represents the natural pattern of rejection. These data provide NHP animal model validation of recent updates to the Banff classification including the assessment of molecular markers for diagnosing AMR. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.
Intervention of PKC-θ as an immunosuppressive regimen

PubMed Central

Sun, Zuoming

2012-01-01

PKC-θ is selectively enriched in T cells and specifically translocates to immunological synapse where it mediates critical T cell receptor signals required for T cell activation, differentiation, and survival. T cells deficient in PKC-θ are defective in their ability to differentiate into inflammatory effector cells that mediate actual immune responses whereas, their differentiation into regulatory T cells (Treg) that inhibits the inflammatory T cells is enhanced. Therefore, the manipulation of PKC-θ activity can shift the ratio between inflammatory effector T cells and inhibitory Tregs, to control T cell-mediated immune responses that are responsible for autoimmunity and allograft rejection. Indeed, PKC-θ-deficient mice are resistant to the development of several Th2 and Th17-dependent autoimmune diseases and are defective in mounting alloimmune responses required for rejection of transplanted allografts and graft-versus-host disease. Selective inhibition of PKC-θ is therefore considered as a potential treatment for prevention of autoimmune diseases and allograft rejection. PMID:22876242
MicroRNA-10b downregulation mediates acute rejection of renal allografts by derepressing BCL2L11

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Xiaoyou; Dong, Changgui; Jiang, Zhengyao

Kidney transplantation is the major therapeutic option for end-stage kidney diseases. However, acute rejection could cause allograft loss in some of these patients. Emerging evidence supports that microRNA (miRNA) dysregulation is implicated in acute allograft rejection. In this study, we used next-generation sequencing to profile miRNA expression in normal and acutely rejected kidney allografts. Among 75 identified dysregulated miRNAs, miR-10b was the most significantly downregulated miRNAs in rejected allografts. Transfecting miR-10b inhibitor into human renal glomerular endothelial cells recapitulated key features of acute allograft rejection, including endothelial cell apoptosis, release of pro-inflammatory cytokines (interleukin-6, tumor necrosis factor α, interferon-γ, andmore » chemokine (C–C motif) ligand 2) and chemotaxis of macrophages whereas transfection of miR-10b mimics had opposite effects. Downregulation of miR-10b directly derepressed the expression of BCL2L11 (an apoptosis inducer) as revealed by luciferase reporter assay. Taken together, miR-10b downregulation mediates many aspects of disease pathogenicity of acute kidney allograft rejection. Restoring miR-10b expression in glomerular endothelial cells could be a novel therapeutic approach to reduce acute renal allograft loss. - Highlights: • miR-10b was the most downregulated microRNAs in acutely rejected renal allografts. • miR-10b downregulation triggered glomerular endothelial cell apoptosis. • miR-10b downregulation induced release of pro-inflammatory cytokines. • miR-10b downregulation derepressed its pro-apoptotic target BCL2L11.« less
Child abuse, early maladaptive schemas, and risky sexual behavior in college women.

PubMed

Roemmele, Melissa; Messman-Moore, Terri L

2011-05-01

Previous research suggests that individuals abused as children are more likely to engage in risky sexual behavior during adulthood. The present study examined early maladaptive schemas as mediators of the child abuse-risky sexual behavior relationship among 653 college women. Self-report surveys assessed three forms of child abuse: Sexual, physical, and emotional, and assessed early maladaptive schemas within two domains: Disconnection/rejection and Other-Directedness. Disconnection/rejection schemas fully mediated the relation between child emotional abuse and number of sexual partners and partially mediated the relationship for sexual and physical abuse. However, when frequency of specific risky sexual acts (e.g., sex without contraception) was examined in the previous six months, only abandonment was a partial mediator. Implications for intervention and future research are discussed.
T cells targeting a neuronal paraneoplastic antigen mediate tumor rejection and trigger CNS autoimmunity with humoral activation.

PubMed

Blachère, Nathalie E; Orange, Dana E; Santomasso, Bianca D; Doerner, Jessica; Foo, Patricia K; Herre, Margaret; Fak, John; Monette, Sébastien; Gantman, Emily C; Frank, Mayu O; Darnell, Robert B

2014-11-01

Paraneoplastic neurologic diseases (PND) involving immune responses directed toward intracellular antigens are poorly understood. Here, we examine immunity to the PND antigen Nova2, which is expressed exclusively in central nervous system (CNS) neurons. We hypothesized that ectopic expression of neuronal antigen in the periphery could incite PND. In our C57BL/6 mouse model, CNS antigen expression limits antigen-specific CD4+ and CD8+ T-cell expansion. Chimera experiments demonstrate that this tolerance is mediated by antigen expression in nonhematopoietic cells. CNS antigen expression does not limit tumor rejection by adoptively transferred transgenic T cells but does limit the generation of a memory population that can be expanded upon secondary challenge in vivo. Despite mediating cancer rejection, adoptively transferred transgenic T cells do not lead to paraneoplastic neuronal targeting. Preliminary experiments suggest an additional requirement for humoral activation to induce CNS autoimmunity. This work provides evidence that the requirements for cancer immunity and neuronal autoimmunity are uncoupled. Since humoral immunity was not required for tumor rejection, B-cell targeting therapy, such as rituximab, may be a rational treatment option for PND that does not hamper tumor immunity. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
The Perfect Storm: HLA Antibodies, Complement, FcγRs and Endothelium in Transplant Rejection

PubMed Central

Thomas, Kimberly A.; Valenzuela, Nicole M.; Reed, Elaine F.

2015-01-01

The pathophysiology of antibody-mediated rejection (AMR) in solid organ transplants is multi-faceted and predominantly caused by antibodies directed against polymorphic donor human leukocyte antigens (HLA). Despite the clearly detrimental impact of HLA antibodies (HLA-Ab) on graft function and survival, the prevention, diagnosis and treatment of AMR remain a challenge. Histological manifestations of AMR reflect signatures of HLA-Ab-triggered injury, specifically endothelial changes, recipient leukocytic infiltrate, and complement deposition. We review the interconnected mechanisms of HLA-Ab-mediated injury that might synergize in a “perfect storm” of inflammation. Characterization of antibody features that are critical for effector functions may help identify HLA-Ab more likely to cause rejection. We also highlight recent advancements that may pave the way for new, more effective therapeutics. PMID:25801125
Emergency ABO-incompatible liver transplant secondary to fulminant hepatic failure: outcome, role of TPE and review of the literature.

PubMed

Maitta, Robert W; Choate, Jacquelyn; Emre, Sukru H; Luczycki, Stephen M; Wu, Yanyun

2012-01-01

The increasing demand for solid organ transplants has brought to light the need to utilize organs in critical situations despite ABO-incompatibility. However, these transplantations are complicated by pre-existing ABO antibodies which may be potentially dangerous and makes the transplantation prone to failure due to rejection with resulting necrosis or intrahepatic biliary complications. We report the clinical outcome of an emergency ABO-incompatible liver transplant (due to fulminant hepatic failure with sudden and rapidly deteriorating mental status) using a modified therapeutic plasma exchange (TPE) protocol. The recipient was O-positive with an initial anti-B titer of 64 and the cadaveric organ was from a B-positive donor. The patient underwent initial TPE during the peri-operative period, followed by a series of postoperative daily TPE, and later a third series of TPE for presumptive antibody-mediated rejection. The latter two were performed in conjunction with the use of IVIg and rituximab. The recipient's anti-B titer was reduced and maintained at 8 or less 8 months post-op. However, an elevation of transaminases 3 months post-transplant triggered a biopsy which was consistent with cellular rejection and with weak C4d positive staining suggestive of antibody mediated rejection. Additional plasma exchange procedures were performed. The patient improved rapidly after modification of her immunosuppression regimen and treatment with plasma exchange. This case illustrates that prompt and aggressive plasma exchange, in conjunction with immunosuppression, is a viable approach to prevent and treat antibody mediated transplant rejection in emergency ABO-incompatible liver transplant. Copyright © 2012 Wiley Periodicals, Inc.
False Elevation of the Blood Tacrolimus Concentration, as Assessed by an Affinity Column-mediated Immunoassay (ACMIA), Led to Acute T Cell-mediated Rejection after Kidney Transplantation.

PubMed

Kono, Momoko; Hasegawa, Jumpei; Ogawa, Hina; Yoshikawa, Kanae; Ishiwatari, Ayumi; Wakai, Sachiko; Tanabe, Kazunari; Shirakawa, Hiroki

2018-05-01

Tacrolimus is the most commonly used immunosuppressant. Because of its narrow therapeutic range, it is necessary to frequently monitor its concentration. We report the case of a 25-year-old man who underwent kidney transplantation whose tacrolimus concentrations, as measured by an affinity column-mediated immunoassay, were falsely elevated. As we reduced the dose of tacrolimus, the recipient developed T cell-mediated rejection. Using the same blood samples, an enzyme-multiplied immunoassay technique showed that the patient's levels of tacrolimus were extremely low. A further examination indicated that the false increase in the tacrolimus concentration was likely due to an unknown interfering substance. We administered methylprednisolone and antithymocyte-globulin. The patient's serum creatinine level decreased and remained stable after these treatments.
Management of children undergoing cardiac transplantation with high Panel Reactive Antibodies.

PubMed

Asante-Korang, Alfred; Jacobs, Jeffrey P; Ringewald, Jeremy; Carapellucci, Jennifer; Rosenberg, Kristin; McKenna, Daniel; McCormack, Jorge; Wilmot, Ivan; Gjeldum, Abigail; Lopez-Cepero, Mayra; Sleasman, John

2011-12-01

Highly sensitised children in need of cardiac transplantation have overall poor outcomes because of increased risk for dysfunction of the cardiac allograft, acute cellular and antibody-mediated rejection, and vasculopathy of the cardiac allograft. Cardiopulmonary bypass and the frequent use of blood products in the operating room and cardiac intensive care unit, as well as the frequent use of homografts, have predisposed potential recipients of transplants to allosensitisation. The expansion in the use of ventricular assist devices and extracorporeal membrane oxygenation has also contributed to increasing rates of allosensitisation in candidates for cardiac transplantation. Antibodies to Human Leukocyte Antigen can be detected before transplantation using several different techniques, the most common being the "complement-dependent lymphocytotoxicity assays". "Solid-phase assays", particularly the "Luminex® single antigen bead method", offer improved specificity and more detailed information regarding specificities of antibodies, leading to improved matching of donors with recipients. Allosensitisation prolongs the time on the waiting list for potential recipients of transplantation and increases the risk of complications and death after transplantation. Aggressive reduction of antibodies to Human Leukocyte Antigen in these high-risk patients is therefore of vital importance for long-term survival of the patient and cardiac allograft. Strategies to decrease Panel Reactive Antibody or percent reactive antibody before transplantation include plasmapheresis, intravenous administration of immunoglobulin, and specific treatment to reduce B-cells, particularly Rituximab. These strategies have resulted in varying degrees of success. Antibody-mediated rejection and cardiac allograft vasculopathy are two of the most important complications of transplantation in patients with high Panel Reactive Antibody. The treatment of antibody-mediated rejection in recipients of cardiac transplants is largely empirical and includes the use of high-dose corticosteroids, plasmapheresis, intravenous administration of immunoglobulins, anti-thymocyte globulin, and Rituximab. Cardiac allograft vasculopathy is believed to be secondary to chronic complement-mediated endothelial injury and chronic vascular rejection. The use of proliferation signal inhibitors, such as sirolimus and everolimus, has been shown to delay the progression of cardiac allograft vasculopathy. In some non-sensitised recipients of cardiac transplants, the de novo formation of antibodies to Human Leukocyte Antigen after transplantation may increase the likelihood of adverse clinical outcomes. The use of serial testing for donor-specific antibodies after cardiac transplantation may be advisable in patients with frequent episodes of rejection and patients with history of sensitisation. Allosensitisation before transplantation can negatively influence outcomes after transplantation. A high incidence of antibody-mediated rejection and graft vasculopathy can result in graft failure and decreased survival. Current strategies to decrease allosensitisation have helped to expand the pool of donors, improve times on the waiting list, and decrease mortality. Centres of transplantation offering desensitisation are currently using plasmapheresis to remove circulating antibodies; intravenous immunoglobulin to inactivate antibodies; cyclophosphamide to suppress B-cell proliferation; and Rituximab to deplete B-lymphocytes. Similar approaches are also used to treat antibody-mediated rejection after transplantation with promising results.
Infections and reduced functioning kidney mass induce chronic rejection in rat kidney allografts.

PubMed

Heemann, U W; Azuma, H; Tullius, S G; Schmid, C; Philipp, T; Tilney, N L

1996-07-01

The etiology of chronic rejection of kidney allografts is unknown, although hyperfiltration, acute rejection, viral infection and initial graft ischemia have been implicated. To test whether endothelial activation may be the link between these factors and chronic rejection, the endotoxin (lipopolysaccharide-LPS), a potent activator of endothelial cells, was evaluated in an established chronic rejection model. Bilaterally nephrectomized Lewis recipients of orthotopically transplanted Fisher 344 kidneys were treated briefly with low dose cyclosporine (1.5 mg/kg/day x 10). Recipients were given a non-lethal dose of LPS (2 mg) i.p. at 8 weeks and compared to allografted controls treated with vehicle. Urine protein was measured every 4 weeks. Rats in the treated group were sacrificed at 12 and 16 weeks, control animals at 12, 16 and 24 weeks (20/group) and examined histologically. In the chronically rejecting control allografts, progressive interstitial and glomerular sclerosis and vascular intimal proliferation had become apparent by 12 weeks. Infiltration of glomeruli, particularly by macrophages (M phi), and the coincident presence of cytokines were prominent, peaking at 16 weeks. LPS treatment accelerated and intensified these changes; proteinuria was more pronounced (16 weeks: 79 mg/24 h vs. 49 mg/24 h, p < 0.05). Numbers of infiltrating M phi peaked at 12 weeks in LPS treated hosts (69 c/FV vs. 27 c/FV in untreated controls, p < 0.01), accompanied by an increased upregulation of MHC class II and cytokine expression, particularly TNF alpha and PDGF around arteries and areas of infiltration. BY 16 weeks, 35 +/- 3% of glomeruli in LPS treated recipients had become sclerotic vs. 15 +/- 6% (p < 0.05) in controls, again associated with increased expression of cytokines (PDGF, TNF alpha, TGF beta), adhesion molecules (ICAM-1) and extracellular matrix proteins. Overall, the extent of chronic rejection of grafts in LPS treated rats at 16 weeks was similar to that developing in non-treated rats at 24 weeks. Activation of graft endothelium and/or host leucocytes increased the pace of graft infiltration and the expression of cytokines and other molecules. These events accelerate the process of chronic rejection.
Anti-type V collagen lymphocytes that express IL-17 and IL-23 induce rejection pathology in fresh and well-healed lung transplants.

PubMed

Yoshida, S; Haque, A; Mizobuchi, T; Iwata, T; Chiyo, M; Webb, T J; Baldridge, L A; Heidler, K M; Cummings, O W; Fujisawa, T; Blum, J S; Brand, D D; Wilkes, D S

2006-04-01

Immunity to collagen V [col(V)] contributes to lung 'rejection.' We hypothesized that ischemia reperfusion injury (IRI) associated with lung transplantation unmasks antigenic col(V) such that fresh and well-healed lung grafts have differential susceptibility to anti-col(V)-mediated injury; and expression of the autoimmune cytokines, IL-17 and IL-23, are associated with this process. Adoptive transfer of col(V)-reactive lymphocytes to WKY rats induced grade 2 rejection in fresh isografts, but induced worse pathology (grade 3) when transferred to isograft recipients 30 days post-transplantation. Immunhistochemistry detected col(V) in fresh and well-healed isografts but not native lungs. Hen egg lysozyme-reactive lymphocytes (HEL, control) did not induce lung disease in any group. Col(V), but not HEL, immunization induced transcripts for IL-17 and IL-23 (p19) in the cells utilized for adoptive transfer. Transcripts for IL-17 were upregulated in fresh, but not well-healed isografts after transfer of col(V)-reactive cells. These data show that IRI predisposes to anti-col(V)-mediated pathology; col(V)-reactive lymphocytes express IL-17 and IL-23; and anti-col(V)-mediated lung disease is associated with local expression of IL-17. Finally, because of similar histologic patterns, the pathology of clinical rejection may reflect the activity of autoimmunity to col(V) and/or alloimmunity.
Parental Rejection Following Sexual Orientation Disclosure: Impact on Internalized Homophobia, Social Support, and Mental Health.

PubMed

Puckett, Julia A; Woodward, Eva N; Mereish, Ethan H; Pantalone, David W

2015-09-01

Sexual minority individuals face unique stressors because of their sexual identity. We explored associations between parental reactions to children's coming out, internalized homophobia (IH), social support, and mental health in a sample of 257 sexual minority adults. Path analyses revealed that higher IH and lower social support mediated the association between past parental rejection and current psychological distress. Mental health providers may benefit clients by utilizing interventions that challenge internalized stereotypes about homosexuality, increase social support, and process parental rejection, as well as focusing on how certain crucial experiences of rejection may impact clients' IH and mental health.
Once hurt, twice shy: Social pain contributes to social anxiety.

PubMed

Fung, Klint; Alden, Lynn E

2017-03-01

Social rejection has been consistently linked to the development of social anxiety. However, mechanisms underlying the relation have been largely unexplored, which presents an obstacle to fully understanding the origins of social anxiety and to the development of effective prevention and treatment strategies. Two studies were conducted to test the hypothesis that the emotion of social pain following rejection promotes the development of social anxiety in subsequent situations. In Study 1, undergraduate participants were exposed to 2 social situations (Cyberball) 2 days apart. Participants who were rejected in the first situation reported higher social anxiety before and during the second situation relative to those who were included. This effect was fully mediated by initial social pain intensity. In Study 2, all participants were initially rejected. Using double-blinded drug administration, participants were randomly assigned to ingest acetaminophen to alleviate the social pain from rejection, or a sugar placebo. As predicted, the acetaminophen group reported lower social anxiety before and during the second situation. Approximately half of the effect was mediated by reduction in social pain. Notably, the immediate effect of acetaminophen was specific to social pain rather than social anxiety. Results were discussed in the context of literature on the etiology of social anxiety and social pain. Future directions were suggested. (PsycINFO Database Record (c) 2017 APA, all rights reserved).
Allograft dendritic cell p40 homodimers activate donor-reactive memory CD8+ T cells

PubMed Central

Tsuda, Hidetoshi; Su, Charles A.; Tanaka, Toshiaki; Ayasoufi, Katayoun; Min, Booki; Valujskikh, Anna; Fairchild, Robert L.

2018-01-01

Recipient endogenous memory T cells with donor reactivity pose an important barrier to successful transplantation and costimulatory blockade–induced graft tolerance. Longer ischemic storage times prior to organ transplantation increase early posttransplant inflammation and negatively impact early graft function and long-term graft outcome. Little is known about the mechanisms enhancing endogenous memory T cell activation to mediate tissue injury within the increased inflammatory environment of allografts subjected to prolonged cold ischemic storage (CIS). Endogenous memory CD4+ and CD8+ T cell activation is markedly increased within complete MHC-mismatched cardiac allografts subjected to prolonged versus minimal CIS, and the memory CD8+ T cells directly mediate CTLA-4Ig–resistant allograft rejection. Memory CD8+ T cell activation within allografts subjected to prolonged CIS requires memory CD4+ T cell stimulation of graft DCs to produce p40 homodimers, but not IL-12 p40/p35 heterodimers. Targeting p40 abrogates memory CD8+ T cell proliferation within the allografts and their ability to mediate CTLA-4Ig–resistant allograft rejection. These findings indicate a critical role for memory CD4+ T cell–graft DC interactions to increase the intensity of endogenous memory CD8+ T cell activation needed to mediate rejection of higher-risk allografts subjected to increased CIS. PMID:29467328
Appearance-based rejection sensitivity as a mediator of the relationship between symptoms of social anxiety and disordered eating cognitions and behaviors.

PubMed

Linardon, Jake; Braithwaite, Rachel; Cousins, Rachel; Brennan, Leah

2017-12-01

Previous research has established a robust relationship between symptoms of social anxiety and disordered eating. However, the mechanisms that may underpin this relationship are unclear. Appearance-based rejection sensitivity (ABRS)-the tendency to anxiously expect and overreact to signs of appearance-based rejection-may be a crucial explanatory mechanism, as ABRS has been shown to maintain social anxiety symptoms and predict disordered eating. We therefore tested whether ABRS mediated the relationship between social anxiety symptoms and various indices of disordered eating (over-evaluation of weight/shape, restraint, binge eating, compulsive exercise, and vomiting). Data from community-based females (n=299) and males (n=87) were analyzed. ABRS was shown to mediate the relationship between social anxiety and the over-evaluation, restraint, binge eating, and compulsive exercise frequency, but not vomiting. These effects also occurred for both females and males separately. Findings demonstrated that ABRS may be an important mechanism explaining why socially anxious individuals report elevated symptoms of disordered eating. Future research testing all proposed mediating variables of the social anxiety-disordered eating link in a single, integrative model is required to identify the most influential mechanisms driving this relationship. Copyright © 2017 Elsevier Ltd. All rights reserved.
Emotional responses to interpersonal rejection

PubMed Central

Leary, Mark R.

2015-01-01

A great deal of human emotion arises in response to real, anticipated, remembered, or imagined rejection by other people. Because acceptance by other people improved evolutionary fitness, human beings developed biopsychological mechanisms to apprise them of threats to acceptance and belonging, along with emotional systems to deal with threats to acceptance. This article examines seven emotions that often arise when people perceive that their relational value to other people is low or in potential jeopardy, including hurt feelings, jealousy, loneliness, shame, guilt, social anxiety, and embarrassment. Other emotions, such as sadness and anger, may occur during rejection episodes, but are reactions to features of the situation other than low relational value. The article discusses the evolutionary functions of rejection-related emotions, neuroscience evidence regarding the brain regions that mediate reactions to rejection, and behavioral research from social, developmental, and clinical psychology regarding psychological and behavioral concomitants of interpersonal rejection. PMID:26869844

Emotional responses to a romantic partner's imaginary rejection: the roles of attachment anxiety, covert narcissism, and self-evaluation.

PubMed

Besser, Avi; Priel, Beatriz

2009-02-01

These studies tested the associations between responses to an induced imaginary romantic rejection and individual differences on dimensions of attachment and covert narcissism. In Study 1 (N=125), we examined the associations between attachment dimensions and emotional responses to a vignette depicting a scenario of romantic rejection, as measured by self-reported negative mood states, expressions of anger, somatic symptoms, and self-evaluation. Higher scores on attachment anxiety, but not on attachment avoidance, were associated with stronger reactions to the induced rejection. Moreover, decreased self-evaluation scores (self-esteem and pride) were found to mediate these associations. In Study 2 (N=88), the relative contributions of covert narcissism and attachment anxiety to the emotional responses to romantic rejection were explored. Higher scores on covert narcissism were associated with stronger reactions to the induced rejection. Moreover, covert narcissism seemed to constitute a specific aspect of attachment anxiety.
Working memory and social functioning in children.

PubMed

McQuade, Julia D; Murray-Close, Dianna; Shoulberg, Erin K; Hoza, Betsy

2013-07-01

This study extends previous research and examines whether working memory (WM) is associated with multiple measures of concurrent social functioning (peer rejection, overall social competence, relational aggression, physical aggression, and conflict resolutions skills) in typically developing fourth- and fifth-grade children (N=116). Poor central executive WM was associated with both broad social impairments (peer rejection and poor overall social competence) and specific social impairments (physical aggression, relational aggression, and impaired conflict resolution skills); poor verbal storage was associated only with greater peer rejection, and spatial storage was not associated with any measures of social impairment. Analyses also examined whether specific impairments in aggressive behavior and conflict resolution skills mediated the association between central executive and broad measures of social functioning. Greater physical aggression and impaired conflict resolution skills were both significant mediators; relational aggression was not. Implications for theory and future research are discussed. Copyright © 2013 Elsevier Inc. All rights reserved.
The perfect storm: HLA antibodies, complement, FcγRs, and endothelium in transplant rejection.

PubMed

Thomas, Kimberly A; Valenzuela, Nicole M; Reed, Elaine F

2015-05-01

The pathophysiology of antibody-mediated rejection (AMR) in solid organ transplants is multifaceted and predominantly caused by antibodies directed against polymorphic donor human leukocyte antigens (HLAs). Despite the clearly detrimental impact of HLA antibodies (HLA-Abs) on graft function and survival, the prevention, diagnosis, and treatment of AMR remain a challenge. The histological manifestations of AMR reflect the signatures of HLA-Ab-triggered injury, specifically endothelial changes, recipient leukocytic infiltrate, and complement deposition. We review the interconnected mechanisms of HLA-Ab-mediated injury that might synergize in a 'perfect storm' of inflammation. Characterization of antibody features that are critical for effector functions may help to identify HLA-Abs that are more likely to cause rejection. We also highlight recent advances that may pave the way for new, more effective therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.
Rejection as a call to arms: inter-racial hostility and support for political action as outcomes of race-based rejection in majority and minority groups.

PubMed

Barlow, Fiona Kate; Sibley, Chris G; Hornsey, Matthew J

2012-03-01

Both majority and minority group members fear race-based rejection, and respond by disparaging the groups that they expect will reject them. It is not clear, however, how this process differs in minority and majority groups. Using large representative samples of White (N= 4,618) and Māori (N= 1,163) New Zealanders, we found that perceptions of race-based rejection predicted outgroup negativity in both groups, but in different ways and for different reasons. For White (but not Māori) New Zealanders, increased intergroup anxiety partially mediated the relationship between cognitions of rejection and outgroup negativity. Māori who expected to be rejected on the basis of their race reported increased ethnic identification and, in part through this, increased support for political action benefiting their own group. This finding supports collective-action models of social change in historically disadvantaged minority groups. © 2011 The British Psychological Society.
Peer Rejection and Aggression and Early Starter Models of Conduct Disorder

PubMed Central

Miller-Johnson, Shari; Coie, John D.; Maumary-Gremaud, Anne; Bierman, Karen

2009-01-01

Peer rejection and aggression in the early school years were examined for their relevance to early starting conduct problems. The sample of 657 boys and girls from 4 geographical locations was followed from 1st through 4th grades. Peer rejection in 1st grade added incrementally to the prediction of early starting conduct problems in 3rd and 4th grades, over and above the effects of aggression. Peer rejection and aggression in 1st grade were also associated with the impulsive and emotionally reactive behaviors found in older samples. Being rejected by peers subsequent to 1st grade marginally added to the prediction of early starting conduct problems in 3rd and 4th grades, controlling for 1st grade ADHD symptoms and aggression. Furthermore, peer rejection partially mediated the predictive relation between early ADHD symptoms and subsequent conduct problems. These results support the hypothesis that the experience of peer rejection in the early school years adds to the risk for early starting conduct problems. PMID:12041708
The Timing of Middle-Childhood Peer Rejection and Friendship: Linking Early Behavior to Early-Adolescent Adjustment

ERIC Educational Resources Information Center

Pedersen, Sara; Vitaro, Frank; Barker, Edward D.; Borge, Anne I. H.

2007-01-01

This study used a sample of 551 children surveyed yearly from ages 6 to 13 to examine the longitudinal associations among early behavior, middle-childhood peer rejection and friendedness, and early-adolescent depressive symptoms, loneliness, and delinquency. The study tested a sequential mediation hypothesis in which (a) behavior problems in the…
Negative Affect in Victimized Children: The Roles of Social Withdrawal, Peer Rejection, and Attitudes toward Bullying

ERIC Educational Resources Information Center

Dill, Edward J.; Vernberg, Eric M.; Fonagy, Peter; Twemlow, Stuart W.; Gamm, Bridget K.

2004-01-01

This study evaluated the validity of mediating pathways in predicting self-assessed negative affect from shyness/social withdrawal, peer rejection, victimization by peers (overt and relational), and the attitude that aggression is legitimate and warranted. Participants were 296 3rd through 5th graders (156 girls, 140 boys) from 10 elementary…
Biomarker evaluation of face transplant rejection: association of donor T cells with target cell injury.

PubMed

Lian, Christine Guo; Bueno, Ericka M; Granter, Scott R; Laga, Alvaro C; Saavedra, Arturo P; Lin, William M; Susa, Joseph S; Zhan, Qian; Chandraker, Anil K; Tullius, Stefan G; Pomahac, Bohdan; Murphy, George F

2014-06-01

This series of 113 sequential biopsies of full facial transplants provides findings of potential translational significance as well as biological insights that could prompt reexamination of conventional paradigms of effector pathways in skin allograft rejection. Serial biopsies before, during, and after rejection episodes were evaluated for clinicopathological assessment that in selected cases included specific biomarkers for donor-versus-recipient T cells. Histologic evidence of rejection included lymphocyte-associated injury to epidermal rete ridges, follicular infundibula, and dermal microvessels. Surprisingly, during active rejection, immune cells spatially associated with target cell injury consisted abundantly or predominantly of lymphocytes of donor origin with an immunophenotype typical of the resident memory T-cell subset. Current dogma assumes that skin allograft rejection is mediated by recipient T cells that attack epidermal targets, and the association of donor T cells with sites of target cell injury raises questions regarding the potential complexity of immune cell interactions in the rejection process. A more histopathologically refined and immune-based biomarker approach to assessment of rejection of facial transplants is now indicated.
Multiple Traumas, Maternal Depression, Mother-Child Relationship, Social Support, and Young Children's Behavioral Problems.

PubMed

Schiff, Miriam; Pat-Horenczyk, Ruth; Ziv, Yuval; Brom, Danny

2017-09-01

This study examined whether maternal depression, mother-child relationships, and maternal perceived social support mediate the associations between child's exposure to multiple traumatic events and behavioral problems. We recruited a representative sample of 904 Israeli (Jewish and Arab) mothers and their 2- to 6-year-old children. Data collection was conducted through structured face-to-face interviews with the mothers between July and November 2011. All measures were completed by the mothers. We used the child's and mother's exposure to political violence questionnaires, Child Behavior Checklist (CBCL), a short version of the Parental Acceptance-Rejection Questionnaire (PARQ), the Center for Epidemiologic Studies Depression Scale (CES-D), and the Medical Outcomes Study (MOS) Social Support Survey. The research study model was tested using path analysis. The model showed a very good fit to the data, suggesting that maternal rejection, maternal depression, and social support play an important role in child's behavioral problems in the context of multiple traumatic events. Higher levels of maternal rejection were significantly associated with greater children behavior problems. Maternal rejection mediated the associations between maternal depressive symptoms and child's behavioral problems. Maternal perceived social support mediated the associations between child's exposure to multiple traumatic events and child's behavioral problems; child's exposure to multiple traumatic events was associated with lower levels of maternal perceived social support. In turn, lower levels of perceived social support were associated with higher levels of behavioral problems. In conclusion, in accordance with the "social stress framework," social support has a mediation role in the association between exposure to traumatic events and child's behavioral problems. Thus, enhancing social support to mothers to young children in the context of multiple traumatic events is essential for children resiliency.
Characterization of the Endothelial Cell Cytoskeleton following HLA Class I Ligation

PubMed Central

Ziegler, Mary E.; Souda, Puneet; Jin, Yi-Ping; Whitelegge, Julian P.; Reed, Elaine F.

2012-01-01

Background Vascular endothelial cells (ECs) are a target of antibody-mediated allograft rejection. In vitro, when the HLA class I molecules on the surface of ECs are ligated by anti-HLA class I antibodies, cell proliferation and survival pathways are activated and this is thought to contribute to the development of antibody-mediated rejection. Crosslinking of HLA class I molecules by anti-HLA antibodies also triggers reorganization of the cytoskeleton, which induces the formation of F-actin stress fibers. HLA class I induced stress fiber formation is not well understood. Methodology and Principal Findings The present study examines the protein composition of the cytoskeleton fraction of ECs treated with HLA class I antibodies and compares it to other agonists known to induce alterations of the cytoskeleton in endothelial cells. Analysis by tandem mass spectrometry revealed unique cytoskeleton proteomes for each treatment group. Using annotation tools a candidate list was created that revealed 12 proteins, which were unique to the HLA class I stimulated group. Eleven of the candidate proteins were phosphoproteins and exploration of their predicted kinases provided clues as to how these proteins may contribute to the understanding of HLA class I induced antibody-mediated rejection. Three of the candidates, eukaryotic initiation factor 4A1 (eIF4A1), Tropomyosin alpha 4-chain (TPM4) and DDX3X, were further characterized by Western blot and found to be associated with the cytoskeleton. Confocal microscopy analysis showed that class I ligation stimulated increased eIF4A1 co-localization with F-actin and paxillin. Conclusions/Significance Colocalization of eIF4A1 with F-actin and paxillin following HLA class I ligation suggests that this candidate protein could be a target for understanding the mechanism(s) of class I mediated antibody-mediated rejection. This proteomic approach for analyzing the cytoskeleton of ECs can be applied to other agonists and various cells types as a method for uncovering novel regulators of cytoskeleton changes. PMID:22247778
The Spectrum of Renal Allograft Failure

PubMed Central

Chand, Sourabh; Atkinson, David; Collins, Clare; Briggs, David; Ball, Simon; Sharif, Adnan; Skordilis, Kassiani; Vydianath, Bindu; Neil, Desley; Borrows, Richard

2016-01-01

Background Causes of “true” late kidney allograft failure remain unclear as study selection bias and limited follow-up risk incomplete representation of the spectrum. Methods We evaluated all unselected graft failures from 2008–2014 (n = 171; 0–36 years post-transplantation) by contemporary classification of indication biopsies “proximate” to failure, DSA assessment, clinical and biochemical data. Results The spectrum of graft failure changed markedly depending on the timing of allograft failure. Failures within the first year were most commonly attributed to technical failure, acute rejection (with T-cell mediated rejection [TCMR] dominating antibody-mediated rejection [ABMR]). Failures beyond a year were increasingly dominated by ABMR and ‘interstitial fibrosis with tubular atrophy’ without rejection, infection or recurrent disease (“IFTA”). Cases of IFTA associated with inflammation in non-scarred areas (compared with no inflammation or inflammation solely within scarred regions) were more commonly associated with episodes of prior rejection, late rejection and nonadherence, pointing to an alloimmune aetiology. Nonadherence and late rejection were common in ABMR and TCMR, particularly Acute Active ABMR. Acute Active ABMR and nonadherence were associated with younger age, faster functional decline, and less hyalinosis on biopsy. Chronic and Chronic Active ABMR were more commonly associated with Class II DSA. C1q-binding DSA, detected in 33% of ABMR episodes, were associated with shorter time to graft failure. Most non-biopsied patients were DSA-negative (16/21; 76.1%). Finally, twelve losses to recurrent disease were seen (16%). Conclusion This data from an unselected population identifies IFTA alongside ABMR as a very important cause of true late graft failure, with nonadherence-associated TCMR as a phenomenon in some patients. It highlights clinical and immunological characteristics of ABMR subgroups, and should inform clinical practice and individualised patient care. PMID:27649571
Stomaching rejection: Self-compassion and self-esteem moderate the impact of daily social rejection on restrictive eating behaviours among college women.

PubMed

Beekman, Janine B; Stock, Michelle L; Howe, George W

2017-11-01

The present study examined whether having high self-esteem or a self-compassionate perspective help mitigate the impact of daily social rejection on negative affect and restrictive eating behaviours. Following a baseline survey assessing self-esteem and self-compassion, 121 college women completed online daily diaries for one week. Negative affect and restrictive eating behaviours. On days when women reported more rejection, they also reported higher restrictive eating behaviours and greater negative affect. Effects were moderated by self-esteem and self-compassion, such that the lower participants were in self-esteem or self-compassion, the stronger the positive relation between rejection and negative affect and restrictive eating. However, only the common humanity/isolation dimension of self-compassion significantly moderated daily effects of rejection when controlling for self-esteem. Mediated moderation results reveal different mechanisms by which self-esteem and self-compassion buffer against rejections' effects on affect and restrictive eating. Self-compassion and self-esteem influence the complex impact that social rejection has on affect and restrictive eating. More than other dimensions of self-compassion or self-esteem, remembering one's common humanity can result in a healthier response to social rejection.
Accelerating rejection-based simulation of biochemical reactions with bounded acceptance probability

NASA Astrophysics Data System (ADS)

Thanh, Vo Hong; Priami, Corrado; Zunino, Roberto

2016-06-01

Stochastic simulation of large biochemical reaction networks is often computationally expensive due to the disparate reaction rates and high variability of population of chemical species. An approach to accelerate the simulation is to allow multiple reaction firings before performing update by assuming that reaction propensities are changing of a negligible amount during a time interval. Species with small population in the firings of fast reactions significantly affect both performance and accuracy of this simulation approach. It is even worse when these small population species are involved in a large number of reactions. We present in this paper a new approximate algorithm to cope with this problem. It is based on bounding the acceptance probability of a reaction selected by the exact rejection-based simulation algorithm, which employs propensity bounds of reactions and the rejection-based mechanism to select next reaction firings. The reaction is ensured to be selected to fire with an acceptance rate greater than a predefined probability in which the selection becomes exact if the probability is set to one. Our new algorithm improves the computational cost for selecting the next reaction firing and reduces the updating the propensities of reactions.
Accelerating rejection-based simulation of biochemical reactions with bounded acceptance probability

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thanh, Vo Hong, E-mail: vo@cosbi.eu; Priami, Corrado, E-mail: priami@cosbi.eu; Department of Mathematics, University of Trento, Trento

Stochastic simulation of large biochemical reaction networks is often computationally expensive due to the disparate reaction rates and high variability of population of chemical species. An approach to accelerate the simulation is to allow multiple reaction firings before performing update by assuming that reaction propensities are changing of a negligible amount during a time interval. Species with small population in the firings of fast reactions significantly affect both performance and accuracy of this simulation approach. It is even worse when these small population species are involved in a large number of reactions. We present in this paper a new approximatemore » algorithm to cope with this problem. It is based on bounding the acceptance probability of a reaction selected by the exact rejection-based simulation algorithm, which employs propensity bounds of reactions and the rejection-based mechanism to select next reaction firings. The reaction is ensured to be selected to fire with an acceptance rate greater than a predefined probability in which the selection becomes exact if the probability is set to one. Our new algorithm improves the computational cost for selecting the next reaction firing and reduces the updating the propensities of reactions.« less
The Basics of Renal Allograft Pathology.

PubMed

Troxell, Megan L; Houghton, Donald C

2014-09-01

Renal allograft biopsy provides critical information in the management of renal transplant patients, and must be analyzed in close collaboration with the clinical team. The histologic correlates of acute T-cell mediated rejection are interstitial inflammation, tubulitis, and endothelialitis; polyomavirus nephropathy is a potential mimic. Evidence of antibody-mediated rejection includes C4d deposition; morphologic acute tissue injury; and donor specific antibodies. Acute tubular injury/necrosis is a reversible cause of impaired graft function, especially in the immediate post-transplant period. Drug toxicity, recurrent disease, chronic injury, and other entities affecting both native and transplant kidneys must also be evaluated. Copyright © 2014 Elsevier Inc. All rights reserved.
C4d-the witness of humoral rejection.

PubMed

de Gouveia, R H; Vitorino, E; Ramos, S; Rebocho, M J; Queirós E Melo, J; Martins, A P; Moura, M L C

2009-04-01

Acute antibody-mediated (humoral) rejection is a major cause of morbidity, graft loss, and mortality among heart transplant patients. Herein we have presented our experience using C4d to characterize humoral rejection. All nonformalin-fixed cardiac graft biopsies (protocol or emergency) received between May 2007 and May 2008 were examined by immunofluorescence for C4d. One hundred twelve endomyocardial biopsies from 25 transplanted patients included 20 males and 5 females of ages ranging from 3 to 71 years. The number of biopsies per subject varied from 1 to 11; the timespan between transplantation and the diagnostic biopsies ranged from days to 8 years. Thirteen biopsies showed acute humoral rejection (intramyocardial capillaries positive for C4d); 31, acute cellular rejection (grades 1R, 2R); 7, both humoral and cellular rejection; and 1, acute humoral rejection and allograft vasculopathy. Some of the positive biopsies belonged to the same person, and some to transplanted individuals with signs and symptoms suggestive of rejection, while others did not. The persistence of humoral rejection, despite the disappearance of a cellular component, correlated with slower clinicoechocardiographic improvement. C4d positivity is a morphologic sign of humoral rejection. It may hasten the appearance and/or worsening of allograft vasculopathy independent of patient age or posttransplantation time.
Rejected by peers-attracted to antisocial media content: rejection-based anger impairs moral judgment among adolescents.

PubMed

Plaisier, Xanthe S; Konijn, Elly A

2013-06-01

Adolescence is an important developmental stage during which both peers and the media have a strong influence. Both peer rejection and the use of morally adverse media are associated with negative developmental outcomes. This study examines processes by which peer rejection might drive adolescents to select antisocial media content by tying together developmental research on peer rejection and research on media effects. Assumed underlying mechanisms are rejection-based anger and frustration and the adolescent's moral judgment. A between-participants experimental design manipulated peer rejection versus acceptance in adolescents (Mage = 13.88 years; N = 74) and young adults (Mage = 21.37 years; N = 75), applying the Cyberball paradigm. Measures included the State Anger Inventory (STAXI) to assess feelings of rejection and the newly devised Media, Morals, and Youth Questionnaire (MMaYQue) to assess media preferences and moral judgment of media content. Using bootstrapping analyses, a double mediation was established: Higher levels of state anger in peer-rejected adolescents induced more tolerable moral judgments of antisocial media content, subsequently instigating a preference for antisocial media content. In contrast, the young adult sample showed no relations between peer rejection and antisocial media preference. Results are discussed within a downward spiral framework of combined peer and media influences. PsycINFO Database Record (c) 2013 APA, all rights reserved
Violent Victimization in the Community and Children's Subsequent Peer Rejection: The Mediating Role of Emotion Dysregulation

ERIC Educational Resources Information Center

Kelly, Brynn M.; Schwartz, David; Gorman, Andrea Hopmeyer; Nakamoto, Jonathan

2008-01-01

This paper describes a short-term longitudinal study of the relation between violent victimization in the community and peer rejection among 199 children (mean age = 9.02 years) attending two urban Los Angeles area elementary schools. We used a multi-informant approach to assess victimization by community violence, peer group victimization, peer…
Rejection triggers liver transplant tolerance: Involvement of mesenchyme-mediated immune control mechanisms in mice.

PubMed

Morita, Miwa; Joyce, Daniel; Miller, Charles; Fung, John J; Lu, Lina; Qian, Shiguang

2015-09-01

Liver tolerance was initially recognized by the spontaneous acceptance of liver allografts in many species. The underlying mechanisms are not completely understood. However, liver transplant (LT) tolerance absolutely requires interferon (IFN)-γ, a rejection-associated inflammatory cytokine. In this study, we investigated the rejection of liver allografts deficient in the IFN-γ receptor and reveal that the liver graft is equipped with machineries capable of counterattacking the host immune response through a mesenchyme-mediated immune control (MMIC) mechanism. MMIC is triggered by T effector (Tef) cell-derived IFN-γ that drives expression of B7-H1 on graft mesenchymal cells leading to Tef cell apoptosis. We describe the negative feedback loop between graft mesenchymal and Tef cells that ultimately results in LT tolerance. Comparable elevations of T-regulatory cells and myeloid-derived suppressor cells were observed in both rejection and tolerance groups and were not dependent on IFN-γ stimulation, suggesting a critical role of Tef cell elimination in tolerance induction. We identify potent MMIC activity in hepatic stellate cells and liver sinusoidal endothelial cells. MMIC is unlikely exclusive to the liver, given that spontaneous acceptance of kidney allografts has been reported, although less commonly, probably reflecting variance in MMIC activity. MMIC may represent an important homeostatic mechanism that supports peripheral tolerance and could be a target for the prevention and treatment of transplant rejection. This study highlights that the graft is an active participant in the equipoise between tolerance and rejection and warrants more attention in the search for tolerance biomarkers. © 2015 by the American Association for the Study of Liver Diseases.
Rejection Triggers Liver Transplant Tolerance: Involvements of Mesenchyme-Mediated Immune Control Mechanisms

PubMed Central

Morita, Miwa; Joyce, Daniel; Miller, Charles; Fung, John J.; Lu, Lina; Qian, Shiguang

2015-01-01

Liver tolerance was initially recognized by the spontaneous acceptance of liver allograft in many species. The underlying mechanisms are not completely understood. We have been inspired by an unexpected phenomenon that the liver transplant tolerance absolutely requires interferon (IFN)-γ, a rejection-associated inflammatory cytokine. In this study, we investigate the rejection of liver allografts deficient in IFN-γ receptor and reveal that the liver graft is equipped with machineries capable of counterattacking the host immune response through a mesenchyme-mediated immune control (MMIC) mechanism. MMIC is triggered by T effectors (Tef) cell-derived IFN-γ to drive the expression of B7-H1 on graft mesenchymal cells leading to Tef cell apoptosis. We describe the negative feedback loop between graft mesenchymal and Tef cells that ultimately results in liver transplant tolerance. Comparable elevations of T regulatory cells and myeloid-derived suppressor cells are seen in both rejection and tolerance groups, and are not dependent on IFN-γ stimulation, suggesting a critical role of Tef cell elimination in tolerance induction. We identify potent MMIC activity in hepatic stellate cells and liver sinusoidal endothelial cells. MMIC is unlikely exclusive to the liver, as spontaneous acceptance of kidney allografts has been reported, although less commonly, probably reflecting variance in MMIC activity. MMCI may represent an important homeostatic mechanism that supports peripheral tolerance, and could be a target for the prevention and treatment of transplant rejection. This study highlights that the graft is actively participant in the equipoise between tolerance and rejection and warrants more attention in the search for tolerance biomarkers. PMID:25998530

Generation of a felinized swine endothelial cell line by expression of feline decay-accelerating factor.

PubMed

Izuhara, Luna; Tatsumi, Norifumi; Miyagawa, Shuji; Iwai, Satomi; Watanabe, Masahito; Yamanaka, Shuichiro; Katsuoka, Yuichi; Nagashima, Hiroshi; Okano, Hirotaka J; Yokoo, Takashi

2015-01-01

Embryonic stem cell research has facilitated the generation of many cell types for the production of tissues and organs for both humans and companion animals. Because ≥30% of pet cats suffer from chronic kidney disease (CKD), xenotransplantation between pigs and cats has been studied. For a successful pig to cat xenotransplant, the immune reaction must be overcome, especially hyperacute rejection. In this study, we isolated the gene for feline decay-accelerating factor (fDAF), an inhibitor of complement proteins, and transfected a swine endothelial cell line with fDAF to "felinize" the pig cells. These fDAF-expressing cells were resistant to feline serum containing anti-pig antibodies, suggesting that felinized pig cells were resistant to hyperacute rejection. Our results suggest that a "felinized" pig kidney can be generated for the treatment of CKD in cats in the future.
Filipino Mothers’ Self-Efficacy in Managing Anger and in Parenting, and Parental Rejection as Predictors of Child Delinquency

PubMed Central

Daganzo, Mary Angeline A.; Peña Alampay, Liane; Lansford, Jennifer E.

2015-01-01

The authors tested a model in which Filipino mothers’ self-efficacy in managing anger/irritation influenced child delinquency via two parenting variables: parental self-efficacy and parental rejection. Structured interviews were conducted with 99 mothers twice with an interval of one year with efficacy beliefs and rejection measured in the first year and child delinquency data collected in the following year. Path analyses showed that self-efficacy in managing anger/irritation negatively predicted child delinquency indirectly through the sequential mediation of parental self-efficacy and parental rejection. Results provided further evidence for the importance of efficacy beliefs, particularly self-efficacy in managing anger/irritation and parental self-efficacy, in the domain of child development. PMID:26635423
Both rejection and tolerance of allografts can occur in the absence of secondary lymphoid tissues

PubMed Central

Kant, Cavit D.; Akiyama, Yoshinobu; Tanaka, Katsunori; Shea, Susan; Yamada, Yohei; Connolly, Sarah E; Marino, Jose; Tocco, Georges; Benichou, Gilles

2014-01-01

In this study, we show that aly/aly mice, which are devoid of lymph nodes and Peyer’s patches, rejected acutely fully allogeneic skin and heart grafts. They mounted potent inflammatory direct alloresponses but failed to develop indirect alloreactivity after transplantation. Remarkably, skin allografts were also rejected acutely by splenectomized aly/aly mice (aly/aly-spl−) devoid of all secondary lymphoid organs. In these recipients, the rejection was mediated by alloreactive CD8+ T cells presumably primed in the bone marrow. In contrast, cardiac transplants were not rejected in aly/aly-spl− mice. Actually, aly/aly-spl− mice having spontaneously accepted a heart allotransplant displayed donor-specific tolerance also accepted skin grafts from the same but not a third-party donor via a mechanism involving CD4+ regulatory T cells producing IL-10 cytokine. Therefore, direct priming of alloreactive T cells, as well as rejection and regulatory tolerance of allogeneic transplants, can occur in recipient mice lacking secondary lymphoid organs. PMID:25535285
Practice Patterns in the Treatment and Monitoring of Acute T Cell-Mediated Kidney Graft Rejection in Canada.

PubMed

Leblanc, Julie; Subrt, Peter; Paré, Michèle; Hartell, David; Sénécal, Lynne; Blydt-Hansen, Tom; Cardinal, Héloïse

2018-01-01

One of the goals of the Canadian National Transplant Research Program (CNTRP) is to develop novel therapies for acute rejection that could positively affect graft outcomes with greater efficacy or less toxicity. To develop innovative management strategies for kidney graft rejection, new modalities need to be compared with current clinical practices. However, there are no standardized practices concerning the management of acute T cell-mediated rejection (TCMR). To describe clinicians' practice patterns in the diagnosis, treatment, and monitoring of acute TCMR in Canada. Survey. Canadian transplant nephrologists and transplant surgeons involved in the management of acute TCMR. We developed an anonymous, web-based survey consisting of questions related to the diagnosis, treatment, and monitoring of TCMR. The survey was disseminated on 3 occasions between June and October 2016 through the Canadian Society of Transplantation (CST) kidney group electronic mailing list. Forty-seven respondents, mostly transplant nephrologists (97%), originating from at least 18 of the 25 Canadian centers offering adult or pediatric kidney transplantation, participated in the study. Surveillance biopsies were used by 28% of respondents to screen for kidney graft rejection. High-dose steroids were used by most of the respondents to treat clinical and subclinical Banff grade 1A and 1B rejections. Nine percent (95% confidence interval [CI]: 1-17) of practitioners used lymphocyte-depleting agents as the first-line approach for the treatment of Banff grade 1B acute rejection. Eighteen percent (95% CI: 7-29) and 36% (95% CI: 8-65) of respondents reported that they would not use high-dose steroids for treating clinical and subclinical borderline rejections, respectively. Seventy percent (95% CI: 54-83) of respondents answered that there was no indication to assess histological response to treatment independent of the change in kidney function. The limitations of this study are its limited sample size and the low representation of pediatric specialists. There is heterogeneity regarding the use of surveillance biopsies, treatment of borderline rejection, and modalities to monitor treatment response among transplant physicians. Our results illustrate the current state of practice patterns across Canada and can be used to inform the design of future trials.
Outside advantage: can social rejection fuel creative thought?

PubMed

Kim, Sharon H; Vincent, Lynne C; Goncalo, Jack A

2013-08-01

Eminently creative people working in fields as disparate as physics and literature refer to the experience of social rejection as fuel for creativity. Yet, the evidence of this relationship is anecdotal, and the psychological process that might explain it is as yet unknown. We theorize that the experience of social rejection may indeed stimulate creativity but only for individuals with an independent self-concept. In 3 studies, we show that individuals who hold an independent self-concept performed more creatively after social rejection relative to inclusion. We also show that this boost in creativity is mediated by a differentiation mind-set, or salient feelings of being different from others. Future research might investigate how the self-concept--for example, various cultural orientations-may shape responses to social rejection by mitigating some of the negative consequences of exclusion and potentially even motivating creative exploration. PsycINFO Database Record (c) 2013 APA, all rights reserved.
Emotion Dysregulation Mediates the Longitudinal Relation between Peer Rejection and Depression: Differential Effects of Gender and Grade

ERIC Educational Resources Information Center

Fussner, Lauren M.; Luebbe, Aaron M.; Mancini, Kathryn J.; Becker, Stephen P.

2018-01-01

The goal of the current investigation was to test emotion dysregulation as a mechanism explaining the longitudinal association between peer rejection and depressive symptoms across 1 school year in middle childhood and to determine whether this process differed based on gender and grade. Youth in Grades 3 through 6 (N = 131; 71 girls) and their…
Underbody Blast Models of TBI Caused by Hyper-Acceleration and Secondary Head Impact

DTIC Science & Technology

2016-02-01

discovery rate (FDR), which controls for the expected proportion of false rejected hypotheses. ANOVA was performed to evaluate the significance in gene...acceleration/deceleration11,27 and blast4,13 have also been designed for the purpose of evaluating coup-contrecoup and blast wave energies potentially... evaluation of different angles/ locations of the projectile impact to the surface of the rat head. Finally, pilot studies were conducted to provide further
Immunological tolerance induced by galectin-1 in rat allogeneic renal transplantation.

PubMed

Xu, Gaosi; Tu, Weiping; Xu, Chengyun

2010-06-01

The existed literatures indicated that galectin-1 has anti-inflammatory effects and plays a pivotal role in autoimmune diseases. Present study was to identify the roles of galectin-1 in acute animal renal allograft rejection. Rat acute rejection models were erected by allogeneic renal transplantation. Galectin-1 injection was performed in different concentrations in renal recipients post-transplantation. Recipient survivals, CD8+ T cell proliferation, production of IFN-gamma, levels of serum CD30, enzyme-linked immunoabsorbent spot assay (ELISPOT) and immunohistochemistry were observed or tested 7days after renal transplantation. Galectin-1 injection can prolong the recipient animal survival, reduce the serum levels of IFN-gamma, soluble CD30, percentage of CD8+ T cell subset, CD8+ T cell-mediated cytotoxicity, and IFN-gamma ELISPOT frequency for allograft recipients. The therapeutic effects of galectin-1 injection on recipient rats were dose-dependent. Galectin-1 plays an important role in CD8+ T cell-mediated renal rejection by inducing immunological tolerance. Copyright 2010 Elsevier B.V. All rights reserved.
Examining Ethnic Differences in Parental Rejection of LGB Youth Sexual Identity

PubMed Central

Richter, Brian E. J.; Lindahl, Kristin M.; Malik, Neena M.

2016-01-01

Upward of 70% of lesbian, gay, and bisexual (LGB) youth experience some degree of parental rejection of their sexual identity, which is problematic in light of research documenting links between parental rejection and psychological difficulties in LGB youth. Additionally, emerging research suggests that ethnic minority LGB youth may be at greater risk to experience parental rejection than ethnic majority LGB youth. However, this research is inconclusive and has significant gaps. The current study is one of the first to include a multiethnic sample of LGB youth and their parents to investigate how ethnicity may be related to parental rejection. Specifically, the current study examined ethnic differences in parental rejection as well as in intrapersonal variables (i.e., homonegativity and traditional gender role beliefs), which are thought to be related both to ethnicity and parental rejection. Additionally, indirect effects of ethnicity on parental rejection through homonegativity and traditional gender role beliefs were examined. Participants included 90 parents (ages 32-63) and their 90 LGB children (ages 15-24). Fifty-nine percent of the sample was ethnic minority. Significant ethnic differences were found in parental rejection and homonegativity, but not in traditional gender role beliefs. Homonegativity was found to fully mediate the relation between ethnicity and parental rejection. These results provide important information on why ethnic minority parents, in general, may have a more difficult time accepting their LGB children than ethnic majority parents. PMID:27571323
Desensitization: Overcoming the Immunologic Barriers to Transplantation

PubMed Central

Choi, Jua; Vo, Ashley; Peng, Alice; Jordan, Stanley C.

2017-01-01

HLA (Human Leucocyte Antigen) sensitization is a significant barrier to successful kidney transplantation. It often translates into difficult crossmatch before transplant and increased risk of acute and chronic antibody mediated rejection after transplant. Over the last decade, several immunomodulatory therapies have emerged allowing for increased access to kidney transplantation for the immunologically disadvantaged group of HLA sensitized end stage kidney disease patients. These include IgG inactivating agents, anti-cytokine antibodies, costimulatory molecule blockers, complement inhibitors, and agents targeting plasma cells. In this review, we discuss currently available agents for desensitization and provide a brief analysis of data on novel biologics, which will likely improve desensitization outcomes, and have potential implications in treatment of antibody mediated rejection. PMID:28127571
Computer-Mediated Intersensory Learning Model for Students with Learning Disabilities

ERIC Educational Resources Information Center

Seok, Soonhwa; DaCosta, Boaventura; Kinsell, Carolyn; Poggio, John C.; Meyen, Edward L.

2010-01-01

This article proposes a computer-mediated intersensory learning model as an alternative to traditional instructional approaches for students with learning disabilities (LDs) in the inclusive classroom. Predominant practices of classroom inclusion today reflect the six principles of zero reject, nondiscriminatory evaluation, appropriate education,…
Dual Pathways from Reactive Aggression to Depressive Symptoms in Children: Further Examination of the Failure Model.

PubMed

Evans, Spencer C; Fite, Paula J

2018-04-13

The failure model posits that peer rejection and poor academic performance are dual pathways in the association between early aggressive behavior and subsequent depressive symptoms. We examined this model using an accelerated longitudinal design while also incorporating proactive and reactive aggression and gender moderation. Children in 1st, 3rd, and 5th grades (n = 912; ages 6-12; 48% female) were rated three times annually by their primary teachers on measures of proactive and reactive aggression, peer rejection, academic performance, and depressive symptoms. Using Bayesian cross-classified estimation to account for nested and planned-missing data, path models were estimated to examine whether early reactive aggression predicted subsequent peer rejection and academic performance, and whether these, in turn, predicted subsequent depressive symptoms. From 1st to 3rd grade, reactive aggression predicted peer rejection (not academic performance), proactive aggression predicted academic performance (not peer rejection), and academic performance and peer rejection both predicted depressive symptoms. From 3rd to 5th grade, however, neither peer rejection nor academic performance predicted subsequent depressive symptoms. Results were not moderated by gender. Overall, these findings provide mixed and limited support for the failure model among school-age children. Early reactive aggression may be a key risk factor for social problems, whereas proactive aggression may be linked to improved academic functioning. The "dual pathways" of peer rejection and academic performance may operate during early but not later elementary school. Limitations and implications are discussed.
Transient blockade of Delta-like Notch ligands prevents allograft rejection mediated by cellular and humoral mechanisms in a mouse model of heart transplantation

PubMed Central

Wood, Sherri; Feng, Jiane; Chung, Jooho; Radojcic, Vedran; Sandy, Ashley R.; Friedman, Ann; Shelton, Amy; Yan, Minhong; Siebel, Christian W.; Bishop, D. Keith; Maillard, Ivan

2015-01-01

Rejection remains a major clinical challenge limiting allograft survival after solid organ transplantation. Both cellular and humoral immunity contribute to this complication, with increased recognition of antibody-mediated damage during acute and chronic rejection. Using a mouse model of MHC-mismatched heart transplantation, we report markedly protective effects of Notch inhibition, dampening both T cell and antibody-driven rejection. T cell-specific pan-Notch blockade prolonged heart allograft survival and decreased IFNγ and IL-4 production by alloreactive T cells, especially when combined with depletion of recipient CD8+ T cells. These effects were associated with decreased infiltration by conventional T cells and an increased proportion of regulatory T cells in the graft. Transient administration of neutralizing antibodies specific for Delta-like1/4 (Dll1/4) Notch ligands in the peri-transplant period led to prolonged acceptance of allogeneic hearts, with superior outcome over Notch inhibition only in T cells. Systemic Dll1/4 inhibition decreased T cell cytokines and graft infiltration, but also germinal center B cell and plasmablast numbers as well as production of donor-specific alloantibodies and complement deposition in the transplanted hearts. Dll1 or Dll4 inhibition alone provided partial protection. Thus, pathogenic signals delivered by Dll1/4 Notch ligands early after transplantation promote organ rejection through several complementary mechanisms. Transient interruption of theses signals represents a new attractive therapeutic strategy to enhance long-term allograft survival. PMID:25687759
Limbic Justice—Amygdala Involvement in Immediate Rejection in the Ultimatum Game

PubMed Central

Fransson, Peter; Petrovic, Predrag; Johannesson, Magnus; Ingvar, Martin

2011-01-01

Imaging studies have revealed a putative neural account of emotional bias in decision making. However, it has been difficult in previous studies to identify the causal role of the different sub-regions involved in decision making. The Ultimatum Game (UG) is a game to study the punishment of norm-violating behavior. In a previous influential paper on UG it was suggested that frontal insular cortex has a pivotal role in the rejection response. This view has not been reconciled with a vast literature that attributes a crucial role in emotional decision making to a subcortical structure (i.e., amygdala). In this study we propose an anatomy-informed model that may join these views. We also present a design that detects the functional anatomical response to unfair proposals in a subcortical network that mediates rapid reactive responses. We used a functional MRI paradigm to study the early components of decision making and challenged our paradigm with the introduction of a pharmacological intervention to perturb the elicited behavioral and neural response. Benzodiazepine treatment decreased the rejection rate (from 37.6% to 19.0%) concomitantly with a diminished amygdala response to unfair proposals, and this in spite of an unchanged feeling of unfairness and unchanged insular response. In the control group, rejection was directly linked to an increase in amygdala activity. These results allow a functional anatomical detection of the early neural components of rejection associated with the initial reactive emotional response. Thus, the act of immediate rejection seems to be mediated by the limbic system and is not solely driven by cortical processes, as previously suggested. Our results also prompt an ethical discussion as we demonstrated that a commonly used drug influences core functions in the human brain that underlie individual autonomy and economic decision making. PMID:21559322
Narrative representations of caregivers and emotion dysregulation as predictors of maltreated children's rejection by peers.

PubMed

Shields, A; Ryan, R M; Cicchetti, D

2001-05-01

This study examined whether maltreated children were more likely than nonmaltreated children to develop poor-quality representations of caregivers and whether these representations predicted children's rejection by peers. A narrative task assessing representations of mothers and fathers was administered to 76 maltreated and 45 nonmaltreated boys and girls (8-12 years old). Maltreated children's representations were more negative/constricted and less positive/coherent than those of nonmaltreated children. Maladaptive representations were associated with emotion dysregulation, aggression, and peer rejection, whereas positive/coherent representations were related to prosocial behavior and peer preference. Representations mediated maltreatment's effects on peer rejection in part by undermining emotion regulation. Findings suggest that representations of caregivers serve an important regulatory function in the peer relationships of at-risk children.
Maternal control, cognitive style, and childhood anxiety: a test of a theoretical model in a multi-ethnic sample.

PubMed

Creveling, C Christiane; Varela, R Enrique; Weems, Carl F; Corey, David M

2010-08-01

This study tested a theoretical model of the interrelations among controlling parenting, negative cognitive styles, children's anxiety, and race/ethnicity. The model suggests that, in general, cognitive style mediates the relation between maternal control and child anxiety but that the set of associations may differ as a function of ethnicity. African American (n = 235), Latin American (n = 56), and European American (n = 136) children completed measures of their anxiety, cognitive schemas reflecting impaired autonomy/performance and disconnection/rejection domains, and maternal control. Results indicated that a disconnection/rejection negative cognitive style mediated the effect of perceived maternal control on childhood anxiety only for the European American group. Maternal control was associated with the impaired autonomy/performance cognitive style for each of the three ethnic groups and with a disconnection/rejection cognitive style only for the European American and Latin American groups. Maternal control had an indirect effect on anxiety through the disconnection/rejection cognitive style for the Latin American group. The results are discussed in terms of how the model presented extends current theories of anxiety problems to African American and Latin American children by noting that significant cultural variations may exist in how parenting practices and cognitive styles relate to children's anxiety levels.
CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface fas ligand expression and amplifies fas-mediated hepatocyte death during allograft rejection.

PubMed

Afford, S C; Randhawa, S; Eliopoulos, A G; Hubscher, S G; Young, L S; Adams, D H

1999-01-18

We propose that a novel mechanism of hepatocyte apoptosis, involving a cooperative interaction between CD40 and Fas, is involved in the hepatocyte loss of chronic liver allograft rejection. We detected increased hepatocyte expression of Fas, Fas ligand (FasL), and CD40 associated with dropout of centrilobular (acinar zone 3) hepatocytes in chronic allograft rejection. Expression of CD40 ligand (CD40L) was also increased but was largely restricted to CD68(+) macrophages. A functional role for CD40 and Fas in hepatocyte apoptosis was demonstrated in vitro using primary human hepatocytes and the HepG2 cell line in both of which apoptosis was induced, not only by cross-linking Fas directly but also via CD40 activation. Our data suggest that CD40 activation induces apoptosis via Fas because (a) ligation of CD40 upregulated hepatocyte FasL expression, and (b) apoptosis induced via activation of CD40 was prevented by a neutralizing monoclonal antibody to FasL. Thus, CD40 engagement triggers apoptosis of human hepatocytes and might amplify Fas-dependent hepatocyte apoptosis in chronic rejection and other inflammatory liver diseases in which Fas-mediated apoptosis is involved.
Response efficacy: the key to minimizing rejection and maximizing acceptance of emotion-based anti-speeding messages.

PubMed

Lewis, I M; Watson, B; White, K M

2010-03-01

This study sought to improve understanding of the persuasive process of emotion-based appeals not only in relation to negative, fear-based appeals but also for appeals based upon positive emotions. In particular, the study investigated whether response efficacy, as a cognitive construct, mediated outcome measures of message effectiveness in terms of both acceptance and rejection of negative and positive emotion-based messages. Licensed drivers (N=406) participated via the completion of an on-line survey. Within the survey, participants received either a negative (fear-based) appeal or one of the two possible positive appeals (pride or humor-based). Overall, the study's findings confirmed the importance of emotional and cognitive components of persuasive health messages and identified response efficacy as a key cognitive construct influencing the effectiveness of not only fear-based messages but also positive emotion-based messages. Interestingly, however, the results suggested that response efficacy's influence on message effectiveness may differ for positive and negative emotion-based appeals such that significant indirect (and mediational) effects were found with both acceptance and rejection of the positive appeals yet only with rejection of the fear-based appeal. As such, the study's findings provide an important extension to extant literature and may inform future advertising message design. Copyright 2009 Elsevier Ltd. All rights reserved.
The Impact of Timing and Graft Dysfunction on Survival and Cardiac Allograft Vasculopathy in Antibody Mediated Rejection

PubMed Central

Clerkin, Kevin J.; Restaino, Susan W.; Zorn, Emmanuel; Vasilescu, Elena R.; Marboe, Charles C.; Mancini, Donna M.

2017-01-01

Background Antibody mediated rejection (AMR) has been associated with increased mortality and cardiac allograft vasculopathy (CAV). Early studies suggested that late AMR was rarely associated with graft dysfunction while recent reports have demonstrated an association with increased mortality. We sought to investigate the timing of AMR and its association with graft dysfunction, mortality, and CAV. Methods This retrospective cohort study identified all adult heart transplant recipients at Columbia University Medical Center from 2004–2013 (689 patients). There were 68 primary cases of AMR, which were stratified by early (<1 year post-OHT) or late (>1-year post-OHT) AMR. Kaplan-Meier survival analysis and modeling was performed with multivariable logistic regression and Cox proportional hazards regression. Results From January 1, 2004 through October 1, 2015 43 patients had early AMR (median 23 days post-OHT) and 25 had late AMR (median 1084 days post-OHT). Graft dysfunction was less common with early compared with late AMR (25.6% vs. 56%, p=0.01). Patients with late AMR had decreased post-AMR survival compared with early AMR (1-year 80% vs. 93%, 5-year 51% vs. 73%, p<0.05). When stratified by graft dysfunction, only those with late AMR and graft dysfunction had worse survival (30-day 79%, 1-year 64%, and 5-year 36%, p<0.006). The association remained irrespective of age, sex, DSA, LVAD use, reason for OHT, and recovery of graft function. Similarly, those with late AMR and graft dysfunction had accelerated development of de-novo CAV (50% at 1 year, HR 5.42, p=0.009), while all other groups were all similar to the general transplant population. Conclusion Late AMR is frequently associated with graft dysfunction. When graft dysfunction is present in late AMR there is an early and sustained increased risk of mortality and rapid development of de-novo CAV despite aggressive treatment. PMID:27423693
Increased levels of circulating nitrates and impaired endothelium-mediated vasodilation suggest multiple roles of nitric oxide during acute rejection of pulmonary allografts.

PubMed

Wiklund, L; Lewis, D H; Sjöquist, P O; Nilsson, F; Tazelaar, H; Miller, V M; McGregor, C G

1997-05-01

Experiments were designed to determine whether changes in pulmonary artery function could be reduced by treatment with a lipid peroxidation inhibitor (H 290/51) during acute rejection of pulmonary allografts. Single lung transplantation was performed in three groups of dogs: group 1 was maintained on immunosuppression for 8 days after operation (immunosuppressed, n = 5); in group 2, immunosuppression was discontinued on postoperative day 5, so that rejection occurred on postoperative day 8 (rejecting, n = 6); in group 3, immunosuppression was discontinued after 5 days, and the lipid peroxidation inhibitor H 290/51 (25 mg/kg) was given perorally for 3 days (rejecting + H 290/51, n = 6). Plasma nitric oxide (NO(x)) was measured by use of chemoluminescence. On postoperative day 8 rejection was observed in groups 2 and 3. Contractions to angiotensin I and endothelium-dependent relaxations to adenosine diphosphate were reduced in pulmonary arteries from rejecting lungs. Responses of rings from dogs treated with H 290/51 were similar to those from rejecting lungs. Rejection did not alter relaxations to exogenous nitric oxide. However, plasma levels of NO(x) increased significantly during rejection independently of treatment with H 290/51. Results of this study confirm that endothelium-dependent relaxation of pulmonary arteries is reduced during acute rejection of lung allografts. The result extends these observations to suggest that treatment with a lipid peroxidation inhibitor neither protects the pulmonary artery function nor affects levels of circulating NO(x). Therefore mechanisms other than lipid peroxidation participate in vascular changes associated with allograft rejection.

The role of innate immunity in acute allograft rejection after lung transplantation.

PubMed

Palmer, Scott M; Burch, Lauranell H; Davis, R Duane; Herczyk, Walter F; Howell, David N; Reinsmoen, Nancy L; Schwartz, David A

2003-09-15

Although innate immunity is crucial to pulmonary host defense and can initiate immune and inflammatory responses independent of adaptive immunity, it remains unstudied in the context of transplant rejection. To investigate the role of innate immunity in the development of allograft rejection, we assessed the impact of two functional polymorphisms in the toll-like receptor 4 (TLR4) associated with endotoxin hyporesponsiveness on the development of acute rejection after human lung transplantation. Patients and donors were screened for the TLR4 Asp299Gly and Thr399Ile polymorphisms by polymerase chain reaction using sequence-specific primers. The rate of acute rejection at 6 months was significantly reduced in recipients, but not in donors, with the Asp299Gly or Thr399Ile alleles as compared with wild type (29 vs. 56%, respectively, p = 0.05). This association was confirmed in Cox proportional hazards and multivariate logistic regression models. Our results suggest activation of innate immunity in lung transplant recipients through TLR4 contributes to the development acute rejection after lung transplantation. Therapies directed at inhibition of innate immune responses mediated by TLR4 may represent a novel and effective means to prevent acute rejection after lung transplantation.
Absence of Activation-induced Cytidine Deaminase, a Regulator of Class Switch Recombination and Hypermutation in B Cells, Suppresses Aorta Allograft Vasculopathy in Mice.

PubMed

Nakanishi, Tomonori; Xu, Xiaoyan; Wynn, Carmen; Yamada, Toshiko; Pan, Fan; Erickson, Laurie; Teo, Haeman; Nakagawa, Terry; Masunaga, Taro; Abe, Jumpei; Akamatsu, Masahiko; Tamura, Kouichi; Jiang, Hongsi

2015-08-01

Antibody-mediated rejection is caused in part by increasing circulation/production of donor-specific antibody (DSA). Activation-induced cytidine deaminase (AID) is a key regulator of class switch recombination and somatic hypermutation of immunoglobulin in B cells, yet its role in antibody-mediated transplant rejection remains unclear. We show here that AID deficiency in mice enables suppression of allograft vasculopathy (AV) after aorta transplantation, a DSA-mediated process. Splenocytes from C57BL/6 J (B6) AID(−/−) mice were used for determining in vitro proliferation responses, alloreactivity, cell surface marker expression, and antibody production. BALB/c mouse aortas were transplanted into B6 AID(−/−) mice with or without FK506 treatment. Blood and aorta grafts were harvested on day 30 after transplantation and were subjected to DSA, histological, and immunohistological analyses. The AID(−/−) splenocytes were comparable to wild type splenocytes in proliferation responses, alloreactivity, and expression of cell surface markers in vitro. However, they completely failed to produce immunoglobulin G, although they were not impaired in immunoglobulin M production relative to controls. Furthermore, BALB/c aorta grafts from B6 AID(−/−) recipient mice on day 30 after transplantation showed reduced signs of AV compared to the grafts from B6 wild type recipient mice which had severe vascular intimal hyperplasia, interstitial fibrosis, and inflammation. Treatment with FK506 produced a synergistic effect in the grafts from AID(−/−) recipients with further reduction of intimal hyperplasia and fibrosis scores. The AID deficiency inhibits DSA-mediated AV after aorta transplantation in mice. We propose that AID could be a novel molecular target for controlling antibody-mediated rejection in organ transplantation.
Combating the sting of rejection with the pleasure of revenge: A new look at how emotion shapes aggression.

PubMed

Chester, David S; DeWall, C Nathan

2017-03-01

How does emotion explain the relationship between social rejection and aggression? Rejection reliably damages mood, leaving individuals motivated to repair their negatively valenced affective state. Retaliatory aggression is often a pleasant experience. Rejected individuals may then harness revenge's associated positive affect to repair their mood. Across 6 studies (total N = 1,516), we tested the prediction that the rejection-aggression link is motivated by expected and actual mood repair. Further, we predicted that this mood repair would occur through the positive affect of retaliatory aggression. Supporting these predictions, naturally occurring (Studies 1 and 2) and experimentally manipulated (Studies 3 and 4) motives to repair mood via aggression moderated the rejection-aggression link. These effects were mediated by sadistic impulses toward finding aggression pleasant (Studies 2 and 4). Suggesting the occurrence of actual mood repair, rejected participants' affective states were equivalent to their accepted counterparts after an act of aggression (Studies 5 and 6). This mood repair occurred through a dynamic interplay between preaggression affect and aggression itself, and was driven by increases in positive affect (Studies 5 and 6). Together, these findings suggest that the rejection-aggression link is driven, in part, by the desire to return to affective homeostasis. Additionally, these findings implicate aggression's rewarding nature as an incentive for rejected individuals' violent tendencies. (PsycINFO Database Record (c) 2017 APA, all rights reserved).
Examining ethnic differences in parental rejection of LGB youth sexual identity.

PubMed

Richter, Brian E J; Lindahl, Kristin M; Malik, Neena M

2017-03-01

Upward of 70% of lesbian, gay, and bisexual (LGB) youth experience some degree of parental rejection of their sexual identity, which is problematic in light of research documenting links between parental rejection and psychological difficulties in LGB youth. Additionally, emerging research suggests that ethnic minority LGB youth may be at greater risk to experience parental rejection than ethnic majority LGB youth. However, this research is inconclusive and has significant gaps. The current study is one of the first to include a multiethnic sample of LGB youth and their parents to investigate how ethnicity may be related to parental rejection. Specifically, the current study examined ethnic differences in parental rejection as well as in intrapersonal variables (i.e., homonegativity and traditional gender role beliefs), which are thought to be related both to ethnicity and parental rejection. Additionally, indirect effects of ethnicity on parental rejection through homonegativity and traditional gender role beliefs were examined. Participants included 90 parents (ages 32-63) and their 90 LGB children (ages 15-24). Fifty-nine percent of the sample were ethnic minority. Significant ethnic differences were found in parental rejection and homonegativity, but not in traditional gender role beliefs. Homonegativity was found to fully mediate the relation between ethnicity and parental rejection. These results provide important information on why ethnic minority parents, in general, may have a more difficult time accepting their LGB children than ethnic majority parents. (PsycINFO Database Record (c) 2017 APA, all rights reserved).
Impact of hyperlipidemia on alloimmunity.

PubMed

Bagley, Jessamyn; Yuan, Jin; Iacomini, John

2017-02-01

Hyperlipidemia is a comorbidity affecting a significant number of transplant patients despite treatment with cholesterol lowering drugs. Recently, it has been shown that hyperlipidemia can significantly alter T-cell responses to cardiac allografts in mice, and graft rejection is accelerated in dyslipidemic mice. Here, we review recent advances in our understanding of hyperlipidemia in graft rejection. Hyperlipidemic mice have significant increases in serum levels of proinflammatory cytokines, and neutralization of interleukin 17 (IL-17) slows graft rejection, suggesting that IL-17 production by Th17 cells was necessary but not sufficient for rejection. Hyperlipidemia also causes an increase in alloreactive T-cell responses prior to antigen exposure. Analysis of peripheral tolerance mechanisms indicated that this was at least in part due to alterations in FoxP3 T cells that led to reduced Treg function and the expansion of FoxP3 CD4 T cells expressing low levels of CD25. Functionally, alterations in Treg function prevented the ability to induce operational tolerance to fully allogeneic heart transplants through costimulatory-molecule blockade, a strategy that requires Tregs. These findings highlight the importance of considering the contribution of inflammatory comorbidities to cardiac allograft rejection, and point to the potential importance of managing hyperlipidemia in the transplant population.
Maladaptive Schemas as Mediators in the Relationship Between Child Sexual Abuse and Displaced Aggression.

PubMed

Estévez, Ana; Ozerinjauregi, Nagore; Herrero-Fernández, David

2016-01-01

Child sexual abuse is one of the most serious forms of abuse due to the psychological consequences that persist even into adulthood. Expressions of anger among child sexual abuse survivors remain common even years after the event. While child sexual abuse has been extensively studied, the expression of displaced aggression has been studied less. Some factors, such as the maladaptive early schemas, might account for this deficiency. The objective of this study was to analyze the relationships between child sexual abuse, displaced aggression, and these schemas according to gender and determine if these early schemas mediate the relationship between child sexual abuse and displaced aggression. A total of 168 Spanish subjects who were victims of child sexual abuse completed measures of childhood trauma, displaced aggression, and early maladaptive schemas. The results depict the relationship between child sexual abuse, displaced aggression, and early maladaptive schemas. Women scored higher than men in child sexual abuse, emotional abuse, disconnection or rejection and impaired autonomy. Mediational analysis found a significant mediation effect of disconnection or rejection on the relationship between child sexual abuse and displaced aggression; however, impaired autonomy did not mediate significantly.
Role of humoral immune reactions as target for antirejection therapy in recipients of a spousal-donor kidney graft.

PubMed

Böhmig, G A; Regele, H; Säemann, M D; Exner, M; Druml, W; Kovarik, J; Hörl, W H; Zlabinger, G J; Watschinger, B

2000-04-01

Excellent graft outcome has been reported for spousal-donor kidney transplantation. In husband-to-wife transplantation, however, a tendency toward inferior graft survival has been described for recipients who were previously pregnant. In our series of spousal-kidney transplantations (nine transplantations; three female recipients), actual graft survival is 100% (median observation time, 339 days). Five patients experienced early allograft rejection. In four transplant recipients, rejection was easily reversible by conventional antirejection therapy. In a multiparous recipient, however, mild interstitial allograft rejection associated with early graft dysfunction was resistant to anticellular treatment (antilymphocyte antibody, tacrolimus rescue therapy). The particular finding of polymorphonuclear neutrophils in peritubular capillaries and the finding of diffuse capillary deposits of the complement split product, C4d, in a posttransplantation biopsy specimen suggested a role of antibody-mediated graft injury. Retrospective flow cytometry cross-matching showed the presence of preformed immunoglobulin G (IgG) antibodies to HLA class I antigens that were not detectable by pretransplantation lymphocytotoxic cross-match testing or screening for panel reactive antibodies. After transplantation, however, complement-fixing antibodies, also presumably triggered by reexposure to spousal-donor HLA antigens, could be detected in the patient's serum. These findings suggested antibody-mediated allograft rejection and led to the initiation of immunoadsorption therapy (14 sessions) with staphylococcal protein A. Selective removal of recipient IgG resulted in complete reversal of graft dysfunction. Our findings suggest that in husband-to-wife transplantation, donor-specific antibodies, presumably triggered by previous pregnancies, might occasionally induce sustained allograft dysfunction. Thus, in this particular setting, a detailed immunologic and histopathologic work-up regarding antibody-mediated allograft dysfunction is warranted because immunoadsorption may be a highly effective treatment modality.
Soluble CD30 and Hepatocyte growth factor as predictive markers of antibody-mediated rejection of the kidney allograft.

PubMed

Pavlova, Yelena; Viklicky, Ondrej; Slatinska, Janka; Bürgelova, Marcela; Süsal, Caner; Skibova, Jelena; Honsová, Eva; Striz, Ilja; Kolesar, Libor; Slavcev, Antonij

2011-07-01

Our retrospective study was aimed to assess the relevance of pre- and post-transplant measurements of serum concentrations of the soluble CD30 molecule (soluble CD30, sCD30) and the cytokine Hepatocyte growth factor (HGF) for prediction of the risk for development of antibody-mediated rejection (AMR) in kidney transplant patients. Evaluation of sCD30, HGF levels and the presence of HLA-specific antibodies in a cohort of 205 patients was performed before, 2weeks and 6months after transplantation. Patients were followed up for kidney graft function and survival for two years. We found a tendency of higher incidence of AMR in retransplanted patients with elevated pre-transplant sCD30 (≥100U/ml) (p=0.051), however no such correlation was observed in first-transplant patients. Kidney recipients with simultaneously high sCD30 and HLA-specific antibodies (sCD30+/Ab+) before transplantation had significantly lower AMR-free survival compared to the other patient groups (p<0.001). HGF concentrations were not associated with the incidence of AMR at any time point of measurement, nevertheless, the combined analysis HGF and sCD30 showed increased incidence of AMR in recipients with elevated pretransplant sCD30 and low HGF levels. the predictive value of pretransplant sCD30 for the development of antibody-mediated rejection after transplantation is significantly potentiated by the co-presence of HLA specific antibodies. The role of HGF as a rejection-protective factor in patients with high pretransplant HGF levels would need further investigation. Copyright © 2011 Elsevier B.V. All rights reserved.
Perceptions of Parenting, Emotional Self-Efficacy, and Anxiety in Youth: Test of a Mediational Model

ERIC Educational Resources Information Center

Niditch, Laura A.; Varela, R. Enrique

2012-01-01

Background: Though associations between parenting styles marked by control (e.g., prevention of autonomous experiences) or rejection (e.g., criticism, arbitrary blame, and withholding of warmth) and youth anxiety have been established in the literature, few studies have examined cognitive mediators purported to explain these associations.…
Simulation of disturbance rejection control of half-car active suspension system using active disturbance rejection control with decoupling transformation

NASA Astrophysics Data System (ADS)

Hasbullah, Faried; Faris, Waleed F.

2017-12-01

In recent years, Active Disturbance Rejection Control (ADRC) has become a popular control alternative due to its easy applicability and robustness to varying processes. In this article, ADRC with input decoupling transformation (ADRC-IDT) is proposed to improve ride comfort of a vehicle with an active suspension system using half-car model. The ride performance of the ADRC-IDT is evaluated and compared with decentralized ADRC control as well as the passive system. Simulation results show that both ADRC and ADRC-IDT manage to appreciably reduce body accelerations and able to cope well with varying conditions typically encountered in an active suspension system. Also, it is sufficient to control only the body motions with both active controllers to improve ride comfort while maintaining good road holding and small suspension working space.
Annual literature review of donor-specific HLA antibodies after organ transplantation.

PubMed

Kaneku, Hugo

2011-01-01

The literature review of post-transplant DSA published in 2011 shows: Observations after kidney and lung transplant in non-sensitized transplant recipients show that monitoring post-transplant HLA antibodies offers limited benefit in predicting acute rejection episodes. It remains to be seen if a different monitoring schedule and/ or studying other organs may show otherwise. Nevertheless, others have shown that monitoring post-transplant antibodies does identify patients at higher risk for chronic rejection. Studies in kidney, heart, and liver patients transplanted in the presence of preformed DSA show that detecting these antibodies early after transplant identifies a group of patients with greater risk for allograft dysfunction. New and larger studies using bortezomib and eculizumab to treat acute antibody-mediated rejection confirm earlier observations that these two therapies are effective in treating and preventing rejections. In general, identification of HLAantibodies and DSA after transplant is associated with higher rates of rejection and poor allograft survival in all organs examined. IgM antibodies appear to play an important role after lung transplants.
Recent Developments in Young-Earth Creationist Geology

NASA Astrophysics Data System (ADS)

Heaton, Timothy H.

2009-10-01

Young-earth creationism has undergone a shift in emphasis toward building of historical models that incorporate Biblical and scientific evidence and the acceptance of scientific conclusions that were formerly rejected. The RATE Group admitted that massive amounts of radioactive decay occurred during earth history but proposed a period of accelerated decay during Noah’s Flood to fit the resulting history into a young-earth timeframe. Finding a mechanism for the acceleration and dealing with the excessive heat and radiation it would generate posed major problems for the project. Catastrophic plate tectonics was proposed to explain continental movements in a short timeframe and serve as a trigger for Noah’s Flood, but other creationists rejected the idea citing hopeless chronological problems. Creationists have also sought to explain the order of the fossil record and the Ice Age in a young-earth timeframe. An examination of these efforts demonstrates the anti-scientific nature of using the Bible as a non-negotiable framework for earth history.
Enhanced Requirement for TNFR2 in Graft Rejection Mediated by Low Affinity Memory CD8+ T Cells During Heterologous Immunity

PubMed Central

Krummey, Scott M.; Chen, Ching-Wen; Guasch, Sara A.; Liu, Danya; Wagener, Maylene; Larsen, Christian P; Ford, Mandy L.

2016-01-01

The affinity of a T cell receptor (TCR) binding to peptide:MHC profoundly impacts the phenotype and function of effector and memory cell differentiation. Little is known about the effect of low affinity priming on memory cell generation and function, which is particularly important in heterologous immunity, when microbe-specific T cells cross-react with allogeneic antigen and mediate graft rejection. We found that low affinity primed memory CD8+ T cells produced high levels of TNF ex vivo in response to heterologous rechallenge compared to high affinity primed memory T cells. Low affinity secondary effectors significantly upregulated TNFR2 on the cell surface and contained a higher frequency of TNFR2hi proliferating cells. Low affinity primed secondary effectors concurrently downregulated TNF production. Importantly, blockade of TNFR2 attenuated graft rejection in low but not high affinity primed animals. These data establish a functional connection between TNF signaling and TCR priming affinity and have implications for the immunomodulation of pathogenic T cell responses during transplantation. PMID:27481849
Graft-Derived CCL2 Increases Graft Injury During Antibody-Mediated Rejection of Cardiac Allografts

PubMed Central

Abe, Toyofumi; Su, Charles A.; Iida, Shoichi; Baldwin, William M.; Nonomura, Norio; Takahara, Shiro; Fairchild, Robert L.

2015-01-01

The pathogenic role of macrophages in antibody-mediated rejection (AMR) remains unclear. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a potent chemotactic factor for monocytes and macrophages. The current studies used a murine model of AMR to investigate the role of graft-derived CCL2 in AMR and how macrophages may participate in antibody-mediated allograft injury. B6.CCR5−/−/CD8−/− recipients rejected MHC-mismatched wild type A/J allografts with high donor-reactive antibody titers and diffuse C4d deposition in the large vessels and myocardial capillaries, features consistent with AMR. In contrast, A/J.CCL2−/− allografts induced low donor-reactive antibody titers and C4d deposition at day 7 post-transplant. Decreased donor-reactive CD4 T cells producing IFN-γ were induced in response to A/J.CCL2−/− vs. wild type allografts. Consequently, A/J.CCL2−/− allograft survival was modestly but significantly longer than A/J allografts. Macrophages purified from wild type allografts expressed high levels of IL-1β and IL-12p40 and this expression and the numbers of classically activated macrophages were markedly reduced in CCL2-deficient allografts on day 7. The results indicate that allograft-derived CCL2 plays an important role in directing classically activated macrophages into allografts during AMR and that macrophages are important contributors to the inflammatory environment mediating graft tissue injury in this pathology, suggesting CCL2 as a therapeutic target for AMR. PMID:25040187
The Impact of HLA Class I-Specific Killer Cell Immunoglobulin-Like Receptors on Antibody-Dependent Natural Killer Cell-Mediated Cytotoxicity and Organ Allograft Rejection.

PubMed

Rajalingam, Raja

2016-01-01

Natural killer (NK) cells of the innate immune system are cytotoxic lymphocytes that play an important roles following transplantation of solid organs and hematopoietic stem cells. Recognition of self-human leukocyte antigen (HLA) class I molecules by inhibitory killer cell immunoglobulin-like receptors (KIRs) is involved in the calibration of NK cell effector capacities during the developmental stage, allowing the subsequent recognition and elimination of target cells with decreased expression of self-HLA class I (due to virus infection or tumor transformation) or HLA class I disparities (in the setting of allogeneic transplantation). NK cells expressing an inhibitory KIR-binding self-HLA can be activated when confronted with allografts lacking a ligand for the inhibitory receptor. Following the response of the adaptive immune system, NK cells can further destroy allograft endothelium by antibody-dependent cell-mediated cytotoxicity (ADCC), triggered through cross-linking of the CD16 Fc receptor by donor-specific antibodies bound to allograft. Upon recognizing allogeneic target cells, NK cells also secrete cytokines and chemokines that drive maturation of dendritic cells to promote cellular and humoral adaptive immune responses against the allograft. The cumulative activating and inhibitory signals generated by ligation of the receptors regulates mature NK cell killing of target cells and their production of cytokines and chemokines. This review summarizes the role of NK cells in allograft rejection and proposes mechanistic concepts that indicate a prominent role for KIR-HLA interactions in facilitating NK cells for Fc receptor-mediated ADCC effector function involved in antibody-mediated rejection of solid organ transplants.
Molecular profiling of subclinical inflammatory lesions in long-term surviving adult liver transplant recipients.

PubMed

Londoño, María-Carlota; Souza, Lara Neves; Lozano, Juan-José; Miquel, Rosa; Abraldes, Juan G; Llovet, Laura-Patricia; Quaglia, Alberto; Rimola, Antoni; Navasa, Miquel; Sánchez-Fueyo, Alberto

2018-04-28

Subclinical inflammatory changes are commonly described in long-term transplant recipients undergoing protocol liver biopsies. The pathogenesis of these lesions remains unclear. The aim of this study was to identify the key molecular pathways driving progressive subclinical inflammatory liver allograft damage. All liver recipients followed at Hospital Clínic Barcelona who were >10 years post-transplant were screened for participation in the study. Patients with recurrence of underlying liver disease, biliary or vascular complications, chronic rejection, and abnormal liver function tests were excluded. Sixty-seven patients agreed to participate and underwent blood and serological tests, transient elastography and a liver biopsy. Transcriptome profiling was performed on RNA extracted from 49 out of the 67 biopsies employing a whole genome next generation sequencing platform. Patients were followed for a median of 6.8 years following the index liver biopsy. Median time since transplantation to liver biopsy was 13 years (10-22). The most frequently observed histological abnormality was portal inflammation with different degrees of fibrosis, present in 45 biopsies (67%). Two modules of 102 and 425 co-expressed genes were significantly correlated with portal inflammation, interface hepatitis and portal fibrosis. These modules were enriched in molecular pathways known to be associated with T cell mediated rejection. Liver allografts showing the highest expression levels for the two modules recapitulated the transcriptional profile of biopsies with clinically apparent rejection and developed progressive damage over time, as assessed by non-invasive markers of fibrosis. A large proportion of adult liver transplant recipients who survive long-term exhibit subclinical histological abnormalities. The transcriptomic profile of these patients' liver tissue closely resembles that of T cell mediated rejection and may result in progressive allograft damage. A large proportion of adult liver transplant recipients who survive for a long time exhibit subclinical histological abnormalities. The expression profile (a measurement of the activity of genes) of liver tissue from a large fraction of these patients closely resembles the profile of T cell mediated rejection. Liver allografts showing the highest expression levels of rejection-related genes developed progressive damage over time. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Perceived Parenting Mediates Serotonin Transporter Gene (5-HTTLPR) and Neural System Function during Facial Recognition: A Pilot Study.

PubMed

Nishikawa, Saori; Toshima, Tamotsu; Kobayashi, Masao

2015-01-01

This study examined changes in prefrontal oxy-Hb levels measured by NIRS (Near-Infrared Spectroscopy) during a facial-emotion recognition task in healthy adults, testing a mediational/moderational model of these variables. Fifty-three healthy adults (male = 35, female = 18) aged between 22 to 37 years old (mean age = 24.05 years old) provided saliva samples, completed a EMBU questionnaire (Swedish acronym for Egna Minnen Beträffande Uppfostran [My memories of upbringing]), and participated in a facial-emotion recognition task during NIRS recording. There was a main effect of maternal rejection on RoxH (right frontal activation during an ambiguous task), and a gene × environment (G × E) interaction on RoxH, suggesting that individuals who carry the SL or LL genotype and who endorse greater perceived maternal rejection show less right frontal activation than SL/LL carriers with lower perceived maternal rejection. Finally, perceived parenting style played a mediating role in right frontal activation via the 5-HTTLPR genotype. Early-perceived parenting might influence neural activity in an uncertain situation i.e. rating ambiguous faces among individuals with certain genotypes. This preliminary study makes a small contribution to the mapping of an influence of gene and behaviour on the neural system. More such attempts should be made in order to clarify the links.
Perceived Parenting Mediates Serotonin Transporter Gene (5-HTTLPR) and Neural System Function during Facial Recognition: A Pilot Study

PubMed Central

Nishikawa, Saori

2015-01-01

This study examined changes in prefrontal oxy-Hb levels measured by NIRS (Near-Infrared Spectroscopy) during a facial-emotion recognition task in healthy adults, testing a mediational/moderational model of these variables. Fifty-three healthy adults (male = 35, female = 18) aged between 22 to 37 years old (mean age = 24.05 years old) provided saliva samples, completed a EMBU questionnaire (Swedish acronym for Egna Minnen Beträffande Uppfostran [My memories of upbringing]), and participated in a facial-emotion recognition task during NIRS recording. There was a main effect of maternal rejection on RoxH (right frontal activation during an ambiguous task), and a gene × environment (G×E) interaction on RoxH, suggesting that individuals who carry the SL or LL genotype and who endorse greater perceived maternal rejection show less right frontal activation than SL/LL carriers with lower perceived maternal rejection. Finally, perceived parenting style played a mediating role in right frontal activation via the 5-HTTLPR genotype. Early-perceived parenting might influence neural activity in an uncertain situation i.e. rating ambiguous faces among individuals with certain genotypes. This preliminary study makes a small contribution to the mapping of an influence of gene and behaviour on the neural system. More such attempts should be made in order to clarify the links. PMID:26418317
Intravenous immunoglobulins and rituximab therapy for severe transplant glomerulopathy in chronic antibody-mediated rejection: a pilot study.

PubMed

Bachelet, Thomas; Nodimar, Celine; Taupin, Jean-Luc; Lepreux, Sebastien; Moreau, Karine; Morel, Delphine; Guidicelli, Gwendaline; Couzi, Lionel; Merville, Pierre

2015-05-01

Outcome of patients with transplant glomerulopathy (TG) is poor. Using B-cell targeting molecules represent a rational strategy to treat TG during chronic antibody-mediated rejection. In this pilot study, 21 patients with this diagnosis received four doses of intravenous immunoglobulins and two doses of rituximab (IVIG/RTX group). They were retrospectively compared with a untreated control group of 10 patients. At 24 months post-biopsy, graft survival was similar and poor between the treated and the untreated group, 47% vs. 40%, respectively, p = 0.69. This absence of response of IVIG/RTX treatment was observed, regardless the phenotype of TG. Baseline estimated glomerular filtration rate (eGFR) and decline in eGFR during the first six months after the treatment were risk factors associated with 24-month graft survival. The IVIG/RTX therapy had a modest effect on the kinetics of donor-specific alloantibodies at M24, compared to the untreated group, not associated with an improvement in graft survival. The mean number of adverse events per patient was higher in the IVIG/RTX group than in the control group (p = 0.03). Taken together, IVIG/RTX treatment for severe TG during chronic antibody-mediated rejection does not seem to change the natural history of TG and is associated with a high incidence of adverse events. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
History of Abuse and Risky Sex among Substance Users: The Role of Rejection Sensitivity and the Need to Belong

PubMed Central

Woerner, Jacqueline; Kopetz, Catalina; Lechner, William V.; Lejuez, Carl

2016-01-01

This study investigates abuse and rejection sensitivity as important correlates of risky sexual behavior in the context of substance use. Victims of abuse may experience heightened sensitivity to acute social rejection and consequently engage in risky sexual behavior in an attempt to restore belonging. Data were collected from 258 patients at a substance use treatment facility in Washington, D.C. Participants' history of abuse and risky sexual behavior were assessed via self-report. To test the mediating role of rejection sensitivity, participants completed a social rejection task (Cyberball) and responded to a questionnaire assessing their reaction to the rejection experience. General risk-taking propensity was assessed using a computerized lab measure. Abuse was associated with increased rejection sensitivity (B = .124, SE = .040, p = .002), which was in turn associated with increased risky sex (B = .06, SE = .028, p = .03) (indirect effect = .0075, SE = .0043; 95% CI [.0006, 0.0178]), but not with other indices of risk-taking. These findings suggest that rejection sensitivity may be an important mechanism underlying the relationship between abuse and risky sexual behavior among substance users. These effects do not extend to other risk behaviors, supporting the notion that risky sex associated with abuse represents a means to interpersonal connection rather than a general tendency toward self-defeating behavior. PMID:27344009

Hypertension accelerates the pace of chronic graft dysfunction in the rat.

PubMed

Szabo, A; Patschan, O; Kuttler, B; Müller, V; Philipp, T; Rettig, R; Heemann, U

1998-01-01

In this study we compared the effects of hypertension on chronic rejection in a rat model of renal transplantation utilizing genetically normotensive (BBOK) and spontaneously hypertensive rats (SHR). SHR received either a BBOK (BBOK-->SHR) or an SHR (SHR-->SHR) kidney; normotensive isografts served as controls. Before transplantation, SHR recipients were treated with hydralazine (50 mg/kg per day). To prevent acute rejection, an anti-CD4 antibody (3 mg/kg per day for 3 weeks) in combination with cyclosporin A (3 mg/kg per day for 1 week) was given to all groups. Six weeks after transplantation, blood pressure was measured, and the kidneys removed for histological and immunohistological analysis. SHR-->SHR developed a significantly higher blood pressure than BBOK-->SHR. Blood pressure in BBOK-->BBOK was significantly lower than in the other two groups. The degree of glomerulosclerosis was similarly increased in allografted (BBOK-->SHR) and SHR-->SHR kidneys as compared with the BBOK-->BBOK kidneys (P < 0.05). Infiltration of ED-1+ monocyte/macrophages and OX19 pan-T-cells was most pronounced in allografts (BBOK-->SHR) and was also increased in SHR-->SHR as compared with BBOK-->BBOK. Our results indicate that hypertension accelerates the morphological and immunohistological changes characteristic of grafts undergoing chronic rejection. However, our findings support the hypothesis that alloantigen-dependent factors are of greater important.
14 CFR 25.109 - Accelerate-stop distance.

Code of Federal Regulations, 2011 CFR

2011-01-01

....109 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT... highest speed reached during the rejected takeoff, assuming the critical engine fails at VEF and the pilot... a full stop on a dry runway from the speed reached as prescribed in paragraph (a)(1)(ii) of this...
14 CFR 25.109 - Accelerate-stop distance.

Code of Federal Regulations, 2010 CFR

2010-01-01

....109 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT... highest speed reached during the rejected takeoff, assuming the critical engine fails at VEF and the pilot... a full stop on a dry runway from the speed reached as prescribed in paragraph (a)(1)(ii) of this...
14 CFR 25.109 - Accelerate-stop distance.

Code of Federal Regulations, 2014 CFR

2014-01-01

....109 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT... highest speed reached during the rejected takeoff, assuming the critical engine fails at VEF and the pilot... a full stop on a dry runway from the speed reached as prescribed in paragraph (a)(1)(ii) of this...
14 CFR 25.109 - Accelerate-stop distance.

Code of Federal Regulations, 2012 CFR

2012-01-01

....109 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT... highest speed reached during the rejected takeoff, assuming the critical engine fails at VEF and the pilot... a full stop on a dry runway from the speed reached as prescribed in paragraph (a)(1)(ii) of this...
14 CFR 25.109 - Accelerate-stop distance.

Code of Federal Regulations, 2013 CFR

2013-01-01

....109 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT... highest speed reached during the rejected takeoff, assuming the critical engine fails at VEF and the pilot... a full stop on a dry runway from the speed reached as prescribed in paragraph (a)(1)(ii) of this...
Can community consciousness be a bad thing? A moderated mediation analysis of heterosexism, mental health, and body appreciation in sexual minority men

PubMed Central

Simpson, Courtney C.; Sutter, Megan; Perrin, Paul B.

2016-01-01

This study examined the connections among heterosexism, mental health, body appreciation, and community consciousness in sexual minority men. Participants (N = 89) completed a national online survey. Simultaneous multiple regression found that heterosexism explained 9.4% of the variance in body appreciation and 25.8% of the variance in mental health; mental health accounted for 28.0% of the variance in body appreciation. Within these models, harassment/rejection heterosexism was a unique positive predictor of mental health and a unique negative predictor of body appreciation; depression was a unique negative predictor of body appreciation. A moderated mediational model found that depression mediated the relationship between harassment/rejection heterosexism and body appreciation, but only in men who endorsed high community consciousness. Intervention research might benefit from helping sexual minority men explore the ways in which body image is affected by heterosexism and mental health, as well as the ways that contemporary Western gay communities might contribute to these connections. PMID:27210047
The Mediator Role of Early Maladaptive Schemas Between Childhood Sexual Abuse and Impulsive Symptoms in Female Survivors of CSA.

PubMed

Estévez, Ana; Ozerinjauregi, Nagore; Herrero-Fernández, David; Jauregui, Paula

2016-04-24

Child abuse is a traumatic experience that may have psychological consequences such as dysfunctional beliefs. The aim of this study was to analyze the impulsive behaviors (alcohol abuse, gambling, drug abuse, eating disorders, Internet abuse, videogame abuse, shopping and sex addiction) in sexual abuse survivors and to study the mediating role of early maladaptive schemas in the appearance of impulsive behaviors in adult female victims. The sample consisted of 182 adult women who had suffered childhood sexual abuse (CSA), mostly referred by associations for the treatment of childhood abuse and maltreatment. Sexual abuse was found to be positively related to the domains of Disconnection/Rejection and Impaired Autonomy. Moreover, these domains were significantly related to impulsivity and impulsive behaviors. Finally, the Disconnection/Rejection domain was found to mediate between CSA and eating disorders and alcohol abuse. These results may provide important guidance for clinical intervention. © The Author(s) 2016.
Can community consciousness be a bad thing? A moderated mediation analysis of heterosexism, mental health and body appreciation in sexual minority men.

PubMed

Simpson, Courtney C; Sutter, Megan; Perrin, Paul B

2016-11-01

This study examined the connections between heterosexism, mental health, body appreciation and community consciousness in sexual minority men (SMM). Participants (n = 89) completed a national online survey. Simultaneous multiple regressions found that heterosexism explained 9.4% of the variance in body appreciation and 25.8% of the variance in mental health; mental health accounted for 28.0% of the variance in body appreciation. Within these models, harassment/rejection heterosexism was a unique positive predictor of mental health problems and a unique negative predictor of body appreciation; depression was a unique negative predictor of body appreciation. A moderated mediational model found that depression mediated the relationship between harassment/rejection heterosexism and body appreciation, but only in men who endorsed high community consciousness. Intervention research might benefit from helping SMM explore the ways in which body image is affected by heterosexism and mental health, as well as the ways that contemporary Western gay communities might contribute to these connections.
Eosinophil count, allergies, and rejection in pediatric heart transplant recipients.

PubMed

Arbon, Kate S; Albers, Erin; Kemna, Mariska; Law, Sabrina; Law, Yuk

2015-08-01

Allograft rejection and long-term immunosuppression remain significant challenges in pediatric heart transplantation. Pediatric recipients are known to have fewer rejection episodes and to develop more allergic conditions than adults. A T-helper 2 cell dominant phenotype, manifested clinically by allergies and an elevated eosinophil count, may be associated with immunologic quiescence in transplant recipients. This study assessed whether the longitudinal eosinophil count and an allergic phenotype were associated with freedom from rejection. This single-center, longitudinal, observational study included 86 heart transplant patients monitored from 1994 to 2011. Post-transplant biannual complete blood counts, allergic conditions, and clinical characteristics related to rejection risk were examined. At least 1 episode of acute cellular rejection (ACR) occurred in 38 patients (44%), antibody-mediated rejection (AMR) occurred in 11 (13%), and 49 patients (57%) were diagnosed with an allergic condition. Patients with ACR or AMR had a lower eosinophil count compared with non-rejectors (p = 0.011 and p = 0.022, respectively). In the multivariable regression analysis, the presence of panel reactive antibodies to human leukocyte antigen I (p = 0.014) and the median eosinophil count (p = 0.011) were the only independent covariates associated with AMR. Eosinophil count (p = 0.010) and female sex (p = 0.009) were independent risk factors for ACR. Allergic conditions or young age at transplant were not protective from rejection. This study demonstrates a novel association between a high eosinophil count and freedom from rejection. Identifying a biomarker for low rejection risk may allow a reduction in immunosuppression. Further investigation into the role of the T-helper 2 cell phenotype and eosinophils in rejection quiescence is warranted. Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
Parental punishment and peer victimization as developmental precursors to physical dating violence involvement among girls

PubMed Central

Hipwell, Alison E.; Stepp, Stephanie D.; Xiong, Shuangyan; Keenan, Kate; Blokland, Arjan; Loeber, Rolf

2012-01-01

The current study examined harsh punishment and peer victimization as developmental precursors to girls’ involvement in physical dating violence (PDV), and the putative mediating effect of rejection sensitivity. The sample comprised 475 African American and European American participants of the longitudinal Pittsburgh Girls Study who were dating at age 17. About 10% of girls reported significant perpetration and/or victimization of physical aggression in the relationship. Results showed that initial level and escalation in harsh punishment (between 10–13 years) and escalation in peer victimization (10–15 years) predicted PDV involvement, but this relationship was not mediated by rejection sensitivity. The results highlight the need to consider the impact of early experience of different forms of aggression on girls’ risk for PDV involvement. PMID:24591807
Neutrophils prime a long-lived effector macrophage phenotype that mediates accelerated helminth expulsion

USDA-ARS?s Scientific Manuscript database

The innate immune cell populations that mediate metazoan parasite expulsion remain largely undefined. We examined the role of innate cells in the immune response to the nematode parasite Nippostrongylus brasiliensis hypothesizing that they may mediate the markedly accelerated CD4+ T cell-independen...
Redox-Dependent Inflammation in Islet Transplantation Rejection

PubMed Central

Barra, Jessie M.; Tse, Hubert M.

2018-01-01

Type 1 diabetes is an autoimmune disease that results in the progressive destruction of insulin-producing pancreatic β-cells inside the islets of Langerhans. The loss of this vital population leaves patients with a lifelong dependency on exogenous insulin and puts them at risk for life-threatening complications. One method being investigated to help restore insulin independence in these patients is islet cell transplantation. However, challenges associated with transplant rejection and islet viability have prevented long-term β-cell function. Redox signaling and the production of reactive oxygen species (ROS) by recipient immune cells and transplanted islets themselves are key players in graft rejection. Therefore, dissipation of ROS generation is a viable intervention that can protect transplanted islets from immune-mediated destruction. Here, we will discuss the newly appreciated role of redox signaling and ROS synthesis during graft rejection as well as new strategies being tested for their efficacy in redox modulation during islet cell transplantation. PMID:29740396
Can we link emotional eating with the emotion regulation skills of adolescents?

PubMed

Vandewalle, Julie; Moens, Ellen; Beyers, Wim; Braet, Caroline

2016-07-01

A recent cross-sectional study showed that maternal rejection is associated with emotional eating of obese youngsters seeking treatment, and that this relation is mediated by maladaptive emotion regulation (ER) of the youngsters. We wanted to build on this study and investigate the relation between parental rejection, maladaptive ER and emotional eating in a community sample using longitudinal data. Participants were 81 youngsters between the ages of 10 and 16 years. Participants completed questionnaires assessing maternal and paternal rejection, ER strategies and emotional eating, at two time moments (M = 71 days between time moments). Latent change models were used to estimate level and change of each variable. Results showed that the levels of maternal rejection, maladaptive ER and emotional eating were related. The indirect effect of the level of maternal rejection on the level of emotional eating through the level of maladaptive ER was marginally significant. On average, maternal rejection showed no change over time, whereas the other variables decreased. The changes in the variables were not related. The findings highlight the importance of assessing the emotional bond between mother and youngster and the ER of youngsters with an emotional eating style.
Individual differences in neural responses to social rejection: the joint effect of self-esteem and attentional control

PubMed Central

Hooker, Christine I.; Miyakawa, Asako; Verosky, Sara; Luerssen, Anna; Ayduk, Özlem N.

2012-01-01

Individuals with low self-esteem have been found to react more negatively to signs of interpersonal rejection than those with high self-esteem. However, previous research has found that individual differences in attentional control can attenuate negative reactions to social rejection among vulnerable, low self-esteem individuals. The current fMRI study sought to elucidate the neurobiological substrate of this buffering effect. We hypothesized and found that while looking at scenes of social rejection (vs negative scenes) low self-esteem high attentional control individuals engaged the rostral anterior cingulate cortex (rACC), an area of the brain associated with emotional control, more than their low self-esteem low attentional control peers. Furthermore, we found that low self-esteem high attentional control individuals evaluated social rejection as less arousing and less rejecting in a separate behavioral task. Importantly, activation in the rACC fully mediated the relationship between the interaction of self-esteem and attentional control and emotional evaluations, suggesting that the rACC activation underlies the buffering effects of attentional control. Results are discussed in terms of individual differences in emotional vulnerability and protection and by highlighting the role of rACC in emotion regulation. PMID:21609969
The detrimental effect of friction on space microgravity robotics

NASA Technical Reports Server (NTRS)

Newman, Wyatt S.; Glosser, Gregory D.; Miller, Jeffrey H.; Rohn, Douglas

1992-01-01

The authors present an analysis of why control systems are ineffective in compensating for acceleration disturbances due to Coulomb friction. Linear arguments indicate that the effects of Coulomb friction on a body are most difficult to reject when the control actuator is separated from the body of compliance. The linear arguments were illustrated in a nonlinear simulation of optimal linear tracking control in the presence of nonlinear friction. The results of endpoint acceleration measurements for four robot designs are presented and are compared with simulation and to equivalent measurements on a human. It is concluded that Coulomb friction in common bearings and transmission induces unacceptable levels of endpoint acceleration, that these accelerations cannot be adequately attenuated by control, and that robots for microgravity work will require special design considerations for inherently low friction.
CD8+IL-17+ T Cells Mediate Neutrophilic Airway Obliteration in T-bet–Deficient Mouse Lung Allograft Recipients

PubMed Central

Dodd-o, Jeffrey M.; Coon, Tiffany A.; Miller, Hannah L.; Ganguly, Sudipto; Popescu, Iulia; O'Donnell, Christopher P.; Cardenes, Nayra; Levine, Melanie; Rojas, Mauricio; Weathington, Nathaniel M.; Zhao, Jing; Zhao, Yutong; McDyer, John F.

2015-01-01

Acute cellular rejection is a known risk factor for the development of obliterative bronchiolitis, which limits the long-term survival of lung transplant recipients. However, the T cell effector mechanisms in both of these processes remain incompletely understood. Using the mouse orthotopic lung transplant model, we investigated whether C57BL/6 T-bet−/− recipients of major histocompatibility complex (MHC)-mismatched BALB/c lung grafts develop rejection pathology and allospecific cytokine responses that differ from wild-type mice. T-bet−/− recipients demonstrated vigorous allograft rejection at 10 days, characterized by neutrophilic inflammation and predominantly CD8+ T cells producing allospecific IL-17 and/or IFN-γ, in contrast to IFN-γ–dominant responses in WT mice. CD4+ T cells produced IL-17 but not IFN-γ responses in T-bet−/− recipients, in contrast to WT controls. Costimulation blockade using anti-CD154 Ab significantly reduced allospecific CD8+IFN-γ+ responses in both T-bet−/− and WT mice but had no attenuating effect on lung rejection pathology in T-bet−/− recipients or on the development of obliterative airway inflammation that occurred only in T-bet−/− recipients. However, neutralization of IL-17A significantly attenuated costimulation blockade–resistant rejection pathology and airway inflammation in T-bet−/− recipients. In addition, CXCL1 (neutrophil chemokine) was increased in T-bet−/− allografts, and IL-17 induced CXCL1 from mouse lung epithelial cells in vitro. Taken together, our data show that T-bet–deficient recipients of complete MHC-mismatched lung allografts develop costimulation blockade–resistant rejection characterized by neutrophilia and obliterative airway inflammation that is predominantly mediated by CD8+IL-17+ T cells. Our data support T-bet–deficient mouse recipients of lung allografts as a viable animal model to study the immunopathogenesis of small airway injury in lung transplantation. PMID:25286244
The effects of interferon-alpha/beta in a model of rat heart transplantation

NASA Technical Reports Server (NTRS)

Slater, A. D.; Klein, J. B.; Sonnenfeld, G.; Ogden, L. L. 2nd; Gray, L. A. Jr

1992-01-01

Interferons have multiple immunologic effects. One such effect is the activation of expression of cell surface antigens. Interferon alpha/beta enhance expression of class I but not class II histocompatibility antigens. Contradictory information has been published regarding the effect of interferon-alpha/beta administration in patients with kidney transplantation. In a model of rat heart transplantation we demonstrated that administration of interferon-alpha/beta accelerated rejection in a dose-dependent fashion in the absence of maintenance cyclosporine. Animals treated with maintenance cyclosporine had evidence of increased rejection at 20 days that was resolved completely at 45 days with cyclosporine alone.
Efficient rejection-based simulation of biochemical reactions with stochastic noise and delays

NASA Astrophysics Data System (ADS)

Thanh, Vo Hong; Priami, Corrado; Zunino, Roberto

2014-10-01

We propose a new exact stochastic rejection-based simulation algorithm for biochemical reactions and extend it to systems with delays. Our algorithm accelerates the simulation by pre-computing reaction propensity bounds to select the next reaction to perform. Exploiting such bounds, we are able to avoid recomputing propensities every time a (delayed) reaction is initiated or finished, as is typically necessary in standard approaches. Propensity updates in our approach are still performed, but only infrequently and limited for a small number of reactions, saving computation time and without sacrificing exactness. We evaluate the performance improvement of our algorithm by experimenting with concrete biological models.
Ex Vivo Expanded Human Regulatory T Cells Delay Islet Allograft Rejection via Inhibiting Islet-Derived Monocyte Chemoattractant Protein-1 Production in CD34+ Stem Cells-Reconstituted NOD-scid IL2rγnull Mice

PubMed Central

Xiao, Fang; Ma, Liang; Zhao, Min; Huang, Guocai; Mirenda, Vincenzo; Dorling, Anthony

2014-01-01

Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused by immune-mediated destruction of insulin-secreting β cells of the pancreas. Near complete dependence on exogenous insulin makes T1DM very difficult to control, with the result that patients are exposed to high blood glucose and risk of diabetic complications and/or intermittent low blood glucose that can cause unconsciousness, fits and even death. Allograft transplantation of pancreatic islets restores normoglycemia with a low risk of surgical complications. However, although successful immediately after transplantation, islets are progressively lost, with most of the patients requiring exogenous insulin within 2 years post-transplant. Therefore, there is an urgent requirement for the development of new strategies to prevent islet rejection. In this study, we explored the importance of human regulatory T cells in the control of islets allograft rejection. We developed a pre-clinical model of human islet transplantation by reconstituting NOD-scid IL2rγnull mice with cord blood-derived human CD34+ stem cells and demonstrated that although the engrafted human immune system mediated the rejection of human islets, their survival was significantly prolonged following adoptive transfer of ex vivo expanded human Tregs. Mechanistically, Tregs inhibited the infiltration of innate immune cells and CD4+ T cells into the graft by down-regulating the islet graft-derived monocyte chemoattractant protein-1. Our findings might contribute to the development of clinical strategies for Treg therapy to control human islet rejection. We also show for the first time that CD34+ cells-reconstituted NOD-scid IL2rγnull mouse model could be beneficial for investigating human innate immunity in vivo. PMID:24594640

C4d Deposition and Cellular Infiltrates as Markers of Acute Rejection in Rat Models of Orthotopic Lung Transplantation

PubMed Central

Murata, Kazunori; Iwata, Takekazu; Nakashima, Shinji; Fox-Talbot, Karen; Qian, Zhiping; Wilkes, David S.; Baldwin, William M.

2008-01-01

Background C4d is a useful marker of antibody-mediated rejection in cardiac and renal transplants, but clinical studies examining correlations between circulating alloantibodies, C4d deposition, and rejection in lung transplants have yielded conflicting results. Methods We studied circulating alloantibody levels and C4d deposition in two rat models of lung transplantation: Brown Norway (BN) to Wistar-Kyoto (WKY) and PVG.R8 to PVG.1U lung allografts. The availability of C6 deficient (C6−) and C6 sufficient (C6+) PVG 1U rats allowed evaluation of the effects of the terminal complement components on graft injury and C4d deposition. Results The lung allografts had histologic features resembling human posttransplant capillaritis, characterized by neutrophilic infiltration of alveoli, edema, and hemorrhage. Immunoperoxidase stains on cross sections of allografts showed intense, diffuse, C4d deposition in a continuous linear pattern on the vascular endothelium. C4d deposits were found in both BN to WKY and PVG R8 to 1U allografts, whereas no staining was detectable in WKY to WKY isografts or native lungs. Complement deposition was associated with vascular disruption in C6−, but not in C6+ recipients. The presence of circulating donor-specific alloantibodies was verified by flow cytometry. Cell-specific staining revealed perivascular accumulation of macrophages and T lymphocytes whereas neutrophils were sequestered in the intravascular and alveolar capillary compartments. Conclusions The deposition of C4d on vascular endothelium as well as the coincident presence of alloantibodies is consistent with previous findings in antibody-mediated rejection of renal and cardiac transplants. Furthermore, the histological features of our allografts support the concept that posttransplant capillaritis is a form of humoral rejection. PMID:18622289
Urinary C‑X‑C motif chemokine 13 is a noninvasive biomarker of antibody‑mediated renal allograft rejection.

PubMed

Chen, Dajin; Zhang, Jian; Peng, Wenhan; Weng, Chunhua; Chen, Jianghua

2018-06-22

Noninvasive monitoring methods of immune status are preferred by transplant recipients. The present study investigated whether urinary C‑X‑C motif chemokine 13 (CXCL13) had the potential to reflect ongoing immune processes within renal allografts. Using an ELISA assay, the level of urinary CXCL13 was quantified in a total of 146 renal allograft recipients and 40 healthy controls at scheduled intervals and at the time of the indicated or protocol biopsy. The results of the present study revealed that urinary CXCL13/creatinine (Cr) was lower in normal transplants compared with in those with acute tubular necrosis (ATN; P=0.001), chronic allograft nephropathy (CAN; P=0.01), and acute rejection (AR; P<0.0001), which was associated with a good diagnostic performance for AR [area under the curve (AUC)=0.818, P<0.0001). In addition, urinary CXCL13/Cr levels in patients with AR were also higher than that of patients with graft dysfunction but no rejection, including ATN and CAN (P=0.034). Notably, urinary CXCL13 distinguished between acute antibody‑mediated rejection (ABMR) and acute cellular rejection, with an AUC of 0.856. Furthermore, patients with steroid‑resistant AR exhibited significantly increased urinary CXCL13/Cr levels than patients with reversible AR (P=0.001). Additionally, elevated levels of urinary CXCL13/Cr within the first month of transplant were predictive of graft function at 3 and 6 months (P=0.044 and P=0.04, respectively). Collectively, the findings of the present study indicated that the noninvasive investigation of urinary CXCL13/Cr may be valuable for the detection of AR, particularly ABMR. In addition, high urinary CXCL13/Cr levels predicted a poor response to steroid treatment and compromised graft function.
Aristotle's Example: The Rhetorical Induction.

ERIC Educational Resources Information Center

Benoit, William Lyon

1980-01-01

Examines the concept of example in Aristotle's inventional theory. Rejects recent claims that the example reasons from part to part, without a mediating generalization, and then explicates Aristotle's view of the example. (JMF)
Perceptions of Intragroup Rejection and Coping Strategies: Malleable Factors Affecting Hispanic Adolescents’ Emotional and Academic Outcomes

PubMed Central

Warren, Michael T.; Crano, William D.; Unger, Jennifer B.

2015-01-01

Understanding psychosocial factors that affect the academic achievement of Hispanic adolescents remains a nationwide priority in the United States. Extending previous studies of the stressful effects of perceived discrimination, this year-long longitudinal study examined the correlates of perceived ethnic in-group rejection, coping strategies and fatalistic beliefs, on depressive symptoms, grades, and college aspirations of 2,214 Hispanic adolescents (54 % female) in Southern California. Based on the transactional model of stress and coping and on self-perception theory, structural equation models revealed that high perceived intragroup rejection (10th grade) and low levels of active coping (11th grade) were associated with depressive symptoms in 11th grade. Also, depressive symptoms partially mediated the link between intragroup rejection and both academic outcomes. Avoidant coping strategies (e.g., watching TV) also predicted depressive symptoms and were positively related to fatalism. In addition, fatalism was negatively related to grades and aspiration to attend college. The findings suggest the need to help adolescents find adequate outlets for communication and to create awareness about the potential effects of intragroup rejection. PMID:24234042
Lipoxygenase products in the urine correlate with renal function and body temperature but not with acute transplant rejection.

PubMed

Reinhold, Stephan W; Scherl, Thomas; Stölcker, Benjamin; Bergler, Tobias; Hoffmann, Ute; Weingart, Christian; Banas, Miriam C; Kollins, Dmitrij; Kammerl, Martin C; Krüger, Bernd; Kaess, Bernhard; Krämer, Bernhard K; Banas, Bernhard

2013-02-01

Acute transplant rejection is the leading cause of graft loss in the first months after kidney transplantation. Lipoxygenase products mediate pro- and anti-inflammatory actions and thus we aimed to correlate the histological reports of renal transplant biopsies with urinary lipoxygenase products concentrations to evaluate their role as a diagnostic marker. This study included a total of 34 kidney transplant recipients: 17 with an acute transplant rejection and 17 controls. LTE4, LTB4, 12-HETE and 15-HETE concentrations were measured by enzyme immunoassay. Urinary lipoxygenase product concentrations were not significantly changed during an acute allograft rejection. Nevertheless, LTB4 concentrations correlated significantly with the body temperature (P ≤ 0.05) 3 months after transplantation, and 12- and 15-HETE concentrations correlated significantly with renal function (P ≤ 0.05) 2 weeks after transplantation. In conclusion, our data show a correlation for LTB4 with the body temperature 3 months after transplantation and urinary 12- and 15-HETE concentrations correlate positively with elevated serum creatinine concentrations but do not predict acute allograft rejection.
Potentiation of T-cell mediated immunity by levamisole.

PubMed Central

Renoux, G; Renoux, M; Teller, M N; McMahon, S; Guillaumin, J M

1976-01-01

Cell-mediated immunity is a requirement for recognition and elimination of cells and for prevention or treatment of a variety of diseases. Therefore, the development of a product potentially active in increasing immunity involves its testing in assays specific for cell-mediated immunity. The effectiveness of a single administration of levamisole was demonstrated in the rejection of isografts in a male to female C57BL/6 system, and on the enhancement of levels of the delayed type hypersensitivity (DTH) to sheep red cells (SRBC). Indeed, in five on nine tests, an injection of 25 mg/kg of levamisole to female recipients either on the day of grafting or 7 days after grafting resulted in a RT50% rejection time of 25 days, compared with 46 days in untreated controls. Levamisole administered at the time of immunization with various doses of SRBC elicited earlier, higher and more sustained DTH levels than in untreated controls. Such induction of T-cell activation was accompanied by a switch on anti-SRBC antibodies from IgM to IgG. These findings confirm and extend data evidencing the ability of levamisole to recruit and activate T cells for an increased or restored cell-mediated immunity. PMID:782749
The Impact of HLA Class I-Specific Killer Cell Immunoglobulin-Like Receptors on Antibody-Dependent Natural Killer Cell-Mediated Cytotoxicity and Organ Allograft Rejection

PubMed Central

Rajalingam, Raja

2016-01-01

Natural killer (NK) cells of the innate immune system are cytotoxic lymphocytes that play an important roles following transplantation of solid organs and hematopoietic stem cells. Recognition of self-human leukocyte antigen (HLA) class I molecules by inhibitory killer cell immunoglobulin-like receptors (KIRs) is involved in the calibration of NK cell effector capacities during the developmental stage, allowing the subsequent recognition and elimination of target cells with decreased expression of self-HLA class I (due to virus infection or tumor transformation) or HLA class I disparities (in the setting of allogeneic transplantation). NK cells expressing an inhibitory KIR-binding self-HLA can be activated when confronted with allografts lacking a ligand for the inhibitory receptor. Following the response of the adaptive immune system, NK cells can further destroy allograft endothelium by antibody-dependent cell-mediated cytotoxicity (ADCC), triggered through cross-linking of the CD16 Fc receptor by donor-specific antibodies bound to allograft. Upon recognizing allogeneic target cells, NK cells also secrete cytokines and chemokines that drive maturation of dendritic cells to promote cellular and humoral adaptive immune responses against the allograft. The cumulative activating and inhibitory signals generated by ligation of the receptors regulates mature NK cell killing of target cells and their production of cytokines and chemokines. This review summarizes the role of NK cells in allograft rejection and proposes mechanistic concepts that indicate a prominent role for KIR–HLA interactions in facilitating NK cells for Fc receptor-mediated ADCC effector function involved in antibody-mediated rejection of solid organ transplants. PMID:28066408
Early subclinical rejection as a risk factor for late chronic humoral rejection.

PubMed

Moreso, Francesc; Carrera, Marta; Goma, Montse; Hueso, Miguel; Sellares, Joana; Martorell, Jaume; Grinyó, Josep M; Serón, Daniel

2012-01-15

Subclinical rejection and interstitial fibrosis and tubular atrophy (IF/TA) in protocol biopsies are associated with outcome. We study the relationship between histologic lesions in early protocol biopsies and histologic diagnoses in late biopsies for cause. Renal transplants with a protocol biopsy performed within the first 6 months posttransplant between 1988 and 2006 were reviewed. Biopsies were evaluated according to Banff criteria, and C4d staining was available in biopsies for cause. Of the 517 renal transplants with a protocol biopsy, 109 had a subsequent biopsy for cause which showed the following histological diagnoses: chronic humoral rejection (CHR) (n=44), IF/TA (n=42), recurrence of the primary disease (n=11), de novo glomerulonephritis (n=7), T-cell-mediated rejection (n=4), and polyoma virus nephropathy (n=1). The proportion of retransplants (15.9% vs. 2.3%, P=0.058) and the prevalence of subclinical rejection were higher in patients with CHR than in patients with IF/TA (52.3% vs. 28.6%, P=0.0253). Demographic donor and recipient characteristics and clinical data at the time of protocol biopsy were not different between groups. Logistic regression analysis showed that subclinical rejection (relative risk, 2.52; 95% confidence interval, 1.1-6.3; P=0.047) but not retransplantation (relative risk, 6.7; 95% confidence interval, 0.8-58.8; P=0.085) was associated with CHR. Subclinical rejection in early protocol biopsies is associated with late appearance of CHR.
High pre-transplant soluble CD30 levels are predictive of the grade of rejection.

PubMed

Rajakariar, Ravindra; Jivanji, Naina; Varagunam, Mira; Rafiq, Mohammad; Gupta, Arun; Sheaff, Michael; Sinnott, Paul; Yaqoob, M M

2005-08-01

In renal transplantation, serum soluble CD30 (sCD30) levels in graft recipients are associated with increased rejection and graft loss. We investigated whether pre-transplant sCD30 concentrations are predictive of the grade of rejection. Pre-transplant sera of 51 patients with tubulointerstitial rejection (TIR), 16 patients with vascular rejection (VR) and an age-matched control group of 41 patients with no rejection (NR) were analyzed for sCD30. The transplant biopsies were immunostained for C4d. The median sCD30 level was significantly elevated in the group with VR (248 Units (U)/mL, range: 92-802) when compared with TIR (103 U/mL, range: 36-309, p<0.001) and NR (179 U/mL, range: 70-343, p<0.03). Moreover, patients with TIR had significantly lower sCD30 levels compared to NR. Based on C4d staining, a TH2 driven process, the median sCD30 levels were significantly raised in C4d+ patients compared with C4d- group (177 U/mL vs. 120 U/mL, p<0.05). sCD30 levels measured at time of transplantation correlate with the grade of rejection. High pre-transplant levels are associated with antibody-mediated rejection which carries a poorer prognosis. sCD30 could be another tool to assess immunological risk prior to transplantation and enable a patient centered approach to immunosuppression.
The relationship between experiences of discrimination and mental health among lesbians and gay men: An examination of internalized homonegativity and rejection sensitivity as potential mechanisms.

PubMed

Feinstein, Brian A; Goldfried, Marvin R; Davila, Joanne

2012-10-01

The current study used path analysis to examine potential mechanisms through which experiences of discrimination influence depressive and social anxiety symptoms. The sample included 218 lesbians and 249 gay men (total N = 467) who participated in an online survey about minority stress and mental health. The proposed model included 2 potential mediators-internalized homonegativity and rejection sensitivity-as well as a culturally relevant antecedent to experiences of discrimination-childhood gender nonconformity. Results indicated that the data fit the model well, supporting the mediating roles of internalized homonegativity and rejection sensitivity in the associations between experiences of discrimination and symptoms of depression and social anxiety. Results also supported the role of childhood gender nonconformity as an antecedent to experiences of discrimination. Although there were not significant gender differences in the overall model fit, some of the associations within the model were significantly stronger for gay men than lesbians. These findings suggest potential mechanisms through which experiences of discrimination influence well-being among sexual minorities, which has important implications for research and clinical practice with these populations. (PsycINFO Database Record (c) 2012 APA, all rights reserved).
Thoracic organ transplantation: laboratory methods.

PubMed

Patel, Jignesh K; Kobashigawa, Jon A

2013-01-01

Although great progress has been achieved in thoracic organ transplantation through the development of effective immunosuppression, there is still significant risk of rejection during the early post-transplant period, creating a need for routine monitoring for both acute antibody and cellular mediated rejection. The currently available multiplexed, microbead assays utilizing solubilized HLA antigens afford the capability of sensitive detection and identification of HLA and non-HLA specific antibodies. These assays are being used to assess the relative strength of donor specific antibodies; to permit performance of virtual crossmatches which can reduce the waiting time to transplantation; to monitor antibody levels during desensitization; and for heart transplants to monitor antibodies post-transplant. For cell mediated immune responses, the recent development of gene expression profiling has allowed noninvasive monitoring of heart transplant recipients yielding predictive values for acute cellular rejection. T cell immune monitoring in heart and lung transplant recipients has allowed individual tailoring of immunosuppression, particularly to minimize risk of infection. While the current antibody and cellular laboratory techniques have enhanced the ability to manage thoracic organ transplant recipients, future developments from improved understanding of microchimerism and graft tolerance may allow more refined allograft monitoring techniques.
Results of a multicenter prospective clinical study in Japan for evaluating efficacy and safety of desensitization protocol based on rituximab in ABO-incompatible kidney transplantation.

PubMed

Takahashi, Kota; Saito, Kazuhide; Takahara, Shiro; Fuchinoue, Shohei; Yagisawa, Takashi; Aikawa, Atsushi; Watarai, Yoshihiko; Yoshimura, Norio; Tanabe, Kazunari; Morozumi, Kunio; Shimazu, Motohide

2017-08-01

Deceased organ donations are rare in Japan, with most kidney transplants performed from a limited number of living donors. Researchers have thus developed highly successful ABO-incompatible transplantation procedures, emphasizing preoperative desensitization and postoperative immunosuppression. A recent open-label, single-arm, multicenter clinical study prospectively examined the efficacy and safety of rituximab/mycophenolate mofetil desensitization in ABO-incompatible kidney transplantation without splenectomy. Mycophenolate mofetil and low dose steroid were started 28 days pretransplant, followed by two doses of rituximab 375 mg/m 2 at day -14 and day -1, and postoperative immunosuppression with tacrolimus or ciclosporin and basiliximab. The primary endpoint was the non-occurrence rate of acute antibody-mediated rejection. Patient survival and graft survival were monitored for 1 year posttransplant. Eighteen patients received rituximab and underwent ABO-incompatible kidney transplantation. CD19-positive peripheral B cell count decreased rapidly after the first rituximab infusion and recovered gradually after week 36. The desensitization protocol was tolerable, and most rituximab-related infusion reactions were mild. No anti-A/B antibody-mediated rejection occurred with this series. One patient developed anti-HLA antibody-mediated rejection (Banff 07 type II) on day 2, which was successfully managed. Patient and graft survival were both 100 % after 1 year. Our desensitization protocol was confirmed to be clinically effective and with acceptable toxicities for ABO-I-KTx (University Hospital Medical Information Network Registration Number: UMIN000006635).
Isolated v-lesion in kidney transplant recipients: Characteristics, association with DSA, and histological follow-up.

PubMed

Rabant, Marion; Boullenger, Fanny; Gnemmi, Viviane; Pellé, Gaëlle; Glowacki, François; Hertig, Alexandre; Brocheriou, Isabelle; Suberbielle, Caroline; Taupin, Jean-Luc; Anglicheau, Dany; Legendre, Christophe; Duong Van Huyen, Jean-Paul; Buob, David

2018-04-01

Isolated v-lesion (IvL) represents a rare and challenging situation in renal allograft biopsies because it is unknown whether IvL truly represents rejection, antibody- or T cell-mediated, or not. This multicentric retrospective study describes the clinicopathological features of IvL with an emphasis on the donor-specific antibody (DSA) status, histological follow-up, and graft survival. Inclusion criteria were the presence of v-lesion with minimal interstitial (i ≤ 1) and microvascular inflammation (g + ptc≤1). C4d-positive biopsies were excluded. We retrospectively found 33 IvL biopsies in 33 patients, mainly performed in the early posttransplantation period (median time 27 days) and clinically indicated in 66.7%. A minority of recipients (5/33, 15.2%) had DSA at the time of biopsy. IvL was treated by anti-rejection therapy in 21 cases (63.6%), whereas 12 (36.4%) were untreated. Seventy percent of untreated patients and 66% of treated patients showed favorable histological evolution on subsequent biopsy. Kidney graft survival in IvL was significantly higher than in a matched cohort of antibody-mediated rejection with arteritis. In conclusion, IvL is not primarily antibody-mediated and may show a favorable evolution. The heterogeneity of IvL pathophysiology on early biopsies should prompt DSA testing as well as close clinical and histological follow-up in all patients with IvL. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.
Dual pathology as a cause of proteinuria in the post-transplant period; report of a case.

PubMed

Tewari, Rohit; Mendonca, Satish; Nijhawan, Vijay

2016-01-01

Proteinuria is common after renal transplantation and affects between 35%-45% of patients during the same year as their transplant. We report a case of dual pathology in the renal allograft as a cause of severe proteinuria. A 38-year-old male presented with end-stage renal disease. He underwent live related renal allograft transplant. His immediate post-transplant period was unremarkable. He developed rise in serum creatinine (2.1 mg/dl) 6 months after transplant and was biopsied. He was diagnosed as a case of acute cellular rejection type Ib with suspicion for antibody mediated rejection. He was treated with methylprednisolone to which he showed a good response with return of serum creatinine to 1.6 mg/dl. Subsequently, he developed a nephrotic range proteinuria 6 months after this episode of rejection. Repeat biopsy was performed. He was diagnosed as a case of immune complex mediated glomerulonephritis (GN) (morphologically consistent with pattern of membranoproliferative glomerulonephritis) with chronic humoral rejection in the form of transplant glomerulopathy (TG). IHC for C4d and immunofluorescence studies were instrumental making the diagnosis. He was treated with steroids and rituximab to which he showed a good response with remission of proteinuria. This case highlights the importance of picking up dual pathology in an allograft biopsy to ensure appropriate therapy. The role of C4d and its correct interpretation is further highlighted, especially with regard to pattern (granular versus linear) and location (glomerular capillaries versus peritubular capillaries).
Dual pathology as a cause of proteinuria in the post-transplant period; report of a case

PubMed Central

Tewari, Rohit; Mendonca, Satish; Nijhawan, Vijay

2016-01-01

Proteinuria is common after renal transplantation and affects between 35%-45% of patients during the same year as their transplant. We report a case of dual pathology in the renal allograft as a cause of severe proteinuria. A 38-year-old male presented with end-stage renal disease. He underwent live related renal allograft transplant. His immediate post-transplant period was unremarkable. He developed rise in serum creatinine (2.1 mg/dl) 6 months after transplant and was biopsied. He was diagnosed as a case of acute cellular rejection type Ib with suspicion for antibody mediated rejection. He was treated with methylprednisolone to which he showed a good response with return of serum creatinine to 1.6 mg/dl. Subsequently, he developed a nephrotic range proteinuria 6 months after this episode of rejection. Repeat biopsy was performed. He was diagnosed as a case of immune complex mediated glomerulonephritis (GN) (morphologically consistent with pattern of membranoproliferative glomerulonephritis) with chronic humoral rejection in the form of transplant glomerulopathy (TG). IHC for C4d and immunofluorescence studies were instrumental making the diagnosis. He was treated with steroids and rituximab to which he showed a good response with remission of proteinuria. This case highlights the importance of picking up dual pathology in an allograft biopsy to ensure appropriate therapy. The role of C4d and its correct interpretation is further highlighted, especially with regard to pattern (granular versus linear) and location (glomerular capillaries versus peritubular capillaries). PMID:28197503
The xenoantibody response and immunoglobulin gene expression profile of cynomolgus monkeys transplanted with hDAF-transgenic porcine hearts.

PubMed

Zahorsky-Reeves, Joanne L; Kearns-Jonker, Mary K; Lam, Tuan T; Jackson, Jeremy R; Morris, Randall E; Starnes, Vaughn A; Cramer, Donald V

2007-03-01

Recent work has indicated a role for anti-Gal alpha 1-3Gal (Gal) and anti-non-Gal xenoantibodies in the primate humoral rejection response against human-decay accelerating factor (hDAF) transgenic pig organs. Our laboratory has shown that anti-porcine xenograft antibodies in humans and non-human primates are encoded by a small number of germline IgV(H) progenitors. In this study, we extended our analysis to identify the IgV(H) genes encoding xenoantibodies in immunosuppressed cynomolgus monkeys (Macaca fascicularis) transplanted with hDAF-transgenic pig organs. Three immunosuppressed monkeys underwent heterotopic heart transplantation with hDAF porcine heart xenografts. Two of three animals were given GAS914, a poly-L-lysine derivative shown to bind to anti-Gal xenoantibodies and neutralize them. One animal rejected its heart at post-operative day (POD) 39; a second animal rejected the transplanted heart at POD 78. The third monkey was euthanized on POD 36 but the heart was not rejected. Peripheral blood leukocytes (PBL) and serum were obtained from each animal before and at multiple time points after transplantation. We analyzed the immune response by enzyme-linked immunosorbent assay (ELISA) to confirm whether anti-Gal or anti-non-Gal xenoantibodies were induced after graft placement. Immunoglobulin heavy-chain gene (V(H)) cDNA libraries were then produced and screened. We generated soluble single-chain antibodies (scFv) to establish the binding specificity of the cloned immunoglobulin genes. Despite immunosuppression, which included the use of the polymer GAS914, the two animals that rejected their hearts showed elevated levels of cytotoxic anti-pig red blood cell (RBC) antibodies and anti-pig aortic endothelial cell (PAEC) antibodies. The monkey that did not reject its graft showed a decline in serum anti-RBC, anti-PAEC, and anti-Gal xenoantibodies when compared with pre-transplant levels. A V(H)3 family gene with a high level of sequence similarity to an allele of V(H)3-11, designated V(H)3-11(cyno), was expressed at elevated levels in the monkey that was not given GAS914 and whose graft was not rejected until POD 78. IgM but not IgG xenoantibodies directed at N-acetyl lactosamine (a precursor of the Gal epitope) were also induced in this animal. We produced soluble scFv from this new gene to determine whether this antibody could bind to the Gal carbohydrate, and demonstrated that this protein was capable of blocking the binding of human serum xenoantibody to Gal oligosaccharide, as had previously been shown with human V(H)3-11 scFv. DAF-transgenic organs transplanted into cynomolgus monkeys induce anti-Gal and anti-non-Gal xenoantibody responses mediated by both IgM and IgG xenoantibodies. Anti-non-Gal xenoantibodies are induced at high levels in animals treated with GAS914. Antibodies that bind to the Gal carbohydrate and to N-acetyl lactosamine are induced in the absence of GAS914 treatment. The animal whose heart remained beating for 78 days demonstrated increased usage of an antibody encoded by a germline progenitor that is structurally related, but distinct from IGHV311. This antibody binds to the Gal carbohydrate but does not induce the rapid rejection of the xenograft when expressed at high levels as early as day 8 post-transplantation.
Assessment of fluctuating pressure gradient using acceleration spectra in near wall flows

NASA Astrophysics Data System (ADS)

Cadel, Daniel; Lowe, K. Todd

2015-11-01

Separation of contributions to the fluctuating acceleration from pressure gradient fluctuations and viscous shear fluctuations in the frequency domain is examined in a turbulent boundary layer. Past work leveraging turbulent accelerations for pressure gradient measurements has neglected the viscous shear term from the momentum equation--an invalid assumption in the case of near wall flows. The present study seeks to account for the influence of the viscous shear term and spectrally reject its contribution, which is thought to be concentrated at higher frequencies. Spectra of velocity and acceleration fluctuations in a flat plate, zero pressure gradient turbulent boundary layer at a momentum thickness Reynolds number of 7500 are measured using a spatially resolving three-component laser Doppler velocimeter. This canonical case data is applied for validation of the spectral approach for future application in more complex aerodynamic flows.
Cautious to a Fault: Self-Protection and the Trajectory of Marital Satisfaction

PubMed Central

Murray, Sandra L.; Holmes, John G.; Derrick, Jaye L.; Harris, Brianna; Griffin, Dale W.; Pinkus, Rebecca T.

2012-01-01

A contextual model of self-protection is proposed to explain when adhering to cautious “if-then” rules in daily interaction erodes marital satisfaction. People can self-protect against partner non-responsiveness by distancing when a partner seems rejecting, promoting a partner’s dependence when feeling unworthy, or by devaluing a partner in the face of costs. The model implies that being less trusting elicits self-protection, and that mismatches between self-protective practices and encountered risk accelerate declines in satisfaction. A longitudinal study of newlyweds revealed that the fit between self-protection practices and risk predicted declines in satisfaction over three years. When people self-protected more initially, satisfaction declined more in low-risk (i.e., low conflict, resilient partner) than high-risk relationships (i.e., high conflict, vulnerable partner). However, when people self-protected less initially, satisfaction declined more in high-risk than low-risk relationships. Process evidence was consistent with moderated mediation: In low-risk relationships only, being less trusting predicted higher levels of self-protective caution that forecast later declines in satisfaction. PMID:25013236
[Treatment of burn wounds with dibunol liniment].

PubMed

Shalonov, P M; Dadabaev, T D; Khalilov, Kh N

1989-01-01

In 40 burned patients with the area of damage from 10 to 40% of the body surface in local treatment with dibunol against the background of active infusion-transfusion therapy, the accelerated rejection of the necrotic crust was noted, which permitted to reduce the period of preparation for autodermoplasty. The antiinflammatory effect of dibunol was established.
Bob Wilson and The Birth of Fermilab

ScienceCinema

Edwin L. Goldwasser

2018-04-17

In the 1960âs the Lawrence Berkeley Laboratory (then The Lawrence Radiation Laboratory) submitted two proposals to build the next high energy physics research laboratory. The first included a 200 GeV accelerator and associated experimental facilities. The cost was $350 million. The Bureau of the Budget rejected that proposal as a âbudget busterâ. It ruled that $250 million was the maximum that could be accepted. The second proposal was for a reduced scope laboratory that met the Bureau of the Budgetâs cost limitation, but it was for a lower energy accelerator and somewhat smaller and fewer experimental facilities. The powerful Congressional Joint Committee on Atomic Energy rejected the reduced scope proposal as inadequate to provide physics results of sufficient interest to justify the cost. It was then that Bob Wilson came forth with a third proposal, coping with that âCatch 22â and leading to the creation of Fermilab. How he did it will be the subject of this colloquium.

Therapeutic inhibition of the complement system. Y2K update.

PubMed

Asghar, S S; Pasch, M C

2000-09-01

Activation of complement is an essential part of the mechanism of pathogenesis of a large number of human diseases; its inhibition by pharmacological means is likely to suppress disease processes in complement mediated diseases. From this point of view low molecular weight synthetic inhibitors of complement are being developed and high molecular weight natural inhibitors of human origin present in plasma or embedded in cell membrane are being purified or produced in their recombinant forms. This review is concerned with high molecular weight inhibitors, some of which are already in clinical use but may be efficacious in many other diseases in which they have not yet been tried. C1-esterase inhibitor (C1-INH) concentrate prepared from human plasma is being successfully used for the treatment of hereditary angioneurotic edema. Recently, C1-INH has been found to be consumed in severe inflammation and has been shown to exert beneficial effects in several inflammatory conditions such as human sepsis, post-operative myocardial dysfunction due to reperfusion injury, severe capillary leakage syndrome after bone marrow transplantation, reperfusion injury after lung transplantation, burn, and cytotoxicity caused by IL-2 therapy in cancer. Factor I has been used for the treatment of factor I deficiency. Recombinant soluble forms of membrane cofactor protein (MCP), and decay accelerating factor (DAF) have not yet been tried in humans but have been shown to be effective in immune complex mediate inflammation in animals. Organs of pigs transgenic for one or more of human membrane regulators of complement namely membrane cofactor protein (MCP), decay accelerating factor (DAF) or CD59, are being produced for transplantation into humans. They have been shown to be resistant to hyperacute rejection in non-human primates; acute vascular rejection is still a problem in their clinical use. It is hoped that these observations together with future developments will make xeno-transplantation in clinical practice a reality. Several recombinant variants of complement receptor 1 (CR1) have been produced. The most effective of these appears to be sCR1-SLe x, sCR1 part of which inhibits complement and carbohydrate Sle x moiety inhibits selectin mediated interactions of neutrophils and lymphocytes with endothelium. Although clinical trials of sCR1 in humans is eagerly awaited, several of the recombinant versions of sCR1 have been shown to suppress ischemia/reperfusion injury, thermal trauma, and immune complex mediated inflammation. They have also been shown to be effective in experimental models of systemic sclerosis, arthritis, myasthenia gravis, Guillain Barré syndrome and glomerulonephritis. Intravenous immunoglobulin, three of the most prominent properties of which are neutralization of autoantibody activity, suppression of autoantibody production and inhibition of complement activity, is being used in several diseases. These include autoimmune thrombocyopenic purpura, Kawasaki disease and several neurological diseases such as myasthenia gravis and Guillain Barre syndrome. In many uncontrolled small scale studies intravenous immunoglobulin has been shown to be effective in many immunological including dermatological diseases; controlled clinical trials in a large number of patients with these diseases is needed to establish the efficacy. It is hoped that in future therapeutic inhibition of complement will be one of the major approaches to combat many human diseases.
Anti-idiotype antibody induced cellular immunity in mice transgenic for human carcinoembryonic antigen.

PubMed

Saha, Asim; Chatterjee, Sunil K; Foon, Kenneth A; Bhattacharya-Chatterjee, Malaya

2006-08-01

In the present study, we have analysed the detailed cellular immune mechanisms involved in tumour rejection in carcinoembryonic antigen (CEA) transgenic mice after immunization with dendritic cells (DC) pulsed with an anti-idiotype (Id) antibody, 3H1, which mimics CEA. 3H1-pulsed DC vaccinations resulted in induction of CEA specific cytotoxic T lymphocyte (CTL) responses in vitro and the rejection of CEA-transfected MC-38 murine colon carcinoma cells, C15, in vivo (Saha et al.,Cancer Res 2004; 64: 4995-5003). These CTL mediated major histocompatibility complex (MHC) class I-restricted tumour cell lysis, production of interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha), and expression of Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL) in response to C15 cells. CTL used perforin-, FasL-, and TRAIL-mediated death pathways to lyse C15 cells, although perforin-mediated killing was the predominant lytic mechanism in vitro. The cytokines IFN-gamma and TNF-alpha synergistically enhanced surface expression of Fas, TRAIL receptor, MHC class I and class II on C15 cells that increased the sensitivity of tumour cells to CTL lysis. CTL activity generated in 3H1-pulsed DC immunized mice was directed against an epitope defined by the idio-peptide LCD-2, derived from 3H1. In vivo lymphocyte depletion experiments demonstrated that induction of CTL response and antitumour immunity was dependent on both CD4+ and CD8+ T cells. The analysis of splenocytes of immunized mice that had rejected C15 tumour growth revealed up-regulated surface expression of memory phenotype Ly-6C and CD44 on both CD4+ and CD8+ T cells. The adoptive transfer experiments also suggested the role of both CD4+ and CD8+ T cells in this model system. Furthermore, mice that had rejected C15 tumour growth, developed tumour-specific immunological memory.
Involvement of dendritic cells in allograft rejection new implications of dendritic cell-endothelial cell interactions.

PubMed

Schlichting, C L; Schareck, W D; Kofler, S; Weis, M

2007-04-01

For almost half a century immunologists have tried to tear down the MHC barrier, which separates two unrelated individuals during transplantation. Latest experimental data suggest that a breakthrough in vitro is imminent. Dendritic cells (DCs), which activate naïve allo-reactive T-cells (TCs), play a central role in the establishment of allo-antigen-specific immunity. Allograft solid organ rejection is initiated at the foreign endothelial cell (EC) layer, which forms an immunogenic barrier for migrating DCs. Thus, DC/EC interactions might play a crucial role in antigen-specific allograft rejection. Organ rejection is mediated by host allo-reactive TCs, which are activated by donor DCs (direct activation) or host DCs (indirect activation). Direct allo-antigen presentation by regulatory dendritic cells (DCreg) can play an instructive role towards tolerance induction. Several groups established that, DCregs, if transplanted beforehand, enter host thymus, spleen, or bone marrow where they might eventually establish allo-antigen-specific tolerance. A fundamental aspect of DC function is migration throughout the entire organism. After solid organ transplantation, host DCs bind to ECs, invade allograft tissues, and finally transmigrate into lymphoid vessels and secondary lymphoid organs, where they present allo-antigens to naïve host TCs. Recent data suggest that in vitro manipulated DCregs may mediate allo-transplantation tolerance induction. However, the fundamental mechanisms on how such DCregs cause host TCs in the periphery towards tolerance remain unclear. One very promising experimental concept is the simultaneous manipulation of DC direct and indirect TC activation/suppression, towards donor antigen-specific allo-transplantation tolerance. The allo-antigen-specific long-term tolerance induction mediated by DCreg pre-transplantation (with simultaneous short-term immunosuppression) has become reproducible in the laboratory animal setting. Despite the shortcomings of laboratory animal studies, strong promises are deriving from these studies for clinical kidney, heart, and liver transplantation.
To be spurned no more: The affective and behavioral consequences of social and nonsocial rejection.

PubMed

Driscoll, Rachel L; Barclay, Pat; Fenske, Mark J

2017-04-01

Social pain is often associated with social rejection and shares neural correlates with the bothersome aspect of physical pain, which may also indicate an overlap in function. Pain has been described as a motivational signal to respond to the source of the pain in an adaptive way, such as by altering behavior. We tested whether social pain causes similarly adaptive alterations in behavior. Participants played computerized ball-tossing tasks with putative players-one who passed to and one who excluded the participant from play-in both a social and nonsocial version. We assessed the behavioral consequences of social pain by comparing the number of throws to each stimulus (social rejector vs. nonsocial rejector) over the course of the task. Posttask questionnaires assessed subjective feelings of social pain. A decrease in throws to the rejecting stimulus was only observed in the social version, indicating that rejection that is social in nature leads to change in behavior. Moreover, participants reported more negative feelings toward the rejecting stimulus in the social than in the nonsocial version. These subjective feelings of social pain mediated the effect of version of the game (social vs. nonsocial) on changes in behavior, indicating that social pain from social rejection causes changes in behavior.
The capacities of earthworms to heal wounds and to destroy allografts are modified by polychlorinated biphenyls (PCB).

PubMed

Cooper, E L; Roch, P

1992-07-01

Earthworms (Lumbricus terrestris) were maintained at 15 degrees C and exposed on filter paper to 10 micrograms/cm2 of the polychlorinated biphenyl (PCB) Aroclor 1254 for 5 days prior to surgical treatments which consisted of wounds, autografts, and allografts. At 1 day after surgery, we observed a higher percentage of healing defects and a significantly greater number of early signs of allograft rejection in exposed worms. Observations for 25 days post-transplantation revealed no response to autografts, but an acceleration of the allograft rejection process in exposed earthworms. We postulate that Aroclor modified host coelomocytes and/or their interactions associated with antigen recognition and inflammation.
Efficient rejection-based simulation of biochemical reactions with stochastic noise and delays

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thanh, Vo Hong, E-mail: vo@cosbi.eu; Priami, Corrado, E-mail: priami@cosbi.eu; Department of Mathematics, University of Trento

2014-10-07

We propose a new exact stochastic rejection-based simulation algorithm for biochemical reactions and extend it to systems with delays. Our algorithm accelerates the simulation by pre-computing reaction propensity bounds to select the next reaction to perform. Exploiting such bounds, we are able to avoid recomputing propensities every time a (delayed) reaction is initiated or finished, as is typically necessary in standard approaches. Propensity updates in our approach are still performed, but only infrequently and limited for a small number of reactions, saving computation time and without sacrificing exactness. We evaluate the performance improvement of our algorithm by experimenting with concretemore » biological models.« less
The secreted form of the p40 subunit of interleukin (IL)-12 inhibits IL-23 functions and abrogates IL-23-mediated antitumour effects

PubMed Central

Shimozato, Osamu; Ugai, Shin-ichi; Chiyo, Masako; Takenobu, Hisanori; Nagakawa, Hiroyasu; Wada, Akihiko; Kawamura, Kiyoko; Yamamoto, Hiroshi; Tagawa, Masatoshi

2006-01-01

Interleukin (IL)-23 is a heterodimeric cytokine consisting of a novel p19 molecule and the p40 subunit of IL-12. Since secreted p40 can act as an antagonist for IL-12, we investigated whether p40 also inhibited IL-23-mediated immunological functions. p40 did not induce interferon (IFN)-γ or IL-17 production from splenocytes but impaired IL-23-induced cytokine production by competitive binding to the IL-23 receptors. Furthermore, a mixed population of murine colon carcinoma Colon 26 cells transduced with the p40 gene and those transduced with the IL-23 gene developed tumours in syngenic mice, whereas the IL-23-expressing Colon 26 cells were completely rejected. p40 also suppressed IFN-γ production of antigen-stimulated splenocytes and IL-23-mediated cytotoxic T-lymphocyte activities in the mice that rejected Colon 26 cells expressing IL-23. p40 can thereby antagonize IL-23 and is a possible therapeutic agent for suppression of IL-23 functions. PMID:16423037
A critical role for transcription factor Smad4 in T cell function independent of transforming growth factor beta receptor signaling

PubMed Central

Gu, Ai-Di; Zhang, Song; Wang, Yunqi; Xiong, Hui; Curtis, Thomas A.; Wan, Yisong Y.

2014-01-01

Summary Transforming growth factor-beta (TGF-β) suppresses T cell function to maintain self-tolerance and to promote tumor immune evasion. Yet how Smad4, a transcription factor component of TGF-β signaling, regulates T cell function remains unclear. Here we have demonstrated an essential role for Smad4 in promoting T cell function during autoimmunity and anti-tumor immunity. Smad4 deletion rescued the lethal autoimmunity resulting from transforming growth factor-beta receptor (TGF-βR) deletion and compromised T-cell-mediated tumor rejection. While Smad4 was dispensable for T cell generation, homeostasis and effector function, it was essential for T cell proliferation following activation in vitro and in vivo. The transcription factor Myc was identified to mediate Smad4-controlled T cell proliferation. This study thus reveals a requirement of Smad4 for T-cell-mediated autoimmunity and tumor rejection, which is beyond the current paradigm. It highlights a TGF-βR-independent role for Smad4 in promoting T cell function, autoimmunity and anti-tumor immunity. PMID:25577439
A critical role for transcription factor Smad4 in T cell function that is independent of transforming growth factor β receptor signaling.

PubMed

Gu, Ai-Di; Zhang, Song; Wang, Yunqi; Xiong, Hui; Curtis, Thomas A; Wan, Yisong Y

2015-01-20

Transforming growth factor-beta (TGF-β) suppresses T cell function to maintain self-tolerance and to promote tumor immune evasion. Yet how Smad4, a transcription factor component of TGF-β signaling, regulates T cell function remains unclear. Here we have demonstrated an essential role for Smad4 in promoting T cell function during autoimmunity and anti-tumor immunity. Smad4 deletion rescued the lethal autoimmunity resulting from transforming growth factor-beta receptor (TGF-βR) deletion and compromised T-cell-mediated tumor rejection. Although Smad4 was dispensable for T cell generation, homeostasis, and effector function, it was essential for T cell proliferation after activation in vitro and in vivo. The transcription factor Myc was identified to mediate Smad4-controlled T cell proliferation. This study thus reveals a requirement of Smad4 for T-cell-mediated autoimmunity and tumor rejection, which is beyond the current paradigm. It highlights a TGF-βR-independent role for Smad4 in promoting T cell function, autoimmunity, and anti-tumor immunity. Copyright © 2015 Elsevier Inc. All rights reserved.
Optimisation of 12 MeV electron beam simulation using variance reduction technique

NASA Astrophysics Data System (ADS)

Jayamani, J.; Termizi, N. A. S. Mohd; Kamarulzaman, F. N. Mohd; Aziz, M. Z. Abdul

2017-05-01

Monte Carlo (MC) simulation for electron beam radiotherapy consumes a long computation time. An algorithm called variance reduction technique (VRT) in MC was implemented to speed up this duration. This work focused on optimisation of VRT parameter which refers to electron range rejection and particle history. EGSnrc MC source code was used to simulate (BEAMnrc code) and validate (DOSXYZnrc code) the Siemens Primus linear accelerator model with the non-VRT parameter. The validated MC model simulation was repeated by applying VRT parameter (electron range rejection) that controlled by global electron cut-off energy 1,2 and 5 MeV using 20 × 107 particle history. 5 MeV range rejection generated the fastest MC simulation with 50% reduction in computation time compared to non-VRT simulation. Thus, 5 MeV electron range rejection utilized in particle history analysis ranged from 7.5 × 107 to 20 × 107. In this study, 5 MeV electron cut-off with 10 × 107 particle history, the simulation was four times faster than non-VRT calculation with 1% deviation. Proper understanding and use of VRT can significantly reduce MC electron beam calculation duration at the same time preserving its accuracy.
Attachment Status Affects Heart Rate Responses to Experimental Ostracism in Inpatients with Depression

PubMed Central

De Rubeis, Jannika; Sütterlin, Stefan; Lange, Diane; Pawelzik, Markus; van Randenborgh, Annette; Victor, Daniela; Vögele, Claus

2016-01-01

Depression is assumed to be both a risk factor for rejection and a result of it, and as such constitutes an important factor in rejection research. Attachment theory has been applied to understand psychological disorders, such as depression, and can explain individual differences in responses to rejection. Research on autonomic nervous system activity to rejection experiences has been contradictory, with opposing strings of argumentation (activating vs. numbing). We investigated autonomic nervous system-mediated peripheral physiological responses (heart rate) to experimentally manipulated ostracism (Cyberball) in 97 depressed patients with organized (n = 52) and disorganized attachment status (n = 45). Controlling for baseline mean heart rate levels, depressed patients with disorganized attachment status responded to ostracism with significantly higher increases in heart rate than depressed patients with organized attachment status (p = .029; ηp2 = .051). These results suggest that attachment status may be a useful indicator of autonomic responses to perceived social threat, which in turn may affect the therapeutic process and the patient-therapist relationship. PMID:26943924
The effect of timing and graft dysfunction on survival and cardiac allograft vasculopathy in antibody-mediated rejection.

PubMed

Clerkin, Kevin J; Restaino, Susan W; Zorn, Emmanuel; Vasilescu, Elena R; Marboe, Charles C; Mancini, Donna M

2016-09-01

Antibody-mediated rejection (AMR) has been associated with increased death and cardiac allograft vasculopathy (CAV). Early studies suggested that late AMR was rarely associated with graft dysfunction, whereas recent reports have demonstrated an association with increased mortality. We investigated the timing of AMR and its association with graft dysfunction, death, and CAV. This retrospective cohort study identified all adult orthotopic heart transplant (OHT) recipients (N = 689) at Columbia University Medical Center from 2004 to 2013. There were 68 primary cases of AMR, which were stratified by early (< 1 year post-OHT) or late (> 1 year post-OHT) AMR. Kaplan-Meier survival analysis and modeling was performed with multivariable logistic regression and Cox proportional hazards regression. From January 1, 2004, through October 1, 2015, early AMR (median 23 days post-OHT) occurred in 43 patients and late AMR (median 1,084 days post-OHT) occurred in 25. Graft dysfunction was less common with early compared with late AMR (25.6% vs 56%, p = 0.01). Patients with late AMR had decreased post-AMR survival compared with early AMR (1 year: 80% vs 93%, 5 years: 51% vs 73%, p < 0.05). When stratified by graft dysfunction, only those with late AMR and graft dysfunction had worse survival (30 days: 79%, 1 year: 64%, 5 years: 36%; p < 0.006). The association remained irrespective of age, sex, donor-specific antibodies, left ventricular assist device use, reason for OHT, and recovery of graft function. Similarly, those with late AMR and graft dysfunction had accelerated development of de novo CAV (50% at 1 year; hazard ratio, 5.42; p = 0.009), whereas all other groups were all similar to the general transplant population. Late AMR is frequently associated with graft dysfunction. When graft dysfunction is present in late AMR, there is an early and sustained increased risk of death and rapid development of de novo CAV despite aggressive treatment. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
Everolimus Inhibits Anti-HLA I Antibody-Mediated Endothelial Cell Signaling, Migration and Proliferation More Potently than Sirolimus

PubMed Central

Jin, Yi-Ping; Valenzuela, Nicole M.; Ziegler, Mary E.; Rozengurt, Enrique; Reed, Elaine F.

2017-01-01

Antibody (Ab) crosslinking of HLA I molecules on the surface of endothelial cells triggers proliferative and pro-survival intracellular signaling, which is implicated in the process of chronic allograft rejection, also known as transplant vasculopathy. The purpose of this study was to investigate the role of mammalian target of rapamycin (mTOR) in HLA I antibody-induced signaling cascades. Everolimus provides a tool to establish how the mTOR signal network regulates HLA I-mediated migration, proliferation, and survival. We found that everolimus inhibits mTORC1 by disassociating Raptor from mTOR, thereby preventing class I-induced phosphorylation of mTOR, p70S6K, S6RP, and 4E-BP1, and resultant class I-stimulated cell migration and proliferation. Furthermore, we found that everolimus inhibits class I-mediated mTORC2 activation (1) by disassociating Rictor and Sin1 from mTOR; (2) by preventing class I-stimulated Akt phosphorylation; and (3) by preventing class I-mediated ERK phosphorylation. These results suggest that everolimus is more effective than sirolimus at antagonizing both mTORC1 and mTORC2, the latter of which is critical in endothelial cell functional changes leading to transplant vasculopathy in solid organ transplantation after HLA I crosslinking. Our findings point to a potential therapeutic effect of everolimus in prevention of chronic antibody-mediated rejection. PMID:24580843
In situ induction of dendritic cell–based T cell tolerance in humanized mice and nonhuman primates

PubMed Central

Jung, Kyeong Cheon; Jeon, Yoon Kyung; Ban, Young Larn; Min, Hye Sook; Kim, Eun Ji; Kim, Ju Hyun; Kang, Byung Hyun; Bae, Youngmee; Yoon, Il-Hee; Kim, Yong-Hee; Lee, Jae-Il; Kim, Jung-Sik; Shin, Jun-Seop; Yang, Jaeseok; Kim, Sung Joo; Rostlund, Emily; Muller, William A.

2011-01-01

Induction of antigen-specific T cell tolerance would aid treatment of diverse immunological disorders and help prevent allograft rejection and graft versus host disease. In this study, we establish a method of inducing antigen-specific T cell tolerance in situ in diabetic humanized mice and Rhesus monkeys receiving porcine islet xenografts. Antigen-specific T cell tolerance is induced by administration of an antibody ligating a particular epitope on ICAM-1 (intercellular adhesion molecule 1). Antibody-mediated ligation of ICAM-1 on dendritic cells (DCs) led to the arrest of DCs in a semimature stage in vitro and in vivo. Ablation of DCs from mice completely abrogated anti–ICAM-1–induced antigen-specific T cell tolerance. T cell responses to unrelated antigens remained unaffected. In situ induction of DC-mediated T cell tolerance using this method may represent a potent therapeutic tool for preventing graft rejection. PMID:22025302
Attachment anxiety is associated with a fear of becoming fat, which is mediated by binge eating

PubMed Central

2017-01-01

Background Previous work demonstrated that individuals with higher levels of attachment anxiety are prone to increased binge eating (Alexander & Siegel, 2013). Given that our society rejects obese individuals and individuals with higher levels of attachment anxiety tend to be highly sensitive to rejection (Downey & Feldman, 1996), it follows that those with increased attachment anxiety may be especially fearful of becoming fat. Methods Undergraduate psychology students (n = 148) completed surveys measuring attachment, binge eating, and fear of becoming fat. Results The data demonstrate that attachment anxiety is positively associated with a fear of becoming fat (β = .30, p < .001) and binge eating mediates this relationship. In other words, binge eating underlies the fear of becoming fat. Discussion These findings contribute to a more refined understanding of binge eating which may create pathways for professionals to develop targeted interventions. PMID:28286709
Mediators involved in the immunomodulatory effects of apoptotic cells.

PubMed

Saas, Philippe; Bonnefoy, Francis; Kury-Paulin, Stephanie; Kleinclauss, François; Perruche, Sylvain

2007-07-15

Immunomodulatory properties are attributed to apoptotic cells. These properties have been used to modulate allogeneic immune responses in experimental transplantation settings. In independent studies, apoptotic cell infusion has been shown to favor hematopoietic cell engraftment, to increase heart graft survival, and to delay the lethal onset of graft-versus-host disease (GVHD). The goal of this review was to discuss how apoptotic cell infusion interferes with graft rejection or host rejection (i.e., GVHD) and to focus on the potential mediators or "perpetuators" involved in apoptotic cell-induced immunomodulation. Particular emphasis on apoptotic cell phagocytosis, transforming growth factor (TGF)-beta secretion, and regulatory T cell induction was performed. Stimulating "naturally" immunosuppressive molecules (i.e., TGF-beta) or immunomodulatory cells ("alternatively-activated" macrophages, certain dendritic cell subsets, or regulatory T cells) in a physiological manner by using apoptotic cell infusion can be a promising way to induce tolerance.
Mediators involved in the immunomodulatory effects of apoptotic cells

PubMed Central

Saas, Philippe; Bonnefoy, Francis; Kury-Paulin, Stephanie; Kleinclauss, François M.; Perruche, Sylvain

2007-01-01

Immunomodulatory properties are attributed to apoptotic cells. These properties have been used to modulate allogeneic immune responses in experimental transplantation settings. In independent studies, apoptotic cell infusion has been shown to favor hematopoietic cell engraftment, to increase heart graft survival and to delay the lethal onset of graft-versus-host disease (GVHD). The goal of this review was to discuss how apoptotic cell infusion interferes with graft rejection or host rejection (i.e., GVHD) and to focus on the potential mediators or “perpetuators” involved in apoptotic cell-induced immunomodulation. Particular emphasis on apoptotic cell phagocytosis, TGF-β secretion and regulatory T cell induction was performed. Stimulating “naturally” immunosuppressive molecules (i.e., TGF-β) or immunomodulatory cells (“alternatively-activated” macrophages, certain DC subsets or regulatory T cells) in a physiological manner by using apoptotic cell infusion can be a promising way to induce tolerance. PMID:17632410
Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection

PubMed Central

Cui, Ye; Liu, Kaifeng; Monzon-Medina, Maria E.; Padera, Robert F.; Wang, Hao; George, Gautam; Toprak, Demet; Abdelnour, Elie; D’Agostino, Emmanuel; Goldberg, Hilary J.; Perrella, Mark A.; Forteza, Rosanna Malbran; Rosas, Ivan O.; Visner, Gary; El-Chemaly, Souheil

2015-01-01

Lung transplantation is the only viable option for patients suffering from otherwise incurable end-stage pulmonary diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Despite aggressive immunosuppression, acute rejection of the lung allograft occurs in over half of transplant recipients, and the factors that promote lung acceptance are poorly understood. The contribution of lymphatic vessels to transplant pathophysiology remains controversial, and data that directly address the exact roles of lymphatic vessels in lung allograft function and survival are limited. Here, we have shown that there is a marked decline in the density of lymphatic vessels, accompanied by accumulation of low-MW hyaluronan (HA) in mouse orthotopic allografts undergoing rejection. We found that stimulation of lymphangiogenesis with VEGF-C156S, a mutant form of VEGF-C with selective VEGFR-3 binding, alleviates an established rejection response and improves clearance of HA from the lung allograft. Longitudinal analysis of transbronchial biopsies from human lung transplant recipients demonstrated an association between resolution of acute lung rejection and decreased HA in the graft tissue. Taken together, these results indicate that lymphatic vessel formation after lung transplantation mediates HA drainage and suggest that treatments to stimulate lymphangiogenesis have promise for improving graft outcomes. PMID:26485284
Reward, addiction, and emotion regulation systems associated with rejection in love.

PubMed

Fisher, Helen E; Brown, Lucy L; Aron, Arthur; Strong, Greg; Mashek, Debra

2010-07-01

Romantic rejection causes a profound sense of loss and negative affect. It can induce clinical depression and in extreme cases lead to suicide and/or homicide. To begin to identify the neural systems associated with this natural loss state, we used functional magnetic resonance imaging to study 10 women and 5 men who had recently been rejected by a partner but reported they were still intensely "in love." Participants alternately viewed a photograph of their rejecting beloved and a photograph of a familiar, individual, interspersed with a distraction-attention task. Their responses while looking at their rejecter included love, despair, good, and bad memories, and wondering why this happened. Activation specific to the image of the beloved occurred in areas associated with gains and losses, craving and emotion regulation and included the ventral tegmental area (VTA) bilaterally, ventral striatum, medial and lateral orbitofrontal/prefrontal cortex, and cingulate gyrus. Compared with data from happily-in-love individuals, the regional VTA activation suggests that mesolimbic reward/survival systems are involved in romantic passion regardless of whether one is happily or unhappily in love. Forebrain activations associated with motivational relevance, gain/loss, cocaine craving, addiction, and emotion regulation suggest that higher-order systems subject to experience and learning also may mediate the rejection reaction. The results show activation of reward systems, previously identified by monetary stimuli, in a natural, endogenous, negative emotion state. Activation of areas involved in cocaine addiction may help explain the obsessive behaviors associated with rejection in love.
A Longitudinal Study of Rejecting and Autonomy-Restrictive Parenting, Rejection Sensitivity, and Socioemotional Symptoms in Early Adolescents.

PubMed

Rowe, Susan L; Gembeck, Melanie J Zimmer; Rudolph, Julia; Nesdale, Drew

2015-08-01

Rejection sensitivity (RS) has been defined as the tendency to readily perceive and overreact to interpersonal rejection. The primary aim of this study was to test key propositions of RS theory, namely that rejecting experiences in relationships with parents are antecedents of early adolescents' future RS and symptomatology. We also expanded this to consider autonomy-restrictive parenting, given the importance of autonomy in early adolescence. Participants were 601 early adolescents (age 9 to 13 years old, 51% boys) from three schools in Australia. Students completed questionnaires at school about parent and peer relationships, RS, loneliness, social anxiety, and depression at two times with a 14-month lag between assessments. Parents also reported on adolescents' difficulties at Time 1 (T1). It was anticipated that more experience of parental rejection, coercion, and psychological control would be associated with adolescents' escalating RS and symptoms over time, even after accounting for peer victimisation, and that RS would mediate associations between parenting and symptoms. Structural equation modelling supported these hypotheses. Parent coercion was associated with adolescents' increasing symptoms of social anxiety and RS over time, and parent psychological control was associated with increasing depressive symptoms over time. Indirect effects via RS were also found, with parent rejection and psychological control linked to higher T1 RS, which was then associated with increasing loneliness and RS. Lastly, in a separate model, peer victimisation and RS, but not parenting practices, were positively associated with concurrent parent reports of adolescents' difficulties.

Interplay between immune responses to HLA and non-HLA self-antigens in allograft rejection.

PubMed

Angaswamy, Nataraju; Tiriveedhi, Venkataswarup; Sarma, Nayan J; Subramanian, Vijay; Klein, Christina; Wellen, Jason; Shenoy, Surendra; Chapman, William C; Mohanakumar, T

2013-11-01

Recent studies strongly suggest an increasing role for immune responses against self-antigens (Ags) which are not encoded by the major histocompatibility complex in the immunopathogenesis of allograft rejection. Although, improved surgical techniques coupled with improved methods to detect and avoid sensitization against donor human leukocyte antigen (HLA) have improved the immediate and short term function of transplanted organs. However, acute and chronic rejection still remains a vexing problem for the long term function of the transplanted organ. Immediately following organ transplantation, several factors both immune and non immune mechanisms lead to the development of local inflammatory milieu which sets the stage for allograft rejection. Traditionally, development of antibodies (Abs) against mismatched donor HLA have been implicated in the development of Ab mediated rejection. However, recent studies from our laboratory and others have demonstrated that development of humoral and cellular immune responses against non-HLA self-Ags may contribute in the pathogenesis of allograft rejection. There are reports demonstrating that immune responses to self-Ags especially Abs to the self-Ags as well as cellular immune responses especially through IL17 has significant pro-fibrotic properties leading to chronic allograft failure. This review summarizes recent studies demonstrating the role for immune responses to self-Ags in allograft immunity leading to rejection as well as present recent evidence suggesting there is interplay between allo- and autoimmunity leading to allograft dysfunction. Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.
The Imminent Manpower Crisis: An Opportunity for Society's Rejects.

ERIC Educational Resources Information Center

Blake, Larry J.

Despite predictions in the 1950's and 1960's that computer technology would reduce job opportunities by 90%, historical data published by the Department of Labor reveal that total manpower demands accelerated from 1947 through 1977 and were primarily satisfied by a decreased demand for farm laborers, an increase in percentage of women in the…
Two-Stage, In Silico Deconvolution of the Lymphocyte Compartment of the Peripheral Whole Blood Transcriptome in the Context of Acute Kidney Allograft Rejection

PubMed Central

Shannon, Casey P.; Balshaw, Robert; Ng, Raymond T.; Wilson-McManus, Janet E.; Keown, Paul; McMaster, Robert; McManus, Bruce M.; Landsberg, David; Isbel, Nicole M.; Knoll, Greg; Tebbutt, Scott J.

2014-01-01

Acute rejection is a major complication of solid organ transplantation that prevents the long-term assimilation of the allograft. Various populations of lymphocytes are principal mediators of this process, infiltrating graft tissues and driving cell-mediated cytotoxicity. Understanding the lymphocyte-specific biology associated with rejection is therefore critical. Measuring genome-wide changes in transcript abundance in peripheral whole blood cells can deliver a comprehensive view of the status of the immune system. The heterogeneous nature of the tissue significantly affects the sensitivity and interpretability of traditional analyses, however. Experimental separation of cell types is an obvious solution, but is often impractical and, more worrying, may affect expression, leading to spurious results. Statistical deconvolution of the cell type-specific signal is an attractive alternative, but existing approaches still present some challenges, particularly in a clinical research setting. Obtaining time-matched sample composition to biologically interesting, phenotypically homogeneous cell sub-populations is costly and adds significant complexity to study design. We used a two-stage, in silico deconvolution approach that first predicts sample composition to biologically meaningful and homogeneous leukocyte sub-populations, and then performs cell type-specific differential expression analysis in these same sub-populations, from peripheral whole blood expression data. We applied this approach to a peripheral whole blood expression study of kidney allograft rejection. The patterns of differential composition uncovered are consistent with previous studies carried out using flow cytometry and provide a relevant biological context when interpreting cell type-specific differential expression results. We identified cell type-specific differential expression in a variety of leukocyte sub-populations at the time of rejection. The tissue-specificity of these differentially expressed probe-set lists is consistent with the originating tissue and their functional enrichment consistent with allograft rejection. Finally, we demonstrate that the strategy described here can be used to derive useful hypotheses by validating a cell type-specific ratio in an independent cohort using the nanoString nCounter assay. PMID:24733377
Vulnerability-specific stress generation: Childhood emotional abuse and the mediating role of depressogenic interpersonal processes.

PubMed

Hernandez, Evelyn M; Trout, Zoë M; Liu, Richard T

2016-12-01

Stress generation in depression (i.e. the tendency for depression-prone individuals to experience more life stress that is in part influenced by the individual) has been well established. However, more research is necessary to clarify the role of specific types of life stress in this effect. The current study extends the stress generation hypothesis by examining whether the type of stress involved is contingent upon the nature of the individual's particular vulnerability. Childhood emotional abuse and interpersonal vulnerability factors were predicted to be associated with prospective interpersonal dependent but not non-interpersonal or independent stress. These interpersonal factors were examined as mediators of the association between childhood emotional abuse and interpersonal stress generation. Data were collected from 185 undergraduate participants at two time-points, four months apart. At baseline, participants completed assessments of depressive symptoms, childhood abuse history, interpersonal risk factors (rejection sensitivity, excessive reassurance-seeking, and negative feedback-seeking), and a diagnostic interview for depression. At the follow-up assessment, participants completed a life stress interview. Childhood emotional abuse prospectively predicted greater interpersonal dependent stress, but not non-interpersonal dependent or independent stress. Only rejection sensitivity mediated this relationship. Consistent with the stress generation hypothesis, neither childhood emotional abuse nor the three interpersonal risk factors predicted independent stress. These findings suggest that targeting interpersonal vulnerabilities in clinical settings, particularly rejection sensitivity, among individuals with a history of childhood emotional abuse, may help to reduce the occurrence of interpersonal dependent stress, thus possibly decreasing risk for depression. Copyright Â© 2016 Elsevier Ltd. All rights reserved.
Late acute humoral rejection in low-risk renal transplant recipients induced with an interleukin-2 receptor antagonist and maintained with standard therapy: preliminary communication.

PubMed

Morales, J; Contreras, L; Zehnder, C; Pinto, V; Elberg, M; Araneda, S; Herzog, C; Calabran, L; Aguiló, J; Ferrario, M; Buckel, E; Fierro, J A

2011-01-01

Low-risk renal transplant recipients treated with standard immunosuppressive therapy including interleukin-2 receptor (IL-2R) antagonist show a low incidence of early rejection episodes but few reports have examined the incidence and severity of late rejection processes. This study evaluated retrospectively cellular and antibody-mediated rejection (AMR) among 42 recipients selected because they showed low panel-reactive-antibodies, short cold ischemia time, no delayed graft function, and therapy including basiliximab (Simulect) induction. The mean observation time was 6.6 years. Sixty-seven percent of donors were deceased. Ten-year patient and death-censored graft survivals were 81% and 78%, respectively. Seven patients lost their kidneys due to nonimmunologic events. The seven recipients who experienced cellular rejection episodes during the first posttransplant year had them reversed with steroids. Five patients displayed late acute AMR causing functional deterioration in four cases including 1 graft loss. De novo sensitization occurred in 48% of recipients including patients without clinical rejection. In conclusion, long-term follow-up of kidney transplant recipients selected by a low immunologic risk showed a persistent risk of de novo sensitization evolving to acute AMR in 11% of cases. Although immunologic events were related to late immunosuppressive reduction, most graft losses were due to nonimmunologic factors. Copyright © 2011 Elsevier Inc. All rights reserved.
Unpacking the psychological weight of weight stigma: A rejection-expectation pathway

PubMed Central

Blodorn, Alison; Major, Brenda; Hunger, Jeffrey; Miller, Carol

2015-01-01

The present research tested the hypothesis that the negative effects of weight stigma among higher body-weight individuals are mediated by expectations of social rejection. Women and men who varied in objective body-weight (body mass index; BMI) gave a speech describing why they would make a good date. Half believed that a potential dating partner would see a videotape of their speech (weight seen) and half believed that a potential dating partner would listen to an audiotape of their speech (weight unseen). Among women, but not men, higher body-weight predicted increased expectations of social rejection, decreased executive control resources, decreased self-esteem, increased self-conscious emotions and behavioral displays of self-consciousness when weight was seen but not when weight was unseen. As predicted, higher body-weight women reported increased expectations of social rejection when weight was seen (versus unseen), which in turn predicted decreased self-esteem, increased self-conscious emotions, and increased stress. In contrast, lower body-weight women reported decreased expectations of social rejection when weight was seen (versus unseen), which in turn predicted increased self-esteem, decreased self-conscious emotions, and decreased stress. Men’s responses were largely unaffected by body-weight or visibility, suggesting that a dating context may not be identity threatening for higher body-weight men. Overall, the present research illuminates a rejection-expectation pathway by which weight stigma undermines higher body-weight women’s health. PMID:26752792
Design, synthesis, and evaluation of 4,6-diaminonicotinamide derivatives as novel and potent immunomodulators targeting JAK3.

PubMed

Nakajima, Yutaka; Aoyama, Naohiro; Takahashi, Fumie; Sasaki, Hiroshi; Hatanaka, Keiko; Moritomo, Ayako; Inami, Masamichi; Ito, Misato; Nakamura, Koji; Nakamori, Fumihiro; Inoue, Takayuki; Shirakami, Shohei

2016-10-01

In organ transplantation, T cell-mediated immune responses play a key role in the rejection of allografts. Janus kinase 3 (JAK3) is specifically expressed in hematopoietic cells and associated with regulation of T cell development via interleukin-2 signaling pathway. Here, we designed novel 4,6-diaminonicotinamide derivatives as immunomodulators targeting JAK3 for prevention of transplant rejection. Our optimization of C4- and C6-substituents and docking calculations to JAK3 protein confirmed that the 4,6-diaminonicotinamide scaffold resulted in potent inhibition of JAK3. We also investigated avoidance of human ether-a-go-go related gene (hERG) inhibitory activity. Selected compound 28 in combination with tacrolimus prevented allograft rejection in a rat heterotopic cardiac transplantation model. Copyright © 2016 Elsevier Ltd. All rights reserved.
Donor-specific HLA alloantibodies: Impact on cardiac allograft vasculopathy, rejection, and survival after pediatric heart transplantation.

PubMed

Tran, Andrew; Fixler, David; Huang, Rong; Meza, Tiffany; Lacelle, Chantale; Das, Bibhuti B

2016-01-01

There is increasing evidence that donor-specific anti-HLA antibodies (DSA) are associated with poor outcomes after cardiac transplantation in adults, but data are limited in children. The objective of this study was to examine the development and consequences of de novo DSA in pediatric recipients of heart transplants. We analyzed 105 pediatric patients who received heart transplants at our center from January 2002 to December 2012. All patients had negative T-cell and B-cell post-transplant crossmatches. Patients underwent HLA antibody screening at 1, 2, 3, 6, and 12 months post-transplant and annually thereafter unless there was suspicion for rejection. HLA class I and II antibodies were identified using Luminex assay. Coronary angiography was performed at 1 year and annually thereafter. Acute cellular rejection, antibody-mediated rejection, and treated clinical rejections were included together as rejection events. Of 105 patients, 45 (43%) developed de novo DSA. DSA-positive patients had significantly higher rates of coronary artery vasculopathy (CAV) compared with DSA-negative patients (36% vs 13%). CAV-free survival at 1 year and 5 years post-transplant for DSA-negative patients was 90% and 25%, respectively, compared with 70% and 0%, respectively, for DSA-positive patients (p < 0.01). DSA-positive patients had 2.5 times more rejection events per year than DSA-negative patients. The 5-year graft survival rate was 72.4% for DSA-negative patients and 21% for DSA-positive patients (p < 0.001). De novo DSA has a strong negative impact on CAV, rejection, and graft survival in pediatric recipients of heart transplants. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
Cytokines affecting CD4+T regulatory cells in transplant tolerance. III. Interleukin-5 (IL-5) promotes survival of alloantigen-specific CD4+ T regulatory cells.

PubMed

Hall, Bruce M; Plain, Karren M; Tran, Giang T; Verma, Nirupama D; Robinson, Catherine M; Nomura, Masaru; Boyd, Rochelle; Hodgkinson, Suzanne J

2017-08-01

CD4 + T cells mediate antigen-specific allograft tolerance, but die in culture without activated lymphocyte derived cytokines. Supplementation of the media with cytokine rich supernatant, from ConA activated spleen cells, preserves the capacity of tolerant cells to transfer tolerance and suppress rejection. rIL-2 or rIL-4 alone are insufficient to maintain these cells, however. We observed that activation of naïve CD4 + CD25 + FOXP3 + Treg with alloantigen and the Th2 cytokine rIL-4 induces them to express interleukin-5 specific receptor alpha (IL-5Rα) suggesting that IL-5, a Th2 cytokine that is produced later in the immune response may promote tolerance mediating Treg. This study examined if recombinant IL-5(rIL-5) promoted survival of tolerant CD4 + , especially CD4 + CD25 + T cells. CD4 + T cells, from DA rats tolerant to fully allogeneic PVG heart allografts surviving over 100days without on-going immunosuppression, were cultured with PVG alloantigen and rIL-5. The ability of these cells to adoptively transfer tolerance to specific-donor allograft and suppress normal CD4 + T cell mediated rejection in adoptive DA hosts was examined. Tolerant CD4 + CD25 + T cells' response to rIL-5 and expression of IL-5Rα was also assessed. rIL-5 was sufficient to promote transplant tolerance mediating CD4 + T cells' survival in culture with specific-donor alloantigen. Tolerant CD4 + T cells cultured with rIL-5 retained the capacity to transfer alloantigen-specific tolerance and inhibited naïve CD4 + T cells' capacity to effect specific-donor graft rejection. rIL-5 promoted tolerant CD4 + CD25 + T cells' proliferation in vitro when stimulated with specific-donor but not third-party stimulator cells. Tolerant CD4 + CD25 + T cells expressed IL-5Rα. This study demonstrated that IL-5 promoted the survival of alloantigen-specific CD4 + CD25 + T cells that mediate transplant tolerance. Copyright © 2017 Elsevier B.V. All rights reserved.
Superconducting gravity gradiometer for sensitive gravity measurements. I. Theory

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chan, H.A.; Paik, H.J.

1987-06-15

Because of the equivalence principle, a global measurement is necessary to distinguish gravity from acceleration of the reference frame. A gravity gradiometer is therefore an essential instrument needed for precision tests of gravity laws and for applications in gravity survey and inertial navigation. Superconductivity and SQUID (superconducting quantum interference device) technology can be used to obtain a gravity gradiometer with very high sensitivity and stability. A superconducting gravity gradiometer has been developed for a null test of the gravitational inverse-square law and space-borne geodesy. Here we present a complete theoretical model of this instrument. Starting from dynamical equations for themore » device, we derive transfer functions, a common mode rejection characteristic, and an error model of the superconducting instrument. Since a gradiometer must detect a very weak differential gravity signal in the midst of large platform accelerations and other environmental disturbances, the scale factor and common mode rejection stability of the instrument are extremely important in addition to its immunity to temperature and electromagnetic fluctuations. We show how flux quantization, the Meissner effect, and properties of liquid helium can be utilized to meet these challenges.« less
Cardiac responses predict decisions: an investigation of the relation between orienting response and decisions in the ultimatum game.

PubMed

Osumi, Takahiro; Ohira, Hideki

2009-10-01

Emotion-based behaviors in humans cannot be fully explained by economic rationality. Particularly, in the ultimatum game, which incorporates conflict between self-interest and fairness, negative emotions evoked by an unfair offer seem to promote an economically irrational decision. In accordance with this suggestion, the previous studies have reported that physiological arousal is associated with rejecting unfair offers. In the present study, we investigated electrocardiogram and electrodermal activities in individuals which received fair, advantageously unfair, and disadvantageously unfair offers to specify the relations of the orienting and the defensive responses with these offers and with the decisions to accept and reject them. The results indicated that when an offer that would be rejected was presented, heart rate initially decelerated more than when an offer that would be accepted was presented. Additionally, there was a linear relationship between the deceleration and unfairness of offers. On the other hand, such different patterns were not seen in late cardiac acceleration or electrodermal response. The results suggest that because of perception of disadvantage and unpleasantness in a social context, the orienting response is evoked when an offer will be rejected. In addition, these results are discussed regarding the effect of the autonomic activity in decision-making.
Everolimus immunosuppression for renal protection, reduction of allograft vasculopathy and prevention of allograft rejection in de-novo heart transplant recipients: could we have it all?

PubMed

Gude, Einar; Gullestad, Lars; Andreassen, Arne K

2017-06-01

De-novo introduction of everolimus (Eve) in heart transplant recipients opens for early reduction of calcineurin inhibitors (CNI) and potential of preserving renal function, attenuate progression of coronary allograft vasculopathy (CAV) and maintain rejection efficacy. The first trials demonstrated adequate rejection prophylaxis and favorable outcomes on CAV, but observed enhanced nephrotoxicity because of insufficient CNI reduction. The SCHEDULE trial compared de-novo Eve with significantly reduced CNI exposure and conversion to CNI-free treatment week 7-11 postheart transplant, with standard CNI immunosuppression. Improved renal function and attenuation of CAV was found among Eve patients, with higher numbers of treated acute rejections observed. With sustained superior renal and CAV related data also after 36 months with the Eve protocol, cardiac function was equally well preserved in both groups. According to the International Society of Heart and Lunge Transplantation registry, mammalian target of rapamycin inhibitor treatment is uncommon during the first postoperative year, with a prevalence of 20% in patients after 5 years. Current evidence suggests a greater benefit from these immunosuppressives if introduced at an earlier timepoint. Immunosuppressive protocols based on Eve treatment in de-novo patients should be further investigated and developed, enabling CNI avoidance before accelerating side-effects lead to irreversible damage.
Continued Bullying Victimization in Adolescents: Maladaptive Schemas as a Mediational Mechanism.

PubMed

Calvete, Esther; Fernández-González, Liria; González-Cabrera, Joaquín M; Gámez-Guadix, Manuel

2018-03-01

Bullying victimization in adolescence is a significant social problem that can become persistent over time for some victims. However, there is an overall paucity of research examining the factors that contribute to continued bullying victimization. Schema therapy proposes a model that can help us understand why bullying victimization can be persistent for some victims. This study examines the role of maladaptive schemas, the key concept in schema therapy, as a mechanism of continued bullying victimization. The hypothesis was that maladaptive schemas of rejection mediate the predictive association between victimization in both the family and at school and future bullying victimization. Social anxiety was also considered, as previous research suggests that it can increase the risk of victimization. The participants were 1328 adolescents (45% female) with a mean age of 15.05 years (SD = 1.37), who completed questionnaires at three time points with a 6-month interval between them. Time 2 maladaptive schemas of rejection significantly mediated the predictive association from Time 1 bullying victimization, family abuse and social anxiety to Time 3 bullying victimization. The findings pertaining to potentially malleable factors, such as maladaptive schemas that maintain continued interpersonal victimization, have important implications for prevention and treatment strategies with adolescents.
New approaches to the prevention of organ allograft rejection and tolerance induction.

PubMed

Bagley, Jessamyn; Tian, Chaorui; Iacomini, John

2007-07-15

The therapeutic use of organ allograft transplantation is dependent on the discovery and clinical application of immunologic strategies to blunt the immune response and prevent graft rejection. It was the discovery of powerful immunotherapeutics such as cyclosporine A and rapamycin that has allowed for the widespread use of organ transplantation to treat organ failure. However, despite the attainment of impressive survival rates 1 year after organ transplantation, a significant number of organ allografts are lost to immune-mediated chronic rejection. Furthermore, significant morbidity and mortality can be associated with the use of currently available immunosuppressive regimens. Thus, the development of novel approaches to prevent of organ allograft rejection remains extremely important. Here we discuss two promising and novel avenues of research. First, the discovery and characterization of naturally occurring immune inhibitory signals have led to recent research aimed at exploiting these pathways to induce peripheral tolerance to alloantigen. Furthermore, we discuss new approaches to the induction of donor-specific tolerance by induction of molecular chimerism and the transfer of alloantigen-expressing mature T cells.
Results of adaptive feedforward on GTA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ziomek, C.D.; Denney, P.M.; Regan, A.H.

1993-01-01

This paper presents the results of the adaptive feedforward system in use on the Ground Test Accelerator (GTA). The adaptive feedforward system was shown to correct repetitive, high-frequency errors in the amplitude and phase of the RF field of the pulsed accelerator. The adaptive feedforward system was designed as an augmentation to the RF field feedback control system and was able to extend the closed-loop bandwidth and disturbance rejection by a factor of ten. Within a second implementation, the adaptive feedforward hardware was implemented in place of the feedback control system and was shown to negate both beam transients andmore » phase droop in the klystron amplifier.« less
Results of adaptive feedforward on GTA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ziomek, C.D.; Denney, P.M.; Regan, A.H.

1993-06-01

This paper presents the results of the adaptive feedforward system in use on the Ground Test Accelerator (GTA). The adaptive feedforward system was shown to correct repetitive, high-frequency errors in the amplitude and phase of the RF field of the pulsed accelerator. The adaptive feedforward system was designed as an augmentation to the RF field feedback control system and was able to extend the closed-loop bandwidth and disturbance rejection by a factor of ten. Within a second implementation, the adaptive feedforward hardware was implemented in place of the feedback control system and was shown to negate both beam transients andmore » phase droop in the klystron amplifier.« less
The Effect of Chronic Kidney Disease on T Cell Alloimmunity

PubMed Central

Winterberg, Pamela D.; Ford, Mandy L.

2017-01-01

Purpose of review Altered differentiation and activation of T cell subsets occur in patients with CKD, but the impact on graft rejection and protective immunity during transplantation are not fully understood. Recent findings Patients with CKD have decreased frequency of naïve T cells, accumulation of activated, terminally differentiated memory cells, and skewed regulatory versus T helper 17 ratio. Naïve and memory T cell subsets do not appear to improve following kidney transplantation. Retained thymic output is associated with acute rejection, while naïve lymphopenia and accumulation of CD8+TEMRA cells correlate with long-term graft dysfunction. CD28null memory cells accumulate during CKD and appear to confer protection against acute rejection under standard immunosuppression and possibly co-stimulation blockade. T cells bearing CD57 are also increased in patients with CKD and may underlie rejection during co-stimulation blockade. Summary The mechanisms by which CKD alters the differentiation and activation status of T cell subsets is poorly understood. Further research is also needed to understand which cell populations mediate rejection under various immunosuppressive regimens. To date, there is little use of animal models of organ failure in transplant immunology research. CKD mouse models may help identify novel pathways and targets to better control alloimmunity in post-transplant. PMID:27926546
Drosophila Ovipositor Extension in Mating Behavior and Egg Deposition Involves Distinct Sets of Brain Interneurons

PubMed Central

Kimura, Ken-ichi; Sato, Chiaki; Koganezawa, Masayuki; Yamamoto, Daisuke

2015-01-01

Oviposition is a female-specific behavior that directly affects fecundity, and therefore fitness. If a fertilized female encounters another male that she has evaluated to be of better quality than her previous mate, it would be beneficial for her to remate with this male rather than depositing her eggs. Females who decided not to remate exhibited rejection behavior toward a courting male and engaged in oviposition. Although recent studies of Drosophila melanogaster identified sensory neurons and putative second-order ascending interneurons that mediate uterine afferents affecting female reproductive behavior, little is known about the brain circuitry that selectively activates rejection versus oviposition behaviors. We identified the sexually dimorphic pC2l and female-specific pMN2 neurons, two distinct classes of doublesex (dsx)-expressing neurons that can initiate ovipositor extension associated with rejection and oviposition behavior, respectively. pC2l interneurons, which induce ovipositor extrusion for rejection in females, have homologues that control courtship behavior in males. Activation of these two classes of neurons appears to be mutually exclusive and each governs hierarchical control of the motor program in the VNC either for rejection or oviposition, contributing centrally to the switching on or off of the alternative motor programs. PMID:25955600
Loss of Myeloid Related Protein-8/14 Exacerbates Cardiac Allograft Rejection

PubMed Central

Shimizu, Koichi; Libby, Peter; Rocha, Viviane Z.; Folco, Eduardo J.; Shubiki, Rica; Grabie, Nir; Jang, Sunyoung; Lichtman, Andrew H.; Shimizu, Ayako; Hogg, Nancy; Simon, Daniel I.; Mitchell, Richard N.; Croce, Kevin

2011-01-01

Background The calcium-binding proteins myeloid-related protein (MRP)-8 (S100A8) and MRP-14 (S100A9) form MRP-8/14 heterodimers (S100A8/A9, calprotectin) that regulate myeloid cell function and inflammatory responses, and serve as early serum markers for monitoring acute allograft rejection. Despite functioning as a pro-inflammatory mediator, the pathophysiological role of MRP-8/14 complexes in cardiovascular disease is incompletely defined. This study investigated the role of MRP-8/14 in cardiac allograft rejection using MRP-14-deficient mice (MRP14-/-) that lack MRP-8/14 complexes. Methods and Results We examined parenchymal rejection (PR) after major histocompatibility complex (MHC) class II allomismatched cardiac transplantation (bm12 donor heart and B6 recipients) in wild-type (WT) and MRP14-/- recipients. Allograft survival averaged 5.9 ± 2.9 weeks (n=10) in MRP14-/- recipients, compared to > 12 weeks (n = 15, p < 0.0001) in WT recipients. Two weeks after transplantation, allografts in MRP14-/- recipients had significantly higher PR scores (2.8 ± 0.8, n=8) than did WT recipients (0.8 ± 0.8, n=12, p<0.0001). Compared to WT recipients, allografts in MRP14-/- recipients had significantly increased T-cell and macrophage infiltration, as well as increased mRNA levels of IFN-γ and IFN-γ–associated chemokines (CXCL9, CXCL10, and CXCL11), IL-6, and IL-17, with significantly higher levels of Th17 cells. MRP14-/- recipients also had significantly more lymphocytes in the adjacent paraaortic lymph nodes than did WT recipients (cell number per lymph node: 23.7 ± 0.7 × 105 for MRP14-/- vs. 6.0 ± 0.2 × 105 for WT, p < 0.0001). The dendritic cells (DCs) of the MRP14-/- recipients of bm12 hearts expressed significantly higher levels of the co-stimulatory molecules CD80 and CD86 than did those of WT recipients 2 weeks after transplantation. Mixed leukocyte reactions using allo-EC-primed MRP14-/- DCs resulted in significantly higher antigen-presenting function than reactions using WT DCs. Ovalbumin-primed MRP14-/- DCs augmented proliferation of OT-II CD4+ T cells with increased IL-2 and IFN-γ production. Cardiac allografts of B6 MHC class II-/- hosts and of B6 WT hosts receiving MRP14-/- DCs had significantly augmented inflammatory cell infiltration and accelerated allograft rejection, compared to WT DCs from transferred recipient allografts. Bone marrow–derived MRP14-/- DCs infected with MRP-8 and MRP-14 retroviral vectors showed significantly decreased CD80 and CD86 expression compared to controls, indicating that MRP-8/14 regulates B7-costimulatory molecule expression. Conclusion Our results indicate that MRP-14 regulates B7 molecule expression and reduces antigen presentation by DCs, and subsequent T-cell priming. The absence of MRP-14 markedly increased T-cell activation and exacerbated allograft rejection, indicating a previously unrecognized role for MRP-14 in immune cell biology. PMID:22144572
Outcomes of Highly Sensitized Patients Undergoing Simultaneous Liver and Kidney Transplantation: A Single-Center Experience With Desensitization.

PubMed

Steggerda, J A; Kang, A; Pan, S-H; Sundaram, V; Nissen, N N; Klein, A S; Todo, T; Annamalai, A; Vo, A; Jordan, S C; Kim, I K

Preformed donor-specific human leukocyte antigen antibodies (DSAs) in patients undergoing simultaneous liver and kidney transplantation (SLKT) are an independent risk factor for poorer patient and renal allograft survival. The outcomes of patients highly sensitized (HS) against HLA antigens undergoing SLKT and select HS SLKT recipients undergoing desensitization at a high-volume desensitization center were investigated. Seventy-five patients undergoing SLKT at a high-volume desensitization center between January 1, 2001, and December 31, 2015, were retrospectively reviewed. HS patients were defined by panel-reactive antibody (PRA) >30% (n = 17 patients), 11 of whom received pre- or perioperative desensitization with high-dose intravenous immunoglobulin (IVIG) ± rituximab. HS patients had significantly higher class I and class II PRA (class I = 41.3% ± 40.0% vs 2.5% ± 6.3%; class II = 45.7% ± 36.4% vs 1.0% ± 2.9%; P < .001), were more likely to be female (P = .05), and more likely to have had a prior transplant (P = .03). HS patients demonstrated greater susceptibility to renal cell-mediated rejection (CMR) (23.5% vs 5.2%, P = .02) compared to nonsensitized patients. Higher renal antibody-mediated rejection (ABMR) was also observed in HS patients, 11.8% vs 3.4%, but did not reach significance (P = .18). Desensitization in select HS SLKT patients was well tolerated but did not improve patient and allograft survival or significantly curtail rejection. HS SLKT recipients demonstrated increased allograft rejection, particularly CMR, but patient and graft survival were not impacted in the first year post-transplant. Select HS SLKT patients tolerated desensitization with high-dose IVIG ± rituximab and may have received additional immunoprotection against ABMR but survival was not affected. Copyright © 2017 Elsevier Inc. All rights reserved.

Histological long-term outcomes from acute antibody-mediated rejection following ABO-compatible liver transplantation.

PubMed

Del Bello, Arnaud; Danjoux, Marie; Congy-Jolivet, Nicolas; Lavayssière, Laurence; Esposito, Laure; Muscari, Fabrice; Kamar, Nassim

2017-04-01

Acute antibody-mediated rejection (aAMR) is an unusual complication after orthotopic ABO-compatible liver transplantation. To date, the clinical and histological long-term outcomes after aAMR are not well known. Herein, we describe nine cases of aAMR that occurred in our liver-transplant center between 2008 and 2016, with an initial and reevaluation liver biopsy available for reexamination. Two patients presented with aAMR at 10.5 (10, 11) days post-transplantation, caused by preformed donor-specific antibodies. Seven other recipients developed de novo donor-specific antibodies and aAMR at 11.2 (3-24) months post-transplantation. Eight of the nine patients received a B-cell targeting agent (rituximab, with or without plasma exchange), associated with polyclonal antibodies (three patients) or intravenous immunoglobulins (three patients). At the last follow up (i.e. 21 [4-90] months post-aAMR), seven patients were alive, including two patients with normal liver tests. Grafts' survival was 66%. A liver biopsy performed at 11.5 (5-48.5) months after the first biopsy showed no significant improvement in aAMR score (from 2 ± 1.3 to 1.6 ± 1.5, P = 0.6), a significant improvement in chronic AMR score (from 37 ± 9 to 25 ± 8, P = 0.003) and an increase in the Metavir score (1.2 ± 0.6 to 2.1 ± 0.9, P = 0.03). In this study, a B-cell-depleting agent seemed to improve the prognosis of aAMR in selected cases, but several patients kept active lesions antibody-mediated rejection. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.
[Identifying the specific causes of kidney allograft loss: A population-based study].

PubMed

Lohéac, Charlotte; Aubert, Olivier; Loupy, Alexandre; Legendre, Christophe

2018-04-01

Results of kidney transplantation have been improving but long-term allograft survival remains disappointing. The objective of the present study was to identify the specific causes of renal allograft loss, to assess their incidence and long-term outcomes. A total of 4783 patients from four French centres, transplanted between January 2004 and January 2014 were prospectively included. A total of 9959 kidney biopsies (protocol and for cause) performed between January 2004 and March 2015 were included. Donor and recipient clinical and biological parameters as well as anti-HLA antibody directed against the donor were included. The main outcome was the long-term kidney allograft survival, including the study of the associated causes of graft loss, the delay of graft loss according to their causes and the determinants of graft loss. There were 732 graft losses during the follow-up period (median time: 4.51 years) with an identified cause in 95.08 %. Kidney allograft survival at 9 years post-transplant was 78 %. The causes of allograft loss were: antibody-mediated rejection (31.69 %), thrombosis (25.55 %), medical intercurrent disease (14.62 %), recurrence of primary renal disease (7.1 %), BK- or CMV-associated nephropathy (n=35, 4.78 %), T cell-mediated rejection (4.78 %), urological disease (2.46 %) and calcineurin inhibitor nephrotoxicity (1.09 %). The main causes of allograft loss were antibody-mediated rejection and thrombosis. These results encourage efforts to prevent and detect these complications earlier in order to improve allograft survival. Copyright © 2018 Association Société de néphrologie. Published by Elsevier Masson SAS. All rights reserved.
Update on the Management of High-Risk Penetrating Keratoplasty.

PubMed

Jabbehdari, Sayena; Rafii, Alireza Baradaran; Yazdanpanah, Ghasem; Hamrah, Pedram; Holland, Edward J; Djalilian, Ali R

2017-03-01

In this article, we review the indications and latest management of high-risk penetrating keratoplasty. Despite the immune-privilege status of the cornea, immune-mediated graft rejection still remains the leading cause of corneal graft failure. This is particularly a problem in the high-risk graft recipients, namely patients with previous graft failure due to rejection and those with inflamed and vascularized corneal beds. A number of strategies including both local and systemic immunosuppression are currently used to increase the success rate of high-risk corneal grafts. Moreover, in cases of limbal stem cell deficiency, limbal stem cells transplantation is employed. Corticosteroids are still the top medication for prevention and treatment in cases of corneal graft rejection. Single and combined administration of immunosuppressive agents e.g. tacrolimus, cyclosporine and mycophenolate are promising adjunctive therapies for prolonging graft survival. In the future, cellular and molecular therapies should allow us to achieve immunologic tolerance even in high-risk grafts.
Four-Dimensional Imaging of T Cells in Kidney Transplant Rejection.

PubMed

Hughes, Andrew D; Lakkis, Fadi G; Oberbarnscheidt, Martin H

2018-06-01

Kidney transplantation is the treatment of choice for ESRD but is complicated by the response of the recipient's immune system to nonself histocompatibility antigens on the graft, resulting in rejection. Multiphoton intravital microscopy, referred to as four-dimensional imaging because it records dynamic events in three-dimensional tissue volumes, has emerged as a powerful tool to study immunologic processes in living animals. Here, we will review advances in understanding the complex mechanisms of T cell-mediated rejection made possible by four-dimensional imaging of mouse renal allografts. We will summarize recent data showing that activated (effector) T cell migration to the graft is driven by cognate antigen presented by dendritic cells that surround and penetrate peritubular capillaries, and that T cell-dendritic cell interactions persist in the graft over time, maintaining the immune response in the tissue. Copyright © 2018 by the American Society of Nephrology.
Polymorphisms in the lectin pathway of complement activation influence the incidence of acute rejection and graft outcome after kidney transplantation.

PubMed

Golshayan, Déla; Wójtowicz, Agnieszka; Bibert, Stéphanie; Pyndiah, Nitisha; Manuel, Oriol; Binet, Isabelle; Buhler, Leo H; Huynh-Do, Uyen; Mueller, Thomas; Steiger, Jürg; Pascual, Manuel; Meylan, Pascal; Bochud, Pierre-Yves

2016-04-01

There are conflicting data on the role of the lectin pathway of complement activation and its recognition molecules in acute rejection and outcome after transplantation. To help resolve this we analyzed polymorphisms and serum levels of lectin pathway components in 710 consecutive kidney transplant recipients enrolled in the nationwide Swiss Transplant Cohort Study, together with all biopsy-proven rejection episodes and 1-year graft and patient survival. Functional mannose-binding lectin (MBL) levels were determined in serum samples, and previously described MBL2, ficolin 2, and MBL-associated serine protease 2 polymorphisms were genotyped. Low MBL serum levels and deficient MBL2 diplotypes were associated with a higher incidence of acute cellular rejection during the first year, in particular in recipients of deceased-donor kidneys. This association remained significant (hazard ratio 1.75, 95% confidence interval 1.18-2.60) in a Cox regression model after adjustment for relevant covariates. In contrast, there was no significant association with rates of antibody-mediated rejection, patient death, early graft dysfunction or loss. Thus, results in a prospective multicenter contemporary cohort suggest that MBL2 polymorphisms result in low MBL serum levels and are associated with acute cellular rejection after kidney transplantation. Since MBL deficiency is a relatively frequent trait in the normal population, our findings may lead to individual risk stratification and customized immunosuppression. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
Pig-to-Primate Islet Xenotransplantation: Past, Present, and Future

PubMed Central

Liu, Zhengzhao; Hu, Wenbao; He, Tian; Dai, Yifan; Hara, Hidetaka; Bottino, Rita; Cooper, David K. C.; Cai, Zhiming; Mou, Lisha

2017-01-01

Islet allotransplantation results in increasing success in treating type 1 diabetes, but the shortage of deceased human donor pancreata limits progress. Islet xenotransplantation, using pigs as a source of islets, is a promising approach to overcome this limitation. The greatest obstacle is the primate immune/inflammatory response to the porcine (pig) islets, which may take the form of rapid early graft rejection (the instant blood-mediated inflammatory reaction) or T-cell-mediated rejection. These problems are being resolved by the genetic engineering of the source pigs combined with improved immunosuppressive therapy. The results of pig-to-diabetic nonhuman primate islet xenotransplantation are steadily improving, with insulin independence being achieved for periods >1 year. An alternative approach is to isolate islets within a micro- or macroencapsulation device aimed at protecting them from the human recipient's immune response. Clinical trials using this approach are currently underway. This review focuses on the major aspects of pig-to-primate islet xenotransplantation and its potential for treatment of type 1 diabetes. PMID:28155815
Antibody-mediated rejection of the lung: A consensus report of the International Society for Heart and Lung Transplantation.

PubMed

Levine, Deborah J; Glanville, Allan R; Aboyoun, Christina; Belperio, John; Benden, Christian; Berry, Gerald J; Hachem, Ramsey; Hayes, Don; Neil, Desley; Reinsmoen, Nancy L; Snyder, Laurie D; Sweet, Stuart; Tyan, Dolly; Verleden, Geert; Westall, Glen; Yusen, Roger D; Zamora, Martin; Zeevi, Adriana

2016-04-01

Antibody-mediated rejection (AMR) is a recognized cause of allograft dysfunction in lung transplant recipients. Unlike AMR in other solid-organ transplant recipients, there are no standardized diagnostic criteria or an agreed-upon definition. Hence, a working group was created by the International Society for Heart and Lung Transplantation with the aim of determining criteria for pulmonary AMR and establishing a definition. Diagnostic criteria and a working consensus definition were established. Key diagnostic criteria include the presence of antibodies directed toward donor human leukocyte antigens and characteristic lung histology with or without evidence of complement 4d within the graft. Exclusion of other causes of allograft dysfunction increases confidence in the diagnosis but is not essential. Pulmonary AMR may be clinical (allograft dysfunction which can be asymptomatic) or sub-clinical (normal allograft function). This consensus definition will have clinical, therapeutic and research implications. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
The relation of child maltreatment to shame and guilt among adolescents: psychological routes to depression and delinquency.

PubMed

Stuewig, Jeffrey; McCloskey, Laura A

2005-11-01

In a longitudinal study of children followed for 8 years into adolescence, the authors investigated how different forms of maltreatment (i.e., harsh parenting, sexual abuse, witnessing domestic violence) in childhood and parenting during adolescence influenced adolescents' shame- and guilt-proneness. Furthermore, the authors examined whether diminished feelings of guilt or heightened feelings of shame were related to delinquent behavior or depression in late adolescence. Results showed that whereas harsh parenting in childhood was related to shame proneness in adolescence, this relationship was mediated by parental rejection in adolescence. Findings confirmed that youth with rejecting parents were more shame-prone and less guilt-prone than other youth. Furthermore, shame-proneness was associated with higher depression when measured 2 years later and guilt-proneness was linked to less delinquent behavior. Results suggest that, as mediators, shame and guilt may provide useful focal points for intervention and prevention efforts in reducing adolescent depression and delinquency.
Immunomodulatory Effect of Mesenchymal Stem Cells on B Cells

PubMed Central

Franquesa, Marcella; Hoogduijn, M. J.; Bestard, O.; Grinyó, J. M.

2012-01-01

The research on T cell immunosuppression therapies has attracted most of the attention in clinical transplantation. However, B cells and humoral immune responses are increasingly acknowledged as crucial mediators of chronic allograft rejection. Indeed, humoral immune responses can lead to renal allograft rejection even in patients whose cell-mediated immune responses are well controlled. On the other hand, newly studied B cell subsets with regulatory effects have been linked to tolerance achievement in transplantation. Better understanding of the regulatory and effector B cell responses may therefore lead to new therapeutic approaches. Mesenchymal stem cells (MSC) are arising as a potent therapeutic tool in transplantation due to their regenerative and immunomodulatory properties. The research on MSCs has mainly focused on their effects on T cells and although data regarding the modulatory effects of MSCs on alloantigen-specific humoral response in humans is scarce, it has been demonstrated that MSCs significantly affect B cell functioning. In the present review we will analyze and discuss the results in this field. PMID:22833744
Emotional alienation as a mediator of the relationship between perceived discrimination and alcohol use among immigrant adolescents in Israel.

PubMed

Walsh, Sophie D; Sagis-Krebs, Maya; Gross, Ashi

2017-04-04

Perceived discrimination has been found to be a predictor of immigrant adolescent involvement in alcohol use, yet the psychological mechanism behind this relationship has not been well explored. Drawing on strain theory and the motivational model of alcohol use, the current study aimed to develop and test a concept of emotional alienation. In the proposed model, it is when experiences of discrimination are internalized into painful feelings of detachment, anger, rejection, and failure that the immigrant adolescent may turn to alcohol use. The study involved 365 at-risk immigrant adolescents, aged 15-19 (62% male, mean age 17.1) from the Former Soviet Union and Ethiopia in Israel, from low SES neighborhoods and community centers for youth at risk. The young people self-reported on experiences of discrimination, daily alcohol use, heavy episodic drinking (HED), and drunkenness, together with a new questionnaire examining emotional alienation developed for the study. Findings showed that experiences of alienation fully mediated the relationship between discrimination and problematic alcohol use (drunkenness and HED). In particular, feelings of self-detachment, failure, and rejection were strongly related to alcohol use. Results suggest an importance of understanding the way in which negative reactions from the host society may be internalized into destructive feelings of failure, shame, and rejection, which may lead a young person to involvement in alcohol use.
Effect of accelerated aging on the cross-link density of medical grade silicones.

PubMed

Mahomed, Aziza; Pormehr, Negin Bagheri

2016-11-25

Four specimens of Nagor silicone of different hardness (soft, medium and hard) were swollen, until they reached equilibrium (i.e. constant mass) in five liquids at 25°C, before and after accelerated aging. For the specimens swollen before accelerated aging, the greatest swelling was obtained in methyl cyclohexane, while for the specimens swollen after accelerated aging, the greatest swelling was obtained in cyclohexane. The cross-link density, υ, was also calculated from the swelling measurements for all the specimens, before and after accelerated aging, using the Flory-Rehner equation. The softer silicones, which swelled the most, had lower υ values than harder silicones. The amount of swelling (measured in terms of ϕ) and υ varied significantly (p<0.05) in some cases, between the different silicone hardness and between different liquids. Furthermore, the cross-link density, υ, significantly (p<0.05) increased after accelerated aging in most liquids.Note: ϕ is defined as the volume fraction of polymer in its equilibrium swollen state. A probability value of statistical significance of 0.05 or 5% was selected, hence if a p value of less than 0.05 was obtained, the null hypothesis was rejected (i.e. significant if p<0.05).
Fetal cardiac cine imaging using highly accelerated dynamic MRI with retrospective motion correction and outlier rejection

PubMed Central

Lloyd, David F.A.; Price, Anthony N.; Kuklisova Murgasova, Maria; Aljabar, Paul; Malik, Shaihan J.; Lohezic, Maelene; Rutherford, Mary A.; Pushparajah, Kuberan; Razavi, Reza; Hajnal, Joseph V.

2017-01-01

Purpose Development of a MRI acquisition and reconstruction strategy to depict fetal cardiac anatomy in the presence of maternal and fetal motion. Methods The proposed strategy involves i) acquisition and reconstruction of highly accelerated dynamic MRI, followed by image‐based ii) cardiac synchronization, iii) motion correction, iv) outlier rejection, and finally v) cardiac cine reconstruction. Postprocessing entirely was automated, aside from a user‐defined region of interest delineating the fetal heart. The method was evaluated in 30 mid‐ to late gestational age singleton pregnancies scanned without maternal breath‐hold. Results The combination of complementary acquisition/reconstruction and correction/rejection steps in the pipeline served to improve the quality of the reconstructed 2D cine images, resulting in increased visibility of small, dynamic anatomical features. Artifact‐free cine images successfully were produced in 36 of 39 acquired data sets; prolonged general fetal movements precluded processing of the remaining three data sets. Conclusions The proposed method shows promise as a motion‐tolerant framework to enable further detail in MRI studies of the fetal heart and great vessels. Processing data in image‐space allowed for spatial and temporal operations to be applied to the fetal heart in isolation, separate from extraneous changes elsewhere in the field of view. Magn Reson Med 79:327–338, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID:28370252
Immune function surveillance: association with rejection, infection and cardiac allograft vasculopathy.

PubMed

Heikal, N M; Bader, F M; Martins, T B; Pavlov, I Y; Wilson, A R; Barakat, M; Stehlik, J; Kfoury, A G; Gilbert, E M; Delgado, J C; Hill, H R

2013-01-01

Rejection, cardiac allograft vasculopathy (CAV), and infection are significant causes of mortality in heart transplantation recipients. Assessing the immune status of a particular patient remains challenging. Although endomyocardial biopsy (EMB) and angiography are effective for the identification of rejection and CAV, respectively, these are expensive, invasive, and may have numerous complications. The aim of this study was to evaluate the immune function and assess its utility in predicting rejection, CAV, and infection in heart transplantation recipients. We prospectively obtained samples at the time of routine EMB and when clinically indicated for measurement of the ImmuKnow assay (IM), 12 cytokines and soluble CD30 (sCD30). EMB specimens were evaluated for acute cellular rejection, and antibody-mediated rejection (AMR). CAV was diagnosed by the development of angiographic coronary artery disease. Infectious episodes occurring during the next 30 days after testing were identified by the presence of positive bacterial or fungal cultures and/or viremia that prompted treatment with antimicrobials. We collected 162 samples from 56 cardiac transplant recipients. There were 31 infection episodes, 7 AMR, and 4 CAV cases. The average IM value was significantly lower during infection, (P = .04). Soluble CD30 concentrations showed significantly positive correlation with infection episodes, (P = .001). Significant positive correlation was observed between interleukin-5(IL-5) and AMR episodes (P = .008). Tumor necrosis factor-α and IL-8 showed significant positive correlation with CAV (P = .001). Immune function monitoring appears promising in predicting rejection, CAV, and infection in cardiac transplantation recipients. This approach may help in more individualized immunosuppression and it may also minimize unnecessary EMBs and cardiac angiographies. Published by Elsevier Inc.
Kidney transplantation: evaluation and clinical outcome of 237 recipients at low, medium, high, or strong immunological risk of rejection.

PubMed

Nascimento, E; Fabreti de Oliveira, R A; Maciel, M D; Pereira, A B; das Mercêz de Lucas, F; Salomão-Filho, A; Pereira, W A; Moreira, J B; Vilaça, S S; de Castro Gontijo, R; Lasmar, M F; Vianna, H R; Magalhâes, A; Calazans, C A C; Simão-Filho, C; Vilela, B

2014-01-01

Donor-specific antibodies (DSAs) play a fundamental role in kidney transplantation. The identification of DSAs is an essential rejection parameter. We evaluated a protocol in 237 patients receiving kidneys from living (LDs) and deceased donors (DDs). Recipients were classified as being at low (LR), medium (MR), high (HR), or strong (SR) risk of rejection based on Luminex panel reactive antibody (PRA)-single antigen beads (SABs). Grafts that survived for 1 year were evaluated. Of the 237 transplanted patients, 129 (54.43%) received a kidney from an LD and 108 (45.57%) from a DD. Of 95 LR recipients receiving kidneys from LDs, 2 patients lost the graft due to non-immunological causes. Of 34 MR recipients, 13 had rejection episodes, and 2 lost the graft by AMR and one by cellular rejection (CR). Of 108 recipients receiving a kidney from a DD, 59 (54.63%) were LR, 31 (28.70%) MR, 11 (10.19%) HR, and 7 (6.48%) SR. Twenty of all transplanted recipients lost their grafts; 4 were due to clinical causes, 4 by cellular rejection, and 12 by antibody-mediated rejection (AMR) with PRA-SAB mean fluorescent intensity of 530 to 12,591. One-year graft survival for LD transplanted LR and MR patients was 97.6% and 94.1%, respectively (P = .004). In DD recipients, the LR vs MR SD was P = .011, and for LR vs HR + SR it was P = .001. For MR vs HR+SR no SD was found (P = .323). Rejections were detected in 51 patients (21.52%). Graft failure occurred in 16 patients (6.75%). A total of 218 (91.98%) recipients maintained good kidney function after 1 year. This protocol based on fluxogram risk assessment of AMR provided fast and precise immunological evaluation of recipients and donors and stratification by immunological risk of AMR. Copyright © 2014 Elsevier Inc. All rights reserved.
Alteration of Cardiac Deformation in Acute Rejection in Pediatric Heart Transplant Recipients.

PubMed

Chanana, Nitin; Van Dorn, Charlotte S; Everitt, Melanie D; Weng, Hsin Yi; Miller, Dylan V; Menon, Shaji C

2017-04-01

The objective of this study is to assess changes in cardiac deformation during acute cellular- and antibody-mediated rejection in pediatric HT recipients. Pediatric HT recipients aged ≤18 years with at least one episode of biopsy-diagnosed rejection from 2006 to 2013 were included. Left ventricular systolic S (SS) and SR (SSr) data were acquired using 2D speckle tracking on echocardiograms obtained within 12 h of right ventricular endomyocardial biopsy. A mixed effect model was used to compare cardiac deformation during CR (Grade ≥ 1R), AMR (pAMR ≥ 2), and mixed rejection (CR and AMR positive) versus no rejection (Grade 0R and pAMR 0 or 1). A total of 20 subjects (10 males, 50%) with 71 rejection events (CR 35, 49%; AMR 21, 30% and mixed 15, 21%) met inclusion criteria. The median time from HT to first biopsy used for analysis was 5 months (IQR 0.25-192 months). Average LV longitudinal SS and SSr were reduced significantly during rejection (SS: -17.2 ± 3.4% vs. -10.7 ± 4.5%, p < 0.001 and SSr: -1.2 ± 0.2 s - 1 vs. -0.9 ± 0.3 s - 1 ; p < 0.001) and in all rejection types. Average LV short-axis radial SS was reduced only in CR compared to no rejection (p = 0.04), while average LV circumferential SS and SSr were reduced significantly in AMR compared to CR (SS: 18.9 ± 4.2% vs. 20.8 ± 8.8%, p = 0.03 and SSr: 1.35 ± 0.8 s - 1 vs. 1.54 ± 0.9 s - 1 ; p = 0.03). In pediatric HT recipients, LV longitudinal SS and SSr were reduced in all rejection types, while LV radial SS was reduced only in CR. LV circumferential SS and SSr further differentiated between CR and AMR with a significant reduction seen in AMR as compared to CR. This novel finding suggests mechanistic differences between AMR- and CR-induced myocardial injury which may be useful in non-invasively predicting the type of rejection in pediatric HT recipients.
Not self-focused attention but negative beliefs affect poor social performance in social anxiety: an investigation of pathways in the social anxiety-social rejection relationship.

PubMed

Voncken, Marisol J; Dijk, Corine; de Jong, Peter J; Roelofs, Jeffrey

2010-10-01

Patients with social anxiety disorder (SAD) not only fear negative evaluation but are indeed less likeable than people without SAD. Previous research shows social performance to mediate this social anxiety-social rejection relationship. This study studied two pathways hypothesized to lead to poor social performance in social anxiety: increased self-focused attention and negative beliefs. State social anxiety was experimentally manipulated in high and low-blushing-fearful individuals by letting half of the participants believe that they blushed intensely during a 5 min getting-acquainted interaction with two confederates. Participants rated their state social anxiety, self-focused attention, and level of negative beliefs. Two confederates and two video-observers rated subsequently likeability (i.e., social rejection) and social performance of the participants. In both groups, the social anxiety-social rejection relationship was present. Although state social anxiety was related to heightened self-focused attention and negative beliefs, only negative beliefs were associated with relatively poor social performance. In contrast to current SAD models, self-focused attention did not play a key-role in poor social performance but seemed to function as a by-product of state social anxiety. Beliefs of being negatively evaluated seem to elicit changes in behavioral repertoire resulting in a poor social performance and subsequent rejection. Copyright 2010 Elsevier Ltd. All rights reserved.
Antenna Linear-Quadratic-Gaussian (LQG) Controllers: Properties, Limits of Performance, and Tuning Procedure

NASA Technical Reports Server (NTRS)

Gawronski, W.

2004-01-01

Wind gusts are the main disturbances that depreciate tracking precision of microwave antennas and radiotelescopes. The linear-quadratic-Gaussian (LQG) controllers - as compared with the proportional-and-integral (PI) controllers significantly improve the tracking precision in wind disturbances. However, their properties have not been satisfactorily understood; consequently, their tuning is a trial-and-error process. A control engineer has two tools to tune an LQG controller: the choice of coordinate system of the controller model and the selection of weights of the LQG performance index. This article analyzes properties of an open- and closed-loop antenna. It shows that the proper choice of coordinates of the open-loop model simplifies the shaping of the closed-loop performance. The closed-loop properties are influenced by the LQG weights. The article shows the impact of the weights on the antenna closed-loop bandwidth, disturbance rejection properties, and antenna acceleration. The bandwidth and the disturbance rejection characterize the antenna performance, while the acceleration represents the performance limit set by the antenna hardware (motors). The article presents the controller tuning procedure, based on the coordinate selection and the weight properties. The procedure rationally shapes the closed-loop performance, as an alternative to the trial-and-error approach.
The neural mechanisms of affect infusion in social economic decision-making: a mediating role of the anterior insula.

PubMed

Harlé, Katia M; Chang, Luke J; van 't Wout, Mascha; Sanfey, Alan G

2012-05-15

Though emotions have been shown to have sometimes dramatic effects on decision-making, the neural mechanisms mediating these biases are relatively unexplored. Here, we investigated how incidental affect (i.e. emotional states unrelated to the decision at hand) may influence decisions, and how these biases are implemented in the brain. Nineteen adult participants made decisions which involved accepting or rejecting monetary offers from others in an Ultimatum Game while undergoing functional magnetic resonance imaging (fMRI). Prior to each set of decisions, participants watched a short video clip aimed at inducing either a sad or neutral emotional state. Results demonstrated that, as expected, sad participants rejected more unfair offers than those in the neutral condition. Neuroimaging analyses revealed that receiving unfair offers while in a sad mood elicited activity in brain areas related to aversive emotional states and somatosensory integration (anterior insula) and to cognitive conflict (anterior cingulate cortex). Sad participants also showed a diminished sensitivity in neural regions associated with reward processing (ventral striatum). Importantly, insular activation uniquely mediated the relationship between sadness and decision bias. This study is the first to reveal how subtle mood states can be integrated at the neural level to influence decision-making. Copyright © 2012 Elsevier Inc. All rights reserved.
Recipient Myd88 Deficiency Promotes Spontaneous Resolution of Kidney Allograft Rejection

PubMed Central

Lerret, Nadine M.; Li, Ting; Wang, Jiao-Jing; Kang, Hee-Kap; Wang, Sheng; Wang, Xueqiong; Jie, Chunfa; Kanwar, Yashpal S.; Abecassis, Michael M.

2015-01-01

The myeloid differentiation protein 88 (MyD88) adapter protein is an important mediator of kidney allograft rejection, yet the precise role of MyD88 signaling in directing the host immune response toward the development of kidney allograft rejection remains unclear. Using a stringent mouse model of allogeneic kidney transplantation, we demonstrated that acute allograft rejection occurred equally in MyD88-sufficient (wild-type [WT]) and MyD88−/− recipients. However, MyD88 deficiency resulted in spontaneous diminution of graft infiltrating effector cells, including CD11b−Gr-1+ cells and activated CD8 T cells, as well as subsequent restoration of near-normal renal graft function, leading to long-term kidney allograft acceptance. Compared with T cells from WT recipients, T cells from MyD88−/− recipients failed to mount a robust recall response upon donor antigen restimulation in mixed lymphocyte cultures ex vivo. Notably, exogenous IL-6 restored the proliferation rate of T cells, particularly CD8 T cells, from MyD88−/− recipients to the proliferation rate of cells from WT recipients. Furthermore, MyD88−/− T cells exhibited diminished expression of chemokine receptors, specifically CCR4 and CXCR3, and the impaired ability to accumulate in the kidney allografts despite an otherwise MyD88-sufficient environment. These results provide a mechanism linking the lack of intrinsic MyD88 signaling in T cells to the effective control of the rejection response that results in spontaneous resolution of acute rejection and long-term graft protection. PMID:25788530
Borderline Personality Disorder Symptoms and Aggression: A Within-Person Process Model

PubMed Central

Scott, Lori N.; Wright, Aidan G. C.; Beeney, Joseph E.; Lazarus, Sophie A.; Pilkonis, Paul A.; Stepp, Stephanie D.

2017-01-01

Theoretical and empirical work suggests that aggression in those with borderline personality disorder (BPD) occurs primarily in the context of emotional reactivity, especially anger and shame, in response to perceived rejection. Using intensive repeated measures, we examined a within-person process model in which perceived rejection predicts increases in aggressive urges and behaviors via increases in negative affect (indirect effect) and in which BPD symptoms exacerbate this process (moderated mediation). Participants were 117 emerging adult women (ages 18–24) with recent histories of aggressive behavior who were recruited from a community-based longitudinal study of at-risk youth. Personality disorder symptoms were assessed by semi-structured clinical interview, and aggressive urges, threats, and behaviors were measured in daily life during a three-week ecological momentary assessment (EMA) protocol. Multilevel path models revealed that within-person increases in perceived rejection predicted increases in negative affect, especially in women with greater BPD symptoms. In turn, increases in negative affect predicted increased likelihood of aggressive urges or behaviors. Further analysis revealed that BPD symptoms predicted greater anger and shame reactivity to perceived rejection, but not to criticism or insult. Additionally, only anger was associated with increases in aggression after controlling for other negative emotions. Whereas BPD symptoms exacerbated the link between perceived rejection and aggression via increases in negative affect (particularly anger), this process was attenuated in women with greater antisocial personality disorder (ASPD) symptoms. These findings suggest that anger reactivity to perceived rejection is one unique pathway, distinct from ASPD, by which BPD symptoms increase risk for aggression. PMID:28383936

Life cycle cost assessment of future low heat rejection engines

NASA Technical Reports Server (NTRS)

Petersen, D. R.

1986-01-01

The Adiabatic Diesel Engine Component Development (ADECD) represents a project which has the objective to accelerate the development of highway truck engines with advanced technology aimed at reduced fuel consumption. The project comprises three steps, including the synthesis of a number of engine candidate designs, the coupling of each with a number of systems for utilizing exhaust gas energy, and the evaluation of each combination in terms of desirability. Particular attention is given to the employed evaluation method and the development of this method. The objective of Life Cycle Cost (LCC) evaluation in the ADECD program was to select the best from among 42 different low heat rejection engine (LHRE)/exhaust energy recovery system configurations. The LCC model is discussed along with a maintenance cost model, the evaluation strategy, the selection of parameter ranges, and a full factorial analysis.
[Behavioral gender differences in school relationships].

PubMed

Postigo Zegarra, Silvia; González Barrón, Remedios; Mateu Marqués, Carmen; Ferrero Berlanga, Javier; Martorell Pallás, Carmen

2009-08-01

Adolescents take on different social roles mediated by gender, which affect the development of their identity and the expression of school violence. The purpose of this work is to study the behavioral differences in bullying depending on gender. The sample (N=641) is aged between 12 and 16 years old. Personal variables are assessed by self-reports, and relational variables by sociometric measures. Results indicate a large incidence of bullying, peer rejection, and school maladjustment among boys. Girls report more relational aggressions, acceptance and social skills, but also higher personal maladjustment. Female victims are rejected the most. Gender differences seem more relevant in relational variables, suggesting the special importance of the relational context in bullying.
The Presence of Pretransplant HLA Antibodies Does Not Impact the Development of Chronic Lung Allograft Dysfunction or CLAD-Related Death.

PubMed

Zazueta, Oscar E; Preston, Sara E; Moniodis, Anna; Fried, Sabrina; Kim, Miae; Townsend, Keri; Wood, Isabelle; Boukedes, Steve; Guleria, Indira; Camp, Phillip; El-Chemaly, Souheil; Rosas, Ivan O; Chandraker, Anil; Milford, Edgar; Goldberg, Hilary J

2017-09-01

Development of donor-specific antibodies (DSA) after lung transplantation is associated with antibody mediated rejection, acute cellular rejection, and bronchiolitis obliterans syndrome; however, the significance of circulating antibodies before transplant remains unclear. We performed a retrospective cohort study including recipients of primary lung transplants between 2008 and 2012. We assessed the impact of circulating HLA and noncytotoxic DSA detected before transplant on development of Chronic Lung Allograft Dysfunction (CLAD) or CLAD-related death. 30% of subjects had circulating class I antibodies alone, 4% Class II, and 14.4% class I and class II at mean fluorescent intensity greater than 1000. Nine percent of the subjects had DSA class I, 9% class II, and 2.4% both DSA classes 1 and 2. Neither the presence of circulating antibodies (adjusted hazard ratio, 0.87; 95% confidence interval, 0.50-1.54) nor the presence of DSA (adjusted hazard ratio, 1.56; 95% confidence interval, 0.77-3.18) before transplant at mean fluorescent intensity greater than 1000 was associated with the development of CLAD or CLAD-related death. Although in previous studies we have shown an increased incidence of antibody-mediated rejection in patients with pretransplant DSA, neither the presence of HLA antibodies nor DSA translated to an increased risk of allograft dysfunction or death if prospective crossmatch testing was negative. Prospective studies are needed to define the impact of pretransplant sensitization on lung transplant recipients.
Immediate and Catastrophic Antibody-Mediated Rejection in a Lung Transplant Recipient With Anti-Angiotensin II Receptor Type 1 and Anti-Endothelin-1 Receptor Type A Antibodies.

PubMed

Cozzi, E; Calabrese, F; Schiavon, M; Feltracco, P; Seveso, M; Carollo, C; Loy, M; Cardillo, M; Rea, F

2017-02-01

Preexisting donor-specific anti-HLA antibodies (DSAs) have been associated with reduced survival of lung allografts. However, antibodies with specificities other than HLA may have a detrimental role on the lung transplant outcome. A young man with cystic fibrosis underwent lung transplantation with organs from a suitable deceased donor. At the time of transplantation, there were no anti-HLA DSAs. During surgery, the patient developed a severe and intractable pulmonary hypertension associated with right ventriular dysfunction, which required arteriovenous extracorporeal membrane oxygenation. After a brief period of clinical improvement, a rapid deterioration in hemodynamics led to the patient's death on postoperative day 5. Postmortem studies showed that lung specimens taken at the end of surgery were compatible with antibody-mediated rejection (AMR), while terminal samples evidenced diffuse capillaritis, blood extravasation, edema, and microthrombi, with foci of acute cellular rejection (A3). Immunological investigations demonstrated the presence of preexisting antibodies against the endothelin-1 receptor type A (ET A R) and the angiotensin II receptor type 1 (AT 1 R), two of the most potent vasoconstrictors reported to date, whose levels slightly rose after transplantation. These data suggest that preexisting anti-ET A R and anti-AT 1 R antibodies may have contributed to the onset of AMR and to the catastrophic clinical course of this patient. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.
Efficacy of induction therapy with ATG and intravenous immunoglobulins in patients with low-level donor-specific HLA-antibodies.

PubMed

Bächler, K; Amico, P; Hönger, G; Bielmann, D; Hopfer, H; Mihatsch, M J; Steiger, J; Schaub, S

2010-05-01

Low-level donor-specific HLA-antibodies (HLA-DSA) (i.e. detectable by single-antigen flow beads, but negative by complement-dependent cytotoxicity crossmatch) represent a risk factor for early allograft rejection. The short-term efficacy of an induction regimen consisting of polyclonal anti-T-lymphocyte globulin (ATG) and intravenous immunoglobulins (IvIg) in patients with low-level HLA-DSA is unknown. In this study, we compared 67 patients with low-level HLA-DSA not having received ATG/IvIg induction (historic control) with 37 patients, who received ATG/IvIg induction. The two groups were equal regarding retransplants, HLA-matches, number and class of HLA-DSA. The overall incidence of clinical/subclinical antibody-mediated rejection (AMR) was lower in the ATG/IvIg than in the historic control group (38% vs. 55%; p = 0.03). This was driven by a significantly lower rate of clinical AMR (11% vs. 46%; p = 0.0002). Clinical T-cell-mediated rejection (TCR) was significantly lower in the ATG/IvIg than in the historic control group (0% vs. 50%; p < 0.0001). Within the first year, allograft loss due to AMR occurred in 7.5% in the historic control and in 0% in the ATG/IvIg group. We conclude that in patients with low-level HLA-DSA, ATG/IvIg induction significantly reduces TCR and the severity of AMR, but the high rate of subclinical AMR suggests an insufficient control of the humoral immune response.
A Minority Stress – Emotion Regulation Model of Sexual Compulsivity among Highly Sexually Active Gay and Bisexual Men

PubMed Central

Pachankis, John E.; Rendina, H. Jonathon; Restar, Arjee; Ventuneac, Ana; Grov, Christian; Parsons, Jeffrey T.

2014-01-01

Objective Sexual compulsivity represents a significant public health concern among gay and bisexual men given its co-occurrence with other mental health problems and HIV infection. The purpose of this study was to examine a model of sexual compulsivity based on minority stress theory and emotion regulation models of mental health among gay and bisexual men. Method Gay and bisexual men in New York City reporting at least nine past-90-day sexual partners (n = 374) completed measures of distal minority stressors (i.e., boyhood gender nonconformity and peer rejection, adulthood perceived discrimination), hypothesized proximal minority stress mediators (i.e., rejection sensitivity, internalized homonegativity), hypothesized universal mediators (i.e., emotion dysregulation, depression and anxiety), and sexual compulsivity. Results The hypothesized model fit the data well (RMSEA = 0.05, CFI = 0.98, TLI = 0.95, SRMR = 0.03). Distal minority stress processes (e.g., peer rejection) were generally found to confer risk for both proximal minority stressors (e.g., internalized homonegativity) and emotion dysregulation. Proximal minority stressors and emotion dysregulation, in turn, generally predicted sexual compulsivity both directly and indirectly through anxiety and depression. Conclusions The final model suggests that gay-specific (e.g., internalized homonegativity) and universal (e.g., emotion dysregulation) processes represent potential treatment targets to attenuate the impact of minority stress on gay and bisexual men's sexual health. Tests of interventions that address these targets to treat sexual compulsivity among gay and bisexual men represent a promising future research endeavor. PMID:25528179
The buffering role of social support on the associations among discrimination, mental health, and suicidality in a transgender sample

PubMed Central

Trujillo, Michael A.; Perrin, Paul B.; Sutter, Megan; Tabaac, Ariella; Benotsch, Eric G.

2017-01-01

INTRODUCTION Per the minority stress framework, trans individuals often experience psychological distress given the unique stress engendered by gender identity-related discrimination. Prior research has identified social support as particularly important for psychological distress and has suggested that social support may moderate this relationship. AIMS: The purpose of the current study was to explore the patterns of connections among discrimination, mental health, and suicidal ideation in trans individuals, and whether social support moderates these relationships. METHODS Participants (N = 78) completed measures of these constructs as part of a national online survey. RESULTS A series of simultaneous multiple regressions found that harassment/rejection discrimination was a unique positive predictor of mental health symptoms and suicidal ideation, with depression positively predicting suicidal ideation. A mediational model indicated that the association between harassment/rejection discrimination and suicidal ideation was fully mediated by depression. Three moderated meditational models were run, and one yielded a significant interaction, such that discrimination predicted suicidal ideation most strongly when participants had low social support from a significant other in comparison to moderate or high support. Further, conditional direct effects identified that discrimination led to ideation only for individuals with low support from friends or a significant other but not for those with moderate or high support. CONCLUSIONS Helping trans individuals cope with harassment and rejection, particularly by drawing on social support, may promote better mental health, which could help reduce suicidality in this population. PMID:29904324
The buffering role of social support on the associations among discrimination, mental health, and suicidality in a transgender sample.

PubMed

Trujillo, Michael A; Perrin, Paul B; Sutter, Megan; Tabaac, Ariella; Benotsch, Eric G

2017-01-01

Per the minority stress framework, trans individuals often experience psychological distress given the unique stress engendered by gender identity-related discrimination. Prior research has identified social support as particularly important for psychological distress and has suggested that social support may moderate this relationship. AIMS: The purpose of the current study was to explore the patterns of connections among discrimination, mental health, and suicidal ideation in trans individuals, and whether social support moderates these relationships. Participants ( N = 78) completed measures of these constructs as part of a national online survey. A series of simultaneous multiple regressions found that harassment/rejection discrimination was a unique positive predictor of mental health symptoms and suicidal ideation, with depression positively predicting suicidal ideation. A mediational model indicated that the association between harassment/rejection discrimination and suicidal ideation was fully mediated by depression. Three moderated meditational models were run, and one yielded a significant interaction, such that discrimination predicted suicidal ideation most strongly when participants had low social support from a significant other in comparison to moderate or high support. Further, conditional direct effects identified that discrimination led to ideation only for individuals with low support from friends or a significant other but not for those with moderate or high support. Helping trans individuals cope with harassment and rejection, particularly by drawing on social support, may promote better mental health, which could help reduce suicidality in this population.
Update on the Management of High-Risk Penetrating Keratoplasty

PubMed Central

Jabbehdari, Sayena; Rafii, Alireza Baradaran; Yazdanpanah, Ghasem; Hamrah, Pedram; Holland, Edward J.; Djalilian, Ali R

2017-01-01

Purpose of review In this article, we review the indications and latest management of high-risk penetrating keratoplasty. Recent findings Despite the immune-privilege status of the cornea, immune-mediated graft rejection still remains the leading cause of corneal graft failure. This is particularly a problem in the high-risk graft recipients, namely patients with previous graft failure due to rejection and those with inflamed and vascularized corneal beds. A number of strategies including both local and systemic immunosuppression are currently used to increase the success rate of high-risk corneal grafts. Moreover, in cases of limbal stem cell deficiency, limbal stem cells transplantation is employed. Summary Corticosteroids are still the top medication for prevention and treatment in cases of corneal graft rejection. Single and combined administration of immunosuppressive agents e.g. tacrolimus, cyclosporine and mycophenolate are promising adjunctive therapies for prolonging graft survival. In the future, cellular and molecular therapies should allow us to achieve immunologic tolerance even in high-risk grafts. PMID:28959505
Identification of Regulatory T Cells in Tolerated Allografts

PubMed Central

Graca, Luis; Cobbold, Stephen P.; Waldmann, Herman

2002-01-01

Induction of transplantation tolerance with certain therapeutic nondepleting monoclonal antibodies can lead to a robust state of peripheral “dominant” tolerance. Regulatory CD4+ T cells, which mediate this form of “dominant” tolerance, can be isolated from spleens of tolerant animals. To determine whether there were any extra-lymphoid sites that might harbor regulatory T cells we sought their presence in tolerated skin allografts and in normal skin. When tolerated skin grafts are retransplanted onto T cell–depleted hosts, graft-infiltrating T cells exit the graft and recolonize the new host. These colonizing T cells can be shown to contain members with regulatory function, as they can prevent nontolerant lymphocytes from rejecting fresh skin allografts, without hindrance of rejection of third party skin. Our results suggest that T cell suppression of graft rejection is an active process that operates beyond secondary lymphoid tissue, and involves the persistent presence of regulatory T cells at the site of the tolerated transplant. PMID:12070291
Local immunomodulation with Fas ligand-engineered biomaterials achieves allogeneic islet graft acceptance.

PubMed

Headen, Devon M; Woodward, Kyle B; Coronel, María M; Shrestha, Pradeep; Weaver, Jessica D; Zhao, Hong; Tan, Min; Hunckler, Michael D; Bowen, William S; Johnson, Christopher T; Shea, Lonnie; Yolcu, Esma S; García, Andrés J; Shirwan, Haval

2018-06-04

Islet transplantation is a promising therapy for type 1 diabetes. However, chronic immunosuppression to control rejection of allogeneic islets induces morbidities and impairs islet function. T effector cells are responsible for islet allograft rejection and express Fas death receptors following activation, becoming sensitive to Fas-mediated apoptosis. Here, we report that localized immunomodulation using microgels presenting an apoptotic form of the Fas ligand with streptavidin (SA-FasL) results in prolonged survival of allogeneic islet grafts in diabetic mice. A short course of rapamycin treatment boosted the immunomodulatory efficacy of SA-FasL microgels, resulting in acceptance and function of allografts over 200 days. Survivors generated normal systemic responses to donor antigens, implying immune privilege of the graft, and had increased CD4 + CD25 + FoxP3 + T regulatory cells in the graft and draining lymph nodes. Deletion of T regulatory cells resulted in acute rejection of established islet allografts. This localized immunomodulatory biomaterial-enabled approach may provide an alternative to chronic immunosuppression for clinical islet transplantation.
Swing-leg trajectory of running guinea fowl suggests task-level priority of force regulation rather than disturbance rejection.

PubMed

Blum, Yvonne; Vejdani, Hamid R; Birn-Jeffery, Aleksandra V; Hubicki, Christian M; Hurst, Jonathan W; Daley, Monica A

2014-01-01

To achieve robust and stable legged locomotion in uneven terrain, animals must effectively coordinate limb swing and stance phases, which involve distinct yet coupled dynamics. Recent theoretical studies have highlighted the critical influence of swing-leg trajectory on stability, disturbance rejection, leg loading and economy of walking and running. Yet, simulations suggest that not all these factors can be simultaneously optimized. A potential trade-off arises between the optimal swing-leg trajectory for disturbance rejection (to maintain steady gait) versus regulation of leg loading (for injury avoidance and economy). Here we investigate how running guinea fowl manage this potential trade-off by comparing experimental data to predictions of hypothesis-based simulations of running over a terrain drop perturbation. We use a simple model to predict swing-leg trajectory and running dynamics. In simulations, we generate optimized swing-leg trajectories based upon specific hypotheses for task-level control priorities. We optimized swing trajectories to achieve i) constant peak force, ii) constant axial impulse, or iii) perfect disturbance rejection (steady gait) in the stance following a terrain drop. We compare simulation predictions to experimental data on guinea fowl running over a visible step down. Swing and stance dynamics of running guinea fowl closely match simulations optimized to regulate leg loading (priorities i and ii), and do not match the simulations optimized for disturbance rejection (priority iii). The simulations reinforce previous findings that swing-leg trajectory targeting disturbance rejection demands large increases in stance leg force following a terrain drop. Guinea fowl negotiate a downward step using unsteady dynamics with forward acceleration, and recover to steady gait in subsequent steps. Our results suggest that guinea fowl use swing-leg trajectory consistent with priority for load regulation, and not for steadiness of gait. Swing-leg trajectory optimized for load regulation may facilitate economy and injury avoidance in uneven terrain.
Swing-Leg Trajectory of Running Guinea Fowl Suggests Task-Level Priority of Force Regulation Rather than Disturbance Rejection

PubMed Central

Blum, Yvonne; Vejdani, Hamid R.; Birn-Jeffery, Aleksandra V.; Hubicki, Christian M.; Hurst, Jonathan W.; Daley, Monica A.

2014-01-01

To achieve robust and stable legged locomotion in uneven terrain, animals must effectively coordinate limb swing and stance phases, which involve distinct yet coupled dynamics. Recent theoretical studies have highlighted the critical influence of swing-leg trajectory on stability, disturbance rejection, leg loading and economy of walking and running. Yet, simulations suggest that not all these factors can be simultaneously optimized. A potential trade-off arises between the optimal swing-leg trajectory for disturbance rejection (to maintain steady gait) versus regulation of leg loading (for injury avoidance and economy). Here we investigate how running guinea fowl manage this potential trade-off by comparing experimental data to predictions of hypothesis-based simulations of running over a terrain drop perturbation. We use a simple model to predict swing-leg trajectory and running dynamics. In simulations, we generate optimized swing-leg trajectories based upon specific hypotheses for task-level control priorities. We optimized swing trajectories to achieve i) constant peak force, ii) constant axial impulse, or iii) perfect disturbance rejection (steady gait) in the stance following a terrain drop. We compare simulation predictions to experimental data on guinea fowl running over a visible step down. Swing and stance dynamics of running guinea fowl closely match simulations optimized to regulate leg loading (priorities i and ii), and do not match the simulations optimized for disturbance rejection (priority iii). The simulations reinforce previous findings that swing-leg trajectory targeting disturbance rejection demands large increases in stance leg force following a terrain drop. Guinea fowl negotiate a downward step using unsteady dynamics with forward acceleration, and recover to steady gait in subsequent steps. Our results suggest that guinea fowl use swing-leg trajectory consistent with priority for load regulation, and not for steadiness of gait. Swing-leg trajectory optimized for load regulation may facilitate economy and injury avoidance in uneven terrain. PMID:24979750
Peroxisome Proliferator-Activated Receptor γ Deficiency in T Cells Accelerates Chronic Rejection by Influencing the Differentiation of CD4+ T Cells and Alternatively Activated Macrophages

PubMed Central

Ye, Ping; Cheng, Chao; Wu, Jie; Wang, Sihua; Sun, Yuan; Liu, Zheng; Xie, Aini; Xia, Jiahong

2014-01-01

Background In a previous study, activation of the peroxisome proliferator–activated receptor γ (PPARγ) inhibited chronic cardiac rejection. However, because of the complexity of chronic rejection and the fact that PPARγ is widely expressed in immune cells, the mechanism of the PPARγ - induced protective effect was unclear. Materials and Methods A chronic rejection model was established using B6.C-H-2bm12KhEg (H-2bm12) mice as donors, and MHC II-mismatched T-cell-specific PPARγ knockout mice or wild type (WT) littermates as recipients. The allograft lesion was assessed by histology and immunohistochemistry. T cells infiltrates in the allograft were isolated, and cytokines and subpopulations were detected using cytokine arrays and flow cytometry. Transcription levels in the allograft were measured by RT-PCR. In vitro, the T cell subset differentiation was investigated after culture in various polarizing conditions. PPARγ-deficient regularory T cells (Treg) were cocultured with monocytes to test their ability to induce alternatively activated macrophages (AAM). Results T cell-specific PPARγ knockout recipients displayed reduced cardiac allograft survival and an increased degree of pathology compared with WT littermates. T cell-specific PPARγ knockout resulted in more CD4+ T cells infiltrating into the allograft and altered the Th1/Th2 and Th17/Treg ratios. The polarization of AAM was also reduced by PPARγ deficiency in T cells through the action of Th2 and Treg. PPARγ-deficient T cells eliminated the pioglitazone-induced polarization of AAM and reduced allograft survival. Conclusions PPARγ-deficient T cells influenced the T cell subset and AAM polarization in chronic allograft rejection. The mechanism of PPARγ activation in transplantation tolerance could yield a novel treatment without side effects. PMID:25383620
Temperamental, Parental, and Contextual Contributors to Early-Emerging Internalizing Problems: A New Integrative Analysis Approach

ERIC Educational Resources Information Center

Mills, Rosemary S. L.; Hastings, Paul D.; Helm, Jonathan; Serbin, Lisa A.; Etezadi, Jamshid; Stack, Dale M.; Schwartzman, Alex E.; Li, Hai Hong

2012-01-01

This study evaluated a comprehensive model of factors associated with internalizing problems (IP) in early childhood, hypothesizing direct, mediated, and moderated pathways linking child temperamental inhibition, maternal overcontrol and rejection, and contextual stressors to IP. In a novel approach, three samples were integrated to form a large…
The moderating effect of the need to belong and classroom composition on belongingness seeking of minority adolescents.

PubMed

Kuo, Fu Wen; Yang, Shu Ching

2017-12-01

This study aimed to elucidate whether the interaction of classroom composition and the need to belong influences belongingness seeking and, if so, to investigate how upward comparison mediates the effects. The analyses were conducted with a cross-sectional sample of 383 Taiwanese aboriginal adolescents (39.7% male) recruited from schools with mixed-sex/ethnicity (n = 113), single-sex (n = 122), and minority-only (n = 148) classrooms. After controlling for socioeconomic status, the moderation analyses indicated that participants with a chronic need to belong in classes with diversity (mixed sex/ethnicity) perceived higher social acceptance, while those with a chronic need to belong in homogeneous classes (single-sex and minority-only) reported greater feelings of rejection. Upward comparison for differentiation was found to influence the indirect effects of the need to belong on feelings of rejection and depression in single-sex and minority-only classes. In particular, the mediating effect of upward comparison was stronger in minority-only classes. Copyright © 2017 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.
The Long-Term Effectiveness of the Family Check-up on Peer Preference: Parent-Child Interaction and Child Effortful Control as Sequential Mediators.

PubMed

Chang, Hyein; Shaw, Daniel S; Shelleby, Elizabeth C; Dishion, Thomas J; Wilson, Melvin N

2017-05-01

We examined the longitudinal effects of the Family Check-Up (FCU) intervention beginning in toddlerhood on children's peer preference at school-age. Specifically, a sequential mediational model was proposed in which the FCU was hypothesized to promote peer preference (i.e., higher acceptance and lower rejection by peers) in middle childhood through its positive effects on parent-child interaction and child effortful control in early childhood. Participants were 731 low-income families (49 % female). Qualities of parent-child interaction were observed during structured activities at 2 to 5 years, child effortful control was assessed using behavioral tasks at 5 years, and peer acceptance and rejection were rated by teachers at 7.5 to 10.5 years. Results indicated that the FCU indirectly predicted peer preference by sequentially improving parent-child interaction and child effortful control. The findings are discussed with respect to implications for understanding mechanisms by which early parenting-focused programs may enhance child functioning across time and context.
The Long-Term Effectiveness of the Family Check-up on Peer Preference: Parent-Child Interaction and Child Effortful Control as Sequential Mediators

PubMed Central

Shaw, Daniel S.; Shelleby, Elizabeth C.; Dishion, Thomas J.; Wilson, Melvin N.

2018-01-01

We examined the longitudinal effects of the Family Check-Up (FCU) intervention beginning in toddlerhood on children’s peer preference at school-age. Specifically, a sequential mediational model was proposed in which the FCU was hypothesized to promote peer preference (i.e., higher acceptance and lower rejection by peers) in middle childhood through its positive effects on parent-child interaction and child effortful control in early childhood. Participants were 731 low-income families (49 % female). Qualities of parent-child interaction were observed during structured activities at 2 to 5 years, child effortful control was assessed using behavioral tasks at 5 years, and peer acceptance and rejection were rated by teachers at 7.5 to 10.5 years. Results indicated that the FCU indirectly predicted peer preference by sequentially improving parent-child interaction and child effortful control. The findings are discussed with respect to implications for understanding mechanisms by which early parenting-focused programs may enhance child functioning across time and context. PMID:27558394
Thermal Stability of Acetohydroxamic Acid/Nitric Acid Solutions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rudisill, T.S.

2002-03-13

The transmutation of transuranic actinides and long-lived fission products in spent commercial nuclear reactor fuel has been proposed as one element of the Advanced Accelerator Applications Program. Preparation of targets for irradiation in an accelerator-driven subcritical reactor would involve dissolution of the fuel and separation of uranium, technetium, and iodine from the transuranic actinides and other fission products. The UREX solvent extraction process is being developed to reject and isolate the transuranic actinides in the acid waste stream by scrubbing with acetohydroxamic acid (AHA). To ensure that a runaway reaction will not occur between nitric acid and AHA, an analoguemore » of hydroxyl amine, thermal stability tests were performed to identify if any processing conditions could lead to a runaway reaction.« less
The Relationship of the Severity and Category of Acute Rejection With Intimal Arteritis Defined in Banff Classification to Clinical Outcomes.

PubMed

Wu, Kaiyin; Budde, Klemens; Schmidt, Danilo; Neumayer, Hans-Helmut; Rudolph, Birgit

2015-08-01

It is unclear if the category of acute rejection with intimal arteritis (ARV) is relevant to short- and long-term clinical outcomes and if the graft outcomes are affected by the severity of intimal arteritis. One hundred forty-eight ARV episodes were reviewed and categorized according to the 2013 Banff criteria of AMR: T cell-mediated rejection with intimal arteritis (v) lesion (TCMRV; n = 78), total antibody-mediated rejection with v lesion (AMRV), which were further divided into suspicious AMRV (n = 37) and AMRV (n = 33). The Banff scores of intimal arteritis (v1, v2 and v3) represented low, moderate, and high ARV severity. The grafts with TCMRV, suspicious AMRV (sAMRV), and AMRV showed similar responses to antirejection therapy, whereas the grafts with v2- or v3-ARV responded significantly poorer compared to those with v1-ARV. The 8-year death-censored graft survival (DCGS) rate was 56.8% of TCMRV versus 34.1% of total AMRV (Log rank, P = 0.03), but the 1- and 5-year DCGS rates were comparable between the 2 groups; moreover, the 1-, 5-, and 8-year DCGS rates of v1-ARV were evidently higher than v2- and v3-ARV (each pairwise comparison to v1-AVR yields P < 0.01); in contrast, the DCGS rates were similar between sAMRV and AMRV. The existing donor-specific antibodies or moderate microvascular inflammation or C4d-positive staining or intensive tubulointerstitial inflammation played a less significant role on the long-term graft survival. Compared to the category, the ARV severity is more closely associated with the initial response to antirejection therapy and long-term graft failure. The sAMRV and AMRV might represent a spectrum of the same disorder.

Rejection sensitivity as a vulnerability marker for depressive symptom deterioration in men

PubMed Central

Lugo, Ricardo G.; Witthöft, Michael; Sütterlin, Stefan; Pawelzik, Markus R.; Vögele, Claus

2017-01-01

Consistent across time and cultures, men and male adolescents older than 14 years of age appear underrepresented in mood disorders, and are far less likely than women to seek psychological help. The much higher rate of suicide amongst males suggests that depression in men might be underreported. One of the core human motives is to seek acceptance by others and avoid rejection. Rejection Sensitivity (RS) has been conceptualized as the cognitive-affective processing disposition to anxiously expect, readily perceive, and intensely respond to cues of rejection in the behavior of others. RS has been previously linked with the onset and course of depression, but—as yet—has not been investigated longitudinally in a clinical population. We investigated the predictive role of RS to symptom deterioration 6 months after end-of- treatment in 72 male inpatients with depressive spectrum disorder. The BDI was administered at intake, end-of-treatment and 6 month follow-up. RS scores were obtained at intake. Rejection Sensitivity had additional predictive power on BDI scores at 6 months follow-up controlling for BDI scores at end-of-treatment (ΔR2 = .095). The results are discussed in terms of the importance of targeting RS during treatment, and highlight the fact that therapeutic follow-up care is paramount. Future research should investigate possible mediators of the RS–relapse-to-depression association, such as self-blame, rumination, neuroticism, pessimism, emotion dysregulation, and low self-esteem. PMID:29049292
Soluble CD30 in patients with antibody-mediated rejection of the kidney allograft.

PubMed

Slavcev, Antonij; Honsova, Eva; Lodererova, Alena; Pavlova, Yelena; Sajdlova, Helena; Vitko, Stefan; Skibova, Jelena; Striz, Ilja; Viklicky, Ondrej

2007-07-01

The aim of our retrospective study was to evaluate the clinical significance of measurement of the soluble CD30 (sCD30) molecule for the prediction of antibody-mediated (humoral) rejection (HR). Sixty-two kidney transplant recipients (thirty-one C4d-positive and thirty-one C4d-negative patients) were included into the study. Soluble CD30 levels were evaluated before transplantation and during periods of graft function deterioration. The median concentrations of the sCD30 molecule were identical in C4d-positive and C4d-negative patients before and after transplantation (65.5 vs. 65.0 and 28.2 vs. 36.0 U/ml, respectively). C4d+ patients who developed DSA de novo had a tendency to have higher sCD30 levels before transplantation (80.7+/-53.6 U/ml, n=8) compared with C4d-negative patients (65.0+/-33.4 U/ml, n=15). Soluble CD30 levels were evaluated as positive and negative (>or=100 U/ml and <100 U/ml respectively) and the sensitivity, specificity and accuracy of sCD30 estimation with regard to finding C4d deposits in peritubular capillaries were determined. The sensitivity of sCD30+ testing was generally below 40%, while the specificity of the test, i.e. the likelihood that if sCD30 testing is negative, C4d deposits would be absent, was 82%. C4d+ patients who developed DSA de novo were evaluated separately; the specificity of sCD30 testing for the incidence of HR in this cohort was 86%. We could not confirm in our study that high sCD30 levels (>or=100 U/ml) might be predictive for the incidence of HR. Negative sCD30 values might be however helpful for identifying patients with a low risk for development of DSA and antibody-mediated rejection.
HLA class I antibodies trigger increased adherence of monocytes to endothelial cells by eliciting an increase in endothelial P-selectin and, depending on subclass, by engaging FcγRs1

PubMed Central

Valenzuela, Nicole M; Mulder, Arend; Reed, Elaine F

2013-01-01

Antibody-mediated rejection of solid organ transplants is characterized by intragraft macrophages. It is incompletely understood how donor specific antibody binding to graft endothelium promotes monocyte adhesion, and what, if any, contribution is made by the Fc region of the antibody. We investigated the mechanisms underlying monocyte recruitment by HLA class I antibody-activated endothelium. We used a panel of murine monoclonal antibodies of different subclasses to crosslink HLA I on human aortic, venous and microvascular endothelial cells, and measured the binding of human monocytic cell lines and peripheral blood monocytes. Both anti-HLA I murine IgG1 and mIgG2a induced endothelial P-selectin, which was required for monocyte adhesion to endothelium irrespective of subclass. Mouse IgG2a but not mIgG1 could bind human FcγRs. Accordingly, HLA I mIgG2a but not mIgG1 treatment of endothelial cells significantly augmented recruitment, predominantly through FcγRI, and, to a lesser extent, FcγRIIa. Moreover, HLA I mIgG2a promoted firm adhesion of monocytes to ICAM-1 through Mac-1, which may explain the prominence of monocytes during antibody mediated rejection. We confirmed these observations using human HLA allele specific monoclonal antibodies and IgG purified from transplant patient sera. HLA I antibodies universally elicit endothelial exocytosis leading to monocyte adherence, implying that P-selectin is a putative therapeutic target to prevent macrophage infiltration during antibody-mediated rejection. Importantly, the subclass of donor specific antibody may influence its pathogenesis. These results imply that hIgG1 and hIgG3 should have a greater capacity to trigger monocyte infiltration into the graft than IgG2 or IgG4 due to enhancement by FcγR interactions. PMID:23690477
A Critical Role for the TLR4/TRIF Pathway in Allogeneic Hematopoietic Cell Rejection by Innate Immune Cells

PubMed Central

Xu, Hong; Yan, Jun; Zhu, Ziqiang; Hussain, Lala-Rukh; Huang, Yiming; Ding, Chuanlin; Bozulic, Larry D.; Wen, Yujie; Ildstad, Suzanne T.

2013-01-01

We show for the first time that signaling through the TLR4/TRIF pathway plays a critical role in allogeneic bone marrow cell (BMC) rejection. This appears to be unique to BMC as organ allografts are rejected mainly via MyD88 signaling. Using T or T/B cell-deficient mice, we found that BMC allorejection occurred early before T cell activation and was T and B cell-independent, suggesting an effector role for innate immune cells in BMC rejection. We further demonstrated the innate immune signaling in BMC allorejection by showing superior engraftment in mice deficient in TRIF or TLR4 but not MyD88 or TLR3. The restored cytotoxicity in TRIF deficient recipients transferred with wildtype F4/80+ or NK1.1+ cells suggests TRIF signaling dependence on macrophages or NK cells in early BMC rejection. Production of the proinflammatory cytokine IL-6 and TRIF relevant chemokine MCP-1 was significantly increased early after bone marrow transplantation. In vivo specific depletion of macrophages or NK innate immune cells in combination with anti-CD154/rapamycin resulted in additive-enhanced allogeneic engraftment. The requirement for irradiation was completely eliminated when both macrophages and NK cells were depleted in combination with anti-CD154/rapamycin to target T and B cells, supporting the hypothesis that two barriers involving innate and adaptive immunity exist in mediating rejection of allogeneic BMC. In summary, our results clearly demonstrate a previously unappreciated role for innate immunity in BMC allorejection via signaling through a unique MyD88-independent TLR4/TRIF mechanism. These findings may have direct clinical impact on strategies for conditioning recipients for stem cell transplantation. PMID:23146386
The influence of structural stigma and rejection sensitivity on young sexual minority men's daily tobacco and alcohol use

PubMed Central

Pachankis, John E.; Hatzenbuehler, Mark L.; Starks, Tyrel J.

2018-01-01

Stigma occurs at both individual and structural levels, but existing research tends to examine the effect of individual and structural forms of stigma in isolation, rather than considering potential synergistic effects. To address this gap, our study examined whether stigma at the individual level, namely gay-related rejection sensitivity, interacts with structural stigma to predict substance use among young sexual minority men. Sexual minority (n = 119) participants completed online measures of our constructs (e.g., rejection sensitivity). Participants currently resided across a broad array of geographic areas (i.e., 24 U.S. states), and had attended high school in 28 states, allowing us to capture sufficient variance in current and past forms of structural stigma, defined as (1) a lack of state-level policies providing equal opportunities for heterosexual and sexual minority individuals and (2) negative state-aggregated attitudes toward sexual minorities. To measure daily substance use, we utilized a daily diary approach, whereby all participants were asked to indicate whether they used tobacco or alcohol on nine consecutive days. Results indicated that structural stigma interacted with rejection sensitivity to predict tobacco and alcohol use, and that this relationship depended on the developmental timing of exposure to structural stigma. In contrast, rejection sensitivity did not mediate the relationship between structural stigma and substance use. These results suggest that psychological predispositions, such as rejection sensitivity, interact with features of the social environment, such as structural stigma, to predict important health behaviors among young sexual minority men. These results add to a growing body of research documenting the multiple levels through which stigma interacts to produce negative health outcomes among sexual minority individuals. PMID:24507912
The evolution of cosmic-ray-mediated magnetohydrodynamic shocks: A two-fluid approach

NASA Astrophysics Data System (ADS)

Jun, Byung-Il; Clarke, David A.; Norman, Michael L.

1994-07-01

We study the shock structure and acceleration efficiency of cosmic-ray mediated Magnetohydrodynamic (MHD) shocks both analytically and numerically by using a two-fluid model. Our model includes the dynamical effect of magnetic fields and cosmic rays on a background thermal fluid. The steady state solution is derived by following the technique of Drury & Voelk (1981) and compared to numerical results. We explore the time evolution of plane-perpendicular, piston-driven shocks. From the results of analytical and numerical studies, we conclude that the mean magnetic field plays an important role in the structure and acceleration efficiency of cosmic-ray mediated MHD shocks. The acceleration of cosmic-ray particles becomes less efficient in the presence of strong magnetic pressure since the field makes the shock less compressive. This feature is more prominent at low Mach numbers than at high Mach numbers.
The evolution of cosmic-ray-mediated magnetohydrodynamic shocks: A two-fluid approach

NASA Technical Reports Server (NTRS)

Jun, Byung-Il; Clarke, David A.; Norman, Michael L.

1994-01-01

We study the shock structure and acceleration efficiency of cosmic-ray mediated Magnetohydrodynamic (MHD) shocks both analytically and numerically by using a two-fluid model. Our model includes the dynamical effect of magnetic fields and cosmic rays on a background thermal fluid. The steady state solution is derived by following the technique of Drury & Voelk (1981) and compared to numerical results. We explore the time evolution of plane-perpendicular, piston-driven shocks. From the results of analytical and numerical studies, we conclude that the mean magnetic field plays an important role in the structure and acceleration efficiency of cosmic-ray mediated MHD shocks. The acceleration of cosmic-ray particles becomes less efficient in the presence of strong magnetic pressure since the field makes the shock less compressive. This feature is more prominent at low Mach numbers than at high Mach numbers.
High pretransplantation soluble CD30 levels: impact in renal transplantation.

PubMed

Giannoli, C; Bonnet, M C; Perrat, G; Houillon, A; Reydet, S; Pouteil-Noble, C; Villar, E; Lefrançois, N; Morelon, E; Dubois, V

2007-10-01

In a retrospective study, the impact of the level of pretransplantation soluble CD30 molecule (sCD30) was evaluated on 3 year transplant survival, as well as the number and grade of acute rejection episodes among kidney recipients engrafted between 2000 and 2002. One hundred and ninety sera of 190 patients sampled on the cross-match day were tested for sCD30 concentrations using an enzyme-linked immunosorbent assay (ELISA) kit (Biotest). For the analysis, a sCD30 cutoff level of 100 U/mL was chosen: 87 (46%) recipients had a level >100, and 103 (54%) <100. All cases (5) of immunological graft loss showed a high sCD30 level. The rate of biopsy-proven acute rejection was 26% in the sCD30 >100 group versus 22% in the sCD30 <100 groups. Among the first graft population (n = 157), the rate was 27% for sCD30 >100 versus 20% for the lower level. The difference was more important for grade II acute rejection (Banff criteria): 6/87 (7%) showed high sCD30 versus 2/103 (2%) with sCD30 <100. This analysis became significant for anti-HLA immunization: 11 (13%) recipients developed anti-HLA class II antibodies in the first group (sCD30 >100) versus 1 (1%) in the second group (sCD30 <100; P < .01). A high pretransplantation sCD30 was not a significant risk factor for an acute rejection episode, but it seemed to be more predictive for antibody-mediated acute rejection and immunological graft loss. However, many recipients showed an increased pretransplantation concentration without any rejection episode or graft loss. Consequently, sCD30 pregraft measurements cannot be used as a predictor for acute kidney rejection among our transplant center, nor as an aid to adapt the immunosuppressive regimen.
Low Immunogenic Endothelial Cells Maintain Morphological and Functional Properties Required for Vascular Tissue Engineering.

PubMed

Lau, Skadi; Eicke, Dorothee; Carvalho Oliveira, Marco; Wiegmann, Bettina; Schrimpf, Claudia; Haverich, Axel; Blasczyk, Rainer; Wilhelmi, Mathias; Figueiredo, Constança; Böer, Ulrike

2018-03-01

The limited availability of native vessels suitable for the application as hemodialysis shunts or bypass material demands new strategies in cardiovascular surgery. Tissue-engineered vascular grafts containing autologous cells are considered ideal vessel replacements due to the low risk of rejection. However, endothelial cells (EC), which are central components of natural blood vessels, are difficult to obtain from elderly patients of poor health. Umbilical cord blood represents a promising alternative source for EC, but their allogeneic origin corresponds with the risk of rejection after allotransplantation. To reduce this risk, the human leukocyte antigen class I (HLA I) complex was stably silenced by lentiviral vector-mediated RNA interference (RNAi) in EC from peripheral blood and umbilical cord blood and vein. EC from all three sources were transduced by 93.1% ± 4.8% and effectively, HLA I-silenced by up to 67% compared to nontransduced (NT) cells or transduced with a nonspecific short hairpin RNA, respectively. Silenced EC remained capable to express characteristic endothelial surface markers such as CD31 and vascular endothelial cadherin important for constructing a tight barrier, as well as von Willebrand factor and endothelial nitric oxide synthase important for blood coagulation and vessel tone regulation. Moreover, HLA I-silenced EC were still able to align under unidirectional flow, to take up acetylated low-density lipoprotein, and to form capillary-like tube structures in three-dimensional fibrin gels similar to NT cells. In particular, addition of adipose tissue-derived mesenchymal stem cells significantly improved tube formation capability of HLA I-silenced EC toward long and widely branched vascular networks necessary for prevascularizing vascular grafts. Thus, silencing HLA I by RNAi represents a promising technique to reduce the immunogenic potential of EC from three different sources without interfering with EC-specific morphological and functional properties required for vascular tissue engineering. This extends the spectrum of available cell sources from autologous to allogeneic sources, thereby accelerating the generation of tissue-engineered vascular grafts in acute clinical cases.
CD4 cells can be more efficient at tumor rejection than CD8 cells.

PubMed

Perez-Diez, Ainhoa; Joncker, Nathalie T; Choi, Kyungho; Chan, William F N; Anderson, Colin C; Lantz, Olivier; Matzinger, Polly

2007-06-15

Researchers designing antitumor treatments have long focused on eliciting tumor-specific CD8 cytotoxic T lymphocytes (CTL) because of their potent killing activity and their ability to reject transplanted organs. The resulting treatments, however, have generally been surprisingly poor at inducing complete tumor rejection, both in experimental models and in the clinic. Although a few scattered studies suggested that CD4 T "helper" cells might also serve as antitumor effectors, they have generally been studied mostly for their ability to enhance the activity of CTL. In this mouse study, we compared monoclonal populations of tumor-specific CD4 and CD8 T cells as effectors against several different tumors, and found that CD4 T cells eliminated tumors that were resistant to CD8-mediated rejection, even in cases where the tumors expressed major histocompatibility complex (MHC) class I molecules but not MHC class II. MHC class II expression on host tissues was critical, suggesting that the CD4 T cells act indirectly. Indeed, the CD4 T cells partnered with NK cells to obtain the maximal antitumor effect. These findings suggest that CD4 T cells can be powerful antitumor effector cells that can, in some cases, outperform CD8 T cells, which are the current "gold standard" effector cell in tumor immunotherapy.
Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model

PubMed Central

Samy, KP; Anderson, DA; Lo, DJ; Mulvihill, MS; Song, M; Farris, AB; Parker, BS; MacDonald, AL; Lu, C; Springer, TA; Kachlany, SC; Reimann, KA; How, T; Leopardi, FV; Franke, KS; Williams, KD; Collins, BH; Kirk, AD

2016-01-01

Costimulation blockade (CoB) via belatacept is a lower morbidity alternative to calcineurin inhibitor (CNI)-based immunosuppression. However, it has higher rates of early acute rejection. These early rejections are mediated in part by memory T cells, which have reduced dependence on the pathway targeted by belatacept, and increased adhesion molecule expression. One such molecule is Leukocyte Function Associated Antigen (LFA)-1. LFA-1 exists in two forms, a commonly expressed, low-affinity form, and a transient, high-affinity form, expressed only during activation. We have shown that antibodies reactive with LFA-1 irrespective of its configuration are effective in eliminating memory T cells, but at the cost of impaired protective immunity. Here we test two novel agents, Leukotoxin A and AL-579, each of which targets the high affinity form of LFA-1, to determine whether this more precise targeting prevents belatacept-resistant rejection. Despite evidence of ex vivo and in vivo ligand-specific activity, neither agent when combined with belatacept proved superior to belatacept monotherapy. Leukotoxin A approached a ceiling of toxicity prior to efficacy, while AL-579 failed to significantly alter the peripheral immune response. These data, and prior studies, suggest that LFA-1 blockade may not be a suitable adjuvant agent for CoB resistant rejection. PMID:27888551
The Role of the Posterior Temporal and Medial Prefrontal Cortices in Mediating Learning from Romantic Interest and Rejection

PubMed Central

Cooper, Jeffrey C.; Dunne, Simon; Furey, Teresa; O'Doherty, John P.

2014-01-01

Romantic interest or rejection can be powerful incentives not merely for their emotional impact, but for their potential to transform, in a single interaction, what we think we know about another person—or ourselves. Little is known, though, about how the brain computes expectations for, and learns from, real-world romantic signals. In a novel “speed-dating” paradigm, we had participants meet potential romantic partners in a series of 5-min “dates,” and decide whether they would be interested in seeing each partner again. Afterward, participants were scanned with functional magnetic resonance imaging while they were told, for the first time, whether that partner was interested in them or rejected them. Expressions of interest and rejection activated regions previously associated with “mentalizing,” including the posterior superior temporal sulcus (pSTS) and rostromedial prefrontal cortex (RMPFC); while pSTS responded to differences from the participant's own decision, RMPFC responded to prediction errors from a reinforcement-learning model of personal desirability. Responses in affective regions were also highly sensitive to participants' expectations. Far from being inscrutable, then, responses to romantic expressions seem to involve a quantitative learning process, rooted in distinct sources of expectations, and encoded in neural networks that process both affective value and social beliefs. PMID:23599165
Scaffold-mediated BMP-2 minicircle DNA delivery accelerated bone repair in a mouse critical-size calvarial defect model.

PubMed

Keeney, Michael; Chung, Michael T; Zielins, Elizabeth R; Paik, Kevin J; McArdle, Adrian; Morrison, Shane D; Ransom, Ryan C; Barbhaiya, Namrata; Atashroo, David; Jacobson, Gunilla; Zare, Richard N; Longaker, Michael T; Wan, Derrick C; Yang, Fan

2016-08-01

Scaffold-mediated gene delivery holds great promise for tissue regeneration. However, previous attempts to induce bone regeneration using scaffold-mediated non-viral gene delivery rarely resulted in satisfactory healing. We report a novel platform with sustained release of minicircle DNA (MC) from PLGA scaffolds to accelerate bone repair. MC was encapsulated inside PLGA scaffolds using supercritical CO2 , which showed prolonged release of MC. Skull-derived osteoblasts transfected with BMP-2 MC in vitro result in higher osteocalcin gene expression and mineralized bone formation. When implanted in a critical-size mouse calvarial defect, scaffolds containing luciferase MC lead to robust in situ protein production up to at least 60 days. Scaffold-mediated BMP-2 MC delivery leads to substantially accelerated bone repair as early as two weeks, which continues to progress over 12 weeks. This platform represents an efficient, long-term nonviral gene delivery system, and may be applicable for enhancing repair of a broad range of tissues types. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2099-2107, 2016. © 2016 Wiley Periodicals, Inc.
Tumor immunology.

PubMed

Mocellin, Simone; Lise, Mario; Nitti, Donato

2007-01-01

Advances in tumor immunology are supporting the clinical implementation of several immunological approaches to cancer in the clinical setting. However, the alternate success of current immunotherapeutic regimens underscores the fact that the molecular mechanisms underlying immune-mediated tumor rejection are still poorly understood. Given the complexity of the immune system network and the multidimensionality of tumor/host interactions, the comprehension of tumor immunology might greatly benefit from high-throughput microarray analysis, which can portrait the molecular kinetics of immune response on a genome-wide scale, thus accelerating the discovery pace and ultimately catalyzing the development of new hypotheses in cell biology. Although in its infancy, the implementation of microarray technology in tumor immunology studies has already provided investigators with novel data and intriguing new hypotheses on the molecular cascade leading to an effective immune response against cancer. Although the general principles of microarray-based gene profiling have rapidly spread in the scientific community, the need for mastering this technique to produce meaningful data and correctly interpret the enormous output of information generated by this technology is critical and represents a tremendous challenge for investigators, as outlined in the first section of this book. In the present Chapter, we report on some of the most significant results obtained with the application of DNA microarray in this oncology field.
Endogenous Memory CD8 T Cells Are Activated Within Cardiac Allografts Without Mediating Rejection

PubMed Central

Setoguchi, Kiyoshi; Hattori, Yusuke; Iida, Shoichi; Baldwin, William M.; Fairchild, Robert L.

2013-01-01

Endogenous memory CD8 T cells infiltrate MHC-mismatched cardiac allografts within 12–24 hours post-transplant in mice and are activated to proliferate and produce IFN-γ. To more accurately assess the graft injury directly imposed by these endogenous memory CD8 T cells, we took advantage of the ability of anti-LFA-1 mAb given to allograft recipients on days 3 and 4 post-transplant to inhibit the generation of primary effector T cells. When compared to grafts from IgG treated recipients on day 7 post-transplant, allografts from anti-LFA-1 mAb treated recipients had increased numbers of CD8 T cells but these grafts had marked decreases in expression levels of mRNA encoding effector mediators associated with graft injury and decreases in donor-reactive CD8 T cells producing IFN-γ. Despite this decreased activity within the allograft, CD8 T cells in allografts from recipients treated with anti-LFA-1 mAb continued to proliferate up to day 7 post-transplant and did not upregulate expression of the exhaustion marker LAG-3 but did have decreased expression of ICOS. These results indicate that endogenous memory CD8 T cells infiltrate and proliferate in cardiac allografts in mice but do not express sufficient levels of functions to mediate overt graft injury and acute rejection. PMID:23914930
A search theory model of patch-to-patch forager movement with application to pollinator-mediated gene flow.

PubMed

Hoyle, Martin; Cresswell, James E

2007-09-07

We present a spatially implicit analytical model of forager movement, designed to address a simple scenario common in nature. We assume minimal depression of patch resources, and discrete foraging bouts, during which foragers fill to capacity. The model is particularly suitable for foragers that search systematically, foragers that deplete resources in a patch only incrementally, and for sit-and-wait foragers, where harvesting does not affect the rate of arrival of forage. Drawing on the theory of job search from microeconomics, we estimate the expected number of patches visited as a function of just two variables: the coefficient of variation of the rate of energy gain among patches, and the ratio of the expected time exploiting a randomly chosen patch and the expected time travelling between patches. We then consider the forager as a pollinator and apply our model to estimate gene flow. Under model assumptions, an upper bound for animal-mediated gene flow between natural plant populations is approximately proportional to the probability that the animal rejects a plant population. In addition, an upper bound for animal-mediated gene flow in any animal-pollinated agricultural crop from a genetically modified (GM) to a non-GM field is approximately proportional to the proportion of fields that are GM and the probability that the animal rejects a field.
Myristoylation of Src kinase mediates Src-induced and high-fat diet-accelerated prostate tumor progression in mice.

PubMed

Kim, Sungjin; Yang, Xiangkun; Li, Qianjin; Wu, Meng; Costyn, Leah; Beharry, Zanna; Bartlett, Michael G; Cai, Houjian

2017-11-10

Exogenous fatty acids provide substrates for energy production and biogenesis of the cytoplasmic membrane, but they also enhance cellular signaling during cancer cell proliferation. However, it remains controversial whether dietary fatty acids are correlated with tumor progression. In this study, we demonstrate that increased Src kinase activity is associated with high-fat diet-accelerated progression of prostate tumors and that Src kinases mediate this pathological process. Moreover, in the in vivo prostate regeneration assay, host SCID mice carrying Src(Y529F)-transduced regeneration tissues were fed a low-fat diet or a high-fat diet and treated with vehicle or dasatinib. The high-fat diet not only accelerated Src-induced prostate tumorigenesis in mice but also compromised the inhibitory effect of the anticancer drug dasatinib on Src kinase oncogenic potential in vivo We further show that myristoylation of Src kinase is essential to facilitate Src-induced and high-fat diet-accelerated tumor progression. Mechanistically, metabolism of exogenous myristic acid increased the biosynthesis of myristoyl CoA and myristoylated Src and promoted Src kinase-mediated oncogenic signaling in human cells. Of the fatty acids tested, only exogenous myristic acid contributed to increased intracellular myristoyl CoA levels. Our results suggest that targeting Src kinase myristoylation, which is required for Src kinase association at the cellular membrane, blocks dietary fat-accelerated tumorigenesis in vivo Our findings uncover the molecular basis of how the metabolism of myristic acid stimulates high-fat diet-mediated prostate tumor progression. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
Theater of Operations Construction in the Desert: A Handbook of Lessons Learned in the Middle East

DTIC Science & Technology

1981-01-01

dehydrates the desert environment. In addition, the wind always carries fine soil particles which abrade building elements, clog mechar:ical devices, and...lower salt rejection, and increased likelihood of scaling and membrane hydrolysis . Manufacturers recommend that feed stream flows not be lower than...undergo accelerated decomposition /aging when stored in high desert heat. This is complicated by the fa~t that many of the tests were designed to be
Measured performance of the GTA rf systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Denney, P.M.; Jachim, S.P.

1993-06-01

This paper describes the performance of the RF systems on the Ground Test Accelerator (GTA). The RF system architecture is briefly described. Among the RF performance results presented are RF field flatness and stability, amplitude and phase control resolution, and control system bandwidth and stability. The rejection by the RF systems of beam-induced disturbances, such as transients and noise, are analyzed. The observed responses are also compared to computer-based simulations of the RF systems for validation.
Measured performance of the GTA rf systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Denney, P.M.; Jachim, S.P.

1993-01-01

This paper describes the performance of the RF systems on the Ground Test Accelerator (GTA). The RF system architecture is briefly described. Among the RF performance results presented are RF field flatness and stability, amplitude and phase control resolution, and control system bandwidth and stability. The rejection by the RF systems of beam-induced disturbances, such as transients and noise, are analyzed. The observed responses are also compared to computer-based simulations of the RF systems for validation.

Multiscale implementation of infinite-swap replica exchange molecular dynamics.

PubMed

Yu, Tang-Qing; Lu, Jianfeng; Abrams, Cameron F; Vanden-Eijnden, Eric

2016-10-18

Replica exchange molecular dynamics (REMD) is a popular method to accelerate conformational sampling of complex molecular systems. The idea is to run several replicas of the system in parallel at different temperatures that are swapped periodically. These swaps are typically attempted every few MD steps and accepted or rejected according to a Metropolis-Hastings criterion. This guarantees that the joint distribution of the composite system of replicas is the normalized sum of the symmetrized product of the canonical distributions of these replicas at the different temperatures. Here we propose a different implementation of REMD in which (i) the swaps obey a continuous-time Markov jump process implemented via Gillespie's stochastic simulation algorithm (SSA), which also samples exactly the aforementioned joint distribution and has the advantage of being rejection free, and (ii) this REMD-SSA is combined with the heterogeneous multiscale method to accelerate the rate of the swaps and reach the so-called infinite-swap limit that is known to optimize sampling efficiency. The method is easy to implement and can be trivially parallelized. Here we illustrate its accuracy and efficiency on the examples of alanine dipeptide in vacuum and C-terminal β-hairpin of protein G in explicit solvent. In this latter example, our results indicate that the landscape of the protein is a triple funnel with two folded structures and one misfolded structure that are stabilized by H-bonds.
Why Does Social Exclusion Hurt? The Relationship Between Social and Physical Pain

ERIC Educational Resources Information Center

MacDonald, Geoff; Leary, Mark R.

2005-01-01

The authors forward the hypothesis that social exclusion is experienced as painful because reactions to rejection are mediated by aspects of the physical pain system. The authors begin by presenting the theory that overlap between social and physical pain was an evolutionary development to aid social animals in responding to threats to inclusion.…
Cosmology and the Sinusoidal Potential

NASA Astrophysics Data System (ADS)

Bartlett, David F.

2006-06-01

The nature of dark matter (and dark energy) remains a mystery. An alternative is being explored by several scientists: changing Newton's (and Einstein's) field equations. The sinusoidal potential is the latest attempt[1]. Here the gravitational law is alternately attractive and repulsive:φ = -GM cos(kor)/r, where λo=2π/ko = 1/20 of the distance from the sun to the center of the Milky Way. The proposal accommodates several structural features of the Milky Way including, paradoxically, its spiral shape and flat rotation curve. The sinusoidal potential's unique feature is strong galactic tidal forces (dg/dr). These may explain why the new planetoid Sedna is securely between the Kuiper Belt and the Oort cloud and why distant comets are more influenced by galactic tides that are in the r, rather than the z-direction.At this meeting I discuss the consequences of the sinusoidal potential for cosmology. Here the alternation of attraction and repulsion gives (i) an open universe, and (ii) gravitational lensing which is usually weak, but occasionally very strong. An open universe is one that, asymptotically, has a size R which varies directly as time t. The open universe conflicts both with the old Einstein-deSitter model (R α t2/3} and the new accelerating one. The evidence for an accelerating universe decisively rejects the Einstein-deSitter model. The rejection of an open (or empty) universe is less secure. This rejection is influenced by the different ways the groups studying the brightness of supernovae use the HST. Surprising additional inputs include neutrino masses, the equivalence principle, LSB galaxies, and "over-luminous" Sn1a. I thank Mostafa Jon Dadras and Patrick Motl for early help and John Cumalat for continual support. [1] D.F. Bartlett, "Analogies between electricity and gravity", Metrologia 41, S115-S124 (2004).
The relationship between parenting attitudes, negative cognition, and the depressive symptoms according to gender in Korean adolescents.

PubMed

Park, Subin; Kim, Bung-Nyun; Park, Min-Hyeon

2016-01-01

Parenting style is one potential contributor to the development of adolescents' cognitions, self-esteem and emotional problems. This study examined the relationship between maternal parenting attitudes and adolescents' negative cognitions, and depressive symptoms according to gender. A total of 401 middle and high school students were recruited (i.e. 221 males and 180 females; mean age, 13.92 ± 1.31 years). The Maternal Behavior Research Instrument assessed maternal parenting attitudes. Analyses examined the relationship between parenting attitudes and affective symptoms, with self-esteem and negative automatic thoughts as mediators of these relations. Maternal rejecting attitudes were positively associated with depressive symptoms via increasing negative autonomic thoughts and decreasing self-esteem among female adolescents. Among male adolescents, maternal rejecting attitudes were associated with low self-esteem, but they were not associated with depressive symptoms. Maternal parenting has a larger impact on the emotional adjustment of females compared to males. Interventions to increase self-esteem and correct negative cognitions may be helpful for depressed female adolescents, specifically for those whose mothers are rejecting.
Implementation science: a reappraisal of our journal mission and scope.

PubMed

Foy, Robbie; Sales, Anne; Wensing, Michel; Aarons, Gregory A; Flottorp, Signe; Kent, Bridie; Michie, Susan; O'Connor, Denise; Rogers, Anne; Sevdalis, Nick; Straus, Sharon; Wilson, Paul

2015-04-17

The implementation of research findings into healthcare practice has become increasingly recognised as a major priority for researchers, service providers, research funders and policymakers over the past decade. Nine years after its establishment, Implementation Science, an international online open access journal, currently publishes over 150 articles each year. This is fewer than 30% of those submitted for publication. The majority of manuscript rejections occur at the point of initial editorial screening, frequently because we judge them to fall outside of journal scope. There are a number of common reasons as to why manuscripts are rejected on grounds of scope. Furthermore, as the field of implementation research has evolved and our journal submissions have risen, we have, out of necessity, had to become more selective in what we publish. We have also expanded our scope, particularly around patient-mediated and population health interventions, and will monitor the impact of such changes. We hope this editorial on our evolving priorities and common reasons for rejection without peer review will help authors to better judge the relevance of their papers to Implementation Science.
Peer and Teacher Effects on the Early Onset of Sexual Intercourse

PubMed Central

Brendgen, Mara; Wanner, Brigitte; Vitaro, Frank

2007-01-01

Objectives. We examined the links between peer rejection and verbal abuse by a teacher during childhood with the early onset of sexual intercourse and the mediating role of delinquent behavior and low self-esteem in this context. Methods. We assessed 312 students (159 girls) in northwestern Quebec annually from kindergarten through seventh grade. Peer identifications were used to assess peer rejection and verbal abuse by teachers from kindergarten through fourth grade. In seventh grade, self-reports were used to assess delinquent behavior, self-esteem, and having sexual intercourse. Multiple sources were used to assess control variables. Results. Multiple imputation-based linear and logistic regressions showed that peer rejection was indirectly associated with a higher risk of early intercourse by its link with lower self-esteem, but only for girls. Verbal abuse by teachers during childhood was directly associated with a higher risk of early sexual intercourse and indirectly by its link with delinquent behavior. Conclusions. The results underline the importance of both peers and teachers in healthy sexual development among youths, especially for girls, and emphasize the need for targeted health and sexual education programs. PMID:17901435
Titanium-Water Thermosyphon Gamma Radiation Exposure and Results

NASA Technical Reports Server (NTRS)

Sanzi, James, L.A; Jaworske, Donald, A.; Goodenow, Debra, A.

2012-01-01

Titanium-water thermosyphons are being considered for use in heat rejection systems for fission power systems. Their proximity to the nuclear reactor will result in some gamma irradiation. Noncondensable gas formation from radiation-induced breakdown of water over time may render portions of the thermosyphon condenser inoperable. A series of developmental thermosyphons were operated at nominal operating temperature under accelerated gamma irradiation, with exposures on the same order of magnitude as that expected in 8 years of heat rejection system operation. Temperature data were obtained during exposure at three locations on each thermosyphon: evaporator, condenser, and condenser end cap. Some noncondensable gas was evident; however, thermosyphon performance was not affected because the noncondensable gas was compressed into the fill tube region at the top of the thermosyphon, away from the heat rejecting fin. The trend appeared to be an increasing amount of noncondensable gas formation with increasing gamma irradiation dose. Hydrogen is thought to be the most likely candidate for the noncondensable gas and hydrogen is known to diffuse through grain boundaries. Post-exposure evaluation of one thermosyphon in a vacuum chamber and at temperature revealed that the noncondensable gas diffused out of the thermosyphon over a relatively short period of time. Further research shows a number of experimental and theoretical examples of radiolysis occurring through gamma radiation alone in pure water.
A joint resolution providing for congressional disapproval under chapter 8 of title 5, United States Code, of the rule submitted by the National Mediation Board relating to representation election procedures.

THOMAS, 111th Congress

Sen. Isakson, Johnny [R-GA

2010-05-11

Senate - 09/23/2010 Motion to proceed to consideration of measure rejected in Senate by Yea-Nay Vote. 43 - 56. Record Vote Number: 239. (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:
Recent Advances in Allograft Vasculopathy

PubMed Central

Merola, Jonathan; Jane-Wit, Daniel D.; Pober, Jordan S.

2017-01-01

Purpose of review Despite considerable advances in controlling acute rejection, the longevity of cardiac and renal allografts remains significantly limited by chronic rejection in the form of allograft vasculopathy (AV). This review discusses recently reported mechanistic insights of AV pathogenesis as well recent clinical evaluations of new therapeutic approaches. Recent findings Although adaptive immunity is the major driver of AV, natural killer cells mediate vasculopathic changes in a transplanted mouse heart following treatment with donor-specific antibody (DSA). However, NK cells may also dampen chronic inflammatory responses by killing donor-derived tissue-resident CD4 T cells that provide help to host B cells, the source of DSA. DSA may directly contribute to vascular inflammation by inducing intracellular signaling cascades that upregulate leukocyte adhesion molecules, facilitating recruitment of neutrophils and monocytes. DSA-mediated complement activation additionally enhances endothelial alloimmunogenicity through activation of non-canonical NF-κB signaling. New clinical studies evaluating mTOR and proteasome inhibitors to target these pathways have been reported. Summary AV is a pathology resultant from several innate and adaptive alloimmune responses. Mechanistic insights from preclinical studies have identified agents that are currently being investigated in clinical trials. PMID:27898462
Characteristics of Donor-Specific Antibodies Associated With Antibody-Mediated Rejection in Lung Transplantation

PubMed Central

Roux, Antoine; Bendib Le Lan, Ines; Holifanjaniaina, Sonia; Thomas, Kimberly A.; Picard, Clément; Grenet, Dominique; De Miranda, Sandra; Douvry, Benoit; Beaumont-Azuar, Laurence; Sage, Edouard; Devaquet, Jérôme; Cuquemelle, Elise; Le Guen, Morgan; Suberbielle, Caroline; Gautreau, Chantal; Stern, Marc; Rossetti, Maura; Hamid, Abdul Monem; Parquin, Francois

2017-01-01

Although donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) are frequently found in recipients after lung transplantation (LT), the characteristics of DSA which influence antibody-mediated rejection (AMR) in LT are not fully defined. We retrospectively analyzed 206 consecutive LT patients of our center (2010–2013). DSAs were detected by using luminex single antigen beads assay and mean fluorescence intensity was assessed. Within the study population, 105 patients had positive DSA. Patients with and without AMR (AMRPos, n = 22, and AMRNeg, n = 83, respectively) were compared. AMRPos patients had significantly greater frequencies of anti-HLA DQ DSA (DQ DSA) than AMRNeg patients (95 vs 58%, respectively, p < 0.0001). Compared to AMRNeg patients, AMRPos patients had higher DQ DSA sum MFI [7,332 (2,067–10,213) vs 681 (0–1,887), p < 0.0001]. DQ DSA when associated with AMR, had more frequent graft loss and chronic lung allograft dysfunction (CLAD). These data suggest (i) that DSA characteristics clearly differ between AMRPos and AMRNeg patients and (ii) the deleterious impact of DQ DSA on clinical outcome. PMID:29075627
Intravenous immunoglobulin in kidney transplantation.

PubMed

Tedla, Fasika M; Roche-Recinos, Andrea; Brar, Amarpali

2015-12-01

Antibody-mediated injury of renal allografts has assumed increasing importance with the availability of potent immunosuppressants directed against T-lymphocytes. Intravenous immunoglobulin (IVIG) has been used for prevention and treatment of antibody-mediated rejection. The review summarizes recent advances that shed light on mechanisms of action of IVIG and outlines current roles of IVIG in kidney transplantation. Observational studies support the use of IVIG for desensitization and treatment of acute rejection. Most studies are small and uncontrolled, but a matched case-control study reported a better survival with incompatible live-donor kidney transplant after desensitization using IVIG-containing regimens compared with dialysis or waiting for compatible transplant. Recent data indicate that variations in glycosylation and amino acid sequence cause the crystallizable fragment of immunoglobulin G to assume specific conformations that have high affinity for canonical crystallizable fragment receptors (FcR) or a newly discovered class of FcRs, labelled type II FcRs. Signaling through type II FcRs appears to trigger anti-inflammatory pathways. Recent discoveries expand our understanding of the mechanism of action of IVIG. Future research is expected to clarify the relevance of these findings to humans and could lead to the development of novel immunomodulatory agents.
IL-17–dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants

PubMed Central

Burlingham, William J.; Love, Robert B.; Jankowska-Gan, Ewa; Haynes, Lynn D.; Xu, Qingyong; Bobadilla, Joseph L.; Meyer, Keith C.; Hayney, Mary S.; Braun, Ruedi K.; Greenspan, Daniel S.; Gopalakrishnan, Bagavathi; Cai, Junchao; Brand, David D.; Yoshida, Shigetoshi; Cummings, Oscar W.; Wilkes, David S.

2007-01-01

Bronchiolitis obliterans syndrome (BOS), a process of fibro-obliterative occlusion of the small airways in the transplanted lung, is the most common cause of lung transplant failure. We tested the role of cell-mediated immunity to collagen type V [col(V)] in this process. PBMC responses to col(II) and col(V) were monitored prospectively over a 7-year period. PBMCs from lung transplant recipients, but not from healthy controls or col(IV)-reactive Goodpasture’s syndrome patients after renal transplant, were frequently col(V) reactive. Col(V)-specific responses were dependent on both CD4+ T cells and monocytes and required both IL-17 and the monokines TNF-α and IL-1β. Strong col(V)-specific responses were associated with substantially increased incidence and severity of BOS. Incidences of acute rejection, HLA-DR mismatched transplants, and induction of HLA-specific antibodies in the transplant recipient were not as strongly associated with a risk of BOS. These data suggest that while alloimmunity initiates lung transplant rejection, de novo autoimmunity mediated by col(V)-specific Th17 cells and monocyte/macrophage accessory cells ultimately causes progressive airway obliteration. PMID:17965778
Desensitization for solid organ and hematopoietic stem cell transplantation

PubMed Central

Zachary, Andrea A; Leffell, Mary S

2014-01-01

Desensitization protocols are being used worldwide to enable kidney transplantation across immunologic barriers, i.e. antibody to donor HLA or ABO antigens, which were once thought to be absolute contraindications to transplantation. Desensitization protocols are also being applied to permit transplantation of HLA mismatched hematopoietic stem cells to patients with antibody to donor HLA, to enhance the opportunity for transplantation of non-renal organs, and to treat antibody-mediated rejection. Although desensitization for organ transplantation carries an increased risk of antibody-mediated rejection, ultimately these transplants extend and enhance the quality of life for solid organ recipients, and desensitization that permits transplantation of hematopoietic stem cells is life saving for patients with limited donor options. Complex patient factors and variability in treatment protocols have made it difficult to identify, precisely, the mechanisms underlying the downregulation of donor-specific antibodies. The mechanisms underlying desensitization may differ among the various protocols in use, although there are likely to be some common features. However, it is likely that desensitization achieves a sort of immune detente by first reducing the immunologic barrier and then by creating an environment in which an autoregulatory process restricts the immune response to the allograft. PMID:24517434
Study of the γ/p discrimination at ∼100 TeV energy range with LHAASO experiment

NASA Astrophysics Data System (ADS)

Tian, Zhen; Wang, Zhen; Liu, Ye; Guo, Yiqing; Ma, Xinhua; Hu, Hongbo

2018-05-01

The observation of high energy γ-rays is essential to unveil the long-standing enigma of the origin and acceleration of Galactic Cosmic Rays (CRs). Given its powerful capability of distinguishing between protons and γ-rays owing to its very large area of underground muon detectors, the LHAASO observatory will be the most sensitive ground-based detectors for γ-rays at 100 TeV with a CRs background rejection rate better than 10-5. To evaluate the very small rejection rate with sufficient precision at energies above 100 TeV, one needs a large number of Monte Carlo events which is time consuming and challenging. As only the μ-poor events are interesting in the calculation of the rejection rate and take up a tiny fraction of the all CRs events, we modify the popular air shower simulation package, CORSIKA, by outputting only the μ-poor events for the following full detector simulation. As a result, our method is fully consistent with the evaluation made with the official CORSIKA at lower energy. Particularly, our improvement significantly escalate the calculation efficiency above 100 TeV, where it can be at least 50 times faster than using all events in simulation. By virtue of this new method, the γ/p discrimination of the LHAASO experiment at energies above 100 TeV is obtained for the first time, which indicates that LHAASO can reject CR backgrounds at a level of 10-5 and 10-9 at 100 TeV and 1 PeV respectively.
Eicosapentenoic Acid Attenuates Allograft Rejection in an HLA-B27/EGFP Transgenic Rat Cardiac Transplantation Model.

PubMed

Liu, Zhong; Hatayama, Naoyuki; Xie, Lin; Kato, Ken; Zhu, Ping; Ochiya, Takahiro; Nagahara, Yukitoshi; Hu, Xiang; Li, Xiao-Kang

2012-01-01

The development of an animal model bearing definite antigens is important to facilitate the evaluation and modulation of specific allo-antigen responses after transplantation. In the present study, heterotopic cardiac transplantation was performed from F344/EGFPTg and F344/HLA-B27Tg rats to F344 rats. The F344 recipients accepted the F344/EGFPTg transplants, whereas they rejected the cardiac tissue from the F344/HLA-B27Tg rats by 39.4 ± 6.5 days, due to high production of anti-HLA-B27 IgM- and IgG-specific antibodies. In addition, immunization of F344 rats with skin grafts from F344/HLA-B27Tg rats resulted in robust production of anti- HLA-B27 IgM and IgG antibodies and accelerated the rejection of a secondary cardiac allograft (7.4 ± 1.9 days). Of interest, the F344 recipients rejected cardiac grafts from double transgenic F344/HLA-B27&EGFPTg rats within 9.0 ± 3.2 days, and this was associated with a significant increase in the infiltration of lymphocytes by day 7, suggesting a role for cellular immune rejection. Eicosapentenoic acid (EPA), one of the ω-3 polyunsaturated fatty acids in fish oil, could attenuate the production of anti-HLA IgG antibodies and B-cell proliferation, significantly prolonging double transgenic F344HLA-B27&EGFPTg to F344 rat cardiac allograft survival (36.1 ± 13.6 days). Moreover, the mRNA expression in the grafts was assessed by quantitative reverse transcription polymerase chain reaction (qRT-PCR), revealing an increase in the expression of the HO-1, IL-10, TGF-β, IDO, and Foxp3 genes in the EPA-treated group. Hence, our data indicate that HLA-B27 and/or GFP transgenic proteins are useful for establishing a unique animal transplantation model to clarify the mechanism underlying the allogeneic cellular and humoral immune response, in which the transplant antigens are specifically presented. Furthermore, we also demonstrated that EPA was effective in the treatment of rat cardiac allograft rejection and may allow the development of novel immunomodulatory strategies for organ transplantation.
Monte Carlo simulation of steady state shock structure including cosmic ray mediation and particle escape

NASA Technical Reports Server (NTRS)

Ellison, D. C.; Jones, F. C.; Eichler, D.

1983-01-01

Both hydrodynamic calculations (Drury and Volk, 1981, and Axford et al., 1982) and kinetic simulations imply the existence of thermal subshocks in high-Mach-number cosmic-ray-mediated shocks. The injection efficiency of particles from the thermal background into the diffusive shock-acceleration process is determined in part by the sharpness and compression ratio of these subshocks. Results are reported for a Monte Carlo simulation that includes both the back reaction of accelerated particles on the inflowing plasma, producing a smoothing of the shock transition, and the free escape of particles allowing arbitrarily large overall compression ratios in high-Mach-number steady-state shocks. Energy spectra and estimates of the proportion of thermal ions accelerated to high energy are obtained.
Monte Carlo simulation of steady state shock structure including cosmic ray mediation and particle escape

NASA Astrophysics Data System (ADS)

Ellison, D. C.; Jones, F. C.; Eichler, D.

1983-08-01

Both hydrodynamic calculations (Drury and Volk, 1981, and Axford et al., 1982) and kinetic simulations imply the existence of thermal subshocks in high-Mach-number cosmic-ray-mediated shocks. The injection efficiency of particles from the thermal background into the diffusive shock-acceleration process is determined in part by the sharpness and compression ratio of these subshocks. Results are reported for a Monte Carlo simulation that includes both the back reaction of accelerated particles on the inflowing plasma, producing a smoothing of the shock transition, and the free escape of particles allowing arbitrarily large overall compression ratios in high-Mach-number steady-state shocks. Energy spectra and estimates of the proportion of thermal ions accelerated to high energy are obtained.
Electrochemically modified dissolved organic matter accelerates the combining photodegradation and biodegradation of 17α-ethinylestradiol in natural aquatic environment.

PubMed

He, Huan; Huang, Bin; Fu, Gen; Xiong, Dan; Xu, Zhixiang; Wu, Xinhao; Pan, Xuejun

2018-06-15

The photochemical conversion and microbial transformation of pollutants mediated by dissolved organic matter (DOM), including 17α-ethinylestradiol (EE2), are often accompanied in natural water. However, there are few studies to explore the connection and mechanism between the two processes. This research aims to investigate the mechanism of DOM after electrochemically modification mediated EE2 combining photodegradation and biodegradation in the environment and it want to explain the natural phenomena of DOM after electrochemical advanced treatment entering the water environment mediated EE2 natural degradation. The results showed that combining photodegradation with biodegradation rates of EE2 mediated by DOM and electrochemically modified DOM (E-DOM) were promoted obviously. The efficiency of EE2 biodegradation was shown to be strongly correlated with electron accepting capacity (EAC) of DOM. Electrochemical modification can increase the EAC of DOM leading to EE2 biodegradation accelerated, and it also can form more triplet-state DOM moieties to promote the EE2 photodegradation in irradiation conditions, due to the increasing of quinone-type structures in DOM. Moreover, cell polymeric secretion (CPS) secreted from the microorganism could be stimulated to an excited state by irradiation, and that also accelerated EE2 degradation. Photolysis combined with biochemical degradation yielded less toxic degradation products. This study shows that the emission of DOM in wastewater after electrochemical treatment could accelerate estrogen degradation and play a positive role on the pollutant transformation in the environment. Copyright © 2018 Elsevier Ltd. All rights reserved.
IFN-γ Blocks CD4+CD25+ Tregs and Abolishes Immune Privilege of Minor Histocompatibility Mismatched Corneal Allografts

PubMed Central

Cunnusamy, Khrishen; Niederkorn, Jerry Y.

2014-01-01

Th1 CD4+ cells are believed to be the primary mediators of corneal allograft rejection. However, rejection of fully allogeneic C57BL/6 corneal allografts soared from 50% to 90% in both INF-γ−/− and anti-IFN-γ-treated BALB/c mice. In contrast, similar deficits in IFN-γ in BALB/c hosts enhanced immune privilege of BALB.B (minor histocompatibility antigen-matched, MHC-mismatched) and NZB (major histocompatibility complex-matched, minor histocompatibility antigen-mismatched) corneal allografts – decreasing rejection from 80% to ~20%. This effect of IFN-γ was independent of CD4+ T cell lineage commitment as both anti-IFN-γ-treated acceptor and rejector mice displayed a Th2 cytokine profile. The presence of IFN-γ prevented the generation of alloantigen-specific CD4+CD25+ Tregs in hosts receiving either MHC only mismatched BALB.B or minor only histocompatibility (minor H)-mismatched NZB corneal allografts. Tregs in these hosts, promoted corneal allograft survival by suppressing Th2 effector cells. By contrast, IFN-γ was necessary for the generation of CD4+CD25+ Tregs that prevented rejection of fully allogeneic C57BL/6 corneal allografts in BALB/c hosts. These findings suggest that MHC-matching in combination with blockade of IFN-γ holds promise as a means of enhancing corneal allograft survival. PMID:24119152
Spleen tyrosine kinase contributes to acute renal allograft rejection in the rat

PubMed Central

Ramessur Chandran, Sharmila; Tesch, Greg H; Han, Yingjie; Woodman, Naomi; Mulley, William R; Kanellis, John; Blease, Kate; Ma, Frank Y; Nikolic-Paterson, David J

2015-01-01

Kidney allografts induce strong T-cell and antibody responses which mediate acute rejection. Spleen tyrosine kinase (Syk) is expressed by most leucocytes, except mature T cells, and is involved in intracellular signalling following activation of the Fcγ-receptor, B-cell receptor and some integrins. A role for Syk signalling has been established in antibody-dependent native kidney disease, but little is known of Syk in acute renal allograft rejection. Sprague–Dawley rats underwent bilateral nephrectomy and received an orthotopic Wistar renal allograft. Recipient rats were treated with a Syk inhibitor (CC0482417, 30 mg/kg/bid), or vehicle, from 1 h before surgery until being killed 5 days later. Vehicle-treated recipients developed severe allograft failure with marked histologic damage in association with dense leucocyte infiltration (T cells, macrophages, neutrophils and NK cells) and deposition of IgM, IgG and C3. Immunostaining identified Syk expression by many infiltrating leucocytes. CC0482417 treatment significantly improved allograft function and reduced histologic damage, although allograft injury was still clearly evident. CC0482417 failed to prevent T-cell infiltration and activation within the allograft. However, CC0482417 significantly attenuated acute tubular necrosis, infiltration of macrophages and neutrophils and thrombosis of peritubular capillaries. In conclusion, this study identifies a role for Syk in acute renal allograft rejection. Syk inhibition may be a useful addition to T-cell-based immunotherapy in renal transplantation. PMID:25529862

Tumour ischaemia by interferon-γ resembles physiological blood vessel regression.

PubMed

Kammertoens, Thomas; Friese, Christian; Arina, Ainhoa; Idel, Christian; Briesemeister, Dana; Rothe, Michael; Ivanov, Andranik; Szymborska, Anna; Patone, Giannino; Kunz, Severine; Sommermeyer, Daniel; Engels, Boris; Leisegang, Matthias; Textor, Ana; Fehling, Hans Joerg; Fruttiger, Marcus; Lohoff, Michael; Herrmann, Andreas; Yu, Hua; Weichselbaum, Ralph; Uckert, Wolfgang; Hübner, Norbert; Gerhardt, Holger; Beule, Dieter; Schreiber, Hans; Blankenstein, Thomas

2017-05-04

The relative contribution of the effector molecules produced by T cells to tumour rejection is unclear, but interferon-γ (IFNγ) is critical in most of the analysed models. Although IFNγ can impede tumour growth by acting directly on cancer cells, it must also act on the tumour stroma for effective rejection of large, established tumours. However, which stroma cells respond to IFNγ and by which mechanism IFNγ contributes to tumour rejection through stromal targeting have remained unknown. Here we use a model of IFNγ induction and an IFNγ-GFP fusion protein in large, vascularized tumours growing in mice that express the IFNγ receptor exclusively in defined cell types. Responsiveness to IFNγ by myeloid cells and other haematopoietic cells, including T cells or fibroblasts, was not sufficient for IFNγ-induced tumour regression, whereas responsiveness of endothelial cells to IFNγ was necessary and sufficient. Intravital microscopy revealed IFNγ-induced regression of the tumour vasculature, resulting in arrest of blood flow and subsequent collapse of tumours, similar to non-haemorrhagic necrosis in ischaemia and unlike haemorrhagic necrosis induced by tumour necrosis factor. The early events of IFNγ-induced tumour ischaemia resemble non-apoptotic blood vessel regression during development, wound healing or IFNγ-mediated, pregnancy-induced remodelling of uterine arteries. A better mechanistic understanding of how solid tumours are rejected may aid the design of more effective protocols for adoptive T-cell therapy.
Blockade of vascular adhesion protein-1 inhibits lymphocyte infiltration in rat liver allograft rejection.

PubMed

Martelius, Timi; Salaspuro, Ville; Salmi, Marko; Krogerus, Leena; Höckerstedt, Krister; Jalkanen, Sirpa; Lautenschlager, Irmeli

2004-12-01

Vascular adhesion protein-1 (VAP-1) has been shown to mediate lymphocyte adhesion to endothelia at sites of inflammation, but its functional role in vivo has not been tested in any rodent model. Here we report the effects of VAP-1 blockade on rat liver allograft rejection. BN recipients of PVG liver allografts (known to develop acute rejection by day 7) were treated with 2 mg/kg anti-VAP-1 (a new anti-rat VAP-1 mAb 174-5) or isotype-matched irrelevant antibody (NS1) every other day (n = 6/group) and one group with anti-VAP-1 2 mg/kg daily (n = 7). On day 7, samples were collected for transplant aspiration cytology, histology, and immunohistochemistry. Lymphocyte infiltration to the graft was clearly affected by VAP-blockade. The total inflammation, mainly the number of active lymphoid cells, in transplant aspiration cytology was significantly decreased in animals treated with anti-VAP-1 (4.7 +/- 1.0 and 2.4 +/- 1.0 corrected increment units, respectively) compared to control (6.6 +/- 1.0) (P < 0.05). In histology, the intensity of portal inflammation was significantly decreased (P < 0.05). The amount of T cells expressing activation markers diminished. This is the first demonstration in any prolonged in vivo model that VAP-1 plays an important role in lymphocyte infiltration to sites of inflammation, and, in particular, liver allograft rejection.
Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model.

PubMed

Samy, K P; Anderson, D J; Lo, D J; Mulvihill, M S; Song, M; Farris, A B; Parker, B S; MacDonald, A L; Lu, C; Springer, T A; Kachlany, S C; Reimann, K A; How, T; Leopardi, F V; Franke, K S; Williams, K D; Collins, B H; Kirk, A D

2017-05-01

Costimulation blockade (CoB) via belatacept is a lower-morbidity alternative to calcineurin inhibitor (CNI)-based immunosuppression. However, it has higher rates of early acute rejection. These early rejections are mediated in part by memory T cells, which have reduced dependence on the pathway targeted by belatacept and increased adhesion molecule expression. One such molecule is leukocyte function antigen (LFA)-1. LFA-1 exists in two forms: a commonly expressed, low-affinity form and a transient, high-affinity form, expressed only during activation. We have shown that antibodies reactive with LFA-1 regardless of its configuration are effective in eliminating memory T cells but at the cost of impaired protective immunity. Here we test two novel agents, leukotoxin A and AL-579, each of which targets the high-affinity form of LFA-1, to determine whether this more precise targeting prevents belatacept-resistant rejection. Despite evidence of ex vivo and in vivo ligand-specific activity, neither agent when combined with belatacept proved superior to belatacept monotherapy. Leukotoxin A approached a ceiling of toxicity before efficacy, while AL-579 failed to significantly alter the peripheral immune response. These data, and prior studies, suggest that LFA-1 blockade may not be a suitable adjuvant agent for CoB-resistant rejection. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.
Expression of decoy receptor 3 in kidneys is associated with allograft survival after kidney transplant rejection.

PubMed

Weng, Shuo-Chun; Shu, Kuo-Hsiung; Wu, Ming-Ju; Wen, Mei-Chin; Hsieh, Shie-Liang; Chen, Nien-Jung; Tarng, Der-Cherng

2015-09-03

Decoy receptor 3 (DcR3) expression in kidneys has been shown to predict progression of chronic kidney disease. We prospectively investigated a cohort comprising 96 renal transplant recipients (RTRs) undergoing graft kidney biopsies. Computer-assisted quantitative immunohistochemical staining value of DcR3 in renal tubular epithelial cells (RTECs) was used to determine the predictive role of DcR3 in kidney disease progression. The primary end point was doubling of serum creatinine and/or graft failure. A multivariate Cox proportional hazards model was used to assess the risk of DcR3 expression in rejected kidney grafts toward the renal end point. In total, RTRs with kidney allograft rejection were evaluated and the median follow-up was 30.9 months. The greater expression of DcR3 immunoreactivity in RTECs was correlated with a higher rate of the histopathological concordance of acute T cell-mediated rejection. Compared with 65 non-progressors, 31 progressors had higher DcR3 expression (HDE) regardless of the traditional risk factors. Cox regression analysis showed HDE was significantly associated with the risk of renal end point with a hazard ratio of 3.19 (95% confidence interval, 1.40 to 7.27; P = 0.006) after adjusting for other variables. In repetitive biopsies, HDE in tissue showed rapid kidney disease progression due to persistent inflammation.
Delinquency as a mediator of the relation between negative affectivity and adolescent alcohol use disorder.

PubMed

Shoal, Gavin D; Gudonis, Lauren C; Giancola, Peter R; Tarter, Ralph E

2007-12-01

This investigation examined mediators of the longitudinal relation between negative affectivity and the development of problematic drinking behavior in adolescent boys and girls. In the present study, 499 early adolescents completed inventories of negative affectivity, attitudes toward delinquency, personal delinquency, and affiliation with delinquent peers. Positive attitudes toward delinquency emerged as the most consistent mediator and strongly predicted drinking frequency in various situations. Compared with personal delinquency, both attitudes toward delinquency and peer delinquency were superior predictors of affect-related drinking. Our results also demonstrated that positive attitudes toward delinquency mediated the relation between negative affectivity and later development of an alcohol use disorder. These findings suggest that a proneness to unpleasant affect impacts adolescent drinking by heightening risk for general rejection of normative behavior, rather than by increasing drinking as a means of managing affect. The importance and implications of testing delinquency variables together in the same model are discussed.
Discrimination, Subjective Wellbeing, and the Role of Gender: A Mediation Model of LGB Minority Stress.

PubMed

Conlin, Sarah E; Douglass, Richard P; Ouch, Staci

2017-10-26

The present study examined the link between discrimination and the three components of subjective wellbeing (positive and negative affect and life satisfaction) among a cisgender sample of lesbian, gay, and bisexual (LGB) adults. Specifically, we investigated internalized homonegativity and expectations of rejection as potential mediators of the links between discrimination and subjective wellbeing among a sample of 215 participants. Results from our structural equation model demonstrated a strong, positive direct link between discrimination and negative affect. Discrimination also had small, negative indirect effects on life satisfaction through our two mediators. Interestingly, neither discrimination nor our two mediators were related with positive affect, demonstrating the need for future research to uncover potential buffers of this link. Finally, our model evidenced configural, metric, and scalar invariance, suggesting that our model applies well for both women and men. Practical implications and future directions for research are discussed.
Parental recall, attachment relating and self-attacking/self-reassurance: their relationship with depression.

PubMed

Irons, C; Gilbert, P; Baldwin, M W; Baccus, J R; Palmer, M

2006-09-01

When things go wrong for people they can become self-critical or focus on positive, reassuring aspects of the self. This study explored the relationship between forms of self-criticism and self-reassurance, recall of parental experiences and attachment style in relation to depressed symptoms in students. A sample of 197 undergraduate students from the UK and Canada completed self-report questionnaires measuring recall of parental styles, attachment, forms of self-criticism, self-reassurance, and depression symptoms. Recall of parents as rejecting and overprotecting was significantly related to both inadequacy and self-hating self-criticism. In contrast, parental warmth was negatively correlated with these forms of self-criticism. In addition, when things go wrong for the person, recall of parental warmth was associated with the ability to be self-reassuring. A mediator analysis suggested that (I) the impact of recall of negative parenting on depression is mediated through the forms of self-criticism and (2) the effect of parental warmth on depression was mediated by the ability to be self-reassuring. The impacts of negative parenting styles may translate into vulnerabilities to depression via the way children (and later adults) develop their self-to-self relating (e.g. as self-critical versus self-reassuring). Hence, there is a need for further research on the link between attachment experiences, recall of parental rejection/warmth and their relationship to internal, self-evaluative and affect systems in creating vulnerabilities to psychopathology.
De novo immune complex deposition in kidney allografts: a series of 32 patients.

PubMed

Lloyd, Isaac E; Ahmed, Faris; Revelo, Monica P; Khalighi, Mazdak A

2018-01-01

Immune complex deposition in kidney allografts can include both recurrent and de novo processes. Recurrent glomerulonephritis is a well-recognized phenomenon and has been shown to be a common cause of allograft failure. De novo immune complex-mediated disease remains relatively poorly characterized, likely owing to the less frequent use of immunofluorescence and electron microscopy in the transplant setting. We performed a retrospective review of kidney allograft biopsies showing glomerular immune complex deposition. Cases with de novo deposits were identified and further organized into two groups depending on whether the immune complex deposition could be clinically and/or histologically classified. Thirty-two patients with de novo immune complex deposition were identified over a 7-year period. A broad range of immune complex-mediated injuries were observed, the majority (63%) of which could be readily classified either clinically or histologically. These included cases of membranous glomerulonephropathy, IgA nephropathy, infection-related glomerulonephritis and glomerulonephritis related to an underlying autoimmune process. A smaller subset of patients (37%) demonstrated immune complex deposition that was difficult to histologically or clinically classify. These patients typically showed mild mesangial immune complex deposition with co-dominant IgG and IgM staining by immunofluorescence microscopy. The presence of concurrent antibody-mediated rejection and donor-specific antibody positivity was significantly higher in the unclassifiable group. The significance of these deposits and their possible relationship to allograft rejection deserves further investigation. Copyright © 2017 Elsevier Inc. All rights reserved.
Outside-in HLA class I signaling regulates ICAM-1 clustering and endothelial cell-monocyte interactions via mTOR in transplant antibody-mediated rejection.

PubMed

Salehi, Sahar; Sosa, Rebecca A; Jin, Yi-Ping; Kageyama, Shoichi; Fishbein, Michael C; Rozengurt, Enrique; Kupiec-Weglinski, Jerzy W; Reed, Elaine F

2018-05-01

Antibody-mediated rejection (AMR) resulting in transplant allograft vasculopathy (TAV) is the major obstacle for long-term survival of solid organ transplants. AMR is caused by donor-specific antibodies to HLA, which contribute to TAV by initiating outside-in signaling transduction pathways that elicit monocyte recruitment to activated endothelium. Mechanistic target of rapamycin (mTOR) inhibitors can attenuate TAV; therefore, we sought to understand the mechanistic underpinnings of mTOR signaling in HLA class I Ab-mediated endothelial cell activation and monocyte recruitment. We used an in vitro model to assess monocyte binding to HLA I Ab-activated endothelial cells and found mTOR inhibition reduced ezrin/radixin/moesin (ERM) phosphorylation, intercellular adhesion molecule 1 (ICAM-1) clustering, and monocyte firm adhesion to HLA I Ab-activated endothelium. Further, in a mouse model of AMR, in which C57BL/6. RAG1 -/- recipients of BALB/c cardiac allografts were passively transferred with donor-specific MHC I antibodies, mTOR inhibition significantly reduced vascular injury, ERM phosphorylation, and macrophage infiltration of the allograft. Taken together, these studies indicate mTOR inhibition suppresses ERM phosphorylation in endothelial cells, which impedes ICAM-1 clustering in response to HLA class I Ab and prevents macrophage infiltration into cardiac allografts. These findings indicate a novel therapeutic application for mTOR inhibitors to disrupt endothelial cell-monocyte interactions during AMR. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.
Donor-specific anti-HLA antibodies with antibody-mediated rejection and long-term outcomes following heart transplantation.

PubMed

Clerkin, Kevin J; Farr, Maryjane A; Restaino, Susan W; Zorn, Emmanuel; Latif, Farhana; Vasilescu, Elena R; Marboe, Charles C; Colombo, Paolo C; Mancini, Donna M

2017-05-01

Donor-specific anti-HLA antibodies (DSA) are common after heart transplantation and are associated with rejection, cardiac allograft vasculopathy, and mortality. A noninvasive diagnostic test for pathologic antibody-mediated rejection (pAMR) does not exist. From January 1, 2010, through August 31, 2013, 221 consecutive adult patients underwent heart transplantation and were followed through October 1, 2015. The primary objective was to determine whether the presence of DSA could detect AMR at the time of pathologic diagnosis. Secondary analyses included association of DSA (stratified by major histocompatibility complex class and de novo status) during AMR with new graft dysfunction, graft loss (mortality or retransplantation), and development of cardiac allograft vasculopathy. During the study period, 69 patients (31.2%) had DSA (24% had de novo DSA), and there were 74 episodes of pAMR in 38 patients. Sensitivity of DSA at any mean fluorescence intensity to detect concurrent pAMR was only 54.3%. The presence of any DSA during pAMR increased the odds of graft dysfunction (odds ratio = 5.37; 95% confidence interval [CI], 1.34-21.47; p = 0.018), adjusting for age, sex, and timing of AMR. Circulating class II DSA after transplantation increased risk of future pAMR (hazard ratio = 2.97; 95% CI, 1.31-6.73; p = 0.009). Patients who developed de novo class II DSA had 151% increased risk of graft loss (contingent on 30-day survival) compared with patients who did not have DSA (95% CI, 1.11-5.69; p = 0.027). DSA were inadequate to diagnose pAMR. Class II DSA provided prognostic information regarding future pAMR, graft dysfunction with pAMR, and graft loss. Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
The regulatory T cell effector molecule fibrinogen-like protein 2 is necessary for the development of rapamycin-induced tolerance to fully MHC-mismatched murine cardiac allografts

PubMed Central

Urbanellis, Peter; Shyu, Wendy; Khattar, Ramzi; Wang, Jihong; Zakharova, Anna; He, Wei; Sadozai, Hassan; Amir, Achiya Z; Shalev, Itay; Phillips, M James; Adeyi, Oyedele; Ross, Heather; Grant, David; Levy, Gary A; Chruscinski, Andrzej

2015-01-01

Therapies that promote tolerance in solid organ transplantation will improve patient outcomes by eliminating the need for long-term immunosuppression. To investigate mechanisms of rapamycin-induced tolerance, C3H/HeJ mice were heterotopically transplanted with MHC-mismatched hearts from BALB/cJ mice and were monitored for rejection after a short course of rapamycin treatment. Mice that had received rapamycin developed tolerance with indefinite graft survival, whereas untreated mice all rejected their grafts within 9 days. In vitro, splenic mononuclear cells from tolerant mice maintained primary CD4+ and CD8+ immune responses to donor antigens consistent with a mechanism that involves active suppression of immune responses. Furthermore, infection with lymphocytic choriomeningitis virus strain WE led to loss of tolerance suggesting that tolerance could be overcome by infection. Rapamycin-induced, donor-specific tolerance was associated with an expansion of regulatory T (Treg) cells in both the spleen and allograft and elevated plasma levels of fibrinogen-like protein 2 (FGL2). Depletion of Treg cells with anti-CD25 (PC61) and treatment with anti-FGL2 antibody both prevented tolerance induction. Tolerant allografts were populated with Treg cells that co-expressed FGL2 and FoxP3, whereas rejecting allografts and syngeneic grafts were nearly devoid of dual-staining cells. We examined the utility of an immunoregulatory gene panel to discriminate between tolerance and rejection. We observed that Treg-associated genes (foxp3, lag3, tgf-β and fgl2) had increased expression and pro-inflammatory genes (ifn-γ and gzmb) had decreased expression in tolerant compared with rejecting allografts. Taken together, these data strongly suggest that Treg cells expressing FGL2 mediate rapamycin-induced tolerance. Furthermore, a gene biomarker panel that includes fgl2 can distinguish between rejecting and tolerant grafts. PMID:24990517
The role of egg-nest contrast in the rejection of brood parasitic eggs.

PubMed

Aidala, Zachary; Croston, Rebecca; Schwartz, Jessica; Tong, Lainga; Hauber, Mark E

2015-04-15

Hosts of avian brood parasites can avoid the reproductive costs of raising genetically unrelated offspring by rejecting parasitic eggs. The perceptual cues and controls mediating parasitic egg discrimination and ejection are well studied: hosts are thought to use differences in egg color, brightness, maculation, size and shape to discriminate between their own and foreign eggs. Most theories of brood parasitism implicitly assume that the primary criteria to which hosts attend when discriminating eggs are differences between the eggs themselves. However, this assumption is confounded by the degree to which chromatic and achromatic characteristics of the nest lining co-vary with egg coloration, so that egg-nest contrast per se might be the recognition cue driving parasitic egg detection. Here, we systematically tested whether and how egg-nest contrast itself contributes to foreign egg discrimination. In an artificial parasitism experiment, we independently manipulated egg color and nest lining color of the egg-ejector American robin (Turdus migratorius), a host of the obligate brood parasitic brown-headed cowbird (Molothrus ater). We hypothesized that the degree of contrast between foreign eggs and the nest background would affect host egg rejection behavior. We predicted that experimentally decreasing egg-nest chromatic and achromatic contrast (i.e. rendering parasitic eggs more cryptic against the nest lining) would decrease rejection rates, while increasing egg-nest contrast would increase rejection rates. In contrast to our predictions, egg-nest contrast was not a significant predictor of egg ejection patterns. Instead, egg color significantly predicted responses to parasitism. We conclude that egg-egg differences are the primary drivers of egg rejection in this system. Future studies should test for the effects of egg-nest contrast per se in predicting parasitic egg recognition in other host-parasite systems, including those hosts building enclosed nests and those parasites laying cryptic eggs, as an alternative to hypothesized effects of egg-egg contrast. © 2015. Published by The Company of Biologists Ltd.
Piezoelectric-based self-powered electronic adjustable impulse switches

NASA Astrophysics Data System (ADS)

Rastegar, Jahangir; Kwok, Philip

2018-03-01

Novel piezoelectric-based self-powered impulse detecting switches are presented. The switches are designed to detect shock loading events resulting in acceleration or deceleration above prescribed levels and durations. The prescribed acceleration level and duration thresholds are adjustable. They are provided with false trigger protection logic. The impulse switches are provided with electronic and logic circuitry to detect prescribed impulse events and reject events such as high amplitude but short duration shocks, and transportation vibration and similar low amplitude and relatively long duration events. They can be mounted directly onto electronics circuit boards, thereby significantly simplifying the electrical and electronic circuitry, simplifying the assembly process and total cost, significantly reducing the occupied volume, and in some applications eliminating the need for physical wiring to and from the impulse switches. The design of prototypes and testing under realistic conditions are presented.
Calcium accelerates SNARE-mediated lipid mixing through modulating α-synuclein membrane interaction.

PubMed

Zhang, Zeting; Jiang, Xin; Xu, Danrui; Zheng, Wenwen; Liu, Maili; Li, Conggang

2018-04-04

α-Synuclein is involved in Parkinson's disease, and its interaction with cell membrane is vital to its pathological and physiological functions. We have shown that Ca 2+ can regulate α-synuclein membrane interaction, but the physiological role of Ca 2+ in modulating α-synuclein membrane interaction is still unexplored. Based on the previous findings that α-synuclein inhibits membrane fusion and its inhibitory effect is highly related to its membrane binding, here we employed solution state Nuclear Magnetic Resonance (NMR) spectroscopy and the ensemble fluorescence fusion assay to show that Ca 2+ can modulate the inhibitory effect of α-synuclein on SNARE-mediated membrane fusion through disrupting α-synuclein membrane interaction, resulting in acceleration of SNARE-mediated membrane fusion. These results suggest a modulatory effect of Ca 2+ on membrane mediated normal function of α-synuclein, which of importance for the study of the Parkinson's disease. Copyright © 2018 Elsevier B.V. All rights reserved.
A Growth Curve Analysis of the Joint Influences of Parenting Affect, Child Characteristics and Deviant Peers on Adolescent Illicit Drug Use

ERIC Educational Resources Information Center

Pires, Paulo; Jenkins, Jennifer M.

2007-01-01

This study purports that parental rejection and warmth are critical to the development of adolescent drug use, and investigates a model that also considers children's vulnerability and deviant peer affiliations. It tests mediation through the proximal risk factor of deviant peers. Poisson growth curve modeling was used to examine participants from…
Acute liver allograft antibody-mediated rejection: an inter-institutional study of significant histopathological features.

PubMed

O'Leary, Jacqueline G; Michelle Shiller, S; Bellamy, Christopher; Nalesnik, Michael A; Kaneku, Hugo; Jennings, Linda W; Isse, Kumiko; Terasaki, Paul I; Klintmalm, Göran B; Demetris, Anthony J

2014-10-01

Acute antibody-mediated rejection (AMR) occurs in a small minority of sensitized liver transplant recipients. Although histopathological characteristics have been described, specific features that could be used (1) to make a generalizable scoring system and (2) to trigger a more in-depth analysis are needed to screen for this rare but important finding. Toward this goal, we created training and validation cohorts of putative acute AMR and control cases from 3 high-volume liver transplant programs; these cases were evaluated blindly by 4 independent transplant pathologists. Evaluations of hematoxylin and eosin (H&E) sections were performed alone without knowledge of either serum donor-specific human leukocyte antigen alloantibody (DSA) results or complement component 4d (C4d) stains. Routine histopathological features that strongly correlated with severe acute AMR included portal eosinophilia, portal vein endothelial cell hypertrophy, eosinophilic central venulitis, central venulitis severity, and cholestasis. Acute AMR inversely correlated with lymphocytic venulitis and lymphocytic portal inflammation. These and other characteristics were incorporated into models created from the training cohort alone. The final acute antibody-mediated rejection score (aAMR score)--the sum of portal vein endothelial cell hypertrophy, portal eosinophilia, and eosinophilic venulitis divided by the sum of lymphocytic portal inflammation and lymphocytic venulitis--exhibited a strong correlation with severe acute AMR in the training cohort [odds ratio (OR) = 2.86, P < 0.001] and the validation cohort (OR = 2.49, P < 0.001). SPSS tree classification was used to select 2 cutoffs: one that optimized specificity at a score > 1.75 (sensitivity = 34%, specificity = 86%) and another that optimized sensitivity at a score > 1.0 (sensitivity = 81%, specificity = 71%). In conclusion, the routine histopathological features of the aAMR score can be used to screen patients for acute AMR via routine H&E staining of indication liver transplant biopsy samples; however, a definitive diagnosis requires substantiation by DSA testing, diffuse C4d staining, and the exclusion of other insults. © 2014 American Association for the Study of Liver Diseases.
Music, Mechanism, and the “Sonic Turn” in Physical Diagnosis

PubMed Central

Pesic, Peter

2016-01-01

The sonic diagnostic techniques of percussion and mediate auscultation advocated by Leopold von Auenbrugger and R. T. H. Laennec developed within larger musical contexts of practice, notation, and epistemology. Earlier, François-Nicolas Marquet proposed a musical notation of pulse that connected felt pulsation with heard music. Though contemporary vitalists rejected Marquet's work, mechanists such as Albrecht von Haller included it into the larger discourse about the physiological manifestations of bodily fluids and fibers. Educated in that mechanistic physiology, Auenbrugger used musical vocabulary to present his work on thoracic percussion; Laennec's musical experience shaped his exploration of the new timbres involved in mediate auscultation. PMID:26349757
Why You Should Believe Cold Fusion is Real

NASA Astrophysics Data System (ADS)

Storms, Edmund K.

2005-03-01

Nuclear reactions are now claimed to be initiated in certain solid materials at an energy too low to overcome the Coulomb barrier. These reactions include fusion, accelerated radioactive decay, and transmutation involving heavy elements. Evidence is based on hundreds of measurements of anomalous energy using a variety of calorimeters at levels far in excess of error, measurement of nuclear products using many normally accepted techniques, observations of many patterns of behavior common to all studies, measurement of anomalous energetic emissions using accepted techniques, and an understanding of most variables that have hindered reproducibility in the past. This evidence can be found at www.LENR-CANR.orgwww.LENR-CANR.org. Except for an accepted theory, the claims have met all requirements normally required before a new idea is accepted by conventional science, yet rejection continues. How long can the US afford to reject a clean and potentially cheap source of energy, especially when other nations are attempting to develop this energy and the need for such an energy source is so great?
Blood biomarkers of kidney transplant rejection, an endless search?

PubMed

Jacquemont, Lola; Soulillou, Jean-Paul; Degauque, Nicolas

2017-07-01

The tailoring of immunosuppressive treatment is recognized as a promising strategy to improve long-term kidney graft outcome. To guide the standard care of transplant recipients, physicians need objective biomarkers that can identify an ongoing pathology with the graft or low intensity signals that will be later evolved to accelerated transplant rejection. The early identification of 'high-risk /low-risk' patients enables the adjustment of standard of caring, including managing the frequency of clinical visits and the immunosuppression dosing. Given their ease of availability and the compatibility with a large technical array, blood-based biomarkers have been widely scrutinized for use as potential predictive and diagnostic biomarkers. Areas covered: Here, the authors report on non-invasive biomarkers, such as modification of immune cell subsets and mRNA and miRNA profiles, identified in the blood of kidney transplant recipients collected before or after transplantation. Expert commentary: Combined with functional tests, the identification of biomarkers will improve our understanding of pathological processes and will contribute to a global improvement in clinical management.
A Pilot Study of Mesenchymal Stem Cell Therapy for Acute Liver Allograft Rejection

PubMed Central

Liu, Zhenwen; Wang, Ying; Xu, Rounan; Sun, Yanling; Zhang, Min; Yu, Xi; Wang, Hongbo; Meng, Lingzhan; Su, Haibin; Jin, Lei

2017-01-01

Abstract Acute allograft rejection remains common after liver transplantation despite modern immunosuppressive agents. In addition, the long‐term side effects of these regimens, including opportunistic infections, are challenging. This study evaluated the safety and clinical feasibility of umbilical cord‐derived mesenchymal stem cell (UC‐MSC) therapy in liver transplant patients with acute graft rejection. Twenty‐seven liver allograft recipients with acute rejection were randomly assigned into the UC‐MSC infusion group or the control group. Thirteen patients received one infusion of UC‐MSCs (1 × 106/kg body weight); one patient received multiple UC‐MSC infusions; 13 patients were used as controls. All enrolled patients received conventional immunosuppressive agents with follow‐up for 12 weeks after UC‐MSC infusions. No side effects occurred in treated patients. Four weeks after UC‐MSC infusions, alanine aminotransferase levels had decreased markedly and remained lower throughout the 12‐week follow‐up period. Importantly, allograft histology was improved after administration of UC‐MSCs. The percentage of regulatory T cells (Tregs) and the Treg/T helper 17 (Th17) cell ratio were significantly increased 4 weeks after infusions; in contrast, the percentage of Th17 cells showed a decreasing trend. In controls, the percentages of Tregs and Th17 cells and the Treg/Th17 ratio were statistically unchanged from the baseline measurements. Transforming growth factor beta 1 and prostaglandin E2 were increased significantly after UC‐MSC infusions; by contrast, there were no significant changes in controls. Our data suggest that UC‐MSC infusion for acute graft rejection following liver transplantation is feasible and may mediate a therapeutic immunosuppressive effect. Stem Cells Translational Medicine 2017;6:2053–2061 PMID:29178564

Modeling the effects of functional performance and post-transplant comorbidities on health-related quality of life after heart transplantation.

PubMed

Butler, Javed; McCoin, Nicole S; Feurer, Irene D; Speroff, Theodore; Davis, Stacy F; Chomsky, Don B; Wilson, John R; Merrill, Walter H; Drinkwater, Davis C; Pierson, Richard N; Pinson, C Wright

2003-10-01

Health-related quality of life and functional performance are important outcome measures following heart transplantation. This study investigates the impact of pre-transplant functional performance and post-transplant rejection episodes, obesity and osteopenia on post-transplant health-related quality of life and functional performance. Functional performance and health-related quality of life were measured in 70 adult heart transplant recipients. A composite health-related quality of life outcome measure was computed via principal component analysis. Iterative, multiple regression-based path analysis was used to develop an integrated model of variables that affect post-transplant functional performance and health-related quality of life. Functional performance, as measured by the Karnofsky scale, improved markedly during the first 6 months post-transplant and was then sustained for up to 3 years. Rejection Grade > or =2 was negatively associated with health-related quality of life, measured by Short Form-36 and reversed Psychosocial Adjustment to Illness Scale scores. Patients with osteopenia had lower Short Form-36 physical scores and obese patients had lower functional performance. Path analysis demonstrated a negative direct effect of obesity (beta = - 0.28, p < 0.05) on post-transplant functional performance. Post-transplant functional performance had a positive direct effect on the health-related quality of life composite score (beta = 0.48, p < 0.001), and prior rejection episodes grade > or =2 had a negative direct effect on this measure (beta = -0.29, p < 0.05). Either directly or through effects mediated by functional performance, moderate-to-severe rejection, obesity and osteopenia negatively impact health-related quality of life. These findings indicate that efforts should be made to devise immunosuppressive regimens that reduce the incidence of acute rejection, weight gain and osteopenia after heart transplantation.
Absence of a fundamental acceleration scale in galaxies

NASA Astrophysics Data System (ADS)

Rodrigues, Davi C.; Marra, Valerio; del Popolo, Antonino; Davari, Zahra

2018-06-01

Dark matter is currently one of the main mysteries of the Universe. There is much strong indirect evidence that supports its existence, but there is yet no sign of a direct detection1-3. Moreover, at the scale of galaxies, there is tension between the theoretically expected dark matter distribution and its indirectly observed distribution4-7. Therefore, phenomena associated with dark matter have a chance of serving as a window towards new physics. The radial acceleration relation8,9 confirms that a non-trivial acceleration scale a0 can be found from the internal dynamics of several galaxies. The existence of such a scale is not obvious as far as the standard cosmological model is concerned10,11, and it has been interpreted as a possible sign of modified gravity12,13. Here, we consider 193 high-quality disk galaxies and, using Bayesian inference, show that the probability of existence of a fundamental acceleration is essentially 0: the null hypothesis is rejected at more than 10σ. We conclude that a0 is of emergent nature. In particular, the modified Newtonian dynamics theory14-17—a well-known alternative to dark matter based on the existence of a fundamental acceleration scale—or any other theory that behaves like it at galactic scales, is ruled out as a fundamental theory for galaxies at more than 10σ.
Sphingosine 1-Phosphate Receptor Modulators and Drug Discovery

PubMed Central

Park, Soo-Jin; Im, Dong-Soon

2017-01-01

Initial discovery on sphingosine 1-phosphate (S1P) as an intracellular second messenger was faced unexpectedly with roles of S1P as a first messenger, which subsequently resulted in cloning of its G protein-coupled receptors, S1P1–5. The molecular identification of S1P receptors opened up a new avenue for pathophysiological research on this lipid mediator. Cellular and molecular in vitro studies and in vivo studies on gene deficient mice have elucidated cellular signaling pathways and the pathophysiological meanings of S1P receptors. Another unexpected finding that fingolimod (FTY720) modulates S1P receptors accelerated drug discovery in this field. Fingolimod was approved as a first-in-class, orally active drug for relapsing multiple sclerosis in 2010, and its applications in other disease conditions are currently under clinical trials. In addition, more selective S1P receptor modulators with better pharmacokinetic profiles and fewer side effects are under development. Some of them are being clinically tested in the contexts of multiple sclerosis and other autoimmune and inflammatory disorders, such as, psoriasis, Crohn’s disease, ulcerative colitis, polymyositis, dermatomyositis, liver failure, renal failure, acute stroke, and transplant rejection. In this review, the authors discuss the state of the art regarding the status of drug discovery efforts targeting S1P receptors and place emphasis on potential clinical applications. PMID:28035084
RoboPol: the optical polarization of gamma-ray-loud and gamma-ray-quiet blazars

NASA Astrophysics Data System (ADS)

Angelakis, E.; Hovatta, T.; Blinov, D.; Pavlidou, V.; Kiehlmann, S.; Myserlis, I.; Böttcher, M.; Mao, P.; Panopoulou, G. V.; Liodakis, I.; King, O. G.; Baloković, M.; Kus, A.; Kylafis, N.; Mahabal, A.; Marecki, A.; Paleologou, E.; Papadakis, I.; Papamastorakis, I.; Pazderski, E.; Pearson, T. J.; Prabhudesai, S.; Ramaprakash, A. N.; Readhead, A. C. S.; Reig, P.; Tassis, K.; Urry, M.; Zensus, J. A.

2016-12-01

We present average R-band optopolarimetric data, as well as variability parameters, from the first and second RoboPol observing season. We investigate whether gamma-ray-loud and gamma-ray-quiet blazars exhibit systematic differences in their optical polarization properties. We find that gamma-ray-loud blazars have a systematically higher polarization fraction (0.092) than gamma-ray-quiet blazars (0.031), with the hypothesis of the two samples being drawn from the same distribution of polarization fractions being rejected at the 3σ level. We have not found any evidence that this discrepancy is related to differences in the redshift distribution, rest-frame R-band luminosity density, or the source classification. The median polarization fraction versus synchrotron-peak-frequency plot shows an envelope implying that high-synchrotron-peaked sources have a smaller range of median polarization fractions concentrated around lower values. Our gamma-ray-quiet sources show similar median polarization fractions although they are all low-synchrotron-peaked. We also find that the randomness of the polarization angle depends on the synchrotron peak frequency. For high-synchrotron-peaked sources, it tends to concentrate around preferred directions while for low-synchrotron-peaked sources, it is more variable and less likely to have a preferred direction. We propose a scenario which mediates efficient particle acceleration in shocks and increases the helical B-field component immediately downstream of the shock.
[Husband to wife kidney transplantation in five multiparous women: sensitization or tolerance after pregnancy?].

PubMed

Ortiz-Arroyo, Víctor M; Granados, Julio; Uribe-Uribe, Norma; de Leo, Claudia; Castelán, Natalia; González, Norma; López, Mayra; Alberú, Josefina

2004-01-01

Pregnancy is a known cause of immunological sensitization and it has been reported graft survival to be lower in husband to wife kidney transplantation if the wife had been pregnant (mutual children) as compare to those cases without pregnancies. Previous exposure to husband HLA antigens during pregnancies may lead to specific sensitization to subsequent allografts. To communicate the fate of kidney allograft in husband to wife transplantation when the recipient had been pregnant. From 682 renal transplants performed at INCMNSZ 5 corresponded to husband to wife transplants. All the recipients were multiparous and had received multiple blood transfusions. Pretransplantation lymphocytotoxic cross-match testing were performed by complement dependent citotoxicity with antihuman globulin added (AHG-CDC), being negative in all cases for T and B cells. All the patients received triple-drug immunosuppressive therapy, additionally, anti-IL2R monoclonal antibodies were used in two cases. Two patients developed: accelerated acute rejection (case 1), and acute humoral rejection (case 5), respectively. Graft in these patients were loss to rejection and transplant nephrectomy accomplished. The remaining three patients (cases 2, 3, and 4) has not had any rejection episode, and have had excellent graft outcome at 34, 30, and 21 months posttransplant, respectively. Why under similar conditions some husband to wife kidney transplant recipients developed an adverse humoral immunological events while others maintain excellent long-term graft outcome? Is it possible to speculate that for some women pregnancy is in fact a sensitizing event, while in others it promotes "immunological acceptance"? At present there is no a test that characterized one and other group. Even though pretransplantation cross-match testing by flow cytometry is more sensitive than AHG-CDC, its negative result is by no means an absolute guarantee that an adverse anamnestic immunological event will not occur.
Studying astrophysical particle acceleration with laser-driven plasmas

NASA Astrophysics Data System (ADS)

Fiuza, Frederico

2016-10-01

The acceleration of non-thermal particles in plasmas is critical for our understanding of explosive astrophysical phenomena, from solar flares to gamma ray bursts. Particle acceleration is thought to be mediated by collisionless shocks and magnetic reconnection. The microphysics underlying these processes and their ability to efficiently convert flow and magnetic energy into non-thermal particles, however, is not yet fully understood. By performing for the first time ab initio 3D particle-in-cell simulations of the interaction of both magnetized and unmagnetized laser-driven plasmas, it is now possible to identify the optimal parameters for the study of particle acceleration in the laboratory relevant to astrophysical scenarios. It is predicted for the Omega and NIF laser conditions that significant non-thermal acceleration can occur during magnetic reconnection of laser-driven magnetized plasmas. Electrons are accelerated by the electric field near the X-points and trapped in contracting magnetic islands. This leads to a power-law tail extending to nearly a hundred times the thermal energy of the plasma and that contains a large fraction of the magnetic energy. The study of unmagnetized interpenetrating plasmas also reveals the possibility of forming collisionless shocks mediated by the Weibel instability on NIF. Under such conditions, both electrons and ions can be energized by scattering out of the Weibel-mediated turbulence. This also leads to power-law spectra that can be detected experimentally. The resulting experimental requirements to probe the microphysics of plasma particle acceleration will be discussed, paving the way for the first experiments of these important processes in the laboratory. As a result of these simulations and theoretical analysis, there are new experiments being planned on the Omega, NIF, and LCLS laser facilities to test these theoretical predictions. This work was supported by the SLAC LDRD program and DOE Office of Science, Fusion Energy Science (FWP 100182).
Forms of aggression, peer relationships, and relational victimization among Chinese adolescent girls and boys: roles of prosocial behavior

PubMed Central

Wang, Shujun; Zhang, Wei; Li, Dongping; Yu, Chengfu; Zhen, Shuangju; Huang, Shihua

2015-01-01

Through a sample of 686 Chinese adolescents (mean age = 13.73 years; 50% girls), we examined the compensatory and moderating effects of prosocial behavior on the direct and indirect associations between forms of aggression and relational victimization mediated by peer relationships among adolescent girls and boys. The results indicated that only adolescent girls’ relationally aggressive behaviors could be directly linked with their experiences of relational victimization, and both relationally and overtly aggressive adolescent boys and girls might be more often rejected by their peers, which, in turn, could make them targets of relational aggression. Next, we found that prosocial behavior indirectly counteracts the effects of aggression on relational victimization through reducing adolescents’ peer rejection and promoting adolescents’ peer attachment. In addition, relationally aggressive girls with high levels of prosocial behavior might be less rejected by peers; however, they might also have lower levels of peer attachment and be more likely to experience relational victimization. Last, adolescent boys scored higher on risks, but lower on the protective factors of relational victimization than girls, which, to some degree, might explain the gender difference in relational victimization. Finally, we discussed the theoretical and practical implications of these findings. PMID:26347704
A Dyadic Perspective on Speech Accommodation and Social Connection: Both Partners' Rejection Sensitivity Matters.

PubMed

Aguilar, Lauren; Downey, Geraldine; Krauss, Robert; Pardo, Jennifer; Lane, Sean; Bolger, Niall

2016-04-01

Findings from confederate paradigms predict that mimicry is an adaptive route to social connection for rejection-sensitive individuals (Lakin, Chartrand, & Arkin, 2008). However, dyadic perspectives predict that whether mimicry leads to perceived connection depends on the rejection sensitivity (RS) of both partners in an interaction. We investigated these predictions in 50 college women who completed a dyadic cooperative task in which members were matched or mismatched in being dispositionally high or low in RS. We used a psycholinguistics paradigm to assess, through independent listeners' judgments (N = 162), how much interacting individuals accommodate phonetic aspects of their speech toward each other. Results confirmed predictions from confederate paradigms in matched RS dyads. However, mismatched dyads showed an asymmetry in levels of accommodation and perceived connection: Those high in RS accommodated more than their low-RS partner but emerged feeling less connected. Mediational analyses indicated that low-RS individuals' nonaccommodation in mismatched dyads helped explain their high-RS partners' relatively low perceived connection to them. Establishing whether mimicry is an adaptive route to social connection requires analyzing mimicry as a dyadic process influenced by the needs of each dyad member. © 2014 Wiley Periodicals, Inc.
A televised entertainment-education drama to promote positive discussion about organ donation.

PubMed

Khalil, Georges E; Rintamaki, Lance S

2014-04-01

This article investigates pathways between the exposure to an entertainment-education (E-E) television drama called Three Rivers and positive discussion of organ donation among viewers of the drama in the United States. A cross-sectional survey was conducted using an online advertising for a period of one week. Survey participants included 1325 adults living in the United States, who had viewed the first episode of Three Rivers on television. Data were collected on recall of events in the storyline, perceived entertainment value, perceived accuracy of the presented health information, rejection of organ donation myths and positive discussion of organ donation and the storyline. Covariates were registration for organ donation, membership to the donation or transplant community and demographic variables. Results show that viewers with high recall of the storyline were more likely to reject myths about organ donation and engage in pro-donation discussions with others. Perceived entertainment value and perceived accuracy acted as mediators in such relationships. The insertion of accurate health information in television drama may be effective in promoting positive discussions about organ donation and myth rejection. Recall of events from the televised E-E drama Three Rivers, entertainment value and accuracy perception were associated with positive discussion.
Determinants of Prosocial Behavior in Included Versus Excluded Contexts

PubMed Central

Cuadrado, Esther; Tabernero, Carmen; Steinel, Wolfgang

2016-01-01

Prosocial behavior (PSB) is increasingly becoming necessary as more and more individuals experience exclusion. In this context it is important to understand the motivational determinants of PSB. Here we report two experiments which analyzed the influence of dispositional (prosocialness; rejection sensitivity) and motivational variables (prosocial self-efficacy; prosocial collective efficacy; trust; anger; social affiliation motivation) on PSB under neutral contexts (Study 1), and once under inclusion or exclusion conditions (Study 2). Both studies provided evidence for the predicted mediation of PSB. Results in both neutral and inclusion and exclusion conditions supported our predictive model of PSB. In the model dispositional variables predicted motivational variables, which in turn predicted PSB. We showed that the investigated variables predicted PSB; this suggests that to promote PSB one could (1) foster prosocialness, prosocial self and collective efficacy, trust in others and affiliation motivation and (2) try to reduce negative feelings and the tendency to dread rejection in an attempt to reduce the negative impact that these variables have on PSB. Moreover, the few differences that emerged in the model between the inclusion and exclusion contexts suggested that in interventions with excluded individuals special care emphasis should be placed on addressing rejection sensitivity and lack of trust. PMID:26779103
Vav1 GEF activity is required for T cell mediated allograft rejection

PubMed Central

Haubert, Dirk; Li, Jianping; Saveliev, Alexander; Calzascia, Thomas; Sutter, Esther; Metzler, Barbara; Kaiser, Daniel; Tybulewicz, Victor L.J.; Weckbecker, Gisbert

2012-01-01

The GDP exchange factor (GEF) Vav1 is a central signal transducer downstream of the T cell receptor and has been identified as a key factor for T cell activation in the context of allograft rejection. Vav1 has been shown to transduce signals both dependent and independent of its GEF function. The most promising approach to disrupt Vav1 activity by pharmacological inhibition would be to target its GEF function. However, the contribution of Vav1 GEF activity for allogeneic T cell activation has not been clarified yet. To address this question, we used knock-in mice bearing a mutated Vav1 with disrupted GEF activity but intact GEF-independent functions. T cells from these mice showed strongly reduced proliferation and activation in response to allogeneic stimulation. Furthermore, lack of Vav1 GEF activity strongly abrogated the in vivo expansion of T cells in a systemic graft-versus-host model. In a cardiac transplantation model, mice with disrupted Vav1 GEF activity show prolonged allograft survival. These findings demonstrate a strong requirement for Vav1 GEF activity for allogeneic T cell activation and graft rejection suggesting that disruption of Vav1 GEF activity alone is sufficient to induce significant immunosuppression. PMID:22456277
Determinants of Prosocial Behavior in Included Versus Excluded Contexts.

PubMed

Cuadrado, Esther; Tabernero, Carmen; Steinel, Wolfgang

2015-01-01

Prosocial behavior (PSB) is increasingly becoming necessary as more and more individuals experience exclusion. In this context it is important to understand the motivational determinants of PSB. Here we report two experiments which analyzed the influence of dispositional (prosocialness; rejection sensitivity) and motivational variables (prosocial self-efficacy; prosocial collective efficacy; trust; anger; social affiliation motivation) on PSB under neutral contexts (Study 1), and once under inclusion or exclusion conditions (Study 2). Both studies provided evidence for the predicted mediation of PSB. Results in both neutral and inclusion and exclusion conditions supported our predictive model of PSB. In the model dispositional variables predicted motivational variables, which in turn predicted PSB. We showed that the investigated variables predicted PSB; this suggests that to promote PSB one could (1) foster prosocialness, prosocial self and collective efficacy, trust in others and affiliation motivation and (2) try to reduce negative feelings and the tendency to dread rejection in an attempt to reduce the negative impact that these variables have on PSB. Moreover, the few differences that emerged in the model between the inclusion and exclusion contexts suggested that in interventions with excluded individuals special care emphasis should be placed on addressing rejection sensitivity and lack of trust.
High Resolution Gamma Ray Spectroscopy at MHz Counting Rates With LaBr3 Scintillators for Fusion Plasma Applications

NASA Astrophysics Data System (ADS)

Nocente, M.; Tardocchi, M.; Olariu, A.; Olariu, S.; Pereira, R. C.; Chugunov, I. N.; Fernandes, A.; Gin, D. B.; Grosso, G.; Kiptily, V. G.; Neto, A.; Shevelev, A. E.; Silva, M.; Sousa, J.; Gorini, G.

2013-04-01

High resolution γ-ray spectroscopy measurements at MHz counting rates were carried out at nuclear accelerators, combining a LaBr 3(Ce) detector with dedicated hardware and software solutions based on digitization and off-line analysis. Spectra were measured at counting rates up to 4 MHz, with little or no degradation of the energy resolution, adopting a pile up rejection algorithm. The reported results represent a step forward towards the final goal of high resolution γ-ray spectroscopy measurements on a burning plasma device.
Titanium-Water Thermosyphon Gamma Radiation Effects and Results

NASA Technical Reports Server (NTRS)

Sanzi, James L.; Jaworske, Donald A.; Goodenow, Debra A.

2012-01-01

Titanium-water thermosyphons are being considered for use in heat rejection systems for fission power systems. Their proximity to the nuclear reactor will result in some exposure to gamma irradiation. Non-condensable gas formation from radiation may breakdown water over time and render a portion of the thermosyphon condenser inoperable. A series of developmental thermosyphons were operated at nominal operating temperature with accelerated gamma irradiation exposures on the same order of magnitude that is expected in eight years of heat rejection system operation. Temperature data were obtained during exposure at three locations on each thermosyphon; evaporator, condenser, and condenser end cap. Some non-condensable gas was evident, however thermosyphon performance was not affected because the non-condensable gas was compressed into the fill tube region at the top of the thermosyphon, away from the heat rejecting fin. The trend appeared to be an increasing amount of non-condensable gas formation with increasing gamma irradiation dose. Hydrogen is thought to be the most likely candidate for the non-condensable gas and hydrogen is known to diffuse through grain boundaries. Post-exposure evaluation of selected thermosyphons at temperature and in a vacuum chamber revealed that the non-condensable gas likely diffused out of the thermosyphons over a relatively short period of time. Further research shows a number of experimental and theoretical examples of radiolysis occurring through gamma radiation alone in pure water.
Blockade of Vascular Adhesion Protein-1 Inhibits Lymphocyte Infiltration in Rat Liver Allograft Rejection

PubMed Central

Martelius, Timi; Salaspuro, Ville; Salmi, Marko; Krogerus, Leena; Höckerstedt, Krister; Jalkanen, Sirpa; Lautenschlager, Irmeli

2004-01-01

Vascular adhesion protein-1 (VAP-1) has been shown to mediate lymphocyte adhesion to endothelia at sites of inflammation, but its functional role in vivo has not been tested in any rodent model. Here we report the effects of VAP-1 blockade on rat liver allograft rejection. BN recipients of PVG liver allografts (known to develop acute rejection by day 7) were treated with 2 mg/kg anti-VAP-1 (a new anti-rat VAP-1 mAb 174–5) or isotype-matched irrelevant antibody (NS1) every other day (n = 6/group) and one group with anti-VAP-1 2 mg/kg daily (n = 7). On day 7, samples were collected for transplant aspiration cytology, histology, and immunohistochemistry. Lymphocyte infiltration to the graft was clearly affected by VAP-blockade. The total inflammation, mainly the number of active lymphoid cells, in transplant aspiration cytology was significantly decreased in animals treated with anti-VAP-1 (4.7 ± 1.0 and 2.4 ± 1.0 corrected increment units, respectively) compared to control (6.6 ± 1.0) (P < 0.05). In histology, the intensity of portal inflammation was significantly decreased (P < 0.05). The amount of T cells expressing activation markers diminished. This is the first demonstration in any prolonged in vivo model that VAP-1 plays an important role in lymphocyte infiltration to sites of inflammation, and, in particular, liver allograft rejection. PMID:15579442
The problem with brain GUTs: conflation of different senses of "prediction" threatens metaphysical disaster.

PubMed

Anderson, Michael L; Chemero, Tony

2013-06-01

Clark appears to be moving toward epistemic internalism, which he once rightly rejected. This results from a double over-interpretation of predictive coding's significance. First, Clark argues that predictive coding offers a Grand Unified Theory (GUT) of brain function. Second, he over-reads its epistemic import, perhaps even conflating causal and epistemic mediators. We argue instead for a plurality of neurofunctional principles.
Bim regulates alloimmune-mediated vascular injury through effects on T-cell activation and death.

PubMed

von Rossum, Anna; Enns, Winnie; Shi, Yu P; MacEwan, Grace E; Malekesmaeli, Mehrnoush; Brinkman, Ryan; Choy, Jonathan C

2014-06-01

Bim is a proapoptotic Bcl-2 protein known to downregulate immune responses and to also be required for antigen-induced T-cell activation. However, it is not known how the effect of Bim on these offsetting processes determines the outcome of allogeneic immune responses. We have defined the role of Bim in regulating alloantigen-driven T-cell responses in a model of vascular rejection. Bim was required for proliferation of CD4 and CD8 T cells, and for interleukin-2 production, in T cells stimulated with alloantigen in vitro. Moreover, a partial reduction in Bim expression was sufficient to attenuate T-cell activation, whereas a complete elimination of Bim was required to prevent CD4 T-cell death in response to cytokine withdrawl. When alloimmune-mediated vascular rejection was examined using an aortic interposition model, there was significantly less intimal thickening in Bim(+/-), but not Bim(-/-), graft recipients. T-cell proliferation in response to allograft arteries was significantly reduced in both Bim(+/-) and Bim(-/-) mice, but cell death was attenuated only in Bim(-/-) animals. Bim controls both T-cell activation and death in response to alloantigen stimulation. These processes act cooperatively to determine the outcome of immune responses in allograft arteries. © 2014 American Heart Association, Inc.
Bim Regulates Alloimmune-Mediated Vascular Injury Through Effects on T Cell Activation and Death

PubMed Central

von Rossum, Anna; Enns, Winnie; Shi, Yu P.; MacEwan, Grace E.; Malekesmaeli, Mehrnoush; Brinkman, Ryan; Choy, Jonathan C.

2014-01-01

Objective Bim is a pro-apoptotic Bcl-2 protein known to down-regulate immune responses and to also be required for antigen-induced T cell activation. However, it is not known how the effect of Bim on these offsetting processes determines the outcome of allogeneic immune responses. We have defined the role of Bim in regulating alloantigen-driven T cell responses in a model of vascular rejection. Approach and Results Bim was required for proliferation of CD4 and CD8 T cells, and for IL-2 production, in T cells stimulated with alloantigen in vitro. Moreover, a partial reduction in Bim expression was sufficient to attenuate T cell activation whereas a complete elimination of Bim was required to prevent CD4 T cell death in response to cytokine withdrawl. When alloimmune-mediated vascular rejection was examined using an aortic interposition model, there was significantly less intimal thickening in Bim+/−, but not Bim−/−, graft recipients. T cell proliferation in response to allograft arteries was significantly reduced in both Bim+/− and Bim−/− mice, but cell death was attenuated only in Bim−/− animals. Conclusions Bim controls both T cell activation and death in response to alloantigen stimulation. These processes act cooperatively to determine the outcome of immune responses in allograft arteries. PMID:24700126
Desensitization for solid organ and hematopoietic stem cell transplantation.

PubMed

Zachary, Andrea A; Leffell, Mary S

2014-03-01

Desensitization protocols are being used worldwide to enable kidney transplantation across immunologic barriers, i.e. antibody to donor HLA or ABO antigens, which were once thought to be absolute contraindications to transplantation. Desensitization protocols are also being applied to permit transplantation of HLA mismatched hematopoietic stem cells to patients with antibody to donor HLA, to enhance the opportunity for transplantation of non-renal organs, and to treat antibody-mediated rejection. Although desensitization for organ transplantation carries an increased risk of antibody-mediated rejection, ultimately these transplants extend and enhance the quality of life for solid organ recipients, and desensitization that permits transplantation of hematopoietic stem cells is life saving for patients with limited donor options. Complex patient factors and variability in treatment protocols have made it difficult to identify, precisely, the mechanisms underlying the downregulation of donor-specific antibodies. The mechanisms underlying desensitization may differ among the various protocols in use, although there are likely to be some common features. However, it is likely that desensitization achieves a sort of immune detente by first reducing the immunologic barrier and then by creating an environment in which an autoregulatory process restricts the immune response to the allograft. © 2014 The Authors. Immunological Reviews Published by John Wiley & Sons Ltd.
Pig but not Human Interferon-γ Initiates Human Cell-Mediated Rejection of Pig Tissue in vivo

NASA Astrophysics Data System (ADS)

Sultan, Parvez; Murray, Allan G.; McNiff, Jennifer M.; Lorber, Marc I.; Askenase, Philip W.; Bothwell, Alfred L. M.; Pober, Jordan S.

1997-08-01

Split-thickness pig skin was transplanted on severe combined immunodeficient mice so that pig dermal microvessels spontaneously inosculated with mouse microvessels and functioned to perfuse the grafts. Pig endothelial cells in the healed grafts constitutively expressed class I and class II major histocompatibility complex molecules. Major histocompatibility complex molecule expression could be further increased by intradermal injection of pig interferon-γ (IFN-γ ) but not human IFN-γ or tumor necrosis factor. Grafts injected with pig IFN-γ also developed a sparse infiltrate of mouse neutrophils and eosinophils without evidence of injury. Introduction of human peripheral blood mononuclear cells into the animals by intraperitoneal inoculation resulted in sparse perivascular mononuclear cell infiltrates in the grafts confined to the pig dermis. Injection of pig skin grafts on mice that received human peripheral blood mononuclear cells with pig IFN-γ (but not human IFN-γ or heat-inactivated pig IFN-γ ) induced human CD4+ and CD8+ T cells and macrophages to more extensively infiltrate the pig skin grafts and injure pig dermal microvessels. These findings suggest that human T cell-mediated rejection of xenotransplanted pig organs may be prevented if cellular sources of pig interferon (e.g., passenger lymphocytes) are eliminated from the graft.

Breaking down the complement system: a review and update on novel therapies.

PubMed

Reddy, Yuvaram N V; Siedlecki, Andrew M; Francis, Jean M

2017-03-01

The complement system represents one of the more primitive forms of innate immunity. It has increasingly been found to contribute to pathologies in the native and transplanted kidney. We provide a concise review of the physiology of the complement cascade, and discuss current and upcoming complement-based therapies. Current agents in clinical use either bind to complement components directly or prevent complement from binding to antibodies affixed to the endothelial surface. These include C1 esterase inhibitors, anti-C5 mAbs, anti-CD20 mAbs, and proteasome inhibitors. Treatment continues to show efficacy in the atypical hemolytic uremic syndrome and antibody-mediated rejection. Promising agents not currently available include CCX168, TP10, AMY-101, factor D inhibitors, coversin, and compstatin. Several new trials are targeting complement inhibition to treat antineutrophilic cystoplasmic antibody (ANCA)-associated vasculitis, C3 glomerulopathy, thrombotic microangiopathy, and IgA nephropathy. New agents for the treatment of the atypical hemolytic uremic syndrome are also in development. Complement-based therapies are being considered for targeted therapy in the atypical hemolytic uremic syndrome and antibody-mediated rejection, C3 glomerulopathy, and ANCA-associated vasculitis. A few agents are currently in use as orphan drugs. A number of other drugs are in clinical trials and, overall, are showing promising preliminary results.
Human Cytomegalovirus Secretome Contains Factors That Induce Angiogenesis and Wound Healing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dumortier, Jerome; Streblow, Daniel N.; Moses, Ashlee V.

2008-07-01

Human cytomegalovirus (HCMV) is implicated in the acceleration of a number of vascular diseases including transplant vascular sclerosis (TVS), the lesion associated with chronic rejection (CR) of solid organ transplants. Although the virus persists in the allograft throughout the course of disease, few cells are directly infected by CMV. This observation is in contrast to the global effects that CMV has on the acceleration of TVS/CR, suggesting that CMV infection indirectly promotes the vascular disease process. Recent transcriptome analysis of CMV-infected heart allografts indicates that the virus induces cytokines and growth factors associated with angiogenesis (AG) and wound healing (WH),more » suggesting that CMV may accelerate TVS/CR through the induction and secretion of AG/WH factors from infected cells. We analyzed virus-free supernatants from HCMV-infected cells (HCMV secretomes) for growth factors, by mass spectrometry and immunoassays, and found that the HCMV secretome contains over 1,000 cellular proteins, many of which are involved in AG/WH. Importantly, functional assays demonstrated that CMV but not herpes simplex virus secretomes not only induce AG/WH but also promote neovessel stabilization and endothelial cell survival for 2 weeks. These findings suggest that CMV acceleration of TVS occurs through virus-induced growth factors and cytokines in the CMV secretome.« less
Assertive Anger Mediates Effects of Dialectical Behaviour-informed Skills Training for Borderline Personality Disorder: A Randomized Controlled Trial.

PubMed

Kramer, Ueli; Pascual-Leone, Antonio; Berthoud, Laurent; de Roten, Yves; Marquet, Pierre; Kolly, Stéphane; Despland, Jean-Nicolas; Page, Dominique

2016-05-01

Dialectical behaviour therapy (DBT)-informed skills training for borderline personality disorder (BPD) aims at the development of specific emotion regulation skills in patients, particularly with regard to the regulation of problematic anger. While the effects of dialectical behaviour skills training have been shown, their processes of change are rarely examined. Neacsiu, Rizvi and Linehan (2010) found that patient's self-reported use of emotion regulation skills was a mediator of therapeutic change in these treatments; however, they found no effect for problematic anger. From an integrative perspective on anger (Pascual-Leone & Greenberg, 2007; Pascual-Leone & Paivio, 2013), there are several forms of anger, varying in their degree of therapeutic productivity. The present add-on randomized controlled trial included n = 41 patients with BPD (n = 21 DBT-informed skills training versus n = 20 treatment as usual). The first study examined the outcome of the DBT-informed skills training encompassing basic components of training in mindfulness, distress tolerance, interpersonal effectiveness and emotion regulation. Results showed that symptom reduction was significantly greater in the DBT-informed skills training, compared with the treatment as usual. The second study used process assessment, for which all patient completers underwent a 50-min-long psychological interview both early and late in treatment, which was rated using the Classification of Affective Meaning States. DBT-informed skills training produced increased levels of primary 'assertive' anger, as compared with the treatment as usual, whereas no effect was found for 'rejecting' secondary anger. Most importantly, we showed that changes in assertive anger mediated the reported symptom reduction, in particular in patient's social roles. We discuss these results in the context of underlying mechanisms of change in DBT skills group treatments, in particular towards developing more productive forms of anger in this patient population. Copyright © 2015 John Wiley & Sons, Ltd. A 20-session dialectical behaviour therapy (DBT)-informed skills training is a promising adjunct intervention for patients with borderline personality disorder, in particular for reducing problems related to social role. Increases in assertive anger mediate the effects of DBT-informed skills training, whereas rejecting anger remains unchanged over the course of treatment. Short-term objectives for intervention might involve the specific increase of assertive anger in BPD, by using DBT-informed skills training; long-term objectives for intervention might involve a specific decrease of rejecting anger in BPD. Copyright © 2015 John Wiley & Sons, Ltd.
Irradiation performance of HTGR recycle fissile fuel

DOE Office of Scientific and Technical Information (OSTI.GOV)

Homan, F.J.; Long, E.L. Jr.

1976-08-01

The irradiation performance of candidate HTGR recycle fissile fuel under accelerated testing conditions is reviewed. Failure modes for coated-particle fuels are described, and the performance of candidate recycle fissile fuels is discussed in terms of these failure modes. The bases on which UO/sub 2/ and (Th,U)O/sub 2/ were rejected as candidate recycle fissile fuels are outlined, along with the bases on which the weak-acid resin (WAR)-derived fissile fuel was selected as the reference recycle kernel. Comparisons are made relative to the irradiation behavior of WAR-derived fuels of varying stoichiometry and conclusions are drawn about the optimum stoichiometry and the rangemore » of acceptable values. Plans for future testing in support of specification development, confirmation of the results of accelerated testing by real-time experiments, and improvement in fuel performance and reliability are described.« less
Gravitational modulation of thermosolutal convection during directional solidification

NASA Astrophysics Data System (ADS)

Murray, B. T.; Coriell, S. R.; McFadden, G. B.; Wheeler, A. A.; Saunders, B. V.

1993-03-01

During directional solidification of a binary alloy at constant velocity, thermosolutal convection may occur due to the temperature and solute gradients associated with the solidification process. For vertical growth in an ideal furnace (lacking horizontal gradients) a quiescent state is possible. The effect of a time-periodic vertical gravitational acceleration (or equivalently vibration) on the onset of thermosolutal convection is calculated based on linear stability using Floquet theory. Numerical calculations for the onset of instability have been carried out for a semiconductor alloy with Schmidt number of 10 and Prandtl number of 0.1 with primary emphasis on large modulation frequencies in a microgravity environment for which the background gravitational acceleration is negligible. The numerical results demonstrate that there is a significant difference in stability depending on whether a heavier or lighter solute is rejected. For large modulation frequencies, the stability behavior can be described by either the method of averaging or an asymptotic resonant mode analysis.
Pleiotrophin mediates hematopoietic regeneration via activation of RAS.

PubMed

Himburg, Heather A; Yan, Xiao; Doan, Phuong L; Quarmyne, Mamle; Micewicz, Eva; McBride, William; Chao, Nelson J; Slamon, Dennis J; Chute, John P

2014-11-01

Hematopoietic stem cells (HSCs) are highly susceptible to ionizing radiation-mediated death via induction of ROS, DNA double-strand breaks, and apoptotic pathways. The development of therapeutics capable of mitigating ionizing radiation-induced hematopoietic toxicity could benefit both victims of acute radiation sickness and patients undergoing hematopoietic cell transplantation. Unfortunately, therapies capable of accelerating hematopoietic reconstitution following lethal radiation exposure have remained elusive. Here, we found that systemic administration of pleiotrophin (PTN), a protein that is secreted by BM-derived endothelial cells, substantially increased the survival of mice following radiation exposure and after myeloablative BM transplantation. In both models, PTN increased survival by accelerating the recovery of BM hematopoietic stem and progenitor cells in vivo. PTN treatment promoted HSC regeneration via activation of the RAS pathway in mice that expressed protein tyrosine phosphatase receptor-zeta (PTPRZ), whereas PTN treatment did not induce RAS signaling in PTPRZ-deficient mice, suggesting that PTN-mediated activation of RAS was dependent upon signaling through PTPRZ. PTN strongly inhibited HSC cycling following irradiation, whereas RAS inhibition abrogated PTN-mediated induction of HSC quiescence, blocked PTN-mediated recovery of hematopoietic stem and progenitor cells, and abolished PTN-mediated survival of irradiated mice. These studies demonstrate the therapeutic potential of PTN to improve survival after myeloablation and suggest that PTN-mediated hematopoietic regeneration occurs in a RAS-dependent manner.
Delinquency as a Mediator of the Relation between Negative Affectivity and Adolescent Alcohol Use Disorder

PubMed Central

Shoal, Gavin D.; Gudonis, Lauren C.; Giancola, Peter R.; Tarter, Ralph E.

2007-01-01

This investigation examined mediators of the longitudinal relation between negative affectivity and the development of problematic drinking behavior in adolescent boys and girls. In the present study, 499 early adolescents completed inventories of negative affectivity, attitudes toward delinquency, personal delinquency, and affiliation with delinquent peers. Positive attitudes toward delinquency emerged as the most consistent mediator and strongly predicted drinking frequency in various situations. Compared with personal delinquency, both attitudes toward delinquency and peer delinquency were superior predictors of affect-related drinking. Our results also demonstrated that positive attitudes toward delinquency mediated the relation between negative affectivity and later development of an alcohol use disorder. These findings suggest that a proneness to unpleasant affect impacts adolescent drinking by heightening risk for general rejection of normative behavior, rather than by increasing drinking as a means of managing affect. The importance and implications of testing delinquency variables together in the same model are discussed. PMID:17490823
Food-Experience Induced Taste Desensitization Modulated by the Drosophila TRPL Channel

PubMed Central

Zhang, Yali V.; Raghuwanshi, Rakesh P.; Shen, Wei L.; Montell, Craig

2013-01-01

Animals tend to reject bitter foods. However, long-term exposure to some unpalatable tastants increases acceptance of the foods. Here, we showed that dietary exposure to the unappealing food but safe additive, camphor, caused the fruit fly, Drosophila melanogaster, to decrease camphor rejection. The TRPL cation channel was a direct target for camphor in gustatory receptor neurons (GRNs), and long-term feeding on a camphor diet led to reversible down-regulation of TRPL protein levels. The turnover of TRPL was controlled by an E3 ubiquitin ligase, Ube3a. The decline in TRPL levels and increased acceptance of camphor reversed after returning the flies long-term to a camphor-free diet. We propose that dynamic regulation of taste receptor levels by ubiquitin-mediated protein degradation comprises an important molecular mechanism that allows an animal to alter taste behavior in response to a changing food environment. PMID:24013593
Familiarity facilitates feature-based face processing.

PubMed

Visconti di Oleggio Castello, Matteo; Wheeler, Kelsey G; Cipolli, Carlo; Gobbini, M Ida

2017-01-01

Recognition of personally familiar faces is remarkably efficient, effortless and robust. We asked if feature-based face processing facilitates detection of familiar faces by testing the effect of face inversion on a visual search task for familiar and unfamiliar faces. Because face inversion disrupts configural and holistic face processing, we hypothesized that inversion would diminish the familiarity advantage to the extent that it is mediated by such processing. Subjects detected personally familiar and stranger target faces in arrays of two, four, or six face images. Subjects showed significant facilitation of personally familiar face detection for both upright and inverted faces. The effect of familiarity on target absent trials, which involved only rejection of unfamiliar face distractors, suggests that familiarity facilitates rejection of unfamiliar distractors as well as detection of familiar targets. The preserved familiarity effect for inverted faces suggests that facilitation of face detection afforded by familiarity reflects mostly feature-based processes.
The Influence of Personality, Parental Behaviors, and Self-Esteem on Internet Addiction: A Study of Chinese College Students

PubMed Central

Yao, Mike Z.; Ko, Deborah M.; Pang, Kaichung

2014-01-01

Abstract A survey of 2,095 college students in five major cities in China was conducted to examine the influence of personality, parental behaviors, and self-esteem on Internet addiction. We found that psychoticism and neuroticism were both positively related to Internet addiction. The influence of parental behaviors on Internet addition was also significant. However, fathers' and mothers' behaviors had different impacts on their children's likelihood of being addicted to the Internet. Specifically, we found that fathers' rejection and overprotection, and mothers' rejection would increase the risk for Internet addiction. Furthermore, the influence of emotional warmth from parents on Internet addiction was partially mediated by self-esteem. Finally, we found that parental behaviors of mothers and fathers affected males and females differently in terms the risk of being addicted to the Internet. PMID:24003966
HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients

PubMed Central

Chapman, Jeremy R.; Coates, Patrick T.; Lewis, Joshua R.; Russ, Graeme R.; Watson, Narelle; Holdsworth, Rhonda; Wong, Germaine

2016-01-01

Background and objectives The current allocation algorithm for deceased donor kidney transplantation takes into consideration HLA mismatches at the ABDR loci but not HLA mismatches at other loci, including HLA-DQ. However, the independent effects of incompatibilities for the closely linked HLA-DQ antigens in the context of HLA-DR antigen matched and mismatched allografts are uncertain. We aimed to determine the effect of HLA-DQ mismatches on renal allograft outcomes. Design, setting, participants, & measurements Using data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the association between HLA-DQ mismatches and acute rejections in primary live and deceased donor kidney transplant recipients between 2004 and 2012 using adjusted Cox regression models. Results Of the 788 recipients followed for a median of 2.8 years (resulting in 2891 person-years), 321 (40.7%) and 467 (59.3%) received zero and one or two HLA-DQ mismatched kidneys, respectively. Compared with recipients who have received zero HLA-DQ mismatched kidneys, those who have received one or two HLA-DQ mismatched kidneys experienced greater numbers of any rejection (50 of 321 versus 117 of 467; P<0.01), late rejections (occurring >6 months post-transplant; 8 of 321 versus 27 of 467; P=0.03), and antibody-mediated rejections (AMRs; 12 of 321 versus 38 of 467; P=0.01). Compared with recipients of zero HLA-DQ mismatched kidneys, the adjusted hazard ratios for any and late rejections in recipients who had received one or two HLA-DQ mismatched kidneys were 1.54 (95% confidence interval [95% CI], 1.08 to 2.19) and 2.85 (95% CI, 1.05 to 7.75), respectively. HLA-DR was an effect modifier between HLA-DQ mismatches and AMR (P value for interaction =0.02), such that the association between HLA-DQ mismatches and AMR was statistically significant in those who have received one or two HLA-DR mismatched kidneys, with adjusted hazard ratio of 2.50 (95% CI, 1.05 to 5.94). Conclusions HLA-DQ mismatches are associated with acute rejection, independent of HLA-ABDR mismatches and initial immunosuppression. Clinicians should be aware of the potential importance of HLA-DQ matching in the assessment of immunologic risk in kidney transplant recipients. PMID:27034399
Development of a Novel Therapeutic Paradigm Utilizing a Mammary Gland-Targeted, Bin 1-Knockout Mouse Model

DTIC Science & Technology

2006-03-01

tumors initiated by treatment with the carcinogen 7, 12- dimethylbenz[α]anthracene (DMBA). In these experiments, the synthetic progesterone ... medroxyprogesterone acetate (MPA) has also been administered to increase tumor frequency, decrease tumor latency and reduce non-tumor related morbidity and...of T cell-mediated rejection. Int. J. Cancer 101, 151-5 (2002). 4. Aldaz, C.M., Liao, Q.Y., LaBate, M. & Johnston, D.A. Medroxyprogesterone acetate
Copyright Considerations in Distance Education and Technology-Mediated Instruction.

ERIC Educational Resources Information Center

Salomon, Kenneth D.

The accelerating development of distance education and the use of technology-mediated instructional materials over interactive computer networks has given rise to heightened interest and thought by faculty and administration alike about related copyright issues. The evolution of distance education from early morning television broadcasts to…
Chronic pancreatitis: Do serum biomarkers provide an association with an inflammageing phenotype?

PubMed

Rasch, Sebastian; Valantiene, Irena; Mickevicius, Artautas; Beer, Sebastian; Rosendahl, Jonas; Charnley, Richard M; Robinson, Stuart M

2016-01-01

Chronic pancreatitis is an inflammatory disorder of the pancreas that is associated with accelerated mortality for patients suffering from this disease. The association between chronic inflammation and accelerated biological ageing has been well described and is often referred to as "inflammageing". In this review we seek to determine how systemic inflammation in chronic pancreatitis may contribute to an accelerated ageing phenotype. A systematic literature search with a predefined search protocol was performed on Medline, Embase and Cochrane libraries according to the PRISMA guidelines. The initial search identified 499 studies. After title, abstract and full text screen of the search results, 20 were included for further evaluation. In the 20 remaining articles 41 inflammatory mediators were identified - mainly involved in chronic inflammation, fibrosis and particularly cardinal features of inflammageing such as sarcopenia and osteoporosis. Chronic pancreatitis is associated with elevated levels of inflammatory mediators many of which are associated with an accelerated ageing phenotype and may explain some of the clinical sequelae of this disease. Copyright © 2016 IAP and EPC. All rights reserved.
Clinical and immunological relevance of antibodies in solid organ transplantation.

PubMed

Mehra, N K; Baranwal, A K

2016-12-01

The two important issues affecting recipients of solid organ transplants and of importance to immunologists are (i) sensitization of the recipient to HLA antigens and the resultant humoral immune response leading to the development of anti-HLA antibodies; and ii) development of robust assays for early detection of humoral rejection post-transplant. Evidence from several studies clearly indicates that presence of circulating anti-HLA antibodies especially donor specific leads to early graft loss and high titres of DSA may even lead to hyperacute or accelerated acute rejection. Long-term graft survival too is adversely affected by the presence of either pre- or post-transplant DSA. HLA matching status of the recipient - donor pair - is an important factor in the modulation of humoral response following transplantation and in a way affects de novo development of DSA. Data collected over the past decade clearly indicate significantly lower level of DSAs in optimally matched donor-recipient pairs. HLA mismatches especially those on HLA-DR and HLA-C loci have wider implications on post-transplant graft survival. The presence of circulating anti-HLA antibodies leads to endothelial damage in the newly grafted organ through complement dependent or independent pathways. Although detection of C4d deposition in renal biopsies serves as an important indicator of humoral rejection, its absence does not preclude the presence of DSAs and humoral rejection, and hence, it cannot be relied upon in every case. The emergence of epitope-based screening for anti-HLA antibodies on Luminex platform with high degree of sensitivity has revolutionized the screening for anti-HLA antibodies and DSAs. Studies indicate that humoral response to non-HLA antigens might also have a detrimental effect on allograft survival. High titres of such circulating antibodies may even lead to hyperacute rejection. Pre-emptive testing of solid organ recipients, especially kidney transplant recipients for anti-HLA and non-HLA antibodies and aggressive post-transplant monitoring of allograft function to detect DSAs using Luminex-based tests, is highly recommended. © 2016 John Wiley & Sons Ltd.
Kinetic Simulations of Particle Acceleration at Shocks

DOE Office of Scientific and Technical Information (OSTI.GOV)

Caprioli, Damiano; Guo, Fan

2015-07-16

Collisionless shocks are mediated by collective electromagnetic interactions and are sources of non-thermal particles and emission. The full particle-in-cell approach and a hybrid approach are sketched, simulations of collisionless shocks are shown using a multicolor presentation. Results for SN 1006, a case involving ion acceleration and B field amplification where the shock is parallel, are shown. Electron acceleration takes place in planetary bow shocks and galaxy clusters. It is concluded that acceleration at shocks can be efficient: >15%; CRs amplify B field via streaming instability; ion DSA is efficient at parallel, strong shocks; ions are injected via reflection and shockmore » drift acceleration; and electron DSA is efficient at oblique shocks.« less
Combination Immunotherapy of B16 Melanoma Using Anti–Cytotoxic T Lymphocyte–Associated Antigen 4 (Ctla-4) and Granulocyte/Macrophage Colony-Stimulating Factor (Gm-Csf)-Producing Vaccines Induces Rejection of Subcutaneous and Metastatic Tumors Accompanied by Autoimmune Depigmentation

PubMed Central

van Elsas, Andrea; Hurwitz, Arthur A.; Allison, James P.

1999-01-01

We examined the effectiveness of cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) blockade, alone or in combination with a granulocyte/macrophage colony-stimulating factor (GM-CSF)–expressing tumor cell vaccine, on rejection of the highly tumorigenic, poorly immunogenic murine melanoma B16-BL6. Recently established tumors could be eradicated in 80% (68/85) of the cases using combination treatment, whereas each treatment by itself showed little or no effect. Tumor rejection was dependent on CD8+ and NK1.1+ cells but occurred irrespective of the presence of CD4+ T cells. Mice surviving a primary challenge rejected a secondary challenge with B16-BL6 or the parental B16-F0 line. The same treatment regimen was found to be therapeutically effective against outgrowth of preestablished B16-F10 lung metastases, inducing long-term survival. Of all mice surviving B16-BL6 or B16-F10 tumors after combination treatment, 56% (38/68) developed depigmentation, starting at the site of vaccination or challenge and in most cases progressing to distant locations. Depigmentation was found to occur in CD4-depleted mice, strongly suggesting that the effect was mediated by CTLs. This study shows that CTLA-4 blockade provides a powerful tool to enhance T cell activation and memory against a poorly immunogenic spontaneous murine tumor and that this may involve recruitment of autoreactive T cells. PMID:10430624
Identification of Therapeutic Targets of Inflammatory Monocyte Recruitment to Modulate the Allogeneic Injury to Donor Cornea.

PubMed

Lapp, Thabo; Zaher, Sarah S; Haas, Carolin T; Becker, David L; Thrasivoulou, Chris; Chain, Benjamin M; Larkin, Daniel F P; Noursadeghi, Mahdad

2015-11-01

We sought to test the hypothesis that monocytes contribute to the immunopathogenesis of corneal allograft rejection and identify therapeutic targets to inhibit monocyte recruitment. Monocytes and proinflammatory mediators within anterior chamber samples during corneal graft rejection were quantified by flow cytometry and multiplex protein assays. Lipopolysaccharide or IFN-γ stimulation of monocyte-derived macrophages (MDMs) was used to generate inflammatory conditioned media (CoM). Corneal endothelial viability was tested by nuclear counting, connexin 43, and propidium iodide staining. Chemokine and chemokine receptor expression in monocytes and MDMs was assessed in microarray transcriptomic data. The role of chemokine pathways in monocyte migration across microvascular endothelium was tested in vitro by chemokine depletion or chemokine receptor inhibitors. Inflammatory monocytes were significantly enriched in anterior chamber samples within 1 week of the onset of symptoms of corneal graft rejection. The MDM inflammatory CoM was cytopathic to transformed human corneal endothelia. This effect was also evident in endothelium of excised human cornea and increased in the presence of monocytes. Gene expression microarrays identified monocyte chemokine receptors and cognate chemokines in MDM inflammatory responses, which were also enriched in anterior chamber samples. Depletion of selected chemokines in MDM inflammatory CoM had no effect on monocyte transmigration across an endothelial blood-eye barrier, but selective chemokine receptor inhibition reduced monocyte recruitment significantly. We propose a role for inflammatory monocytes in endothelial cytotoxicity in corneal graft rejection. Therefore, targeting monocyte recruitment offers a putative novel strategy to reduce donor endothelial cell injury in survival of human corneal allografts.
Intragraft Molecular Pathways Associated with Tolerance Induction in Renal Transplantation.

PubMed

Gallon, Lorenzo; Mathew, James M; Bontha, Sai Vineela; Dumur, Catherine I; Dalal, Pranav; Nadimpalli, Lakshmi; Maluf, Daniel G; Shetty, Aneesha A; Ildstad, Suzanne T; Leventhal, Joseph R; Mas, Valeria R

2018-02-01

The modern immunosuppression regimen has greatly improved short-term allograft outcomes but not long-term allograft survival. Complications associated with immunosuppression, specifically nephrotoxicity and infection risk, significantly affect graft and patient survival. Inducing and understanding pathways underlying clinical tolerance after transplantation are, therefore, necessary. We previously showed full donor chimerism and immunosuppression withdrawal in highly mismatched allograft recipients using a bioengineered stem cell product (FCRx). Here, we evaluated the gene expression and microRNA expression profiles in renal biopsy samples from tolerance-induced FCRx recipients, paired donor organs before implant, and subjects under standard immunosuppression (SIS) without rejection and with acute rejection. Unlike allograft samples showing acute rejection, samples from FCRx recipients did not show upregulation of T cell- and B cell-mediated rejection pathways. Gene expression pathways differed slightly between FCRx samples and the paired preimplantation donor organ samples, but most of the functional gene networks overlapped. Notably, compared with SIS samples, FCRx samples showed upregulation of genes involved in pathways, like B cell receptor signaling. Additionally, prediction analysis showed inhibition of proinflammatory regulators and activation of anti-inflammatory pathways in FCRx samples. Furthermore, integrative analyses (microRNA and gene expression profiling from the same biopsy sample) identified the induction of regulators with demonstrated roles in the downregulation of inflammatory pathways and maintenance of tissue homeostasis in tolerance-induced FCRx samples compared with SIS samples. This pilot study highlights the utility of molecular intragraft evaluation of pathways related to FCRx-induced tolerance and the use of integrative analyses for identifying upstream regulators of the affected downstream molecular pathways. Copyright © 2018 by the American Society of Nephrology.
Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation.

PubMed

van Elsas, A; Hurwitz, A A; Allison, J P

1999-08-02

We examined the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade, alone or in combination with a granulocyte/macrophage colony-stimulating factor (GM-CSF)-expressing tumor cell vaccine, on rejection of the highly tumorigenic, poorly immunogenic murine melanoma B16-BL6. Recently established tumors could be eradicated in 80% (68/85) of the cases using combination treatment, whereas each treatment by itself showed little or no effect. Tumor rejection was dependent on CD8(+) and NK1.1(+) cells but occurred irrespective of the presence of CD4(+) T cells. Mice surviving a primary challenge rejected a secondary challenge with B16-BL6 or the parental B16-F0 line. The same treatment regimen was found to be therapeutically effective against outgrowth of preestablished B16-F10 lung metastases, inducing long-term survival. Of all mice surviving B16-BL6 or B16-F10 tumors after combination treatment, 56% (38/68) developed depigmentation, starting at the site of vaccination or challenge and in most cases progressing to distant locations. Depigmentation was found to occur in CD4-depleted mice, strongly suggesting that the effect was mediated by CTLs. This study shows that CTLA-4 blockade provides a powerful tool to enhance T cell activation and memory against a poorly immunogenic spontaneous murine tumor and that this may involve recruitment of autoreactive T cells.

Immune response and histology of humoral rejection in kidney transplantation.

PubMed

González-Molina, Miguel; Ruiz-Esteban, Pedro; Caballero, Abelardo; Burgos, Dolores; Cabello, Mercedes; Leon, Miriam; Fuentes, Laura; Hernandez, Domingo

2016-01-01

The adaptive immune response forms the basis of allograft rejection. Its weapons are direct cellular cytotoxicity, identified from the beginning of organ transplantation, and/or antibodies, limited to hyperacute rejection by preformed antibodies and not as an allogenic response. This resulted in allogenic response being thought for decades to have just a cellular origin. But the experimental studies by Gorer demonstrating tissue damage in allografts due to antibodies secreted by B lymphocytes activated against polymorphic molecules were disregarded. The special coexistence of binding and unbinding between antibodies and antigens of the endothelial cell membranes has been the cause of the delay in demonstrating the humoral allogenic response. The endothelium, the target tissue of antibodies, has a high turnover, and antigen-antibody binding is non-covalent. If endothelial cells are attacked by the humoral response, immunoglobulins are rapidly removed from their surface by shedding and/or internalization, as well as degrading the components of the complement system by the action of MCP, DAF and CD59. Thus, the presence of complement proteins in the membrane of endothelial cells is transient. In fact, the acute form of antibody-mediated rejection was not demonstrated until C4d complement fragment deposition was identified, which is the only component that binds covalently to endothelial cells. This review examines the relationship between humoral immune response and the types of acute and chronic histological lesion shown on biopsy of the transplanted organ. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.
Relevance of MICA and other non-HLA antibodies in clinical transplantation.

PubMed

Sumitran-Holgersson, Suchitra

2008-10-01

The clinical importance of HLA-specific antibodies for organ allograft outcome is well established. In the past few years, there has been an increasing interest in non-HLA antigens as targets of injury in organ transplant recipients. This increased interest has been spurred by the fact that HLA-identical kidney transplants also undergo immunological rejections. Polymorphisms within non-HLA genes associated with evoking an immune response to alloantigens are currently being studied for their association with transplant outcome. Non-HLA antigens, such as the polymorphic MHC class I-related chain A (MICA), expressed on endothelial cells have been implicated in the pathogenesis of hyperacute, acute and chronic organ allograft rejections. Use of endothelial cells as targets may clarify the specificities of other clinically relevant non-HLA antibodies in graft rejections. This review summarizes past and current knowledge of the clinical importance and specificities of non-HLA antibodies, and mechanisms by which these antibodies may contribute to graft destruction in clinical transplantation. The aims of current research into the role of non-HLA antigens and their genetics in predicting outcome are to develop an improved insight into the basic science of transplantation and to develop a risk or prognostic index for use in the clinical setting. Non-HLA antibody responses are receiving increasing interest in acute and chronic rejection and specificity, affinity, and pathogenicity need to be investigated to estimate their contribution. Undoubtedly, this will continue to be an area of interest in terms of fully understanding the role of non-HLA antigens as targets of immune-mediated injury and the potential for clinical intervention.
A Comparison of Three Tests of Mediation

ERIC Educational Resources Information Center

Warbasse, Rosalia E.

2009-01-01

A simulation study was conducted to evaluate the performance of three tests of mediation: the bias-corrected and accelerated bootstrap (Efron & Tibshirani, 1993), the asymmetric confidence limits test (MacKinnon, 2008), and a multiple regression approach described by Kenny, Kashy, and Bolger (1998). The evolution of these methods is reviewed and…
Antenna Linear-Quadratic-Gaussian (LQG) Ccontrollers: Properties, Limits of Performance, and Tuning

NASA Technical Reports Server (NTRS)

Gawronski, Wodek K.

2004-01-01

The LQG controllers significantly improve antenna tracking precision, but their tuning is a trial-and-error process. A control engineer has two tools to tune an LQG controller: the choice of coordinate system of the controller, and the selection of weights of the LQG performance index. The paper selects the coordinates of the open-loop model that simplify the shaping of the closed-loop performance. and analyzes the impact of thc weights on the antenna closed-loop bandwidth, disturbance rejection properties, and antenna acceleration. Finally, it presents the LQG controller tuning procedure that rationally shapes the closed-loop performance.
Honesty mediates the relationship between serotonin and reaction to unfairness

PubMed Central

Takahashi, Hidehiko; Takano, Harumasa; Camerer, Colin F.; Ideno, Takashi; Okubo, Shigetaka; Matsui, Hiroshi; Tamari, Yuki; Takemura, Kazuhisa; Arakawa, Ryosuke; Kodaka, Fumitoshi; Yamada, Makiko; Eguchi, Yoko; Murai, Toshiya; Okubo, Yoshiro; Kato, Motoichiro; Ito, Hiroshi; Suhara, Tetsuya

2012-01-01

How does one deal with unfair behaviors? This subject has long been investigated by various disciplines including philosophy, psychology, economics, and biology. However, our reactions to unfairness differ from one individual to another. Experimental economics studies using the ultimatum game (UG), in which players must decide whether to accept or reject fair or unfair offers, have also shown that there are substantial individual differences in reaction to unfairness. However, little is known about psychological as well as neurobiological mechanisms of this observation. We combined a molecular imaging technique, an economics game, and a personality inventory to elucidate the neurobiological mechanism of heterogeneous reactions to unfairness. Contrary to the common belief that aggressive personalities (impulsivity or hostility) are related to the high rejection rate of unfair offers in UG, we found that individuals with apparently peaceful personalities (straightforwardness and trust) rejected more often and were engaged in personally costly forms of retaliation. Furthermore, individuals with a low level of serotonin transporters in the dorsal raphe nucleus (DRN) are honest and trustful, and thus cannot tolerate unfairness, being candid in expressing their frustrations. In other words, higher central serotonin transmission might allow us to behave adroitly and opportunistically, being good at playing games while pursuing self-interest. We provide unique neurobiological evidence to account for individual differences of reaction to unfairness. PMID:22371595
A televised entertainment-education drama to promote positive discussion about organ donation

PubMed Central

Khalil, Georges E.; Rintamaki, Lance S.

2014-01-01

This article investigates pathways between the exposure to an entertainment-education (E-E) television drama called Three Rivers and positive discussion of organ donation among viewers of the drama in the United States. A cross-sectional survey was conducted using an online advertising for a period of one week. Survey participants included 1325 adults living in the United States, who had viewed the first episode of Three Rivers on television. Data were collected on recall of events in the storyline, perceived entertainment value, perceived accuracy of the presented health information, rejection of organ donation myths and positive discussion of organ donation and the storyline. Covariates were registration for organ donation, membership to the donation or transplant community and demographic variables. Results show that viewers with high recall of the storyline were more likely to reject myths about organ donation and engage in pro-donation discussions with others. Perceived entertainment value and perceived accuracy acted as mediators in such relationships. The insertion of accurate health information in television drama may be effective in promoting positive discussions about organ donation and myth rejection. Recall of events from the televised E-E drama Three Rivers, entertainment value and accuracy perception were associated with positive discussion. PMID:24399264
Honesty mediates the relationship between serotonin and reaction to unfairness.

PubMed

Takahashi, Hidehiko; Takano, Harumasa; Camerer, Colin F; Ideno, Takashi; Okubo, Shigetaka; Matsui, Hiroshi; Tamari, Yuki; Takemura, Kazuhisa; Arakawa, Ryosuke; Kodaka, Fumitoshi; Yamada, Makiko; Eguchi, Yoko; Murai, Toshiya; Okubo, Yoshiro; Kato, Motoichiro; Ito, Hiroshi; Suhara, Tetsuya

2012-03-13

How does one deal with unfair behaviors? This subject has long been investigated by various disciplines including philosophy, psychology, economics, and biology. However, our reactions to unfairness differ from one individual to another. Experimental economics studies using the ultimatum game (UG), in which players must decide whether to accept or reject fair or unfair offers, have also shown that there are substantial individual differences in reaction to unfairness. However, little is known about psychological as well as neurobiological mechanisms of this observation. We combined a molecular imaging technique, an economics game, and a personality inventory to elucidate the neurobiological mechanism of heterogeneous reactions to unfairness. Contrary to the common belief that aggressive personalities (impulsivity or hostility) are related to the high rejection rate of unfair offers in UG, we found that individuals with apparently peaceful personalities (straightforwardness and trust) rejected more often and were engaged in personally costly forms of retaliation. Furthermore, individuals with a low level of serotonin transporters in the dorsal raphe nucleus (DRN) are honest and trustful, and thus cannot tolerate unfairness, being candid in expressing their frustrations. In other words, higher central serotonin transmission might allow us to behave adroitly and opportunistically, being good at playing games while pursuing self-interest. We provide unique neurobiological evidence to account for individual differences of reaction to unfairness.
Vav1 GEF activity is required for T cell mediated allograft rejection.

PubMed

Haubert, Dirk; Li, Jianping; Saveliev, Alexander; Calzascia, Thomas; Sutter, Esther; Metzler, Barbara; Kaiser, Daniel; Tybulewicz, Victor L J; Weckbecker, Gisbert

2012-06-01

The GDP exchange factor (GEF) Vav1 is a central signal transducer downstream of the T cell receptor and has been identified as a key factor for T cell activation in the context of allograft rejection. Vav1 has been shown to transduce signals both dependent and independent of its GEF function. The most promising approach to disrupt Vav1 activity by pharmacological inhibition would be to target its GEF function. However, the contribution of Vav1 GEF activity for allogeneic T cell activation has not been clarified yet. To address this question, we used knock-in mice bearing a mutated Vav1 with disrupted GEF activity but intact GEF-independent functions. T cells from these mice showed strongly reduced proliferation and activation in response to allogeneic stimulation. Furthermore, lack of Vav1 GEF activity strongly abrogated the in vivo expansion of T cells in a systemic graft-versus-host model. In a cardiac transplantation model, mice with disrupted Vav1 GEF activity show prolonged allograft survival. These findings demonstrate a strong requirement for Vav1 GEF activity for allogeneic T cell activation and graft rejection suggesting that disruption of Vav1 GEF activity alone is sufficient to induce significant immunosuppression. Copyright © 2012 Elsevier B.V. All rights reserved.
Transgenic expression of human heme oxygenase-1 in pigs confers resistance against xenograft rejection during ex vivo perfusion of porcine kidneys.

PubMed

Petersen, Björn; Ramackers, Wolf; Lucas-Hahn, Andrea; Lemme, Erika; Hassel, Petra; Queisser, Anna-Lisa; Herrmann, Doris; Barg-Kues, Brigitte; Carnwath, Joseph W; Klose, Johannes; Tiede, Andreas; Friedrich, Lars; Baars, Wiebke; Schwinzer, Reinhard; Winkler, Michael; Niemann, Heiner

2011-01-01

The major immunological hurdle to successful porcine-to-human xenotransplantation is the acute vascular rejection (AVR), characterized by endothelial cell (EC) activation and perturbation of coagulation. Heme oxygenase-1 (HO-1) and its derivatives have anti-apoptotic, anti-inflammatory effects and protect against reactive oxygen species, rendering HO-1 a promising molecule to control AVR. Here, we report the production and characterization of pigs transgenic for human heme oxygenase-1 (hHO-1) and demonstrate significant protection in porcine kidneys against xenograft rejection in ex vivo perfusion with human blood and transgenic porcine aortic endothelial cells (PAEC) in a TNF-α-mediated apoptosis assay. Transgenic and non-transgenic PAEC were tested in a TNF-α-mediated apoptosis assay. Expression of adhesion molecules (ICAM-1, VCAM-1, and E-selectin) was measured by real-time PCR. hHO-1 transgenic porcine kidneys were perfused with pooled and diluted human AB blood in an ex vivo perfusion circuit. MHC class-II up-regulation after induction with IFN-γ was compared between wild-type and hHO-1 transgenic PAEC. Cloned hHO-1 transgenic pigs expressed hHO-1 in heart, kidney, liver, and in cultured ECs and fibroblasts. hHO-1 transgenic PAEC were protected against TNF-α-mediated apoptosis. Real-time PCR revealed reduced expression of adhesion molecules like ICAM-1, VCAM-1, and E-selectin. These effects could be abrogated by the incubation of transgenic PAECs with the specific HO-1 inhibitor zinc protoporphorine IX (Zn(II)PPIX, 20 μm). IFN-γ induced up-regulation of MHC class-II molecules was significantly reduced in PAECs from hHO-1 transgenic pigs. hHO-1 transgenic porcine kidneys could successfully be perfused with diluted human AB-pooled blood for a maximum of 240 min (with and without C1 inh), while in wild-type kidneys, blood flow ceased after ∼60 min. Elevated levels of d-Dimer and TAT were detected, but no significant consumption of fibrinogen and antithrombin was determined. Microthrombi could not be detected histologically. These results are encouraging and warrant further studies on the biological function of heme oxygenase-I expression in hHO-1 transgenic pigs in the context of xenotransplantation. © 2011 John Wiley & Sons A/S.
Pleiotrophin mediates hematopoietic regeneration via activation of RAS

PubMed Central

Himburg, Heather A.; Yan, Xiao; Doan, Phuong L.; Quarmyne, Mamle; Micewicz, Eva; McBride, William; Chao, Nelson J.; Slamon, Dennis J.; Chute, John P.

2014-01-01

Hematopoietic stem cells (HSCs) are highly susceptible to ionizing radiation–mediated death via induction of ROS, DNA double-strand breaks, and apoptotic pathways. The development of therapeutics capable of mitigating ionizing radiation–induced hematopoietic toxicity could benefit both victims of acute radiation sickness and patients undergoing hematopoietic cell transplantation. Unfortunately, therapies capable of accelerating hematopoietic reconstitution following lethal radiation exposure have remained elusive. Here, we found that systemic administration of pleiotrophin (PTN), a protein that is secreted by BM-derived endothelial cells, substantially increased the survival of mice following radiation exposure and after myeloablative BM transplantation. In both models, PTN increased survival by accelerating the recovery of BM hematopoietic stem and progenitor cells in vivo. PTN treatment promoted HSC regeneration via activation of the RAS pathway in mice that expressed protein tyrosine phosphatase receptor-zeta (PTPRZ), whereas PTN treatment did not induce RAS signaling in PTPRZ-deficient mice, suggesting that PTN-mediated activation of RAS was dependent upon signaling through PTPRZ. PTN strongly inhibited HSC cycling following irradiation, whereas RAS inhibition abrogated PTN-mediated induction of HSC quiescence, blocked PTN-mediated recovery of hematopoietic stem and progenitor cells, and abolished PTN-mediated survival of irradiated mice. These studies demonstrate the therapeutic potential of PTN to improve survival after myeloablation and suggest that PTN-mediated hematopoietic regeneration occurs in a RAS-dependent manner. PMID:25250571
Generation of Antigen Microarrays to Screen for Autoantibodies in Heart Failure and Heart Transplantation.

PubMed

Chruscinski, Andrzej; Huang, Flora Y Y; Nguyen, Albert; Lioe, Jocelyn; Tumiati, Laura C; Kozuszko, Stella; Tinckam, Kathryn J; Rao, Vivek; Dunn, Shannon E; Persinger, Michael A; Levy, Gary A; Ross, Heather J

2016-01-01

Autoantibodies directed against endogenous proteins including contractile proteins and endothelial antigens are frequently detected in patients with heart failure and after heart transplantation. There is evidence that these autoantibodies contribute to cardiac dysfunction and correlate with clinical outcomes. Currently, autoantibodies are detected in patient sera using individual ELISA assays (one for each antigen). Thus, screening for many individual autoantibodies is laborious and consumes a large amount of patient sample. To better capture the broad-scale antibody reactivities that occur in heart failure and post-transplant, we developed a custom antigen microarray technique that can simultaneously measure IgM and IgG reactivities against 64 unique antigens using just five microliters of patient serum. We first demonstrated that our antigen microarray technique displayed enhanced sensitivity to detect autoantibodies compared to the traditional ELISA method. We then piloted this technique using two sets of samples that were obtained at our institution. In the first retrospective study, we profiled pre-transplant sera from 24 heart failure patients who subsequently received heart transplants. We identified 8 antibody reactivities that were higher in patients who developed cellular rejection (2 or more episodes of grade 2R rejection in first year after transplant as defined by revised criteria from the International Society for Heart and Lung Transplantation) compared with those who did have not have rejection episodes. In a second retrospective study with 31 patients, we identified 7 IgM reactivities that were higher in heart transplant recipients who developed antibody-mediated rejection (AMR) compared with control recipients, and in time course studies, these reactivities appeared prior to overt graft dysfunction. In conclusion, we demonstrated that the autoantibody microarray technique outperforms traditional ELISAs as it uses less patient sample, has increased sensitivity, and can detect autoantibodies in a multiplex fashion. Furthermore, our results suggest that this autoantibody array technology may help to identify patients at risk of rejection following heart transplantation and identify heart transplant recipients with AMR.
Generation of Antigen Microarrays to Screen for Autoantibodies in Heart Failure and Heart Transplantation

PubMed Central

Chruscinski, Andrzej; Huang, Flora Y. Y.; Nguyen, Albert; Lioe, Jocelyn; Tumiati, Laura C.; Kozuszko, Stella; Tinckam, Kathryn J.; Rao, Vivek; Dunn, Shannon E.; Persinger, Michael A.; Levy, Gary A.; Ross, Heather J.

2016-01-01

Autoantibodies directed against endogenous proteins including contractile proteins and endothelial antigens are frequently detected in patients with heart failure and after heart transplantation. There is evidence that these autoantibodies contribute to cardiac dysfunction and correlate with clinical outcomes. Currently, autoantibodies are detected in patient sera using individual ELISA assays (one for each antigen). Thus, screening for many individual autoantibodies is laborious and consumes a large amount of patient sample. To better capture the broad-scale antibody reactivities that occur in heart failure and post-transplant, we developed a custom antigen microarray technique that can simultaneously measure IgM and IgG reactivities against 64 unique antigens using just five microliters of patient serum. We first demonstrated that our antigen microarray technique displayed enhanced sensitivity to detect autoantibodies compared to the traditional ELISA method. We then piloted this technique using two sets of samples that were obtained at our institution. In the first retrospective study, we profiled pre-transplant sera from 24 heart failure patients who subsequently received heart transplants. We identified 8 antibody reactivities that were higher in patients who developed cellular rejection (2 or more episodes of grade 2R rejection in first year after transplant as defined by revised criteria from the International Society for Heart and Lung Transplantation) compared with those who did have not have rejection episodes. In a second retrospective study with 31 patients, we identified 7 IgM reactivities that were higher in heart transplant recipients who developed antibody-mediated rejection (AMR) compared with control recipients, and in time course studies, these reactivities appeared prior to overt graft dysfunction. In conclusion, we demonstrated that the autoantibody microarray technique outperforms traditional ELISAs as it uses less patient sample, has increased sensitivity, and can detect autoantibodies in a multiplex fashion. Furthermore, our results suggest that this autoantibody array technology may help to identify patients at risk of rejection following heart transplantation and identify heart transplant recipients with AMR. PMID:26967734
Checkpoint Blockade Cancer Immunotherapy Targets Tumour-Specific Mutant Antigens

PubMed Central

Gubin, Matthew M.; Zhang, Xiuli; Schuster, Heiko; Caron, Etienne; Ward, Jeffrey P.; Noguchi, Takuro; Ivanova, Yulia; Hundal, Jasreet; Arthur, Cora D.; Krebber, Willem-Jan; Mulder, Gwenn E.; Toebes, Mireille; Vesely, Matthew D.; Lam, Samuel S.K.; Korman, Alan J.; Allison, James P.; Freeman, Gordon J.; Sharpe, Arlene H.; Pearce, Erika L.; Schumacher, Ton N.; Aebersold, Ruedi; Rammensee, Hans-Georg; Melief, Cornelis J. M.; Mardis, Elaine R.; Gillanders, William E.; Artyomov, Maxim N.; Schreiber, Robert D.

2014-01-01

The immune system plays key roles in determining the fate of developing cancers by not only functioning as a tumour promoter facilitating cellular transformation, promoting tumour growth and sculpting tumour cell immunogenicity1–6, but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion1,2,7. Yet clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer induced immunosuppression. In many individuals, immunosuppression is mediated by Cytotoxic T-Lymphocyte Associated Antigen-4 (CTLA-4) and Programmed Death-1 (PD-1), two immunomodulatory receptors expressed on T cells8,9. Monoclonal antibody (mAb) based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits—including durable responses—to patients with different malignancies10–13. However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Herein, we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T cell rejection antigens following αPD-1 and/or αCTLA-4 therapy of mice bearing progressively growing sarcomas and show that therapeutic synthetic long peptide (SLP) vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Whereas, mutant tumour antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with αPD-1- and/or αCTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens (TSMA) are not only important targets of checkpoint blockade therapy but also can be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments. PMID:25428507
Effects of buprenorphine on responses to social stimuli in healthy adults

PubMed Central

Bershad, Anya K.; Seiden, Jacob A.; de Wit, Harriet

2015-01-01

In addition to its classical role in mediating responses to pain, the opioid system is strongly implicated in the regulation of social behavior. In young laboratory animals, low doses of opioid analgesic drugs reduce responses to isolation distress and increase play behavior. However, little is known about how opioid drugs affect responses to social stimuli in humans. Here we examined the effects of buprenorphine, a mu-opioid partial agonist and kappa-antagonist, on three dimensions of social processing; i) responses to simulated social rejection, ii) attention to emotional facial expressions, and iii) emotional responses to images with and without social content. Healthy adults (N = 36) attended two sessions during which they received either placebo or 0.2mg sublingual buprenorphine in randomized order, under double-blind conditions. Ninety minutes after drug administration, they completed three behavioral tasks: i) a virtual ball-toss game in which they were first included and then excluded by the other players; ii) an attention task in which they were shown pairs of faces (one emotional and one neutral), while the direction of their gazes was recorded using electrooculography, and iii) a picture-viewing task, in which they rated standardized images with and without social content. During the ball-toss game, buprenorphine decreased perceived social rejection. During the attention task, the drug reduced initial attention to fearful facial expressions, without influencing attention to angry, happy, and sad faces. Finally, during the picture-viewing task, buprenorphine increased ratings of positivity of images with social content, without affecting ratings of nonsocial images. These results suggest that even at low doses, opioid analgesic drugs reduce responses to some types of negative social stimuli, while enhancing positive responses to social stimuli. This provides further support for the role of the opioid system in mediating responses to social rejection and social reward. PMID:26409030
Inhibition of JAK3 and PKC via Immunosuppressive Drugs Tofacitinib and Sotrastaurin Inhibits Proliferation of Human B Lymphocytes In Vitro.

PubMed

Martina, M N; Ramirez Bajo, M J; Bañon-Maneus, E; Moya Rull, D; Hierro-Garcia, N; Revuelta, I; Campistol, J M; Rovira, J; Diekmann, F

2016-11-01

Antibody-mediated response in solid organ transplantation is critical for graft dysfunction and loss. The use of immunosuppressive agents partially inhibits the B-lymphocyte response leading to a risk of acute and chronic antibody-mediated rejection. This study evaluated the impact of JAK3 and PKC inhibitors tofacitinib (Tofa) and sotrastaurin (STN), respectively, on B-cell proliferation, apoptosis, and activation in vitro. Human B cells isolated from peripheral blood of healthy volunteers were cocultured with CD40 ligand-transfected fibroblasts as feeder cells in the presence of interleukin (IL) 2, IL-10, and IL-21. The cocultures were treated with immunosuppressants Tofa, STN, and rapamycin (as a control), to analyze the proliferation and apoptosis of B cells by means of Cyquant and flow cytometry, respectively. CD27 and IgG staining were applied to evaluate whether treatments modified the activation of B cells. Tofa and STN were able to inhibit B-cell proliferation to the same extent as rapamycin, without inducing cell apoptosis. After 6 days in coculture with feeder cells, all B cells showed CD27 memory B-cell phenotype. None of the immunosuppressive treatments modified the proportion between class-switched and non-class-switched memory B cells observed in nontreated cultures. The high predominance of CD27 + CD24 + phenotype was not modified by any immunosuppressive treatment. Our results show that Tofa and STN can suppress B-cell antibody responses to an extent similar to rapamycin, in vitro; therefore these compounds may be a useful therapy against antibody-mediated rejection in transplantation. Copyright Â© 2016. Published by Elsevier Inc.
The stress-response dampening hypothesis: how self-esteem and stress act as mechanisms between negative parental bonds and alcohol-related problems in emerging adulthood.

PubMed

Backer-Fulghum, Lindsey M; Patock-Peckham, Julie A; King, Kevin M; Roufa, Lindsay; Hagen, Leslie

2012-04-01

The stress dampening model (Marlatt, 1987; Sayette, 1993; Sher, 1987) suggests certain individuals may use alcohol to escape from their negative life experiences. Pathological reasons for drinking (e.g., using alcohol as a means to cope) reflect the degree to which individuals are motivated to use alcohol in order to dampen or alleviate the stress they are experiencing (Johnson, Schwitters, Wilson, Nagoshi, & McClearn, 1985). Direct and mediational links among parental bonds (rejection, care, overprotection, autonomy, and neglect), self-esteem, stress, pathological reasons for drinking, and alcohol-related problems were explored. A Structural Equation Model with (405 students; 164 women, 241 men) college students was examined. Three path mediational analyses revealed several mediated pathways. Greater feelings of perceived father/mother neglectfulness (i.e., offspring feeling parents do not show up for them) were indirectly linked to more alcohol-related problems (e.g., indicative of alcohol use or dependence in emerging adulthood) through increased stress and pathological reasons for drinking. Furthermore, higher levels of father rejection (i.e., perception of feeling unwanted) were indirectly linked to more pathological reasons for drinking through low self-esteem and increased stress. However, greater feelings of mother care (affectionate and attentive) were indirectly linked to fewer pathological reasons for drinking through higher self-esteem and lower levels of stress. Moreover, high self-esteem was found to be indirectly linked to fewer alcohol-related problems through decreased stress and pathological reasons for drinking. These findings suggest several specific pathways for using alcohol to self-medicate (i.e., consume alcohol for a specific purpose) or dampen feelings of stress. Copyright © 2011 Elsevier Ltd. All rights reserved.
Pre-transplant soluble CD30 in combination with total DSA but not pre-transplant C1q-DSA predicts antibody-mediated graft loss in presensitized high-risk kidney transplant recipients.

PubMed

Schaefer, S M; Süsal, C; Opelz, G; Döhler, B; Becker, L E; Klein, K; Sickmüller, S; Waldherr, R; Macher-Goeppinger, S; Schemmer, P; Beimler, J; Zeier, M; Morath, C

2016-02-01

Presensitized kidney transplant recipients are at high-risk for early antibody-mediated rejection. We studied the impact of pre- and post-transplant donor-specific human leukocyte antigen (HLA) antibodies (DSA) and T-cell-activation on the occurrence of antibody-mediated rejection episodes (AMR) and graft loss (AMR-GL) in a unique cohort of 80 desensitized high-risk kidney transplant recipients. Patients with pre-transplant DSA demonstrated more AMR episodes than patients without DSA, but did not show a significantly increased rate of AMR-GL. The rates of AMR and AMR-GL were not significantly increased in patients with complement split product (C1q)-binding pre-transplant DSA. Pre-transplant C1q-DSA became undetectable post-transplant in 11 of 13 (85%) patients; 2 (18%) of these 11 patients showed AMR but no AMR-GL. In contrast, the post-transplant presence of C1q-DSA was associated with significantly higher rates of AMR (86 vs 33 vs 0%; P < 0.001) and AMR-GL (86 vs 0 vs 0%; log-rank P < 0.001) compared with post-transplant DSA without C1q-binding or the absence of DSA. Patients with both pre-transplant DSA and evidence of pre-transplant T-cell-activation as indicated by soluble CD30-positivity showed a significantly increased risk for AMR-GL [HR = 11.1, 95% confidence interval (CI) = 1.68-73.4; log-rank P = 0.013]. In these high-risk patients, AMR-GL was associated with total DSA in combination with T-cell-activation pre-transplant, and de novo or persistent C1q-binding DSA post-transplant. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Chemokines, their receptors, and transplant outcome.

PubMed

Colvin, Bridget L; Thomson, Angus W

2002-07-27

Organ transplant rejection is mediated largely by circulating peripheral leukocytes induced to infiltrate the graft by various inflammatory stimuli. Of these, chemotactic cytokines called chemokines, expressed by inflamed graft tissues, as well as by early innate-responding leukocytes that infiltrate the graft, are responsible for the recruitment of alloreactive leukocytes. This report discusses the impact of these leukocyte-directing proteins on transplant outcome and novel therapeutic approaches for antirejection therapy based on targeting of chemokines and/or their receptors.
Outcome after Desensitization in HLA or ABO-Incompatible Kidney Transplant Recipients: A Single Center Experience.

PubMed

Kauke, Teresa; Klimaschewski, Sandra; Schoenermarck, Ulf; Fischereder, Michael; Dick, Andrea; Guba, Markus; Stangl, Manfred; Werner, Jens; Meiser, Bruno; Habicht, Antje

2016-01-01

The shortage of deceased donors led to an increase of living donor kidney (LDK) transplantations performed in the presence of donor-specific antibodies (DSA) or ABO incompatibility (ABOi) using various desensitization protocols. We herein analyzed 26 ABOi and 8 Luminex positive DSA patients who were successfully desensitized by anti-CD20, antigen-specific immunoadsorption and/or plasmapheresis to receive an LDK transplant. Twenty LDK recipients with non-donor-specific HLA-antibodies (low risk) and 32 without anti-HLA antibodies (no risk) served as control groups. 1-year graft survival rate and renal function was similar in all 4 groups (creatinine: 1.63 ± 0.5 vs 1.78 ± 0.6 vs 1.64 ± 0.5 vs 1.6 ± 0.3 mg/dl in ABOi, DSA, low risk and no risk group). The incidence of acute T-cell mediated rejections did not differ between the 4 groups (15% vs 12, 5% vs 15% vs 22% in ABOi, DSA, low risk and no risk), while antibody-mediated rejections were only found in the DSA (25%) and ABOi (7.5%) groups. Incidence of BK nephropathy (BKVN) was significantly more frequent after desensitization as compared to controls (5/34 vs 0/52, p = 0.03). We demonstrate favorable short-term allograft outcome in LDK transplant recipients after desensitization. However, the desensitization was associated with an increased risk of BKVN.
Antibody-Mediated Rejection in Human Cardiac Allografts: Evaluation of Immunoglobulins and Complement Activation Products C4d and C3d as Markers

PubMed Central

Rodriguez, E. R.; Skojec, Diane V.; Tan, Carmela D.; Zachary, Andrea A.; Kasper, Edward K.; Conte, John V.; Baldwin, William M.

2005-01-01

Antibody-mediated rejection (AMR) in human heart transplantation is an immunopathologic process in which injury to the graft is in part the result of activation of complement and it is poorly responsive to conventional therapy. We evaluated by immunofluorescence (IF), 665 consecutive endomyocardial biopsies from 165 patients for deposits of immunoglobulins and complement. Diffuse IF deposits in a linear capillary pattern greater than 2+ were considered significant. Clinical evidence of graft dysfunction was correlated with complement deposits. IF 2+ or higher was positive for IgG, 66%; IgM, 12%; IgA, 0.6%; C1q, 1.8%; C4d, 9% and C3d, 10%. In 3% of patients, concomitant C4d and C3d correlated with graft dysfunction or heart failure. In these 5 patients AMR occurred 56–163 months after transplantation, and they responded well to therapy for AMR but not to treatment with steroids. Systematic evaluation of endomyocardial biopsies is not improved by the use of antibodies for immunoglobulins or C1q. Concomitant use of C4d and C3d is very useful to diagnose AMR, when correlated with clinical parameters of graft function. AMR in heart transplant patients can occur many months or years after transplant. PMID:16212640

Parental Child-Rearing Strategies Influence Self-Regulation, Socio-Emotional Adjustment, and Psychopathology in Early Adulthood: Evidence from a Retrospective Cohort Study

PubMed Central

Baker, Courtney N.; Hoerger, Michael

2012-01-01

This study examined the association between recollected parental child-rearing strategies and individual differences in self-regulation, socio-emotional adjustment, and psychopathology in early adulthood. Undergraduate participants (N = 286) completed the EMBU – a measure of retrospective accounts of their parents’ child-rearing behaviors – as well as self-report measures of self-regulation and socio-emotional adjustment across the domains of eating disorder symptoms, physically risky behavior, interpersonal problems, personal financial problems, and academic maladjustment. A subset of participants also completed the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF). Parental warmth was found to be related to overall better self-regulation and improved interpersonal and academic adjustment. In contrast, both parental rejection and overcontrol were found to be related to general deficits in self-regulation as well as adjustment difficulties and psychopathology. Parental rejection was most closely related to internalizing clinical presentations like anxiety, depression, and somatization, whereas overcontrol was most aligned with increased hypomanic activation and psychoticism. Mediation analyses demonstrated that the relationships between parental child-rearing strategies and socio-emotional adjustment and psychopathology were partially mediated by self-regulation. Future directions are suggested, including basic and translational research related to better understanding the roles of parental child-rearing and self-regulation in the development of internalizing symptoms, activation, and psychotic symptoms. PMID:22423172
Antibody mediated rejection associated with complement factor h-related protein 3/1 deficiency successfully treated with eculizumab.

PubMed

Noone, D; Al-Matrafi, J; Tinckam, K; Zipfel, P F; Herzenberg, A M; Thorner, P S; Pluthero, F G; Kahr, W H A; Filler, G; Hebert, D; Harvey, E; Licht, C

2012-09-01

Antibody mediated rejection (AMR) activates the classical complement pathway and can be detrimental to graft survival. AMR can be accompanied by thrombotic microangiopathy (TMA). Eculizumab, a monoclonal C5 antibody prevents induction of the terminal complement cascade (TCC) and has recently emerged as a therapeutic option for AMR. We present a highly sensitized 13-year-old female with end-stage kidney disease secondary to spina bifida-associated reflux nephropathy, who developed severe steroid-, ATG- and plasmapheresis-resistant AMR with TMA 1 week post second kidney transplant despite previous desensitization therapy with immunoglobulin infusions. Eculizumab rescue therapy resulted in a dramatic improvement in biochemical (C3; creatinine) and hematological (platelets) parameters within 6 days. The patient was proven to be deficient in complement Factor H-related protein 3/1 (CFHR3/1), a plasma protein that regulates the complement cascade at the level of C5 conversion and has been involved in the pathogenesis of atypical hemolytic uremic syndrome caused by CFH autoantibodies (DEAP-HUS). CFHR1 deficiency may have worsened the severe clinical progression of AMR and possibly contributed to the development of donor-specific antibodies. Thus, screening for CFHR3/1 deficiency should be considered in patients with severe AMR associated with TMA. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.
Parental acceptance, postpartum depression, and maternal sensitivity: mediating and moderating processes.

PubMed

Crockenberg, Susan C; Leerkes, Esther M

2003-03-01

Mothers (n = 92), fathers (n = 84), and their infants (60% male) participated in a longitudinal study of postpartum depression and maternal sensitivity. Mothers completed questionnaire measures of remembered parental acceptance, depressive symptoms, and infant distress to novelty and limits. Mothers and partners reported on marital aggression and avoidance. Maternal sensitivity was observed in the laboratory at 6 months. Characteristics of mothers, partners, and infants combined to predict postpartum depression and maternal sensitivity. Remembered parental rejection predicted postpartum depressive symptoms with prenatal depression controlled; self-esteem mediated this effect. Paternal acceptance buffered against postpartum depression when infants were highly reactive and when partners were aggressive. Paternal acceptance reduced the impact of postpartum depression on maternal sensitivity; having an aggressive marital partner exacerbated the effect.
Music, Mechanism, and the "Sonic Turn" in Physical Diagnosis.

PubMed

Pesic, Peter

2016-04-01

The sonic diagnostic techniques of percussion and mediate auscultation advocated by Leopold von Auenbrugger and R. T. H. Laennec developed within larger musical contexts of practice, notation, and epistemology. Earlier, François-Nicolas Marquet proposed a musical notation of pulse that connected felt pulsation with heard music. Though contemporary vitalists rejected Marquet's work, mechanists such as Albrecht von Haller included it into the larger discourse about the physiological manifestations of bodily fluids and fibers. Educated in that mechanistic physiology, Auenbrugger used musical vocabulary to present his work on thoracic percussion; Laennec's musical experience shaped his exploration of the new timbres involved in mediate auscultation. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Assembly and Turnover of Short Actin Filaments by the Formin INF2 and Profilin*

PubMed Central

Gurel, Pinar S.; A, Mu; Guo, Bingqian; Shu, Rui; Mierke, Dale F.; Higgs, Henry N.

2015-01-01

INF2 (inverted formin 2) is a formin protein with unique biochemical effects on actin. In addition to the common formin ability to accelerate actin nucleation and elongation, INF2 can also sever filaments and accelerate their depolymerization. Although we understand key attributes of INF2-mediated severing, we do not understand the mechanism by which INF2 accelerates depolymerization subsequent to severing. Here, we show that INF2 can create short filaments (<60 nm) that continuously turn over actin subunits through a combination of barbed end elongation, severing, and WH2 motif-mediated depolymerization. This pseudo-steady state condition occurs whether starting from actin filaments or monomers. The rate-limiting step of the cycle is nucleotide exchange of ADP for ATP on actin monomers after release from the INF2/actin complex. Profilin addition has two effects: 1) to accelerate filament turnover 6-fold by accelerating nucleotide exchange and 2) to shift the equilibrium toward polymerization, resulting in longer filaments. In sum, our findings show that the combination of multiple interactions of INF2 with actin can work in concert to increase the ATP turnover rate of actin. Depending on the ratio of INF2:actin, this increased flux can result in rapid filament depolymerization or maintenance of short filaments. We also show that high concentrations of cytochalasin D accelerate ATP turnover by actin but through a different mechanism from that of INF2. PMID:26124273
Explanation of Two Anomalous Results in Statistical Mediation Analysis

ERIC Educational Resources Information Center

Fritz, Matthew S.; Taylor, Aaron B.; MacKinnon, David P.

2012-01-01

Previous studies of different methods of testing mediation models have consistently found two anomalous results. The first result is elevated Type I error rates for the bias-corrected and accelerated bias-corrected bootstrap tests not found in nonresampling tests or in resampling tests that did not include a bias correction. This is of special…
Time gating for energy selection and scatter rejection: High-energy pulsed neutron imaging at LANSCE

NASA Astrophysics Data System (ADS)

Swift, Alicia; Schirato, Richard; McKigney, Edward; Hunter, James; Temple, Brian

2015-09-01

The Los Alamos Neutron Science Center (LANSCE) is a linear accelerator in Los Alamos, New Mexico that accelerates a proton beam to 800 MeV, which then produces spallation neutron beams. Flight path FP15R uses a tungsten target to generate neutrons of energy ranging from several hundred keV to ~600 MeV. The beam structure has micropulses of sub-ns width and period of 1.784 ns, and macropulses of 625 μs width and frequency of either 50 Hz or 100 Hz. This corresponds to 347 micropulses per macropulse, or 1.74 x 104 micropulses per second when operating at 50 Hz. Using a very fast, cooled ICCD camera (Princeton Instruments PI-Max 4), gated images of various objects were obtained on FP15R in January 2015. Objects imaged included blocks of lead and borated polyethylene; a tungsten sphere; and a tungsten, polyethylene, and steel cylinder. Images were obtained in 36 min or less, with some in as little as 6 min. This is novel because the gate widths (some as narrow as 10 ns) were selected to reject scatter and other signal not of interest (e.g. the gamma flash that precedes the neutron pulse), which has not been demonstrated at energies above 14 MeV. This proof-of-principle experiment shows that time gating is possible above 14MeV and is useful for selecting neutron energy and reducing scatter, thus forming clearer images. Future work (simulation and experimental) is being undertaken to improve camera shielding and system design and to precisely determine optical properties of the imaging system.
Streamlined research funding using short proposals and accelerated peer review: an observational study.

PubMed

Barnett, Adrian G; Herbert, Danielle L; Campbell, Megan; Daly, Naomi; Roberts, Jason A; Mudge, Alison; Graves, Nicholas

2015-02-07

Despite the widely recognised importance of sustainable health care systems, health services research remains generally underfunded in Australia. The Australian Centre for Health Services Innovation (AusHSI) is funding health services research in the state of Queensland. AusHSI has developed a streamlined protocol for applying and awarding funding using a short proposal and accelerated peer review. An observational study of proposals for four health services research funding rounds from May 2012 to November 2013. A short proposal of less than 1,200 words was submitted using a secure web-based portal. The primary outcome measures are: time spent preparing proposals; a simplified scoring of grant proposals (reject, revise or accept for interview) by a scientific review committee; and progressing from submission to funding outcomes within eight weeks. Proposals outside of health services research were deemed ineligible. There were 228 eligible proposals across 4 funding rounds: from 29% to 79% were shortlisted and 9% to 32% were accepted for interview. Success rates increased from 6% (in 2012) to 16% (in 2013) of eligible proposals. Applicants were notified of the outcomes within two weeks from the interview; which was a maximum of eight weeks after the submission deadline. Applicants spent 7 days on average preparing their proposal. Applicants with a ranking of reject or revise received written feedback and suggested improvements for their proposals, and resubmissions composed one third of the 2013 rounds. The AusHSI funding scheme is a streamlined application process that has simplified the process of allocating health services research funding for both applicants and peer reviewers. The AusHSI process has minimised the time from submission to notification of funding outcomes.
Accelerating population balance-Monte Carlo simulation for coagulation dynamics from the Markov jump model, stochastic algorithm and GPU parallel computing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Zuwei; Zhao, Haibo, E-mail: klinsmannzhb@163.com; Zheng, Chuguang

2015-01-15

This paper proposes a comprehensive framework for accelerating population balance-Monte Carlo (PBMC) simulation of particle coagulation dynamics. By combining Markov jump model, weighted majorant kernel and GPU (graphics processing unit) parallel computing, a significant gain in computational efficiency is achieved. The Markov jump model constructs a coagulation-rule matrix of differentially-weighted simulation particles, so as to capture the time evolution of particle size distribution with low statistical noise over the full size range and as far as possible to reduce the number of time loopings. Here three coagulation rules are highlighted and it is found that constructing appropriate coagulation rule providesmore » a route to attain the compromise between accuracy and cost of PBMC methods. Further, in order to avoid double looping over all simulation particles when considering the two-particle events (typically, particle coagulation), the weighted majorant kernel is introduced to estimate the maximum coagulation rates being used for acceptance–rejection processes by single-looping over all particles, and meanwhile the mean time-step of coagulation event is estimated by summing the coagulation kernels of rejected and accepted particle pairs. The computational load of these fast differentially-weighted PBMC simulations (based on the Markov jump model) is reduced greatly to be proportional to the number of simulation particles in a zero-dimensional system (single cell). Finally, for a spatially inhomogeneous multi-dimensional (multi-cell) simulation, the proposed fast PBMC is performed in each cell, and multiple cells are parallel processed by multi-cores on a GPU that can implement the massively threaded data-parallel tasks to obtain remarkable speedup ratio (comparing with CPU computation, the speedup ratio of GPU parallel computing is as high as 200 in a case of 100 cells with 10 000 simulation particles per cell). These accelerating approaches of PBMC are demonstrated in a physically realistic Brownian coagulation case. The computational accuracy is validated with benchmark solution of discrete-sectional method. The simulation results show that the comprehensive approach can attain very favorable improvement in cost without sacrificing computational accuracy.« less
Elucidating the relation between childhood emotional abuse and depressive symptoms in adulthood: The mediating role of maladaptive interpersonal processes

PubMed Central

Massing-Schaffer, Maya; Liu, Richard T.; Kraines, Morganne A.; Choi, Jimmy Y.; Alloy, Lauren B.

2015-01-01

Objective The purpose of this study is to assess the potential unique and relative mediating effects of three interpersonal risk factors (i.e., excessive reassurance-seeking [ERS], negative feedback seeking [NFS], and rejection sensitivity [RS]) in the relationship between childhood emotional abuse (CEA) and depressive symptoms. Method One hundred eighty-five undergraduates were followed over a four-month interval. Participants completed assessments of childhood abuse history, ERS, NFS, and RS, and depressive symptoms at baseline, as well as depressive symptoms at four-month followup. Results Findings from single-mediator analyses indicated that RS and NFS, but not ERS, mediated the relationship between CEA and prospective depressive symptoms, after accounting for childhood sexual and physical abuse, as well as baseline depressive symptoms. In our multi-mediator model, only RS remained a significant mediator of the relationship between CEA and prospective depressive symptoms. Conclusions The current study provides preliminary evidence that negative behavioral styles may function as a mechanism linking prior experiences of CEA to subsequent depressive symptoms. Clinical implications of these findings suggest that targeting maladaptive behavioral tendencies, particularly RS, may be an effective adjunct in behavioral modification treatments of CEA victims at risk for depression. PMID:26246650
Childhood Conduct Problems and Young Adult Outcomes Among Women with Childhood ADHD

PubMed Central

Owens, Elizabeth B.; Hinshaw, Stephen P.

2015-01-01

We tested whether conduct problems predicted young adult functioning and psychiatric symptoms among women diagnosed with ADHD during childhood, in the context of three potential adolescent mediators: internalizing problems, peer rejection, and school failure and disciplinary problems. We controlled for childhood ADHD severity, IQ, and demographic factors, and in the mediational tests, for adolescent conduct problems. Data emanated from 140 participants in the Berkeley Girls with ADHD Longitudinal Study. We used bootstrapping methods to assess indirect effects (mediators). Both childhood (F1,118 change = 9.00, p = .003, R2 change = .069) and adolescent (F1,109 change = 10.41, p = .002, R2 change = .083) conduct problems were associated with worse overall functioning during young adulthood, controlling for initial ADHD severity, child IQ, and demographics. Results were similar when predicting psychiatric symptoms. Adolescent school failure and disciplinary problems mediated the relations between childhood conduct problems and both young-adult functioning and externalizing problems; adolescent internalizing problems and peer conflict mediated the relation between childhood conduct problems and young-adult internalizing problems. As is true for boys, childhood and adolescent conduct problems are associated with poor adult outcomes among girls with ADHD, with school failure and disciplinary problems, internalizing problems, and peer conflict functioning as mediators of these relations. PMID:26854507
Exploring revictimization process among Turkish women: The role of early maladaptive schemas on the link between child abuse and partner violence.

PubMed

Atmaca, Sinem; Gençöz, Tülin

2016-02-01

The purpose of the current study is to explore the revictimization process between child abuse and neglect (CAN), and intimate partner violence (IPV) based on the schema theory perspective. For this aim, 222 married women recruited in four central cities of Turkey participated in the study. Results indicated that early negative CAN experiences increased the risk of being exposed to later IPV. Specifically, emotional abuse and sexual abuse in the childhood predicted the four subtypes of IPV, which are physical, psychological, and sexual violence, and injury, while physical abuse only associated with physical violence. To explore the mediational role of early maladaptive schemas (EMSs) on this association, first, five schema domains were tested via Parallel Multiple Mediation Model. Results indicated that only Disconnection/Rejection (D/R) schema domains mediated the association between CAN and IPV. Second, to determine the particular mediational roles of each schema, eighteen EMS were tested as mediators, and results showed that Emotional Deprivation Schema and Vulnerability to Harm or Illness Schema mediated the association between CAN and IPV. These findings provided an empirical support for the crucial roles of EMSs on the effect of revictimization process. Clinical implications were discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.
Isothermal Crystallization Behavior of Cocoa Butter at 17 and 20 °C with and without Limonene.

PubMed

Rigolle, Annelien; Goderis, Bart; Van Den Abeele, Koen; Foubert, Imogen

2016-05-04

Differential scanning calorimetry and real-time X-ray diffraction using synchrotron radiation were used to elucidate isothermal cocoa butter crystallization at 17 and 20 °C in the absence and presence of different limonene concentrations. At 17 °C, a three-step crystallization process was visible for pure cocoa butter, whereby first an unknown structure with long spacings between a 2L and 3L structure was formed that rapidly transformed into the more stable α structure, which in turn was converted into more stable β' crystals. At 20 °C, an α-mediated β' crystallization was observed. The addition of limonene resulted in a reduction of the amount of unstable crystals and an acceleration of polymorphic transitions. At 17 °C, the crystallization process was accelerated due to the acceleration of the formation of more stable polymorphic forms, whereas there were insufficient α crystals for an α-mediated β' nucleation at 20 °C, resulting in a slower crystallization process.
Long-term outcomes of kidney transplantation across a positive complement-dependent cytotoxicity crossmatch.

PubMed

Riella, Leonardo V; Safa, Kassem; Yagan, Jude; Lee, Belinda; Azzi, Jamil; Najafian, Nader; Abdi, Reza; Milford, Edgar; Mah, Helen; Gabardi, Steven; Malek, Sayeed; Tullius, Stefan G; Magee, Colm; Chandraker, Anil

2014-06-27

More than 30% of potential kidney transplant recipients have pre-existing anti-human leukocyte antigen antibodies. This subgroup has significantly lower transplant rates and increased mortality. Desensitization has become an important tool to overcome this immunological barrier. However, limited data is available regarding long-term outcomes, in particular for the highest risk group with a positive complement-dependent cytotoxicity crossmatch (CDC XM) before desensitization. Between 2002 and 2010, 39 patients underwent living-kidney transplantation across a positive CDC XM against their donors at our center. The desensitization protocol involved pretransplant immunosuppression, plasmapheresis, and low-dose intravenous immunoglobulin±rituximab. Measured outcomes included patient survival, graft survival, renal function, rates of rejection, infection, and malignancy. The mean and median follow-up was 5.2 years. Patient survival was 95% at 1 year, 95% at 3 years, and 86% at 5 years. Death-censored graft survival was 94% at 1 year, 88% at 3 years, and 84% at 5 years. Uncensored graft survival was 87% at 1 year, 79% at 3 years, and 72% at 5 years. Twenty-four subjects (61%) developed acute antibody-mediated rejection of the allograft and one patient lost her graft because of hyperacute rejection. Infectious complications included pneumonia (17%), BK nephropathy (10%), and CMV disease (5%). Skin cancer was the most prevalent malignancy in 10% of patients. There were no cases of lymphoproliferative disorder. Mean serum creatinine was 1.7±1 mg/dL in functioning grafts at 5 years after transplantation. Despite high rates of early rejection, desensitization in living-kidney transplantation results in acceptable 5-year patient and graft survival rates.
Mediation Analysis with Survival Outcomes: Accelerated Failure Time vs. Proportional Hazards Models.

PubMed

Gelfand, Lois A; MacKinnon, David P; DeRubeis, Robert J; Baraldi, Amanda N

2016-01-01

Survival time is an important type of outcome variable in treatment research. Currently, limited guidance is available regarding performing mediation analyses with survival outcomes, which generally do not have normally distributed errors, and contain unobserved (censored) events. We present considerations for choosing an approach, using a comparison of semi-parametric proportional hazards (PH) and fully parametric accelerated failure time (AFT) approaches for illustration. We compare PH and AFT models and procedures in their integration into mediation models and review their ability to produce coefficients that estimate causal effects. Using simulation studies modeling Weibull-distributed survival times, we compare statistical properties of mediation analyses incorporating PH and AFT approaches (employing SAS procedures PHREG and LIFEREG, respectively) under varied data conditions, some including censoring. A simulated data set illustrates the findings. AFT models integrate more easily than PH models into mediation models. Furthermore, mediation analyses incorporating LIFEREG produce coefficients that can estimate causal effects, and demonstrate superior statistical properties. Censoring introduces bias in the coefficient estimate representing the treatment effect on outcome-underestimation in LIFEREG, and overestimation in PHREG. With LIFEREG, this bias can be addressed using an alternative estimate obtained from combining other coefficients, whereas this is not possible with PHREG. When Weibull assumptions are not violated, there are compelling advantages to using LIFEREG over PHREG for mediation analyses involving survival-time outcomes. Irrespective of the procedures used, the interpretation of coefficients, effects of censoring on coefficient estimates, and statistical properties should be taken into account when reporting results.
The role of aquatic fungi in transformations of organic matter mediated by nutrients

Treesearch

Cynthia J. Tant; Amy D. Rosemond; Andrew S. Mehring; Kevin A. Kuehn; John M. Davis

2015-01-01

1. We assessed the key role of aquatic fungi in modifying coarse particulate organic matter (CPOM) by affecting its breakdown rate, nutrient concentration and conversion to fine particulate organic matter (FPOM). Overall, we hypothesised that fungal-mediated conditioning and breakdown of CPOM would be accelerated when nutrient concentrations are increased and tested...
False consensus and adolescent peer contagion: examining discrepancies between perceptions and actual reported levels of friends' deviant and health risk behaviors.

PubMed

Prinstein, Mitchell J; Wang, Shirley S

2005-06-01

Adolescents' perceptions of their friends' behavior strongly predict adolescents' own behavior, however, these perceptions often are erroneous. This study examined correlates of discrepancies between adolescents' perceptions and friends' reports of behavior. A total of 120 11th-grade adolescents provided data regarding their engagement in deviant and health risk behaviors, as well as their perceptions of the behavior of their best friend, as identified through sociometric assessment. Data from friends' own report were used to calculate discrepancy measures of adolescents' overestimations and estimation errors (absolute value of discrepancies) of friends' behavior. Adolescents also completed a measure of friendship quality, and a sociometric assessment yielding measures of peer acceptance/rejection and aggression. Findings revealed that adolescents' peer rejection and aggression were associated with greater overestimations of friends' behavior. This effect was partially mediated by adolescents' own behavior, consistent with a false consensus effect. Low levels of positive friendship quality were significantly associated with estimation errors, but not overestimations specifically.
Rejecting a bad option feels like choosing a good one.

PubMed

Perfecto, Hannah; Galak, Jeff; Simmons, Joseph P; Nelson, Leif D

2017-11-01

Across 4,151 participants, the authors demonstrate a novel framing effect, attribute matching, whereby matching a salient attribute of a decision frame with that of a decision's options facilitates decision-making. This attribute matching is shown to increase decision confidence and, ultimately, consensus estimates by increasing feelings of metacognitive ease. In Study 1, participants choosing the more attractive of two faces or rejecting the less attractive face reported greater confidence in and perceived consensus around their decision. Using positive and negative words, Study 2 showed that the attribute's extremity moderates the size of the effect. Study 3 found decision ease mediates these changes in confidence and consensus estimates. Consistent with a misattribution account, when participants were warned about this external source of ease in Study 4, the effect disappeared. Study 5 extended attribute matching beyond valence to objective judgments. The authors conclude by discussing related psychological constructs as well as downstream consequences. (PsycINFO Database Record (c) 2017 APA, all rights reserved).
The need to belong can motivate belief in God.

PubMed

Gebauer, Jochen E; Maio, Gregory R

2012-04-01

The need to belong can motivate belief in God. In Study 1, 40 undergraduates read bogus astrophysics articles "proving" God's existence or not offering proof. Participants in the proof-for-God condition reported higher belief in God (compared to control) when they chronically imagined God as accepting but lower belief in God when they imagined God as rejecting. Additionally, in Study 2 (72 undergraduates), these effects did not occur when participants' belongingness need was satisfied by priming close others. Study 3 manipulated 79 Internet participants' image of God. Chronic believers in the God-is-rejecting condition reported lower religious behavioral intentions than chronic believers in the God-is-accepting condition, and this effect was mediated by lower desires for closeness with God. In Study 4 (106 Internet participants), chronic believers with an accepting image of God reported that their belief in God is motivated by belongingness needs. © 2011 The Authors. Journal of Personality © 2012, Wiley Periodicals, Inc.
Induction of transplantation tolerance to fully mismatched cardiac allografts by T cell mediated delivery of alloantigen

PubMed Central

Tian, Chaorui; Yuan, Xueli; Jindra, Peter T.; Bagley, Jessamyn; Sayegh, Mohamed H.; Iacomini, John

2010-01-01

Induction of transplantation tolerance has the potential to allow for allograft acceptance without the need for life-long immunosuppression. Here we describe a novel approach that uses delivery of alloantigen by mature T cells to induce tolerance to fully allogeneic cardiac grafts. Adoptive transfer of mature alloantigen-expressing T cells into myeloablatively conditioned mice results in long-term acceptance of fully allogeneic heart transplants without evidence of chronic rejection. Since myeloablative conditioning is clinically undesirable we further demonstrated that adoptive transfer of mature alloantigen-expressing T cells alone into mice receiving non-myeloablative conditioning resulted in long-term acceptance of fully allogeneic heart allografts with minimal evidence of chronic rejection. Mechanistically, tolerance induction involved both deletion of donor-reactive host T cells and the development of regulatory T cells. Thus, delivery of alloantigen by mature T cells induces tolerance to fully allogeneic organ allografts in non-myeloablatively conditioned recipients, representing a novel approach for tolerance induction in transplantation. PMID:20452826

Overcoming status quo bias in the human brain.

PubMed

Fleming, Stephen M; Thomas, Charlotte L; Dolan, Raymond J

2010-03-30

Humans often accept the status quo when faced with conflicting choice alternatives. However, it is unknown how neural pathways connecting cognition with action modulate this status quo acceptance. Here we developed a visual detection task in which subjects tended to favor the default when making difficult, but not easy, decisions. This bias was suboptimal in that more errors were made when the default was accepted. A selective increase in subthalamic nucleus (STN) activity was found when the status quo was rejected in the face of heightened decision difficulty. Analysis of effective connectivity showed that inferior frontal cortex, a region more active for difficult decisions, exerted an enhanced modulatory influence on the STN during switches away from the status quo. These data suggest that the neural circuits required to initiate controlled, nondefault actions are similar to those previously shown to mediate outright response suppression. We conclude that specific prefrontal-basal ganglia dynamics are involved in rejecting the default, a mechanism that may be important in a range of difficult choice scenarios.
Spontaneous rectus sheath haematoma in a deceased donor renal transplant recipient: a rare complication.

PubMed

Sreenivas, Jayaram; Karthikeyan, Vilvapathy Senguttuvan; SampathKumar, Nathee; Umesha, Lingaraju

2016-02-04

Rectus sheath haematoma (RSH) is rarely thought of as a cause of abdominal pain in renal transplant recipients. A 36-year-old woman, a post-deceased donor renal allograft transplant recipient for chronic interstitial nephritis, on triple drug immunosuppression (tacrolimus, mycophenolate mofetil and prednisolone) with basiliximab induction, developed acute vascular rejection and acute tubular injury with suspected antibody-mediated rejection. While on plasmapheresis and haemodialysis for delayed graft function, she developed acute left lower abdominal pain on the 16th postoperative day with tender swelling in the left paraumbilical region. CT of the abdomen showed a large haematoma in the left rectus sheath with no extension. The patient underwent haematoma evacuation through a left paramedian incision and had an uneventful recovery. Serum creatinine stabilised at 0.8 mg/dL and she is on regular follow-up with excellent graft function at 6 months. Diagnosis requires a high index of suspicion, and prompt treatment prevents morbidity and can expedite patient recovery. 2016 BMJ Publishing Group Ltd.
Spontaneous rectus sheath haematoma in a deceased donor renal transplant recipient: a rare complication

PubMed Central

Sreenivas, Jayaram; Karthikeyan, Vilvapathy Senguttuvan; SampathKumar, Nathee; Umesha, Lingaraju

2016-01-01

Rectus sheath haematoma (RSH) is rarely thought of as a cause of abdominal pain in renal transplant recipients. A 36-year-old woman, a post-deceased donor renal allograft transplant recipient for chronic interstitial nephritis, on triple drug immunosuppression (tacrolimus, mycophenolate mofetil and prednisolone) with basiliximab induction, developed acute vascular rejection and acute tubular injury with suspected antibody-mediated rejection. While on plasmapheresis and haemodialysis for delayed graft function, she developed acute left lower abdominal pain on the 16th postoperative day with tender swelling in the left paraumbilical region. CT of the abdomen showed a large haematoma in the left rectus sheath with no extension. The patient underwent haematoma evacuation through a left paramedian incision and had an uneventful recovery. Serum creatinine stabilised at 0.8 mg/dL and she is on regular follow-up with excellent graft function at 6 months. Diagnosis requires a high index of suspicion, and prompt treatment prevents morbidity and can expedite patient recovery. PMID:26847807
[The effects of interpretation bias for social events and automatic thoughts on social anxiety].

PubMed

Aizawa, Naoki

2015-08-01

Many studies have demonstrated that individuals with social anxiety interpret ambiguous social situations negatively. It is, however, not clear whether the interpretation bias discriminatively contributes to social anxiety in comparison with depressive automatic thoughts. The present study investigated the effects of negative interpretation bias and automatic thoughts on social anxiety. The Social Intent Interpretation-Questionnaire, which measures the tendency to interpret ambiguous social events as implying other's rejective intents, the short Japanese version of the Automatic Thoughts Questionnaire-Revised, and the Anthropophobic Tendency Scale were administered to 317 university students. Covariance structure analysis indicated that both rejective intent interpretation bias and negative automatic thoughts contributed to mental distress in social situations mediated by a sense of powerlessness and excessive concern about self and others in social situations. Positive automatic thoughts reduced mental distress. These results indicate the importance of interpretation bias and negative automatic thoughts in the development and maintenance of social anxiety. Implications for understanding of the cognitive features of social anxiety were discussed.
Targeting Sirtuin-1 prolongs murine renal allograft survival and function

PubMed Central

Levine, Matthew H.; Wang, Zhonglin; Xiao, Haiyan; Jiao, Jing; Wang, Liqing; Bhatti, Tricia R.; Hancock, Wayne W.; Beier, Ulf H.

2016-01-01

Current immunosuppressive medications used after transplantation have significant toxicities. Foxp3+ T-regulatory (Treg) cells can prevent allograft rejection without compromising protective host immunity. Interestingly, inhibiting the class III histone/protein deacetylase Sirtuin-1 can augment Foxp3+ Treg suppressive function through increasing Foxp3 acetylation. Here we determined whether Sirtuin-1 targeting can stabilize biological allograft function. BALB/c kidney allografts were transplanted into C57BL/6 recipients with a CD4-conditional deletion of Sirtuin-1 (Sirt1fl/flCD4cre) or mice treated with a Sirtuin-1 specific inhibitor (EX-527), and the native kidneys removed. Blood chemistries and hematocrit were followed weekly. Sirt1fl/flCD4cre recipients showed markedly longer survival and improved kidney function. Sirt1fl/flCD4cre recipients exhibited donor specific tolerance, accepted BALB/c, but rejected third-party C3H cardiac allografts. C57BL/6 recipients of BALB/c renal allografts that were treated with EX-527 showed improved survival and renal function at 1, but not 10 mg/kg/day. Pharmacologic inhibition of Sirtuin-1 also improved renal allograft survival and function with dosing effects having relevance to outcome. Thus, inhibiting Sirtuin-1 can be a useful asset in controlling T-cell mediated rejection. However, effects on non-T cells that could adversely affect allograft survival and function merit consideration. PMID:27083279
Rapamycin-treated human endothelial cells preferentially activate allogeneic regulatory T cells

PubMed Central

Wang, Chen; Yi, Tai; Qin, Lingfeng; Maldonado, Roberto A.; von Andrian, Ulrich H.; Kulkarni, Sanjay; Tellides, George; Pober, Jordan S.

2013-01-01

Human graft endothelial cells (ECs) can act as antigen-presenting cells to initiate allograft rejection by host memory T cells. Rapamycin, an mTOR inhibitor used clinically to suppress T cell responses, also acts on DCs, rendering them tolerogenic. Here, we report the effects of rapamycin on EC alloimmunogenicity. Compared with mock-treated cells, rapamycin-pretreated human ECs (rapa-ECs) stimulated less proliferation and cytokine secretion from allogeneic CD4+ memory cells, an effect mimicked by shRNA knockdown of mTOR or raptor in ECs. The effects of rapamycin persisted for several days and were linked to upregulation of the inhibitory molecules PD-L1 and PD-L2 on rapa-ECs. Additionally, rapa-ECs produced lower levels of the inflammatory cytokine IL-6. CD4+ memory cells activated by allogeneic rapa-ECs became hyporesponsive to restimulation in an alloantigen-specific manner and contained higher percentages of suppressive CD4+CD25hiCD127loFoxP3+ cells that did not produce effector cytokines. In a human-mouse chimeric model of allograft rejection, rapamycin pretreatment of human arterial allografts increased graft EC expression of PD-L1 and PD-L2 and reduced subsequent infiltration of allogeneic effector T cells into the artery intima and intimal expansion. Preoperative conditioning of allograft ECs with rapamycin could potentially reduce immune-mediated rejection. PMID:23478407
Genetically-engineered pig-to-baboon liver xenotransplantation: histopathology of xenografts and native organs.

PubMed

Ekser, Burcin; Klein, Edwin; He, Jing; Stolz, Donna B; Echeverri, Gabriel J; Long, Cassandra; Lin, Chih Che; Ezzelarab, Mohamed; Hara, Hidetaka; Veroux, Massimiliano; Ayares, David; Cooper, David K C; Gridelli, Bruno

2012-01-01

Orthotopic liver transplantation was carried out in baboons using wild-type (WT, n = 1) or genetically-engineered pigs (α1,3-galactosyltransferase gene-knockout, GTKO), n = 1; GTKO pigs transgenic for human CD46, n = 7) and a clinically-acceptable immunosuppressive regimen. Biopsies were obtained from the WT pig liver pre-Tx and at 30 min, 1, 2, 3, 4 and 5 h post-transplantation. Biopsies of genetically-engineered livers were obtained pre-Tx, 2 h after reperfusion and at necropsy (4-7 days after transplantation). Tissues were examined by light, confocal, and electron microscopy. All major native organs were also examined. The WT pig liver underwent hyperacute rejection. After genetically-engineered pig liver transplantation, hyperacute rejection did not occur. Survival was limited to 4-7 days due to repeated spontaneous bleeding in the liver and native organs (as a result of profound thrombocytopenia) which necessitated euthanasia. At 2 h, graft histology was largely normal. At necropsy, genetically-engineered pig livers showed hemorrhagic necrosis, platelet aggregation, platelet-fibrin thrombi, monocyte/macrophage margination mainly in liver sinusoids, and vascular endothelial cell hypertrophy, confirmed by confocal and electron microscopy. Immunohistochemistry showed minimal deposition of IgM, and almost absence of IgG, C3, C4d, C5b-9, and of a cellular infiltrate, suggesting that neither antibody- nor cell-mediated rejection played a major role.
Emotional Reactivity, Behavior Problems, and Social Adjustment at School Entry in a High-risk Sample

PubMed Central

Kalvin, Carla B.; Bierman, Karen L.; Gatzke-Kopp, Lisa M.

2016-01-01

Prior research suggests that heightened emotional reactivity to emotionally distressing stimuli may be associated with elevated internalizing and externalizing behaviors, and contribute to impaired social functioning. These links were explored in a sample of 169 economically-disadvantaged kindergarteners (66 % male; 68 % African American, 22 % Hispanic, 10 % Caucasian) oversampled for elevated aggression. Physiological measures of emotional reactivity (respiratory sinus arrhythmia [RSA], heart rate [HR], and cardiac pre-ejection period [PEP]) were collected, and teachers and peers provided ratings of externalizing and internalizing behavior, prosocial competence, and peer rejection. RSA withdrawal, HR reactivity, and PEP shortening (indicating increased arousal) were correlated with reduced prosocial competence, and RSA withdrawal and HR reactivity were correlated with elevated internalizing problems. HR reactivity was also correlated with elevated externalizing problems and peer rejection. Linear regressions controlling for age, sex, race, verbal proficiency, and resting physiology showed that HR reactivity explained unique variance in both teacher-rated prosocial competence and peer rejection, and contributed indirectly to these outcomes through pathways mediated by internalizing and externalizing problems. A trend also emerged for the unique contribution of PEP reactivity to peer-rated prosocial competence. These findings support the contribution of emotional reactivity to behavior problems and social adjustment among children living in disadvantaged urban contexts, and further suggest that elevated reactivity may confer risk for social difficulties in ways that overlap only partially with internalizing and externalizing behavior problems. PMID:26943804
Cross-talk from β-Adrenergic Receptors Modulates α2A-Adrenergic Receptor Endocytosis in Sympathetic Neurons via Protein Kinase A and Spinophilin*

PubMed Central

Cottingham, Christopher; Lu, Roujian; Jiao, Kai; Wang, Qin

2013-01-01

Inter-regulation of adrenergic receptors (ARs) via cross-talk is a long appreciated but mechanistically unclear physiological phenomenon. Evidence from the AR literature and our own extensive studies on regulation of α2AARs by the scaffolding protein spinophilin have illuminated a potential novel mechanism for cross-talk from β to α2ARs. In the present study, we have characterized a mode of endogenous AR cross-talk in native adrenergic neurons whereby canonical βAR-mediated signaling modulates spinophilin-regulated α2AAR endocytosis through PKA. Our findings demonstrate that co-activation of β and α2AARs, either by application of endogenous agonist or by simultaneous stimulation with distinct selective agonists, results in acceleration of endogenous α2AAR endocytosis in native neurons. We show that receptor-independent PKA activation by forskolin is sufficient to accelerate α2AAR endocytosis and that α2AAR stimulation alone drives accelerated endocytosis in spinophilin-null neurons. Endocytic response acceleration by β/α2AAR co-activation is blocked by PKA inhibition and lost in spinophilin-null neurons, consistent with our previous finding that spinophilin is a substrate for phosphorylation by PKA that disrupts its interaction with α2AARs. Importantly, we show that α2AR agonist-mediated α2AAR/spinophilin interaction is blocked by βAR co-activation in a PKA-dependent fashion. We therefore propose a novel mechanism for cross-talk from β to α2ARs, whereby canonical βAR-mediated signaling coupled to PKA activation results in phosphorylation of spinophilin, disrupting its interaction with α2AARs and accelerating α2AAR endocytic responses. This mechanism of cross-talk has significant implications for endogenous adrenergic physiology and for therapeutic targeting of β and α2AARs. PMID:23965992
Maladaptive schemas as mediators of the relationship between previous victimizations in the family and dating violence victimization in adolescents.

PubMed

Calvete, Esther; Gámez-Guadix, Manuel; Fernández-Gonzalez, Liria; Orue, Izaskun; Borrajo, Erika

2018-07-01

This study examined whether exposure to family violence, both in the form of direct victimization and witnessing violence, predicted dating violence victimization in adolescents through maladaptive schemas. A sample of 933 adolescents (445 boys and 488 girls), aged between 13 and 18 (M = 15.10), participated in a three-year longitudinal study. They completed measures of exposure to family violence, maladaptive schemas of disconnection/rejection, and dating violence victimization. The findings indicate that witnessing family violence predicts the increase of dating violence victimization over time, through the mediation of maladaptive schemas in girls, but not in boys. Direct victimization in the family predicts dating violence victimization directly, without the mediation of schemas. In addition, maladaptive schemas contribute to the perpetuation of dating violence victimization over time. These findings provide new opportunities for preventive interventions, as maladaptive schemas can be modified. Copyright © 2018 Elsevier Ltd. All rights reserved.
Adult attachment as mediator between recollections of childhood and satisfaction with life.

PubMed

Hinnen, Chris; Sanderman, Robbert; Sprangers, Mirjam A G

2009-01-01

In accordance with attachment theory, the present study investigates whether internal working models of attachment mediated the association between childhood memories and satisfaction about life in adulthood. A convenient sample of 437 participants completed questionnaires assessing a broad range of childhood memories, working models of attachment and life satisfaction. After controlling for demographics, relational status and living condition, Baron and Kenny's mediation criteria were met for the association between memories about childhood, adult attachment and life satisfaction. That is, family warmth and harmony and parental support were associated with attachment security while parental rejection and adverse childhood events (e.g., abuse, parental psychopathology) were associated with an insecure attachment style. More securely attached individuals were in turn more satisfied about their current life than insecurely attached individuals. Sobel test confirmed these findings. These finding are in accordance with attachment theory and highlight the importance of this theory for understanding how early childhood experiences may impact adult life.
The Spectrum of Histopathological Changes in the Renal Allograft - a 12 Months Protocol Biopsy Study

PubMed Central

Severova-Andreevska, Galina; Grcevska, Ladislava; Petrushevska, Gordana; Cakalaroski, Koco; Sikole, Aleksandar; Stojceva–Taneva, Olivera; Danilovska, Ilina; Ivanovski, Ninoslav

2018-01-01

INTRODUCTION: Renal transplantation became a routine and successful medical treatment for Chronic Kidney Disease in the last 30 years all over the world. Introduction of Luminex based Single Antigen Beads (SAB) and recent BANFF consensus of histopathological phenotypes of different forms of rejection enables more precise diagnosis and changes the therapeutic approach. The graft biopsies, protocol or cause, indicated, remain a golden diagnostic tool for clinical follow up of kidney transplant recipients (KTR). AIM: The study aimed to analyse the histopathological changes in renal grafts 12 months after the surgery in KTR with satisfactory kidney function. MATERIAL AND METHODS: A 12-month protocol biopsy study was performed in a cohort of 50 Kidney transplant recipients (42 from living and 8 from deceased donors). Usual work-up for suitable donors and recipients, standard surgical procedure, basic principles of peri and postoperative care and follow up were done in all KTR. Sequential quadruple immunosuppression including induction with Anti-thymocyte globulin (ATG) or Interleukin-2R antagonist (IL-2R), and triple drug maintenance therapy with Calcineurin Inhibitors (CNI), Mycophenolate Mofetil (MMF) and Steroids were prescribed to all pts. Different forms of Glomerulonephritis (16), Hypertension (10), End Stage Renal Disease (13), Hereditary Nephropathies (6), Diabetes (3) and Vesicoureteral Reflux (2) were the underlying diseases. All biopsies were performed under ultrasound guidance. The 16 gauge needles with automated “gun” were used to take 2 cores of tissue. The samples were stained with HE, PAS, Trichrome Masson and Silver and reviewed by the same pathologist. A revised and uploaded BANFF 2013 classification in 6 categories (Cat) was used. RESULTS: Out of 48 biopsies, 15 (31%) were considered as normal, 4 (8%), Borderline (BL-Cat 3), 5 (10%) as Interstitial Fibrosis/Tubular Atrophy (IF/TA-Cat 5), 5 (10%) were classified as non-immunological (Cat 6), 2 as a pure antibody-mediated rejection (ABMR-Cat 2) and T-cell Mediated Rejection (TCMR-Cat 4). The remaining 17 samples were classified as a “mixed” rejection: 7 (41%) ABMR + IF/TA, 5 (29%) ABMR + BL + IF/TA, 2 (11%) BL + IF/TA, 1 (5%) ABMR + BL, 1 (5%) ABMR + TCMR and 1 (5%) TCMR + IF/TA. The mean serum creatinine at the time of the biopsy was 126.7 ± 23.4 µmol/L, while GFR-MDRD 63.4 ± 20.7 ml/min, which means that the majority of the findings were subclinical. Among the non-immunological histological findings (Cat 6), 3 cases belonged to CNI toxicity, 1 to BK nephropathy and 1 to recurrence of the primary disease. CONCLUSION: Our 12-month protocol biopsy study revealed the presence of different forms of mixed subclinical rejection. Use of recent BANFF classification and scoring system enables more precise diagnosis and subsequently different approach to the further treatment of the KTR. More correlative long-term studies including Anti HLA antibodies and Endothelial Cell Activation- Associated Transcripts (ENDAT) are needed. PMID:29731924
Emerging concepts in biomarker discovery; The US-Japan workshop on immunological molecular markers in oncology

PubMed Central

Tahara, Hideaki; Sato, Marimo; Thurin, Magdalena; Wang, Ena; Butterfield, Lisa H; Disis, Mary L; Fox, Bernard A; Lee, Peter P; Khleif, Samir N; Wigginton, Jon M; Ambs, Stefan; Akutsu, Yasunori; Chaussabel, Damien; Doki, Yuichiro; Eremin, Oleg; Fridman, Wolf Hervé; Hirohashi, Yoshihiko; Imai, Kohzoh; Jacobson, James; Jinushi, Masahisa; Kanamoto, Akira; Kashani-Sabet, Mohammed; Kato, Kazunori; Kawakami, Yutaka; Kirkwood, John M; Kleen, Thomas O; Lehmann, Paul V; Liotta, Lance; Lotze, Michael T; Maio, Michele; Malyguine, Anatoli; Masucci, Giuseppe; Matsubara, Hisahiro; Mayrand-Chung, Shawmarie; Nakamura, Kiminori; Nishikawa, Hiroyoshi; Palucka, A Karolina; Petricoin, Emanuel F; Pos, Zoltan; Ribas, Antoni; Rivoltini, Licia; Sato, Noriyuki; Shiku, Hiroshi; Slingluff, Craig L; Streicher, Howard; Stroncek, David F; Takeuchi, Hiroya; Toyota, Minoru; Wada, Hisashi; Wu, Xifeng; Wulfkuhle, Julia; Yaguchi, Tomonori; Zeskind, Benjamin; Zhao, Yingdong; Zocca, Mai-Britt; Marincola, Francesco M

2009-01-01

Supported by the Office of International Affairs, National Cancer Institute (NCI), the "US-Japan Workshop on Immunological Biomarkers in Oncology" was held in March 2009. The workshop was related to a task force launched by the International Society for the Biological Therapy of Cancer (iSBTc) and the United States Food and Drug Administration (FDA) to identify strategies for biomarker discovery and validation in the field of biotherapy. The effort will culminate on October 28th 2009 in the "iSBTc-FDA-NCI Workshop on Prognostic and Predictive Immunologic Biomarkers in Cancer", which will be held in Washington DC in association with the Annual Meeting. The purposes of the US-Japan workshop were a) to discuss novel approaches to enhance the discovery of predictive and/or prognostic markers in cancer immunotherapy; b) to define the state of the science in biomarker discovery and validation. The participation of Japanese and US scientists provided the opportunity to identify shared or discordant themes across the distinct immune genetic background and the diverse prevalence of disease between the two Nations. Converging concepts were identified: enhanced knowledge of interferon-related pathways was found to be central to the understanding of immune-mediated tissue-specific destruction (TSD) of which tumor rejection is a representative facet. Although the expression of interferon-stimulated genes (ISGs) likely mediates the inflammatory process leading to tumor rejection, it is insufficient by itself and the associated mechanisms need to be identified. It is likely that adaptive immune responses play a broader role in tumor rejection than those strictly related to their antigen-specificity; likely, their primary role is to trigger an acute and tissue-specific inflammatory response at the tumor site that leads to rejection upon recruitment of additional innate and adaptive immune mechanisms. Other candidate systemic and/or tissue-specific biomarkers were recognized that might be added to the list of known entities applicable in immunotherapy trials. The need for a systematic approach to biomarker discovery that takes advantage of powerful high-throughput technologies was recognized; it was clear from the current state of the science that immunotherapy is still in a discovery phase and only a few of the current biomarkers warrant extensive validation. It was, finally, clear that, while current technologies have almost limitless potential, inadequate study design, limited standardization and cross-validation among laboratories and suboptimal comparability of data remain major road blocks. The institution of an interactive consortium for high throughput molecular monitoring of clinical trials with voluntary participation might provide cost-effective solutions. PMID:19534815
The Effect of the Pore Entrance on Particle Motion in Slit Pores: Implications for Ultrathin Membranes

PubMed Central

Delavari, Armin; Baltus, Ruth

2017-01-01

Membrane rejection models generally neglect the effect of the pore entrance on intrapore particle transport. However, entrance effects are expected to be particularly important with ultrathin membranes, where membrane thickness is typically comparable to pore size. In this work, a 2D model was developed to simulate particle motion for spherical particles moving at small Re and infinite Pe from the reservoir outside the pore into a slit pore. Using a finite element method, particles were tracked as they accelerated across the pore entrance until they reached a steady velocity in the pore. The axial position in the pore where particle motion becomes steady is defined as the particle entrance length (PEL). PELs were found to be comparable to the fluid entrance length, larger than the pore size and larger than the thickness typical of many ultrathin membranes. Results also show that, in the absence of particle diffusion, hydrodynamic particle–membrane interactions at the pore mouth result in particle “funneling” in the pore, yielding cross-pore particle concentration profiles focused at the pore centerline. The implications of these phenomena on rejection from ultrathin membranes are examined. PMID:28796197
The Influence of Immunosuppressive Agents on the Risk of De Novo Donor-Specific HLA Antibody Production in Solid Organ Transplant Recipients

PubMed Central

O'Leary, Jacqueline G.; Samaniego, Millie; Barrio, Marta Crespo; Potena, Luciano; Zeevi, Adriana; Djamali, Arjang; Cozzi, Emanuele

2016-01-01

Production of de novo donor-specific antibodies (dnDSA) is a major risk factor for acute and chronic antibody-mediated rejection and graft loss after all solid organ transplantation. In this article, we review the data available on the risk of individual immunosuppressive agents and their ability to prevent dnDSA production. Induction therapy with rabbit antithymocyte globulin may achieve a short-term decrease in dnDSA production in moderately sensitized patients. Rituximab induction may be beneficial in sensitized patients, and in abrogating rebound antibody response in patients undergoing desensitization or treatment for antibody-mediated rejection. Use of bortezomib for induction therapy in at-risk patients is of interest, but the benefits are unproven. In maintenance regimens, nonadherent and previously sensitized patients are not suitable for aggressive weaning protocols, particularly early calcineurin inhibitor withdrawal without lymphocyte-depleting induction. Early conversion to mammalian target of rapamycin inhibitor monotherapy has been reported to increase the risk of dnDSA formation, but a combination of mammalian target of rapamycin inhibitor and reduced-exposure calcineurin inhibitor does not appear to alter the risk. Early steroid therapy withdrawal in standard-risk patients after induction has no known dnDSA penalty. The available data do not demonstrate a consistent effect of mycophenolic acid on dnDSA production. Risk minimization for dnDSA requires monitoring of adherence, appropriate risk stratification, risk-based immunosuppression intensity, and prospective DSA surveillance. PMID:26680372
Donor Polymorphisms in Genes Related to B-Cell Biology Associated With Antibody-Mediated Rejection After Heart Transplantation.

PubMed

Marrón-Liñares, Grecia M; Núñez, Lucía; Crespo-Leiro, María G; Álvarez-López, Eloy; Barge-Caballero, Eduardo; Barge-Caballero, Gonzalo; Couto-Mallón, David; Pradas-Irun, Concepción; Muñiz, Javier; Tan, Carmela; Rodríguez, E Rene; Vázquez-Rodríguez, José Manuel; Hermida-Prieto, Manuel

2018-04-25

Heart transplantation (HT) is a well-established lifesaving treatment for endstage cardiac failure. Antibody-mediated rejection (AMR) represents one of the main problems after HT because of its diagnostic complexity and the poor evidence for supporting treatments. Complement cascade and B-cells play a key role in AMR and contribute to graft damage. This study explored the importance of variants in genes related to complement pathway and B-cell biology in HT and AMR in donors and in donor-recipient pairs.Methods and Results:Genetic variants in 112 genes (51 complement and 61 B-cell biology genes) were analyzed on next-generation sequencing in 28 donor-recipient pairs, 14 recipients with and 14 recipients without AMR. Statistical analysis was performed with SNPStats, R, and EPIDAT3.1. We identified one single nucleotide polymorphism (SNP) in donors in genes related to B-cell biology,interleukin-4 receptor subunitα (p.Ile75Val-IL4Rα), which correlated with the development of AMR. Moreover, in the analysis of recipient-donor genotype discrepancies, we identified another SNP, in this case inadenosine deaminase(ADA; p.Val178(p=)), which was related to B-cell biology, associated with the absence of AMR. Donor polymorphisms and recipient-donor discrepancies in genes related to the biology of B-cells, could have an important role in the development of AMR. In contrast, no variants in donor or in donor-recipient pairs in complement pathways seem to have an impact on AMR.
Outcome after Desensitization in HLA or ABO-Incompatible Kidney Transplant Recipients: A Single Center Experience

PubMed Central

Kauke, Teresa; Klimaschewski, Sandra; Schoenermarck, Ulf; Fischereder, Michael; Dick, Andrea; Guba, Markus; Stangl, Manfred; Werner, Jens; Meiser, Bruno; Habicht, Antje

2016-01-01

Background The shortage of deceased donors led to an increase of living donor kidney (LDK) transplantations performed in the presence of donor-specific antibodies (DSA) or ABO incompatibility (ABOi) using various desensitization protocols. Methods We herein analyzed 26 ABOi and 8 Luminex positive DSA patients who were successfully desensitized by anti-CD20, antigen-specific immunoadsorption and/or plasmapheresis to receive an LDK transplant. Twenty LDK recipients with non-donor-specific HLA-antibodies (low risk) and 32 without anti-HLA antibodies (no risk) served as control groups. Results 1-year graft survival rate and renal function was similar in all 4 groups (creatinine: 1.63 ± 0.5 vs 1.78 ± 0.6 vs 1.64 ± 0.5 vs 1.6 ± 0.3 mg/dl in ABOi, DSA, low risk and no risk group). The incidence of acute T-cell mediated rejections did not differ between the 4 groups (15% vs 12, 5% vs 15% vs 22% in ABOi, DSA, low risk and no risk), while antibody-mediated rejections were only found in the DSA (25%) and ABOi (7.5%) groups. Incidence of BK nephropathy (BKVN) was significantly more frequent after desensitization as compared to controls (5/34 vs 0/52, p = 0.03). Conclusion We demonstrate favorable short-term allograft outcome in LDK transplant recipients after desensitization. However, the desensitization was associated with an increased risk of BKVN. PMID:26730981
A minority stress--emotion regulation model of sexual compulsivity among highly sexually active gay and bisexual men.

PubMed

Pachankis, John E; Rendina, H Jonathon; Restar, Arjee; Ventuneac, Ana; Grov, Christian; Parsons, Jeffrey T

2015-08-01

Sexual compulsivity represents a significant public health concern among gay and bisexual men, given its co-occurrence with other mental health problems and HIV infection. The purpose of this study was to examine a model of sexual compulsivity based on minority stress theory and emotion regulation models of mental health among gay and bisexual men. Gay and bisexual men in New York City reporting at least nine past-90-day sexual partners (n = 374) completed measures of distal minority stressors (i.e., boyhood gender nonconformity and peer rejection, adulthood perceived discrimination), hypothesized proximal minority stress mediators (i.e., rejection sensitivity, internalized homonegativity), hypothesized universal mediators (i.e., emotion dysregulation, depression, and anxiety), and sexual compulsivity. The hypothesized model fit the data well (RMSEA = 0.05, CFI = 0.98, TLI = 0.95, SRMR = 0.03). Distal minority stress processes (e.g., adulthood discrimination) were generally found to confer risk for both proximal minority stressors (e.g., internalized homonegativity) and emotion dysregulation. Proximal minority stressors and emotion dysregulation, in turn, generally predicted sexual compulsivity both directly and indirectly through anxiety and depression. The final model suggests that gay-specific (e.g., internalized homonegativity) and universal (e.g., emotion dysregulation) processes represent potential treatment targets to attenuate the impact of minority stress on gay and bisexual men's sexual health. Tests of interventions that address these targets to treat sexual compulsivity among gay and bisexual men represent a promising future research endeavor. (c) 2015 APA, all rights reserved).
The inferior impact of antibody-mediated rejection on the clinical outcome of kidney allografts that develop de novo thrombotic microangiopathy.

PubMed

Wu, Kaiyin; Budde, Klemens; Schmidt, Danilo; Neumayer, Hans-Hellmut; Lehner, Lukas; Bamoulid, Jamal; Rudolph, Birgit

2016-02-01

Antibody-mediated rejection (AMR) can induce and develop thrombotic microangiopathy (TMA) in renal allografts. A definitive AMR (dAMR) co-presents three diagnostic features. A suspicious AMR (sAMR) is designated when one of the three features is missing. Thirty-two TMA cases overlapping with AMR (AMR+ TMA) were studied, which involved 14 cases of sAMR+ TMA and 18 cases of dAMR+ TMA. Thirty TMA cases free of AMR features (AMR- TMA) were enrolled as control group. The ratio of complete response to treatment was similar between AMR- TMA and AMR+ TMA group (23.3% vs. 12.5%, p = 0.33), or between sAMR+ TMA and dAMR+ TMA group (14.3% vs. 11.1%, p = 0.79). At eight yr post-transplantation, the death-censored graft survival (DCGS) rate of AMR- TMA group was 62.8%, which was significantly higher than 28.0% of AMR+ TMA group (p = 0.01), but similar between sAMR+ TMA and dAMR+ TMA group (30.0% vs. 26.7%, p = 0.92). Overall, the intimal arteritis and the broad HLA (Human leukocyte antigens) mismatches were closely associated with over time renal allograft failure. The AMR+ TMA has inferior long-term graft survival, but grafts with sAMR+ TMA or dAMR+ TMA have similar characteristics and clinical courses. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Accelerating Approximate Bayesian Computation with Quantile Regression: application to cosmological redshift distributions

NASA Astrophysics Data System (ADS)

Kacprzak, T.; Herbel, J.; Amara, A.; Réfrégier, A.

2018-02-01

Approximate Bayesian Computation (ABC) is a method to obtain a posterior distribution without a likelihood function, using simulations and a set of distance metrics. For that reason, it has recently been gaining popularity as an analysis tool in cosmology and astrophysics. Its drawback, however, is a slow convergence rate. We propose a novel method, which we call qABC, to accelerate ABC with Quantile Regression. In this method, we create a model of quantiles of distance measure as a function of input parameters. This model is trained on a small number of simulations and estimates which regions of the prior space are likely to be accepted into the posterior. Other regions are then immediately rejected. This procedure is then repeated as more simulations are available. We apply it to the practical problem of estimation of redshift distribution of cosmological samples, using forward modelling developed in previous work. The qABC method converges to nearly same posterior as the basic ABC. It uses, however, only 20% of the number of simulations compared to basic ABC, achieving a fivefold gain in execution time for our problem. For other problems the acceleration rate may vary; it depends on how close the prior is to the final posterior. We discuss possible improvements and extensions to this method.

Selective role for RGS12 as a Ras/Raf/MEK scaffold in nerve growth factor-mediated differentiation

PubMed Central

Willard, Melinda D; Willard, Francis S; Li, Xiaoyan; Cappell, Steven D; Snider, William D; Siderovski, David P

2007-01-01

Regulator of G-protein signaling (RGS) proteins accelerate GTP hydrolysis by heterotrimeric G-protein α subunits and thus inhibit signaling by many G protein-coupled receptors. Several RGS proteins have a multidomain architecture that adds further complexity to their roles in cell signaling in addition to their GTPase-accelerating activity. RGS12 contains a tandem repeat of Ras-binding domains but, to date, the role of this protein in Ras-mediated signal transduction has not been reported. Here, we show that RGS12 associates with the nerve growth factor (NGF) receptor tyrosine kinase TrkA, activated H-Ras, B-Raf, and MEK2 and facilitates their coordinated signaling to prolonged ERK activation. RGS12 is required for NGF-mediated neurite outgrowth of PC12 cells, but not outgrowth stimulated by basic fibroblast growth factor. siRNA-mediated knockdown of RGS12 expression also inhibits NGF-induced axonal growth in dissociated cultures of primary dorsal root ganglia neurons. These data suggest that RGS12 may play a critical, and receptor-selective, role in coordinating Ras-dependent signals that are required for promoting and/or maintaining neuronal differentiation. PMID:17380122
An externally oriented style of thinking as a moderator of responses to affective films in women.

PubMed

Davydov, Dmitry M; Luminet, Olivier; Zech, Emmanuelle

2013-02-01

This study was conducted to test the hypothesis that differences in alexithymia would moderate coupling in physiological and subjective-experiential responses to two affective films, which were shown to induce a common negative (sad) feeling, but to provoke different hyper- or hypo-arousal physiological responses (e.g., heart rate acceleration or deceleration) associated with antipathic or empathic context, respectively (Davydov et al., 2011). Only women were studied as persons showing more reactivity to sad films than men. Reactivity was evaluated for facial behavior, physiological arousal, and subjective experience. Some other affective and cognitive disposition factors (e.g., depression and defensiveness) were considered for evaluating their probable mediation of the alexithymia's effects. While subjective experience was not affected by alexithymia, high scorers on the externally-oriented thinking factor showed reduced physiological reactivity in both film conditions. These effects were mediated through different disposition factors: either low affectivity (low depressed mood), which mediated alexithymia's effect on hyper-arousal responses (e.g., decrease of heart rate acceleration), or impression management (other-deception), which mediated alexithymia's effect on hypo-arousal responses (e.g., decrease of heart rate deceleration). Copyright © 2012 Elsevier B.V. All rights reserved.
Atrial Natriuretic Peptide Accelerates Human Endothelial Progenitor Cell-Stimulated Cutaneous Wound Healing and Angiogenesis.

PubMed

Lee, Tae Wook; Kwon, Yang Woo; Park, Gyu Tae; Do, Eun Kyoung; Yoon, Jung Won; Kim, Seung-Chul; Ko, Hyun-Chang; Kim, Moon-Bum; Kim, Jae Ho

2018-05-26

Atrial natriuretic peptide (ANP) is a powerful vasodilating peptide secreted by cardiac muscle cells, and endothelial progenitor cells (EPCs) have been reported to stimulate cutaneous wound healing by mediating angiogenesis. To determine whether ANP can promote the EPC-mediated repair of injured tissues, we examined the effects of ANP on the angiogenic properties of EPCs and on cutaneous wound healing. In vitro, ANP treatment enhanced the migration, proliferation, and endothelial tube-forming abilities of EPCs. Furthermore, small interfering RNA-mediated silencing of natriuretic peptide receptor-1, which is a receptor for ANP, abrogated ANP-induced migration, tube formation, and proliferation of EPCs. In a murine cutaneous wound model, administration of either ANP or EPCs had no significant effect on cutaneous wound healing or angiogenesis in vivo, whereas the co-administration of ANP and EPCs synergistically potentiated wound healing and angiogenesis. In addition, ANP promoted the survival and incorporation of transplanted EPCs into newly formed blood vessels in wounds. These results suggest ANP accelerates EPC-mediated cutaneous wound healing by promoting the angiogenic properties and survival of transplanted EPCs. This article is protected by copyright. All rights reserved. © 2018 by the Wound Healing Society.
IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury.

PubMed

Lefaucheur, Carmen; Viglietti, Denis; Bentlejewski, Carol; Duong van Huyen, Jean-Paul; Vernerey, Dewi; Aubert, Olivier; Verine, Jérôme; Jouven, Xavier; Legendre, Christophe; Glotz, Denis; Loupy, Alexandre; Zeevi, Adriana

2016-01-01

Antibodies may have different pathogenicities according to IgG subclass. We investigated the association between IgG subclasses of circulating anti-human HLA antibodies and antibody-mediated kidney allograft injury. Among 635 consecutive kidney transplantations performed between 2008 and 2010, we enrolled 125 patients with donor-specific anti-human HLA antibodies (DSA) detected in the first year post-transplant. We assessed DSA characteristics, including specificity, HLA class specificity, mean fluorescence intensity (MFI), C1q-binding, and IgG subclass, and graft injury phenotype at the time of sera evaluation. Overall, 51 (40.8%) patients had acute antibody-mediated rejection (aABMR), 36 (28.8%) patients had subclinical ABMR (sABMR), and 38 (30.4%) patients were ABMR-free. The MFI of the immunodominant DSA (iDSA, the DSA with the highest MFI level) was 6724±464, and 41.6% of patients had iDSA showing C1q positivity. The distribution of iDSA IgG1-4 subclasses among the population was 75.2%, 44.0%, 28.0%, and 26.4%, respectively. An unsupervised principal component analysis integrating iDSA IgG subclasses revealed aABMR was mainly driven by IgG3 iDSA, whereas sABMR was driven by IgG4 iDSA. IgG3 iDSA was associated with a shorter time to rejection (P<0.001), increased microcirculation injury (P=0.002), and C4d capillary deposition (P<0.001). IgG4 iDSA was associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy lesions (P<0.001 for all comparisons). Integrating iDSA HLA class specificity, MFI level, C1q-binding status, and IgG subclasses in a Cox survival model revealed IgG3 iDSA and C1q-binding iDSA were strongly and independently associated with allograft failure. These results suggest IgG iDSA subclasses identify distinct phenotypes of kidney allograft antibody-mediated injury. Copyright © 2016 by the American Society of Nephrology.
Multilevel Mechanisms of Implementation Strategies in Mental Health: Integrating Theory, Research, and Practice

PubMed Central

2015-01-01

A step toward the development of optimally effective, efficient, and feasible implementation strategies that increase evidence-based treatment integration in mental health services involves identification of the multilevel mechanisms through which these strategies influence implementation outcomes. This article (a) provides an orientation to, and rationale for, consideration of multilevel mediating mechanisms in implementation trials, and (b) systematically reviews randomized controlled trials that examined mediators of implementation strategies in mental health. Nine trials were located. Mediation-related methodological deficiencies were prevalent and no trials supported a hypothesized mediator. The most common reason was failure to engage the mediation target. Discussion focuses on directions to accelerate implementation strategy development in mental health. PMID:26474761
Catalysis by a de novo zinc-mediated protein interface: implications for natural enzyme evolution and rational enzyme engineering.

PubMed

Der, Bryan S; Edwards, David R; Kuhlman, Brian

2012-05-08

Here we show that a recent computationally designed zinc-mediated protein interface is serendipitously capable of catalyzing carboxyester and phosphoester hydrolysis. Although the original motivation was to design a de novo zinc-mediated protein-protein interaction (called MID1-zinc), we observed in the homodimer crystal structure a small cleft and open zinc coordination site. We investigated if the cleft and zinc site at the designed interface were sufficient for formation of a primitive active site that can perform hydrolysis. MID1-zinc hydrolyzes 4-nitrophenyl acetate with a rate acceleration of 10(5) and a k(cat)/K(M) of 630 M(-1) s(-1) and 4-nitrophenyl phosphate with a rate acceleration of 10(4) and a k(cat)/K(M) of 14 M(-1) s(-1). These rate accelerations by an unoptimized active site highlight the catalytic power of zinc and suggest that the clefts formed by protein-protein interactions are well-suited for creating enzyme active sites. This discovery has implications for protein evolution and engineering: from an evolutionary perspective, three-coordinated zinc at a homodimer interface cleft represents a simple evolutionary path to nascent enzymatic activity; from a protein engineering perspective, future efforts in de novo design of enzyme active sites may benefit from exploring clefts at protein interfaces for active site placement.
Mediation Analysis with Survival Outcomes: Accelerated Failure Time vs. Proportional Hazards Models

PubMed Central

Gelfand, Lois A.; MacKinnon, David P.; DeRubeis, Robert J.; Baraldi, Amanda N.

2016-01-01

Objective: Survival time is an important type of outcome variable in treatment research. Currently, limited guidance is available regarding performing mediation analyses with survival outcomes, which generally do not have normally distributed errors, and contain unobserved (censored) events. We present considerations for choosing an approach, using a comparison of semi-parametric proportional hazards (PH) and fully parametric accelerated failure time (AFT) approaches for illustration. Method: We compare PH and AFT models and procedures in their integration into mediation models and review their ability to produce coefficients that estimate causal effects. Using simulation studies modeling Weibull-distributed survival times, we compare statistical properties of mediation analyses incorporating PH and AFT approaches (employing SAS procedures PHREG and LIFEREG, respectively) under varied data conditions, some including censoring. A simulated data set illustrates the findings. Results: AFT models integrate more easily than PH models into mediation models. Furthermore, mediation analyses incorporating LIFEREG produce coefficients that can estimate causal effects, and demonstrate superior statistical properties. Censoring introduces bias in the coefficient estimate representing the treatment effect on outcome—underestimation in LIFEREG, and overestimation in PHREG. With LIFEREG, this bias can be addressed using an alternative estimate obtained from combining other coefficients, whereas this is not possible with PHREG. Conclusions: When Weibull assumptions are not violated, there are compelling advantages to using LIFEREG over PHREG for mediation analyses involving survival-time outcomes. Irrespective of the procedures used, the interpretation of coefficients, effects of censoring on coefficient estimates, and statistical properties should be taken into account when reporting results. PMID:27065906
On the maximum energy of shock-accelerated cosmic rays at ultra-relativistic shocks

NASA Astrophysics Data System (ADS)

Reville, B.; Bell, A. R.

2014-04-01

The maximum energy to which cosmic rays can be accelerated at weakly magnetised ultra-relativistic shocks is investigated. We demonstrate that for such shocks, in which the scattering of energetic particles is mediated exclusively by ion skin-depth scale structures, as might be expected for a Weibel-mediated shock, there is an intrinsic limit on the maximum energy to which particles can be accelerated. This maximum energy is determined from the requirement that particles must be isotropized in the downstream plasma frame before the mean field transports them far downstream, and falls considerably short of what is required to produce ultra-high-energy cosmic rays. To circumvent this limit, a highly disorganized field is required on larger scales. The growth of cosmic ray-induced instabilities on wavelengths much longer than the ion-plasma skin depth, both upstream and downstream of the shock, is considered. While these instabilities may play an important role in magnetic field amplification at relativistic shocks, on scales comparable to the gyroradius of the most energetic particles, the calculated growth rates have insufficient time to modify the scattering. Since strong modification is a necessary condition for particles in the downstream region to re-cross the shock, in the absence of an alternative scattering mechanism, these results imply that acceleration to higher energies is ruled out. If weakly magnetized ultra-relativistic shocks are disfavoured as high-energy particle accelerators in general, the search for potential sources of ultra-high-energy cosmic rays can be narrowed.
They Are Laughing at Me: Cerebral Mediation of Cognitive Biases in Social Anxiety

PubMed Central

Kreifelts, Benjamin; Brück, Carolin; Ritter, Jan; Ethofer, Thomas; Domin, Martin; Lotze, Martin; Jacob, Heike

2014-01-01

The fear of embarrassment and humiliation is the central element of social anxiety. This frequent condition is associated with cognitive biases indicating increased sensitivity to signals of social threat, which are assumed to play a causal role in the maintenance of social anxiety. Here, we employed laughter, a potent medium for the expression of acceptance and rejection, as an experimental stimulus in participants selected for varying degrees of social anxiety to identify cerebral mediators of cognitive biases in social anxiety using functional magnetic resonance imaging in combination with mediation analysis. We directly demonstrated that cerebral activation patterns within the dorsal attention network including the left dorsolateral and dorsomedial prefrontal cortex mediate the influence of social anxiety on laughter perception. This mediation proved to be specific for social anxiety after correction for measures of general state and trait anxiety and occurred most prominently under bimodal audiovisual laughter presentation when compared with monomodal auditory or visual laughter cues. Considering the possibility to modulate cognitive biases and cerebral activity by neuropsychological trainings, non-invasive electrophysiological stimulation and psychotherapy, this study represents a starting point for a whole line of translational research projects and identifies promising targets for electrophysiological interventions aiming to alleviate cognitive biases and symptom severity in social anxiety. PMID:24918625
They are laughing at me: cerebral mediation of cognitive biases in social anxiety.

PubMed

Kreifelts, Benjamin; Brück, Carolin; Ritter, Jan; Ethofer, Thomas; Domin, Martin; Lotze, Martin; Jacob, Heike; Schlipf, Sarah; Wildgruber, Dirk

2014-01-01

The fear of embarrassment and humiliation is the central element of social anxiety. This frequent condition is associated with cognitive biases indicating increased sensitivity to signals of social threat, which are assumed to play a causal role in the maintenance of social anxiety. Here, we employed laughter, a potent medium for the expression of acceptance and rejection, as an experimental stimulus in participants selected for varying degrees of social anxiety to identify cerebral mediators of cognitive biases in social anxiety using functional magnetic resonance imaging in combination with mediation analysis. We directly demonstrated that cerebral activation patterns within the dorsal attention network including the left dorsolateral and dorsomedial prefrontal cortex mediate the influence of social anxiety on laughter perception. This mediation proved to be specific for social anxiety after correction for measures of general state and trait anxiety and occurred most prominently under bimodal audiovisual laughter presentation when compared with monomodal auditory or visual laughter cues. Considering the possibility to modulate cognitive biases and cerebral activity by neuropsychological trainings, non-invasive electrophysiological stimulation and psychotherapy, this study represents a starting point for a whole line of translational research projects and identifies promising targets for electrophysiological interventions aiming to alleviate cognitive biases and symptom severity in social anxiety.
The suppression of inflammatory macrophage-mediated cytotoxicity and proinflammatory cytokine production by transgenic expression of HLA-E.

PubMed

Maeda, Akira; Kawamura, Takuji; Ueno, Takehisa; Usui, Noriaki; Eguchi, Hiroshi; Miyagawa, Shuji

2013-12-01

Macrophages participate in xenogenic rejection and represent a major biological obstacle to successful xenotransplantation. The signal inhibitory regulatory protein α (SIRPα) receptor was reported to be a negative regulator of macrophage phagocytic activity via interaction with CD47, its ligand. Because a majority of human macrophages express the inhibitory receptor CD94/NKG2A, which binds specifically to the human leukocyte antigen (HLA)-E and contains immunoreceptor tyrosine-based inhibition motifs (ITIMs), the inhibitory function of HLA class I molecules, HLA-E, on macrophage-mediated cytolysis was examined. The suppressive effect against proinflammatory cytokine production by macrophages was also examined. Complementary DNA (cDNA) of HLA-E, and CD47 were prepared and transfected into swine endothelial cells (SEC). The expression of the modified genes was evaluated by flow cytometry and macrophage-mediated cytolysis was assessed using in vitro generated macrophages. Transgenic expression of HLA-E significantly suppressed the macrophage-mediated cytotoxicity. HLA-E transgenic expression demonstrated a significant suppression equivalent to CD47 transgenic expression. Furthermore, transgenic HLA-E suppressed the production of pro-inflammatory cytokines by inflammatory macrophages. These results indicate that generating transgenic HLA-E pigs might protect porcine grafts from, not only NK cytotoxicity, but also macrophage-mediated cytotoxicity. © 2013 Elsevier B.V. All rights reserved.
Remarkable rate acceleration of SmI3-mediated iodination of acetates of Baylis-Hillman adducts in ionic liquid: facile synthesis of (Z)-allyl iodides*

PubMed Central

Liu, Yun-Kui; Zheng, Hui; Xu, Dan-Qian; Xu, Zhen-Yuan; Zhang, Yong-Min

2006-01-01

Stereoselective transformation of Baylis-Hillman acetates 1 into corresponding (Z)-allyl iodides 2 has been achieved by treatment of 1 with samarium triiodide in THF. Remarkable rate acceleration of samarium triiodide-mediated iodination of 1 was found when ionic liquid 1-n-butyl-3-methyl-imidazolium tetrafluroborate ([bmim]BF4) was used as reaction media in stead of THF. This novel approach proceeds readily at 50 °C within a few minutes to afford (Z)-allyl iodides 2 in excellent yields. A mechanism involving stereoselective iodination of the acetates of Baylis-Hillman adducts by samarium triiodide is described, in which a six-membered ring transition state played a key role in the stereoselective formation of 2. PMID:16502505
Childhood conduct problems and young adult outcomes among women with childhood attention-deficit/hyperactivity disorder (ADHD).

PubMed

Owens, Elizabeth B; Hinshaw, Stephen P

2016-02-01

We tested whether conduct problems predicted young adult functioning and psychiatric symptoms among women diagnosed with attention-deficit/hyperactivity disorder (ADHD) during childhood, in the context of 3 potential adolescent mediators: internalizing problems, peer rejection, and school failure and disciplinary problems. We controlled for childhood ADHD severity, IQ, and demographic factors, and in the mediational tests, for adolescent conduct problems. Data came from 140 participants in the Berkeley Girls With ADHD Longitudinal Study. We used bootstrapping methods to assess indirect effects (mediators). Both childhood, F(1, 118) change = 9.00, p = .003, R2 change = .069, and adolescent, F(1, 109) change = 10.41, p = .002, R2 change = .083, conduct problems were associated with worse overall functioning during young adulthood, controlling for initial ADHD severity, child IQ, and demographics. Results were similar when predicting psychiatric symptoms. Adolescent school failure and disciplinary problems mediated the relations between childhood conduct problems and both young adult functioning and externalizing problems; adolescent internalizing problems and peer conflict mediated the relation between childhood conduct problems and young adult internalizing problems. As is true for boys, childhood and adolescent conduct problems are associated with poor adult outcomes among girls with ADHD, with school failure and disciplinary problems, internalizing problems, and peer conflict functioning as mediators of these relations. (c) 2016 APA, all rights reserved).
Emotion regulation and childhood aggression: longitudinal associations.

PubMed

Röll, Judith; Koglin, Ute; Petermann, Franz

2012-12-01

Accumulating evidence suggests that emotion dysregulation is associated with psychopathology. This paper provides a review of recent longitudinal studies that investigate the relationship between emotion regulation and aggressive behavior in childhood age. While there is substantial evidence for assuming a close relation of emotion regulation and aggressive behavior, moderating and mediating factors like gender and peer rejection have been established. Furthermore, results suggest emotion dysregulation as an important risk factor of aggressive behavior. Several directions for future research are pointed out to further validate and refine the reviewed relationships.
Psychoneuroimmunology in Pregnancy: Immune Pathways Linking Stress with Maternal Health, Adverse Birth Outcomes, and Fetal Development

PubMed Central

Christian, Lisa M.

2011-01-01

It is well-established that psychological stress promotes immune dysregulation in nonpregnant humans and animals. Stress promotes inflammation, impairs antibody responses to vaccination, slows wound healing, and suppresses cell-mediated immune function. Importantly, the immune system changes substantially to support healthy pregnancy, with attenuation of inflammatory responses and impairment of cell-mediated immunity. This adaptation is postulated to protect the fetus from rejection by the maternal immune system. Thus, stress-induced immune dysregulation during pregnancy has unique implications for both maternal and fetal health, particularly preterm birth. However, very limited research has examined stress-immune relationships in pregnancy. The application of psychoneuroimmunology research models to the perinatal period holds great promise for elucidating biological pathways by which stress may affect adverse pregnancy outcomes, maternal health, and fetal development. PMID:21787802
Did You Reject Me for Someone Else? Rejections That Are Comparative Feel Worse.

PubMed

Deri, Sebastian; Zitek, Emily M

2017-12-01

Rejections differ. For those who are rejected, one important difference is whether they are rejected for someone else (comparative rejection) or no one at all (noncomparative rejection). We examined the effect of this distinction on emotional reactions to a rejection in four studies ( N = 608), one of which was fully preregistered. Our results show that comparative rejections feel worse than noncomparative rejections and that this may be because such rejections lead to an increased sense of exclusion and decreased belonging. Furthermore, we found evidence that, by default, people react to a rejection as though it were comparative-that is, in the absence of any information about whether they have been rejected for someone or no one, they react as negatively as if they were rejected for someone. Our discussion focuses on the implications of these findings, including why people often seek out information in the wake of a rejection.
Intravenous infusion of apoptotic cells simultaneously with allogeneic hematopoietic grafts alters anti-donor humoral immune responses.

PubMed

Perruche, Sylvain; Kleinclauss, François; Bittencourt, Marcelo de Carvalho; Paris, Dominique; Tiberghien, Pierre; Saas, Philippe

2004-08-01

Intravenous infusion of apoptotic donor or third-party leukocytes simultaneously with an allogeneic donor bone marrow (BM) graft favors engraftment across major histocompatibility barriers. While verifying that such apoptotic cell infusion might not also be associated with antibody (Ab)-mediated allo-immune responses, we found, rather strikingly, that apoptotic cell infusion could in fact successfully prevent a humoral allo-immunization against a BM graft in mice. Indeed, among recipients having rejected their BM graft, prior apoptotic cell infusion was associated with a near absence of Ab-mediated allo-responses, while such an immunization was frequently observed in the absence of apoptotic cell infusion. This was also observed when infusing host apoptotic cells, thus showing that the prevention of immunization was linked to the apoptotic state of the cells rather than mediated by residual anti-recipient activity. In vivo anti-transforming growth factor-beta (TGF-beta) treatment resulted in the loss of this apoptotic cell infusion-associated protective effect on humoral allo-responses. Further studies will determine whether apoptotic cell infusion, in addition to hematopoietic graft facilitation might also contribute to preventing deleterious Ab-mediated allo-responses in various transplantation settings.
Caveat emptor: limitations of the automated reconstruction of metabolic pathways in Plasmodium.

PubMed

Ginsburg, Hagai

2009-01-01

The functional reconstruction of metabolic pathways from an annotated genome is a tedious and demanding enterprise. Automation of this endeavor using bioinformatics algorithms could cope with the ever-increasing number of sequenced genomes and accelerate the process. Here, the manual reconstruction of metabolic pathways in the functional genomic database of Plasmodium falciparum--Malaria Parasite Metabolic Pathways--is described and compared with pathways generated automatically as they appear in PlasmoCyc, metaSHARK and the Kyoto Encyclopedia for Genes and Genomes. A critical evaluation of this comparison discloses that the automatic reconstruction of pathways generates manifold paths that need an expert manual verification to accept some and reject most others based on manually curated gene annotation.
Study on Misalignment Angle Compensation during Scale Factor Matching for Two Pairs of Accelerometers in a Gravity Gradient Instrument

PubMed Central

Huang, Xiangqing; Deng, Zhongguang; Xie, Yafei; Fan, Ji; Hu, Chenyuan

2018-01-01

A method for automatic compensation of misalignment angles during matching the scale factors of two pairs of the accelerometers in developing the rotating accelerometer gravity gradient instrument (GGI) is proposed and demonstrated in this paper. The purpose of automatic scale factor matching of the four accelerometers in GGI is to suppress the common mode acceleration of the moving-based platforms. However, taking the full model equation of the accelerometer into consideration, the other two orthogonal axes which is the pendulous axis and the output axis, will also sense the common mode acceleration and reduce the suppression performance. The coefficients from the two axes to the output are δO and δP respectively, called the misalignment angles. The angle δO, coupling with the acceleration along the pendulous axis perpendicular to the rotational plane, will not be modulated by the rotation and gives little contribution to the scale factors matching. On the other hand, because of coupling with the acceleration along the centripetal direction in the rotating plane, the angle δP would produce a component with 90 degrees phase delay relative to the scale factor component. Hence, the δP component coincides exactly with the sensitive direction of the orthogonal accelerometers. To improve the common mode acceleration rejection, the misalignment angle δP is compensated by injecting a trimming current, which is proportional to the output of an orthogonal accelerometer, into the torque coil of the accelerometer during the scale factor matching. The experimental results show that the common linear acceleration suppression achieved three orders after the scale factors balance and five orders after the misalignment angles compensation, which is almost down to the noise level of the used accelerometers of 1~2 × 10−7 g/√Hz (1 g ≈ 9.8 m/s2). PMID:29670021
Study on Misalignment Angle Compensation during Scale Factor Matching for Two Pairs of Accelerometers in a Gravity Gradient Instrument.

PubMed

Huang, Xiangqing; Deng, Zhongguang; Xie, Yafei; Fan, Ji; Hu, Chenyuan; Tu, Liangcheng

2018-04-18

A method for automatic compensation of misalignment angles during matching the scale factors of two pairs of the accelerometers in developing the rotating accelerometer gravity gradient instrument (GGI) is proposed and demonstrated in this paper. The purpose of automatic scale factor matching of the four accelerometers in GGI is to suppress the common mode acceleration of the moving-based platforms. However, taking the full model equation of the accelerometer into consideration, the other two orthogonal axes which is the pendulous axis and the output axis, will also sense the common mode acceleration and reduce the suppression performance. The coefficients from the two axes to the output are δ O and δ P respectively, called the misalignment angles. The angle δ O , coupling with the acceleration along the pendulous axis perpendicular to the rotational plane, will not be modulated by the rotation and gives little contribution to the scale factors matching. On the other hand, because of coupling with the acceleration along the centripetal direction in the rotating plane, the angle δ P would produce a component with 90 degrees phase delay relative to the scale factor component. Hence, the δ P component coincides exactly with the sensitive direction of the orthogonal accelerometers. To improve the common mode acceleration rejection, the misalignment angle δ P is compensated by injecting a trimming current, which is proportional to the output of an orthogonal accelerometer, into the torque coil of the accelerometer during the scale factor matching. The experimental results show that the common linear acceleration suppression achieved three orders after the scale factors balance and five orders after the misalignment angles compensation, which is almost down to the noise level of the used accelerometers of 1~2 × 10 −7 g/√Hz (1 g ≈ 9.8 m/s²).

Anti-huCD20 Antibody Therapy for Antibody-Mediated Rejection of Renal Allografts in a Mouse Model

PubMed Central

Abe, Toyofumi; Ishii, Daisuke; Gorbacheva, Victoria; Kohei, Naoki; Tsuda, Hidetoshi; Tanaka, Toshiaki; Dvorina, Nina; Nonomura, Norio; Takahara, Shiro; Valujskikh, Anna; Baldwin, William M.; Fairchild, Robert L.

2016-01-01

We have reported that B6.CCR5−/− mice reject renal allografts with high serum donor-specific antibody (DSA) titers and marked C4d deposition in grafts, features consistent with AMR. B6.huCD20/CCR5−/− mice, where human CD20 expression is restricted to B cells, rejected A/J renal allografts by day 26 post-transplant with DSA first detected in serum on day 5 post-transplant and increased thereafter. Recipient treatment with anti-huCD20 mAb prior to the transplant and weekly up to 7 weeks post-transplant promoted long-term allograft survival (> 100 days) with low DSA titers. To investigate the effect of B cell depletion at the time serum DSA was first detected, recipients were treated with anti-huCD20 mAb on days 5, 8 and 12 post-transplant. This regimen significantly reduced DSA titers and graft inflammation on day 15 post-transplant and prolonged allograft survival > 60 days. However, DSA returned to the titers observed in control treated recipients by day 30 post-transplant and histological analyses on day 60 post-transplant indicated severe interstitial fibrosis. These results indicate that anti-huCD20 mAb had the greatest effect as a prophylactic treatment and that the distinct kinetics of DSA responses accounts for acute renal allograft failure versus the development of fibrosis. PMID:25731734
Emotional Reactivity, Behavior Problems, and Social Adjustment at School Entry in a High-risk Sample.

PubMed

Kalvin, Carla B; Bierman, Karen L; Gatzke-Kopp, Lisa M

2016-11-01

Prior research suggests that heightened emotional reactivity to emotionally distressing stimuli may be associated with elevated internalizing and externalizing behaviors, and contribute to impaired social functioning. These links were explored in a sample of 169 economically-disadvantaged kindergarteners (66 % male; 68 % African American, 22 % Hispanic, 10 % Caucasian) oversampled for elevated aggression. Physiological measures of emotional reactivity (respiratory sinus arrhythmia [RSA], heart rate [HR], and cardiac pre-ejection period [PEP]) were collected, and teachers and peers provided ratings of externalizing and internalizing behavior, prosocial competence, and peer rejection. RSA withdrawal, HR reactivity, and PEP shortening (indicating increased arousal) were correlated with reduced prosocial competence, and RSA withdrawal and HR reactivity were correlated with elevated internalizing problems. HR reactivity was also correlated with elevated externalizing problems and peer rejection. Linear regressions controlling for age, sex, race, verbal proficiency, and resting physiology showed that HR reactivity explained unique variance in both teacher-rated prosocial competence and peer rejection, and contributed indirectly to these outcomes through pathways mediated by internalizing and externalizing problems. A trend also emerged for the unique contribution of PEP reactivity to peer-rated prosocial competence. These findings support the contribution of emotional reactivity to behavior problems and social adjustment among children living in disadvantaged urban contexts, and further suggest that elevated reactivity may confer risk for social difficulties in ways that overlap only partially with internalizing and externalizing behavior problems.
The ARC1 E3 ligase gene is frequently deleted in self-compatible Brassicaceae species and has a conserved role in Arabidopsis lyrata self-pollen rejection.

PubMed

Indriolo, Emily; Tharmapalan, Pirashaanthy; Wright, Stephen I; Goring, Daphne R

2012-11-01

Self-pollen rejection is an important reproductive regulator in flowering plants, and several different intercellular signaling systems have evolved to elicit this response. In the Brassicaceae, the self-incompatibility system is mediated by the pollen S-locus Cys-Rich/S-locus Protein11 (SCR/SP11) ligand and the pistil S Receptor Kinase (SRK). While the SCR/SP11-SRK recognition system has been identified in several species across the Brassicaceae, less is known about the conservation of the SRK-activated cellular responses in the stigma, following self-pollen contact. The ARM Repeat Containing1 (ARC1) E3 ubiquitin ligase functions downstream of SRK for the self-incompatibility response in Brassica, but it has been suggested that ARC1 is not required in Arabidopsis species. Here, we surveyed the presence of ARC1 orthologs in several recently sequenced genomes from Brassicaceae species that had diversified ∼20 to 40 million years ago. Surprisingly, the ARC1 gene was deleted in several species that had lost the self-incompatibility trait, suggesting that ARC1 may lose functionality in the transition to self-mating. To test the requirement of ARC1 in a self-incompatible Arabidopsis species, transgenic ARC1 RNA interference Arabidopsis lyrata plants were generated, and they exhibited reduced self-incompatibility responses resulting in successful fertilization. Thus, this study demonstrates a conserved role for ARC1 in the self-pollen rejection response within the Brassicaceae.
Thin terrestrial sediment deposits on intertidal sandflats: effects on pore-water solutes and juvenile bivalve burial behaviour

NASA Astrophysics Data System (ADS)

Hohaia, A.; Vopel, K.; Pilditch, C. A.

2014-04-01

Nearshore zones experience increased sedimentation due to coastal development and enhanced loads of fine terrestrial sediment (hereafter, TS) in river waters. Deposition of TS can alter seabed biogeochemical processes but the effects on benthic ecosystem functioning are unknown. The results of a past experiment with defaunated, intertidal sediment suggest that a decrease in the oxygenation of this sediment by a thin (mm) TS deposit causes substrate rejection (refusal to bury) by post-settlement juvenile recruits of the tellinid bivalve Macomona liliana. We further examined this behaviour, asking if such deposits negatively affect burial when applied to intertidal sediment that is oxygenated by bioturbation (C) or depleted of dead and living organic matter (D). We observed recruits on the surface of four treatments: C, D, and the same sediments to which we added a 1.7-1.9 mm layer of TS (CTS, DTS). The TS deposit decreased the oxygenation and the pH of the underlying intertidal sediment (CTS) confirming previous results, but significantly increased but not decreased the probability of burial, irrespectively of treatment. Juveniles more likely buried into C than into D. The mechanism that caused previously observed substrate rejection by post-settlement juvenile M. liliana remains unclear but our results suggest that contact of the recruits with the TS deposit does not cause substrate rejection. We now hypothesise that conditioning of sediment by bioturbation can mediate negative effects of TS deposits on the recruits' burial behaviour.
GEANT4-based full simulation of the PADME experiment at the DAΦNE BTF

NASA Astrophysics Data System (ADS)

Leonardi, E.; Kozhuharov, V.; Raggi, M.; Valente, P.

2017-10-01

A possible solution to the dark matter problem postulates that dark particles can interact with Standard Model particles only through a new force mediated by a “portal”. If the new force has a U(1) gauge structure, the “portal” is a massive photon-like vector particle, called dark photon or A‧. The PADME experiment at the DAΦNE Beam-Test Facility (BTF) in Frascati is designed to detect dark photons produced in positron on fixed target annihilations decaying to dark matter (e+e-→γA‧) by measuring the final state missing mass. The experiment will be composed of a thin active diamond target where a 550 MeV positron beam will impinge to produce e+e- annihilation events. The surviving beam will be deflected with a magnet while the photons produced in the annihilation will be measured by a calorimeter composed of BGO crystals. To reject the background from Bremsstrahlung gamma production, a set of segmented plastic scintillator vetoes will be used to detect positrons exiting the target with an energy lower than that of the beam, while a fast small angle calorimeter will be used to reject the e+e-→γγ(γ) background. To optimize the experimental layout in terms of signal acceptance and background rejection, the full layout of the experiment was modelled with the GEANT4 simulation package. In this paper we will describe the details of the simulation and report on the results obtained with the software.
Expression of a Chimeric Antigen Receptor Specific for Donor HLA Class I Enhances the Potency of Human Regulatory T Cells in Preventing Human Skin Transplant Rejection.

PubMed

Boardman, D A; Philippeos, C; Fruhwirth, G O; Ibrahim, M A A; Hannen, R F; Cooper, D; Marelli-Berg, F M; Watt, F M; Lechler, R I; Maher, J; Smyth, L A; Lombardi, G

2017-04-01

Regulatory T cell (Treg) therapy using recipient-derived Tregs expanded ex vivo is currently being investigated clinically by us and others as a means of reducing allograft rejection following organ transplantation. Data from animal models has demonstrated that adoptive transfer of allospecific Tregs offers greater protection from graft rejection compared to polyclonal Tregs. Chimeric antigen receptors (CAR) are clinically translatable synthetic fusion proteins that can redirect the specificity of T cells toward designated antigens. We used CAR technology to redirect human polyclonal Tregs toward donor-MHC class I molecules, which are ubiquitously expressed in allografts. Two novel HLA-A2-specific CARs were engineered: one comprising a CD28-CD3ζ signaling domain (CAR) and one lacking an intracellular signaling domain (ΔCAR). CAR Tregs were specifically activated and significantly more suppressive than polyclonal or ΔCAR Tregs in the presence of HLA-A2, without eliciting cytotoxic activity. Furthermore, CAR and ΔCAR Tregs preferentially transmigrated across HLA-A2-expressing endothelial cell monolayers. In a human skin xenograft transplant model, adoptive transfer of CAR Tregs alleviated the alloimmune-mediated skin injury caused by transferring allogeneic peripheral blood mononuclear cells more effectively than polyclonal Tregs. Our results demonstrated that the use of CAR technology is a clinically applicable refinement of Treg therapy for organ transplantation. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.
Psychological control by parents is associated with a higher child weight.

PubMed

Rodenburg, Gerda; Kremers, Stef P J; Oenema, Anke; van de Mheen, Dike

2011-10-01

In this examination of the association between parenting style and child weight, the neglected concept of 'psychological control' has been added to the generally accepted parenting dimensions 'support' and 'behavioural control'. Also explored is whether the potential association between parenting and child weight is moderated by socio-demographic variables (child's age/ethnicity, and parent's education level). A cross-sectional study was performed among 1,665 parent-child dyads. The children's mean age was 8 years. Their height and weight were measured to calculate their body mass index (BMI). Parents completed a questionnaire to measure the three parenting dimensions. Based on these dimensions, five parenting styles were defined: the authoritative, permissive, authoritarian, neglecting and rejecting parenting style. Child BMI z-scores were regressed on parenting style, adjusting for parental BMI, child ethnicity, and parent's education level. Rejecting parenting, characterized by high psychological control, low support and low behavioural control, is the only parenting style significantly related to child BMI z-scores (β = 0.074, p < 0.001). The positive association was not moderated by socio-demographic variables. By adding the dimension of psychological control to the concept of parenting, this study has further elucidated the mechanisms whereby parenting may affect child weight. Demonstrating that 'rejecting parenting' is associated with a higher child weight, emphasizes the need for longitudinal studies in which parenting style is measured three-dimensionally. Potential mediating effects of parental feeding style and children's eating style, as well as age moderation, should be included in these studies.
Microelectromechanical accelerometer with resonance-cancelling control circuit including an idle state

DOEpatents

Chu, Dahlon D.; Thelen, Jr., Donald C.; Campbell, David V.

2001-01-01

A digital feedback control circuit is disclosed for use in an accelerometer (e.g. a microelectromechanical accelerometer). The digital feedback control circuit, which periodically re-centers a proof mass in response to a sensed acceleration, is based on a sigma-delta (.SIGMA..DELTA.) configuration that includes a notch filter (e.g. a digital switched-capacitor filter) for rejecting signals due to mechanical resonances of the proof mass and further includes a comparator (e.g. a three-level comparator). The comparator generates one of three possible feedback states, with two of the feedback states acting to re-center the proof mass when that is needed, and with a third feedback state being an "idle" state which does not act to move the proof mass when no re-centering is needed. Additionally, the digital feedback control system includes an auto-zero trim capability for calibration of the accelerometer for accurate sensing of acceleration. The digital feedback control circuit can be fabricated using complementary metal-oxide semiconductor (CMOS) technology, bi-CMOS technology or bipolar technology and used in single- and dual-proof-mass accelerometers.
The Development of the Differential MEMS Vector Hydrophone

PubMed Central

Zhang, Guojun; Liu, Mengran; Shen, Nixin; Wang, Xubo; Zhang, Wendong

2017-01-01

To solve the problem that MEMS vector hydrophones are greatly interfered with by the vibration of the platform and flow noise in applications, this paper describes a differential MEMS vector hydrophone that could simultaneously receive acoustic signals and reject acceleration signals. Theoretical and simulation analyses have been carried out. Lastly, a prototype of the differential MEMS vector hydrophone has been created and tested using a standing wave tube and a vibration platform. The results of the test show that this hydrophone has a high sensitivity, Mv = −185 dB (@ 500 Hz, 0 dB reference 1 V/μPa), which is almost the same as the previous MEMS vector hydrophones, and has a low acceleration sensitivity, Mv = −58 dB (0 dB reference 1 V/g), which has decreased by 17 dB compared with the previous MEMS vector hydrophone. The differential MEMS vector hydrophone basically meets the requirements of acoustic vector detection when it is rigidly fixed to a working platform, which lays the foundation for engineering applications of MEMS vector hydrophones. PMID:28594384
How to investigate a child with excessive growth?

PubMed

Coutant, Régis; Donzeau, Aurélie; Decrequy, Anne; Louvigné, Mathilde; Bouhours-Nouet, Natacha

2017-06-01

The diagnostic approach to tall stature in children is based on collecting birth data (macrosomia), sizes and family puberty, a family history of constitutional or pathological tall stature, search for a delay of development, dysmorphia, disproportion, analysis of the growth velocity (normal or accelerated), general examination and assessment of puberty, and bone age. When there is a history of psychomotor retardation, a family history of pathological tall stature, or a disproportion in the clinical examination, the genetic causes of tall stature will be mentioned. The most frequent causes are Marfan syndrome and similar, Sotos syndrome, Beckwith-Wiedemann syndrome, Klinefelter syndrome, and MEN2B. There are many genetic syndromes with tall stature, justifying consultation with the geneticist. When the speed of growth is accelerated, first of all it evokes puberty and early pseudopuberty, obesity and acromegaly. Finally, when the growth velocity is regular, and the parents are of tall stature, it evokes constitutional tall stature: this is the most frequent diagnosis, to retain after having rejected pathological tall statures. Copyright © 2017 Elsevier Masson SAS. All rights reserved.
Function of endoplasmic reticulum calcium ATPase in innate immunity-mediated programmed cell death

PubMed Central

Zhu, Xiaohong; Caplan, Jeffrey; Mamillapalli, Padmavathi; Czymmek, Kirk; Dinesh-Kumar, Savithramma P

2010-01-01

Programmed cell death (PCD) initiated at the pathogen-infected sites during the plant innate immune response is thought to prevent the development of disease. Here, we describe the identification and characterization of an ER-localized type IIB Ca2+-ATPase (NbCA1) that function as a regulator of PCD. Silencing of NbCA1 accelerates viral immune receptor N- and fungal-immune receptor Cf9-mediated PCD, as well as non-host pathogen Pseudomonas syringae pv. tomato DC3000 and the general elicitor cryptogein-induced cell death. The accelerated PCD rescues loss-of-resistance phenotype of Rar1, HSP90-silenced plants, but not SGT1-silenced plants. Using a genetically encoded calcium sensor, we show that downregulation of NbCA1 results in the modulation of intracellular calcium signalling in response to cryptogein elicitor. We further show that NbCAM1 and NbrbohB function as downstream calcium decoders in N-immune receptor-mediated PCD. Our results indicate that ER-Ca2+-ATPase is a component of the calcium efflux pathway that controls PCD during an innate immune response. PMID:20075858
Sensory Hair Cells: An Introduction to Structure and Physiology.

PubMed

McPherson, Duane R

2018-06-18

Sensory hair cells are specialized secondary sensory cells that mediate our senses of hearing, balance, linear acceleration, and angular acceleration (head rotation). In addition, hair cells in fish and amphibians mediate sensitivity to water movement through the lateral line system, and closely related electroreceptive cells mediate sensitivity to low-voltage electric fields in the aquatic environment of many fish species and several species of amphibian.Sensory hair cells share many structural and functional features across all vertebrate groups, while at the same time they are specialized for employment in a wide variety of sensory tasks. The complexity of hair cell structure is large, and the diversity of hair cell applications in sensory systems exceeds that seen for most, if not all, sensory cell types. The intent of this review is to summarize the more significant structural features and some of the more interesting and important physiological mechanisms that have been elucidated thus far. Outside vertebrates, hair cells are only known to exist in the coronal organ of tunicates. Electrical resonance, electromotility, and their exquisite mechanical sensitivity all contribute to the attractiveness of hair cells as a research subject.
Radioprotection by polysaccharides alone and in combination with aminothiols

NASA Astrophysics Data System (ADS)

Patchen, Myra L.; Macvittie, Thomas J.; Solberg, Brian D.; D'Alesandro, Michele M.; Brook, Itzhak

We demonstrated that glucan, a beta-1,3 polysaccharide immunomodulator, enhances survival of mice when administered before radiation exposure. Glucan's prophylactic survival-enhancing effects are mediated by several mechanisms including (1) increasing macrophage-mediated resistance to potentially lethal postirradiation opportunistic infections, (2) increasing the Do of hematopoietic progenitor cells, and (3) accelerating hematopoietic reconstitution. In addition, even when administered shortly after some otherwise lethal doses of radiation, glucan increases survival. Glucan's therapeutic survival-enhancing effects are also mediated through its ability to enhance macrophage function and to accelerate hematopoietic reconstitution; glucan's therapeutic potential, however, is ultimately dependent on the survival of a critical number of hematopoietic stem cells capable of responding to glucan's stimulatory effects. Preirradiation administration of the traditional aminothiol radioprotectants WR-2721 and WR-3689 has been previously demonstrated to be an extremely effective means to increase hematopoietic stem cell survival. Therapeutic glucan treatment administered in combination with preirradiation WR-2721 or WR-3689 treatment synergistically increases both hematopoietic reconstitution and survival. Such combined modality treatments offer new promise in treating acute radiation injury.
The Role of Particle-Mediated DNA Vaccines in Biodefense Preparedness

DTIC Science & Technology

2005-06-17

vaccines in biodefense preparedness Hansi J. Deana,T, Joel Haynesa, Connie Schmaljohnb aPowderJect Vaccines , Inc. 8551 Research Way, Middleton, WI 53562...accepted 25 January 2005 Available online 12 April 2005Abstract Particle-mediated epidermal delivery (PMED) of DNA vaccines is based on the acceleration...recent years, data have accumulated on the utility of PMED for delivery of DNA vaccines against a number of viral pathogens, including filoviruses
Regulatory immune cells and functions in autoimmunity and transplantation immunology.

PubMed

Papp, Gabor; Boros, Peter; Nakken, Britt; Szodoray, Peter; Zeher, Margit

2017-05-01

In physiological circumstances, various tolerogenic mechanisms support the protection of self-structures during immune responses. However, quantitative and/or qualitative changes in regulatory immune cells and mediators can evoke auto-reactive immune responses, and upon susceptible genetic background, along with the presence of other concomitant etiological factors, autoimmune disease may develop. In transplant immunology, tolerogenic mechanisms are also critical, since the balance between of alloantigen-reactive effector cells and the regulatory immune cells will ultimately determine whether a graft is accepted or rejected. Better understanding of the immunological tolerance and the potential modulations of immune regulatory processes are crucial for developing effective therapies in autoimmune diseases as well as in organ transplantation. In this review, we focus on the novel insights regarding the impaired immune regulation and other relevant factors contributing to the development of auto-reactive and graft-reactive immune responses in autoimmune diseases and transplant rejection, respectively. We also address some promising approaches for modification of immune-regulatory processes and tolerogenic mechanisms in autoimmunity and solid organ transplantation, which may be beneficial in future therapeutic strategies. Copyright © 2017 Elsevier B.V. All rights reserved.
Changes in leucocyte migration after renal transplantation

PubMed Central

Smith, M. G. M.; Eddleston, A. L. W. F.; Dominguez, J. A.; Evans, D. B.; Bewick, M.; Williams, Roger

1969-01-01

The leucocyte migration test, an in-vitro measure of cellular immunity, has been used to follow the changes in cell-mediated hypersensitivity to kidney and histocompatibility antigens in three patients after renal transplantation. Inhibition of leucocyte migration, indicating strong sensitization to the antigens used, occurred in each patient, starting five to seven days after transplantation. Satisfactory renal function had not been established in any of the patients at this time. In one case inhibition of leucocyte migration persisted almost continuously until the 24th day and was associated with poor renal function proved histologically to be due to rejection. Treatment with increased dosage of prednisone was associated with a rapid reversion to normal of the migration index and improvement in renal function. Later, inhibition of migration occurred again, and shortly afterwards the graft ceased to function. In the other two cases the migration index became normal without alteration in immunosuppressive therapy and a satisfactory diuresis followed. It is suggested that this simple test should prove useful in the specific diagnosis of rejection and in control of immunosuppressive therapy. ImagesFig. 3Fig. 4 PMID:4899455
Clinical implications of basic science discoveries: nociceptive neurons as targets to control immunity--potential relevance for transplantation.

PubMed

Larregina, A T; Divito, S J; Morelli, A E

2015-06-01

Increasing evidence indicates the existence of a complex cross-regulation between the most important biosensors of the human body: The immune and nervous systems. Cytokines control body temperature and trigger autoimmune disorders in the central nervous system, whereas neuropeptides released in peripheral tissues and lymphoid organs modulate inflammatory (innate) and adaptive immune responses. Surprisingly, the effects of nerve fibers and the antidromic release of its pro-inflammatory neuropeptides on the leukocytes of the immune system that mediate graft rejection are practically unknown. In the transplantation field, such area of research remains practically unexplored. A recent study by Riol-Blanco et al has revealed new details on how nociceptive nerves regulate the pro-inflammatory function of leukocytes in peripheral tissues. Although the mechanism(s) by which neuroinflammation affects the immune response against the allograft remains unknown, recent data suggest that this new area of research is worth exploring for potential development of novel complementary therapies for prevention/treatment of graft rejection. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
Unstable identity compatibility: how gender rejection sensitivity undermines the success of women in science, technology, engineering, and mathematics fields.

PubMed

Ahlqvist, Sheana; London, Bonita; Rosenthal, Lisa

2013-09-01

Although the perceived compatibility between one's gender and science, technology, engineering, and mathematics (STEM) identities (gender-STEM compatibility) has been linked to women's success in STEM fields, no work to date has examined how the stability of identity over time contributes to subjective and objective STEM success. In the present study, 146 undergraduate female STEM majors rated their gender-STEM compatibility weekly during their freshman spring semester. STEM women higher in gender rejection sensitivity, or gender RS, a social-cognitive measure assessing the tendency to perceive social-identity threat, experienced larger fluctuations in gender-STEM compatibility across their second semester of college. Fluctuations in compatibility predicted impaired outcomes the following school year, including lower STEM engagement and lower academic performance in STEM (but not non-STEM) classes, and significantly mediated the relationship between gender RS and STEM engagement and achievement in the 2nd year of college. The week-to-week changes in gender-STEM compatibility occurred in response to negative academic (but not social) experiences.
Usage of semantic representations in recognition memory.

PubMed

Nishiyama, Ryoji; Hirano, Tetsuji; Ukita, Jun

2017-11-01

Meanings of words facilitate false acceptance as well as correct rejection of lures in recognition memory tests, depending on the experimental context. This suggests that semantic representations are both directly and indirectly (i.e., mediated by perceptual representations) used in remembering. Studies using memory conjunction errors (MCEs) paradigms, in which the lures consist of component parts of studied words, have reported semantic facilitation of rejection of the lures. However, attending to components of the lures could potentially cause this. Therefore, we investigated whether semantic overlap of lures facilitates MCEs using Japanese Kanji words in which a whole-word image is more concerned in reading. Experiments demonstrated semantic facilitation of MCEs in a delayed recognition test (Experiment 1), and in immediate recognition tests in which participants were prevented from using phonological or orthographic representations (Experiment 2), and the salient effect on individuals with high semantic memory capacities (Experiment 3). Additionally, analysis of the receiver operating characteristic suggested that this effect is attributed to familiarity-based memory judgement and phantom recollection. These findings indicate that semantic representations can be directly used in remembering, even when perceptual representations of studied words are available.
Anxious and angry rejection sensitivity, social withdrawal, and retribution in high and low ambiguous situations.

PubMed

Zimmer-Gembeck, Melanie J; Nesdale, Drew

2013-02-01

Rejection sensitivity (RS) is a tendency to expect, perceive, and overreact to rejection. Our objective was to examine whether anxious and angry RS have specific associations with negative social reactions, and whether responses are intensified in situations of high rejection ambiguity. In two studies, youth (N = 464 and N = 371) reported their RS and anticipated responses to social scenarios. In Study 1, all scenarios portrayed overt rejection events. In Study 2, participants were randomly assigned to conditions portraying overt or ambiguous rejection. Greater rejection expectation was associated with more negative reactions to rejection. Moreover, as expected, anxiety about rejection was uniquely associated with withdrawal, and anger about rejection was uniquely associated with retribution (i.e., reactive aggression). In the second study, RS persons responded more negatively than others to both overt and high ambiguous rejections, but retribution was intensified among participants high in rejection expectation when rejection was ambiguous, and withdrawal was intensified among participants high in anxious RS in overt rejection situations. Consistent with the revised RS model, there are different patterns of emotions, cognitions, and behaviors in response to high and low ambiguous rejection events, which are heightened in youth sensitive to rejection. © 2012, Wiley Periodicals, Inc.

Cognitive and functional correlates of accelerated long-term forgetting in temporal lobe epilepsy.

PubMed

Audrain, Samantha; McAndrews, Mary P

2018-03-30

While we know that hippocampal dysfunction is responsible for the memory deficits that patients with temporal lobe epilepsy exhibit at relatively short study-test delays, the role of this region in accelerated long-term forgetting (ALF) is not yet clear. In the present study, we probed the role of the hippocampus in ALF by directly comparing memory for associations to memory that could be supported by item recognition during a forced choice recognition task over delays ranging from 15-min to 72-h. We additionally examined resting-state functional connectivity between the hippocampus and cortical regions known to be involved in processing these types of stimuli, as well as the relationship between ALF and various clinical variables including structural abnormality in the hippocampus, lateralization of epileptic focus, presence of seizures across the retention period, and standardized composite memory scores. We found evidence of accelerated forgetting for item stimuli (but not associative stimuli) by 6 h post-learning, which became statistically reliable by 72-h. This finding suggests that unlike controls, patients were unable to utilize novelty to reject the incorrect object-scene pair. While none of the examined clinical variables were related to long-term forgetting, reduced resting-state functional connectivity between the affected anterior hippocampus and unaffected lateral temporal cortex predicted forgetting of item stimuli over the 72-h delay. Implications for the role of the hippocampus in accelerated long-term forgetting, and existing theories of systems consolidation in this context are discussed. Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.
SIPP, a Novel Mitochondrial Phosphate Carrier, Mediates in Self-Incompatibility1[OPEN

PubMed Central

2017-01-01

In Solanaceae, the S-specific interaction between the pistil S-RNase and the pollen S-Locus F-box protein controls self-incompatibility (SI). Although this interaction defines the specificity of the pollen rejection response, the identification of three pistil essential modifier genes unlinked to the S-locus (HT-B, 120K, and NaStEP) unveils a higher degree of complexity in the pollen rejection pathway. We showed previously that NaStEP, a stigma protein with homology with Kunitz-type protease inhibitors, is essential to SI in Nicotiana spp. During pollination, NaStEP is taken up by pollen tubes, where potential interactions with pollen tube proteins might underlie its function. Here, we identified NaSIPP, a mitochondrial protein with phosphate transporter activity, as a novel NaStEP-interacting protein. Coexpression of NaStEP and NaSIPP in pollen tubes showed interaction in the mitochondria, although when expressed alone, NaStEP remains mostly cytosolic, implicating NaSIPP-mediated translocation of NaStEP into the organelle. The NaSIPP transcript is detected specifically in mature pollen of Nicotiana spp.; however, in self-compatible plants, this gene has accumulated mutations, so its coding region is unlikely to produce a functional protein. RNA interference suppression of NaSIPP in Nicotiana spp. pollen grains disrupts the SI by preventing pollen tube inhibition. Taken together, our results are consistent with a model whereby the NaStEP and NaSIPP interaction, in incompatible pollen tubes, might destabilize the mitochondria and contribute to arrest pollen tube growth. PMID:28874520
Disability pride protects self-esteem through the rejection-identification model.

PubMed

Bogart, Kathleen R; Lund, Emily M; Rottenstein, Adena

2018-02-01

The rejection-identification model (RIM) argues that the negative impacts of stigma, such as decreased self-esteem, may be mitigated when members of the stigmatized group choose to identify with each other rather than with the majority culture. A previously unstudied potential RIM stigma-reduction mechanism is disability pride, which views disability as a source of valuable, enriching, and positive experience. Impairment, personal, and environmental factors based on the International Classification of Functioning, Disability and Health (ICF) predict whether people will categorize themselves as disabled, but predictors of pride have received little examination. The purpose of this study was to (a) explore whether ICF factors predict disability pride, and (b) assess whether disability pride mediates a relationship between stigma and self-esteem, supporting RIM. Research Method/Design: Participants completed an Internet-based survey assessing pride, self-esteem, and ICF factors. Disability was not mentioned in recruitment materials to prevent selection biases. People who reported at least 1 impairment (n = 710) were included in analyses. ICF personal and environmental factors (stigma, social support, and being a person of color), but not impairment factors, predicted disability pride. Supporting RIM, disability pride partially mediated the relationship between stigma and self-esteem. Disability pride is a promising way to protect self-esteem against stigma. Disability pride is still a rare phenomenon. Given that pride is associated with social support, stigma, and, to a lesser extent, ethnicity, but not impairment characteristics, interventions might focus on personal and environmental factors like these to promote pride. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
Indoleamine 2,3-dioxygenase (IDO) and Treg Support are Critical for CTLA4Ig-Mediated Long-term Solid Organ Allograft Survival

PubMed Central

Sucher, Robert; Fischler, Klaus; Oberhuber, Rupert; Kronberger, Irmgard; Margreiter, Christian; Ollinger, Robert; Schneeberger, Stefan; Fuchs, Dietmar; Werner, Ernst R.; Watschinger, Katrin; Zelger, Bettina; Tellides, George; Pilat, Nina; Pratschke, Johann; Margreiter, Raimund; Wekerle, Thomas; Brandacher, Gerald

2011-01-01

Co-stimulatory blockade of CD28-B7 interaction with CTLA4Ig is a well-established strategy to induce transplantation tolerance. Although previous in vitro studies suggest that CTLA4Ig up-regulates expression of the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in dendritic cells, the relationship of CTLA4Ig and IDO in in vivo organ transplantation remains unclear. Here we studied if concerted immunomodulation in vivo by CTLA4Ig depends on IDO. C57BL/6 recipients receiving a fully MHC-mismatched BALB/c heart graft treated with CTLA4Ig + donor specific transfusion (DST) showed indefinite graft survival [>100 days] without signs of chronic rejection or donor specific antibody formation. Recipients with long-term surviving grafts had significantly higher systemic IDO activity as compared to rejectors, which markedly correlated with intragraft IDO and Foxp3 levels. IDO inhibition with 1-methyl-DL-tryptophan, either at transplant or at POD 50, abrogated CTLA4Ig+DST-induced long-term graft survival. Importantly, IDO1 knock-out recipients experienced acute rejection and graft survival comparable to controls. In addition, αCD25 mAb-mediated depletion of Tregs resulted in decreased IDO activity and again prevented CTLA4Ig+DST induced indefinite graft survival. Our results suggest that CTLA4Ig-induced tolerance to murine cardiac allografts is critically dependent on synergistic cross-linked interplay of IDO and Tregs. These results have important implications for the clinical development of this co-stimulatory blocker. PMID:22131334
Report from a consensus conference on antibody-mediated rejection in heart transplantation

PubMed Central

Kobashigawa, Jon; Crespo-Leiro, Maria G.; Ensminger, Stephan M.; Reichenspurner, Hermann; Angelini, Annalisa; Berry, Gerald; Burke, Margaret; Czer, Lawrence; Hiemann, Nicola; Kfoury, Abdallah G.; Mancini, Donna; Mohacsi, Paul; Patel, Jignesh; Pereira, Naveen; Platt, Jeffrey L.; Reed, Elaine F.; Reinsmoen, Nancy; Rodriguez, E. Rene; Rose, Marlene L.; Russell, Stuart D.; Starling, Randy; Suciu-Foca, Nicole; Tallaj, Jose; Taylor, David O.; Van Bakel, Adrian; West, Lori; Zeevi, Adriana; Zuckermann, Andreas

2012-01-01

BACKGROUND The problem of AMR remains unsolved because standardized schemes for diagnosis and treatment remains contentious. Therefore, a consensus conference was organized to discuss the current status of antibody-mediated rejection (AMR) in heart transplantation. METHODS The conference included 83 participants (transplant cardiologists, surgeons, immunologists and pathologists) representing 67 heart transplant centers from North America, Europe, and Asia who all participated in smaller break-out sessions to discuss the various topics of AMR and attempt to achieve consensus. RESULTS A tentative pathology diagnosis of AMR was established, however, the pathologist felt that further discussion was needed prior to a formal recommendation for AMR diagnosis. One of the most important outcomes of this conference was that a clinical definition for AMR (cardiac dysfunction and/or circulating donor-specific antibody) was no longer believed to be required due to recent publications demonstrating that asymptomatic (no cardiac dysfunction) biopsy-proven AMR is associated with subsequent greater mortality and greater development of cardiac allograft vasculopathy. It was also noted that donor-specific antibody is not always detected during AMR episodes as the antibody may be adhered to the donor heart. Finally, recommendations were made for the timing for specific staining of endomyocardial biopsy specimens and the frequency by which circulating antibodies should be assessed. Recommendations for management and future clinical trials were also provided. CONCLUSIONS The AMR Consensus Conference brought together clinicians, pathologists and immunologists to further the understanding of AMR. Progress was made toward a pathology AMR grading scale and consensus was accomplished regarding several clinical issues. PMID:21300295
Graft Immunocomplex Capture Fluorescence Analysis to Detect Donor-Specific Antibodies and HLA Antigen Complexes in the Allograft.

PubMed

Nakamura, Tsukasa; Ushigome, Hidetaka; Watabe, Kiyoko; Imanishi, Yui; Masuda, Koji; Matsuyama, Takehisa; Harada, Shumpei; Koshino, Katsuhiro; Iida, Taku; Nobori, Shuji; Yoshimura, Norio

2017-04-01

Immunocomplex capture fluorescence analysis (ICFA) is an attractive method to detect donor-specific anti-HLA antibodies (DSA) and HLA antigen complexes. Currently, antibody-mediated rejection (AMR) due to DSA is usually diagnosed by C4d deposition and serological DSA detection. Conversely, there is a discrepancy between these findings frequently. Thereupon, our graft ICFA technique may contribute to establish the diagnosis of AMR. Graft samples were obtained by a percutaneous needle biopsy. Then, the specimen was dissolved in PBS by the lysis buffer. Subsequently, HLA antigens were captured by anti-HLA beads. Then, DSA-HLA complexes were detected by PE-conjugated anti-human IgG antibodies, where DSA had already reacted with the allograft in vivo, analyzed by a Luminex system. A ratio (sample MFI/blank beads MFI) was calculated: ≥ 1.0 was determined as positive. We found that DSA-HLA complexes in the graft were successfully detected from only slight positive 1.03 to 79.27 in a chronic active AMR patient by graft ICFA. Next, positive graft ICFA had predicted the early phase of AMR (MFI ratio: 1.38) even in patients with no serum DSA. Finally, appropriate therapies for AMR deleted DSA deposition (MFI ratio from 0.3 to 0.7) from allografts. This novel application would detect early phase or incomplete pathological cases of AMR, which could lead to a correct diagnosis and initiation of appropriate therapies. Moreover, graft ICFA might address a variety of long-standing questions in terms of DSA. AMR: Antibody-mediated rejection; DSA: Donor-specific antibodies; ICFA: Immunocomplex capture fluorescence analysis.
Domain Specificity in Relationship History, Social-Information Processing, and Violent Behavior in Early Adulthood

PubMed Central

Pettit, Gregory S.; Lansford, Jennifer E.; Malone, Patrick S.; Dodge, Kenneth A.; Bates, John E.

2013-01-01

Using prospective longitudinal data, we tested 5 hypotheses: (a) that the relation between earlier developmental experiences (peer social rejection and victimization in a romantic relationship) and adult violent behavior toward peers and romantic partners is specific to relationship domain; (b) that the relation between social-information processing (SIP) biases and subsequent violence is also specific to relational domain (romantic partner vs. peer); (c) that the relation between developmental experiences and SIP biases is domain specific; (d) that domain-specific SIP mediates the impact of earlier developmental experiences on later violent behavior; and (e) that harsh parenting early in life is a domain-general predictor of SIP and later violent behavior. Harsh parenting was assessed through interviews with parents when their children were age 5 years. Classroom sociometric assessments indexing peer rejection were completed in elementary school, and self-report of victimization by romantic partners was provided at age 18 years. SIP was assessed via interview at age 22 years, and violent behavior was measured via self-and partner report at ages 23 years and 24 years. Structural equation analyses revealed specificity in the relation between developmental experiences and violence and in the prediction to and from SIP in the peer domain, but not in the romantic-relationship domain. The impact of early harsh treatment on violence toward peers was mediated by SIP biases in the peer domain. These findings provide support for domain specificity in the peer domain but for cross-domain generality in the romantic relationship domain in the development of violent behavior in early adulthood. PMID:20085394
Social Competence in Childhood Brain Tumor Survivors: Feasibility and Preliminary Outcomes of a Peer-Mediated Intervention

PubMed Central

Devine, Katie A.; Bukowski, William M.; Sahler, Olle Jane Z.; Ohman-Strickland, Pamela; Smith, Tristram H.; Lown, E. Anne; Patenaude, Andrea Farkas; Korones, David N.; Noll, Robert B.

2016-01-01

Objective Evaluate the acceptability, feasibility, and preliminary outcomes of a peer-mediated intervention to improve social competence of brain tumor survivors and classmates. Methods Twelve childhood brain tumor survivors and 217 classroom peers in intervention (n = 8) or comparison (n = 4) classrooms completed measures of social acceptance and reputation at two time points in the year. The intervention (5–8 sessions over 4–6 weeks) taught peer leaders skills for engaging classmates. Individual and classroom outcomes were analyzed with ANCOVA. Results Recruitment rates of families of brain tumor survivors (81%) and schools (100%) were adequate. Peer leaders reported satisfaction with the intervention. Preliminary outcome data trended toward some benefit in increasing the number of friend nominations for survivors of brain tumors but no changes in other peer-reported metrics. Preliminary results also suggested some positive effects on classroom levels of victimization and rejection. Conclusions A peer-mediated intervention was acceptable to families of brain tumor survivors and feasible to implement in schools. Findings warrant a larger trial to evaluate improvements for children with brain tumors and their peers. PMID:27355881
Body esteem, peer difficulties and perceptions of physical health in overweight and obese urban children aged 5 to 7 years.

PubMed

Williams, N A; Fournier, J; Coday, M; Richey, P A; Tylavsky, F A; Hare, M E

2013-11-01

To determine whether there is an association between body mass index (BMI) and body esteem in young overweight and obese urban children, and to test peer relationship difficulties and perceived physical health as mediators of this relationship. Child self-reported body esteem, and parent-reported child peer relationship difficulties (being bullied by peers and peer rejection) and physical health perceptions were obtained from 218 overweight and obese children aged 5-7 years (81% racial/ethnic minority, M BMI = 25.3) and their primary caregivers. Higher BMI was associated with lower body esteem for both girls and boys. This relation was mediated by poor physical health for boys but not for girls. Peer relationship difficulties did not mediate the observed association between BMI and body esteem in either group; however, girls with higher BMI experienced more bullying and being bullied by peers was associated with lower body esteem in girls. Intervening with perceptions of physical health may buffer overweight and obese boys from developing low body esteem in early childhood. © 2012 John Wiley & Sons Ltd.
Body Esteem, Peer Difficulties, and Perceptions of Physical Health in Overweight and Obese Urban Children Ages 5 to 7 Years

PubMed Central

Williams, Natalie A.; Fournier, Jennifer; Coday, Mace; Richey, Phyllis A.; Tylavsky, Frances A.; Hare, Marion E.

2012-01-01

Objective To determine whether there is an association between body mass index (BMI) and body esteem in young overweight and obese urban children, and to test peer relationship difficulties and perceived physical health as mediators of this relationship. Methods Child self-reported body esteem, and parent-reported child peer relationship difficulties (being bullied by peers and peer rejection) and physical health perceptions were obtained from 218 overweight and obese children ages 5–7 years (81% racial/ethnic minority, M BMI = 25.3) and their primary caregivers. Results Higher BMI was associated with lower body esteem for both girls and boys. This relation was mediated by poor physical health for boys but not for girls. Peer relationship difficulties did not mediate the observed association between BMI and body esteem in either group; however, girls with higher BMI experienced more bullying and being bullied by peers was associated with lower body esteem in girls. Conclusions Intervening with perceptions of physical health may buffer overweight and obese boys from developing low body esteem in early childhood. PMID:22882115
Fatigue Failure of External Hexagon Connections on Cemented Implant-Supported Crowns.

PubMed

Malta Barbosa, João; Navarro da Rocha, Daniel; Hirata, Ronaldo; Freitas, Gileade; Bonfante, Estevam A; Coelho, Paulo G

2018-01-17

To evaluate the probability of survival and failure modes of different external hexagon connection systems restored with anterior cement-retained single-unit crowns. The postulated null hypothesis was that there would be no differences under accelerated life testing. Fifty-four external hexagon dental implants (∼4 mm diameter) were used for single cement-retained crown replacement and divided into 3 groups: (3i) Full OSSEOTITE, Biomet 3i (n = 18); (OL) OEX P4, Osseolife Implants (n = 18); and (IL) Unihex, Intra-Lock International (n = 18). Abutments were torqued to the implants, and maxillary central incisor crowns were cemented and subjected to step-stress-accelerated life testing in water. Use-level probability Weibull curves and probability of survival for a mission of 100,000 cycles at 200 N (95% 2-sided confidence intervals) were calculated. Stereo and scanning electron microscopes were used for failure inspection. The beta values for 3i, OL, and IL (1.60, 1.69, and 1.23, respectively) indicated that fatigue accelerated the failure of the 3 groups. Reliability for the 3i and OL (41% and 68%, respectively) was not different between each other, but both were significantly lower than IL group (98%). Abutment screw fracture was the failure mode consistently observed in all groups. Because the reliability was significantly different between the 3 groups, our postulated null hypothesis was rejected.
Increased T Cell Immunosenescence and Accelerated Maturation Phenotypes in Older Kidney Transplant Recipients.

PubMed

Schaenman, J M; Rossetti, M; Sidwell, T; Groysberg, V; Sunga, G; Korin, Y; Liang, E; Zhou, X; Abdallah, B; Lum, E; Bunnapradist, S; Pham, T; Danovitch, G; Reed, E F

2018-06-15

Older kidney transplant recipients experience increased rates of infection and death, and less rejection, compared with younger patients. However, little is known about immune dysfunction in older compared with younger kidney transplant recipients and whether it is associated with infection. We evaluated T cell phenotypes including maturation, immune senescence, and exhaustion in a novel investigation into differences in older compared with younger patients receiving identical immune suppression regimens. We evaluated PBMC from 60 kidney transplant recipients (23 older and 37 matched younger patients) by multiparameter immune phenotyping. Older kidney transplant recipients demonstrated decreased frequency of naïve CD4+ and CD8+ T cells, and increased frequency of terminally differentiated, immune senescent, and NK T cells expressing KLRG1. There was a trend towards increased frequency of T cell immune senescence in patients experiencing infection in the first year after transplantation, which reached statistical significance in a multivariate analysis. This pilot study reveals immune dysfunction in older compared with younger transplant recipients, and suggests a likely mechanism for increased vulnerability to infection. The ability to assess T cell maturation and immune senescence in transplant recipients offers the potential for risk stratification and customization of immune suppression to prevent infection and rejection after transplantation. Copyright © 2018. Published by Elsevier Inc.
Developmental Precursors of Moral Disengagement and the Role of Moral Disengagement in the Development of Antisocial Behavior

PubMed Central

Shaw, Daniel S.; Moilanen, Kristin L.

2010-01-01

The purpose of the study was to advance our understanding of the developmental precursors of Moral Disengagement (MD) and the role of MD in the development of antisocial behavior from early risk among an ethnically diverse sample of 187 low-income boys followed prospectively from ages 1.5 to 17. Results indicated associations between early rejecting parenting, neighborhood impoverishment, and child empathy and later MD. The link between some of these early constructs and later antisocial behavior was mediated by MD. Finally, in an exploratory path model both MD and biases in social information processing were found to mediate separate paths from early risk factors to later antisocial behavior. Results were partially consistent with the notion that adolescent MD was predicted by a combination of early family, neighborhood, and child risk factors, and that MD may be a mechanism underlying some boys' risk of antisocial behavior. PMID:19777337
Implicit self-esteem compensation: automatic threat defense.

PubMed

Rudman, Laurie A; Dohn, Matthew C; Fairchild, Kimberly

2007-11-01

Four experiments demonstrated implicit self-esteem compensation (ISEC) in response to threats involving gender identity (Experiment 1), implicit racism (Experiment 2), and social rejection (Experiments 3-4). Under conditions in which people might be expected to suffer a blow to self-worth, they instead showed high scores on 2 implicit self-esteem measures. There was no comparable effect on explicit self-esteem. However, ISEC was eliminated following self-affirmation (Experiment 3). Furthermore, threat manipulations increased automatic intergroup bias, but ISEC mediated these relationships (Experiments 2-3). Thus, a process that serves as damage control for the self may have negative social consequences. Finally, pretest anxiety mediated the relationship between threat and ISEC (Experiment 3), whereas ISEC negatively predicted anxiety among high-threat participants (Experiment 4), suggesting that ISEC may function to regulate anxiety. The implications of these findings for automatic emotion regulation, intergroup bias, and implicit self-esteem measures are discussed. (c) 2007 APA, all rights reserved.
NK cells are biologic and biochemical targets of 6-mercaptopurine in Crohn's disease patients.

PubMed

Yusung, Susy; McGovern, Dermot; Lin, Lin; Hommes, Daniel; Lagishetty, Venu; Braun, Jonathan

2017-02-01

NK cells, which contribute to immune defense against certain viral infections and neoplasia, are emerging as modifiers of chronic immunologic diseases including transplant rejection and autoimmune diseases. Immunobiology and genetic studies have implicated NK cells as a modifier of Crohn's disease, a condition often treated with thiopurine agents such as 6-mercaptopurine (6-MP). Here, we demonstrate that thiopurines mediate NK cell apoptosis via a caspase 3 and 9 inclusive pathway, and that this process is triggered by thiopurine-mediated inhibition of Rac1. We also show that CD patients in clinical remission maintained on 6-MP have decreased NK cell Rac1 activity, and decreased NK cell numbers in their intestinal biopsies. These observations suggest that thiopurine targeting of NK cells may be a previously unappreciated therapeutic action of these agents in IBD. Copyright © 2016 Elsevier Inc. All rights reserved.
Child impulsiveness-inattention, early peer experiences, and the development of early onset conduct problems.

PubMed

Snyder, James; Prichard, Joy; Schrepferman, Lynn; Patrick, M Renee; Stoolmiller, Mike

2004-12-01

The conjoint influence of child impulsiveness-inattention (I/I) and peer relationships on growth trajectories of conduct problems was assessed in a community sample of 267 boys and girls. I/I reliably predicted teacher- and parent-reported conduct problems at kindergarten entry and growth in those problems over the next 2 years for boys and girls. The relation of boys' I/I to conduct problems was mediated, in part, by peer rejection and involvement in coercive exchanges with peers. The relation of girls' I/I to conduct problems was less clearly mediated by peer processes, but peer difficulties had additive effects. The impact of peer relationships on trajectories of conduct problems was apparent to parents as well as to teachers. Although I/I increments risk for early and persisting conduct problems in concert with poor peer relationships, it does so in complex and gender-specific ways.
Metaphor and music emotion: Ancient views and future directions.

PubMed

Pannese, Alessia; Rappaz, Marc-André; Grandjean, Didier

2016-08-01

Music is often described in terms of emotion. This notion is supported by empirical evidence showing that engaging with music is associated with subjective feelings, and with objectively measurable responses at the behavioural, physiological, and neural level. Some accounts, however, reject the idea that music may directly induce emotions. For example, the 'paradox of negative emotion', whereby music described in negative terms is experienced as enjoyable, suggests that music might move the listener through indirect mechanisms in which the emotional experience elicited by music does not always coincide with the emotional label attributed to it. Here we discuss the role of metaphor as a potential mediator in these mechanisms. Drawing on musicological, philosophical, and neuroscientific literature, we suggest that metaphor acts at key stages along and between physical, biological, cognitive, and contextual processes, and propose a model of music experience in which metaphor mediates between language, emotion, and aesthetic response. Copyright © 2016 Elsevier Inc. All rights reserved.
Gal alpha (1,3)Gal, the major xenoantigen(s) recognised in pigs by human natural antibodies.

PubMed

Sandrin, M S; McKenzie, I F

1994-10-01

The transplantation of pig organs to humans (xenotransplantation) is now receiving serious consideration because of the shortage of human donors for organ transplants of kidney, liver and heart, and of islet cell transplantation for diabetes. The problem with such xenografts would be hyperacute rejection--mediated by natural antibodies in humans to pig antigens, complement fixation to endothelial cells, and the rapid onset of intravascular coagulation. It is now clear that the major target of the natural IgM and IgG antibodies is the terminal carbohydrate epitope Gal alpha(1,3)Gal, formed by the alpha 1,3galactosyl transferase, which places a terminal galactose residue in an alpha-linkage to another galactose. The alpha 1,3galactosyl transferase in the pig gives rise to very high endothelial cell expression of Gal alpha(1,3)Gal, a ready explanation for the hyperacute rejection of vascularized organs. In addition the parenchuma of liver and kidneys have high levels of Gal alpha-(1,3)Gal. These tissues will all fail in a pig-to-human transplant in what can now be precisely defined in terms of antigen and antibody. We have already made some suggestions for removal of anti-Gal alpha(1,3)Gal antibodies and if the procedure were technically feasible xenotransplantation could be attempted now, especially in patients doomed to a certain death because of the absence of a donor (especially for liver where ex vivo perfusion could be performed). However, the immune system is far from simple, as is shown by the healthy status of mice lacking MHC Class I, Class II or both Class I & II molecules. Perhaps the curtain is about to go up to reveal a new scene! Islets differ from the other tissues and may well not undergo acute antibody-mediated hyperacute rejection--it will be of interest to see how these fare in xenotransplantation models or even in patients. Again, normal individuals do not have anti-islet antibodies; but a proportion of diabetic patients do have such antibodies--whether these will cause hyperacute or acute rejection or are markers of immunity of T-cell type, remains to be seen. Whatever, the area is exciting, is progressing rapidly and, as indicated elsewhere, within a few years we should know whether modified pig tissue can be grafted to some patients. The isolation of the cDNA clone encoding the pig alpha 1,3 galactosyl transferase is an essential first step in the production of a transgenic pig lacking the alpha 1,3Galactosyltransferase and therefore the Gal alpha(1,3)Gal epitope, and such animals could serve as donor for human transplantation.
Theory of mind deficits partly mediate impaired social decision-making in schizophrenia.

PubMed

Yang, Liuqing; Li, Peifu; Mao, Haiying; Wang, Huiling; Shu, Chang; Bliksted, Vibeke; Zhou, Yuan

2017-05-05

Using paradigms from game theory, researchers have reported abnormal decision-making in social context in patients with schizophrenia. However, less is known about the underpinnings of the impairment. This study aimed to test whether theory of mind (ToM) deficits and/or neurocognitive dysfunctions mediate impaired social decision-making in patients with schizophrenia. We compared thirty-five patients with schizophrenia to thirty-eight matched healthy controls with regard to social decision-making using the mini Ultimatum Game (mini UG), a paradigm from game theory. Additionally, we assessed ToM using the Theory of Mind Picture Stories Task, a mental state attribution task, and assessed neurocognition using the Brief Assessment of Cognition in Schizophrenia. Mediation analyses were performed on the data. In contrast to the behavioral pattern of healthy controls in the mini UG, the patients with schizophrenia significantly accepted more disadvantageous offers and rejected more advantageous offers, and showed reduced sensitivity to the fairness-related context changes in the mini UG. Impaired ToM and neurocognition were also found in the patients. Mediation analyses indicated that ToM but not neurocognition partially mediated the group differences on the disadvantageous and advantageous offers in the mini UG. Patients with schizophrenia exhibited impaired social decision-making. This impairment can be partly explained by their ToM deficits rather than neurocognitive deficits. However, the exact nature of the ToM deficits that mediate impaired social decision-making needs to be identified in future.
The role of childhood trauma, early maladaptive schemas, emotional schemas and experimental avoidance on depression: A structural equation modeling.

PubMed

Rezaei, Mehdi; Ghazanfari, Firoozeh; Rezaee, Fatemeh

2016-12-30

The present investigation was designed to examine disconnection and rejection (DR) schemas, negative emotional schemas (NESs) and experimental avoidance (EA) as mediating variables of the relationship between the childhood trauma (CT) and depression. Specifically we examined the mediating role of NESs and EA between DR schemas and depression. The study sample consist of 439 female college students (M age =22.47; SD=6.0), of whom 88 met the criteria for current major depressive disorder (MDD) and 351 who had history of MDD in the last 12 months. Subjects were assessed by Structured Clinical Interview for DSM-IV (SCID) and completed the Childhood Trauma Questionnaire (CTQ), the Early Maladaptive Schemas Questionnaire (SQ-SF), the Leahy Emotional Schemas Scale (LESS), the Acceptance and Action Questionnaire (AAQ-II), and the Beck Depression Inventory-II (BDI-II). The findings showed that DR schemas were mediator of the relationship CT and depression but CT through the NESs and EA did not predict depression. NESs were mediator of the relationship between DR schemas and depression and EA was mediator of the relationship between DR schemas and depression. In general, results suggest that intervention of depressed women may need to target the changing of DR schemas, NESs and reduction of EA. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

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