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Sample records for aggressive immunosuppressive therapy

  1. Immunosuppressive drug therapy.

    PubMed

    Hartono, Choli; Muthukumar, Thangamani; Suthanthiran, Manikkam

    2013-09-01

    The first successful kidney transplantation between monozygotic identical twins did not require any immunosuppressive drugs. Clinical application of azathioprine and glucocorticosteroids allowed the transfer of organs between genetically disparate donors and recipients. Transplantation is now the standard of care, a life-saving procedure for patients with failed organs. Progress in our understanding of the immunobiology of rejection has been translated to the development of immunosuppressive agents targeting T cells, B cells, plasma cells, costimulatory signals, complement products, and antidonor antibodies. Modern immunopharmacologic interventions have contributed to the clinical success observed following transplantation but challenges remain in personalizing immunosuppressive therapy.

  2. Tracheal allotransplantation after withdrawal of immunosuppressive therapy.

    PubMed

    Delaere, Pierre; Vranckx, Jan; Verleden, Geert; De Leyn, Paul; Van Raemdonck, Dirk

    2010-01-14

    Reconstruction of long-segment tracheal defects requires a vascularized allograft. We report successful tracheal allotransplantation after indirect revascularization of the graft in a heterotopic position. Immunosuppressive therapy was administered before the operation, and the tracheal allograft was wrapped in the recipient's forearm fascia. Once revascularization was achieved, the mucosal lining was replaced progressively with buccal mucosa from the recipient. At 4 months, the tracheal chimera was fully lined with mucosa, which consisted of respiratory epithelium from the donor and buccal mucosa from the recipient. After withdrawal of immunosuppressive therapy, the tracheal allograft was moved to its correct anatomical position with an intact blood supply. No treatment-limiting adverse effects occurred.

  3. Immunosuppressive effects of silicon phthalocyanine photodynamic therapy.

    PubMed

    Reddan, J C; Anderson, C Y; Xu, H; Hrabovsky, S; Freye, K; Fairchild, R; Tubesing, K A; Elmets, C A

    1999-07-01

    The purpose of this study was to determine if silicon phthalocyanine 4 (Pc 4), a second-generation photosensitizer being evaluated for the photodynamic therapy (PDT) of solid tumors, was immunosuppressive. Mice treated with Pc 4 PDT 3 days before dinitrofluorobenzene sensitization showed significant suppression of their cell-mediated immune response when compared to mice that were not exposed to PDT. The response was dose dependent, required both Pc 4 and light and occurred at a skin site remote from that exposed to the laser. The immunosuppression could not be reversed by in vivo pre-treatment of mice with antibodies to tumor necrosis factor-alpha or interleukin-10. These results provide evidence that induction of cell-mediated immunity is suppressed after Pc 4 PDT. Strategies that prevent PDT-mediated immunosuppression may therefore enhance the efficacy of this therapeutic modality.

  4. Optimisation of immunosuppressive therapy using pharmacokinetic principles.

    PubMed

    Grevel, J

    1992-11-01

    Clinical experience with immunosuppressive therapy is more extensive in the area of preventing the rejection of transplanted organs than in the treatment of autoimmune diseases. Among the many pharmacological agents presently in use, only prednisone (or methylprednisolone) and cyclosporin require dosage individualisation. Sources of interindividual variability in the pharmacokinetics of prednisone have been identified and are guiding the selection of individual dosage rates. As an alternative, a single timed concentration can determine an apparent value for prednisone clearance from which an individual dosage can be calculated. In contrast, numerous sources of inter- and intraindividual variability in cyclosporin pharmacokinetics prevent the easy selection of safe and effective starting dose rates. Indeed, test doses of cyclosporin followed by series of blood samples and the calculation of individual pharmacokinetic parameters are needed to assure successful immunosuppression right from the start. Furthermore, only continued monitoring sustains immunotherapy vis-à-vis intraindividual variability and a narrow therapeutic range of cyclosporin concentrations.

  5. [Gas gangrene with ulcerative colitis under immunosuppressive therapy: report of a case].

    PubMed

    Jackisch, T; Freitag, M; Ludwig, K

    2006-02-01

    We report on a 30-year-old male with ulcerative colitis who developed a spontaneous gas gangrene in the right limb, the gluteal muscles and the retroperitoneal region under immunosuppressive therapy. In spite of immediate aggressive surgical and antibiotic therapy the massive infection led to septicemia and ultimately death. Clostridium septicum was identified with multiple local manifestations in the skeletal muscles. Gas gangrene is extremely rare in patients with ulcerative colitis or Crohn's disease and immunosuppression. The therapeutic options are discussed and the relevant present literature is reviewed.

  6. Gene Therapy Shows Promise for Aggressive Lymphoma

    MedlinePlus

    ... fullstory_163824.html Gene Therapy Shows Promise for Aggressive Lymphoma Over one-third of patients appeared disease- ... 2017 (HealthDay News) -- An experimental gene therapy for aggressive non-Hodgkin lymphoma beat back more than a ...

  7. New Immunosuppressive Therapies in Uveitis Treatment

    PubMed Central

    Mérida, Salvador; Palacios, Elena; Navea, Amparo; Bosch-Morell, Francisco

    2015-01-01

    Uveitis is an inflammatory process that initially starts in the uvea, but can also affect other adjacent eye structures, and is currently the fourth cause of blindness in developed countries. Corticoids are probably the most widespread treatment, but resorting to other immunosuppressive treatments is a frequent practice. Since the implication of different cytokines in uveitis has been well demonstrated, the majority of recent treatments for this disease include inhibitors or antibodies against these. Nevertheless, adequate treatment for each uveitis type entails a difficult therapeutic decision as no clear recommendations are found in the literature, despite the few protocolized clinical assays and many case-control studies done. This review aims to present, in order, the mechanisms and main indications of the most modern immunosuppressive drugs against cytokines. PMID:26270662

  8. [Tapering and termination of immunosuppressive therapy : Systemic lupus erythematosus].

    PubMed

    Aringer, M; Leuchten, N; Fischer-Betz, R

    2017-02-01

    Similar to patients with other rheumatic diseases, patients with systemic lupus erythematosus (SLE) nowadays can also have the desire to terminate immunosuppressive and immunomodulatory medications. In order to provide appropriate advice to patients, the two main issues are the risk of severe adverse events under long-term therapy with any drug and the perceived risk of a flare, in particular of severe flares. The risks of long-term therapy vary greatly between drugs, ranging from severe unacceptable risks with cyclophosphamide and higher dose glucocorticoids to low risks usually outweighed by long-term benefits with hydroxychloroquine. The individual risk of flares is often difficult to estimate but clinical remission and at least 3 years of immunosuppression are recommended for lupus nephritis. The duration of remission can also be shorter in cases of milder forms of disease. This review article tries to put the available evidence into a clinical perspective and to derive concrete recommendations.

  9. Aggressive Adolescents Benefit from Massage Therapy.

    ERIC Educational Resources Information Center

    Diego, Miguel A.; Field, Tiffany; Hernandez-Reif, Maria; Shaw, Jon A.; Rothe, Eugenio M.; Castellanos, Daniel; Mesner, Linda

    2002-01-01

    Seventeen aggressive adolescents were assigned to a massage therapy group or a relaxation therapy group to receive 20-minute therapy sessions, twice a week for five weeks. The massaged adolescents had lower anxiety after the first and last sessions. By the end of the study, they also reported feeling less hostile and they were perceived by their…

  10. Treatment of Hepatitis C in Patients Undergoing Immunosuppressive Drug Therapy

    PubMed Central

    Ooka, Kohtaro; Lim, Joseph K.

    2016-01-01

    Abstract With 185 million people chronically infected globally, hepatitis C is a leading bloodborne infection. All-oral regimens of direct acting agents have superior efficacy compared to the historical interferon-based regimens and are significantly more tolerable. However, trials of both types of regimens have often excluded patients on immunosuppressive medications for reasons other than organ transplantation. Yet, these patients—most often suffering from malignancy or autoimmune diseases—could stand to benefit from these treatments. In this study, we systematically review the literature on the treatment of hepatitis C in these neglected populations. Research on patients with organ transplants is more robust and this literature is reviewed here non-systematically. Our systematic review produced 2273 unique works, of which 56 met our inclusion criteria and were used in our review. The quality of data was low; only 3 of the 56 studies were randomized controlled trials. Sustained virologic response was reported sporadically. Interferon-containing regimens achieved this end-point at rates comparable to that in immunocompetent individuals. Severe adverse effects and death were rare. Data on all-oral regimens were sparse, but in the most robust study, rates of sustained virologic response were again comparable to immunocompetent individuals (40/41). Efficacy and safety of interferon-containing regimens and all-oral regimens were similar to rates in immunocompetent individuals; however, there were few interventional trials. The large number of case reports and case series makes conclusions vulnerable to publication bias. While firm conclusions are challenging, given the dearth of high-quality studies, our results demonstrate that antiviral therapy can be safe and effective. The advent of all-oral regimens offers patients and clinicians greatly increased chances of cure and fewer side effects. Preliminary data reveal that these regimens may confer such benefits in

  11. Adherence to immunosuppressive therapy following liver transplantation: an integrative review

    PubMed Central

    Oliveira, Ramon Antônio; Turrini, Ruth Natália Teresa; Poveda, Vanessa de Brito

    2016-01-01

    ABSTRACT Objective: to investigate the evidence available in the literature on non-adherence to immunosuppressive therapy among patients undergoing liver transplantation. Method: integrative literature review, including research whose sample consisted of patients aged over 18 years undergoing liver transplantation. It excluded those containing patients undergoing multiple organ transplants. For the selection of articles, Medline / Pubmed, CINAHL, LILACS, Scopus and Embase were searched. The search period corresponded to the initial date of indexation of different bases, up to the deadline of February 10, 2015, using controlled and uncontrolled descriptors: liver transplantation, hepatic transplantation, liver orthotopic transplantation, medication adherence, medication non-adherence, medication compliance and patient compliance. Results: were located 191 investigations, 10 of which met the objectives of the study and were grouped into four categories, namely: educational process and non-adherence; non-adherence related to the number of daily doses of immunosuppressive medications; detection methods for non-adherence and side effects of therapy. Conclusion: there were risk factors related to the health service, such as control and reduction of the number of doses; related to the individual, such as being male, divorced, alcohol or other substances user, exposed to low social support and being mentally ill. PMID:27579933

  12. Effect of Immunosuppressive Therapy on Proteinogram in Rats

    PubMed Central

    Kędzierska, Karolina; Sindrewicz, Krzysztof; Sporniak-Tutak, Katarzyna; Bober, Joanna; Stańczyk-Dunaj, Małgorzata; Dołęgowska, Barbara; Kaliszczak, Robert; Sieńko, Jerzy; Kabat-Koperska, Joanna; Gołembiewska, Edyta; Ciechanowski, Kazimierz

    2016-01-01

    Background It has been observed that the use of immunosuppressive drugs in patients after transplantation of vascularized organs may be associated with changes in the concentration of certain fractions of plasma proteins. The concentration of these proteins was correlated with an increased risk of occurrence of stage 3 chronic kidney disease (CKD). This article examines the effect of the most commonly used immunosuppressive drugs on the concentration of plasma proteins in Wistar rats. Material/methods The study involved 36 rats grouped according to the immunosuppressive regimen used (tacrolimus, mycophenolate mofetil, cyclosporine A, rapamycin, and prednisone). The rats in all study groups were treated with a 3-drug protocol for 6 months. The treatment dose was adjusted based on available data in the literature. No drugs were administered to the control group. The rats were sacrificed and blood samples collected to determine the concentration of plasma proteins using electrophoresis technique. Results Statistically significant differences were observed between protein concentrations within the studied groups. The differences related to the proteins with masses of 195 kDa, 170 kDa, 103 kDa, and 58 kDa. Conclusions (1) Immunosuppressive drugs caused changes in the proteinogram of plasma proteins. (2) The strongest effect on rat plasma proteins was exerted by a regimen based on rapamycin. Intermediate, weak, and weakest effects were observed in regimens based on cyclosporine A, tacrolimus, and mycophenolate mofetil, respectively. PMID:27288069

  13. Immunizations in Children with Inflammatory Bowel Disease Treated with Immunosuppressive Therapy

    PubMed Central

    Bousvaros, Athos

    2014-01-01

    The vast majority of patients with inflammatory bowel disease (IBD) will receive immunosuppressive therapy at some point for their disease, whether for the short term (such as a course of corticosteroids) or long term (such as maintenance therapy with immunomodulators or biologics). The systemic immunosuppression places patients at increased risk for infections. Therefore, it is important that patients are up-to-date with immunizations to minimize vaccine-preventable infections. However, the literature shows that the rate of immunization in patients with IBD is low. Ideally, the vaccination status is checked at diagnosis, and patients are immunized with the vaccines they need. Drawing titers is helpful in cases in which vaccination history is unclear or to confirm that titers are at an adequate level in cases in which patients have been vaccinated. Current guidelines recommend that patients with IBD follow the same routine immunization schedule as healthy children, but patients should not be administered live vaccines if they are receiving immunosuppressive therapy. Therefore, it is ideal to administer any necessary vaccinations as early as possible, prior to starting immunosuppressive therapy. Patients may receive inactivated vaccines regardless of immunosuppressive status. The IBD literature suggests that inactivated vaccines are safe and do not worsen disease activity. In general, patients with IBD mount an immune response to vaccines, but the response may be lower if patients are receiving immunosuppressive therapy, especially tumor necrosis factor inhibitors. PMID:25013388

  14. Molecular Targeted Therapies of Aggressive Thyroid Cancer

    PubMed Central

    Ferrari, Silvia Martina; Fallahi, Poupak; Politti, Ugo; Materazzi, Gabriele; Baldini, Enke; Ulisse, Salvatore; Miccoli, Paolo; Antonelli, Alessandro

    2015-01-01

    Differentiated thyroid carcinomas (DTCs) that arise from follicular cells account >90% of thyroid cancer (TC) [papillary thyroid cancer (PTC) 90%, follicular thyroid cancer (FTC) 10%], while medullary thyroid cancer (MTC) accounts <5%. Complete total thyroidectomy is the treatment of choice for PTC, FTC, and MTC. Radioiodine is routinely recommended in high-risk patients and considered in intermediate risk DTC patients. DTC cancer cells, during tumor progression, may lose the iodide uptake ability, becoming resistant to radioiodine, with a significant worsening of the prognosis. The lack of specific and effective drugs for aggressive and metastatic DTC and MTC leads to additional efforts toward the development of new drugs. Several genetic alterations in different molecular pathways in TC have been shown in the past few decades, associated with TC development and progression. Rearranged during transfection (RET)/PTC gene rearrangements, RET mutations, BRAF mutations, RAS mutations, and vascular endothelial growth factor receptor 2 angiogenesis pathways are some of the known pathways determinant in the development of TC. Tyrosine kinase inhibitors (TKIs) are small organic compounds inhibiting tyrosine kinases auto-phosphorylation and activation, most of them are multikinase inhibitors. TKIs act on the aforementioned molecular pathways involved in growth, angiogenesis, local, and distant spread of TC. TKIs are emerging as new therapies of aggressive TC, including DTC, MTC, and anaplastic thyroid cancer, being capable of inducing clinical responses and stabilization of disease. Vandetanib and cabozantinib have been approved for the treatment of MTC, while sorafenib and lenvatinib for DTC refractory to radioiodine. These drugs prolong median progression-free survival, but until now no significant increase has been observed on overall survival; side effects are common. New efforts are made to find new more effective and safe compounds and to personalize the therapy in

  15. Immunosuppressive therapy for transplant-ineligible aplastic anemia patients.

    PubMed

    Schrezenmeier, Hubert; Körper, Sixten; Höchsmann, Britta

    2015-02-01

    Aplastic anemia is a rare life-threatening bone marrow failure that is characterized by bicytopenia or pancytopenia in the peripheral blood and a hypoplastic or aplastic bone marrow. The patients are at risk of infection and hemorrhage due to neutropenia and thrombocytopenia and suffer from symptoms of anemia. The main treatment approaches are allogeneic stem cell transplantation and immunosuppression. Here, we review current standard immunosuppression and the attempts that have been made in the past two decades to improve results: review of recent developments also reveals that sometimes not only the advent of new drugs, good ideas and well-designed clinical trials decide the progress in the field but also marketing considerations of pharmaceutical companies. Aplastic anemia experts unfortunately had to face the situation that efficient drugs were withdrawn simply for marketing considerations. We will discuss the current options and challenges in first-line treatment and management of relapsing and refractory patients with an emphasis on adult patients. Some promising new approaches are currently under investigation in prospective, randomized trials.

  16. Persistent Hypotony Associated with Immunosuppressive Therapy in Glaucoma Drainage Implant Surgery

    PubMed Central

    Duch, Susana; Milla, Elena; Stirbu, Oana; Andreu, David

    2016-01-01

    Purpose To describe the histopathology of non-valved implant capsules in three cases of persistent postoperative hypotony after the restrictive tube ligature was released in patients receiving immunosuppressive therapy. Observations The macroscopic appearance of the capsules 3 and 4 months postoperatively was immature and loose. Microscopic examination disclosed extremely irregular thin tissue, with thicknesses ranging from 0.02 to 0.6 mm, depending on the capsular location studied. Withdrawal of immunosuppressive therapy did not facilitate rebuilding of new capsules. Replacement with a valved implant device was necessary in two cases; the third case recovered with tapering of prednisone. Conclusions and Importance The use of chronic systemic immunosuppressive therapy might interfere with capsular formation around the plates of drainage devices inducing persistent hypotony. In these cases, the use of valved implants might be safer. PMID:27790128

  17. Less is more: the detrimental consequences of immunosuppressive therapy in the treatment of type-1 diabetes.

    PubMed

    Askenasy, Nadir

    2015-01-01

    The prevalent current approach to type 1 diabetes (T1D) is the abrogation of pathogenic potential by immunosuppressive therapy, an intuitive approach aiming to slow down disease progression by the reduction of pathogenic burden. In spite of promising initial results in rodent models, there has been little efficacy of most lymphoreductive strategies in human subjects. Our analysis suggests that lymphopenia is the common denominator of ineffective immunosuppressive therapies: Immune rebound from lymphopenia is associated per se with increased susceptibility to immune reactivity, including relapse of autoimmunity. In addition, immune homeostasis and self-tolerance are not restored. These considerations raise the following question: What is the allowed degree of immunosuppressive therapy that does not elicit recurrent autoimmunity. More effective therapeutic strategies include targeted deletion of pathogenic cells, preferably in the pancreatic islets and regional lymphatics using selective T cell activation markers, re-education and remodeling of effector responses.

  18. Amniotic membrane transplantation ineffective as additional therapy in patients with aggressive Mooren’s ulcer

    PubMed Central

    2013-01-01

    Background Mooren’s ulcer is a severe ulcerative inflammation of the cornea. The exact pathogenesis remains unclear. Therefore many therapies of Mooren’s ulcer are recommended in literature. To shed more light on the ongoing question of optimal treatment of severe progressive Mooren’s ulcer, we here report on a retrospective case series of patients treated with systemic immunosuppressive therapy and additional amniotic membrane transplantation. Methods Medical records from seven patients (eleven eyes), 4 male and 3 female, with severe progressive Mooren’s ulcer were analysed retrospectively. The mean follow up was 88.4 ± 80.8 months (range 12–232 month). A HLA-typing was performed in all patients. A systemic immunosuppressive therapy was administered in all patients. The amniotic membrane was transplanted after the base of the ulcer was resected. Results Multiple amniotic membrane transplantations were necessary in six patients. The visual outcome of all patients was poor. No patient achieved a visual acuity better than 20/630 Snellen chart. Five patients were positive for HLA-DQ2 and four patients were positive for HLA-DR17(3). Conclusions The aggressive and highly inflammatory form of Mooren’s ulcer is difficult to treat and the progression of the disease is hard to influence positively even under systemic immunosuppressive therapy. Therefore, the main intention of therapy is to achieve a stable epithelialized corneal surface without the risk of perforation. Amniotic membrane transplantation is not able to cure severe forms of Mooren’s ulcer. However it supports the immunosuppressive therapy in acute situations as in critical corneal thinning. PMID:24345289

  19. Paroxysmal nocturnal hemoglobinuria and telomere length predicts response to immunosuppressive therapy in pediatric aplastic anemia.

    PubMed

    Narita, Atsushi; Muramatsu, Hideki; Sekiya, Yuko; Okuno, Yusuke; Sakaguchi, Hirotoshi; Nishio, Nobuhiro; Yoshida, Nao; Wang, Xinan; Xu, Yinyan; Kawashima, Nozomu; Doisaki, Sayoko; Hama, Asahito; Takahashi, Yoshiyuki; Kudo, Kazuko; Moritake, Hiroshi; Kobayashi, Masao; Kobayashi, Ryoji; Ito, Etsuro; Yabe, Hiromasa; Ohga, Shouichi; Ohara, Akira; Kojima, Seiji

    2015-12-01

    Acquired aplastic anemia is an immune-mediated disease characterized by severe defects in stem cell number resulting in hypocellular marrow and peripheral blood cytopenias. Minor paroxysmal nocturnal hemoglobinuria populations and a short telomere length were identified as predictive biomarkers of immunosuppressive therapy responsiveness in aplastic anemia. We enrolled 113 aplastic anemia patients (63 boys and 50 girls) in this study to evaluate their response to immunosuppressive therapy. The paroxysmal nocturnal hemoglobinuria populations and telomere length were detected by flow cytometry. Forty-seven patients (42%) carried a minor paroxysmal nocturnal hemoglobinuria population. The median telomere length of aplastic anemia patients was -0.99 standard deviation (SD) (range -4.01-+3.01 SD). Overall, 60 patients (53%) responded to immunosuppressive therapy after six months. Multivariate logistic regression analysis identified the absence of a paroxysmal nocturnal hemoglobinuria population and a shorter telomere length as independent unfavorable predictors of immunosuppressive therapy response at six months. The cohort was stratified into a group of poor prognosis (paroxysmal nocturnal hemoglobinuria negative and shorter telomere length; 37 patients) and good prognosis (paroxysmal nocturnal hemoglobinuria positive and/or longer telomere length; 76 patients), respectively. The response rates of the poor prognosis and good prognosis groups at six months were 19% and 70%, respectively (P<0.001). The combined absence of a minor paroxysmal nocturnal hemoglobinuria population and a short telomere length is an efficient predictor of poor immunosuppressive therapy response, which should be considered while deciding treatment options: immunosuppressive therapy or first-line hematopoietic stem cell transplantation. The trial was registered in www.umin.ac.jp with number UMIN000017972.

  20. Giant Condyloma Acuminata in Indonesian Females with SLE under Immunosuppressant and Steroid Therapy

    PubMed Central

    2016-01-01

    Introduction. Immunosuppressant and steroid therapy in systemic lupus erythematosus (SLE) increases the risk of human papillomavirus (HPV) infections, one of which is giant condyloma acuminata (GCA). To our knowledge, there is no report evaluating the correlation between immunosuppressive and steroid therapy in patients with SLE and the prevalence of GCA. Case Report. A 42-year-old female was diagnosed with SLE a year ago and has been treated with steroids and immunosuppressive drugs. In the last few months she presented GCA involving the genital area recurring almost every two months. Type 6 and 11 HPVs were identified in vulva, vagina, and cervix. Methods. PubMed, EBSCO, and Cochrane Library literature were searched from inception to July 2015. Authors screened all titles and abstracts and read full text article, and two case-control studies were found relevant. Results. SLE patients in both studies were under immunosuppressive and steroid therapy. Condyloma acuminata was diagnosed at 108 months (latest) and 1 month (earliest) after SLE. Type 6, 11, 16, 42, and oncogenic group of HPV were identified. Conclusions. GCA is a type of HPV infection seldom observed in SLE patients. Therefore, their correlation is still unclear. Period of time since SLE was diagnosed and GCA varies from months to years. A more thorough physical and laboratory examination leading to HPV and other infectious disease is recommended. PMID:27843658

  1. Systemic therapy with immunosuppressive agents and retinoids in hidradenitis suppurativa: a systematic review.

    PubMed

    Blok, J L; van Hattem, S; Jonkman, M F; Horváth, B

    2013-02-01

    Hidradenitis suppurativa (HS) is a difficult disease to treat. Although the pathogenesis of this inflammatory skin disease is largely unknown, the important role of the immune system has been demonstrated in both experimental and clinical studies. Clinicians are therefore increasingly prescribing systemic treatments with immunosuppressive agents, but the more traditionally used systemic retinoids, especially isotretinoin, also remain relatively common therapies. In order to provide an overview of all currently available systemic immunosuppressive agents and retinoids for the treatment of HS, a systematic search was performed using the Medline and Embase databases. All published papers concerning systemic retinoids or immunosuppressive treatments for HS in adults were included. The primary endpoints were the percentages of significant responders, moderate responders and nonresponders. Other endpoints were the relapse rate and adverse events. In total 87 papers were included, comprising 518 patients with HS who were treated with systemic retinoids, biological agents or another immunosuppressive agents, including colchicine, ciclosporin, dapsone or methotrexate. The highest response rates were observed with infliximab, adalimumab and acitretin. Overall, the quality of evidence was low and differed between the agents, making direct comparisons difficult. However, based on the amount of evidence, infliximab and adalimumab were the most effective agents. Acitretin was also effective in HS, although the quality of the evidence was low. The therapeutic effect of isotretinoin is questionable. Randomized controlled trials are needed to confirm the effectiveness of acitretin, and to identify the most effective immunosuppressive agents in HS.

  2. Interleukin-2 therapy reverses some immunosuppressive effects of skeletal unloading

    NASA Technical Reports Server (NTRS)

    Armstrong, Jason W.; Balch, Signe; Chapes, Stephen K.

    1994-01-01

    Using antiorthostatic suspension, we characterized hematopoietic changes that may be responsible for the detrimental effect of skeletal unloading on macrophage development. Skeletally unloaded mice had suppressed macrophage development in unloaded and loaded bones, which indicated a systemic effect. Bone marrow cells from unloaded mice secreted less macrophage colony-stimulating factor and interleukin-6 than control mice. Additionally, T-lymphocyte proliferation was reduced after skeletal unloading. We show that polyethylene glycol-interleukin-2 therapy reversed the effects of skeletal unloading on macrophage development and cell proliferation.

  3. Immunosuppressive Therapy in Patients with Aplastic Anemia: A Single-Center Retrospective Study

    PubMed Central

    Jalaeikhoo, Hasan; Khajeh-Mehrizi, Ahmad

    2015-01-01

    Background Aplastic anemia (AA) is a rare disease in which hematopoietic stem cells are severely diminished resulting in hypocellular bone marrow and pancytopenia. Etiology of AA includes auto immunity, toxins, infection, ionizing radiation, drugs and rare genetic disorders, but in the majority of cases no cause can be identified. In the present study we assessed response rate, survival, relapse and clonal evolution in patients with AA treated with immunosuppressive therapy. Methods Patients with AA who received immunosuppressive therapy between May 1998 and September 2013 were included in this study. Patients with non-severe AA (NSAA) were treated with cyclosporine (CsA) and danazol while patients with severe AA (SAA) as well as patients with NSAA who progressed to SAA after beginning of the treatment, were candidates for receiving antithymocyte globulin in addition to CsA and danazol. Results Among the 63 studied patients, 29 (46%) had NSAA and 34 (54%) had SAA. Three months after treatment, overall response was 58.6% in NSAA and 12.9% in patients with SAA. Survival of all patients at 5, 10 and 15 years were 73%, 55% and 49%, respectively. Survival rates were significantly higher in patients with NSAA compared to patients with SAA as well as in patients who responded at 6 months compared to non-responders. The relapse risk was 39.7% at 10 years. Relapse occurred in patients who discontinued the therapy more than those who continued taking CsA (p value<0.01). The risk of clonal evolution was 9.9% at 10 years and 22.8% at 15 years after treatment. Conclusion This long-term retrospective study indicated that immunosuppressive therapy should be recommended to patients with AA. Also, our experience indicated that immunosuppressive therapy should not be discontinued after response to therapy in patients with both NSAA and SAA due to high risk of relapse. Low dose of CsA should be continued indefinitely. PMID:25970182

  4. Enhancing T cell therapy by overcoming the immunosuppressive tumor microenvironment.

    PubMed

    Arina, Ainhoa; Corrales, Leticia; Bronte, Vincenzo

    2016-02-01

    Immune response to tumors can be successfully oriented for therapeutic purposes, as shown by the clinical efficacy of checkpoint blockade in extending the survival of patients with certain solid and hematologic neoplasms. Nonetheless, numerous patients do not benefit from these new treatments. Tumor-specific CD8(+) T lymphocytes, either endogenously revived by checkpoint interference or adoptively transferred after in vitro expansion and retargeting, can be extremely efficient in controlling metastatic disease but have to overcome a number of restraints imposed by growing tumors. This immune escape relies on a profound modification of the tumor environment, which is rendered less permissive to lymphocyte arrival, persistence, and functional activity. We review here emerging findings on the main negative circuits limiting the efficacy of cancer immunotherapy, as well as novel and conventional approaches that can translate into rational combination therapies.

  5. Pharmacodynamic monitoring of immunosuppressive effects indicates reduced cyclosporine activity during telaprevir therapy.

    PubMed

    Roos, Katja; Gotthardt, Daniel; Giese, Thomas; Schnitzler, Paul; Stremmel, Wolfgang; Czock, David; Eisenbach, Christoph

    2014-09-01

    Drug interactions with immunosuppressive drugs are a major problem associated with protease inhibitor-based antiviral triple therapy for hepatitis C virus (HCV) reinfection after liver transplantation. In this retrospective cohort study, we analyzed biomarkers of the immunosuppressive effects of cyclosporine A (CSA) by quantifying nuclear factor of activated T cells (NFAT)-regulated gene expression during telaprevir (TVR) therapy in 5 liver transplant patients. Furthermore, dose adjustments and blood concentrations of CSA as well as the clinical course were analyzed. We observed a clear impact of TVR not only on doses and blood concentrations but also on the immunosuppressive effects of CSA. Despite apparently adequate CSA trough concentrations, the CSA peak concentration decreased to 68% (range = 44%-90%). This was associated with a 1.9-fold (1.6- to 4.1-fold) increase in the residual gene activity of NFAT-regulated genes, which indicated reduced immunosuppressive activity of CSA with TVR co-medication. The median dose of CSA was reduced to 25% (range = 16%-48%) and 31% (range = 22%-64%) after 1 and 2 weeks, respectively. The CSA drug clearance was reduced to 38.7% (range = 31.0%-49.4%). We report excellent antiviral efficacy. At the end of the observation period, all patients were HCV RNA-negative (1 patient at 18 weeks, 1 patient at 12 weeks, and 3 patients at 4 weeks after the end of therapy). Safety was acceptable, with mild acute rejection and reactivation of cytomegalovirus being the most serious adverse events. One patient with histologically proven recurrent cholestatic hepatitis before therapy underwent retransplantation during the course of antiviral therapy. In conclusion, the immunomonitoring of NFAT-regulated gene expression indicated reduced immunosuppressive activity of CSA during antiviral therapy with TVR in our cohort of liver transplant patients. Thus, the immunosuppressive effects of CSA may be overestimated if one is looking

  6. Newer immunosuppressive drugs: their potential role in rheumatoid arthritis therapy.

    PubMed

    Drosos, Alexandros A

    2002-01-01

    Rheumatoid arthritis (RA) is a chronic immune-mediated disease characterised by chronic synovitis, which leads to cartilage damage and joint destruction. It is generally a progressive disease with radiographic evidence of joint damage, functional status decline and premature mortality. Proinflammatory cytokines, such as interleukin 1 and tumour necrosis factor alpha, play an important role in maintaining the chronicity of RA and mediating tissue damage. New approaches in the therapy of RA with anticytokine biological agents, which neutralise or block cytokines or their receptors, are now the first generation antirheumatic drugs in clinical practice. A better understanding of the signal transduction systems and gene regulation by transcription factors involved in cytokine production has opened the way for the discovery of novel therapeutic compounds useful in treating patients with RA. Overactivation of selective kinases or aberrant function of downstream transcription factors could help convert a normal immune response to a chronic disease state. This provides a unique opportunity for novel therapeutic interventions, since specific signal transduction or transcription factor targets might interrupt the perpetuation mechanisms in RA. The availability of potent and selective p38 mitogen activated protein kinase inhibitors provide a means in further dissecting the pathways implicated in cytokine production, which in turn maintain the chronicity of RA. Many studies conclude that these compounds are very useful in the treatment of chronic synovitis and therefore are very promising for RA treatment.

  7. Multifocal aggressive squamous cell carcinomas induced by prolonged voriconazole therapy: a case report.

    PubMed

    Morice, C; Acher, A; Soufir, N; Michel, M; Comoz, F; Leroy, D; Verneuil, L

    2010-01-01

    Voriconazole is a treatment for severe fungal infections. Prolonged voriconazole therapy may induce skin reactions, with 1% of severe photosensitivity accidents. Recently the imputability of voriconazole in skin carcinogenesis has been suggested. This report concerns a 55-year-old man suffering from pulmonary aspergillosis who presented a phototoxic reaction a few months after introduction of voriconazole, followed by multiple squamous cell carcinomas of sun-exposed skin areas. After voriconazole discontinuation, no new carcinoma was observed. The detection of EBV and HPV in skin lesions was negative. Exploration of gene mutations involved in skin carcinogenesis showed two variants of the MICR gene. The occurrence of multiple, recurrent, aggressive squamous cell carcinomas is rare with voriconazole, but its imputability is strongly suggested. A plausible hypothesis is that several factors including voriconazole uptake, immunosuppression, and genetic background could explain the phenotype of fast-developing skin carcinomas. Voriconazole therapy should be accompanied by stringent photoprotection and skin monitoring.

  8. Progressive renal disease despite immunosuppressive therapy in a patient with Wegener s granulomatosis.

    PubMed

    Klein, I; Vervoort, G; Steenbergen, E; Wetzels, J

    2008-03-01

    We present a patient with Morbus Wegener and crescentic glomerulonephritis. Treatment with cyclophosphamide and prednisolone resulted in the disappearance of signs and symptoms of systemic inflammation. However, renal function deteriorated. Renal biopsy showed evidence of continuing capillary necrosis. Renal function improved with added plasmapheresis treatment. This case report illustrates that in patients with vasculitis necrotizing glomerulonephritis may remain active despite immunosuppressive therapy, even in the absence of extrarenal disease activity.

  9. The critically ill immunosuppressed patient

    SciTech Connect

    Parrillo, J.E.; Masur, H. )

    1987-01-01

    This book discusses the papers on the diagnosis and management of immunosuppressed patient. Some of the topics are: life-threatening organ failure in immunosuppressed patients; diagnosis and therapy of respiratory disease in the immunosuppressed patient; CNS complication of immunosuppression; infections; antineoplastic therapy of immunosuppressed patient; radiation therapy-issues in critically ill patient; AIDS; and management of bone marrow transplant patients.

  10. Metastatic Thymoma-Associated Myasthenia Gravis: Favorable Response to Steroid Pulse Therapy Plus Immunosuppressive Agent

    PubMed Central

    Qi, Guoyan; Liu, Peng; Dong, Huimin; Gu, Shanshan; Yang, Hongxia; Xue, Yinping

    2017-01-01

    Background Our study retrospectively reviewed the therapeutic effect of steroid pulse therapy in combination with an immunosuppressive agent in myasthenia gravis (MG) patients with metastatic thymoma. Material/Methods MG patients with metastatic thymoma that underwent methylprednisolone pulse therapy plus cyclophosphamide were retrospectively analyzed. Patients initially received methylprednisolone pulse therapy followed by oral methylprednisolone. Cyclophosphamide was prescribed simultaneously at the beginning of treatment. Clinical outcomes, including therapeutic efficacy and adverse effects of MG and thymoma, were assessed. Results Twelve patients were recruited. According to histological classification, 4 cases were type B2 thymoma, 3 were type B3, 2 were type B1, and 1 was type AB. After combined treatment for 15 days, both the thymoma and MG responded dramatically to high-dose methylprednisolone plus cyclophosphamide. The symptoms of MG were improved in all patients, with marked improvement in 6 patients and basic remission in 4. Interestingly, complete remission of thymoma was achieved in 5 patients and partial remission in 7 patients. Myasthenic crisis was observed in 1 patient and was relieved after intubation and ventilation. Adverse reactions were observed in 7 patients (58.3%), most commonly infections, and all were resolved without discontinuation of therapy. During the follow-up, all patients were stabilized except for 1 with pleural metastasis who received further treatment and another 1 who died from myasthenic crisis. Conclusions The present study in a series of MG patients with metastatic thymoma indicated that steroid pulse therapy in combination with immunosuppressive agents was an effective and well-tolerated for treatment of both metastatic thymoma and MG. Glucocorticoid pulse therapy plus immunosuppressive agents should therefore be considered in MG patients with metastatic thymoma. PMID:28278141

  11. Hepatitis B Virus Reactivation in the Setting of Cancer Chemotherapy and Other Immunosuppressive Drug Therapy.

    PubMed

    Gonzalez, Stevan A; Perrillo, Robert P

    2016-06-01

    Hepatitis B virus reactivation (HBVr) is an important complication of immunosuppressive drug therapy (ISDT). It can occur with active or resolved hepatitis B virus (HBV) infection with a clinical spectrum that ranges from mild elevations in liver tests to fulminant hepatic failure. The risk of it occurring is determined by the interplay between HBV serological status, level of viremia, and the immunosuppressive potency of the drug(s) used. Reactivation is most common during treatment of hematologic malignancies but also occurs with chemotherapy for breast cancer and numerous other solid organ malignancies, organ transplant, and immune suppression for nonmalignant conditions. The expansion of new biologic treatments for malignant and nonmalignant disorders has enlarged the population at risk. Increased awareness of HBVr among healthcare providers who prescribe ISDT, adoption of routine HBV screening, and linking the results of screening to antiviral prophylaxis are needed to reduce the incidence of this potentially fatal but preventable disorder.

  12. Immunosuppressive therapy exacerbates autoimmunity in NOD mice and diminishes the protective activity of regulatory T cells.

    PubMed

    Kaminitz, Ayelet; Mizrahi, Keren; Yaniv, Isaac; Stein, Jerry; Askenasy, Nadir

    2010-09-01

    Mounting evidence indicates that immunosuppressive therapy and autologous bone marrow transplantation are relatively inefficient approaches to treat autoimmune diabetes. In this study we assessed the impact of immunosuppression on inflammatory insulitis in NOD mice, and the effect of radiation on immunomodulation mediated by adoptive transfer of various cell subsets. Sublethal radiation of NOD females at the age of 14 weeks (onset of hyperglycemia) delayed the onset of hyperglycemia, however two thirds of the mice became diabetic. Adoptive transfer of splenocytes into irradiated NON and NOD mice precipitated disease onset despite increased contents of CD25(+)FoxP3(+) T cells in the pancreas and regional lymphatics. Similar phenotypic changes were observed when CD25(+) T cells were infused after radiation, which also delayed disease onset without affecting its incidence. Importantly, irradiation increased the susceptibility to diabetes in NOD and NON mice (71-84%) as compared to immunomodulation with splenocytes and CD25(+) T cells in naïve recipients (44-50%). Although irradiation had significant and durable influence on pancreatic infiltrates and the fractions of functional CD25(+)FoxP3(+) Treg cells were elevated by adoptive cell transfer, this approach conferred no protection from disease progression. Irradiation was ineffective both in debulking of pathogenic clones and in restoring immune homeostasis, and the consequent homeostatic expansion evolves as an unfavorable factor in attempts to restore self-tolerance and might even provoke uncontrolled proliferation of pathogenic clones. The obstacles imposed by immunosuppression on abrogation of autoimmune insulitis require replacement of non-specific immunosuppressive therapy by selective immunomodulation that does not cause lymphopenia.

  13. Aggressive thyroid cancer: targeted therapy with sorafenib.

    PubMed

    Corrado, Alda; Ferrari, Silvia M; Politti, Ugo; Mazzi, Valeria; Miccoli, Mario; Materazzi, Gabriele; Antonelli, Alessandro; Ulisse, Salvatore; Fallahi, Poupak; Miccoli, Paolo

    2017-03-01

    Sorafenib (Nexavar), is a multikinase inhibitor, which has demonstrated both antiproliferative and antiangiogenic properties in vitro and in vivo, inhibiting the activity of targets present in the tumoral cells (c-RAF [proto-oncogene serine/threonine-protein kinase], BRAF, (V600E)BRAF, c-KIT, and FMS-like tyrosine kinase 3) and in tumor vessels (c-RAF, vascular endothelial growth factor receptor [VEGFR]-2, VEGFR-3, and platelet-derived growth factor receptor β). Sorafenib was initially approved for the treatment of hepatocellular carcinoma and advanced renal cell carcinoma. Experimental studies have demonstrated that sorafenib has both antiproliferative and antiangiogenic properties in vitro and in vivo, against thyroid cancer cells. Furthermore, several completed (or ongoing) studies have evaluated the long-term efficacy and tolerability of sorafenib in patients with papillary, follicular and medullary aggressive thyroid cancer. The results of the different studies showed good clinical responses and stabilization of the disease and suggested that sorafenib is a promising therapeutic option in patients with advanced thyroid cancer that is not responsive to traditional therapeutic strategies (such as radioiodine). Currently, USA Food and Drug Administration has approved the use of sorafenib for metastatic differentiated thyroid cancer.

  14. Relationship between vitamin D status and immunosuppressive therapy in kidney transplant recipients

    PubMed Central

    Filipov, Jean Jeanov; Zlatkov, Borelli Kirilov; Dimitrov, Emil Paskalev; Svinarov, Dobrin

    2015-01-01

    There is a growing body of evidence for the protective role of vitamin D in diabetes mellitus (DM), infection, cancer, cardiovascular disease, immune disorders and kidney function. Considering the reported high prevalence of vitamin D insufficiency among kidney transplant recipients (KTRs), the aim of this study was to assess the influence of immunosuppressive therapy and other factors on vitamin D status in such patients. The study included 289 KTRs (189 males and 100 females) who consented to participate. The first test for 25-hydrohyvitamin D [25(OH)D] was performed by a validated liquid chromatography–tandem mass spectrometry method. Influence of immunosuppressive drugs and previously reported predictors on vitamin D status was assessed by descriptive statistics, univariate and multivariate regression. Our results showed that only 53 patients (18.34%) of the studied KTRs were vitamin D sufficient. In addition to a well expected positive association between serum 25(OH)D and summer blood sampling (p < 0.05) and inverse relationship between vitamin D status and DM, gender (female) and body mass index, serum 25(OH)D was found to be inversely associated with calcineurin inhibitors (CNI) (p < 0.05) and unaffected by other immunosuppressive agents. Our study demonstrated high prevalence of vitamin D insufficiency after kidney transplantation in the studied cohort of patients. Apart from female gender, winter months, DM and overweight, the use of CNI could be considered an additional significant predictor of lower 25(OH)D in Bulgarian KTRs. PMID:26019648

  15. Hepatotoxicity and liver enzyme alteration in patients with immunobullous diseases receiving immunosuppressive therapy.

    PubMed

    Shahshahani, Mostafa M; Azizahari, Sahar; Soori, Tahere; Manavi, Saeed; Balighi, Kamran; Daneshpazhooh, Maryam; Davatchi, Cheida S; Esmaili, Nasife

    2011-12-01

    To avoid complications of high dose corticosteroid, pemphigus patients are usually co-treated with other immunosuppressive agents. Liver enzyme abnormality occurs commonly during treatment and occasionally causes discontinuation of drugs. To assess the rate of therapy-induced hepatotoxicity in patients with immunobullous diseases, we conducted a study of 250 pemphigus patients under immunosuppressive therapy prospectively. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) plasma levels were recorded before the start of treatment and every week under treatment (up to 3 weeks). Hepatotoxicity was defined as the rise in the ALT plasma levels to greater than twice the upper normal limit. Approximately 81% of patients received prednisolone and azathioprine. Approximately 12% received only prednisolone. Hepatotoxicity occurred in 2.9% (n = 8) of patients after 1 week, in 7.8% (n = 20) after 2 weeks and in 11.5% (n = 29) after 3 weeks. No patient had jaundice or other clinical manifestations of hepatitis. The mean values of ALT and AST before the start of treatment were 20.7 ± 13.7 and 17.6 ± 10.8 U/L, respectively that grew to 47.5 ± 28.5 and 26.8 ± 14.5 U/L, 3 weeks after the initiation of treatment. Distribution of changes was not significantly different among groups of age, sex, immunosuppressive drugs and isoniazid consumption. Under usual treatment of pemphigus, hepatotoxicity occurs in 10% of patients during the first 3 weeks of therapy that does not seem to be associated with azathioprine or mycophenolate mofetil exclusively. High doses of prednisolone may play a role.

  16. Knowledge-based immunosuppressive therapy for kidney transplant patients--from theoretical model to clinical integration.

    PubMed

    Seeling, Walter; Plischke, Max; de Bruin, Jeroen S; Schuh, Christian

    2015-01-01

    Immunosuppressive therapy is a risky necessity after a patient received a kidney transplant. To reduce risks, a knowledge-based system was developed that determines the right dosage of the immunosuppresive agent Tacrolimus. A theoretical model, to classify medication blood levels as well as medication adaptions, was created using data from almost 500 patients, and over 13.000 examinations. This model was then translated into an Arden Syntax knowledge base, and integrated directly into the hospital information system of the Vienna General Hospital. In this paper we give an overview of the construction and integration of such a system.

  17. Pemphigus vulgaris in a patient with arthritis and uveitis: successful treatment with immunosuppressive therapy and acyclovir.

    PubMed

    Pranteda, G; Carlesimo, M; Bottoni, U; Di Napoli, A; Muscianese, M; Pimpinelli, F; Cordiali, P; Laganà, B; Pranteda, G; Di Carlo, A

    2014-01-01

    A case of pemphigus vulgaris in a 41-year-old man with undifferentiated arthritis and uveitis is described. Histology of labial mucosa showed acantholytic, necrotic, and multinucleated giant keratinocytes having some nuclear inclusions suggestive of a virus infection. Specific serological tests revealed IgG positivity for HSV-1, CMV, and EBV, while real-time polymerase chain reaction assay from a biopsy of the mucosal lesion showed the presence of HSV-1/2 DNA. Treatment with prednisone, methotrexate, and acyclovir induced the complete remission of mucosal and joint symptoms, which then relapsed after interruption of antiviral therapy or immunosuppressive therapy. Therefore, a combined treatment with low doses of prednisone, methotrexate, and acyclovir was restarted and during 18 months of follow-up no recurrence was registered. Correlations between pemphigus and the herpes virus infection and also between autoimmune arthritis and herpetic agents have been well documented, but the exact role of the herpes virus in these disorders still needs further discussion. Our case strongly suggests that when autoimmune disorders do not respond to immunosuppressive agents, a viral infection should be suspected, researched, and treated.

  18. Invasive aspergillosis successfully treated by combined antifungal therapy and immunosuppressive monotherapy two months following heart transplantation.

    PubMed

    Urbanowicz, Tomasz; Żabicki, Bartłomiej; Baszyńska-Wachowiak, Hanna; Straburzyńska-Migaj, Ewa; Juszkat, Robert; Grajek, Stefan; Jemielity, Marek

    2016-06-01

    Invasive aspergillosis is becoming increasingly prevalent, especially following transplantation. Invasive aspergillosis is associated with mortality. Successful therapy is related to early diagnosis and proper therapy. We present the case of a 61-year-old man suffering from invasive aspergillosis 2 months following heart transplantation. He was suffering from hypertrophic cardiomyopathy and he underwent orthotropic heart transplantation. He was readmitted to the Department of Cardiology 69 days following transplantation due to symptoms of productive cough for 5 days. It was accompanied by chest pain, shortness of breath, and fever up to 39°C. He was slightly cyanotic and confused on physical examination. The patient's status deteriorated within the following 2 days. On bronchoscopic specimen examinations Aspergillus mould filaments were detected and the serum galactomannan index was 12.162. His blood saturation decreased to 85%. C-reactive protein serum level increased to 273 mg/l. The patient was admitted to the intensive care unit and intubated due to severe respiratory insufficiency. Computed tomography revealed massive, mostly homogeneous consolidation. The patient was treated with 200 mg of voriconazole and 50 mg of caspofungin daily. Caspofungin therapy was continued for 23 days and voriconazole was administered parenterally for 62 days. Voriconazole therapy was continued orally for 9 months. During combined antifungal therapy, the galactomannan serum index constantly decreased from 12.1 to 0.33 (end-point of caspofungin therapy) and to 0.23 (end-point of voriconazole parenteral administration). His immunosuppressive therapy was limited to calcineurin inhibitor (tacrolimus) monotherapy. Post-treatment imaging 9 months after diagnosis confirmed the efficacy of therapy as a lack of pulmonary infiltration associated with left apical peribronchial scarring as a result of treatment. The present case proved the efficiency of combined (voriconazole and caspofungin

  19. Invasive aspergillosis successfully treated by combined antifungal therapy and immunosuppressive monotherapy two months following heart transplantation

    PubMed Central

    Żabicki, Bartłomiej; Baszyńska-Wachowiak, Hanna; Straburzyńska-Migaj, Ewa; Juszkat, Robert; Grajek, Stefan; Jemielity, Marek

    2016-01-01

    Invasive aspergillosis is becoming increasingly prevalent, especially following transplantation. Invasive aspergillosis is associated with mortality. Successful therapy is related to early diagnosis and proper therapy. We present the case of a 61-year-old man suffering from invasive aspergillosis 2 months following heart transplantation. He was suffering from hypertrophic cardiomyopathy and he underwent orthotropic heart transplantation. He was readmitted to the Department of Cardiology 69 days following transplantation due to symptoms of productive cough for 5 days. It was accompanied by chest pain, shortness of breath, and fever up to 39°C. He was slightly cyanotic and confused on physical examination. The patient's status deteriorated within the following 2 days. On bronchoscopic specimen examinations Aspergillus mould filaments were detected and the serum galactomannan index was 12.162. His blood saturation decreased to 85%. C-reactive protein serum level increased to 273 mg/l. The patient was admitted to the intensive care unit and intubated due to severe respiratory insufficiency. Computed tomography revealed massive, mostly homogeneous consolidation. The patient was treated with 200 mg of voriconazole and 50 mg of caspofungin daily. Caspofungin therapy was continued for 23 days and voriconazole was administered parenterally for 62 days. Voriconazole therapy was continued orally for 9 months. During combined antifungal therapy, the galactomannan serum index constantly decreased from 12.1 to 0.33 (end-point of caspofungin therapy) and to 0.23 (end-point of voriconazole parenteral administration). His immunosuppressive therapy was limited to calcineurin inhibitor (tacrolimus) monotherapy. Post-treatment imaging 9 months after diagnosis confirmed the efficacy of therapy as a lack of pulmonary infiltration associated with left apical peribronchial scarring as a result of treatment. The present case proved the efficiency of combined (voriconazole and caspofungin

  20. Peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood aplastic anemia.

    PubMed

    Sakaguchi, Hirotoshi; Nishio, Nobuhiro; Hama, Asahito; Kawashima, Nozomu; Wang, Xinan; Narita, Atsushi; Doisaki, Sayoko; Xu, Yinyan; Muramatsu, Hideki; Yoshida, Nao; Takahashi, Yoshiyuki; Kudo, Kazuko; Moritake, Hiroshi; Nakamura, Kazuhiro; Kobayashi, Ryoji; Ito, Etsuro; Yabe, Hiromasa; Ohga, Shouichi; Ohara, Akira; Kojima, Seiji

    2014-08-01

    Predicting the response to immunosuppressive therapy could provide useful information to help the clinician define treatment strategies for patients with aplastic anemia. In our current study, we evaluated the relationship between telomere length of lymphocytes at diagnosis and the response to immunosuppressive therapy in 64 children with aplastic anemia, using flow fluorescence in situ hybridization. Median age of patients was ten years (range 1.5-16.2 years). Severity of the disease was classified as very severe in 23, severe in 21, and moderate in 20 patients. All patients were enrolled in multicenter studies using antithymocyte globulin and cyclosporine. The response rate to immunosuppressive therapy at six months was 52% (33 of 64). The probability of 5-year failure-free survival and overall survival were 56% (95% confidence interval (CI): 41-69%) and 97% (95%CI: 87-99%), respectively. Median telomere length in responders was -0.4 standard deviation (SD) (-2.7 to +3.0 SD) and -1.5 SD (-4.0 to +1.6 (SD)) in non-responders (P<0.001). Multivariate analysis showed that telomere length shorter than -1.0 SD (hazard ratio (HR): 22.0; 95%CI: 4.19-115; P<0.001), platelet count at diagnosis less than 25×10(9)/L (HR: 13.9; 95%CI: 2.00-96.1; P=0.008), and interval from diagnosis to immunosuppressive therapy longer than 25 days (HR: 4.81; 95%CI: 1.15-20.1; P=0.031) were the significant variables for poor response to immunosuppressive therapy. Conversely to what has been found in adult patients, measurement of the telomere length of lymphocytes at diagnosis is a promising assay in predicting the response to immunosuppressive therapy in children with aplastic anemia.

  1. Fludarabine, cyclophosphamide, doxorubicin (FCD), and rituximab: a remission induction therapy for aggressive pediatric post-transplant lymphoproliferative disease (PTLD).

    PubMed

    Giraldi, Eugenia; Provenzi, Massimo; Fiocchi, Roberto; Colledan, Michele; Cornelli, Pieremilio; Torre, Giuliano; Rambaldi, Alessandro; Conter, Valentino

    2011-08-01

    Management of aggressive, usually late-occurring, post-transplant lymphoproliferative disorders (PTLDs), a life-threatening complication after solid organ transplants, remains controversial. Four children affected by aggressive CD20+ PTLDs received a chemo-immunotherapy regimen for remission induction based on fludarabine, cyclophosphamide, doxorubicin, and rituximab, associated with a rapid discontinuation of immunosuppression (IS). Subsequent consolidation chemotherapy consisted of Berlin-Frankfurt-Münster-modified blocks. All patients achieved a complete remission, which persisted for 25, 68+, 80+, and 103+ months after diagnosis. Therapy was well tolerated. No patients developed allograft rejection during PTLD treatment. Our experience suggests that this chemo-immunotherapeutic approach may be an effective treatment strategy while allowing for a concomitant discontinuation of IS.

  2. Radiographic assessment of photodynamic therapy as an adjunctive treatment on induced periodontitis in immunosuppressed rats

    PubMed Central

    FERNANDES, Leandro Araújo; MARTINS, Thiago Marchi; de ALMEIDA, Juliano Milanezi; THEODORO, Letícia Helena; GARCIA, Valdir Gouveia

    2010-01-01

    Objective The aim of this study was to assess radiographically the effect of photodynamic therapy (PDT) as an adjunctive treatment to scaling and root planing (SRP) on induced periodontitis in dexamethasone-induced immunosuppressed rats. Material and Methods The animals were divided into 2 groups: ND group (n=60): saline treatment; D group (n=60): dexamethasone treatment. In both ND and D groups, periodontal disease was induced by the placement of a ligature in the left first mandibular molar. After 7 days, ligature was removed and all animals received SRP, being divided according to the following treatments: SRP: saline and PDT: phenothiazinium dye (TBO) plus laser irradiation. Ten animals per treatment were killed at 7, 15 and 30 days. The distance between the cementoenamel junction and the height of the alveolar bone crest in the mesial surface of the mandibular left first molars was determined in millimeters in each radiograph. The radiographic values were analyzed statistically by ANOVA and Tukey's test at a p value <0.05. Results Intragroup radiographic assessment (ND and D groups) showed that there was statistically significant less bone loss in the animals treated with PDT in all experimental periods compared to those submitted to SRP. Intergroup radiographic analysis (ND and D groups) demonstrated that there was greater bone loss in the ND group treated with SRP compared to the D group treated with PDT at 7 and 30 days. Conclusion PDT was an effective adjunctive treatment to SRP on induced periodontitis in dexamethasone-induced immunosuppressed rats. PMID:20857000

  3. Unilateral Migratory Relapsing Orbital Myositis While on Immunosuppressant Therapy: An Uncommon Entity.

    PubMed

    Singh, Swati; Mittal, Ruchi; Padhan, Prasanta; Tripathy, Devjyoti

    A young healthy female presented with acute onset left ocular pain, restricted ocular motility, and binocular diplopia. CT imaging showed left lateral rectus myositis that resolved with oral corticosteroids. Two sequential relapses occurred subsequently involving the superior rectus-levator complex followed by the medial rectus. Biopsy revealed orbital inflammatory disease with lymphocytic vasculitis. Detailed systemic work up was normal. The second relapse was seen while on long-term oral methotrexate although initial disease remission had been achieved with the same drug. A changeover to oral azathioprine was able to achieve disease remission after the second relapse. All relapses involved the same side and the contralateral orbit was not affected. This report presents the curious phenomenon of unilateral migratory relapsing orbital myositis of unknown cause that recurred even while on immunosuppressant therapy. It highlights the unpredictable nature of this uncommon entity and the challenges faced in managing such cases.

  4. Immunosuppressive therapy mitigates immunological rejection of human embryonic stem cell xenografts.

    PubMed

    Swijnenburg, Rutger-Jan; Schrepfer, Sonja; Govaert, Johannes A; Cao, Feng; Ransohoff, Katie; Sheikh, Ahmad Y; Haddad, Munif; Connolly, Andrew J; Davis, Mark M; Robbins, Robert C; Wu, Joseph C

    2008-09-02

    Given their self-renewing and pluripotent capabilities, human embryonic stem cells (hESCs) are well poised as a cellular source for tissue regeneration therapy. However, the host immune response against transplanted hESCs is not well characterized. In fact, controversy remains as to whether hESCs have immune-privileged properties. To address this issue, we used in vivo bioluminescent imaging to track the fate of transplanted hESCs stably transduced with a double-fusion reporter gene consisting of firefly luciferase and enhanced GFP. We show that survival after transplant is significantly limited in immunocompetent as opposed to immunodeficient mice. Repeated transplantation of hESCs into immunocompetent hosts results in accelerated hESC death, suggesting an adaptive donor-specific immune response. Our data demonstrate that transplanted hESCs trigger robust cellular and humoral immune responses, resulting in intragraft infiltration of inflammatory cells and subsequent hESC rejection. Moreover, we have found CD4(+) T cells to be an important modulator of hESC immune-mediated rejection. Finally, we show that immunosuppressive drug regimens can mitigate the anti-hESC immune response and that a regimen of combined tacrolimus and sirolimus therapies significantly prolongs survival of hESCs for up to 28 days. Taken together, these data suggest that hESCs are immunogenic, trigger both cellular and humoral-mediated pathways, and, as a result, are rapidly rejected in xenogeneic hosts. This process can be mitigated by a combined immunosuppressive regimen as assessed by molecular imaging approaches.

  5. Alternative pharmacologic therapy for aggressive central giant cell granuloma: denosumab.

    PubMed

    Schreuder, Willem H; Coumou, Annet W; Kessler, Peter A H W; de Lange, Jan

    2014-07-01

    In the search for new pharmacologic therapies for central giant cell granuloma (CGCG), proteins that are essential to osteoclastogenesis are intriguing potential targets. In the present case report, we describe a 25-year-old patient with an aggressive CGCG of the maxilla, who was successfully treated with the antiresorptive agent denosumab, after other pharmacologic treatment had failed to achieve regression or stabilization of the tumor. Denosumab could be a promising alternative to potentially mutilating surgery for CGCG. However, more research is needed before definite conclusions can be drawn about the potential role of this agent in the treatment of CGCG.

  6. Autoimmune Hepatitis: Progress from Global Immunosuppression to Personalised Regulatory T Cell Therapy

    PubMed Central

    Than, Nwe Ni; Jeffery, Hannah C.; Oo, Ye H.

    2016-01-01

    Autoimmune hepatitis (AIH) is an immune mediated liver injury. The precise aetiology of AIH is still unknown but current evidence suggests both genetic and environmental factors are involved. Breakdown in peripheral self-tolerance, and impaired functions of FOXP3+ regulatory T cell along with effector cell resistance to suppression at the tissue level seem to play an important role in AIH immunopathogenesis. AIH is predominantly a T lymphocytes driven disease but B lymphocytes are also involved in the immunopathology. Innate immune cells are crucial in the initial onset of disease and their response is followed by adaptive T (Th1, Th17, and cytotoxic T cells) and B cell responses evidenced by liver histology and peripheral blood serology. Standard treatment regimens involving steroid and immunosuppressive medications lead to global immune suppression requiring life-long therapy with many side effects. Biologic therapies have been attempted but duration of remission is short-lived. Future direction of diagnosis and treatment for AIH should be guided by “omics” and the immunology profile of the individual patient and clinicians should aim to deliver personalised medicine for their patients. Cell therapy such as infusion of autologous, antigen-specific, and liver-homing regulatory T cells to restore hepatic immune tolerance may soon be a potential future treatment for AIH patients. PMID:27446862

  7. Dermatomyositis: observations on the use of immunosuppressive therapy and review of literature. Cairo--Glasgow study group.

    PubMed Central

    El-Ghobarey, A.; Balint, G.; de Ceulaer, K.; Dick, W. C.; Buchanan, W. W.; Hadidi, T.; Hassan, T. A.

    1978-01-01

    Seven young adults, six of whom were male, all suffering from dermatomyositis unassociated with malignancy are described. These patients were not adequately controlled with high doses of corticosteroids but all responded when immunosuppressive therapy was also given. Images Fig. 4 Fig. 5 PMID:733682

  8. High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS

    PubMed Central

    Hutton, George J.; Racke, Michael K.; Popat, Uday; Devine, Steven M.; Steinmiller, Kaitlyn C.; Griffith, Linda M.; Muraro, Paolo A.; Openshaw, Harry; Sayre, Peter H.; Stuve, Olaf; Arnold, Douglas L.; Wener, Mark H.; Georges, George E.; Wundes, Annette; Kraft, George H.; Bowen, James D.

    2017-01-01

    Objective: To evaluate the safety, efficacy, and durability of multiple sclerosis (MS) disease stabilization after high-dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation (HCT). Methods: High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT-MS) is a phase II clinical trial of HDIT/HCT for patients with relapsing-remitting (RR) MS who experienced relapses with disability progression (Expanded Disability Status Scale [EDSS] 3.0–5.5) while on MS disease-modifying therapy. The primary endpoint was event-free survival (EFS), defined as survival without death or disease activity from any one of: disability progression, relapse, or new lesions on MRI. Participants were evaluated through 5 years posttransplant. Toxicities were reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (AE). Results: Twenty-five participants were evaluated for transplant and 24 participants underwent HDIT/HCT. Median follow-up was 62 months (range 12–72). EFS was 69.2% (90% confidence interval [CI] 50.2–82.1). Progression-free survival, clinical relapse-free survival, and MRI activity-free survival were 91.3% (90% CI 74.7%–97.2%), 86.9% (90% CI 69.5%–94.7%), and 86.3% (90% CI 68.1%–94.5%), respectively. AE due to HDIT/HCT were consistent with expected toxicities and there were no significant late neurologic adverse effects noted. Improvements were noted in neurologic disability with a median change in EDSS of −0.5 (interquartile range −1.5 to 0.0; p = 0.001) among participants who survived and completed the study. Conclusion: HDIT/HCT without maintenance therapy was effective for inducing long-term sustained remissions of active RRMS at 5 years. ClinicalTrials.gov identifier: NCT00288626. Classification of evidence: This study provides Class IV evidence that participants with RRMS experienced sustained remissions with toxicities as expected from HDIT/HCT. PMID:28148635

  9. High-dose immunosuppressive therapy for severe systemic sclerosis: initial outcomes

    PubMed Central

    McSweeney, Peter A.; Nash, Richard A.; Sullivan, Keith M.; Storek, Jan; Crofford, Leslie J.; Dansey, Roger; Mayes, Maureen D.; McDonagh, Kevin T.; Nelson, J. Lee; Gooley, Theodore A.; Holmberg, Leona A.; Chen, C. S.; Wener, Mark H.; Ryan, Katherine; Sunderhaus, Julie; Russell, Ken; Rambharose, John; Storb, Rainer; Furst, Daniel E.

    2010-01-01

    Systemic sclerosis (SSc) is a multisystem disease of presumed autoimmune pathogenesis for which no proven effective treatment exists. High-dose immunosuppressive therapy (HDIT) has been proposed as an investigational treatment for severe autoimmune diseases. Nineteen patients with poor-prognosis SSc underwent HDIT. The median age was 40 years (range, 23–61 years), the median modified Rodnan skin score (a measure of dermal sclerosis) was 31, and the median DLCO was 57%. Conditioning therapy involved 800 cGy total body irradiation (TBI) (± lung shielding to approximately 200 cGy), 120 mg/kg cyclophosphamide, and 90 mg/kg equine antithymocyte globulin. CD34-selected granulocyte–colony-stimulating factor–mobilized autologous blood stem cells provided hematopoietic rescue. With median follow-up at 14.7 months, the Kaplan-Meier estimated 2-year survival rate was 79%. Three patients died of treatment complications and one of disease progression. Two of the first 8 patients had fatal regimen-related pulmonary injury, a complication not found among 11 subsequent patients who received lung shielding for TBI. Overall, internal organ functions were stable to slightly worse after HDIT, and 4 patients had progressive or nonresponsive disease. As measured by modified Rodnan skin scores and modified health assessment questionnaire disability index (mHAQ-DI) scores, significant disease responses occurred in 12 of 12 patients evaluated at 1 year after HDIT. In conclusion, though important treatment-related toxicities occurred after HDIT for SSc, modifications of initial approaches appear to reduce treatment risks. Responses in skin and mHAQ-DI scores exceed those reported with other therapies, suggesting that HDIT is a promising new therapy for SSc that should be evaluated in prospective randomized studies. PMID:12176878

  10. Bone marrow transplantation versus immunosuppressive therapy in patients with acquired severe aplastic anemia.

    PubMed

    Bacigalupo, Andrea; Giammarco, Sabrina; Sica, Simona

    2016-08-01

    Standard front-line treatment for acquired aplastic anemia (AA) for patients is either immunosuppressive therapy (IST) or bone marrow transplantation (BMT), usually from an HLA identical sibling. Whereas long-term survival is comparable with either treatment, important differences remain: IST patients may have incomplete or no recovery, are exposed to late clonal disorders and relapse of the original disease. Transplantation is a curative treatment, but patients are exposed to transplant-related complications both acute and chronic, such as chronic graft versus host disease (cGvHD). In the year 2000, a study by the European Group for Blood and Marrow Transplantation (EBMT), looked at failure free survival (FFS), in patients receiving first-line BMT from an HLA identical sibling, or the first-line IST. Young patients with low neutrophil counts benefited of the first-line BMT; the opposite was true for older patients with higher neutrophil counts; and a third intermediate group of patients had comparable survival irrespective of the first-line therapy. We have now studied a more recent cohort of patients to assess whether things have changed over the years. We have found similar results, although overall survival has improved, as a consequence of changes in the IST and BMT protocols.

  11. Immunosuppressive Medications.

    PubMed

    Wiseman, Alexander C

    2016-02-05

    Immunosuppressive agents are commonly used in the nephrologist's practice in the treatment of autoimmune and immune-mediated diseases and transplantation, and they are investigational in the treatment of AKI and ESRD. Drug development has been rapid over the past decades as mechanisms of the immune response have been better defined both by serendipity (the discovery of agents with immunosuppressive activity that led to greater understanding of the immune response) and through mechanistic study (the study of immune deficiencies and autoimmune diseases and the critical pathways or mutations that contribute to disease). Toxicities of early immunosuppressive agents, such as corticosteroids, azathioprine, and cyclophosphamide, stimulated intense investigation for agents with more specificity and less harmful effects. Because the mechanisms of the immune response were better delineated over the past 30 years, this specialty is now bestowed with a multitude of therapeutic options that have reduced rejection rates and improved graft survival in kidney transplantation, provided alternatives to cytotoxic therapy in immune-mediated diseases, and opened new opportunities for intervention in diseases both common (AKI) and rare (atypical hemolytic syndrome). Rather than summarizing clinical indications and clinical trials for all currently available immunosuppressive medications, the purpose of this review is to place these agents into mechanistic context together with a brief discussion of unique features of development and use that are of interest to the nephrologist.

  12. Immunosuppressive Medications

    PubMed Central

    2016-01-01

    Immunosuppressive agents are commonly used in the nephrologist’s practice in the treatment of autoimmune and immune-mediated diseases and transplantation, and they are investigational in the treatment of AKI and ESRD. Drug development has been rapid over the past decades as mechanisms of the immune response have been better defined both by serendipity (the discovery of agents with immunosuppressive activity that led to greater understanding of the immune response) and through mechanistic study (the study of immune deficiencies and autoimmune diseases and the critical pathways or mutations that contribute to disease). Toxicities of early immunosuppressive agents, such as corticosteroids, azathioprine, and cyclophosphamide, stimulated intense investigation for agents with more specificity and less harmful effects. Because the mechanisms of the immune response were better delineated over the past 30 years, this specialty is now bestowed with a multitude of therapeutic options that have reduced rejection rates and improved graft survival in kidney transplantation, provided alternatives to cytotoxic therapy in immune-mediated diseases, and opened new opportunities for intervention in diseases both common (AKI) and rare (atypical hemolytic syndrome). Rather than summarizing clinical indications and clinical trials for all currently available immunosuppressive medications, the purpose of this review is to place these agents into mechanistic context together with a brief discussion of unique features of development and use that are of interest to the nephrologist. PMID:26170177

  13. Trial of Early Aggressive Therapy in Polyarticular Juvenile Idiopathic Arthritis

    PubMed Central

    Wallace, Carol A.; Giannini, Edward H.; Spalding, Steven J.; Hashkes, Philip J.; O’Neil, Kathleen M.; Zeft, Andrew S.; Szer, Ilona S.; Ringold, Sarah; Brunner, Hermine I.; Schanberg, Laura E.; Sundel, Robert P.; Milojevic, Diana; Punaro, Marilynn G.; Chira, Peter; Gottlieb, Beth S.; Higgins, Gloria C.; Ilowite, Norman T.; Kimura, Yukiko; Hamilton, Stephanie; Johnson, Anne; Huang, Bin; Lovell, Daniel J.

    2011-01-01

    OBJECTIVES To determine if aggressive treatment initiated early in the course of rheumatoid factor positive or negative polyarticular juvenile idiopathic arthritis (poly-JIA) can induce clinical inactive disease (CID) within 6 months. METHODS Between May 2007 and October 2010 a multi-center, prospective, double blind, randomized, placebo controlled trial of two aggressive treatments was conducted in 85 children aged 2 to 16 years with polyarticular JIA of less than 12 months duration. Patients received either methotrexate 0.5 mg/kg/wk SQ (40 mg max), etanercept 0.8 mg/kg/wk (50 mg max), prednisolone 0.5 mg/kg/d (60 mg max) tapered to 0 by 17 weeks (Arm 1), or methotrexate (same dose as Arm 1), etanercept placebo, and prednisolone placebo (Arm 2). The primary outcome was CID at 6 months. An exploratory phase determined the rate of clinical remission on medication (6 months of continuous CID) at 12 months. RESULTS By 6 months, 17 of 42 (40%) of patients in Arm 1 and 10 of 43 (23%) in Arm 2 had achieved CID (X2 = 2.91; p = 0.088). After 12 months, 9 patients in Arm 1 and 3 in Arm 2 achieved clinical remission on medication (p = 0.0534). There were no significant inter-arm differences in adverse events. CONCLUSIONS Although this study did not meet its primary endpoint, early aggressive therapy in this cohort of children with recent onset polyarticular JIA resulted in substantial proportions of patients in both arms achieving CID by 6 months and clinical remission on medication within 12 months of treatment. PMID:22183975

  14. The effect of conventional immunosuppressive therapy on cytokine serum levels in pemphigus vulgaris patients.

    PubMed

    Mortazavi, Hossein; Esmaili, Nafiseh; Khezri, Somayeh; Khamesipour, Ali; Vasheghani Farahani, Iman; Daneshpazhooh, Maryam; Rezaei, Nima

    2014-06-01

    Pemphigus vulgaris is an autoimmune disease, in which the role of Th17 cytokines needs to be further explored. This study was performed to assess serum levels of three interleukins (IL) required for Th17 differentiation (IL-1β, IL-6 and IL-23) and two specific Th17 cytokines (IL-17 and IL-22) in a group of patients with pemphigus vulgaris, at baseline, 3 weeks and 6 months after treatment. Correlations between anti-desmogleins and cytokines with disease severity as well as the influence of therapy on the above factors were assessed. Forty-three first-admitted pemphigus vulgaris patients with the active disease entered the study, but only 31 completed the study. Forty-five healthy volunteers were recruited as a control group. The patients were treated with conventional immunosuppressive therapy (oral prednisolone and azathioprine). Cytokines and anti-desmogleins were measured, using enzyme-linked immunosorbent assay. General linear model was used to evaluate the changes over time. In patients at baseline, mean serum level of IL-6 was higher, while mean levels of IL-1β and IL-22 were lower than the controls. After 3 weeks of therapy, IL-1β and IL-6 levels showed a decreasing trend, whereas IL-22 showed an increasing trend. Mean anti-desmogleins 1 and 3 values decreased significantly during the time. Anti-desmoglein values were significantly correlated with disease severity. In conclusion, IL-1β and IL-6 could be involved in the pathogenesis of pemphigus vulgaris. The positive trend of IL-22 is a new finding and should be confirmed by further studies.

  15. Epstein-Barr virus-associated posttransplantation lymphoproliferative disorder after high-dose immunosuppressive therapy and autologous CD34-selected hematopoietic stem cell transplantation for severe autoimmune diseases.

    PubMed

    Nash, Richard A; Dansey, Roger; Storek, Jan; Georges, George E; Bowen, James D; Holmberg, Leona A; Kraft, George H; Mayes, Maureen D; McDonagh, Kevin T; Chen, Chien-Shing; Dipersio, John; Lemaistre, C Fred; Pavletic, Steven; Sullivan, Keith M; Sunderhaus, Julie; Furst, Daniel E; McSweeney, Peter A

    2003-09-01

    High-dose immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) is currently being evaluated for the control of severe autoimmune diseases. The addition of antithymocyte globulin (ATG) to high-dose chemoradiotherapy in the high-dose immunosuppressive therapy regimen and CD34 selection of the autologous graft may induce a higher degree of immunosuppression compared with conventional autologous HSCT for malignant diseases. Patients may be at higher risk of transplant-related complications secondary to the immunosuppressed state, including Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disorder (PTLD), but this is an unusual complication after autologous HSCT. Fifty-six patients (median age, 42 years; range, 23-61 years) with either multiple sclerosis (n = 26) or systemic sclerosis (n = 30) have been treated. The median follow-up has been 24 months (range, 2-60 months). Two patients (multiple sclerosis, n = 1; systemic sclerosis, n = 1) had significant reactivations of herpesvirus infections early after HSCT and then developed aggressive EBV-PTLD and died on days +53 and +64. Multiorgan clonal B-cell infiltrates that were EBV positive by molecular studies or immunohistology were identified at both autopsies. Both patients had positive screening skin tests for equine ATG (Atgam) and had been converted to rabbit ATG (Thymoglobulin) from the first dose. Of the other 54 patients, 2 of whom had partial courses of rabbit ATG because of a reaction to the intravenous infusion of equine ATG, only 1 patient had a significant clinical reactivation of a herpesvirus infection (herpes simplex virus 2) early after HSCT, and none developed EBV-PTLD. The T-cell count in the peripheral blood on day 28 was 0/microL in all 4 patients who received rabbit ATG; this was significantly less than in patients who received equine ATG (median, 174/microL; P =.001; Mann-Whitney ranked sum test). Although the numbers are limited

  16. The Use of Immunosuppressant Therapy for Multiple Sclerosis in Italy: A Multicenter Retroprospective Study

    PubMed Central

    D’Amico, Emanuele; Leone, Carmela; Graziano, Giusi; Amato, Maria Pia; Bergamaschi, Roberto; Cavalla, Paola; Coniglio, Gabriella; Di Battista, Giancarlo; Ferrò, Maria Teresa; Granella, Franco; Granieri, Enrico; Lugaresi, Alessandra; Lus, Giacomo; Millefiorini, Enrico; Pozzilli, Carlo; Tedeschi, Gioacchino; Zappia, Mario; Comi, Giancarlo; Trojano, Maria; Lepore, Vito; Patti, Francesco

    2016-01-01

    Introduction Immunosuppressive agents (ISA) have been used in multiple sclerosis (MS) for decades, frequently as off label licensed therapies. Given the new MS treatment landscape, what place do ISA have in combating MS? Methods We conducted a retrospective multicentre study to investigate the frequency of ISA prescription in 17 Italian MS centres, and to describe the clinical factors related to ISA use. Results Out of 6,447 MS patients, 2,034 (31.6%) were treated with ISA, with Azathioprine being the most frequently used ISA overall. MS patients treated with ISA alone were more frequently affected by the progressive course (both primary and secondary) of the disease (RRR 5.82, 95% CI 4.14–8.16, p<0.0001), had higher EDSS (RRR 3.69, 95% CI 2.61–5.21, p<0.0001), higher assignment age (RRR 1.04, 95% CI 1.03–1.06, p<0.0001) than patients treated with only disease modifying drugs (DMDs). Conclusions Progressive course, higher EDSS, higher assignment age were the strongest predictors of ISA prescription and use in our population. PMID:27348606

  17. Myelodysplastic syndrome evolving from aplastic anemia treated with immunosuppressive therapy: efficacy of hematopoietic stem cell transplantation

    PubMed Central

    Kim, Sung-Yong; Le Rademacher, Jennifer; Antin, Joseph H.; Anderlini, Paolo; Ayas, Mouhab; Battiwalla, Minoo; Carreras, Jeanette; Kurtzberg, Joanne; Nakamura, Ryotaro; Eapen, Mary; Deeg, H. Joachim

    2014-01-01

    A proportion of patients with aplastic anemia who are treated with immunosuppressive therapy develop clonal hematologic disorders, including post-aplastic anemia myelodysplastic syndrome. Many will proceed to allogeneic hematopoietic stem cell transplantation. We identified 123 patients with post-aplastic anemia myelodysplastic syndrome who from 1991 through 2011 underwent allogeneic hematopoietic stem cell transplantation, and in a matched-pair analysis compared outcome to that in 393 patients with de novo myelodysplastic syndrome. There was no difference in overall survival. There were no significant differences with regard to 5-year probabilities of relapse, non-relapse mortality, relapse-free survival and overall survival; these were 14%, 40%, 46% and 49% for post-aplastic anemia myelodysplastic syndrome, and 20%, 33%, 47% and 49% for de novo myelodysplastic syndrome, respectively. In multivariate analysis, relapse (hazard ratio 0.71; P=0.18), non-relapse mortality (hazard ratio 1.28; P=0.18), relapse-free survival (hazard ratio 0.97; P=0.80) and overall survival (hazard ratio 1.02; P=0.88) of post-aplastic anemia myelodysplastic syndrome were similar to those of patients with de novo myelodysplastic syndrome. Cytogenetic risk was independently associated with overall survival in both groups. Thus, transplant success in patients with post-aplastic anemia myelodysplastic syndrome was similar to that in patients with de novo myelodysplastic syndrome, and cytogenetics was the only significant prognostic factor for post-aplastic anemia myelodysplastic syndrome patients. PMID:25107891

  18. Myelodysplastic syndrome evolving from aplastic anemia treated with immunosuppressive therapy: efficacy of hematopoietic stem cell transplantation.

    PubMed

    Kim, Sung-Yong; Le Rademacher, Jennifer; Antin, Joseph H; Anderlini, Paolo; Ayas, Mouhab; Battiwalla, Minoo; Carreras, Jeanette; Kurtzberg, Joanne; Nakamura, Ryotaro; Eapen, Mary; Deeg, H Joachim

    2014-12-01

    A proportion of patients with aplastic anemia who are treated with immunosuppressive therapy develop clonal hematologic disorders, including post-aplastic anemia myelodysplastic syndrome. Many will proceed to allogeneic hematopoietic stem cell transplantation. We identified 123 patients with post-aplastic anemia myelodysplastic syndrome who from 1991 through 2011 underwent allogeneic hematopoietic stem cell transplantation, and in a matched-pair analysis compared outcome to that in 393 patients with de novo myelodysplastic syndrome. There was no difference in overall survival. There were no significant differences with regard to 5-year probabilities of relapse, non-relapse mortality, relapse-free survival and overall survival; these were 14%, 40%, 46% and 49% for post-aplastic anemia myelodysplastic syndrome, and 20%, 33%, 47% and 49% for de novo myelodysplastic syndrome, respectively. In multivariate analysis, relapse (hazard ratio 0.71; P=0.18), non-relapse mortality (hazard ratio 1.28; P=0.18), relapse-free survival (hazard ratio 0.97; P=0.80) and overall survival (hazard ratio 1.02; P=0.88) of post-aplastic anemia myelodysplastic syndrome were similar to those of patients with de novo myelodysplastic syndrome. Cytogenetic risk was independently associated with overall survival in both groups. Thus, transplant success in patients with post-aplastic anemia myelodysplastic syndrome was similar to that in patients with de novo myelodysplastic syndrome, and cytogenetics was the only significant prognostic factor for post-aplastic anemia myelodysplastic syndrome patients.

  19. Immunization of Children Receiving Immunosuppressive Therapy for Cancer or Hematopoietic Stem Cell Transplantation

    PubMed Central

    Shetty, Avinash K.; Winter, Mary A.

    2012-01-01

    In the past 3 decades, the number of immunocompromised children has increased steadily because of dramatic improvement in survival rates in certain malignancies as a result of intensive curative treatment regimens and an increase in the number of children undergoing life-saving hematopoietic stem cell transplantation (HSCT). Children receiving immunosuppressive therapy for cancer, as well as HSCT recipients, will benefit from vaccination but warrant close evaluation for a variety of reasons, such as the risk of developing severe infections, serious adverse events following certain vaccines, and decreased vaccine efficacy caused by poor immune response to vaccination. Various professional organizations have published vaccination guidelines for immunocompromised patients. Given their heterogeneity, recommendations for the immunization of immunocompromised patients may not be universally applicable. The safety of many commonly used vaccines has not been established in immunocompromised children. In addition, no large-scale vaccine studies have evaluated the clinical outcome of disease prevention in this population. All killed vaccines are generally safe, while live vaccines may be administered to immunocompromised children in select circumstances, depending on the degree of altered immunocompetence and the underlying primary condition. Healthcare providers should be knowledgeable about the indications, contraindications, and precautions for vaccine administration in immunocompromised patients. To protect immunocompromised patients, all family, household contacts, and healthcare workers should also be immunized with all routinely recommended vaccines. Pediatricians play a crucial role in identifying and effectively communicating the risks and benefits of vaccines to immunocompromised patients and their parents. PMID:23049460

  20. A simple method to predict response to immunosuppressive therapy in patients with myelodysplastic syndrome.

    PubMed

    Saunthararajah, Yogen; Nakamura, Ryotaro; Wesley, Robert; Wang, Qiong J; Barrett, A John

    2003-10-15

    Immunosuppression with antithymocyte globulin (ATG) or cyclosporine (CSA) can be used to treat the cytopenia associated with myelodysplastic syndrome (MDS). Previously, we identified HLA-DR15, younger age, and shorter duration of red cell transfusion dependence as pretreatment variables that correlate significantly with a response. Using these pretreatment variables we have devised a simple method to prospectively identify patients with low or high probabilities of response to immunosuppression. The ability of this system to predict response was confirmed in a separate cohort of 23 patients with MDS treated with immunosuppression.

  1. Temozolomide therapy in patients with aggressive pituitary adenomas or carcinomas.

    PubMed

    Losa, Marco; Bogazzi, Fausto; Cannavo, Salvo; Ceccato, Filippo; Curtò, Lorenzo; De Marinis, Laura; Iacovazzo, Donato; Lombardi, Giuseppe; Mantovani, Giovanna; Mazza, Elena; Minniti, Giuseppe; Nizzoli, Maurizio; Reni, Michele; Scaroni, Carla

    2016-02-01

    Temozolomide is effective in some patients with progressive pituitary adenoma or carcinoma. We report a survey study of Italian patients treated with Temozolomide because of aggressive pituitary adenoma or carcinoma resistant to standard therapies. Italian endocrinologists were surveyed and asked to participate into the study. A questionnaire was sent to all those who agreed and had used Temozolomide in at least one patient with pituitary tumor. Database was closed in December 2013. A literature review was also performed. Thirty-one patients were included into the analysis. Mean age at start of Temozolomide treatment was 58.3 ± 1.9 years (± standard error). Six of the 31 (19.4%) Italian patients had a pituitary carcinoma. Twenty-five patients (80.6%) had disease control during Temozolomide treatment, while 6 patients (19.4%) had disease progression. Median follow-up after beginning Temozolomide was 43 months. Thirteen patients had tumor growth after stopping Temozolomide. The 2-year progression-free survival was 47.7% (95% CI 29.5-65.9%), while the 2-year disease control duration was 59.1% (95% CI 39.1-79.1%). Eleven patients died of progressive disease and other two patients of unrelated causes. The 2-year and 4-year overall survival rates were 83.9% (95% CI 70.7-97.1%) and 59.6% (95% CI 40.0-79.2%), respectively. Temozolomide is an additional effective therapeutic option for the treatment of aggressive pituitary tumors. The drug is well tolerated and causes few severe adverse effects. Recurrence of the tumor can occur after an initial positive response and usually portends a grim outcome.

  2. Chronic Hepatitis E Infection in a Persistently Immunosuppressed Patient Unable to Be Eliminated after Ribavirin Therapy

    PubMed Central

    Miyoshi, Masato; Kakinuma, Sei; Tanabe, Yoko; Ishii, Koji; Li, Tian-Cheng; Wakita, Takaji; Tsuura, Yukio; Watanabe, Hideki; Asahina, Yasuhiro; Watanabe, Mamoru; Ikeda, Takaaki

    2016-01-01

    Recent case reports have shown that hepatitis E virus (HEV) infection can cause chronic hepatitis in immunosuppressed or immunocompromised patients. A 37-year-old woman suffered from prolonged elevation of aminotransferases after chemotherapy for Burkitt's lymphoma and was diagnosed with chronic hepatitis E due to a transfusion during chemotherapy. After an 8-month administration of ribavirin, complete HEV clearance was not achieved, likely due to prolonged hypogammaglobulinemia. This case indicates that HEV infection should be ruled out during liver dysfunction in immunosuppressed or immunocompromised patients and suggests that an alternative therapeutic strategy for such patients will be needed. PMID:27725541

  3. Tonsillar Kaposi sarcoma in a patient with membranous glomerulonephritis on immunosuppressive therapy.

    PubMed

    Al-Brahim, Nabeel; Zaki, Ashraf H; El-Merhi, Khaled; Ahmad, Mahmoud S

    2013-07-01

    Kaposi sarcoma is a malignant vascular neoplasm uncommonly seen in immunosuppressed patients. Herein we report an unusual case of tonsillar Kaposi sarcoma in a patient with membranous glomerulonephritis treated with prednisolone and cyclosporine. The patient presented after 10 months of starting the treatment with a tonsillar mass. Histological examination was typical of monomorphic spindle cell proliferation with slit-like vascular channels. The tumor cells expressed CD34, D2-40 and positive nuclear stain for HHV-8. Kaposi sarcoma is associated with immunosuppression and rarely occurs in the tonsil. Clinicians should be aware of this rare presentation of Kaposi sarcoma.

  4. Immunosuppressive Therapy and Bone Marrow Transplantation for Aplastic Anaemia--The CMC Experience.

    PubMed

    George, Biju; Mathews, Vikram; Viswabandya, Auro; Abraham, Aby; Ganapule, Abhijeet; Fouzia, N A; Korula, Anu; Lakshmi, Kavitha N; Chandy, Mammen; Srivastava, Alok

    2015-03-01

    This is a single centre experience on the use of immunosuppressive therapy (IST) and stem cell transplantation (SCT) in patients with aplastic anaemia. Between 1985 and December 2013, 530 patients underwent IST while 214 underwent allogeneic SCT. Overall response rate with the use of IST was 58% with higher responses seen in adults (65.1%) compared to children (35.8%) [p = 0.001]. At a median follow up of 34 months (range: 1 - 264), 5 year KM estimates for OS for the entire group is 68.2 ± 2.2%. Loss of response or relapse was seen in 27 responders while clonal evolution to PNH was seen in 8 patients and transformation to MDS or AML was seen in 3. The 5 yr OS for children (45.7 ± 4.7%) was significantly lower than the OS of age groups 16-30 (75.6 ± 3.6%), 31-50 years (76.2 ± 4.2%) and > 50 years (73.0 ±4.2%) (p = 0.0001). SCT was performed in 214 patients with engraftment seen in 91%. The incidence of grade II-IV acute graft versus host disease (GVHD) was 38.4% with grade III-IV GVHD in 11.7%. Chronic GVHD was seen in 47.5% of evaluable patients with majority (73%) being limited chronic GVHD. At a median follow up of 32 months (range: 1 - 244), the 5 year KM estimates of OS for the entire cohort is 64.8 ± 3.3%); The 5 yr OS was significantly higher with the use of Flu/Cy (5 yr OS of 73.8 ± 3.6%) compared to Cy/ATG (5 yr OS of 44.4 ± 9.6%) or Flu/Bu conditioning (5 yr OS of 52.4 ± 8.9%) [p = 0.001]. Imp: SCT and IST offer good response rates and survival in Indian patients with AA except in children receiving IST.

  5. Immunosuppressive Myeloid Cells' Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy.

    PubMed

    Kamran, Neha; Kadiyala, Padma; Saxena, Meghna; Candolfi, Marianela; Li, Youping; Moreno-Ayala, Mariela A; Raja, Nicholas; Shah, Diana; Lowenstein, Pedro R; Castro, Maria G

    2017-01-04

    Survival of glioma (GBM) patients treated with the current standard of care remains dismal. Immunotherapeutic approaches that harness the cytotoxic and memory potential of the host immune system have shown great benefit in other cancers. GBMs have developed multiple strategies, including the accumulation of myeloid-derived suppressor cells (MDSCs) to induce immunosuppression. It is therefore imperative to develop multipronged approaches when aiming to generate a robust anti-tumor immune response. Herein, we tested whether combining MDSC depletion or checkpoint blockade would augment the efficacy of immune-stimulatory herpes simplex type-I thymidine kinase (TK) plus Fms-like tyrosine kinase ligand (Flt3L)-mediated immune stimulatory gene therapy. Our results show that MDSCs constitute >40% of the tumor-infiltrating immune cells. These cells express IL-4Rα, inducible nitric oxide synthase (iNOS), arginase, programmed death ligand 1 (PDL1), and CD80, molecules that are critically involved in antigen-specific T cell suppression. Depletion of MDSCs strongly enhanced the TK/Flt3L gene therapy-induced tumor-specific CD8 T cell response, which lead to increased median survival and percentage of long-term survivors. Also, combining PDL1 or CTLA-4 immune checkpoint blockade greatly improved the efficacy of TK/Flt3L gene therapy. Our results, therefore, indicate that blocking MDSC-mediated immunosuppression holds great promise for increasing the efficacy of gene therapy-mediated immunotherapies for GBM.

  6. Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model.

    PubMed Central

    Jones-Hughes, Tracey; Snowsill, Tristan; Haasova, Marcela; Coelho, Helen; Crathorne, Louise; Cooper, Chris; Mujica-Mota, Ruben; Peters, Jaime; Varley-Campbell, Jo; Huxley, Nicola; Moore, Jason; Allwood, Matt; Lowe, Jenny; Hyde, Chris; Hoyle, Martin; Bond, Mary; Anderson, Rob

    2016-01-01

    BACKGROUND End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation, followed by immunosuppressive therapy (induction and maintenance therapy) to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES To review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect(®), Novartis Pharmaceuticals UK Ltd) and rabbit anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin(®), Sanofi) as induction therapy, and immediate-release tacrolimus (TAC) (Adoport(®), Sandoz; Capexion(®), Mylan; Modigraf(®), Astellas Pharma; Perixis(®), Accord Healthcare; Prograf(®), Astellas Pharma; Tacni(®), Teva; Vivadex(®), Dexcel Pharma), prolonged-release tacrolimus (Advagraf(®) Astellas Pharma), belatacept (BEL) (Nulojix(®), Bristol-Myers Squibb), mycophenolate mofetil (MMF) (Arzip(®), Zentiva; CellCept(®), Roche Products; Myfenax(®), Teva), mycophenolate sodium (MPS) (Myfortic(®), Novartis Pharmaceuticals UK Ltd), sirolimus (SRL) (Rapamune(®), Pfizer) and everolimus (EVL) (Certican(®), Novartis) as maintenance therapy in adult renal transplantation. METHODS Clinical effectiveness searches were conducted until 18 November 2014 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science (via ISI), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted until 18 November 2014 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Database (via Wiley Online Library), Web of Science (via ISI

  7. Nanoparticles and direct immunosuppression

    PubMed Central

    Ngobili, Terrika A

    2016-01-01

    Targeting the immune system with nanomaterials is an intensely active area of research. Specifically, the capability to induce immunosuppression is a promising complement for drug delivery and regenerative medicine therapies. Many novel strategies for immunosuppression rely on nanoparticles as delivery vehicles for small-molecule immunosuppressive compounds. As a consequence, efforts in understanding the mechanisms in which nanoparticles directly interact with the immune system have been overshadowed. The immunological activity of nanoparticles is dependent on the physiochemical properties of the nanoparticles and its subsequent cellular internalization. As the underlying factors for these reactions are elucidated, more nanoparticles may be engineered and evaluated for inducing immunosuppression and complementing immunosuppressive drugs. This review will briefly summarize the state-of-the-art and developments in understanding how nanoparticles induce immunosuppressive responses, compare the inherent properties of nanomaterials which induce these immunological reactions, and comment on the potential for using nanomaterials to modulate and control the immune system. PMID:27229901

  8. Combination Immunosuppressive Therapy Including Rituximab for Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis in Adult-Onset Still's Disease

    PubMed Central

    Schäfer, Eva Johanna; Jung, Wolfram

    2016-01-01

    Hemophagocytic lymphopcytosis (HLH) is a life-threatening condition. It can occur either as primary form with genetic defects or secondary to other conditions, such as hematological or autoimmune diseases. Certain triggering factors can predispose individuals to the development of HLH. We report the case of a 25-year-old male patient who was diagnosed with HLH in the context of adult-onset Still's disease (AOSD) during a primary infection with Epstein-Barr virus (EBV). During therapy with anakinra and dexamethasone, he was still symptomatic with high-spiking fevers, arthralgia, and sore throat. His laboratory values showed high levels of ferritin and C-reactive protein. His condition improved after the addition of rituximab and cyclosporine to his immunosuppressive regimen with prednisolone and anakinra. This combination therapy led to a sustained clinical and serological remission of his condition. While rituximab has been used successfully for HLH in the context of EBV-associated lymphoma, its use in autoimmune diseases is uncommon. We hypothesize that the development of HLH was triggered by a primary EBV infection and that rituximab led to elimination of EBV-infected B-cells, while cyclosporine ameliorated the cytokine excess. We therefore propose that this combination immunosuppressive therapy might be successfully used in HLH occurring in the context of autoimmune diseases. PMID:28018698

  9. Immunosuppressive therapy for kidney transplantation in children and adolescents: systematic review and economic evaluation.

    PubMed Central

    Haasova, Marcela; Snowsill, Tristan; Jones-Hughes, Tracey; Crathorne, Louise; Cooper, Chris; Varley-Campbell, Jo; Mujica-Mota, Ruben; Coelho, Helen; Huxley, Nicola; Lowe, Jenny; Dudley, Jan; Marks, Stephen; Hyde, Chris; Bond, Mary; Anderson, Rob

    2016-01-01

    BACKGROUND End-stage renal disease is a long-term irreversible decline in kidney function requiring kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation followed by induction and maintenance immunosuppressive therapy to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES To systematically review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect,(®) Novartis Pharmaceuticals) and rabbit antihuman thymocyte immunoglobulin (Thymoglobuline,(®) Sanofi) as induction therapy and immediate-release tacrolimus [Adoport(®) (Sandoz); Capexion(®) (Mylan); Modigraf(®) (Astellas Pharma); Perixis(®) (Accord Healthcare); Prograf(®) (Astellas Pharma); Tacni(®) (Teva); Vivadex(®) (Dexcel Pharma)], prolonged-release tacrolimus (Advagraf,(®) Astellas Pharma); belatacept (BEL) (Nulojix,(®) Bristol-Myers Squibb), mycophenolate mofetil (MMF) [Arzip(®) (Zentiva), CellCept(®) (Roche Products), Myfenax(®) (Teva), generic MMF is manufactured by Accord Healthcare, Actavis, Arrow Pharmaceuticals, Dr Reddy's Laboratories, Mylan, Sandoz and Wockhardt], mycophenolate sodium, sirolimus (Rapamune,(®) Pfizer) and everolimus (Certican,(®) Novartis Pharmaceuticals) as maintenance therapy in children and adolescents undergoing renal transplantation. DATA SOURCES Clinical effectiveness searches were conducted to 7 January 2015 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science [via Institute for Scientific Information (ISI)], Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (HTA) (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted to 15 January 2015 using a costs or economic literature search filter in MEDLINE

  10. Serum markers for severe Clostridium difficile infection in immunosuppressed hospitalized patients.

    PubMed

    Pant, Chaitanya; Sferra, Thomas J; Ondrade, Christina; Bass, Pat F; Deshpande, Abhishek; Burton, Cary V

    2011-01-01

    Clostridium difficile infection (CDI) has emerged as the leading cause of nosocomial diarrhea in the developed world. The prompt recognition of severe CDI is essential in providing early aggressive therapy. Though previous studies have identified leukocytosis, azotemia, and hypoalbuminemia as markers to differentiate severe from non-severe CDI in the general patient population, there is little data in immunosuppressed patients. We conducted a retrospective chart review of immunosuppressed patients with CDI to identify serum markers associated with severe CDI. Twenty-nine immunosuppressed patients with CDI (nine with severe disease) were identified. Those with severe disease were older and had evidence of renal dysfunction. The white blood cell count, platelet, and albumin levels were the same in the severe and non-severe immunosuppressed CDI patients. Therefore, recognized serum markers of severe CDI are not universally useful in immunosuppressed patients. Moreover, the clinician must be aware that immunosuppressed patients can develop severe CDI while remaining leukopenic.

  11. Reinforcement Behavior Therapy by Kindergarten Teachers on Preschool Children’s Aggression: A Randomized Controlled Trial

    PubMed Central

    Yektatalab, Shahrzad; Alipour, Abdolrasool; Edraki, Mitra; Tavakoli, Pouran

    2016-01-01

    Background: Aggression is a kind of behavior that causes damage or harm to others. The prevalence of aggression is 8–20% in 3–6 years old children. The present study aimed to assess the effect of training kindergarten teachers regarding reinforcement behavior therapy on preschoolers’ aggression. Methods: In this cluster randomized control trial, 14 out of 35 kindergarten and preschool centers of Mohr city, Iran, were chosen using random cluster sampling and then randomly assigned to an intervention and a control group. All 370 kindergarten and preschool children in 14 kindergarten were assessed by preschoolers’ aggression questionnaire and 60 children who obtained a minimum aggression score of 117.48 for girls and 125.77 for boys were randomly selected. The teachers in the intervention group participated in 4 educational sessions on behavior therapy and then practiced this technique under the supervision of the researcher for two months. Preschoolers’ aggression questionnaire was computed in both intervention and control groups before and after a two-month period. Results: The results demonstrated a significant statistical difference in the total aggression score (P=0.01), verbal (P=0.02) and physical (P=0.01) aggression subscales scores in the intervention group in comparison to the control group after the intervention. But the scores of relational aggression (P=0.09) and impulsive anger (P=0.08) subscales were not statistically different in the intervention group compared to the controls. Conclusion: This study highlighted the importance of teaching reinforcement behavior therapy by kindergarten teachers in decreasing verbal and physical aggression in preschoolers. Trial Registration Number: IRCT2014042617436N1 PMID:26793733

  12. Pemphigus mouse model as a tool to evaluate various immunosuppressive therapies.

    PubMed

    Takae, Yujiro; Nishikawa, Takeji; Amagai, Masayuki

    2009-03-01

    Pemphigus vulgaris (PV) is an autoimmune bullous disease caused by immunoglobulin G (IgG) autoantibodies against desmoglein 3 (Dsg3). We have generated an active disease mouse model for PV by adoptive transfer of Dsg3(-/-) lymphocytes. In this study, we investigated the benefits and limitations of this model as a tool to evaluate various immunosuppressive therapeutic strategies. We used the following three measurements to evaluate the effects of the drugs during the time course: Dsg3 enzyme-linked immunosorbent assay scores that represent the level of production of anti-Dsg3 IgG, body weight loss that reflects the severity of oral erosions and PV score that reflects the extent of skin lesions. We examined various immunosuppressive agents currently used to treat patients with PV model mice in preventive protocol. Cyclophosphamide almost completely suppressed the production of anti-Dsg3 IgG, development of body weight loss and the appearance of the PV phenotype in contrast with the control group without the drug. Azathioprine, cyclosporin A and tacrolimus hydrate also showed suppressive effects to various degrees. However, methylprednisolone and dexamethasone failed to show significant effects in contrast to the findings reported in humans. Knowing the advantages and limitations of this model will provide an important foundation for the future evaluation and development of novel therapeutic strategies.

  13. The immunosuppressive effects of phthalocyanine photodynamic therapy in mice are mediated by CD4+ and CD8+ T cells and can be adoptively transferred to naive recipients.

    PubMed

    Yusuf, Nabiha; Katiyar, Santosh K; Elmets, Craig A

    2008-01-01

    Photodynamic therapy (PDT) is a promising treatment modality for malignant tumors but it is also immunosuppressive which may reduce its therapeutic efficacy. The purpose of our study was to elucidate the role of CD4+ and CD8+ T cells in PDT immunosuppression. Using silicon phthalocyanine 4 (Pc4) as photosensitizer, nontumor-bearing CD4 knockout (CD4-/-) mice and their wild type (WT) counterparts were subjected to Pc4-PDT in a manner identical to that used for tumor regression (1 cm spot size, 0.5 mg kg(-1) Pc4, 110 J cm(-2) light) to assess the effect of Pc4-PDT on cell-mediated immunity. There was a decrease in immunosuppression in CD4-/- mice compared with WT mice. We next examined the role of CD8+ T cells in Pc4-PDT-induced immunosuppression using CD8-/- mice following the same treatment regimen used for CD4-/- mice. Similar to CD4-/- mice, CD8-/- mice exhibited less immunosuppression than WT mice. Pc4-PDT-induced immunosuppression could be adoptively transferred with spleen cells from Pc4-PDT treated donor mice to syngenic naive recipients (P < 0.05) and was mediated primarily by T cells, although macrophages were also found to play a role. Procedures that limit PDT-induced immunosuppression but do not affect PDT-induced regression of tumors may prove superior to PDT alone in promoting long-term antitumor responses.

  14. Inhibition of Fatty Acid Oxidation Modulates Immunosuppressive Functions of Myeloid-Derived Suppressor Cells and Enhances Cancer Therapies.

    PubMed

    Hossain, Fokhrul; Al-Khami, Amir A; Wyczechowska, Dorota; Hernandez, Claudia; Zheng, Liqin; Reiss, Krzystoff; Valle, Luis Del; Trillo-Tinoco, Jimena; Maj, Tomasz; Zou, Weiping; Rodriguez, Paulo C; Ochoa, Augusto C

    2015-11-01

    Myeloid-derived suppressor cells (MDSC) promote tumor growth by inhibiting T-cell immunity and promoting malignant cell proliferation and migration. The therapeutic potential of blocking MDSC in tumors has been limited by their heterogeneity, plasticity, and resistance to various chemotherapy agents. Recent studies have highlighted the role of energy metabolic pathways in the differentiation and function of immune cells; however, the metabolic characteristics regulating MDSC remain unclear. We aimed to determine the energy metabolic pathway(s) used by MDSC, establish its impact on their immunosuppressive function, and test whether its inhibition blocks MDSC and enhances antitumor therapies. Using several murine tumor models, we found that tumor-infiltrating MDSC (T-MDSC) increased fatty acid uptake and activated fatty acid oxidation (FAO). This was accompanied by an increased mitochondrial mass, upregulation of key FAO enzymes, and increased oxygen consumption rate. Pharmacologic inhibition of FAO blocked immune inhibitory pathways and functions in T-MDSC and decreased their production of inhibitory cytokines. FAO inhibition alone significantly delayed tumor growth in a T-cell-dependent manner and enhanced the antitumor effect of adoptive T-cell therapy. Furthermore, FAO inhibition combined with low-dose chemotherapy completely inhibited T-MDSC immunosuppressive effects and induced a significant antitumor effect. Interestingly, a similar increase in fatty acid uptake and expression of FAO-related enzymes was found in human MDSC in peripheral blood and tumors. These results support the possibility of testing FAO inhibition as a novel approach to block MDSC and enhance various cancer therapies.

  15. Pneumocystis jirovecii pneumonia in non-HIV-infected patients in the era of novel immunosuppressive therapies.

    PubMed

    Tasaka, Sadatomo; Tokuda, Hitoshi

    2012-12-01

    In human immunodeficiency virus (HIV)-infected patients, Pneumocystis jirovecii pneumonia (PCP) is a well-known opportunistic infection, and its management has been established. However, PCP is an emerging threat to immunocompromised patients without HIV infection, such as those receiving novel immunosuppressive therapeutics for malignancy, organ transplantation, or connective tissue diseases. Clinical manifestations of PCP are quite different between patients with and without HIV infections. In patients without HIV infection, PCP rapidly progresses, is difficult to diagnose correctly, and causes severe respiratory failure with a poor prognosis. High-resolution computed tomography findings are different between PCP patients with HIV infection and those without. These differences in clinical and radiologic features are the result of severe or dysregulated inflammatory responses that are evoked by a relatively small number of Pneumocystis organisms in patients without HIV infection. In recent years, the usefulness of PCR and serum β-D-glucan assay for rapid and noninvasive diagnosis of PCP has been revealed. Although corticosteroid adjunctive to anti-Pneumocystis agents has been shown to be beneficial in some populations, the optimal dose and duration remain to be determined. Recent investigations revealed that Pneumocystis colonization is prevalent, and that asymptomatic carriers are at risk for developing PCP and can serve as the reservoir for the spread of Pneumocystis by person-to-person transmission. These findings suggest the need for chemoprophylaxis in immunocompromised patients without HIV infection, although its indication and duration are still controversial. Because a variety of novel immunosuppressive therapeutics have been emerging in medical practice, further innovations in the diagnosis and treatment of PCP are needed.

  16. Pneumocystis jirovecii pneumonia in non-HIV-infected patients in the era of novel immunosuppressive therapies.

    PubMed

    Tasaka, Sadatomo; Tokuda, Hitoshi

    2014-11-01

    In human immunodeficiency virus (HIV)-infected patients, Pneumocystis jirovecii pneumonia (PCP) is a well-known opportunistic infection, and its management has been established. However, PCP is an emerging threat to immunocompromised patients without HIV infection, such as those receiving novel immunosuppressive therapeutics for malignancy, organ transplantation, or connective tissue diseases. Clinical manifestations of PCP are quite different between patients with and without HIV-infections. In patients without HIV infection, PCP rapidly progresses, is difficult to diagnose correctly, and causes severe respiratory failure with a poor prognosis. High-resolution computed tomography findings are different between PCP patients with HIV infection and those without. These differences in clinical and radiologic features are the result of severe or dysregulated inflammatory responses that are evoked by a relatively small number of Pneumocystis organisms in patients without HIV infection. In recent years, the usefulness of PCR and serum β-D-glucan assay for rapid and noninvasive diagnosis of PCP has been revealed. Although corticosteroid adjunctive to anti-Pneumocystis agents has been shown to be beneficial in some populations, the optimal dose and duration remain to be determined. Recent investigations revealed that Pneumocystis colonization is prevalent, and that asymptomatic carriers are at riskfor developing PCP and can serve as the reservoir for the spread of Pneumocystis by person-to-person transmission. These findings suggest the need for chemoprophylaxis in immunocompromised patients without HIV infection, although its indication and duration are still controversial. Because a variety of novel immunosuppressive therapeutics have been emerging in medical practice, further innovations in the diagnosis and treatment of PCP are needed.

  17. Impact of Single Nucleotide Polymorphisms (SNPs) on Immunosuppressive Therapy in Lung Transplantation

    PubMed Central

    Ruiz, Jesus; Herrero, María José; Bosó, Virginia; Megías, Juan Eduardo; Hervás, David; Poveda, Jose Luis; Escrivá, Juan; Pastor, Amparo; Solé, Amparo; Aliño, Salvador Francisco

    2015-01-01

    Lung transplant patients present important variability in immunosuppressant blood concentrations during the first months after transplantation. Pharmacogenetics could explain part of this interindividual variability. We evaluated SNPs in genes that have previously shown correlations in other kinds of solid organ transplantation, namely ABCB1 and CYP3A5 genes with tacrolimus (Tac) and ABCC2, UGT1A9 and SLCO1B1 genes with mycophenolic acid (MPA), during the first six months after lung transplantation (51 patients). The genotype was correlated to the trough blood drug concentrations corrected for dose and body weight (C0/Dc). The ABCB1 variant in rs1045642 was associated with significantly higher Tac concentration, at six months post-transplantation (CT vs. CC). In the MPA analysis, CT patients in ABCC2 rs3740066 presented significantly lower blood concentrations than CC or TT, three months after transplantation. Other tendencies, confirming previously expected results, were found associated with the rest of studied SNPs. An interesting trend was recorded for the incidence of acute rejection according to NOD2/CARD15 rs2066844 (CT: 27.9%; CC: 12.5%). Relevant SNPs related to Tac and MPA in other solid organ transplants also seem to be related to the efficacy and safety of treatment in the complex setting of lung transplantation. PMID:26307985

  18. Impact of Single Nucleotide Polymorphisms (SNPs) on Immunosuppressive Therapy in Lung Transplantation.

    PubMed

    Ruiz, Jesus; Herrero, María José; Bosó, Virginia; Megías, Juan Eduardo; Hervás, David; Poveda, Jose Luis; Escrivá, Juan; Pastor, Amparo; Solé, Amparo; Aliño, Salvador Francisco

    2015-08-25

    Lung transplant patients present important variability in immunosuppressant blood concentrations during the first months after transplantation. Pharmacogenetics could explain part of this interindividual variability. We evaluated SNPs in genes that have previously shown correlations in other kinds of solid organ transplantation, namely ABCB1 and CYP3A5 genes with tacrolimus (Tac) and ABCC2, UGT1A9 and SLCO1B1 genes with mycophenolic acid (MPA), during the first six months after lung transplantation (51 patients). The genotype was correlated to the trough blood drug concentrations corrected for dose and body weight (C0/Dc). The ABCB1 variant in rs1045642 was associated with significantly higher Tac concentration, at six months post-transplantation (CT vs. CC). In the MPA analysis, CT patients in ABCC2 rs3740066 presented significantly lower blood concentrations than CC or TT, three months after transplantation. Other tendencies, confirming previously expected results, were found associated with the rest of studied SNPs. An interesting trend was recorded for the incidence of acute rejection according to NOD2/CARD15 rs2066844 (CT: 27.9%; CC: 12.5%). Relevant SNPs related to Tac and MPA in other solid organ transplants also seem to be related to the efficacy and safety of treatment in the complex setting of lung transplantation.

  19. First-line treatment for severe aplastic anemia in children: bone marrow transplantation from a matched family donor versus immunosuppressive therapy.

    PubMed

    Yoshida, Nao; Kobayashi, Ryoji; Yabe, Hiromasa; Kosaka, Yoshiyuki; Yagasaki, Hiroshi; Watanabe, Ken-Ichiro; Kudo, Kazuko; Morimoto, Akira; Ohga, Shouichi; Muramatsu, Hideki; Takahashi, Yoshiyuki; Kato, Koji; Suzuki, Ritsuro; Ohara, Akira; Kojima, Seiji

    2014-12-01

    The current treatment approach for severe aplastic anemia in children is based on studies performed in the 1980s, and updated evidence is required. We retrospectively compared the outcomes of children with acquired severe aplastic anemia who received immunosuppressive therapy within prospective trials conducted by the Japanese Childhood Aplastic Anemia Study Group or who underwent bone marrow transplantation from an HLA-matched family donor registered in the Japanese Society for Hematopoietic Cell Transplantation Registry. Between 1992 and 2009, 599 children (younger than 17 years) with severe aplastic anemia received a bone marrow transplant from an HLA-matched family donor (n=213) or immunosuppressive therapy (n=386) as first-line treatment. While the overall survival did not differ between patients treated with immunosuppressive therapy or bone marrow transplantation [88% (95% confidence interval: 86-90) versus 92% (90-94)], failure-free survival was significantly inferior in patients receiving immunosuppressive therapy than in those undergoing bone marrow transplantation [56% (54-59) versus 87% (85-90); P<0.0001]. There was no significant improvement in outcomes over the two time periods (1992-1999 versus 2000-2009). In multivariate analysis, age <10 years was identified as a favorable factor for overall survival (P=0.007), and choice of first-line immunosuppressive therapy was the only unfavorable factor for failure-free survival (P<0.0001). These support the current algorithm for treatment decisions, which recommends bone marrow transplantation when an HLA-matched family donor is available in pediatric severe aplastic anemia.

  20. [Case report of introducing MMF and steroids as an immunosuppressive therapy after living-donor liver transplantation for a patient with the diabetic nephropathy].

    PubMed

    Kuramitsu, Shotaro; Iguchi, Tomohiro; Ninomiya, Mizuki; Yamashita, Yo-ichi; Harimoto, Norifumi; Ikegami, Toru; Uchiyama, Hideaki; Yoshizumi, Tomoharu; Soejima, Yuji; Shirabe, Ken; Kawanaka, Hirofumi; Ikeda, Tetsuo; Furuta, Toshiya; Tamada, Ryuichiro; Maehara, Yoshihiko

    2014-03-01

    Calcineurin inhibitor (CNI) combined with mycophenolate mofetil (MMF) and steroid is mainly used as immunosuppressive therapy after the living-donor liver transplantation (LDLT). However, the nephrotoxicity caused by CNI remains a critical problem for patients with chronic renal failure, especially on early postoperative period. A 62-year-old woman with decompensated liver cirrhosis secondary to hepatitis B (Child-Pugh C, MELD score 11 points) and chronic renal failure due to diabetic nephropathy (Cr 1.56 mg/dl, GFR 27 ml/min/1.73 m2) experienced LDLT. During the reconstruction of hepatic vein, the supra-and infra-hepatic vena cava was totally clamped. The estimated right lobe liver graft volume was 540 g, representing 51.3% of the standard liver volume of the recipient. Because of the perioperative renal dysfunction due to diabetic nephropathy and the total clamping the vena cava which induced the congestion kidney, MMF (1500 mg/day) and steroid (250 mg/day converted into predonisolone) were mainly introduced as an immunosuppressive therapy after LDLT. The low-dose CNI, tacrolimus also induced the nephrotoxicity and was given for only a short time. Finally, according to the postoperative renal function, the low-dose CNI, cyclosporin (50 mg/day) was able to be added to the introduced immunosuppressive therapy. After having left the hospital, MMF (1500 mg/day), steroid (20 mg/day converted into predonisolone) and cyclosporin (75 mg/day) continued to be given as the immunosuppressive therapy and neither acute graft rejection nor drug-induced renal dysfunction was occurred. This is a case report of introducing with mainly MMF and steroid as an immunosuppressive therapy after LDLT for a patient with perioperative renal dysfunction.

  1. The Effects of Rm-CSF and Ril-6 Therapy on Immunosuppressed Antiorthostatically Suspended Mice

    NASA Technical Reports Server (NTRS)

    Armstong, Jason W.; Kirby-Dobbels, Kathy; Chapes, Steven K.

    1995-01-01

    Antiorthostatically suspended mice had suppressed macrophage development in both unloaded and loaded bones, indicating a systemic effect. Bone marrow cells from those mice secreted less macrophage colony-stimulating factor (M-CSF) and interleukin-6 (IL-6) than did control mice. Because M-CSF and IL-6 are important to bone marrow macrophage maturation, we formulated the hypothesis that suppressed macrophage development occurred as a result of the depressed levels of either M-CSF or IL-6. To test the hypothesis, mice were administered recombinant M-CSF or IL-6 intraperitoneally. We showed that recombinant M-CSF therapy, but not recombinant IL-6 therapy, reversed the suppressive effects of orthostatic suspension on macrophage development. These data suggest that bone marrow cells that produce M-CSF are affected by antiorthostatic suspension and may contribute to the inhibited maturation of bone marrow macrophage progenitors.

  2. The Role of Aggressive Corticosteroid Therapy in Patients With Juvenile Dermatomyositis: A Propensity Score Analysis

    PubMed Central

    Seshadri, Roopa; Feldman, Brian M.; Ilowite, Norman; Cawkwell, Gail; Pachman, Lauren M.

    2010-01-01

    Objective To compare outcomes at 36 months in patients newly diagnosed with juvenile dermatomyositis (DM) treated with aggressive versus standard therapy. Methods At diagnosis, 139 untreated juvenile DM patients were given aggressive therapy (intravenous methylprednisolone or oral prednisone 5–30 mg/kg/day; n = 76) or standard therapy (1–2 mg/kg/day; n = 63) by the treating physician. Aggressive therapy patients were more ill at diagnosis. Matching was based on the propensity for aggressive therapy because propensity scoring can reduce confounding by indication. Logistic regression of the matched data determined predictors of outcomes, controlling for clinical confounders and propensity score. Outcomes comprised Disease Activity Score (DAS) for skin and muscle, range of motion (ROM), and calcification. Results Sex, race, and age were similar between groups, and initial DAS weakness and ROM significantly predicted the therapy chosen. Based on propensity scores, 42 patients from each group were well matched. In the matched pairs, there were no significant differences in outcomes. Methotrexate use (odds ratio [OR] 3.6, 95% confidence interval [95% CI] 1.15–11.5) and duration of untreated disease (OR 1.2, 95% CI 1–1.38) were associated with ROM loss, hydroxychloroquine use (OR 11.2, 95% CI 3.7–33) and calcification (OR 6.8, 95% CI 1.8–25.4) with persistent rash, abnormal baseline lactate dehydrogenase (OR 11.2, 95% CI 1.4–92) and age at onset (OR 1.3, 95% CI 1–1.4) with weakness, and duration of untreated disease (OR 1.2, 95% CI 1–1.39) with calcification. Conclusion Using a retrospective, nonrandomized design with propensity score matching, there was little difference in efficacy outcomes between aggressive and standard therapy; however, the sickest patients were treated with aggressive therapy and were not included in the matched analysis. Comprehensive clinical studies are needed to determine therapeutic pathways to the best outcome. PMID:18576304

  3. From immunosuppression to tolerance.

    PubMed

    Adams, David H; Sanchez-Fueyo, Alberto; Samuel, Didier

    2015-04-01

    The past three decades have seen liver transplantation becoming a major therapeutic approach in the management of end-stage liver diseases. This is due to the dramatic improvement in survival after liver transplantation as a consequence of the improvement of surgical and anaesthetic techniques, of post-transplant medico-surgical management and of prevention of disease recurrence and other post-transplant complications. Improved use of post-transplant immunosuppression to prevent acute and chronic rejection is a major factor in these improved results. The liver has been shown to be more tolerogenic than other organs, and matching of donor and recipients is mainly limited to ABO blood group compatibility. However, long-term immunosuppression is required to avoid severe acute and chronic rejection and graft loss. With the current immunosuppression protocols, the risk of acute rejection requiring additional therapy is 10-40% and the risk of chronic rejection is below 5%. However, the development of histological lesions in the graft in long-term survivors suggest atypical forms of graft rejection may develop as a consequence of under-immunosuppression. The backbone of immunosuppression remains calcineurin inhibitors (CNI) mostly in association with steroids in the short-term and mycophenolate mofetil or mTOR inhibitors (everolimus). The occurrence of post-transplant complications related to the immunosuppressive therapy has led to the development of new protocols aimed at protecting renal function and preventing the development of de novo cancer and of dysmetabolic syndrome. However, there is no new class of immunosuppressive drugs in the pipeline able to replace current protocols in the near future. The aim of a full immune tolerance of the graft is rarely achieved since only 20% of selected patients can be weaned successfully off immunosuppression. In the future, immunosuppression will probably be more case oriented aiming to protect the graft from rejection and at

  4. CAR T-Cell Therapy: The Role of Physical Barriers and Immunosuppression in Lymphoma.

    PubMed

    Enblad, Gunilla; Karlsson, Hannah; Loskog, Angelica S I

    2015-08-01

    Chimeric antigen receptor (CAR) T-cells have shown remarkable results in patients with B-cell leukemia and lymphoma. However, while CAR T-cells have shown complete responses in a majority of patients with acute lymphoblastic leukemia (ALL), lymphomas are more difficult to treat. Different CAR designs and conditioning protocols seem to affect the persistence of patient responses. However, factors that determine if patients receiving the same CARs will respond or not remain obscure. In Sweden, a phase I/IIa trial using third-generation CAR T-cells is ongoing in which we intend to compare tumor biology and immunology, in each patient, to treatment response. CAR T-cell therapy is a powerful tool to add to the treatment options for this patient group but we need to perform the necessary basic research on the multifactorial mechanisms of action to give patients the best possible option of survival. Such studies are also crucial to expand the success of CAR T-cells beyond CD19+ B-cell malignancy. This review will focus on possible barriers of treating lymphoma to define factors that need to be investigated to develop the next generation of CAR T-cell therapy.

  5. New immunosuppressive agents in pediatric transplantation.

    PubMed

    Nguyen, Christina; Shapiro, Ron

    2014-01-01

    Immunosuppressive therapy in pediatrics continues to evolve. Over the past decade, newer immunosuppressive agents have been introduced into adult and pediatric transplant patients with the goal of improving patient and allograft survival. Unfortunately, large-scale randomized clinical trials are not commonly performed in children. The purpose of this review is to discuss the newer immunosuppressive agents available for induction therapy, maintenance immunosuppression, and the treatment of rejection.

  6. Immunosuppressive therapy with horse anti-thymocyte globulin and cyclosporine as treatment for fulminant aplastic anemia in children.

    PubMed

    Yagasaki, Hiroshi; Shichino, Hiroyuki; Ohara, Akira; Kobayashi, Ryoji; Yabe, Hiromasa; Ohga, Shouichi; Hamamoto, Kazuko; Ohtsuka, Yoshitoshi; Shimada, Hiroyuki; Inoue, Masami; Muramatsu, Hideki; Takahashi, Yoshiyuki; Kojima, Seiji

    2014-05-01

    Patients with severe aplastic anemia (SAA) and an absolute neutrophil count (ANC) of 0 typically have fatal outcomes. We defined fulminant AA (FAA) as ANC = 0 for at least 2 weeks prior to and after immunosuppressive therapy (IST). We analyzed the outcomes of 35 children with FAA among 288 children who enrolled in a prospective study for AA (AA-97 study). AA was classified as FAA (n = 35), very SAA (vSAA; n = 129), or SAA (n = 124). All of the children received the IST with horse anti-thymocyte globulin (ATG) and cyclosporine (CsA). A significantly lower response rate at 6 months was seen in children with FAA when compared to those with vSAA or SAA (40.0, 63.6, and 63.7 %, respectively; p = 0.027). Of 20 nonresponder patients in the FAA group, 11 were rescued by alternative donor transplantation, and 5 patients showed a late response after 6 months. Consequently, no significant difference was noted in overall survival when comparing the FAA, vSAA, and SAA groups (88.5, 95.8, and 96.8 %). These findings indicate that IST with ATG and CsA is justified as a first-line treatment for children with FAA who lack a human leukocyte antigen-matched sibling donor.

  7. Aggressive therapy improves cirrhosis in glycogen storage disease type IX.

    PubMed

    Tsilianidis, Laurie A; Fiske, Laurie M; Siegel, Sara; Lumpkin, Chris; Hoyt, Kate; Wasserstein, Melissa; Weinstein, David A

    2013-06-01

    Glycogen storage disease type IX (GSD IX) is described as a benign condition that often does not require treatment. Most patients with the disease are thought to outgrow the childhood manifestations, which include hepatomegaly, poor growth, and ketosis with or without hypoglycemia. Long term complications including fibrosis and cirrhosis have seldom been reported in the most common subtype, GSD IXα. We present two cases of children with GSD IXα who had fibrosis at the time of diagnosis in addition to the commonly reported disease manifestations. Structured therapy with frequent doses of uncooked cornstarch and protein supplementation was initiated, and both children responded with improved growth velocity, increased energy, decreased hepatomegaly and improved well-being. Additionally, radiographic features of fibrosis improved. We propose that GSD IXα is not a benign condition. Even in patients with a less severe presentation, consideration of a structured treatment regimen to improve quality of life appears warranted.

  8. De-escalating therapy in gastric aggressive lymphoma

    PubMed Central

    Cuccurullo, Rosanna; Govi, Silvia; Ferreri, Andrés JM

    2014-01-01

    The treatment of primary gastric diffuse large B-cell lymphoma (DLBCL) has changed radically over the last 10–15 years, with the abandonment of routine gastrectomy in favor of more conservative therapies. Low-level evidence suggests that consolidation radiotherapy could be avoided in patients with limited-stage DLBCL of the stomach who achieve complete remission after rituximab-CHOP combination. Small, recent prospective trials suggest that selected patients with limited-stage Helicobacter pylori (H. pylori)-positive DLBCL of the stomach and favorable prognostic factors can be managed with antibiotics alone, with excellent disease control and cure rates, keeping chemo-radiotherapy for unresponsive patients. This recommendation should equally regard patients with mucosa-associated lymphoid tissue-related or de novo DLBCL. Future studies should be focused on the establishment of reliable variables able to distinguish the best candidates for exclusive treatment with H. pylori eradication from those who need for conventional chemo-immunotherapy. PMID:25083073

  9. Immunosuppressive therapy in patients with congestive cardiomyopathy and myocardial uptake of Gallium-67

    SciTech Connect

    O'Connell, J.B.; Robinson, J.A.; Henkin, R.E.; Gunnar, R.M.

    1981-10-01

    Thirty-nine patients with idiopathic congestive cardiomyopathy underwent gallium-67 scintigraphy. Twenty had no evidence of myocardial uptake (group I) and 19 had demonstrable myocardial gallium-67 activity (group II). There was no significant difference in age, sex, duration of symptoms, antecedent viral illness, left ventricular end-diastolic pressure, pulmonary artery systolic pressure, or ejection fraction between the two groups. Fifteen patients in group II were treated with prednisone and azathioprine for a minimum of 8 months. Nine of 15 patients were clinically unchanged and gallium-67 scans remained positive (group IIa). Six patients had significant improvement and resolution of myocardial gallium-67 uptake (group IIb). The mean change in ejection fraction was +0.2% in group I, -4.8% in Group IIa, and +13.8% in group IIb. There were five deaths in group I (25% mortality), three in group IIa (33% mortality), and no deaths in group IIb. The only significant difference between patients in group IIa and those in group IIb was a greater left ventricular posterior wall thickness in group IIa patients. Twenty control patients without cardiac disease had negative gallium-67 scans. We conclude that gallium-67 myocardial scintigraphy may be a useful test for predicting the response to prednisone and azathioprine therapy.

  10. Immunosuppressive therapy in patients with congestive cardiomyopathy and myocardial uptake of gallium-67

    SciTech Connect

    O'Connell, J.B.; Robinson, J.A.; Henkin, R.E.; Gunnar, R.M.

    1981-10-01

    Thirty-nine patients with idiopathic congestive cardiomyopathy underwent gallium-67 scintigraphy. Twenty had no evidence of myocardial uptake (group I) and 19 had demonstrable myocardial gallium-67 activity (group II). There was no significant difference in age, sex, duration of symptoms, antecedent viral illness, left ventricular end-diastolic pressure, pulmonary artery systolic pressure, or ejection fraction between the two groups. Fifteen patients in group II were treated with prednisone and azathioprine for a minimum of 8 months. Nine of 15 patients were clinically unchanged and gallium-67 scans remained positive (group IIa). Six patients had significant improvement and resolution of myocardial gallium-67 uptake (group IIb). The mean change in ejection fraction was +0.2% in group I, -4.8% in Group IIa, and +13.8% in group IIb. There were five deaths in group I (25% mortality), three in group IIa (33% mortality), and no deaths in group IIb. The only significant difference between patients in group IIa and those in group IIb was a greater left ventricular posterior wall thickness in group IIa patients. Twenty control patients without cardiac disease had negative gallium-67 scans. We conclude that gallium-67 myocardial scintigraphy may be a useful test for predicting the response to prednisone and azathioprine therapy.

  11. Immunosuppressive therapy in bone marrow aplasia: the stroma functions normally to support hematopoiesis.

    PubMed

    Novitzky, N; Jacobs, P

    1995-12-01

    In aplastic anemia (AA) patients responsive to antilymphocyte globulin (ALG) therapy, abnormalities in both stroma and progenitor cell (PC) pool have been described. The relevance of each pathophysiologic defect was characterized in 16 individuals, and data were compared to results from seven normal volunteers. Bone marrow mononuclear cells were split into two fractions. Stromal layers (SL) were prepared from the first, and a CD34+ enriched population was obtained by immunomagnetic selection from the second. In cross-culture experiments, 1 x 10(4) of the latter from patients or controls were seeded on preformed SL, and adhesive PC were scored for the formation of blast colonies (CFU-Bl) on day 5 of culture. Nonadherent progenitors were recovered and quantitated in a standard clonogenic assay (CFU-GM). There were significantly fewer CD34+ cells in the AA group (median 0.65%, SD 0.39%, vs. 1.62%, SD 1.4%; p = 0.002). No morphological or cytologic differences between normal and aplastic SL were detected. Both equally supported the growth of CFU-Bl from normal progenitors (mean 117, SD 20.4, and 103.1, SD 30.4), while this value was reduced for the aplastic PC (mean 41.06, SD 42.9; p = 0.0002, exact two-tailed test). Similarly, the AA nonadherent PC had a decreased CFU-GM growth (mean 142.6, SD 104.8, vs. mean 361.7; SD 91.3), with a lower total clonogenic output (p = 0.0009). We conclude that aplastic stroma appropriately supports the growth of normal progenitors, whereas the depressed clonogenicity of the corresponsing population derived from AA is unrelated to their attachment to SL but intrinsic to the CD34+ cells, whether adherent or not.

  12. High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS)

    PubMed Central

    Nash, Richard A.; Hutton, George J.; Racke, Michael K.; Popat, Uday; Devine, Steven M.; Griffith, Linda M.; Muraro, Paolo A.; Openshaw, Harry; Sayre, Peter H.; Stüve, Olaf; Arnold, Douglas L.; Spychala, Meagan E.; McConville, Kaitlyn C.; Harris, Kristina M.; Phippard, Deborah; Georges, George E.; Wundes, Annette; Kraft, George H.; Bowen, James D.

    2016-01-01

    IMPORTANCE Most patients with relapsing-remitting (RR) multiple sclerosis (MS) who receive approved disease-modifying therapies experience breakthrough disease and accumulate neurologic disability. High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic cell transplant (HCT) may, in contrast, induce sustained remissions in early MS. OBJECTIVE To evaluate the safety, efficacy, and durability of MS disease stabilization through 3 years after HDIT/HCT. DESIGN, SETTING, AND PARTICIPANTS Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) is an ongoing, multicenter, single-arm, phase 2 clinical trial of HDIT/HCT for patients with RRMS who experienced relapses with loss of neurologic function while receiving disease-modifying therapies during the 18 months before enrolling. Participants are evaluated through 5 years after HCT. This report is a prespecified, 3-year interim analysis of the trial. Thirty-six patients with RRMS from referral centers were screened; 25 were enrolled. INTERVENTIONS Autologous peripheral blood stem cell grafts were CD34+ selected; the participants then received high-dose treatment with carmustine, etoposide, cytarabine, and melphalan as well as rabbit antithymocyte globulin before autologous HCT. MAIN OUTCOMES AND MEASURES The primary end point of HALT-MS is event-free survival defined as survival without death or disease activity from any one of the following outcomes: (1) confirmed loss of neurologic function, (2) clinical relapse, or (3) new lesions observed on magnetic resonance imaging. Toxic effects are reported using National Cancer Institute Common Terminology Criteria for Adverse Events. RESULTS Grafts were collected from 25 patients, and 24 of these individuals received HDIT/HCT. The median follow-up period was 186 weeks (interquartile range, 176–250) weeks). Overall event-free survival was 78.4% (90% CI, 60.1%–89.0%) at 3 years. Progression-free survival and clinical relapse

  13. Teratogenesis and immunosuppressive treatment.

    PubMed

    Danesi, R; Del Tacca, M

    2004-04-01

    Despite the potential risks to the mother and fetus caused by immunosuppressive drugs, uneventful pregnancies are now frequent among transplant recipients. Although there is no apparent increase in the type or incidence of malformations in the newborns or evidence of graft dysfunction, pregnancy-related complications, including premature termination and low birth weight, may be more frequent. To prevent graft rejection due to the increased immunologic reactivity of the transplant recipient during pregnancy, it is reasonable to wait 2 years after transplantation before conception, to have stable graft function and to be on low drug doses for maintenance immunosuppression. Among the immunosuppressive agents, corticosteroids may induce a number of treatment-related complications, including diabetes and osteoporosis; however, the incidence of fetal malformations during corticosteroid treatment is about 3.5%, a value close to that of the general population. Among immunosuppressive antibodies, no evidence of developmental toxicity has been demonstrated with basiliximab. On the contrary, some concerns have been raised about azathioprine, since its use has been associated with fetal abnormalities in animals; however, clinical data so far have indicated only a small teratogenic risk. Therefore, immunosuppressive therapy with selected drugs and antibodies does not apparently increase the risk of birth defects and may be continued in pregnancy. Finally, although breast-feeding is not recommended, because of drug transfer into maternal milk, the available clinical data do not support this limitation because of the low amount of drug absorbed by the infant and the absence of clinical toxicity in published case reports.

  14. Maintenance electroconvulsive therapy for aggression and self-injurious behavior in two adolescents with autism and catatonia.

    PubMed

    Haq, Aazaz U; Ghaziuddin, Neera

    2014-01-01

    Frequent aggression toward others and repetitive self-injurious behaviors (SIB) can be features of catatonia in patients with autism. Similar to catatonia secondary to other etiologies, catatonia associated with autism responds well to treatment with benzodiazepines and/or electroconvulsive therapy (ECT). The authors report here on two adolescent patients with autism who presented with severe aggression, one of whom also engaged in repetitive SIB. With ongoing treatment with maintenance ECT, dramatic reduction in aggression and SIB were noted, allowing both patients a reasonable quality of life in their own homes. Attempts to taper off ECT coincided with return of aggression symptoms, although not SIB.

  15. Clinical Lessons to Be Learned from Patients Developing Chronic Myeloid Leukemia While on Immunosuppressive Therapy after Solid Organ Transplantation: Yet Another Case after Orthotopic Heart Transplantation

    PubMed Central

    Oberender, Christian; Kleeberg, Lorenz; Nienhues, Nicola; Dörken, Bernd; Riess, Hanno

    2014-01-01

    Chronic myeloid leukemia developing after transplantation of solid organs and concomitant immunosuppression is a rare but still significant clinical phenomenon. We here describe an additional case of a 62-year-old male patient developing CML after orthotopic heart transplantation and medication with cyclosporine A, mofetil-mycophenolate, and steroids. Initial antileukemic therapy was imatinib at a standard dose and within 15 months of therapy a complete cytogenetic response was noted. In this report we discuss the clinical implications of these rare but biologically important cases. PMID:25478254

  16. Dexa-BEAM as salvage therapy in patients with primary refractory aggressive non-Hodgkin lymphoma.

    PubMed

    Atta, Johannes; Chow, Kai U; Weidmann, Eckhart; Mitrou, Paris S; Hoelzer, Dieter; Martin, Hans

    2007-02-01

    Although aggressive NHL in relapse after remission can still be cured by second-line treatment followed by high-dose therapy and autologous stem cell transplantation, the long-term prognosis of patients who fail to obtain remission after first-line therapy remains extremely poor. We retrospectively evaluated a series of 29 consecutive patients with primary refractory high-grade NHL who were treated with Dexa-BEAM (DB) as uniform salvage therapy at a single institution. Twenty-nine patients with aggressive NHL primary refractory to CHOP or CHOP-like induction therapy with a median age of 47 (range, 22 - 64) years received 1 - 2 cycles of DB and were candidates for subsequent autologous stem cell (PBSC) mobilization and transplantation (PBSCT). Follow-up of all patients was updated in March 2004. Eight of 29 patients (28%) responded to one cycle of DB (1 complete/7 partial remissions); 2 of whom are alive after PBSCT (1 autologous/1 matched unrelated donor), 1 patient died after autologous PBSCT. Reasons for failure to proceed to high-dose therapy in spite of response to DB were recurrent progressive disease (n = 2), septicemia (n = 1), and allogeneic transplant-related mortality after mobilization failure to DB (n = 2). Twenty-one patients failed to respond to DB and died of progressive disease. Overall survival was 7% after 41 months. We conclude that Dexa-BEAM salvage therapy is not effective in patients with truly primary refractory high-grade NHL. The efficiency of rituximab combined with Dexa-BEAM or novel chemotherapeutic strategies needs to be established.

  17. Peripheral Nerve Society Guideline on the classification, diagnosis, investigation, and immunosuppressive therapy of non-systemic vasculitic neuropathy: executive summary.

    PubMed

    Collins, Michael P; Dyck, P James B; Gronseth, Gary S; Guillevin, Loïc; Hadden, Robert D M; Heuss, Dieter; Léger, Jean-Marc; Notermans, N C; Pollard, John D; Said, Gérard; Sobue, Gen; Vrancken, A F J E; Kissel, John T

    2010-09-01

    -demyelinating electrodiagnostic features (Good Practice Points from class II/III evidence). Proposed exclusionary criteria for NSVN--favoring the alternate diagnosis of systemic vasculitic neuropathy--were clinicopathologic evidence of other-organ involvement; anti-neutrophil cytoplasmic antibody (ANCAs); cryoglobulins; sedimentation rate ≥100 mm/h; and medical condition/drug predisposing to systemic vasculitis (Good Practice Points supported by class III evidence). Three class III studies on treatment of NSVN were identified, which were insufficient to permit a level C recommendation. Therefore, the group reviewed the literature on treatment of primary small-to-medium vessel systemic vasculitides prior to deriving Good Practice Points on treatment of NSVN. Principal treatment recommendations were: (1) corticosteroid (CS) monotherapy for at least 6 months is considered first-line; (2) combination therapy should be used for rapidly progressive NSVN and patients who progress on CS monotherapy; (3) immunosuppressive options include cyclophosphamide, azathioprine, and methotrexate; (4) cyclophosphamide is indicated for severe neuropathies, generally administered in IV pulses to reduce cumulative dose and side effects; (5) in patients achieving clinical remission with combination therapy, maintenance therapy should be continued for 18-24 months with azathioprine or methotrexate; and (6) clinical trials to address all aspects of treatment are needed.

  18. Successful surgical drainage and aggressive medical therapy in a preterm neonate with Bacillus cereus meningitis.

    PubMed

    Drazin, Doniel; Lehman, Deborah; Danielpour, Moise

    2010-01-01

    Bacillus cereus meningitis is a rare disease with a very high mortality rate in neonates. The authors present the rare case of a premature infant with B. cereus bacteremia and subsequent intracranial abscesses. In addition to aggressive medical therapy, surgical drainage was performed via a left frontal mini-craniotomy. At 15 months of age, the patient had mild developmental delay, cortical blindness, and sensorineural hearing loss. The clinical case is described and difficulties in the management of B. cereus meningoencephalitis in infants are discussed.

  19. A Rapid Biochemical and Radiological Response to the Concomitant Therapy with Temozolomide and Radiotherapy in an Aggressive ACTH Pituitary Adenoma.

    PubMed

    Misir Krpan, Ana; Dusek, Tina; Rakusic, Zoran; Solak, Mirsala; Kraljevic, Ivana; Bisof, Vesna; Ozretic, David; Kastelan, Darko

    2017-01-01

    Background and Importance. In the last eight years temozolomide (TMZ) has been used as the last-line treatment modality for aggressive pituitary tumors to be applied after the failure of surgery, medical therapy, and radiotherapy. The objective was to achieve a rapid control of tumor growth and hormone normalization with concurrent chemoradiotherapy in a patient with very aggressive ACTH pituitary adenoma. Clinical Presentation. We describe a patient with an aggressive ACTH-producing adenoma treated with concurrent temozolomide and radiotherapy. The patient suffered from an aggressive ACTH adenoma resistant to surgical and medical treatment. After two months of concurrent temozolomide and radiotherapy, cortisol normalization and significant tumor shrinkage were observed. After 22 months of follow-up, there is still no evidence of tumor recurrence. Conclusion. Concurrent treatment with temozolomide and irradiation appears to be highly effective in the achievement of the tumor volume control as well as in the control of ACTH secretion in aggressive ACTH adenoma.

  20. A Rapid Biochemical and Radiological Response to the Concomitant Therapy with Temozolomide and Radiotherapy in an Aggressive ACTH Pituitary Adenoma

    PubMed Central

    2017-01-01

    Background and Importance. In the last eight years temozolomide (TMZ) has been used as the last-line treatment modality for aggressive pituitary tumors to be applied after the failure of surgery, medical therapy, and radiotherapy. The objective was to achieve a rapid control of tumor growth and hormone normalization with concurrent chemoradiotherapy in a patient with very aggressive ACTH pituitary adenoma. Clinical Presentation. We describe a patient with an aggressive ACTH-producing adenoma treated with concurrent temozolomide and radiotherapy. The patient suffered from an aggressive ACTH adenoma resistant to surgical and medical treatment. After two months of concurrent temozolomide and radiotherapy, cortisol normalization and significant tumor shrinkage were observed. After 22 months of follow-up, there is still no evidence of tumor recurrence. Conclusion. Concurrent treatment with temozolomide and irradiation appears to be highly effective in the achievement of the tumor volume control as well as in the control of ACTH secretion in aggressive ACTH adenoma. PMID:28357143

  1. Intensive immunosuppression in multiple sclerosis.

    PubMed

    Zaffaroni, M; Ghezzi, A; Comi, G

    2006-03-01

    Immunosuppressive drugs have been used out of label in multiple sclerosis (MS) for over 30 years and around 10% of patients are actually under immunosuppressive treatment. The rationale for immunosuppression in MS lies in the hypothesis that MS is an inflammatory immune-mediated disease that can take advantage of strong anti-inflammatory activity. Azathioprine, methotrexate, cyclophosphamide and mitoxantrone are the most utilised agents, but only the latter has been approved for clinically active MS. Many of them are safe in combination with interferon-beta and are under investigation in controlled trials. Plasma exchange is limited to catastrophic attacks in refractory MS whilst bone marrow transplantation is considered in patients with an extremely severe, active disease as the final option in escalation therapy. Although immunosuppressants are best effective in induction therapy, their use is limited by toxicity and potential long-term risk.

  2. Targeted therapy in uterine serous carcinoma: an aggressive variant of endometrial cancer.

    PubMed

    Black, Jonathan D; English, Diana P; Roque, Dana M; Santin, Alessandro D

    2014-01-01

    Uterine serous carcinoma (USC) is a highly aggressive variant of endometrial cancer. Although it only represents less than 10% of all cases, it accounts for a disproportionate number of deaths from endometrial cancer. Comprehensive surgical staging followed by carboplatin and paclitaxel chemotherapy represents the mainstay of USC therapy. Vaginal cuff brachytherapy is also of potential benefit in USC. Recent whole-exome sequencing studies have demonstrated gain of function of the HER2/NEU gene, as well as driver mutations in the PIK3CA/AKT/mTOR and cyclin E/FBXW7 oncogenic pathways in a large number of USCs. These results emphasize the relevance of these novel therapeutic targets for biologic therapy of chemotherapy-resistant recurrent USC.

  3. Photodynamic therapy in the treatment of aggressive periodontitis: A systematic review

    PubMed Central

    Doufexi, Aikaterini-Ellisavet

    2016-01-01

    Background Aggressive periodontitis (AgP) is a severe form of periodontal diseases with rapid destruction of the supporting bone around teeth. The efficacy of PDT in suppressing periodontal pathogens may be crucial in adopting new protocols for the treatment of AgP. Thus, the aim of this systematic review was to investigate the possible role of PDT in the treatment of AgP as an adjunctive therapy or monotherapy. Material and Methods A systematic search of the literature was performed. Additionally, the references from all the selected full-text studies were searched for relevant articles. Two reviewers screened independently titles and abstracts or full text copies. Quality assessment of all the included studies was held. Results Initial screening of electronic databases yielded 418 potentially relevant publications. After screening of the titles and full-text examination, five studies were included in the systematic review. Four publications evaluated the effects of PDT adjunctive to SRP in patients with AgP: two of them compared the clinical outcomes of SRP and PDT with a control group that received therapy with SRP and antibiotics (metronidazole and amoxicillin); two publications included SRP and PDT in the test group, and SRP alone in the control group. In one study, PDT was tested as a monotherapy compared with SRP alone. Conclusions Within the limitations of this review, PDT may exhibit a beneficial role in the therapy of aggressive periodontitis after repeated applications. In the future, more methodologically sound, long-term randomized clinical trials are needed to be conducted. Key words:Photodynamic therapy, periodontitis, systematic review. PMID:26595837

  4. Immunosuppressive mechanisms in glioblastoma.

    PubMed

    Nduom, Edjah K; Weller, Michael; Heimberger, Amy B

    2015-11-01

    Despite maximal surgical and medical therapy, the treatment of glioblastoma remains a seriously vexing problem, with median survival well under 2 years and few long-term survivors. Targeted therapy has yet to produce significant advances in treatment of these lesions in spite of advanced molecular characterization of glioblastoma and glioblastoma cancer stem cells. Recently, immunotherapy has emerged as a promising mode for some of the hardest to treat tumors, including metastatic melanoma. Although immunotherapy has been evaluated in glioblastoma in the past with limited success, better understanding of the failures of these therapies could lead to more successful treatments in the future. Furthermore, there is a persistent challenge for the use of immune therapy to treat glioblastoma secondary to the existence of redundant mechanisms of tumor-mediated immune suppression. Here we will address these mechanisms of immunosuppression in glioblastoma and therapeutic approaches.

  5. Everolimus in combination with cyclosporin a as pre- and posttransplantation immunosuppressive therapy in nonmyeloablative allogeneic hematopoietic stem cell transplantation.

    PubMed

    Junghanss, Christian; Rathsack, Susanne; Wacke, Rainer; Weirich, Volker; Vogel, Heike; Drewelow, Bernd; Mueller, Sabrina; Altmann, Simone; Freund, Mathias; Lange, Sandra

    2012-07-01

    Everolimus (RAD001) is an mTOR inhibitor that has been successfully used as an immunosuppressant in solid-organ transplantation. Data in allogeneic hematopoietic stem cell transplantation (HSCT) is limited. This study aimed to investigate pharmacokinetics, safety, and efficacy of RAD001 in a canine allogeneic HSCT model. First, pharmacokinetics of RAD001 were performed in healthy dogs in order to determine the appropriate dosing. Doses of 0.25 mg RAD001 twice daily in combination with 15 mg/kg cyclosporin A (CsA) twice daily were identified as appropriate starting doses to achieve the targeted range of RAD001 (3-8 μg/L) when orally administered. Subsequently, 10 dogs were transplanted using 2 Gy total body irradiation (TBI) for conditioning and 0.25 mg RAD001 twice daily plus 15 mg/kg CsA twice daily for pre- and posttransplantation immunosuppression. Seven of the 10 transplanted dogs were maintained at the starting RAD001 dose throughout the study. For the remaining 3 dogs, dose adjustments were necessary. RAD001 accumulation over time did not occur. All dogs initially engrafted. Five dogs eventually rejected the graft (weeks 10, 10, 13, 27, and 56). Two dogs died of pneumonia (weeks 8 and 72) but were chimeric until then. Total cholesterol rose from median 4.1 mmol/L (3.5-5.7 mmol/L) before HSCT to 6.0 mmol/l (5.0-8.5 mmol/l) at day 21 after HSCT, but remained always within normal range. Changes in creatinine and triglyceride values were not observed. Long-term engraftment rates were inferior to sirolimus/CsA and mycophenolate mofetil (MMF)/CsA regimen, respectively. RAD001/CsA caused a more pronounced reduction of platelet counts to median 2 × 10(9)/L (range: 0-21 × 10(9)/L) and longer time to platelet recovery of 21 days (range: 14-24 days) compared with MMF/CsA. CsA c(2h) levels were significantly enhanced in the RAD001/CsA regimen, but c(0h) and area under the curve from 0 to 12 hours (AUC(0-12h)) values did not differ compared with an MMF

  6. Epstein-Barr virus-positive multiple myeloma developing after immunosuppressant therapy for rheumatoid arthritis: a case report and review of literature

    PubMed Central

    Sekiguchi, Yasunobu; Shimada, Asami; Ichikawa, Kunimoto; Wakabayashi, Mutsumi; Sugimoto, Keiji; Ikeda, Keigo; Sekikawa, Iwao; Tomita, Shigeki; Izumi, Hiroshi; Nakamura, Noriko; Sawada, Tomohiro; Ohta, Yasunori; Komatsu, Norio; Noguchi, Masaaki

    2015-01-01

    A 61-year-old woman was diagnosed as having rheumatoid arthritis (RA) and began treatment with salazosulfapyridine (SASP) and methotrexate (MTX) in 2008; the administration of concomitant tacrolimus (TAC) was initiated in 2010. She subsequently developed concurrent multiple myeloma (MM), immunoglobulin G (IgG)-κ type, in 2012. A portion of the tumor cells tested positive for Epstein-Barr virus-encoded small RNA (EBER). MTX treatment was discontinued in 2014, and the exacerbation of MM ensued. The patient received two cycles of bortezomib plus dexamethasone (BD) therapy and attained a complete response (CR). She then underwent an autologous peripheral blood stem cell transplantation. The Epstein-Barr (EB) virus infection arising from the increased RA disease activity and immunosuppressant medication might have influenced the development of MM in this case. Most reported patients with EB virus-positive plasmacytoma are in a state of immunosuppression, and this condition may fall within the category of other iatrogenic immunodeficiency-associated lymphoproliferative disorders. No other reports of plasmacytoma occurring in a background of RA or after TAC or MTX therapy have been made, and the present case is the first such report. PMID:25973110

  7. Immunosuppressive therapy after solid-organ transplantation: does the INTERMED identify patients at risk of poor adherence?

    PubMed Central

    Michaud, Laurent; Ludwig, Gundula; Berney, Sylvie; Rodrigues, Stéphanie; Niquille, Anne; Santschi, Valérie; Favre, Anne-Sophie; Lange, Anne-Catherine; Michels, Annemieke A.; Vrijens, Bernard; Bugnon, Olivier; Pilon, Nathalie; Pascual, Manuel; Venetz, Jean-Pierre; Stiefel, Friedrich; Schneider, Marie-Paule

    2016-01-01

    Background: Lack of adherence to medication is a trigger of graft rejection in solid-organ transplant (SOT) recipients. Objective: This exploratory study aimed to assess whether a biopsychosocial evaluation using the INTERMED instrument before transplantation could identify SOT recipients at risk of suboptimal post-transplantation adherence to immunosuppressant drugs. We hypothesized that complex patients (INTERMED>20) might have lower medication adherence than noncomplex patients (INTERMED≤20). Methods: Each patient eligible for transplantation at the University Hospital of Lausanne, Switzerland, has to undergo a pre-transplantation psychiatric evaluation. In this context the patient was asked to participate in our study. The INTERMED was completed pre-transplantation, and adherence to immunosuppressive medication was monitored post-transplantation by electronic monitors for 12 months. The main outcome measure was the implementation and persistence to two calcineurin inhibitors, cyclosporine and tacrolimus, according to the dichotomized INTERMED score (>20 or ≤20). Results: Among the 50 SOT recipients who completed the INTERMED, 32 entered the study. The complex (N=11) and noncomplex patients (N=21) were similar in terms of age, sex and transplanted organ. Implementation was 94.2% in noncomplex patients versus 87.8% in complex patients (non-significant p-value). Five patients were lost to follow-up: one was non-persistent, and four refused electronic monitoring. Of the four patients who refused monitoring, two were complex and withdrew early, and two were noncomplex and withdrew later in the study. Conclusion: Patients identified as complex pre-transplant by the INTERMED tended to deviate from their immunosuppressant regimen, but the findings were not statistically significant. Larger studies are needed to evaluate this association further, as well as the appropriateness of using a nonspecific biopsychosocial instrument such as INTERMED in highly morbid

  8. Unusually Aggressive Primary Testicular Diffuse Large B Cell Lymphoma with Post Therapy Extensive Metastasis

    PubMed Central

    Goel, Shalini; Mohapatra, Ishani; Gajendra, Smeeta; Gupta, Sunil

    2016-01-01

    Primary Testicular Lymphoma (PTL) is a rare intermediate to high grade tumour, diffuse large cell being the most common type. Unlike nodal Diffuse Large B-Cell Lymphoma (DLBCL), testicular DLBCL has a less aggressive course and better prognosis. Metastasis is uncommon in testicular DLBCL. Commonly involved sites are contralateral testes, Waldeyer’s ring, skin, lung, Central Nervous System (CNS) and prostate, however the kidneys, liver, bone marrow, pleura and bones are more rarely involved. We report a case of testicular DLBCL which has metastasized to skin and bone marrow with an aggressive clinical course in a year, in-spite of combined modality of therapy given to the patient. Bone marrow infiltration is common and well documented with nodal DLBCL, however there is no published literature for simultaneous bone marrow and skin infiltration in testicular DLBCL till date. Other large studies done in the west have shown that distinct metastasis is usually common but the median progression-free survival is usually in years. This case stresses on shorter period of progression after standard treatment protocol in this part of the world, thus highlighting the need for other extensive studies to define specific treatment protocol for testicular DLBCL. PMID:27630854

  9. Novel targeted therapies in uterine serous carcinoma, an aggressive variant of endometrial cancer.

    PubMed

    Menderes, Gulden; Clark, Mitchell; Santin, Alessandro D

    2016-04-01

    Uterine serous carcinoma (USC) is a rare but aggressive subtype of endometrial cancer. Although it represents only 10% of all endometrial cancer cases, USC accounts for up to 40% of all endometrial cancer-related recurrences and subsequent deaths. With such a dismal prognosis, there is an expanding role for novel targeted approaches in the treatment of USC. Recent whole-exome sequencing studies have demonstrated gain of function of the HER2/NEU gene, as well as driver mutations in the PIK3CA/AKT/mTOR and cyclin E/FBXW7 oncogenic pathways in a large number of USCs. The results emphasize the relevance of these novel therapeutic targets for biologic therapy of USC, which will be reviewed in this article.

  10. Histoplasmosis in immunosuppressed patients.

    PubMed

    Kauffman, C A; Israel, K S; Smith, J W; White, A C; Schwarz, J; Brooks, G F

    1978-06-01

    Infection with Histoplasma capsulatum in 58 patients whose immune responses were suppressed (Immunosuppressed patients) (16 from the present series and 42 described previously) was analyzed. The most common underlying diseases were Hodgkin's disease (29 per cent), chronic lymphocytic leukemia (19 per cent) and acute lymphocytic leukemia (17 per cent). Sixty-three per cent of the patients had received cytotoxic drugs, and 57 per cent had taken corticosteroids. Widely disseminated infection occurred in 88 per cent of the patients, with predominant involvement of lungs and organs of the reticuloendothelial system. Localized pulmonary infection was present in the remaining patients. The most useful diagnostic method was bone marrow biopsy with microscopic examination for the intracellular yeast form of H. capsulatum. Biopsy of oral lesions, lung, liver and lymph node also proved diagnostically helpful. Growth of H. capsulatum in culture was frequently too slow to be beneficial in diagnosing histoplasmosis in ill patients. Serologic methods were of little diagnostic help in this population of immunosuppressed patients. The response to amphotericin B therapy was excellent (6.7 per cent mortality rate) in those patients in whom the diagnosis was established early and in whom a full course of antifungal therapy could be given. In contrast, the mortality rate in patients who received no antifungal therapy or less than 1 g of amphotericin B was 100 per cent.

  11. Low-dose 5-fluorouracil adjuvant in laser therapy for HPV lesions in immunosuppressed patients and cases of difficult control.

    PubMed

    Speck, N M G; Ribalta, J C L; Focchi, J; Costa, R R L; Kesselring, F; Freitas, V G

    2004-01-01

    The authors established a protocol for the use of 5-fluorouracil (5FU) adjuvant in lasertherapy for clinical and subclinical HPV infection in immunosuppressed patients, persistent lesions and as reinforcement treatment in cases of poor progress. Sixty-four patients were evaluated, of whom 26 were immunosuppressed, 34 presented persistent lesions and four received intravaginal reinforcement treatment with 2.5 g 5% 5FU every two weeks, or biweekly vulvar reinforcement after lasertherapy. On average, five 5FU courses were used, but in the immunossuppressed patients its use was maintained indefinitely. The rate of complete response was 66%, but the immunossuppressed patients showed less response (46.2%) when compared with the persistent lesion/reinforcement treatment group (78.9%). The responses were positive in the two groups when compared to that with no response. We deem the use of low-dose 5FU an excellent alternative in cases of difficult HPV progress, presenting a low cost and minimal side-effects.

  12. Concurrent Epstein-Barr virus associated NK/T cell lymphoma after immunosuppressive therapy for aplastic anemia: report of a case and review of literature.

    PubMed

    Yin, Guangli; Ni, Ying; Xiao, Zhengrui; He, Guangsheng; Miao, Kourong

    2015-01-01

    Aplastic anemia (AA) patients with prolonged immunosuppression have a risk of development of lymphoproliferative disorders (LPDs), especially combined with Epstein-Barr virus (EBV) infection. However, development of nature killer/T (NK/T) cell lymphoma, in a nontransplantation setting, has not been documented for AA patients with immunosuppressive therapy (IST). Herein, we described a middle-aged man, Han ethnic, who presented with swelled parotid gland after a long history of IST for AA. Fever, night sweating, weight loss had not been found. Increased heterotypic lymphocytes had been detected in the left side of parotid gland demonstrated as cCD3(+), CD56(+), GranB(+), TIA-1(+), MUM-1(+), KI-67 (50%-75%)(++), Bcl-6(-), MPO(-) by immunohistochemistry, and in-situ hybridization (ISH) indicated EBER positive. Chromosome analysis by R banding method revealed 46, XY [20]. NK/T cell lymphoma concurrent with aplastic anemia was diagnosed and a mild chemotherapy regimen including vincristine, prednisone, L-asparaginase was administered. The parotid mass was gradually regressed after the first cycle of chemotherapy. The patient discharged from the hospital voluntarily and lost the follow-up.

  13. Pilot study using tacrolimus rather than cyclosporine plus antithymocyte globulin as an immunosuppressive therapy regimen option for severe aplastic anemia in adults.

    PubMed

    Zhu, Xianmin; Guan, Jun; Xu, Jinhuan; Wei, Jia; Jiang, Lijun; Yin, Jin; Zhao, Lei; Zhang, Yicheng

    2014-09-01

    Severe aplastic anemia (SAA), which is considered to be an immune-mediated destruction of bone marrow stem cells with pancytopenia and hypoplasia, can be successfully treated with immunosuppressive therapy or hematopoietic stem cell transplantation (HSCT). Between January 2009 and December 2012, thirteen patients diagnosed with SAA were treated with tacrolimus plus rabbit antithymocyte globulin (ATG)-based immunosuppressive therapy (IST). The outcomes were then compared with our previous data for twenty-four patients administered with cyclosporine (CsA) plus rabbit ATG-based IST. All 37 cases accepted methylpredenisolone and recombinant human granulocyte colony-stimulating factor (rhG-CSF) from the first day that rabbit ATG was initiated. A total of 7 (54%) of the 13 patients in the tacrolimus group and 10 (42%) of the 24 cases in the ATG+CsA group achieved the criteria for complete response (CR); the partial response (PR) rate was 31% in the tacrolimus group and 33% in the ATG+CsA group. The median follow-up duration of the tacrolimus group and ATG+CsA group patients was 28 months and 27 months, respectively. Two patients in the tacrolimus group who were red blood cell- and platelet transfusion-dependent died, one of sepsis and the other of cerebral hemorrhage, whereas one patient died from serious infection on the 5th day after ATG was initiated in the ATG+CsA group. No clonal transformation to paroxysmal nocturnal hemoglobinuria (PNH) was observed in either group. Our data provide a possibility of using tacrolimus as part of an IST regimen for SAA in adults who have no opportunity of HSCT from human leukocyte antigen (HLA)-matched sibling donors.

  14. Postmortem Analyses Unveil the Poor Efficacy of Decontamination, Anti-Inflammatory and Immunosuppressive Therapies in Paraquat Human Intoxications

    PubMed Central

    Dinis-Oliveira, Ricardo Jorge; de Pinho, Paula Guedes; Santos, Liliana; Teixeira, Helena; Magalhães, Teresa; Santos, Agostinho; de Lourdes Bastos, Maria; Remião, Fernando; Duarte, José Alberto; Carvalho, Félix

    2009-01-01

    Background Fatalities resulting from paraquat (PQ) self-poisonings represent a major burden of this herbicide. Specific therapeutic approaches have been followed to interrupt its toxic pathway, namely decontamination measures to prevent PQ absorption and to increase its excretion from organism, as well as the administration of anti-inflammatory and immunosuppressive drugs. Until now, none of the postmortem studies resulting from human PQ poisonings have assessed the relationship of these therapeutic measures with PQ toxicokinetics and related histopathological lesions, these being the aims of the present study. Methodology/Principal Findings For that purpose, during 2008, we collected human fluids and tissues from five forensic autopsies following fatal PQ poisonings. PQ levels were measured by gas chromatography-ion trap mass spectrometry. Structural inflammatory lesions were evaluated by histological and immunohistochemistry analysis. The samples of cardiac blood, urine, gastric and duodenal wall, liver, lung, kidney, heart and diaphragm, showed quantifiable levels of PQ even at 6 days post-intoxication. Structural analysis showed diffused necrotic areas, intense macrophage activation and leukocyte infiltration in all analyzed tissues. By immunohistochemistry it was possible to observe a strong nuclear factor kappa-B (NF-κB) activation and excessive collagen deposition. Conclusions/Significance Considering the observed PQ levels in all analyzed tissues and the expressive inflammatory reaction that ultimately leads to fibrosis, we conclude that the therapeutic protocol usually performed needs to be reviewed, in order to increase the efficacy of PQ elimination from the body as well as to diminish the inflammatory process. PMID:19779613

  15. [(11)C]DAC-PET for noninvasively monitoring neuroinflammation and immunosuppressive therapy efficacy in rat experimental autoimmune encephalomyelitis model.

    PubMed

    Xie, Lin; Yamasaki, Tomoteru; Ichimaru, Naotsugu; Yui, Joji; Kawamura, Kazunori; Kumata, Katsushi; Hatori, Akiko; Nonomura, Norio; Zhang, Ming-Rong; Li, Xiao-Kang; Takahara, Shiro

    2012-03-01

    Neuroimaging measures have potential for monitoring neuroinflammation to guide treatment before the occurrence of significant functional impairment or irreversible neuronal damage in multiple sclerosis (MS). N-Benzyl-N-methyl-2-(7-[(11)C]methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl) acetamide ([(11)C]DAC), a new developed positron emission tomography (PET) probe for translocator protein 18 kDa (TSPO), has been adopted to evaluate the neuroinflammation and treatment effects of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. [(11)C]DAC-PET enabled visualization of neuroinflammation lesion of EAE by tracing TSPO expression in the spinal cords; the maximal uptake value reached in day 11 and 20 EAE rats with profound inflammatory cell infiltration compared with control, day 0 and 60 EAE rats. Biodistribution studies and in vitro autoradiography confirmed these in vivo imaging results. Doubling immunohistochemical studies showed the infiltration and expansion of CD4+ T cells and CD11b+ microglia; CD68+ macrophages were responsible for the increased TSPO levels visualized by [(11)C]DAC-PET. Furthermore, mRNA level analysis of the cytokines by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) revealed that TSPO+/CD4 T cells, TSPO+ microglia and TSPO+ macrophages in EAE spinal cords were activated and secreted multiple proinflammation cytokines to mediate inflammation lesions of EAE. EAE rats treated with an immunosuppressive agent: 2-amino-2-[2-(4-octylphenyl)ethyl] propane-1,3-diolhydrochloride (FTY720), which exhibited an absence of inflammatory cell infiltrates, displaying a faint radioactive signal compared with the high accumulation of untreated EAE rats. These results indicated that [(11)C] DAC-PET imaging is a sensitive tool for noninvasively monitoring the neuroinflammation response and evaluating therapeutic interventions in EAE.

  16. Prolactinoma ErbB receptor expression and targeted therapy for aggressive tumors.

    PubMed

    Cooper, Odelia; Mamelak, Adam; Bannykh, Serguei; Carmichael, John; Bonert, Vivien; Lim, Stephen; Cook-Wiens, Galen; Ben-Shlomo, Anat

    2014-06-01

    As ErbB signaling is a determinant of prolactin synthesis, role of ErbB receptors was tested for prolactinoma outcomes and therapy. The objective of this study was to characterize ErbB receptor expression in prolactinomas and then perform a pilot study treating resistant prolactinomas with a targeted tyrosine kinase inhibitor (TKI). Retrospective analysis of prolactinomas and pilot study for dopamine agonist resistant prolactinomas in tertiary referral center. We performed immunofluorescent staining of a tissue array of 29 resected prolactinoma tissues for EGFR, ErbB2, ErbB3, and ErbB4 correlated with clinical features. Two patients with aggressive resistant prolactinomas enrolled and completed trial. They received lapatinib 1,250 mg daily for 6 months with tumor and hormone assessments. Main outcome measures were positive tumor staining of respective ErbB receptors, therapeutic reduction of prolactin levels and tumor shrinkage. Treated PRL levels and tumor volumes were suppressed in both subjects treated with TKI. EGFR expression was positive in 82 % of adenomas, ErbB2 in 92 %, ErbB3 in 25 %, and ErbB4 in 71 %, with ErbB2 score > EGFR > ErbB4 > ErbB3. Higher ErbB3 expression was associated with optic chiasm compression (p = 0.03), suprasellar extension (p = 0.04), and carotid artery encasement (p = 0.01). Higher DA response rates were observed in tumors with higher ErbB3 expression. Prolactinoma expression of specific ErbB receptors is associated with tumor invasion, symptoms, and response to dopamine agonists. Targeting ErbB receptors may be effective therapy in patients with resistant prolactinomas.

  17. Ethanol immunosuppression in vitro

    SciTech Connect

    Kaplan, D.R.

    1986-03-01

    Ethanol in concentrations equivalent to levels achieved by the ingestion of moderate to large amounts of alcoholic beverages has been shown to inhibit mitogen and anti-CD3 stimulated human T lymphocyte proliferation. This inhibition was monophasic suggesting that ethanol affected a single limiting component of T cell proliferation. In experiments designed to test the effect of ethanol on various aspects of proliferation, it was demonstrated that ethanol inhibited the capacity of exogenously supplied interleukin 2 to stimulate proliferation of T cells that had previously acquired interleukin 2 receptors in a monophasic, dose-dependent manner. Moreover, there was no suppression of interleukin 2 production or interleukin 2 receptor acquisition. Thus, ethanol was shown to mediate immunosuppression by a mechanism specific to one component of proliferation. Additive inhibition of T cell proliferation was seen with ethanol plus cyclosporin A which inhibits interleukin 2 production. The level of inhibition with 250 ng/ml cyclosporin A alone was equivalent to the level seen with 62 ng/ml cyclosporin A plus 20 mM (94 mg%) ethanol. Ethanol also suppressed an immune effector mechanism. NK cytotoxicity was depressed in a monophasic, dose-dependent manner. Thus, ethanol might be considered as a possible adjunct in immunosuppressive therapy.

  18. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study

    PubMed Central

    McSweeney, Peter A.; Crofford, Leslie J.; Abidi, Muneer; Chen, Chien-Shing; Godwin, J. David; Gooley, Theodore A.; Holmberg, Leona; Henstorf, Gretchen; LeMaistre, C. Fred; Mayes, Maureen D.; McDonagh, Kevin T.; McLaughlin, Bernadette; Molitor, Jerry A.; Nelson, J. Lee; Shulman, Howard; Storb, Rainer; Viganego, Federico; Wener, Mark H.; Seibold, James R.; Sullivan, Keith M.; Furst, Daniel E.

    2007-01-01

    More effective therapeutic strategies are required for patients with poor-prognosis systemic sclerosis (SSc). A phase 2 single-arm study of high-dose immunosuppressive therapy (HDIT) and autologous CD34-selected hematopoietic cell transplantation (HCT) was conducted in 34 patients with diffuse cutaneous SSc. HDIT included total body irradiation (800 cGy) with lung shielding, cyclophosphamide (120 mg/kg), and equine antithymocyte globulin (90 mg/kg). Neutrophil and platelet counts were recovered by 9 (range, 7 to 13) and 11 (range, 7 to 25) days after HCT, respectively. Seventeen of 27 (63%) evaluable patients who survived at least 1 year after HDIT had sustained responses at a median follow-up of 4 (range, 1 to 8) years. There was a major improvement in skin (modified Rodnan skin score, −22.08; P < .001) and overall function (modified Health Assessment Questionnaire Disability Index, −1.03; P < .001) at final evaluation. Importantly, for the first time, biopsies confirmed a statistically significant decrease of dermal fibrosis compared with baseline (P < .001). Lung, heart, and kidney function, in general, remained clinically stable. There were 12 deaths during the study (transplantation-related, 8; SSc-related, 4). The estimated progression-free survival was 64% at 5 years. Sustained responses including a decrease in dermal fibrosis were observed exceeding those previously reported with other therapies. HDIT and autologous HCT for SSc should be evaluated in a randomized clinical trial. PMID:17452515

  19. The immunosuppressive effects of phthalocyanine photodynamic therapy in mice are mediated by CD4+ and CD8+ T cells and can be adoptively transferred to naïve recipients

    PubMed Central

    Yusuf, Nabiha; Katiyar, Santosh K; Elmets, Craig A

    2013-01-01

    Photodynamic therapy (PDT) is a promising treatment modality for malignant tumors but it is also immunosuppressive which may reduce its therapeutic efficacy. The purpose of our study was to elucidate the role of CD4+ and CD8+ T-cells in PDT immunosuppression. Using silicon phthalocyanine 4 (Pc4) as photosensitizer, non-tumor bearing CD4 knockout (CD4−/−) mice and their wild type (WT) counterparts were subjected to Pc4-PDT in a manner identical to that used for tumor regression (1 cm spot size, 0.5 mg/kg Pc4, 110 J/cm2 light) to assess the effect of Pc4-PDT on cell-mediated immunity. There was a decrease in immunosuppression in CD4−/− mice as compared to WT mice. We next examined the role of CD8+ T-cells in Pc4-PDT induced immunosuppression using CD8−/− mice following the same treatment regimen used for CD4−/− mice. Similar to CD4−/− mice, CD8−/− mice exhibited less immunosuppression than WT mice. Pc4-PDT induced immunosuppression could be adoptively transferred with spleen cells from Pc4-PDT treated donor mice to syngenic naive recipients (p<0.05) and was mediated primarily by T cells, although macrophages were also found to play a role. Procedures that limit PDT induced immunosuppression but do not affect PDT induced regression of tumors may prove superior to PDT alone in promoting long term anti-tumor responses. PMID:18208456

  20. Maintenance periodontal therapy after systemic antibiotic and regenerative therapy of generalized aggressive periodontitis. A case report with 10-year follow-up.

    PubMed

    Siqueira, Sergio Júnior; Ribeiro, Fernanda Vieira; Villalpando, Karina Teixeira; Cirano, Fabiano Ribeiro; Pimentel, Suzana Peres

    2015-05-01

    Aggressive periodontitis (AgP) is an inflammatory disease characterized by rapid attachment loss and bone destruction. This case report presents the 10-year results in a subject with generalized AgP treated by a regenerative periodontal therapeutic approach and the adjunctive use of antibiotics, following a systematic maintenance periodontal therapy. The use of enamel matrix derivatives (EMD) and adjunctive antibiotic therapy to treat AgP yielded improvements in clinical parameters and radiographic bony fill. This combined therapeutic approach following a systematic supportive periodontal therapy supports the long-term maintenance of teeth with previous advanced periodontal defects, demonstrating successful stability after 10-years follow-up. Clinical Relevance: The combined treatment protocol using EMD plus adjunctive antibiotic therapy, associated with a systematic supportive periodontal therapy, benefits the long-term maintenance of teeth with previous advanced periodontal defects in subjects presenting AgP, supporting this approach as an alternative in the treatment of AgP.

  1. [Systemic and neurological uses of immunosuppressive agents].

    PubMed

    Schnider, C; Seebach, J D; Ribi, C; Spertini, F

    2013-05-01

    Involvement of the central or peripheral nervous system, frequently present in systemic inflammatory immune disorders, has to be considered a severe threat and requires aggressive immunosuppressive treatment to achieve rapid remission. This is usually obtained with high-dose systemic corticosteroids combined with cyclophosphamide. Once remission is obtained, immunosuppressive agents with a more favorable safety profile are needed to exert a corticosteroid-sparing effect and minimize adverse events. New therapeutic approaches are currently developed to treat autoimmune diseases, mostly linked to the definition of new indications for biological agents such as TNF-alpha antagonists and rituximab.

  2. Poor Recognition of Risk Factors for Hepatitis B by Physicians Prescribing Immunosuppressive Therapy: A Call for Universal Rather than Risk-Based Screening

    PubMed Central

    Visram, Alissa; Chan, Kelvin K. W.; McGee, Phyllis; Boro, Jordana

    2015-01-01

    Background Reactivation of hepatitis B virus (HBV) during immunosuppressive therapy (IST) can lead to severe and even fatal hepatitis but can be largely prevented with prophylactic antiviral therapy. Screening for HBV prior to starting IST is recommended. Both risk-based and universal screening have been recommended by different societies. For effective risk-based screening, physicians must be aware of risk factors for chronic HBV infection. Methods The HBV screening practices prior to starting IST of rheumatologists, medical and hematological oncologists were evaluated by survey and chart review. Country of origin, the primary risk factor for HBV exposure, was determined in all patients. Results Of 140 rheumatology, 79 medical oncology and 53 hematology patients reviewed, 81%, 11% and 81% were deemed to be at high risk of HBV reactivation by their physicians respectively, however only 27%, 6% and 62% (p<0.0001) were actually screened for HBV prior to starting IST. For patients from HBV-endemic regions, more hematology patients (53%) were correctly identified by their physicians as being at high risk of reactivation than rheumatology patients (2.4%, p=0.0001) or medical oncology patients (15%, p=0.009). However actual screening rates were not increased in patients from endemic regions. A total of 81 patients were screened for HBsAg; 2 were positive. Of the 33 patients screened for anti-HBc, 10 (30%) were positive. Conclusions Hematologists, rheumatologists and medical oncologists had low rates of screening for HBV prior to prescribing IST, largely due to poor identification of those at risk for infection. Risk-based screening strategies are unlikely to be effective and should be replaced by universal screening. PMID:25875198

  3. Central nervous system recurrence of desmoplastic small round cell tumor following aggressive multimodal therapy: A case report

    PubMed Central

    UMEDA, KATSUTSUGU; SAIDA, SATOSHI; YAMAGUCHI, HIDEKI; OKAMOTO, SHINYA; OKAMOTO, TAKESHI; KATO, ITARU; HIRAMATSU, HIDEFUMI; IMAI, TSUYOSHI; KODAIRA, TAKESHI; HEIKE, TOSHIO; ADACHI, SOUICHI; WATANABE, KEN-ICHIRO

    2016-01-01

    Patients with desmoplastic small round cell tumors (DSRCTs) have an extremely poor outcome despite the use of aggressive therapy. The current study presents the case of 16-year-old male with metastatic DSRCT, in which multimodal therapy, including intensive chemotherapies using frequent autologous stem cell support, gross resection of primary and metastatic lesions, and whole abdominopelvic intensity-modulated radiation therapy, was administered. Subsequent to these treatments, there was no evidence of active disease. However, cerebellar and pineal body lesions, and bone metastasis to the left humerus were detected 1 year and 2 months after the initial diagnosis. Combination chemotherapy with irinotecan and temozolomide was initially effective against the central nervous system (CNS) metastatic lesions; however, the patient succumbed due to progressive CNS disease after seven courses of combination chemotherapy. Additional studies are required to accumulate information regarding CNS recurrence of DSRCT. PMID:26870296

  4. [Modern immunosuppression after solid organ transplantation].

    PubMed

    Beimler, J; Morath, C; Zeier, M

    2014-02-01

    The one common factor in solid organ transplantation is the need for lifelong maintenance immunosuppression. Drug regimens after organ transplantation typically comprise a combination of different immunosuppressive drugs. In most cases a triple drug regimen with different mechanisms of action is used. The aim is to improve both patient and graft survival while minimizing potential side effects of immunosuppressive medication. The basis of most immunosuppressive regimens is calcineurin inhibitors in combination with mycophenolic acid. There are various stages of immunosuppression after solid organ transplantation involving induction therapy, initial and long-term maintenance therapy. In each phase an individual combination of immunosuppressants is set up depending on the risk profile of the individual patient to prevent transplant rejection and organ loss. Based on these considerations, concepts of calcineurin inhibitor or steroid reduction have been established in transplant medicine in recent years. The key role in terms of development of new immunosuppressive strategies is taken by kidney transplantation, the most common solid organ transplantation performed.

  5. Sub-100 nm Gold Nanomatryoshkas Improve Photo-thermal Therapy Efficacy in Large and Highly Aggressive Triple Negative Breast Tumors

    PubMed Central

    Bishnoi, Sandra; Urban, Alexander; Charron, Heather; Mitchell, Tamika; Shea, Martin; Nanda, Sarmistha; Schiff, Rachel; Halas, Naomi; Joshi, Amit

    2014-01-01

    There is an unmet need for efficient near-infrared photothermal transducers for the treatment of highly aggressive cancers and large tumors where the penetration of light can be substantially reduced, and the intra-tumoral nanoparticle transport is restricted due to the presence of hypoxic or nectrotic regions. We report the performance advantages obtained by sub 100 nm gold nanomatryushkas, comprising of concentric gold-silica-gold layers compared to conventional ~150 nm silica core gold nanoshells for photothermal therapy of triple negative breast cancer. We demonstrate that a 33% reduction in silica-core-gold-shell nanoparticle size, while retaining near-infrared plasmon resonance, and keeping the nanoparticle surface charge constant, results in a four to five fold tumor accumulation of nanoparticles following equal dose of injected gold for both sizes. The survival time of mice bearing large (>1000 mm3) and highly aggressive triple negative breast tumors is doubled for the nanomatryushka treatment group under identical photo-thermal therapy conditions. The higher absorption cross-section of a nanomatryoshka results in a higher efficiency of photonic to thermal energy conversion and coupled with 4-5X accumulation within large tumors results in superior therapy efficacy. PMID:25051221

  6. Sub-100nm gold nanomatryoshkas improve photo-thermal therapy efficacy in large and highly aggressive triple negative breast tumors.

    PubMed

    Ayala-Orozco, Ciceron; Urban, Cordula; Bishnoi, Sandra; Urban, Alexander; Charron, Heather; Mitchell, Tamika; Shea, Martin; Nanda, Sarmistha; Schiff, Rachel; Halas, Naomi; Joshi, Amit

    2014-10-10

    There is an unmet need for efficient near-infrared photothermal transducers for the treatment of highly aggressive cancers and large tumors where the penetration of light can be substantially reduced, and the intra-tumoral nanoparticle transport is restricted due to the presence of hypoxic or necrotic regions. We report the performance advantages obtained by sub 100nm gold nanomatryushkas, comprising concentric gold-silica-gold layers compared to conventional ~150nm silica core gold nanoshells for photothermal therapy of triple negative breast cancer. We demonstrate that a 33% reduction in silica-core-gold-shell nanoparticle size, while retaining near-infrared plasmon resonance, and keeping the nanoparticle surface charge constant, results in a four to five fold tumor accumulation of nanoparticles following equal dose of injected gold for both sizes. The survival time of mice bearing large (>1000mm(3)) and highly aggressive triple negative breast tumors is doubled for the nanomatryushka treatment group under identical photo-thermal therapy conditions. The higher absorption cross-section of a nanomatryoshka results in a higher efficiency of photonic to thermal energy conversion and coupled with 4-5× accumulation within large tumors results in superior therapy efficacy.

  7. Comparison of long-term outcomes between children with aplastic anemia and refractory cytopenia of childhood who received immunosuppressive therapy with antithymocyte globulin and cyclosporine.

    PubMed

    Hama, Asahito; Takahashi, Yoshiyuki; Muramatsu, Hideki; Ito, Masafumi; Narita, Atsushi; Kosaka, Yoshiyuki; Tsuchida, Masahiro; Kobayashi, Ryoji; Ito, Etsuro; Yabe, Hiromasa; Ohga, Shouichi; Ohara, Akira; Kojima, Seiji

    2015-11-01

    The 2008 World Health Organization classification proposed a new entity in childhood myelodysplastic syndrome, refractory cytopenia of childhood. However, it is unclear whether this morphological classification reflects clinical outcomes. We retrospectively reviewed bone marrow morphology in 186 children (median age 8 years; range 1-16 years) who were enrolled in the prospective study and received horse antithymocyte globulin and cyclosporine between July 1999 and November 2008. The median follow-up period was 87 months (range 1-146 months). Out of 186 patients, 62 (33%) were classified with aplastic anemia, 94 (49%) with refractory cytopenia of childhood, and 34 (18%) with refractory cytopenia with multilineage dysplasia. Aplastic anemia patients received granulocyte colony-stimulating factor more frequently and for longer durations than other patients (P<0.01). After six months, response rates to immunosuppressive therapy were not significantly different among the 3 groups. Acquisition of chromosomal abnormalities was observed in 5 patients with aplastic anemia, 4 patients with refractory cytopenia of childhood, and 3 patients with refractory cytopenia with multilineage dysplasia. Although the cumulative incidence of total clonal evolution at ten years was not significantly different among the 3 groups, the cumulative incidence of monosomy 7 development was significantly higher in aplastic anemia than in the other groups (P=0.02). Multivariate analysis revealed that only granulocyte colony-stimulating factor administration duration of 40 days or more was a significant risk factor for monosomy 7 development (P=0.02). These findings suggest that even the introduction of a strict morphological distinction from hypoplastic myelodysplastic syndrome cannot eradicate clonal evolution in children with aplastic anemia.

  8. The Rosenzweig Picture-Frustration Study "Extra-Aggression" Score as an Indicator in Cognitive Restructuring Therapy for Male Perpetrators of Domestic Violence

    ERIC Educational Resources Information Center

    Norman, Michael; Ryan, Lawrence J.

    2008-01-01

    It was hypothesized that male perpetrators of domestic violence in the early stages of a 1-year process of cognitive restructuring therapy would manifest on the Rosenzweig Picture-Frustration Study higher levels of extra-aggressiveness than in later stages of the therapy process. A sample of male batterers in the process of treatment took the…

  9. Cognitive behavioral therapy to reduce overt aggression behavior in Chinese young male violent offenders.

    PubMed

    Chen, Chen; Li, Chun; Wang, Hong; Ou, Jian-Jun; Zhou, Jian-Song; Wang, Xiao-Ping

    2014-01-01

    This 9-week study was designed to determine whether a commercial cognitive-behavioral training program could effectively reduce overt aggression behavior in Chinese young male violent offenders. Sixty-six participants were randomly assigned to receive routine intervention alone (control group) or routine intervention plus Williams LifeSkills Training (WLST group) in a 1:1 ratio. The primary outcome was change scores on the Modified Overt Aggression Scale (MOAS) from baseline to one week following end of training. Secondary outcomes were change scores on the Barratt Impulsiveness Scale-11 (BIS-11) and Cook-Medley Hostility Scale (CMHS). There were significant between-group differences in change of MOAS total score (P < .001) and all sub-scores (Ps < .01) except aggression against property. Between-group differences were also observed in change of BIS-11 and CMHS total score (Ps < 0.05). All results favored the WLST group. These findings suggest WLST has the potential to be an effective intervention to reduce overt aggressive behavior in young male violent offenders.

  10. Electroconvulsive therapy in adolescents with intellectual disability and severe self-injurious behavior and aggression: a retrospective study.

    PubMed

    Consoli, Angele; Cohen, Johan; Bodeau, Nicolas; Guinchat, Vincent; Wachtel, Lee; Cohen, David

    2013-01-01

    Efficacious intervention for severe, treatment-refractory self-injurious behavior and aggression (SIB/AGG) in children and adolescents with intellectual disability and concomitant psychiatric disorders remains a complex and urgent issue. The aim of this study is to assess the efficacy of electroconvulsive therapy (ECT) on severe and treatment-resistant SIB/AGG in young people with intellectual disability and current psychiatric disorder. We reviewed the charts of all patients (N = 4) who received ECT in the context of SIB/AGG with resistance to behavioral interventions, milieu therapy and pharmacotherapy from 2007 to 2011. We scored the daily rate of SIB/AGG per patient for each hospital day. Inter rater reliability was good (intraclass correlations = 0.91). We used a mixed generalized linear model to assess whether the following explanatory variables (time, ECT) influenced the course of SIB/AGG over time, the dependant variable. The sample included two girls and two boys. The mean age at admission was 13.8 years old [range 12-14]. The patients had on average 19 ECT sessions [range 16-26] and one patient received maintenance ECT. There was no effect of time before and after ECT start. ECT was associated with a significant decrease in SIB/AGG scores (p < 0.001): mean aggression score post-ECT was half the pre-ECT value. ECT appears beneficial in severe, treatment-resistant SHBA in adolescents with intellectual disability.

  11. Development of targeted therapy in uterine serous carcinoma, a biologically aggressive variant of endometrial cancer.

    PubMed

    El-Sahwi, Karim S; Schwartz, Peter E; Santin, Alessandro D

    2012-01-01

    Endometrial cancer (EC) is the most common female genital malignancy in the USA. Most carcinomas arising from the uterus are estrogen dependent and are associated with obesity and hypertension. They are designated type I ECs and typically, due to their early diagnosis secondary to postmenopausal bleeding, have a good prognosis. By contrast, type II ECs develop in older patients, are not hormone dependent and are responsible for most recurrences and deaths from EC. Uterine serous cancer constitutes up to 10% of all endometrial tumors, and represents the most biologically aggressive variant of type II EC. This article will describe the most salient molecular markers that have been identified in uterine serous cancer, thus far with emphasis on the use of erbB2 (HER2/neu) as the first of a series of therapeutic markers for the treatment of this highly-aggressive subset of ECs.

  12. Surgery induced immunosuppression.

    PubMed

    Hogan, Brian V; Peter, Mark B; Shenoy, Hrishikesh G; Horgan, Kieran; Hughes, Thomas A

    2011-02-01

    Surgery and anaesthesia result in a variety of metabolic and endocrine responses, which result in a generalised state of immunosuppression in the immediate post-operative period. Surgery induced immunosuppression has been implicated in the development of post-operative septic complications and tumour metastasis formation. In addition the effectiveness of many treatments in the adjuvant setting is dependent on a functioning immune system. By understanding the mechanisms contributing to surgery-induced immunosuppression, surgeons may undertake strategies to minimise its effect and reduce potential short-term and long-term consequences to patients.

  13. Cynomolgus monkeys are successfully and persistently infected with hepatitis E virus genotype 3 (HEV-3) after long-term immunosuppressive therapy.

    PubMed

    Gardinali, Noemi Rovaris; Guimarães, Juliana Rodrigues; Melgaço, Juliana Gil; Kevorkian, Yohan Britto; Bottino, Fernanda de Oliveira; Vieira, Yasmine Rangel; da Silva, Aline Campos de Azevedo; Pinto, Douglas Pereira; da Fonseca, Laís Bastos; Vilhena, Leandro Schiavo; Uiechi, Edilson; da Silva, Maria Cristina Carlan; Moran, Julio; Marchevsky, Renato Sérgio; Cruz, Oswaldo Gonçalves; Otonel, Rodrigo Alejandro Arellano; Alfieri, Amauri Alcindo; de Oliveira, Jaqueline Mendes; Gaspar, Ana Maria Coimbra; Pinto, Marcelo Alves

    2017-01-01

    Epidemiological studies found that hepatitis E virus genotype 3 (HEV-3) infection was associated with chronic hepatitis and cirrhosis in immunocompromised patients. Our study aimed to investigate the relationship between the host immunosuppressive status and the occurrence of HEV-related chronic hepatitis. Here we describe a successful experimental study, using cynomolgus monkeys previously treated with tacrolimus, a potent calcineurin inhibitor immunosuppressant, and infected with a Brazilian HEV-3 strain isolated from naturally infected pigs. HEV infected monkeys were followed up during 160 days post infection (dpi) by clinical signs; virological, biochemical and haematological parameters; and liver histopathology. The tacrolimus blood levels were monitored throughout the experiment. Immunosuppression was confirmed by clinical and laboratorial findings, such as: moderate weight loss, alopecia, and herpes virus opportunistic infection. In this study, chronic HEV infection was characterized by the mild increase of liver enzymes serum levels; persistent RNA viremia and viral faecal shedding; and liver histopathology. Three out of four immunosuppressed monkeys showed recurrent HEV RNA detection in liver samples, evident hepatocellular ballooning degeneration, mild to severe macro and microvesicular steatosis (zone 1), scattered hepatocellular apoptosis, and lobular focal inflammation. At 69 dpi, liver biopsies of all infected monkeys revealed evident ballooning degeneration (zone 3), discrete hepatocellular apoptosis, and at most mild portal and intra-acinar focal inflammation. At 160 dpi, the three chronically HEV infected monkeys showed microscopic features (piecemeal necrosis) corresponding to chronic hepatitis in absence of fibrosis and cirrhosis in liver parenchyma. Within 4-months follow up, the tacrolimus-immunosuppressed cynomolgus monkeys infected with a Brazilian swine HEV-3 strain exhibited more severe hepatic lesions progressing to chronic hepatitis

  14. Cynomolgus monkeys are successfully and persistently infected with hepatitis E virus genotype 3 (HEV-3) after long-term immunosuppressive therapy

    PubMed Central

    Guimarães, Juliana Rodrigues; Melgaço, Juliana Gil; Kevorkian, Yohan Britto; Bottino, Fernanda de Oliveira; Vieira, Yasmine Rangel; da Silva, Aline Campos de Azevedo; Pinto, Douglas Pereira; da Fonseca, Laís Bastos; Vilhena, Leandro Schiavo; Uiechi, Edilson; da Silva, Maria Cristina Carlan; Moran, Julio; Marchevsky, Renato Sérgio; Cruz, Oswaldo Gonçalves; Otonel, Rodrigo Alejandro Arellano; Alfieri, Amauri Alcindo; de Oliveira, Jaqueline Mendes; Gaspar, Ana Maria Coimbra; Pinto, Marcelo Alves

    2017-01-01

    Epidemiological studies found that hepatitis E virus genotype 3 (HEV-3) infection was associated with chronic hepatitis and cirrhosis in immunocompromised patients. Our study aimed to investigate the relationship between the host immunosuppressive status and the occurrence of HEV-related chronic hepatitis. Here we describe a successful experimental study, using cynomolgus monkeys previously treated with tacrolimus, a potent calcineurin inhibitor immunosuppressant, and infected with a Brazilian HEV-3 strain isolated from naturally infected pigs. HEV infected monkeys were followed up during 160 days post infection (dpi) by clinical signs; virological, biochemical and haematological parameters; and liver histopathology. The tacrolimus blood levels were monitored throughout the experiment. Immunosuppression was confirmed by clinical and laboratorial findings, such as: moderate weight loss, alopecia, and herpes virus opportunistic infection. In this study, chronic HEV infection was characterized by the mild increase of liver enzymes serum levels; persistent RNA viremia and viral faecal shedding; and liver histopathology. Three out of four immunosuppressed monkeys showed recurrent HEV RNA detection in liver samples, evident hepatocellular ballooning degeneration, mild to severe macro and microvesicular steatosis (zone 1), scattered hepatocellular apoptosis, and lobular focal inflammation. At 69 dpi, liver biopsies of all infected monkeys revealed evident ballooning degeneration (zone 3), discrete hepatocellular apoptosis, and at most mild portal and intra-acinar focal inflammation. At 160 dpi, the three chronically HEV infected monkeys showed microscopic features (piecemeal necrosis) corresponding to chronic hepatitis in absence of fibrosis and cirrhosis in liver parenchyma. Within 4-months follow up, the tacrolimus-immunosuppressed cynomolgus monkeys infected with a Brazilian swine HEV-3 strain exhibited more severe hepatic lesions progressing to chronic hepatitis

  15. Rapidly Progressive Interstitial Lung Disease Associated with Dermatomyositis Treated with Combination of Immunosuppressive Therapy, Direct Hemoperfusion with a Polymyxin B Immobilized Fiber Column and Intravenous Immunoglobulin.

    PubMed

    Takai, Motohisa; Katsurada, Naoko; Nakashita, Tamao; Misawa, Masafumi; Mochizuki, Takahiro; Kaneko, Norihiro; Motojima, Shinji; Aoshima, Masahiro

    2015-01-01

    Rapidly progressive interstitial lung disease (ILD) is associated with dermatomyositis (DM) and has a high mortality rate even with immunosuppressive agents. For such cases, there is no evidence on the combined effect of direct hemoperfusion with a Polymyxin B immobilized fiber column and intravenous immunoglobulin. We herein report a case of 61-year-old woman who presented with respiratory failure. She showed ILD associated with DM which did not improve with immunosuppressive agents, but was improved with the addition of both direct hemoperfusion with a Polymyxin B immobilized fiber column and intravenous immunoglobulin.

  16. Risk factors for complications after ileocolonic resection for Crohn’s disease with a major focus on the impact of preoperative immunosuppressive and biologic therapy: A retrospective international multicentre study

    PubMed Central

    Spinelli, Antonino; Suzuki, Yasuo; Saad-Hossne, Rogerio; Teixeira, Fabio Vieira; de Albuquerque, Idblan Carvalho; da Silva, Rodolff Nunes; de Barcelos, Ivan Folchini; Takeuchi, Ken; Yamada, Akihiro; Shimoyama, Takahiro; da Silva Kotze, Lorete Maria; Sacchi, Matteo; Danese, Silvio; Kotze, Paulo Gustavo

    2015-01-01

    Background Author note: TY, AS, YS, FVT and PGK designed the study. All authors did data collection and gave scientific contribution to the study design and discussion. TY, AS and PGK drafted the article. All authors read and approved the final version of the manuscript.In the era of biologic agents, risk factors for complications following resection for Crohn’s disease have not been fully identified. In particular, the association of preoperative use of immunosuppressive and biologic agents with the incidence of complications after resection remains to be elucidated. Aim This retrospective multicentre study aimed to identify risk factors for complications after ileocolonic resection for Crohn’s disease, with a major focus on the impact of preoperative immunosuppressive and biologic therapy. Methods A total of 231 consecutive patients who underwent ileocolonic resections for active Crohn’s disease in seven inflammatory bowel disease referral centres from three countries (Japan, Brazil and Italy) were included. The following variables were investigated as potential risk factors: age at surgery, gender, behaviour of Crohn’s disease (perforating vs. non-perforating disease), smoking, preoperative use (within eight weeks before surgery) of steroids, immunosuppressants and biologic agents, previous resection, blood transfusion, surgical procedure (open vs. laparoscopic approach), and type of anastomosis (side-to-side vs. end-to-end). Postoperative complications occurring within 30 days after surgery were recorded. Results The rates of overall complications, intra-abdominal sepsis, and anastomotic leak were 24%, 12% and 8%, respectively. Neither immunosuppressive nor biologic therapy prior to surgery was significantly associated with the incidence of overall complications, intra-abdominal sepsis or anastomotic leak. In multivariate analysis, blood transfusion, perforating disease and previous resection were significant risk factors for overall complications (odds

  17. CHOP Chemotherapy for Aggressive Non-Hodgkin Lymphoma with and without HIV in the Antiretroviral Therapy Era in Malawi

    PubMed Central

    Gopal, Satish; Fedoriw, Yuri; Kaimila, Bongani; Montgomery, Nathan D.; Kasonkanji, Edwards; Moses, Agnes; Nyasosela, Richard; Mzumara, Suzgo; Varela, Carlos; Chikasema, Maria; Makwakwa, Victor; Itimu, Salama; Tomoka, Tamiwe; Kamiza, Steve; Dhungel, Bal M.; Chimzimu, Fred; Kampani, Coxcilly; Krysiak, Robert; Richards, Kristy L.; Shea, Thomas C.; Liomba, N. George

    2016-01-01

    There are no prospective studies of aggressive non-Hodgkin lymphoma (NHL) treated with CHOP in sub-Saharan Africa. We enrolled adults with aggressive NHL in Malawi between June 2013 and May 2015. Chemotherapy and supportive care were standardized, and HIV+ patients received antiretroviral therapy (ART). Thirty-seven of 58 patients (64%) were HIV+. Median age was 47 years (IQR 39–56), and 35 (60%) were male. Thirty-five patients (60%) had stage III/IV, 43 (74%) B symptoms, and 28 (48%) performance status ≥2. B-cell NHL predominated among HIV+ patients, and all T-cell NHL occurred among HIV- individuals. Thirty-one HIV+ patients (84%) were on ART for a median 9.9 months (IQR 1.1–31.7) before NHL diagnosis, median CD4 was 121 cells/μL (IQR 61–244), and 43% had suppressed HIV RNA. HIV+ patients received a similar number of CHOP cycles compared to HIV- patients, but more frequently developed grade 3/4 neutropenia (84% vs 31%, p = 0.001), resulting in modestly lower cyclophosphamide and doxorubicin doses with longer intervals between cycles. Twelve-month overall survival (OS) was 45% (95% CI 31–57%). T-cell NHL (HR 3.90, p = 0.017), hemoglobin (HR 0.82 per g/dL, p = 0.017), albumin (HR 0.57 per g/dL, p = 0.019), and IPI (HR 2.02 per unit, p<0.001) were associated with mortality. HIV was not associated with mortality, and findings were similar among patients with diffuse large B-cell lymphoma. Twenty-three deaths were from NHL (12 HIV+, 11 HIV-), and 12 from CHOP (9 HIV+, 3 HIV-). CHOP can be safe, effective, and feasible for aggressive NHL in Malawi with and without HIV. PMID:26934054

  18. Response of an aggressive periosteal aneurysmal bone cyst (ABC) of the radius to denosumab therapy.

    PubMed

    Pauli, Chantal; Fuchs, Bruno; Pfirrmann, Christian; Bridge, Julia A; Hofer, Silvia; Bode, Beata

    2014-01-20

    Aneurysmal bone cyst (ABC), once considered a reactive lesion, has been proven to be a neoplasia characterized by rearrangements of the USP6-gene. Aggressive local growth and recurrences are common and therapeutic options may be limited due to the vicinity of crucial structures. We describe a case of a locally aggressive, multinucleated giant cell-containing lesion of the forearm of a 21-year old woman, treated with denosumab for recurrent, surgically uncontrollable disease. Under the influence of this RANKL inhibitor, the tumor showed a marked reduction of the content of the osteoclastic giant cells and an extensive metaplastic osteoid production leading to the bony containment, mostly located intracortically in the proximal radius. The diagnosis of a periosteal ABC was confirmed by FISH demonstrating USP6 gene rearrangement on the initial biopsy. Function conserving surgery could be performed, enabling reconstruction of the affected bone. Inhibition of RANKL with denosumab may offer therapeutic option for patients not only with giant cell tumors but also with ABCs.

  19. Rates and Durability of Response to Salvage Radiation Therapy Among Patients With Refractory or Relapsed Aggressive Non-Hodgkin Lymphoma

    SciTech Connect

    Tseng, Yolanda D.; Chen, Yu-Hui; Catalano, Paul J.; Ng, Andrea

    2015-01-01

    Purpose: To evaluate the response rate (RR) and time to local recurrence (TTLR) among patients who received salvage radiation therapy for relapsed or refractory aggressive non-Hodgkin lymphoma (NHL) and investigate whether RR and TTLR differed according to disease characteristics. Methods and Materials: A retrospective review was performed for all patients who completed a course of salvage radiation therapy between January 2001 and May 2011 at Brigham and Women's Hospital/Dana-Farber Cancer Institute. Separate analyses were conducted for patients treated with palliative and curative intent. Predictors of RR for each subgroup were assessed using a generalized estimating equation model. For patients treated with curative intent, local control (LC) and progression-free survival were estimated with the Kaplan-Meier method; predictors for TTLR were evaluated using a Cox proportional hazards regression model. Results: Salvage radiation therapy was used to treat 110 patients to 121 sites (76 curative, 45 palliative). Salvage radiation therapy was given as part of consolidation in 18% of patients treated with curative intent. Median dose was 37.8 Gy, with 58% and 36% of curative and palliative patients, respectively, receiving 39.6 Gy or higher. The RR was high (86% curative, 84% palliative). With a median follow-up of 4.8 years among living patients, 5-year LC and progression-free survival for curative patients were 66% and 34%, respectively. Refractory disease (hazard ratio 3.3; P=.024) and lack of response to initial chemotherapy (hazard ratio 4.3; P=.007) but not dose (P=.93) were associated with shorter TTLR. Despite doses of 39.6 Gy or higher, 2-year LC was only 61% for definitive patients with refractory disease or disease that did not respond to initial chemotherapy. Conclusions: Relapsed or refractory aggressive NHL is responsive to salvage radiation therapy, and durable LC can be achieved in some cases. However, refractory disease is associated with a shorter

  20. Long-term outcome of patients with acquired chronic pure red cell aplasia (PRCA) following immunosuppressive therapy: a final report of the nationwide cohort study in 2004/2006 by the Japan PRCA collaborative study group.

    PubMed

    Hirokawa, Makoto; Sawada, Kenichi; Fujishima, Naohito; Teramura, Masanao; Bessho, Masami; Dan, Kazuo; Tsurumi, Hisashi; Nakao, Shinji; Urabe, Akio; Fujisawa, Shin; Yonemura, Yuji; Kawano, Fumio; Oshimi, Kazuo; Sugimoto, Koichi; Matsuda, Akira; Karasawa, Masamitsu; Arai, Ayako; Komatsu, Norio; Harigae, Hideo; Omine, Mitsuhiro; Ozawa, Keiya; Kurokawa, Mineo

    2015-06-01

    Immunosuppressive therapy has been employed as the initial treatment for acquired chronic pure red cell aplasia (PRCA), such as idiopathic, thymoma-associated, or large granular lymphocyte (LGL) leukaemia-associated PRCA, which is thought to be immune-mediated. To explore the overall long-term outcome following immunosuppression and to identify the risk factors for death in these disorders, we conducted nationwide surveys in Japan 2004 and 2006, and identified a total of 185 patients with acquired chronic PRCA, including 72 idiopathic, 41 thymoma-associated and 14 LGL leukaemia-associated cases of PRCA for whom data was available. The present study evaluated 127 patients with these three subsets of PRCA. The median overall survival has not yet been reached in idiopathic PRCA. The estimated median overall survival times in patients with thymoma-associated and LGL leukaemia-associated PRCA were 142·1 and 147·8 months, respectively. Twenty-two deaths were reported, and the response to induction therapy and relapse of anaemia were found to be associated with death. The major causes of death were infection in seven patients and organ failure in another seven patients. The results suggest that maintenance therapy and the management of infectious complications are crucial for improving the prognosis of chronic PRCA.

  1. The Rosenzweig Picture-Frustration Study "extra-aggression" score as an indicator in cognitive restructuring therapy for male perpetrators of domestic violence.

    PubMed

    Norman, Michael; Ryan, Lawrence J

    2008-04-01

    It was hypothesized that male perpetrators of domestic violence in the early stages of a 1-year process of cognitive restructuring therapy would manifest on the Rosenzweig Picture-Frustration Study higher levels of extra-aggressiveness than in later stages of the therapy process. A sample of male batterers in the process of treatment took the Rosenzweig instrument. The resulting responses were rated by trained scorers. Chi-square calculations revealed that batterers in the first quarter of treatment manifested Rosenzweig responses indicative of extra-aggressiveness, whereas in the fourth quarter, batterers manifested Rosenzweig responses indicative of im-aggression. The data are discussed relative to implications for domestic violence treatment and the use of the Rosenzweig instrument as an index of treatment progress.

  2. [Traveling with immunosuppression].

    PubMed

    Birkenfeld, G

    2014-03-01

    The rapidly increasing number of patients with immunosuppression is followed by their expectation to lead-as much as possible-a "normal" life, including long-distance travel. The advice and preventive measures for diseases associated with travelling depend overall on the mode of the patient's immunosuppression. This report explains the individual preventive possibilities, limits and risks for travellers with asplenia, common variable immunodeficiency, chronic inflammatory bowel and rheumatic diseases, HIV, as well as for patients having undergone solid organ or bone marrow transplantation or chemotherapy.

  3. Immunosuppressive effects of lead

    USGS Publications Warehouse

    Franson, J. Christian; Feierabend, J.Scott; Russell, A.Brooke

    1986-01-01

    Immunosuppressive effects of lead were reported as early as 1966, when it was noted that lead increased the sensitivity of rats to bacterial endotoxins (Selye et al. 1966). Since then a substantial body of literature has demonstrated adverse effects of lead on the immune system in a variety of laboratory animals, but very little has been done in this area with avian species. Such immunosuppressive effects could be of significance to waterfowl populations, considering the potential for lead ingestion by waterfowl and subsequent exposure of these birds to disease agents.

  4. Cutaneous malignancies in immunosuppressed organ transplant recipients.

    PubMed

    Seda, Ivette M Sosa; Zubair, Adeel; Brewer, Jerry D

    2014-01-01

    During the past century, organ transplantation has delivered the miracle of life to more than 500,000 patients in need. Secondary malignancies have developed as an unforeseen consequence of intense immunosuppressive regimens. Cutaneous malignancies have been recognized as the most frequent cancer that arises post-transplantation. Among organ transplant recipients (OTRs), skin cancer is a substantial cause of morbidity and potential mortality. The authors discuss epidemiology and clinical presentation of cutaneous malignancies; associated risk factors; recommendation for the care of immunosuppressed OTRs, and emerging therapies on the horizon.

  5. The influence of macrophages on mesenchymal stromal cell therapy: passive or aggressive agents?

    PubMed

    Carty, F; Mahon, B P; English, K

    2017-04-01

    Mesenchymal stromal cells (MSC) have emerged as promising cell therapies for multiple conditions based on demonstrations of their potent immunomodulatory and regenerative capacities in models of inflammatory disease. Understanding the effects of MSC on T cells has dominated the majority of work carried out in this field to date; recently, however, a number of studies have shown that the therapeutic effect of MSC requires the presence of macrophages. It is timely to review the mechanisms and manner by which MSC modulate macrophage populations in order to design more effective MSC therapies and clinical studies. A complex cross-talk exists through which MSC and macrophages communicate, a communication that is not controlled exclusively by MSC. Here, we examine the evidence that suggests that MSC not only respond to inflammatory macrophages and adjust their secretome accordingly, but also that macrophages respond to encounters with MSC, creating a feedback loop which contributes to the immune regulation observed following MSC therapy. Future studies examining the effects of MSC on macrophages should consider the antagonistic role that macrophages play in this exchange.

  6. Targeted molecular-genetic imaging and ligand-directed therapy in aggressive variant prostate cancer.

    PubMed

    Ferrara, Fortunato; Staquicini, Daniela I; Driessen, Wouter H P; D'Angelo, Sara; Dobroff, Andrey S; Barry, Marc; Lomo, Lesley C; Staquicini, Fernanda I; Cardó-Vila, Marina; Soghomonyan, Suren; Alauddin, Mian M; Flores, Leo G; Arap, Marco A; Lauer, Richard C; Mathew, Paul; Efstathiou, Eleni; Aparicio, Ana M; Troncoso, Patricia; Navone, Nora M; Logothetis, Christopher J; Marchiò, Serena; Gelovani, Juri G; Sidman, Richard L; Pasqualini, Renata; Arap, Wadih

    2016-10-24

    Aggressive variant prostate cancers (AVPC) are a clinically defined group of tumors of heterogeneous morphologies, characterized by poor patient survival and for which limited diagnostic and treatment options are currently available. We show that the cell surface 78-kDa glucose-regulated protein (GRP78), a receptor that binds to phage-display-selected ligands, such as the SNTRVAP motif, is a candidate target in AVPC. We report the presence and accessibility of this receptor in clinical specimens from index patients. We also demonstrate that human AVPC cells displaying GRP78 on their surface could be effectively targeted both in vitro and in vivo by SNTRVAP, which also enabled specific delivery of siRNA species to tumor xenografts in mice. Finally, we evaluated ligand-directed strategies based on SNTRVAP-displaying adeno-associated virus/phage (AAVP) particles in mice bearing MDA-PCa-118b, a patient-derived xenograft (PDX) of castration-resistant prostate cancer bone metastasis that we exploited as a model of AVPC. For theranostic (a merging of the terms therapeutic and diagnostic) studies, GRP78-targeting AAVP particles served to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) gene, which has a dual function as a molecular-genetic sensor/reporter and a cell suicide-inducing transgene. We observed specific and simultaneous PET imaging and treatment of tumors in this preclinical model of AVPC. Our findings demonstrate the feasibility of GPR78-targeting, ligand-directed theranostics for translational applications in AVPC.

  7. Generalized aggressive periodontitis: microbiological composition and clinical parameters in non-surgical therapy.

    PubMed

    Usin, María M; Tabares, Sandra M; Menso, Julieta; de Albera, Estela R; Sembaj, Adela

    2016-12-01

    The aim of this study was to determine the variations in periodontal parameters and microbiological composition in periodontal pockets at the baseline and 3 and 6 months post treatmentin patients with Generalized Aggressive Periodontitis(GAP) undergoing non surgical periodontal treatment combined with chlorhexidine and systemic antibiotics. Medical and dental history was taken from 10 subjects, average age 30.6±2.7 years, diagnosed with GAP. A non surgical periodontal treatment combined with 0.12% chlorhexidine, 875 mg amoxicillin and 500 mg metronidazole every 12 hours for ten days was conducted. At each visit, the following measurements wererecorded: bacterial plaque (BP), bleeding on probing (BOP), probing depth (PD), clinical attachment level (CAL), hypermobility, and furcation lesions, and a sample of subgingivalplaque was taken from the site of the deepest probing depth of each sextant to identify Porphyromonas gingivalis, Treponemadenticola, Tannerella forsythia, Prevotella intermedia and Aggregatibacter actinomycetemcomitans using molecular biology techniques. After 6 months, the Wilcoxon test showed an increase of 0.97 mm in CAL (p=0.0047) and 2.54 mm in PD(p=0.009). A healthy site was defined as having a PD <5 mm, negative BOP and no pathogenic bacteria detected at 6 months, indicating significant improvement (p=0.008), with OR (95%CI) =4.7 (1.102220.11).With the treatment protocol used in this study, 6 months after treatment, patients had an approximately 4- fold higher possibility of presenting PD <5 mm and periodontal pockets without periodontal pathogenic bacteria.

  8. Targeted molecular-genetic imaging and ligand-directed therapy in aggressive variant prostate cancer

    PubMed Central

    Ferrara, Fortunato; Staquicini, Daniela I.; Driessen, Wouter H. P.; D’Angelo, Sara; Dobroff, Andrey S.; Barry, Marc; Lomo, Lesley C.; Staquicini, Fernanda I.; Cardó-Vila, Marina; Soghomonyan, Suren; Alauddin, Mian M.; Flores, Leo G.; Arap, Marco A.; Lauer, Richard C.; Mathew, Paul; Efstathiou, Eleni; Aparicio, Ana M.; Troncoso, Patricia; Navone, Nora M.; Logothetis, Christopher J.; Marchiò, Serena; Gelovani, Juri G.; Sidman, Richard L.; Pasqualini, Renata; Arap, Wadih

    2016-01-01

    Aggressive variant prostate cancers (AVPC) are a clinically defined group of tumors of heterogeneous morphologies, characterized by poor patient survival and for which limited diagnostic and treatment options are currently available. We show that the cell surface 78-kDa glucose-regulated protein (GRP78), a receptor that binds to phage-display-selected ligands, such as the SNTRVAP motif, is a candidate target in AVPC. We report the presence and accessibility of this receptor in clinical specimens from index patients. We also demonstrate that human AVPC cells displaying GRP78 on their surface could be effectively targeted both in vitro and in vivo by SNTRVAP, which also enabled specific delivery of siRNA species to tumor xenografts in mice. Finally, we evaluated ligand-directed strategies based on SNTRVAP-displaying adeno-associated virus/phage (AAVP) particles in mice bearing MDA-PCa-118b, a patient-derived xenograft (PDX) of castration-resistant prostate cancer bone metastasis that we exploited as a model of AVPC. For theranostic (a merging of the terms therapeutic and diagnostic) studies, GRP78-targeting AAVP particles served to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) gene, which has a dual function as a molecular-genetic sensor/reporter and a cell suicide-inducing transgene. We observed specific and simultaneous PET imaging and treatment of tumors in this preclinical model of AVPC. Our findings demonstrate the feasibility of GPR78-targeting, ligand-directed theranostics for translational applications in AVPC. PMID:27791181

  9. The Relationship Between the Level of Program Integrity and Pre- and Post-Test Changes of Responsive-Aggression Regulation Therapy (Re-ART) Outpatient: A Pilot Study.

    PubMed

    Hoogsteder, Larissa M; van Horn, Joan E; Stams, Geert Jan J M; Wissink, Inge B; Hendriks, Jan

    2016-03-01

    Responsive-Aggression Regulation Therapy (Re-ART) Outpatient is a cognitive behavioral-based intervention for adolescents and young adults (16-24 years) with severe aggressive behavioral problems. This pilot study (N = 26) examined the level of program integrity (PI; that is, the delivery of the intervention as it is originally intended) of Re-ART. We also investigated the pre- and post-test changes in several outcome variables, and the relation between the level of PI and these changes. Participants were recruited from three different outpatient forensic settings. Results showed that the PI of half of the treatments was not sufficient (e.g., the intensity of the program was too low and some standard modules were not offered). In addition, this pilot study demonstrated that sufficient PI was related to positive changes in aggression, cognitive distortions, social support, coping (reported by therapist), and distrust (responsiveness to treatment).

  10. Usefulness of immunosuppression for giant cell myocarditis.

    PubMed

    Cooper, Leslie T; Hare, Joshua M; Tazelaar, Henry D; Edwards, William D; Starling, Randall C; Deng, Mario C; Menon, Santosh; Mullen, G Martin; Jaski, Brian; Bailey, Kent R; Cunningham, Madeleine W; Dec, G William

    2008-12-01

    Giant cell myocarditis (GCM) is a rare and highly lethal disorder. The only multicenter case series with treatment data lacked cardiac function assessments and had a retrospective design. We conducted a prospective, multicenter study of immunosuppression including cyclosporine and steroids for acute, microscopically-confirmed GCM. From June 1999 to June 2005 in a standard protocol, 11 subjects received high dose steroids and cyclosporine, and 9 subjects received muromonab-CD3. In these, 7 of 11 were women, the mean age was 60 +/- 15 years, and the mean time from symptom onset to presentation was 27 +/- 33 days. During 1 year of treatment, 1 subject died of respiratory complications on day 178, and 2 subjects received heart transplantations on days 2 and 27, respectively. Serial endomyocardial biopsies revealed that after 4 weeks of treatment the degree of necrosis, cellular inflammation, and giant cells decreased (p = 0.001). One patient who completed the trial subsequently died of a fatal GCM recurrence after withdrawal of immunosuppression. Her case demonstrates for the first time that there is a risk of recurrent, sometimes fatal, GCM after cessation of immunosuppression. In conclusion, this prospective study of immunosuppression for GCM confirms retrospective case reports that such therapy improves long-term survival. Additionally, withdrawal of immunosuppression can be associated with fatal GCM recurrence.

  11. Evaluation of Novel Targeted Therapies in Aggressive Biology Sarcoma Patients after progression from US FDA approved Therapies

    PubMed Central

    Subbiah, Vivek; Hess, Kenneth R.; Khawaja, Muhammad Rizwan; Wagner, Michael J.; Tang, Chad; Naing, Aung; Fu, Siqing; Janku, Filip; Piha-Paul, Sarina; Tsimberidou, Apostolia M.; Herzog, Cynthia E.; Ludwig, Joseph A.; Patel, Shreyaskumar; Ravi, Vinod; Benjamin, Robert S.; Meric-Bernstam, Funda; Hong, David S.

    2016-01-01

    Prognosis of patients with advanced sarcoma after progression from FDA approved therapies remains grim. In this study, clinical outcomes of 100 patients with advanced sarcoma who received treatment on novel targeted therapy trials were evaluated. Outcomes of interest included best response, clinical benefit rate, progression-free survival (PFS) and overall survival (OS). Median patient age was 48 years (range 14–80). Patients had received a median of 2 prior lines of systemic treatment. Phase I treatments were anti-VEGF–based (n = 45), mTOR inhibitor–based (n = 15), and anti-VEGF + mTOR inhibitor–based (n = 17) or involved other targets (n = 23). Best responses included partial response (n = 4) and stable disease (n = 57). Clinical benefit rate was 36% (95% confidence interval 27–46%). Median OS was 9.6 months (95% Confidence Interval 8.1–14.2); median PFS was 3.5 months (95% Confidence Interval 2.4–4.7). RMH prognostic score of 2 or 3 was associated with lower median OS (log-rank p-value < 0.0001) and PFS (log-rank p-value 0.0081). Receiving cytotoxic chemotherapy as part of phase I trial was also associated with shorter median OS (log-rank p-value 0.039). Patients with advanced sarcoma treated on phase I clinical trials had a clinical benefit rate of 36% and RMH score predicted survival. PMID:27748430

  12. Dogs, zoonoses and immunosuppression.

    PubMed

    Robinson, R A; Pugh, R N

    2002-06-01

    Dogs are the source of a wide range of zoonotic infections that pose a significant threat to human health. This is particularly the case for immunocompromised people, although there are few robust studies that determine immunosuppression as a risk factor for transmission of zoonoses from dogs to humans. An increasing proportion of human society is immunodeficient, principally through the advent of HIV infection and through more people, particularly the expanding elderly group, being subjected to immunosuppressive agents. This is happening at a time when more such people are capitalizing on the acknowledged benefits of dog ownership, making for a potentially dangerous mix. Enteric pathogens (for example, Salmonella, Campylobacter and Cryptosporidium species, that may be canine derived) are a frequent risk to the health of immunocompromised persons. Veterinarians and physicians can be criticised for not communicating with each other, and for not providing adequate risk assessment to pet owners. There is scope for voluntary groups to provide information and support for the immunosuppressed who wish to keep their dogs. Key recommendations are to maintain a clean personal environment and intact mucocutaneous barriers. Public health professionals could help rectify the current communications gap between veterinary and medical staff and so facilitate in the appropriate management of dog-owning immunocompromised people.

  13. Mechanistic Insights into Molecular Targeting and Combined Modality Therapy for Aggressive, Localized Prostate Cancer

    PubMed Central

    Dal Pra, Alan; Locke, Jennifer A.; Borst, Gerben; Supiot, Stephane; Bristow, Robert G.

    2016-01-01

    Radiation therapy (RT) is one of the mainstay treatments for prostate cancer (PCa). The potentially curative approaches can provide satisfactory results for many patients with non-metastatic PCa; however, a considerable number of individuals may present disease recurrence and die from the disease. Exploiting the rich molecular biology of PCa will provide insights into how the most resistant tumor cells can be eradicated to improve treatment outcomes. Important for this biology-driven individualized treatment is a robust selection procedure. The development of predictive biomarkers for RT efficacy is therefore of utmost importance for a clinically exploitable strategy to achieve tumor-specific radiosensitization. This review highlights the current status and possible opportunities in the modulation of four key processes to enhance radiation response in PCa by targeting the: (1) androgen signaling pathway; (2) hypoxic tumor cells and regions; (3) DNA damage response (DDR) pathway; and (4) abnormal extra-/intracell signaling pathways. In addition, we discuss how and which patients should be selected for biomarker-based clinical trials exploiting and validating these targeted treatment strategies with precision RT to improve cure rates in non-indolent, localized PCa. PMID:26909338

  14. Optimizing immunosuppressive drug dosing in pediatric renal transplantation. Part of a special series on Paediatric Pharmacology, guest edited by Gianvincenzo Zuccotti, Emilio Clementi, and Massimo Molteni.

    PubMed

    Cattaneo, Dario; Vinks, Alexander A

    2012-02-01

    Kidney transplantation in pediatric patients has become a successful and routine procedure, with overall 1-year patient and graft survival rates exceeding 95%. These success rates, however, are not maintained in the long-term, as reported 10-year graft survival rates are in the 50-60% range. Further improvement of long-term allograft survival in pediatric transplantation requires specific focus on long term complications such as increased cardiovascular risk and over-immunosuppression, two linked conditions. One approach to avoid inadequate immunosuppression is to more aggressively tailor immunosuppressive treatment based on individual patient needs. This strategy is currently pursued in the pediatric transplant setting by implementation of individualized therapeutic management of drug concentrations and total exposure. In addition, there is increasing evidence that pharmacogenetic testing may equally benefit individualized immunosuppressive therapy through the identification of SNPs and haplotypes predictive of encoding of proteins involved in drug transport, metabolism and response (efficacy/toxicity). The next challenge will be to provide real time web-based access to all patient information including pharmacokinetic, pharmacodynamic and genotyping data as part of a dosing algorithm or decision support tool with the ultimate goal to adaptively predict and control immunosuppressant exposure and response in individual patients to improve long-term outcomes after kidney transplantation.

  15. Management of HBV Infection During Immunosuppressive Treatment

    PubMed Central

    Marzano, Alfredo

    2009-01-01

    The literature on hepatitis B virus (HBV) in immunocompromised patients is heterogeneous and refers mainly to the pre-antivirals era. Currently, a rational approach to the problem of hepatitis B in these patients provides for: a) the evaluation of HBV markers and of liver condition in all subjects starting immunosuppressive therapies (baseline), b) the treatment with antivirals (therapy) of active carriers, c) the pre-emptive use of antivirals (prophylaxis) in inactive carriers, especially if they are undergoing immunosuppressive therapies judged to be at high risk, d) the biochemical and HBsAg monitoring (or universal prophylaxis in case of high risk immunosuppression, as in onco-haematologic patients and bone marrow transplantation) in subjects with markers of previous contact with HBV (HBsAg-negative and antiHBc-positive), in order to prevent reverse seroconversion. Moreover in solid organ transplants it is suggested a strict adherence to the criteria of allocation based on the virological characteristics of both recipients and donors and the universal prophylaxis or therapy with nucleos(t)ides analogs PMID:21415959

  16. The Effects of Aggression on Symptom Severity and Treatment Response in a Trial of Cognitive Behavioral Therapy for Panic Disorder

    PubMed Central

    Cassiello-Robbins, Clair; Conklin, Laren R.; Anakwenze, Ujunwa; Gorman, Jack M.; Woods, Scott W.; Shear, M. Katherine; Barlow, David H.

    2015-01-01

    Background Previous research suggests that patients with panic disorder exhibit higher levels of aggression than patients with other anxiety disorders. This aggression is associated with more severe symptomatology and interpersonal problems. However, few studies have examined whether higher levels of aggression are associated with a worse treatment response in this population. Methods The present study sought to examine the association of aggression with panic disorder symptom severity in a sample of 379 patients who participated in a trial examining long-term strategies for the treatment of panic disorder. Results We found that aggression was significantly associated with higher baseline levels of panic disorder symptoms, anxiety, depression, and functional impairment. Further, we found that patients higher in aggression did not achieve the same level of improvement in general anxiety symptoms during treatment compared to patients lower in aggression, even when controlling for baseline anxiety symptom severity. Conclusion These results suggest that more research is needed concerning patients with anxiety disorders with higher aggression, as they may be a group in need of additional treatment considerations. PMID:25987198

  17. Efficacy of Photodynamic Therapy and Lasers as an Adjunct to Scaling and Root Planing in the Treatment of Aggressive Periodontitis – A Clinical and Microbiologic Short Term Study

    PubMed Central

    Sarkar, Indranil; Rajan, Padma; Pai, Jagdish; Malagi, Sachin; Bharmappa, Radhika; Kamath, Vinesh

    2016-01-01

    Introduction Aggressive periodontitis comprises a group of rare, severe, rapidly progressive form of periodontitis. Conventional treatment includes mechanical debridement augmented with adjunctive antimicrobial therapy. Development of antibiotic resistance has led to use of lasers. Photodynamic therapy (PDT) is a novel non-invasive therapeutic approach with increased site and pathogen specificity. This study compares PDT and Lasers as an adjunct to conventional Scaling in the treatment of patients with aggressive periodontitis. Materials and Methods Fifteen untreated aggressive periodo-ntitis patients were randomly assigned in a split mouth design for one of the following treatment modalities: 1) SRP alone; (2) SRP + Diode Laser irradiation with 810 nm at 1W, continuous mode for 30 sec per tooth; (3) SRP + PDT on “0” day; (4) SRP + PDT on “0”, 7th and 21st day. The clinical parameters included PI, BOP, PPD, CAL recorded at the baseline & 3rd month. The site with greatest probing pocket depth (PPD) was selected from each quadrant for bacterial sampling and cultured for Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis & Prevotella intermedia. Results Statistically significant reduction in clinical & microbial parameters was seen. Sites 4 showed a greater reduction compared to other groups. Conclusion Photodynamic therapy is a valuable treatment modality adjunctive to conventional scaling and root planing. PMID:27042576

  18. Current state of renal transplant immunosuppression: Present and future

    PubMed Central

    Kalluri, Hari Varun; Hardinger, Karen L

    2012-01-01

    For kidney transplant recipients, immunosuppression commonly consists of combination treatment with a calcineurin inhibitor, an antiproliferative agent and a corticosteroid. Many medical centers use a sequential immunosuppression regimen where an induction agent, either an anti-thymocyte globulin or interleukin-2 receptor antibody, is given at the time of transplantation to prevent early acute rejection which is then followed by a triple immunosuppressive maintenance regimen. Very low rejection rates have been achieved at many transplant centers using combinations of these agents in a variety of protocols. Yet, a large number of recipients suffer chronic allograft injury and adverse events associated with drug therapy. Regimens designed to limit or eliminate calcineurin inhibitors and/or corticosteroid use are actively being pursued. An ideal immunosuppressive regimen limits toxicity and prolongs the functional life of the graft. This article contains a critical analysis of clinical data on currently available immunosuppressive strategies and an overview of therapeutic moieties in development. PMID:24175197

  19. BTG1 expression correlates with pathogenesis, aggressive behaviors and prognosis of gastric cancer: a potential target for gene therapy.

    PubMed

    Zheng, Hua-chuan; Li, Jing; Shen, Dao-fu; Yang, Xue-feng; Zhao, Shuang; Wu, Ya-zhou; Takano, Yasuo; Sun, Hong-zhi; Su, Rong-jian; Luo, Jun-sheng; Gou, Wen-feng

    2015-08-14

    Here, we found that BTG1 overexpression inhibited proliferation, migration and invasion, induced G2/M arrest, differentiation, senescence and apoptosis in BGC-823 and MKN28 cells (p < 0.05). BTG1 transfectants showed a higher mRNA expression of Cyclin D1 and Bax, but a lower mRNA expression of cdc2, p21, mTOR and MMP-9 than the control and mock (p < 0.05). After treated with cisplatin, MG132, paclitaxel and SAHA, both BTG1 transfectants showed lower mRNA viability and higher apoptosis than the control in both time- and dose-dependent manners (p < 0.05) with the hypoexpression of chemoresistance-related genes (slug, CD147, GRP78, GRP94, FBXW7 TOP1, TOP2 and GST-π). BTG1 expression was restored after 5-aza-2'-deoxycytidine treatment in gastric cancer cells. BTG1 expression was statistically lower in gastric cancer than non-neoplastic mucosa and metastatic cancer in lymph node (p < 0.05). BTG1 expression was positively correlated with depth of invasion, lymphatic and venous invasion, lymph node metastasis, TNM staging and worse prognosis (p < 0.05). The diffuse-type carcinoma showed less BTG1 expression than intestinal- and mixed-type ones (p < 0.05). BTG1 overexpression suppressed tumor growth and lung metastasis of gastric cancer cells by inhibiting proliferation, enhancing autophagy and apoptosis in xenograft models. It was suggested that down-regulated BTG1 expression might promote gastric carcinogenesis partially due to its promoter methylation. BTG1 overexpression might reverse the aggressive phenotypes and be employed as a potential target for gene therapy of gastric cancer.

  20. Long-term responses and outcomes following immunosuppressive therapy in large granular lymphocyte leukemia-associated pure red cell aplasia: a Nationwide Cohort Study in Japan for the PRCA Collaborative Study Group.

    PubMed

    Fujishima, Naohito; Sawada, Ken-ichi; Hirokawa, Makoto; Oshimi, Kazuo; Sugimoto, Koichi; Matsuda, Akira; Teramura, Masanao; Karasawa, Masamitsu; Arai, Ayako; Yonemura, Yuji; Nakao, Shinji; Urabe, Akio; Omine, Mitsuhiro; Ozawa, Keiya

    2008-10-01

    Large granular lymphocyte leukemia-associated pure red cell aplasia accounts for a significant portion of secondary pure red cell aplasia cases. However, because of its rarity, long-term responses and relapse rates after immunosuppressive therapy are largely unknown. We conducted a nationwide survey in Japan and collected 185 evaluable patients. Fourteen patients with large granular lymphocyte leukemia-associated pure red cell aplasia were evaluated. Cyclophosphamide, cyclosporine A and prednisolone produced remissions in 6/8, 1/4 and 0/2 patients respectively. Seven and 5 patients were maintained on cyclophosphamide or cyclosporine A respectively. Two patients relapsed after stopping cyclophosphamide, and 2 patients relapsed during maintenance therapy with cyclosporine A. The median relapse-free survival in the cyclophosphamide - and the cyclosporine A groups was 53 and 123 months respectively. Large granular lymphocyte leukemia-associated pure red cell aplasia showed a good response to either cyclophosphamide or cyclosporine A. Most patients continued to receive maintenance therapy and it remains uncertain whether cyclophosphamide or cyclosporine A can induce a maintenance-free hematologic response in large granular lymphocyte leukemia-associated pure red cell aplasia.

  1. Good response of an aggressive rare variant of signet ring cell carcinoma of prostate with hormonal therapy.

    PubMed

    Tiwari, Deviprasad; Nayak, Brusabhanu; Seth, Amlesh

    2017-03-08

    Primary signet ring cell carcinoma (SRCC) of the prostate is a rare entity, characterised by its aggressive nature and dismal prognosis. We report a case of an advanced SRCC of the prostate presenting as a large pelvic mass with obstructive uropathy and rectal involvement managed by complete androgen blockade. At 24 months follow-up, the patient has no evidence of progression or metastasis. Aggressive management with multimodality approach combining surgery, radiation and hormonal ablation can result in long disease-free survival in some patients, despite the aggressive nature of this disease.

  2. [Problems with immunosuppressive agents in nephropathies with chronic renal failure].

    PubMed

    Savoldi, S; Mesiano, P; Rocchietti, M

    2008-01-01

    Immunosuppressive treatment is widely used in transplant patients, who often have chronic renal failure, while its use in nephropathies of native kidneys with chronic renal insufficiency is still limited. In recent years a number of papers have reported advantages of its use also in this setting. A prerequisite for immunosuppression in this condition is accurate renal histology, in order to define the etiology, activity/chronicity index and prognosis. Although clinicians agree on the use of aggressive treatment for secondary nephropathies, the approach to primary forms in the presence of chronic renal failure remains controversial, as does the definition of a ''point of no return'' beyond which treatment could be ineffective or unsafe. Nonrandomized studies found that immunosuppressive drugs such as cyclophosphamide can be useful in membranous nephropathy with renal insufficiency. The use of immunosuppressive drugs in IgA nephropathy in the presence of established renal insufficiency seems to improve renal survival with a limited occurrence of side effects. Since the pharmacokinetics of the current immunosuppressive agents (steroids, azathioprine, cyclophosphamide, chlorambucil, mycophenolate mofetil) is modified by renal insufficiency, attention should be paid to reducing drug doses and monitoring toxicity. Immunosuppressive treatment is a critical procedure in patients with chronic renal failure, in whom an increased risk of infection is already present. In conclusion, on the basis of the data of the literature, we can hypothesize that the ''point of no return'' exceeds the threshold generally considered safe by clinicians. Nevertheless, a strict definition of a cutoff value for renal function to establish whether or not a certain treatment should be given is not applicable in clinical practice, where the choice of an immunosuppressive approach must be tailored to the individual patient based on a global evaluation including renal histology, clinical conditions

  3. Salmonella-Based Therapy Targeting Indoleamine 2,3-Dioxygenase Coupled with Enzymatic Depletion of Tumor Hyaluronan Induces Complete Regression of Aggressive Pancreatic Tumors

    PubMed Central

    Manuel, Edwin R.; Chen, Jeremy; D'Apuzzo, Massimo; Lampa, Melanie G.; Kaltcheva, Teodora I.; Thompson, Curtis B.; Ludwig, Thomas; Chung, Vincent; Diamond, Don J.

    2015-01-01

    Bacterial-based therapies are emerging as effective cancer treatments and hold promise for refractory neoplasms such as pancreatic ductal adenocarcinoma (PDAC), which has not shown significant improvement in therapy for over twenty-five years. Using a novel combination of shIDO-ST, a Salmonella-based therapy targeting the immunosuppressive molecule indoleamine 2,3-dioxygenase (IDO), with an enzyme, PEGPH20, which depletes extracellular matrix hyaluronan, we observed extended survival with frequent total regression of autochthonous and orthotopic PDAC tumors. This was associated with migration and accumulation of activated polymorphonuclear neutrophils (PMN) from spleens into tumors, which was not observed using a scrambled control (shScr-ST). Purified splenic PMNs from PEGPH20/shIDO-ST-treated mice exhibited significant IDO knockdown and were able to kill tumor targets ex-vivo through mechanisms involving FasL and serine proteases. In addition, CD8+ T cells were observed to contribute to late control of pancreatic tumors. Collectively, our data demonstrate that entry of shIDO-ST and PMNs into otherwise impermeable desmoplastic tumors is facilitated by PEGPH20-mediated HA removal, further highlighting an important component of effective treatment for PDAC. PMID:26134178

  4. Sternoclavicular Osteomyelitis in an Immunosuppressed Patient: A Case Report and Review of the Literature.

    PubMed

    Khan, Kamran; Wozniak, Susan E; Mehrabi, Erfan; Giannone, Anna Lucia; Dave, Mitul

    2015-12-28

    BACKGROUND Sternoclavicular osteomyelitis is a rare disease, with less than 250 cases identified in the past 50 years. We present a rare case of sternoclavicular osteomyelitis in an immunosuppressed patient that developed from a conservatively treated dislocation. CASE REPORT A 62-year-old white man with a history of metastatic renal cell carcinoma presented to the emergency department (ED) with a dislocated left sternoclavicular joint. He was managed conservatively and subsequently discharged. However, over subsequent days he began to experience pain, fever, chills, and night sweats. He presented to the ED again and imaging revealed osteomyelitis. In the operating room, the wound was aggressively debrided and a wound vac (vacuum-assisted closure) was placed. He was diagnosed with sternoclavicular osteomyelitis and placed on a 6-week course of intravenous Nafcillin. CONCLUSIONS Chemotherapy patients who sustain joint trauma normally associated with a low risk of infection should be monitored thoroughly, and the option to discontinue immunosuppressive therapy should be considered if signs of infection develop.

  5. Sternoclavicular Osteomyelitis in an Immunosuppressed Patient: A Case Report and Review of the Literature

    PubMed Central

    Khan, Kamran; Wozniak, Susan E.; Mehrabi, Erfan; Giannone, Anna Lucia; Dave, Mitul

    2015-01-01

    Patient: Male, 62 Final Diagnosis: Sternoclavicular osteomyelitis Symptoms: — Medication: — Clinical Procedure: Debridement Specialty: Infectious Diseases Objective: Rare disease Background: Sternoclavicular osteomyelitis is a rare disease, with less than 250 cases identified in the past 50 years. We present a rare case of sternoclavicular osteomyelitis in an immunosuppressed patient that developed from a conservatively treated dislocation. Case Report: A 62-year-old white man with a history of metastatic renal cell carcinoma presented to the emergency department (ED) with a dislocated left sternoclavicular joint. He was managed conservatively and subsequently discharged. However, over subsequent days he began to experience pain, fever, chills, and night sweats. He presented to the ED again and imaging revealed osteomyelitis. In the operating room, the wound was aggressively debrided and a wound vac (vacuum-assisted closure) was placed. He was diagnosed with sternoclavicular osteomyelitis and placed on a 6-week course of intravenous Nafcillin. Conclusions: Chemotherapy patients who sustain joint trauma normally associated with a low risk of infection should be monitored thoroughly, and the option to discontinue immunosuppressive therapy should be considered if signs of infection develop. PMID:26708708

  6. Clinical Significance of Enteric Protozoa in the Immunosuppressed Human Population

    PubMed Central

    Stark, D.; Barratt, J. L. N.; van Hal, S.; Marriott, D.; Harkness, J.; Ellis, J. T.

    2009-01-01

    Summary: Globally, the number of immunosuppressed people increases each year, with the human immunodeficiency virus (HIV) pandemic continuing to spread unabated in many parts of the world. Immunosuppression may also occur in malnourished persons, patients undergoing chemotherapy for malignancy, and those receiving immunosuppressive therapy. Components of the immune system can be functionally or genetically abnormal as a result of acquired (e.g., caused by HIV infection, lymphoma, or high-dose steroids or other immunosuppressive medications) or congenital illnesses, with more than 120 congenital immunodeficiencies described to date that either affect humoral immunity or compromise T-cell function. All individuals affected by immunosuppression are at risk of infection by opportunistic parasites (such as the microsporidia) as well as those more commonly associated with gastrointestinal disease (such as Giardia). The outcome of infection by enteric protozoan parasites is dependent on absolute CD4+ cell counts, with lower counts being associated with more severe disease, more atypical disease, and a greater risk of disseminated disease. This review summarizes our current state of knowledge on the significance of enteric parasitic protozoa as a cause of disease in immunosuppressed persons and also provides guidance on recent advances in diagnosis and therapy for the control of these important parasites. PMID:19822892

  7. Toward the definition of immunosuppressive regimens with antitumor activity.

    PubMed

    Casadio, F; Croci, S; D'Errico Grigioni, A; Corti, B; Grigioni, W F; Landuzzi, L; Lollini, P-L

    2005-06-01

    Immunosuppressive therapies associated with organ transplantation produce an increased risk of cancer development. Malignancies are increased in transplant recipients because of the impaired immune system. Moreover, experimental data point to a tumor-promoting activity of various immunosuppressive agents. In this study, we compared the effects of 4 immunosuppressive agents with different mechanisms of action (cyclosporine, rapamycin, mycophenolic acid, and leflunomide) on the in vitro growth of various tumor cell lines and umbilical vein endothelial cells. To varying degrees rapamycin (10 ng/mL), mycophenolic acid (300 nmol/L), and leflunomide (30 micromol/L) highly inhibited the growth of human rhabdomyosarcoma, hepatocellular carcinoma, colorectal carcinoma, and endothelial cells. In contrast, cyclosporine (100 ng/mL) did not affect their growth. Our data suggest that regimens containing rapamycin, mycophenolic acid, or leflunomide, which have both immunosuppressive and antitumor activities, should be preferred in transplant recipients to minimize the risk of tumors.

  8. Aggressive Behavior

    MedlinePlus

    ... Listen Español Text Size Email Print Share Aggressive Behavior Page Content Article Body My child is sometimes very aggressive. What is the best ... once they are quiet and still reinforces this behavior, so your child learns that time out means “quiet and still.” ...

  9. Prevention of infection caused by immunosuppressive drugs in gastroenterology

    PubMed Central

    Orlicka, Katarzyna; Barnes, Eleanor

    2013-01-01

    Immunosuppressive therapy is frequently used to treat gastrointestinal diseases such as inflammatory bowel disease, autoimmune hepatitis, IgG4-related disease (autoimmune pancreatitis and sclerosing cholangitis) and in the post-transplantation setting. These drugs interfere with the immune system. The main safety concern with their use is the risk of infections. Certain infections can be prevented or their impact minimized. Physicians must adopt preventative strategies and should have a high degree of suspicion to recognize infections early and treat appropriately. This article reviews the risk factors for infections, the mechanism of action of immunosuppressive therapy and proposes preventive strategies. PMID:23819020

  10. Immunosuppressive drugs and fetal outcome.

    PubMed

    Coscia, Lisa A; Constantinescu, Serban; Davison, John M; Moritz, Michael J; Armenti, Vincent T

    2014-11-01

    Successful pregnancies have been reported in all types of solid-organ transplant recipients on a variety of immunosuppressive regimens. Immunosuppression is essential to maintain the transplanted organ and maternal health, thus the safety of these medications continues to be studied. This article reviews information in the literature and data from the National Transplantation Pregnancy Registry (NTPR) in the United States related to immunosuppressive medication and pregnancy. Although most maintenance immunosuppressive regimens have not been shown to affect the outcome of posttransplant pregnancies, mycophenolic acid products are associated with an increased incidence of spontaneous abortion and an increase in the incidence and a specific pattern of birth defects. When counseling transplant recipients about the prospect and safety of pregnancy, the health of the mother, her graft, and the developing fetus must all be taken into account.

  11. [Immunosuppression and infection in transplant recipients].

    PubMed

    Martín-Dávila, Pilar; Blanes, Marino; Fortún, Jesús

    2007-02-01

    Recognizing a foreign element is an inherent characteristic of living beings and guarantees their survival. Evading this defense mechanism is one of the most difficult requirements for transplant success, but it leads to a series of consequences, mainly related to infection. T lymphocytes are the cornerstone of the allogenic response. These cells recognize intracellular and extracellular antigens over HLA molecules in host cells. As a consequence, lymphocytic expansion occurring on several levels is produced, and a humoral or cellular response is the final result. The immunosuppression regimens used in transplantation include induction, maintenance and rescue therapy. Induction therapy serves primarily to decrease the proportion of T-cell precursors and to lower the efficacy of antigen presentation. With respect to maintenance therapy, cyclosporine and tacrolimus inhibit cytokine transcription, azathioprine, and mycophenolate mofetil inhibit nucleotide synthesis, and sirolimus and everolimus inhibit transduction of growth factor signals. As a consequence of immunosuppression, opportunistic microorganisms may appear with endogenic reactivation of latent infection or from an exogenous origin. Prevention of these infections by proper knowledge of the risk factors, rapid diagnosis, and adequate management are fundamental to guarantee the survival of the patient.

  12. Signaling aggression.

    PubMed

    van Staaden, Moira J; Searcy, William A; Hanlon, Roger T

    2011-01-01

    From psychological and sociological standpoints, aggression is regarded as intentional behavior aimed at inflicting pain and manifested by hostility and attacking behaviors. In contrast, biologists define aggression as behavior associated with attack or escalation toward attack, omitting any stipulation about intentions and goals. Certain animal signals are strongly associated with escalation toward attack and have the same function as physical attack in intimidating opponents and winning contests, and ethologists therefore consider them an integral part of aggressive behavior. Aggressive signals have been molded by evolution to make them ever more effective in mediating interactions between the contestants. Early theoretical analyses of aggressive signaling suggested that signals could never be honest about fighting ability or aggressive intentions because weak individuals would exaggerate such signals whenever they were effective in influencing the behavior of opponents. More recent game theory models, however, demonstrate that given the right costs and constraints, aggressive signals are both reliable about strength and intentions and effective in influencing contest outcomes. Here, we review the role of signaling in lieu of physical violence, considering threat displays from an ethological perspective as an adaptive outcome of evolutionary selection pressures. Fighting prowess is conveyed by performance signals whose production is constrained by physical ability and thus limited to just some individuals, whereas aggressive intent is encoded in strategic signals that all signalers are able to produce. We illustrate recent advances in the study of aggressive signaling with case studies of charismatic taxa that employ a range of sensory modalities, viz. visual and chemical signaling in cephalopod behavior, and indicators of aggressive intent in the territorial calls of songbirds.

  13. [Behcet's disease therapy review].

    PubMed

    Vidaller Palacín, A; Robert Olalla, J; Sanuy Jiménez, B; Rufi Rigau, G; Folch Civit, J; Charte González, A

    2002-11-01

    Behçet's disease is an inflammatory process of unknown origin, which usually presents with recurrent oral ulcers, genital aphthae, uveitis and cutaneous lesions. However, a wide variety of clinical manifestations have been reported, and virtually any organ system may be affected, showing central nervous system, joints, blood vessels or gastrointestinal tract involvement. Therapeutic approach remains complex, and varies in basis of the affected organs. Complex aphthosis may respond to topical therapy, colchicine and dapsone. If this therapy does not result in adequate disease control, thalidomide, oral prednisone and methotrexate may be useful. When severe ocular lesions or systemic manifestations are present, therapies tend to be more aggressive, usually combining corticosteroids with immunosuppressive agents as cyclosporin, azathioprine, cyclophosphamide, interferon-alfa-2a, and chlorambucil.

  14. Immunosuppressive agents and interstitial lung disease: what are the risks?

    PubMed

    Meyer, Keith C

    2014-06-01

    Idiopathic pulmonary fibrosis is unlikely to respond to immunosuppressive therapies, and patients with idiopathic pulmonary fibrosis may be harmed by such therapy. In contrast, some forms of interstitial lung disease can respond well to treatment with immunosuppressive drug therapies. Such agents can, however, be associated with significant risk of adverse effects such as infection, diabetes, osteoporosis, myopathy, bone marrow suppression, hepatitis, urinary tract injury, and drug-induced pneumonitis. Treating clinicians must be aware of potential adverse reactions to any immunosuppressive drug that they prescribe for their patients, and they should implement appropriate pre-therapy screening (e.g., tuberculosis, hepatitis, renal insufficiency) and monitoring that is recommended to avoid/minimize risk during the treatment period. Some disorders (e.g., cellular non-specific interstitial pneumonia, organizing pneumonia, or sarcoidosis) may respond very well to immunosuppressive therapies including corticosteroids as monotherapy, and the use of steroid-sparing agents can minimize corticosteroid side effects and may enhance treatment efficacy for disorders such as sarcoidosis or connective tissue disease-associated forms of interstitial lung disease.

  15. Treating Comorbid Anxiety and Aggression in Children

    ERIC Educational Resources Information Center

    Levy, Karyn; Hunt, Caroline; Heriot, Sandra

    2007-01-01

    Objective: The aim of the study was to evaluate the effectiveness of an intervention that targeted both anxious and aggressive behaviors in children with anxiety disorders and comorbid aggression by parent report. Method: The effects of a cognitive-behavioral therapy intervention targeting comorbid anxiety and aggression problems were compared…

  16. Intensification of Antiretroviral Therapy through Addition of Enfuvirtide in Naive HIV-1-Infected Patients with Severe Immunosuppression Does Not Improve Immunological Response: Results of a Randomized Multicenter Trial (ANRS 130 Apollo)

    PubMed Central

    Fagard, Catherine; Grondin, Carine; Descamps, Diane; Yazdanpanah, Yazdan; Charpentier, Charlotte; Colin de Verdiere, Nathalie; Tabuteau, Sophie; Raffi, François; Cabie, André; Chene, Geneviève; Yeni, Patrick

    2013-01-01

    We studied whether addition of enfuvirtide (ENF) to a background combination antiretroviral therapy (cART) would improve the CD4 cell count response at week 24 in naive patients with advanced HIV disease. ANRS 130 Apollo is a randomized study, conducted in naive HIV-1-infected patients, either asymptomatic with CD4 counts of <100/mm3 or stage B/C disease with CD4 counts of <200/mm3. Patients received tenofovir-emtricitabine with lopinavir-ritonavir (LPV/r) or efavirenz and were randomized to receive ENF for 24 weeks (ENF arm) or not (control arm). The primary endpoint was the proportion of patients with CD4 counts of ≥200/mm3 at week 24. A total of 195 patients were randomized: 73% had stage C disease, 78% were male, the mean age was 44 years, the median CD4 count was 30/mm3, and the median HIV-1 RNA load was 5.4 log10 copies/ml. Eighty-one percent of patients received LPV/r. One patient was lost to follow-up, and eight discontinued the study (four in each arm). The proportions of patients with CD4 counts of ≥200/mm3 at week 24 were 34% and 38% in the ENF and control arms, respectively (P = 0.53). The proportions of patients with HIV-1 RNA loads of <50 copies/ml were 74% and 58% at week 24 in the ENF and control arms, respectively (P < 0.02), and the proportion reached 79% in both arms at week 48. Twenty (20%) and 12 patients (13%) in the ENF and control arms, respectively, experienced at least one AIDS event during follow-up (P = 0.17). Although inducing a more rapid virological response, addition of ENF to a standard cART does not improve the immunological outcome in naive HIV-infected patients with severe immunosuppression. PMID:23165467

  17. Intensification of antiretroviral therapy through addition of enfuvirtide in naive HIV-1-infected patients with severe immunosuppression does not improve immunological response: results of a randomized multicenter trial (ANRS 130 Apollo).

    PubMed

    Joly, Véronique; Fagard, Catherine; Grondin, Carine; Descamps, Diane; Yazdanpanah, Yazdan; Charpentier, Charlotte; Colin de Verdiere, Nathalie; Tabuteau, Sophie; Raffi, François; Cabie, André; Chene, Geneviève; Yeni, Patrick

    2013-02-01

    We studied whether addition of enfuvirtide (ENF) to a background combination antiretroviral therapy (cART) would improve the CD4 cell count response at week 24 in naive patients with advanced HIV disease. ANRS 130 Apollo is a randomized study, conducted in naive HIV-1-infected patients, either asymptomatic with CD4 counts of <100/mm(3) or stage B/C disease with CD4 counts of <200/mm(3). Patients received tenofovir-emtricitabine with lopinavir-ritonavir (LPV/r) or efavirenz and were randomized to receive ENF for 24 weeks (ENF arm) or not (control arm). The primary endpoint was the proportion of patients with CD4 counts of ≥ 200/mm(3) at week 24. A total of 195 patients were randomized: 73% had stage C disease, 78% were male, the mean age was 44 years, the median CD4 count was 30/mm(3), and the median HIV-1 RNA load was 5.4 log(10) copies/ml. Eighty-one percent of patients received LPV/r. One patient was lost to follow-up, and eight discontinued the study (four in each arm). The proportions of patients with CD4 counts of ≥ 200/mm(3) at week 24 were 34% and 38% in the ENF and control arms, respectively (P = 0.53). The proportions of patients with HIV-1 RNA loads of <50 copies/ml were 74% and 58% at week 24 in the ENF and control arms, respectively (P < 0.02), and the proportion reached 79% in both arms at week 48. Twenty (20%) and 12 patients (13%) in the ENF and control arms, respectively, experienced at least one AIDS event during follow-up (P = 0.17). Although inducing a more rapid virological response, addition of ENF to a standard cART does not improve the immunological outcome in naive HIV-infected patients with severe immunosuppression.

  18. Effect of Surgical Periodontal Therapy on Serum C-reactive Protein Levels Using ELISA in Both Chronic and Aggressive Periodontitis Patient

    PubMed Central

    Gupta, Bharat; Patil, Neha; Yadav, Manoj; Tripathi, Shashank; Sinha, Saurabh; Sharma, Saurabh; Gupta, Saurabh

    2015-01-01

    Background Periodontitis can be defined as a local inflammatory process which mediates destruction of periodontal tissues & is triggered by bacterial insult. In periodontal infections, the levels of C reactive proteins are elevated as compared to the levels in a periodontally healthy individual. The study was done to determine the relative levels of serum CRP in aggressive, chronic and periodontally healthy subjects and to evaluate the effect of surgical periodontal therapy on serum C-reactive protein levels. Materials and Methods Serum samples were collected from 150 participants (50 healthy control patients (non-periodontitis), 50 patients with chronic periodontitis and aggressive periodontitis. Serum C- reactive protein levels were assessed by means of immunoturbidimetric assay at baseline for subjects in all the 3 groups and 3 months after completion of surgical therapy. Results The mean baseline C-reactive protein (CRP) concentrations in the Groups I, II and III were 1.65±0.57 mg/L, 3.03±2.14 mg/L and 3.09±2.27 mg/L respectively. After treatment, the mean C-reactive protein (CRP) levels in Groups II and III reduced from 3.03±1.67 mg/L to 1.46±1.67 mg/L and from 3.09±1.21 to 1.43±1.21 mg/L respectively. Similar results were found for probing depth and all indexes in Group II and III after treatment. Also, the mean attachment loss in Groups II and III reduced, so the results were highly significant. Conclusion Successful periodontal treatment results in significant decrease in serum C-reactive protein (CRP) levels in otherwise healthy subjects. PMID:26557605

  19. Immunosuppressive Therapy-Related Kaposi Sarcoma

    MedlinePlus

    ... Kaposi sarcoma is found in patients who have acquired immunodeficiency syndrome (AIDS). Epidemic Kaposi sarcoma occurs in patients who have ... combines treatment for Kaposi sarcoma with treatment for AIDS. For the treatment of epidemic Kaposi sarcoma, combined ...

  20. [Successful autologous haematopoietic stem cell transplantation in severe, therapy-resistant childhood Crohn's disease. Report on the first case in Hungary].

    PubMed

    Kriván, Gergely; Szabó, Dolóresz; Kállay, Krisztián; Benyó, Gábor; Kassa, Csaba; Sinkó, János; Goda, Vera; Arató, András; Veres, Gábor

    2014-05-18

    The biological therapy of Crohn's disease, such as infliximab is a powerful approach in the therapy of inflammatory bowel diseases. However, in some patients with aggressive disease course, even a combined immunosuppressive therapy will not result in permanent remission. Hematopoietic stem cell transplantation has emerged as a new potential therapeutic tool for inflammatory bowel diseases. The authors report the case of a 15-year-old boy with severe Crohn's disease resistant to combined immunosuppressive therapy. After a 3-years course of unsuccessful conventional therapy including infliximab, autologous hematopoietic stem cell transplantation was performed which resulted in a complete remission. One year after transplantation the patient has relapsed, but he could be treated effectively with conventional therapy regiments. To the best of knowledge of the authors, this is the first report in Hungary presenting hematopoietic stem cell therapy in patient with severe Crohn's disease.

  1. Immunosuppressive drugs in ulcerative colitis: twisting facts to suit theories?

    PubMed Central

    Sands, B E

    2006-01-01

    Immunosuppressive drugs have become a mainstay of therapy for the inflammatory bowel diseases. Although robust evidence exists in support of the use of these drugs in Crohn's disease, a close evaluation of the available data in ulcerative colitis reveals a much weaker evidence base. In particular, randomised controlled trials of azathioprine, the most commonly used immunosuppressive agent, do not provide rich evidence of efficacy whereas observational cohorts suggest this agent is effective, particularly in patients with relapsing disease who require corticosteroids. Ciclosporin is also effective in the most refractory cases but its efficacy needs to be carefully weighed against the possibility of rare but life threatening complications. Although the evidence base in support of immunosuppressive drugs in ulcerative colitis is not as strong as in Crohn's disease, these agents clearly have a role in the treatment of this disease. PMID:16531519

  2. The microbial community shifts of subgingival plaque in patients with generalized aggressive periodontitis following non-surgical periodontal therapy: a pilot study.

    PubMed

    Han, Jing; Wang, Peng; Ge, Shaohua

    2017-02-07

    The object of this study is to characterize the bacterial community of subgingival plaque of two subjects with generalized aggressive periodontitis (GAgP) pre- and post-treatment. We picked two patients with GAgP and used high-throughput 16S rDNA sequencing. V4 hypervariable region was picked for PCR amplification of subgingival samples. Then, the PCR products were sequenced through Illumina MiSeq platform. One month after therapy, both the clinical features and periodontal parameters improved obviously. Moreover, the composition and structure of subgingival bacterial community changed after initial periodontal therapy. Also, the composition of the subgingival microbiota was highly individualized among different patients. Bacteroidetes, Spirochaetes and Fusobacteria were related to pathogenicity of GAgP while Actinobacteria and Proteobacteria seemed associated with clinical symptoms resolution. In this study, we found the subgingival bacterial community was high in species richness but dominated by a few species or phylotypes, with significant shifts of microbiota that occurred after treatment. This study demonstrated the shift of the subgingival bacterial community before and after treatment by high-throughput 16S rDNA sequencing, and provided a concise method for analysis of microbial community for periodontal diseases.

  3. Prospective evaluation of aggressive medical therapy for atherosclerotic renal artery stenosis, with renal artery stenting reserved for previously injured heart, brain, or kidney.

    PubMed

    Hanzel, George; Balon, Helena; Wong, Oliver; Soffer, Daniel; Lee, Daniel Taehee; Safian, Robert David

    2005-11-01

    Sixty-six patients with atherosclerotic renal artery stenosis (RAS) and serum creatinine < or =2.0 mg/dl were treated with antihypertensive therapy, a statin, and aspirin. Renal stenting was reserved for patients with injuries to the heart, brain, or kidneys. The primary end point was stenotic kidney glomerular filtration rate (GFR) at 21 months; secondary end points included major adverse clinical events, serum creatinine, total GFR, and blood pressure (BP). After baseline evaluation, 26 of 66 patients underwent renal stenting because of injuries to the heart, brain, or kidneys. After 21 months, 6 medical patients required renal stenting, and 5 patients experienced late clinical events (2 medical patients, 3 stent patients). There was no difference in final BP between groups. Whereas medical patients experienced 6% and 8% decreases in total and stenotic kidney GFR, stent patients experienced 7% and 11% increases in total kidney (p = 0.006) and stenotic kidney (p = 0.02) GFR. There was no difference in final serum creatinine. In conclusion, patients with atherosclerotic RAS and baseline creatinine < or =2.0 mg/dl can be safely managed with aggressive medical therapy, with a small decrease in GFR. For patients who develop injuries to the heart, brain, or kidneys, renal artery stenting may further reduce hypertension and improve renal function.

  4. Reversible Cerebral Vasoconstriction Syndrome Promptly Diagnosed with Magnetic Resonance Imaging Including Magnetic Resonance Angiography During Immunosuppressive Therapy in a 16-Year-Old Girl with Refractory Cytopenia of Childhood

    PubMed Central

    Ueki, Hideaki; Sanayama, Yasushi; Miyajima, Akiyo; Tsuchimochi, Taichiro; Igarashi, Shunji; Sunami, Shosuke

    2016-01-01

    Reversible cerebral vasoconstriction syndrome (RCVS) is a syndrome characterized by severe headache with segmental vasoconstriction of the cerebral arteries that resolves within 12 weeks. A 16-year-old girl with refractory cytopenia of childhood, who was receiving the immunosuppressant cyclosporine, developed severe headache and was diagnosed with RCVS using magnetic resonance imaging, including magnetic resonance angiography (MRA). MRA is a non-invasive and very effective technique for diagnosing RCVS. MRA should be performed at the onset of severe headache during immunosuppressant administration for children with hematological disorders and may prevent sequelae such as posterior reversible encephalopathy syndrome or ischemic attack. PMID:27994838

  5. Ocular toxoplasmosis in immunosuppressed nonhuman primates

    SciTech Connect

    Holland, G.N.; O'Connor, G.R.; Diaz, R.F.; Minasi, P.; Wara, W.M.

    1988-06-01

    To investigate the role of cellular immunodeficiency in recurrent toxoplasmic retinochoroiditis, six Cynomolgus monkeys (Macaca fascicularis) with healed toxoplasmic lesions of the retina were immunosuppressed by total lymphoid irradiation. Three months prior to irradiation 30,000 Toxoplasma gondii organisms of the Beverley strain had been inoculated onto the macula of eye in each monkey via a pars plana approach. Toxoplasmic retinochoroiditis developed in each animal, and lesions were allowed to heal without treatment. During total lymphoid irradiation animals received 2000 centigrays (cGy) over a 7-week period. Irradiation resulted in an immediate drop in total lymphocyte counts and decreased ability to stimulate lymphocytes by phytohemagglutinin. Weekly ophthalmoscopic examinations following irradiation failed to show evidence of recurrent ocular disease despite persistent immunodeficiency. Four months after irradiation live organisms were reinoculated onto the nasal retina of the same eye in each animal. Retinochoroidal lesions identical to those seen in primary disease developed in five of six animals. Toxoplasma organisms therefore were able to proliferate in ocular tissue following the administration of immunosuppressive therapy. This study fails to support the hypothesis that cellular immunodeficiency alone will initiate recurrent toxoplasmic retinochoroiditis. Results suggest that reactivation of disease from encysted organisms involves factors other than suppression of Toxoplasma proliferation. If reactivation occurs by other mechanisms, however, cellular immunodeficiency then may allow development of extensive disease.

  6. Neural Mechanisms of Cognitive-Behavioral Therapy for Aggression in Children and Adolescents: Design of a Randomized Controlled Trial Within the National Institute for Mental Health Research Domain Criteria Construct of Frustrative Non-Reward

    PubMed Central

    Wyk, Brent C. Vander; Eilbott, Jeffrey A.; McCauley, Spencer A.; Ibrahim, Karim; Crowley, Michael J.; Pelphrey, Kevin A.

    2016-01-01

    Abstract Objective: We present the rationale and design of a randomized controlled trial of cognitive-behavioral therapy (CBT) for aggression in children and adolescents, which is conducted in response to the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) approach initiative. Specifically, the study is focused on the brain-behavior associations within the RDoC construct of frustrative non-reward. On the behavioral level, this construct is defined by reactions elicited in response to withdrawal or prevention of reward, most notably reactive aggression. This study is designed to test the functional magnetic resonance (fMRI) and electrophysiological (EEG) correlates of aggression and its reduction after CBT. Methods: Eighty children and adolescents with high levels of aggression across multiple traditional diagnostic categories, ages 8–16, will be randomly assigned to receive 12 sessions of CBT or 12 sessions of supportive psychotherapy. Clinical outcomes will be measured by the ratings of aggressive behavior collected at baseline, midpoint, and endpoint evaluations, and by the Improvement Score of the Clinical Global Impressions Scale assigned by an independent evaluator (blinded rater). Subjects will also perform a frustration-induction Go-NoGo task and a task of emotional face perception during fMRI scanning and EEG recording at baseline and endpoint. Results: Consistent with the NIMH strategic research priorities, if functional neuroimaging and EEG variables can identify subjects who respond to CBT for aggression, this can provide a neuroscience-based classification scheme that will improve treatment outcomes for children and adolescents with aggressive behavior. Conclusions: Demonstrating that a change in the key nodes of the emotion regulation circuitry is associated with a reduction of reactive aggression will provide evidence to support the validity of the frustrative non-reward construct. PMID:26784537

  7. In vitro correlates of in vivo therapy with cyclosporine to immunosuppress rejection of heterotopic rat cardiac allografts across strong (RT-1) plus weak (non-RT-1) histocompatibility differences.

    PubMed

    Miyagawa, S; Stepkowski, S M; Lawen, J G; Rutzky, L P; Kahan, B D

    1991-11-01

    This study correlated different oral cyclosporine doses with in vivo graft survival, blood and tissue drug levels, and in vitro immune performances. Wistar-Furth (WFu, RT-1u) hosts engrafted with heterotopic cardiac transplants from strongly histoincompatible Buffalo (BUF, RT-1b) rats were treated postoperatively with 14-day courses of different doses of CsA delivered per gavage. There was a graded prolongation of graft survival--namely, no effect at the 1.5 mg/kg dose; a modest effect at 3 mg/kg; a therapeutic effect at 5 mg/kg; and long-term unresponsiveness at 10 mg/kg. Whole blood, serum, and tissue CsA concentrations correlated with drug dose. On day 7 posttransplantation--that is, during the peak of the immune response of untreated recipients and midway during the period of daily CsA therapy--in vitro immune performances were examined in each experimental group. On the one hand, the mixed lymphocyte reaction of WFu host splenic T cells toward donor-type BUF stimulators poorly reflected the administered CsA dose. On the other hand, there was a good correlation between drug dose and both impaired cell-mediated lympholysis and reduced frequency of alloantigen-specific T cytotoxic cell precursors f(CTL)p. Animals treated with therapeutic doses of CsA showed different patterns of T cell-mediated lympholysis: 3 mg/kg did not prevent anti-BUF Tc cell sensitization; 5 mg/kg maintained f(CTL)p levels similar to the normal controls; and 10 mg/kg significantly reduced Tc clones against donor but not third-party targets. These data demonstrate that the fate of alloantigen-specific Tc clones activated in vivo depends upon the local drug concentration. Furthermore, the present studies suggest that CML and f(CTL)p afford useful in vitro indices of in vivo immunosuppression with CsA in rat cardiac allograft recipients.

  8. Association of Human Leukocyte Antigen DRB1*15 and DRB1*15:01 Polymorphisms with Response to Immunosuppressive Therapy in Patients with Aplastic Anemia: A Meta-Analysis

    PubMed Central

    Liu, Shan; Li, Qing; Zhang, Ying; Li, Qiushuang; Ye, Baodong; Wu, Dijiong; Wu, Li; Lu, Hanti; Ji, Conghua

    2016-01-01

    This study aimed to review and quantitatively analyze (1) the association of aplastic anemia (AA) with human leukocyte antigen (HLA)-DRB1*15 and HLA-DRB1*15:01 polymorphisms and (2) the association of HLA-DRB1*15 and HLA-DRB1*15:01 polymorphisms with response to immunosuppressive therapy (IST) in AA. Published studies have reported conflicting and heterogeneous results regarding the association of HLA-DRB1*15 and HLA-DRB1*15:01 polymorphisms with response to IST in AA. The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Chinese BioMedical Literature, Wangfang and Chinese Social Sciences Citation Index databases were searched. All relevant publications were searched through December 2015. Odds ratio (OR), risk ratio (RR), and 95% confidence intervals (CI) for the comparison between case–control or cohort studies were evaluated. Finally, 24 articles were identified. For HLA-DRB1*15 and HLA-DRB1*15:01, the OR (95% CI) was 2.24(1.33–3.77), P < 0.01 and 2.50(1.73–3.62), P < 0.01, respectively; and the overall pooled RR was 1.72 (1.30–2.29), P < 0.01 and 1.59 (1.29–1.96), P < 0.01, respectively. Statistical evidence showed no publication bias (P > 0.05). Sensitivity analyses revealed that the results were statistically robust. The meta-analysis suggested that HLA-DRB1*15 and HLA-DRB1*15:01 polymorphisms might be associated with increased AA risk in Asians. IST might be more effective in HLA-DRB1*15+ and HLA-DRB1*15:01+ Asian patients with AA than in HLA-DRB1*15− and HLA-DRB1*15:01− Asian patients with AA. Future studies with adequate methodological quality on gene–gene and gene–environment interactions and gene treatment may yield valid results. PMID:27611583

  9. The utility of animal models in developing immunosuppressive agents.

    PubMed

    McDaid, James; Scott, Christopher J; Kissenpfennig, Adrien; Chen, Huifang; Martins, Paulo N

    2015-07-15

    The immune system comprises an integrated network of cellular interactions. Some responses are predictable, while others are more stochastic. While in vitro the outcome of stimulating a single type of cell may be stereotyped and reproducible, in vivo this is often not the case. This phenomenon often merits the use of animal models in predicting the impact of immunosuppressant drugs. A heavy burden of responsibility lies on the shoulders of the investigator when using animal models to study immunosuppressive agents. The principles of the three R׳s: refine (less suffering,), reduce (lower animal numbers) and replace (alternative in vitro assays) must be applied, as described elsewhere in this issue. Well designed animal model experiments have allowed us to develop all the immunosuppressive agents currently available for treating autoimmune disease and transplant recipients. In this review, we examine the common animal models used in developing immunosuppressive agents, focusing on drugs used in transplant surgery. Autoimmune diseases, such as multiple sclerosis, are covered elsewhere in this issue. We look at the utility and limitations of small and large animal models in measuring potency and toxicity of immunosuppressive therapies.

  10. [Molecular mechanisms of action of some immunosuppressive drugs].

    PubMed

    Liberman, Ana C; Druker, Jimena; Refojo, Damián; Arzt, Eduardo

    2008-01-01

    A number of natural and synthetic substances are used in the treatment of immunological disorders. The immunosuppressive drugs are widely utilized in clinical treatments of autoimmune disorders, in the prevention of transplant rejection as well as in non-autoimmune diseases such as allergy. The design of immunosuppressive therapies is based on the control of the exacerbated immune response. The pathophysiologic mean of this concept is to modulate the action of mononuclear cells, being T cells the main targets. Immunosuppressive agents have different molecular targets, and an important drawback in their use is that they also inhibit the normal immune system response. Depending on their mode of action, immunosuppressive drugs can be classified in four different groups: antinflammatory drugs of the corticosteroid family, inhibitors of the calcineurin pathway, cytototoxic or antiproliferative drugs and specific antibodies. In this article, we focus on the molecular action of immunosuppressive drugs such as steroids, cyclosporine, tacrolimus, azathioprine, cyclophosphamide, sirolimus, mycophenolate mofetil, leflunomide and specific antibodies, providing data to characterize and improve the use of these agents.

  11. Pyridoxine deficiency: new approaches in immunosuppression and chemotherapy.

    PubMed

    Trakatellis, A; Dimitriadou, A; Trakatelli, M

    1997-10-01

    Pyridoxine deficiency leads to impairment of immune responses. It appears that the basic derangement is the decreased rate of production of one-carbon units necessary for the synthesis of nucleic acids. The key factor is a pyridoxine enzyme, serine hydroxymethyltransferase. This enzyme is very low in resting lymphocytes but increases significantly under the influence of antigenic or mitogenic stimuli, thus supplying the increased demand for nucleic acid synthesis during an immune response. Serine hydroxymethyltransferase activity is depressed by deoxypyridoxine, a potent antagonist of pyridoxal phosphate, and also by known immunosuppressive or antiproliferative agents. The combination of these agents is additive. Our results lead us to suggest the following medical applications: (a) combination of deoxypyridoxine with immunosuppressive or chemotherapeutic drugs may be effective in cases of immunosuppressive therapy or organ transplantation, (b) the development of special agents directed against the serine hydroxymethyltransferase apoprotein may prove to be a valuable medical tool, since this enzyme presents an excellent target for chemotherapy, (c) lymphocytes of individual patients could be used to design tailor-made specific immunosuppressive or chemotherapeutic treatment, and (d) the serine hydroxymethyltransferase activity of lymphocyte culture presents an excellent indicator for the evaluation of potency of immunosuppressive, chemotherapeutic or genotoxic compounds in a simple and rapid test.

  12. Infusional etoposide, cyclophosphamide, vincristine, doxorubicin, and prednisone +/- rituximab as first-line therapy for aggressive non-Hodgkin lymphoma

    PubMed Central

    Lamar, Zanetta S.; Fino, Nora; Palmer, Jodi; Gruber, Lindsey; Morris, Bonny B.; RaetskayaSolntseva, Olga; Kennedy, LeAnne; Vaidya, Rakhee; Hurd, David; Zamkoff, Kenneth

    2015-01-01

    Introduction Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (DA-EPOCH) was developed in an effort to overcome inadequate drug concentrations and to compensate for increased drug clearance. The goal of this study was to examine risk factors and outcomes in patients with aggressive non-Hodgkin lymphoma (aNHL) treated with DA-EPOCH. Patients and Methods We report 136 patients with previously untreated aNHL treated with infusional DA-EPOCH chemotherapy +/- rituximab from 2005-2013. Overall survival was estimated by Kaplan Meier methods. Univariate and multivariate logistic regression was used to determine factors associated with experiencing death, progression, or relapse at two years. Results The overall response rate was 82%. Relapse-free survival at 1, 3, and 5 years was 68%, 63%, and 52% with 95% CIs [0.59,0.85], [0.54,0.70], and [0.31,0.70], respectively. Patients with T-cell aNHL had increased risk of death, progression or relapse [OR:3.5, 95% CI: 1.4, 8.8] compared to those with B-cell aNHL. In multivariate analysis, current smoking, disease in the bone marrow and number of cycles completed were independent predictors of death or relapse. Conclusion Our data suggests EPOCH+/-R is active in both B and T-cell aNHL. Toxicity did not significantly delay treatment or negatively impact outcomes. Dose adjustment by hematopoietic nadir had no impact on outcomes. The impact of smoking during chemotherapy should be further evaluated. PMID:26725264

  13. The Influence of Immunosuppressive Agents on the Risk of De Novo Donor-Specific HLA Antibody Production in Solid Organ Transplant Recipients.

    PubMed

    OʼLeary, 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.

  14. 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

  15. Long-term genotoxic effects of immunosuppressive drugs on lymphocytes of kidney transplant recipients.

    PubMed

    Lizotti Cilião, Heloísa; Batista de Oliveira Camargo-Godoy, Rossana; Mazzaron Barcelos, Gustavo Rafael; Zanuto, Amanda; Daher Alvares Delfino, Vinicius; de Syllos Cólus, Ilce Mara

    2016-08-01

    Immunosuppressive therapy can prevent rejection after organ transplantation. However, increased cancer risk is a serious complication among patients undergoing such therapy. We have evaluated whether prolonged use of immunosuppressive drugs is genotoxic. DNA instability was assessed, using the comet and micronucleus assays, in blood lymphocytes of 76 kidney transplant patients. DNA damage detected by the comet assay increased with time after transplantation. The estimated glomerular filtration rate of the patients did not influence the incidence of DNA damage. No association between micronucleated mononucleated cells and time elapsed after transplantation was observed. Our results suggest that prolonged use of immunosuppressive drugs in kidney transplant patients can induce genetic instability.

  16. Sterile post-traumatic immunosuppression

    PubMed Central

    Islam, Md Nahidul; Bradley, Benjamin A; Ceredig, Rhodri

    2016-01-01

    After major trauma, the human immune system initiates a series of inflammatory events at the injury site that is later followed by suppression of local inflammation favoring the repair and remodeling of the damaged tissues. This local immune response involves complex interactions between resident cells such as macrophages and dendritic cells, soluble mediators such as cytokines and chemokines, and recruited cells such as neutrophils, monocytes and mesenchymal stromal cells. If of sufficient magnitude, these initial immune responses nevertheless have systemic consequences resulting in a state called post-traumatic immunosuppression (PTI). However, controversy exists regarding the exact immunological changes occurring in systemic compartments triggered by these local immune responses. PTI is one of the leading causes of post-surgical mortality and makes patients vulnerable to hospital-acquired infections, multiple organ failure and many other complications. In addition, hemorrhage, blood transfusion, immunesenescence and immunosuppressant drugs aggravate PTI. PTI has been intensively studied, but published results are frequently cloudy. The purpose of this review is to focus on the contributions made by different responsive modalities to immunosuppression following sterile trauma and to try to integrate these into an overall scheme of PTI. PMID:27195120

  17. The role of immunosuppression of mesenchymal stem cells in tissue repair and tumor growth.

    PubMed

    Han, Zhipeng; Jing, Yingying; Zhang, Shanshan; Liu, Yan; Shi, Yufang; Wei, Lixin

    2012-03-05

    Mesenchymal stem cells (MSCs) have acquired great interests for their potential use in the clinical therapy of many diseases because of their functions including multiple lineage differentiation, low immunogenicity and immunosuppression. Many studies suggest that MSCs are strongly immunosuppressive in vitro and in vivo. MSCs exert a profound inhibitory effect on the proliferation of T cells, B cells, dendritic cells and natural killer cells. In addition, several soluble factors have been reported to involved in the immunosuppressive effects by MSCs such as TGF-β, HGF, PGE2, IDO and iNOS. These results suggest that MSCs can be used in the therapy of immune disorder diseases, prevention of organ transplantation rejection and tissue injury. In recent study, we demonstrated that MSCs in tumor inflammatory microenvironment might be elicited of immunosuppressive function. Thus, the application of MSCs in cancer therapy might have negative effect by helping tumor cells escaping from the immune surveillance.

  18. Suicide plus immune gene therapy prevents post-surgical local relapse and increases overall survival in an aggressive mouse melanoma setting.

    PubMed

    Villaverde, Marcela S; Combe, Kristell; Duchene, Adriana G; Wei, Ming X; Glikin, Gerardo C; Finocchiaro, Liliana M E

    2014-09-01

    In an aggressive B16-F10 murine melanoma model, we evaluated the effectiveness and antitumor mechanisms triggered by a surgery adjuvant treatment that combined a local suicide gene therapy (SG) with a subcutaneous genetic vaccine (Vx) composed of B16-F10 cell extracts and lipoplexes carrying the genes of human interleukin-2 and murine granulocyte and macrophage colony stimulating factor. Pre-surgical SG treatment, neither alone nor combined with Vx was able to slow down the fast evolution of this tumor. After surgery, both SG and SG + Vx treatments, significantly prevented (in 50% of mice) or delayed (in the remaining 50%) post-surgical recurrence, as well as significantly prolonged recurrence-free (SG and SG + Vx) and overall median survival (SG + Vx). The treatment induced the generation of a pseudocapsule wrapping and separating the tumor from surrounding host tissue. Both, SG and the subcutaneous Vx, induced this envelope that was absent in the control group. On the other hand, PET scan imaging of the SG + Vx group suggested the development of an effective systemic immunostimulation that enhanced (18)FDG accrual in the thymus, spleen and vertebral column. When combined with surgery, direct intralesional injection of suicide gene plus distal subcutaneous genetic vaccine displayed efficacy and systemic antitumor immune response without host toxicity. This suggests the potential value of the assayed approach for clinical purposes.

  19. HLA-Mismatched Renal Transplantation without Maintenance Immunosuppression

    PubMed Central

    Kawai, Tatsuo; Cosimi, A. Benedict; Spitzer, Thomas R.; Tolkoff-Rubin, Nina; Suthanthiran, Manikkam; Saidman, Susan L.; Shaffer, Juanita; Preffer, Frederic I.; Ding, Ruchuang; Sharma, Vijay; Fishman, Jay A.; Dey, Bimalangshu; Ko, Dicken S.C.; Hertl, Martin; Goes, Nelson B.; Wong, Waichi; Williams, Winfred W.; Colvin, Robert B.; Sykes, Megan; Sachs, David H.

    2010-01-01

    Summary Five patients with end-stage renal disease received combined bone marrow and kidney transplants from HLA single-haplotype mismatched living related donors, with the use of a nonmyeloablative preparative regimen. Transient chimerism and reversible capillary leak syndrome developed in all recipients. Irreversible humoral rejection occurred in one patient. In the other four recipients, it was possible to discontinue all immunosuppressive therapy 9 to 14 months after the transplantation, and renal function has remained stable for 2.0 to 5.3 years since transplantation. The T cells from these four recipients, tested in vitro, showed donor-specific unresponsiveness and in specimens from allograft biopsies, obtained after withdrawal of immunosuppressive therapy, there were high levels of P3 (FOXP3) messenger RNA (mRNA) but not granzyme B mRNA. PMID:18216355

  20. Immunosuppressive drugs for the treatment of autoimmune pancreatitis.

    PubMed

    Pezzilli, Raffaele

    2014-01-01

    Autoimmune pancreatitis is one of the few diseases of the pancreas characterized by the possibility of curing the illness using immunosuppressant drugs. In this paper, the therapeutic approach used to treat autoimmune pancreatitis patients and the clinical outcome related to each treatment modality were reviewed. Steroids are useful in alleviating the symptoms of the acute presentation of autoimmune pancreatitis, but some questions remain open, such as a shared definition of the disease's remission as well as autoimmune pancreatitis relapse, the dosage of steroids in the symptomatic phase of the disease and the duration of steroid therapy. Finally, it should be determined if other immunosuppressive nonsteroidal drugs could become first-line therapy in patients with autoimmune pancreatitis without jaundice and without atrophic pancreas.

  1. Is mycophenolate more than just an immunosuppressant?--An overview.

    PubMed

    Iyer, Abishek; Brown, Lindsay

    2009-02-01

    The development of immunosuppressant compounds, such as cyclosporine and tacrolimus was crucial to the success of transplant surgery and for treatment of autoimmune diseases. However, immunosuppressant therapy may increase the concentrations of reactive oxygen species (ROS), inducing oxidative damage such as an increased vascular damage. The major source of ROS in the vascular endothelial cells is NADPH oxidase. The subunit structure and function of this enzyme complex in vascular cells differs from that in phagocytic leucocytes. The enzyme subunits Nox1, Nox2 and Nox4 are only found in vascular cells. The GTP-dependent protein subunit Rac 1 needs to be activated for this enzyme to function. Inhibiting this protein subunit should reduce NADPH oxidase-induced oxidative stress. In the cardiovascular system, oxidative stress is observed as hypertension, hypertrophy, fibrosis, conduction abnormalities and endothelial dysfunction, as well as cardiac allograft vasculopathy in transplant patients. In contrast to cyclosporine and tacrolimus, the immunosuppressant mycophenolate inhibits the Rac 1 subunit thus inhibiting NADPH oxidase in the vasculature. This may reduce oxidative stress, prevent the development of cardiac allograft vasculopathy, decrease the deterioration of vascular function and improve cardiovascular function chronically in transplant patients. This overview discusses whether this antioxidant immunosuppressive property could translate into a more general protective role for mycophenolate in the prevention of cardiovascular disease.

  2. The in vitro and vivo effects of nuclear and cytosolic parafibromin expression on the aggressive phenotypes of colorectal cancer cells: a search of potential gene therapy target.

    PubMed

    Zheng, Hua-Chuan; Liu, Jia-Jie; Li, Jing; Wu, Ji-Cheng; Yang, Lei; Zhao, Gui-Feng; Zhao, Xin; Jiang, Hua-Mao; Huang, Ke-Qiang; Li, Zhi-Jie

    2017-02-16

    Down-regulated parafibromin is positively linked to the pathogenesis of parathyroid, lung, breast, ovarian, gastric and colorectal cancers. Here, we found that wild-type (WT) parafibromin overexpression suppressed proliferation, tumor growth, induced cell cycle arrest and apoptosis in colorectal cancer cells (p<0.05), but it was the converse for mutant-type (MT, mutation in nucleus localization sequence) parafibromin (p<0.05). Both WT and MT transfectants inhibited migration and invasion, and caused better differentiation (p<0.05) of cancer cells. WT parafibromin transfectants showed the overexpression of Cyclin B1, Cyclin D1, Cyclin E, p38, p53, and AIF in HCT-15 and HCT-116 cells, while MT parafibromin only up-regulated p38 expression. There was lower mRNA expression of bcl-2 in parafibromin transfectants than the control and mock, while higher expression of c-myc, Cyclin D1, mTOR, and Raptor. According to transcriptomic analysis, WT parafibromin suppressed PI3K-Akt and FoxO signaling pathways, while MT one promoted PI3K-Akt pathway, focal adhesion, and regulation of actin cytoskeleton. Parafibromin was less expressed in colorectal cancer than paired mucosa (p<0.05), and inversely correlated with its differentiation at both mRNA and protein levels (p<0.05). These findings indicated that WT parafibromin might reverse the aggressive phenotypes of colorectal cancer cells and be employed as a target for gene therapy. Down-regulated parafibromin expression might be closely linked to colorectal carcinogenesis and cancer differentiation.

  3. Should aggressive thoracic therapy be performed in patients with synchronous oligometastatic non-small cell lung cancer? A meta-analysis

    PubMed Central

    Li, Dianhe; Wang, Haofei; Qiu, Min; Li, Na

    2017-01-01

    Background We performed a meta-analysis to compare overall survival (OS) outcomes in patients with synchronous oligometastatic non-small cell lung cancer (NSCLC) who underwent aggressive thoracic therapy (ATT) with those who did not. Methods A systematic review of controlled trials of ATT on survival in synchronous oligometastatic NSCLC was conducted. Hazard ratio (HR) for the main endpoint OS was pooled using a fixed-effects model. Subgroup analysis was performed in patients with single organ metastases, or with different numbers of brain metastases, or with different stages of thoracic disease. Pooled survival curves of OS were constructed. Results Seven eligible retrospective observational cohort studies were identified including 668 synchronous oligometastatic NSCLC patients, of whom 227 (34.0%) received ATT. For patients with synchronous oligometastatic NSCLC, ATT was associated with a significant improvement of OS (HR, 0.48; 95% CI, 0.39–0.60; P<0.00001). In subgroup analysis, the association with OS was similar or even strengthened, with a HR of 0.42 (95% CI, 0.31–0.56) in single organ metastases group, 0.49 (95% CI, 0.31–0.75) in solitary brain metastasis group, and 0.38 (95% CI, 0.20–0.73) in thoracic stage I–II group, respectively. The pooled cumulative survival rates for patients received ATT were 74.9% at 1 year, 52.1% at 2 years, 23.0% at 3 years, and 12.6% at 4 years. The corresponding pooled survival for patients who did not receive ATT were 32.3%, 13.7%, 3.7%, and 2.0%, respectively. Conclusions Survival benefit from ATT is common in synchronous oligometastatic patients. Selected patients with synchronous oligometastatic NSCLC could also achieve long-term survival with ATT. PMID:28275479

  4. Rapid autologous marrow recovery and eradication of infectious mononucleosis despite severe immunosuppression following second transplantation for aplastic anemia.

    PubMed

    Rossbach, H C; Hosler, K M; Chamizo, W; Mueller, T; Grana, N H; Lacson, A G; Barbosa, J L

    1999-01-01

    A patient with aplastic anemia failed to respond to immunosuppressive therapy and first marrow transplantation (BMT). Recovery of autologous hematopoiesis was rapid following a second stem cell transplant with a non-myeloablative preparatory regimen. The autologous immune response to infectious mononucleosis (IM) 4 weeks post-transplant was normal despite recent and ongoing severe immunosuppression.

  5. A case of gas gangrene in an immunosuppressed Crohn's patient.

    PubMed

    Kiel, Natalie; Ho, Vincent; Pascoe, Andrew

    2011-09-07

    Clostridium septicum (C. septicum) gas gangrene is well documented in the literature, typically in the setting of trauma or immunosuppression. In this paper, we report a unique case of spontaneous clostridial myonecrosis in a patient with Crohn's disease and sulfasalazine-induced neutropenia. The patient presented with left thigh pain, vomiting and diarrhea. Blood tests demonstrated a profound neutropenia, and magnetic resonance imaging of the thigh confirmed extensive myonecrosis. The patient underwent emergency hip disarticulation, followed by hemicolectomy. C. septicum was cultured from the blood. Following completion of antibiotic therapy, the patient developed myonecrosis of the right pectoral muscle necessitating further debridement, and remains on lifelong prophylactic antibiotic therapy.

  6. Cat scratch disease in an immunosuppressed patient with systemic lupus erythematosus.

    PubMed

    Vargas-Hitos, J A; Sabio, J M; Navarrete-Navarrete, N; Arenas-Miras, M del M; Zamora-Pasadas, M; Jiménez-Alonso, J

    2016-03-01

    Cat scratch disease is an infectious disorder transmitted by cats that typically affects children and young adults. Immunosuppression is a well-known risk factor for the development of severe and atypical forms of the disease; hence it is under-diagnosed in patients with compromised immunity. We are reporting the first case of cat scratch disease, which presented as fever and fatigue, in a patient with systemic lupus erythematosus while receiving immunosuppressant therapy after a kidney transplant.

  7. Opportunistic Infections—Coming to the Limits of Immunosuppression?

    PubMed Central

    Fishman, Jay A.

    2013-01-01

    Possible etiologies of infection in the solid organ recipient are diverse, ranging from common bacterial and viral pathogens to opportunistic pathogens that cause invasive disease only in immunocompromised hosts. The recognition of infectious syndromes in this population is limited by alterations in the clinical manifestations by immunosuppression. The risk of serious infections in the organ transplant patient is determined by the interaction between the patients’ recent and distant epidemiological exposures and all factors that contribute to the patient’s net state of immune suppression. This risk is altered by antimicrobial prophylaxis and changes in immunosuppressive therapies. In addition to the direct effects of infection, opportunistic infections, and the microbiome may adversely shape the host immune responses with diminished graft and patient survivals. Antimicrobial therapies are more complex than in the normal host with a significant incidence of drug toxicity and a propensity for drug interactions with the immunosuppressive agents used to maintain graft function. Rapid and specific microbiologic diagnosis is essential. Newer microbiologic assays have improved the diagnosis and management of opportunistic infections. These tools coupled with assays that assess immune responses to infection and to graft antigens may allow optimization of management for graft recipients in the future. PMID:24086067

  8. Opportunistic infections--coming to the limits of immunosuppression?

    PubMed

    Fishman, Jay A

    2013-10-01

    Possible etiologies of infection in the solid organ recipient are diverse, ranging from common bacterial and viral pathogens to opportunistic pathogens that cause invasive disease only in immunocompromised hosts. The recognition of infectious syndromes in this population is limited by alterations in the clinical manifestations by immunosuppression. The risk of serious infections in the organ transplant patient is determined by the interaction between the patients' recent and distant epidemiological exposures and all factors that contribute to the patient's net state of immune suppression. This risk is altered by antimicrobial prophylaxis and changes in immunosuppressive therapies. In addition to the direct effects of infection, opportunistic infections, and the microbiome may adversely shape the host immune responses with diminished graft and patient survivals. Antimicrobial therapies are more complex than in the normal host with a significant incidence of drug toxicity and a propensity for drug interactions with the immunosuppressive agents used to maintain graft function. Rapid and specific microbiologic diagnosis is essential. Newer microbiologic assays have improved the diagnosis and management of opportunistic infections. These tools coupled with assays that assess immune responses to infection and to graft antigens may allow optimization of management for graft recipients in the future.

  9. [Discontinuation of immunosuppressive and immunomodulatory drugs in connective tissue diseases].

    PubMed

    Targońska-Stępniak, Bożena

    2015-01-01

    Remission in connective tissue diseases became a realistic goal of therapy nowadays. However, there is lack of recommendations on the management after achieving a remission. Chronic exposure to immunosuppressive or immunomodulatory drugs may be associated with adverse events, that is why temporal withdrawal or discontinuation of treatment is advisable. In patients with rheumatoid arthritis (RA) who achieve sustained remission lasting for 6-12 months, an attempt to withdraw biological disease modifying antirheumatic drugs (bDMARDs) may be considered. In most patients with established RA discontinuation of bDMARDs is accompanied by a disease flare, butthe risk of loss of good therapeutic response is lower in case of slowly tapering by expanding the interval between doses or reducing the dose of bDMARDs. Patients with early RA are more likely to have successful discontinuation of therapy. Discontinuation of conventional DMARDs (cDMARDs) is usually associated with a disease flare, that is why tapering of doses is advised rather than stopping cDMARDs. DMARDs free remission occurs relatively rare, more often in patients with seronegative RA and with early onset of modifying treatment. In lupus nephritis (LN) patients with persistent, long-term remission, progressive tapering of doses of immunosuppressive drugs and glucocorticoids is recommended, with treatment discontinuation as a goal. An attempt of treatment withdrawal may be taken in patients remaining in LN complete remission as a consequence of maintenance therapy for 3 years.The process of slow tapering of doses preceding discontinuation of drugs, may last several months. The therapy with antimalarial drugs may be helpful to maintain remission after the treatment discontinuation. There is few data on treatment discontinuation in patients with systemic lupus erythematosus (SLE) without kidney involvement. Immunosuppressive drugs withdrawal is usually performed in patients with stable serological and clinically

  10. Adlerian Therapy with Aggressive Children.

    ERIC Educational Resources Information Center

    Kizer, Betty

    Alfred Adler devised a theory that was holistic, social, teleological, and phenomenological. Adler believed that the basis of problems with children originated in the child's inability to cooperate with society, feelings of inferiority, and a lack of a goal in life. Adler felt the child's life should be examined through the child's eyes.…

  11. Diverticulitis in immunosuppressed patients: A fatal outcome requiring a new approach?

    PubMed Central

    Brandl, Andreas; Kratzer, Theresa; Kafka-Ritsch, Reinhold; Braunwarth, Eva; Denecke, Christian; Weiss, Sascha; Atanasov, Georgi; Sucher, Robert; Biebl, Matthias; Aigner, Felix; Pratschke, Johann; Öllinger, Robert

    2016-01-01

    Background Diagnosis and treatment of diverticulitis in immunosuppressed patients are more challenging than in immunocompetent patients, as maintenance immunosuppressive therapies may mask symptoms or impair the patient’s ability to counteract the local and systemic infective sequelae of diverticulitis. The purpose of this study was to compare the in-hospital mortality and morbidity due to diverticulitis in immunosuppressed and immunocompetent patients and identify risk factors for lethal outcomes. Methods This retrospective study included consecutive in-patients who received treatment for colonic diverticulitis at our institution between April 2008 and April 2014. Patients were divided into immunocompetent and immunosuppressed groups. Primary end points were mortality and morbidity during treatment. Risk factors for death were evaluated. Results Of the 227 patients included, 15 (6.6%) were on immunosuppressive therapy for solid organ transplantation, autoimmune disease, or cerebral metastasis. Thirteen of them experienced colonic perforation and showed higher morbidity (p = 0.039). Immunosuppressed patients showed longer stays in hospital (27.6 v. 14.5 d, p = 0.016) and in the intensive care unit (9.8 v. 1.1 d, p < 0.001), a higher rate of emergency operations (66% v. 29.2%, p = 0.004), and higher in-hospital mortality (20% v. 4.7%, p = 0.045). Age, perforated diverticulitis with diffuse peritonitis, emergency operation, C-reactive protein > 20 mg/dL, and immunosuppressive therapy were significant predictors of death. Age (hazard ratio [HR] 2.57, p = 0.008) and emergency operation (HR 3.03, p = 0.003) remained significant after multivariate analysis. Conclusion Morbidity and mortality due to sigmoid diverticulitis is significantly higher in immunosuppressed patients. Early diagnosis and treatment considering elective sigmoid resection for patients with former episodes of diverticulitis who are wait-listed for transplant is crucial to prevent death. PMID:27240131

  12. Halo naevi and café au lait macule regression in a renal transplant patient on immunosuppression.

    PubMed

    Lolatgis, Helena; Varigos, George; Braue, Anna; Scardamaglia, Laura; Boyapati, Ann; Winship, Ingrid

    2015-11-01

    A case of halo naevi and café au lait macule regression in a renal transplant patient receiving long-term immunosuppressive therapy is described. We propose the direct transfer of an auto-reactive antibody, CD8 T-cells or tumour necrosis factor α from the transplant donor to the recipient as a possible cause. We have also considered insufficient immunosuppressive therapy as a possible mechanism.

  13. A Rationale for Age-Adapted Immunosuppression in Organ Transplantation.

    PubMed

    Krenzien, Felix; ElKhal, Abdallah; Quante, Markus; Rodriguez Cetina Biefer, Hector; Hirofumi, Uehara; Gabardi, Steven; Tullius, Stefan G

    2015-11-01

    Demographic changes are associated with a steady increase of older patients with end-stage organ failure in need for transplantation. As a result, the majority of transplant recipients are currently older than 50 years, and organs from elderly donors are more frequently used. Nevertheless, the benefit of transplantation in older patients is well recognized, whereas the most frequent causes of death among older recipients are potentially linked to side effects of their immunosuppressants.Immunosenescence is a physiological part of aging linked to higher rates of diabetes, bacterial infections, and malignancies representing the major causes of death in older patients. These age-related changes impact older transplant candidates and may have significant implications for an age-adapted immunosuppression. For instance, immunosenescence is linked to lower rates of acute rejections in older recipients, whereas the engraftment of older organs has been associated with higher rejection rates. Moreover, new-onset diabetes mellitus after transplantation is more frequent in the elderly, potentially related to corticosteroids, calcineurin inhibitors, and mechanistic target of rapamycin inhibitors.This review presents current knowledge for an age-adapted immunosuppression based on both, experimental and clinical studies in and beyond transplantation. Recommendations of maintenance and induction therapy may help to improve graft function and to design future clinical trials in the elderly.

  14. Adverse Symptoms of Immunosuppressants: A Survey of Canadian Transplant Clinicians.

    PubMed

    Harrison, J J; Mansell, H; Blydt-Hansen, T

    2017-02-26

    Adverse symptoms of immunosuppressants (ASI) impact quality of life (QOL) in solid organ transplant recipients, however standardized approaches for active ASI surveillance and intervention are lacking. While management is highly clinician-dependent, clinician views remain largely unexplored. We surveyed Canadian Society of Transplantation members on their perceptions of ASI including frequency, perceived QOL impact, causal attribution, management strategies and success. Sixty-one clinicians participated in the survey of 12 ASI (tremor, diarrhea, nausea, constipation, dyspnea, insomnia, edema, dyspnea, arthralgia, acne, mouth sores, paresthesias), for a 22% response rate. Forty-nine completed the survey (80% completion rate). Diarrhea, dyspepsia and insomnia were most frequent, requiring management in ≥ 2% of patients by 96%, 90% and 82% of respondents, respectively. Diarrhea, insomnia and dyspnea were deemed to have an important QOL impact by 92%, 82% and 69%. Immunosuppressants were universally implicated as causative of tremor, diarrhea, acne and mouth sores. Over 80% reported success in managing mouth sores, dyspepsia and constipation. Management strategies included adjustment of immunosuppressant or other medications, drug therapy and non-pharmacologic approaches, and varied according to perceived causal attribution. More study is needed to compare clinician and patient views. These results will be used to establish priorities for further investigation of ASI. This article is protected by copyright. All rights reserved.

  15. Hyperpolarized 13C MR Markers of Renal Tumor Aggressiveness

    DTIC Science & Technology

    2013-10-01

    reliably distinguish renal cancer aggressiveness for optimal triage of therapies . Hyperpolarized (HP) 13C magnetic resonance spectroscopic imaging (MRSI...reliably distinguish renal cancer aggressiveness for optimal triage of therapies . Hyperpolarized (HP) 13C magnetic resonance spectroscopic imaging (MRSI) is... cancer and normal tissues were obtained from nephrectomy specimens and sliced using Krumdieck slicer. With a precision gauge micrometer, the slice

  16. AGGRESSIVE TREATMENT OF SPONTANEOUS PNEUMOTHORAX

    PubMed Central

    Hecker, Sydney P.; Jamplis, Robert W.; Mitchell, Sidney P.

    1962-01-01

    In analysis of the results of treatment of 48 episodes of spontaneous pneumothorax, aggressive treatment by means of closed intercostal drainage with constant suction was found to achieve the aims of therapy more effectively than conservative measures of bed rest with or without needle aspiration. In general, full expansion of the lung was more quickly restored, recurrence was of lesser incidence, the period in hospital was shorter and the time away from work was reduced. ImagesFigure 1. PMID:13905846

  17. Inhibition of mouse breast adenocarcinoma growth by ablation with intratumoral alpha-irradiation combined with inhibitors of immunosuppression and CpG.

    PubMed

    Confino, Hila; Schmidt, Michael; Efrati, Margalit; Hochman, Ilan; Umansky, Viktor; Kelson, Itzhak; Keisari, Yona

    2016-10-01

    It has been demonstrated that aggressive in situ tumor destruction (ablation) could lead to the release of tumor antigens, which can stimulate anti-tumor immune responses. We developed an innovative method of tumor ablation based on intratumoral alpha-irradiation, diffusing alpha-emitters radiation therapy (DaRT), which efficiently ablates local tumors and enhances anti-tumor immunity. In this study, we investigated the anti-tumor potency of a treatment strategy, which combines DaRT tumor ablation with two approaches for the enhancement of anti-tumor reactivity: (1) neutralization of immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and (2) boost the immune response by the immunoadjuvant CpG. Mice bearing DA3 mammary adenocarcinoma with metastases were treated with DaRT wires in combination with a MDSC inhibitor (sildenafil), Treg inhibitor (cyclophosphamide at low dose), and the immunostimulant, CpG. Combination of all four therapies led to a complete rejection of primary tumors (in 3 out of 20 tumor-bearing mice) and to the elimination of lung metastases. The treatment with DaRT and Treg or MDSC inhibitors (without CpG) also resulted in a significant reduction in tumor size, reduced the lung metastatic burden, and extended survival compared to the corresponding controls. We suggest that the therapy with DaRT combined with the inhibition of immunosuppressive cells and CpG reinforced both local and systemic anti-tumor immune responses and displayed a significant anti-tumor effect in tumor-bearing mice.

  18. Long-term follow-up of tandem high-dose therapy with autologous stem cell support for adults with high-risk age-adjusted international prognostic index aggressive non-Hodgkin Lymphomas: a GOELAMS pilot study.

    PubMed

    Monjanel, Hélène; Deconinck, Eric; Perrodeau, Elodie; Gastinne, Thomas; Delwail, Vincent; Moreau, Anne; François, Sylvie; Berthou, Christian; Gyan, Emmanuel; Milpied, Noël

    2011-06-01

    Single high-dose therapy (HDT) followed by autologous peripheral blood stem cell (PBSC) support improves complete response and overall survival (OS) in untreated aggressive non-Hodgkin's lymphoma (NHL). However, patients with a high age-adjusted international prognostic index (aa-IPI equal to 3) still have poor clinical outcome despite high dose intensity regimen. To improve complete response in this subgroup, the French Groupe Ouest-Est des Leucémies et Autres Maladies du Sang (GOELAMS) conducted a pilot phase II trial (073) evaluating tandem HDT with PBSC support in a series of 45 patients with aa-IPI equal to 3 untreated aggressive non-Hodgkin's lymphoma. After induction with an anthracyclin-containing regimen, responders underwent tandem HDT conditioned by high-dose mitoxantrone plus cytarabine for the first HDT and total-body irradiation (TBI), carmustine, etoposide, and cyclophosphamide for the second HDT. Thirty-one patients out of 41 evaluable patients completed the program. There were 4 toxic deaths. The complete response rate was 49%. With a median follow-up of 114 months for surviving patients, the OS was 51%, and 19 out of the 22 patients (86%) who reached a complete response are alive and relapse-free. Recent prospective evaluation of quality of life and comorbidities of surviving patients does not reveal long-term toxicities of the procedure. In the era of monoclonal antibodies and response-adapted therapy, the role of tandem HDT still need to be determined.

  19. Aggression in Huntington's disease: a systematic review of rates of aggression and treatment methods.

    PubMed

    Fisher, Caroline A; Sewell, Katherine; Brown, Anahita; Churchyard, Andrew

    2014-01-01

    Aggression is commonly reported in individuals with Huntington's disease (HD). While correlating factors for aggression are often speculated about, features that are associated with, and contribute to, aggression in this population have not been clearly determined. This systematic review investigates rates of aggression and treatment options for aggression in HD. A number of key findings were revealed. Studies reporting on rates of aggression revealed that its prevalence is high, falling between 22 and 66 percent in the majority of studies. Aggression may be more common in males with HD, and is also found in higher rates in individuals who experience frequent falls, have obsessive-compulsive symptoms and suicidal ideation. There is little research investigating antecedents for aggression in HD. A wide variety of psychotropic medications have been reported in the literature to treat individuals with HD and aggressive behaviour. However, due to methodological limitations, no treatment recommendations can be made, based on the current literature. Two non-medication therapies have been investigated, behaviour support and sensory modulation intervention. However, again, due to methodological limitations with these studies, further research is needed before they can be recommended as frontline interventions. This review highlights the need for further methodologically rigorous studies investigating the treatment of aggression in HD.

  20. Immunotherapy: A promising approach to reverse sepsis-induced immunosuppression.

    PubMed

    Patil, Naeem K; Bohannon, Julia K; Sherwood, Edward R

    2016-09-01

    Sepsis is defined as life-threatening organ dysfunction caused by dysregulated host responses to infection (Third International Consensus definition for Sepsis and septic shock). Despite decades of research, sepsis remains the leading cause of death in intensive care units. More than 40 clinical trials, most of which have targeted the sepsis-associated pro-inflammatory response, have failed. Thus, antibiotics and fluid resuscitation remain the mainstays of supportive care and there is intense need to discover and develop novel, targeted therapies to treat sepsis. Both pre-clinical and clinical studies over the past decade demonstrate unequivocally that sepsis not only causes hyper-inflammation, but also leads to simultaneous adaptive immune system dysfunction and impaired antimicrobial immunity. Evidences for immunosuppression include immune cell depletion (T cells most affected), compromised T cell effector functions, T cell exhaustion, impaired antigen presentation, increased susceptibility to opportunistic nosocomial infections, dysregulated cytokine secretion, and reactivation of latent viruses. Therefore, targeting immunosuppression provides a logical approach to treat protracted sepsis. Numerous pre-clinical studies using immunomodulatory agents such as interleukin-7, anti-programmed cell death 1 antibody (anti-PD-1), anti-programmed cell death 1 ligand antibody (anti-PD-L1), and others have demonstrated reversal of T cell dysfunction and improved survival. Therefore, identifying immunosuppressed patients with the help of specific biomarkers and administering specific immunomodulators holds significant potential for sepsis therapy in the future. This review focusses on T cell dysfunction during sepsis and discusses the potential immunotherapeutic agents to boost T cell function during sepsis and improve host resistance to infection.

  1. Current methods of the analysis of immunosuppressive agents in clinical materials: A review.

    PubMed

    Mika, Adriana; Stepnowski, Piotr

    2016-08-05

    More than 100000 solid organ transplantations are performed every year worldwide. Calcineurin (cyclosporine A, tacrolimus), serine/threonine kinase (sirolimus, everolimus) and inosine monophosphate dehydrogenase inhibitor (mycophenolate mofetil), are the most common drugs used as immunosuppressive agents after solid organ transplantation. Immunosuppressive therapy, although necessary after transplantation, is associated with many adverse consequences, including the formation of secondary metabolites of drugs and the induction of their side effects. Calcineurin inhibitors are associated with nephrotoxicity, cardiotoxicity and neurotoxicity; moreover, they increase the risk of many diseases after transplantation. The review presents a study of the movement of drugs in the body, including the processes of absorption, distribution, localisation in tissues, biotransformation and excretion, and also their accompanying side effects. Therefore, there is a necessity to monitor immunosuppressants, especially because these drugs are characterised by narrow therapeutic ranges. Their incorrect concentrations in a patient's blood could result in transplant rejection or in the accumulation of toxic effects. Immunosuppressive pharmaceuticals are macrolide lactones, peptides, and high molecular weight molecules that can be metabolised to several metabolites. Therefore the two main analytical methods used for their determination are high performance liquid chromatography with various detection methods and immunoassay methods. Despite the rapid development of new analytical methods of analysing immunosuppressive agents, the application of the latest generation of detectors and increasing sensitivity of such methods, there is still a great demand for the development of highly selective, sensitive, specific, rapid and relatively simple methods of immunosuppressive drugs analysis.

  2. Alcohol and Aggression.

    ERIC Educational Resources Information Center

    Gustafson, Roland

    1994-01-01

    Reviews the acute effects of alcohol on aggressive responding. From experimental studies that use human subjects, it is concluded that a moderate dose of alcohol does not increase aggression if subjects are unprovoked. Under provocative situations, aggression is increased as a function of alcohol intoxication, provided that subjects are restricted…

  3. In Search for Equilibrium: Immunosuppression Versus Opportunistic Infection

    PubMed Central

    Yousuf, Tariq; Kramer, Jason; Kopiec, Adam; Jones, Brody; Iskandar, Joy; Ahmad, Khansa; Keshmiri, Hesam; Dia, Muhyaldeen

    2016-01-01

    Post-transplant immunosuppression is necessary to prevent organ rejection. Immunosuppression itself can introduce complications arising from opportunistic infections. We present a case of disseminated blastomycosis manifested only as a skin lesion in an asymptomatic patient post-orthotopic heart transplantation. A 64-year-old female who had recently undergone orthotopic heart transplant for end-stage ischemic cardiomyopathy presented for a scheduled routine cardiac biopsy. The patient had no current complaints other than a crusted plaque noticed at her nasal tip. It initially manifested 6 months after surgery as a pimple that she repeatedly tried to manipulate resulting in redness and crust formation. Her immunosuppressive and prophylactic medications included: mycophenolate, tacrolimus, prednisone, bactrim, acyclovir, valganciclovir, pyrimethamine/sulfadiazine, and fluconazole. On physical examination, she was flushed, with a large and exquisitely tender crusted necrotic lesion involving almost the entire half of the nose anteriorly, the left forehead and right side of the neck. She had decreased air entry over the right lung field as well. A computed tomography (CT) image of the chest was ordered to investigate this concerning physical exam finding in the post-transplant state of this patient on immunosuppressive therapy. Chest CT revealed bilateral nodular pulmonary infiltrates with confluence in the posterior right upper lobe. Blood cultures for aerobic and anerobic organisms were negative. Both excisional biopsy of the nasal cutaneous ulcer and bronchial biopsy demonstrated numerous fungal yeast forms morphologically consistent with Blastomyces. Cultures of both specimens grew Blastomyces dermatitidis, with methicillin-resistant Staphylococcus aureus (MRSA) superinfection of the nose. She received 14 days of intravenous (IV) amphotericin B for disseminated blastomycosis and 7 days of IV vancomycin for MRSA. Her symptoms and cutaneous lesions improved and she

  4. Tolerance in Organ Transplantation: From Conventional Immunosuppression to Extracellular Vesicles

    PubMed Central

    Monguió-Tortajada, Marta; Lauzurica-Valdemoros, Ricardo; Borràs, Francesc E.

    2014-01-01

    Organ transplantation is often the unique solution for organ failure. However, rejection is still an unsolved problem. Although acute rejection is well controlled, the chronic use of immunosuppressive drugs for allograft acceptance causes numerous side effects in the recipient and do not prevent chronic allograft dysfunction. Different alternative therapies have been proposed to replace the classical treatment for allograft rejection. The alternative therapies are mainly based in pre-infusions of different types of regulatory cells, including DCs, MSCs, and Tregs. Nevertheless, these approaches lack full efficiency and have many problems related to availability and applicability. In this context, the use of extracellular vesicles, and in particular exosomes, may represent a cell-free alternative approach in inducing transplant tolerance and survival. Preliminary approaches in vitro and in vivo have demonstrated the efficient alloantigen presentation and immunomodulation abilities of exosomes, leading to alloantigen-specific tolerance and allograft acceptance in rodent models. Donor exosomes have been used alone, processed by recipient antigen-presenting cells, or administered together with suboptimal doses of immunosuppressive drugs, achieving specific allograft tolerance and infinite transplant survival. In this review, we gathered the latest exosome-based strategies for graft acceptance and discuss the tolerance mechanisms involved in organ tolerance mediated by the administration of exosomes. We will also deal with the feasibility and difficulties that arise from the application of this strategy into the clinic. PMID:25278936

  5. BK virus replication following kidney transplant: does the choice of immunosuppressive regimen influence outcomes?

    PubMed

    Acott, Phillip; Babel, Nina

    2012-01-01

    The increasing prevalence of BK virus nephropathy (BKVN) observed in recent years, with its consequent impact on kidney allograft survival rates, has focused attention on the relationship between immunosuppression regimens and risk of BK virus reactivation. The adoption of more potent immunosuppressive regimens over the last two decades, notably tacrolimus with mycophenolic acid and corticosteroids, appears to be associated with higher rates of BK activation. There is also evidence of a specific increase in risk for tacrolimus-based immunosuppression vs. cyclosporine, which in vitro data suggest may be at least partly due to differences in antiviral activity. Early concerns that mammalian target of rapamycin (mTOR) inhibitor use was associated with development of BKVN do not appear to have been borne out. Protocol-driven BK virus screening is recommended to facilitate early diagnosis and intervention, which primarily comprises the controlled reduction or discontinuation of immunosuppressive drugs. Although a consensus on the optimal strategy for immunosuppression modification is still lacking, early diagnosis of BK reactivation and pre-emptive modification of immunosuppression has resulted in a marked improvement in graft outcomes. Typically, intervention consists of reducing calcineurin inhibitor exposure before or after antimetabolite dose reduction, withdrawal of one agent from a triple therapy regimen, or switching between agents within a therapeutic class. A benefit for antiviral therapy is not yet confirmed. While more data are required, the current evidence base is adequate to justify routine screening with early modification of the intensity and nature of the immunosuppression regimen to reduce the toll of BKVN in the kidney transplant population.

  6. Taste-immunosuppression engram: reinforcement and extinction.

    PubMed

    Niemi, Maj-Britt; Härting, Margarete; Kou, Wei; Del Rey, Adriana; Besedovsky, Hugo O; Schedlowski, Manfred; Pacheco-López, Gustavo

    2007-08-01

    Several Pavlovian conditioning paradigms have documented the brain's abilities to sense immune-derived signals or immune status, associate them with concurrently relevant extereoceptive stimuli, and reinstate such immune responses on demand. Specifically, the naturalistic relation of food ingestion with its possible immune consequences facilitates taste-immune associations. Here we demonstrate that the saccharin taste can be associated with the immunosuppressive agent cyclosporine A, and that such taste-immune associative learning is subject to reinforcement. Furthermore, once consolidated, this saccharin-immunosuppression engram is resistant to extinction when avoidance behavior is assessed. More importantly, the more this engram is activated, either at association or extinction phases, the more pronounced is the conditioned immunosuppression.

  7. The mutually regulatory loop of epithelial-mesenchymal transition and immunosuppression in cancer progression.

    PubMed

    Chen, Limo; Heymach, John V; Qin, F Xiao-Feng; Gibbons, Don L

    2015-05-01

    Epithelial-mesenchymal transition and immunosuppression are crucial for cancer metastasis and treatment resistance. The mechanism by which these distinct processes are co-opted remains incompletely understood. Our recent work has exposed the "dirty affairs" of the 2 at the tumor site, thus calling for a combined therapy to break such a dangerous liaison.

  8. Developing New Immunosuppression for the Next Generation of Transplant Recipients: The Path Forward.

    PubMed

    Stegall, M D; Morris, R E; Alloway, R R; Mannon, R B

    2016-04-01

    The development of new immunosuppressive drugs has slowed markedly over the past several years, and the outlook that improved therapy will be available to the next generation of transplant recipients is bleak. In this viewpoint, the authors outline some of important barriers to new drug development and suggest specific steps that the transplant community can take to overcome them.

  9. Hearing regulates Drosophila aggression.

    PubMed

    Versteven, Marijke; Vanden Broeck, Lies; Geurten, Bart; Zwarts, Liesbeth; Decraecker, Lisse; Beelen, Melissa; Göpfert, Martin C; Heinrich, Ralf; Callaerts, Patrick

    2017-02-21

    Aggression is a universal social behavior important for the acquisition of food, mates, territory, and social status. Aggression in Drosophila is context-dependent and can thus be expected to involve inputs from multiple sensory modalities. Here, we use mechanical disruption and genetic approaches in Drosophila melanogaster to identify hearing as an important sensory modality in the context of intermale aggressive behavior. We demonstrate that neuronal silencing and targeted knockdown of hearing genes in the fly's auditory organ elicit abnormal aggression. Further, we show that exposure to courtship or aggression song has opposite effects on aggression. Our data define the importance of hearing in the control of Drosophila intermale aggression and open perspectives to decipher how hearing and other sensory modalities are integrated at the neural circuit level.

  10. Gelsemium alkaloids, immunosuppressive agents from Gelsemium elegans.

    PubMed

    Xu, You-Kai; Liao, Shang-Gao; Na, Zhi; Hu, Hua-Bin; Li, Yan; Luo, Huai-Rong

    2012-09-01

    Bioassay-guided isolation of the stems of Gelsemium elegans has led to the isolation of two new Gelsemium alkaloids, 21-(2-oxopropyl)-koumine (1) and 11-methoxygelselegine (2), and two known alkaloids, koumine (3) and gelselegine (4). The structures of 1-2 were determined by spectroscopic (for both) and single-crystal X-ray diffraction (for 1) analysis. All compounds isolated were evaluated for their potential as immunosuppressive agents and the data suggested that Gelsemium alkaloids of different structural types possibly have potential as immunosuppressive agents.

  11. Vaccination against pox diseases under immunosuppressive conditions.

    PubMed

    Mayr, A; Danner, K

    1978-01-01

    Pox diseases, caused either by smallpox virus or zoonotic pox viruses or animals, continue to be of potential danger to a non-vaccinated population. Mass vaccinations will become necessary and will then also be administered to persons with immunological aberrations. The vaccines which are presently used against smallpox cause severe complications in such hosts. In contrast, the attenuated vaccinia virus strain MVA is safe even under the conditions of immunosuppression and is recommended for the production of smallpox vaccines. Because of the special epizootic situations and the numerous immunosuppressive factors present in developing countries, the use of such a safe pox vaccine there is of crucial importance.

  12. Tuberculous pyomyositis in an immunosuppressed patient.

    PubMed

    Osorio, Johanna; Barreto, Jackeline; Benavides, Jhonattan; López, Óscar; Cuenca, Ángela; García, Esperanza

    2016-02-23

    Tuberculous pyomyositis is a rare manifestation of extrapulmonary tuberculosis, most common in immunosuppressed patients, with clinical manifestations similar to pyomyositis of other etiologies, although with a lower age of presentation; notable risk factors include prior tuberculosis infection and pharmacological immunosuppression. Diagnosis depends on a high clinical suspicion of the infection in a susceptible population, given that microbiological isolation is often impossible. The response to treatment and prognosis are good. The case presented here is noteworthy given the rarity of this manifestation of tuberculosis and the slow response to first-line TB management in an HIV patient, despite susceptible microbiological isolation.

  13. Benign familial Degos disease worsening during immunosuppression.

    PubMed

    Powell, J; Bordea, C; Wojnarowska, F; Farrell, A M; Morris, P J

    1999-09-01

    We describe a 61-year-old woman with skin lesions consistent with those found in Degos disease, both in clinical and in histological appearance. She had had several of these lesions for many years, as had her mother, sister and niece. In 1991, she underwent cadaveric renal transplantation and was treated with immunosuppression: prednisolone, azathioprine and cyclosporin. At that time, she developed many more characteristic skin lesions, and these were slightly larger and more noticeable than those she had had previously. She and the other affected family members appear to fit into the more benign subgroup of Degos disease, and it seems that her immunosuppression aggravated her cutaneous disease.

  14. Orthodontic Management in Aggressive Periodontitis.

    PubMed

    Gyawali, Rajesh; Bhattarai, Bhagabat

    2017-01-01

    Aggressive periodontitis is a type of periodontitis with early onset and rapid progression and mostly affecting young adults who occupy a large percentage of orthodontic patients. The role of the orthodontist is important in screening the disease, making a provisional diagnosis, and referring it to a periodontist for immediate treatment. The orthodontist should be aware of the disease not only before starting the appliance therapy, but also during and after the active mechanotherapy. The orthodontic treatment plan, biomechanics, and appliance system may need to be modified to deal with the teeth having reduced periodontal support. With proper force application and oral hygiene maintenance, orthodontic tooth movement is possible without any deleterious effect in the tooth with reduced bone support. With proper motivation and interdisciplinary approach, orthodontic treatment is possible in patients with controlled aggressive periodontitis.

  15. Orthodontic Management in Aggressive Periodontitis

    PubMed Central

    Bhattarai, Bhagabat

    2017-01-01

    Aggressive periodontitis is a type of periodontitis with early onset and rapid progression and mostly affecting young adults who occupy a large percentage of orthodontic patients. The role of the orthodontist is important in screening the disease, making a provisional diagnosis, and referring it to a periodontist for immediate treatment. The orthodontist should be aware of the disease not only before starting the appliance therapy, but also during and after the active mechanotherapy. The orthodontic treatment plan, biomechanics, and appliance system may need to be modified to deal with the teeth having reduced periodontal support. With proper force application and oral hygiene maintenance, orthodontic tooth movement is possible without any deleterious effect in the tooth with reduced bone support. With proper motivation and interdisciplinary approach, orthodontic treatment is possible in patients with controlled aggressive periodontitis. PMID:28299350

  16. Application of Operational Tolerance Signatures Are Limited by Variability and Type of Immunosuppression in Renal Transplant Recipients: A Cross-Sectional Study

    PubMed Central

    Bottomley, Matthew J.; Chen, Mian; Fuggle, Sue; Harden, Paul N.; Wood, Kathryn J.

    2017-01-01

    Background Renal transplant recipients (RTR) frequently develop complications relating to chronic immunosuppression. Identifying RTR who could safely reduce immunosuppression is therefore highly desirable. We hypothesized that “signatures” described in RTR who have stopped immunosuppression but maintained stable graft function (“operational tolerance”) may enable identification of immunosuppressed RTR who are candidates for immunosuppression minimization. However, the effect of immunosuppression itself on these signatures and circulating B-cell populations is currently unknown. Methods We undertook a cross-sectional study of 117 RTR to assess the effect of immunosuppression upon circulating B cell populations, humoral alloresponse and 2 previously published “signatures” of operational tolerance. Results Immunosuppression associated with alterations in both published “signatures.” Azathioprine associated with a decrease in transitional and naive B-cell numbers and calcineurin inhibition associated with an increase in the number of circulating plasmablasts. However, only azathioprine use associated with the presence of donor-specific anti-HLA IgG antibodies. Calcineurin inhibition associated with an increase in total serum IgM but not IgG. Data were corrected for age, time since last transplant, and other immunosuppression. Conclusions Current signatures of operational tolerance may be significantly affected by immunosuppressive regimen, which may hinder use in their current form in clinical practice. Calcineurin inhibition may prevent the development of long-lasting humoral alloresponses, whereas azathioprine therapy may be associated with donor specific antibody development. PMID:28349125

  17. Effects of an immunosuppressive treatment on the rat prostate

    PubMed Central

    Grabowska, Marta; Kędzierska, Karolina; Michałek, Katarzyna; Słuczanowska-Głąbowska, Sylwia; Grabowski, Maciej; Piasecka, Małgorzata; Kram, Andrzej; Rotter, Iwona; Rył, Aleksandra; Laszczyńska, Maria

    2016-01-01

    The aim of this study was to determine the influence of different combinations of immunosuppressive drugs on the morphology, ultrastructure, and expression of proliferating cell nuclear antigen and cytoskeleton proteins in the rat dorsolateral prostate. The studies were conducted on 48 male Wistar rats. The animals were divided into eight groups: a control group and seven experimental groups. For 6 months, the animals in the experimental groups were administered a combination of drugs including rapamycin (Rapa), cyclosporin A, tacrolimus (Tac), mycophenolate mofetil, and prednisone (Pred), according to the standard three-drug regimens for immunosuppressive therapy used in clinical practice. An evaluation of the morphology and ultrastructure was conducted, and a quantitative evaluation of the expression of proliferating cell nuclear antigen and desmin- and cytokeratin-positive cells with weak, moderate, and strong expression was performed. The combination of Rapa, Tac, and Pred caused the smallest morphological and ultrastructural changes in the rat prostate cells. In the case of rats whose treatment was switched to Rapa monotherapy, a decreased percentage of proliferating cells of both the glandular epithelium and the stroma was found. Decreases in body weight and changes in the expression of cytokeratin and desmin were observed in all the experimental rats. The combination of Rapa, Tac, and Pred would seem to be the most beneficial for patients who do not suffer from prostate diseases. Our results justify the use of inhibitors of the mammalian target of Rapa in the treatment of patients with prostate cancer. The changes in the expression of cytoskeleton proteins may be the result of direct adverse effects of the immunosuppressive drugs, which are studied in this article, on the structure and organization of intermediate filament proteins. PMID:27672312

  18. Putative bronchopulmonary flagellated protozoa in immunosuppressed patients.

    PubMed

    Kilimcioglu, Ali Ahmet; Havlucu, Yavuz; Girginkardesler, Nogay; Celik, Pınar; Yereli, Kor; Özbilgin, Ahmet

    2014-01-01

    Flagellated protozoa that cause bronchopulmonary symptoms in humans are commonly neglected. These protozoal forms which were presumed to be "flagellated protozoa" have been previously identified in immunosuppressed patients in a number of studies, but have not been certainly classified so far. Since no human cases of bronchopulmonary flagellated protozoa were reported from Turkey, we aimed to investigate these putative protozoa in immunosuppressed patients who are particularly at risk of infectious diseases. Bronchoalveolar lavage fluid samples of 110 immunosuppressed adult patients who were admitted to the Department of Chest Diseases, Hafsa Sultan Hospital of Celal Bayar University, Manisa, Turkey, were examined in terms of parasites by light microscopy. Flagellated protozoal forms were detected in nine (8.2%) of 110 cases. Metronidazole (500 mg b.i.d. for 30 days) was given to all positive cases and a second bronchoscopy was performed at the end of the treatment, which revealed no parasites. In conclusion, immunosuppressed patients with bronchopulmonary symptoms should attentively be examined with regard to flagellated protozoa which can easily be misidentified as epithelial cells.

  19. Adherence to immunosuppression: a prospective diary study.

    PubMed

    Gordon, E J; Prohaska, T R; Gallant, M P; Siminoff, L A

    2007-12-01

    Immunosuppression adherence among kidney transplant recipients is essential for graft survival. However, nonadherence is common, jeopardizing graft survival. Besides skipping dosages, little is known about other forms of medication nonadherence and their underlying reasons. This study sought to examine patients' extent of medication adherence over time and reasons for nonadherence. Thirty-nine new kidney transplant recipients were asked to complete a month-long medication-taking diary that included reporting medication nonadherence such as skipped medications, medications taken early or late, taking dosages greater or less than prescribed, and the reason for each occurrence of nonadherence. Of the 20 (51%) patients who completed the diary, 11 (55%) reported at least 1 form of nonadherence. Eleven patients reported taking their immunosuppression at least 1 hour later than the prescribed time, 1 patient reported skipping medication, but no patients reported changing the dosage on their own. Immunosuppression was taken on average 1.5 hours after the prescribed time. Of those patients who took their medications late, there were on average 3.1 occasions of taking it late. The most common reasons for this behavior included health care-related issues, followed by oversleeping, being away from home, work-related barriers, and forgetting. The majority of kidney transplant recipients took medications later than prescribed during 1 month. Future research should determine the clinical impact on graft function of late administration of immunosuppression. Interventions should be designed to better assist kidney recipients with taking medications on time, especially when they are away from home.

  20. Putative Bronchopulmonary Flagellated Protozoa in Immunosuppressed Patients

    PubMed Central

    Kilimcioglu, Ali Ahmet; Havlucu, Yavuz; Çelik, Pınar; Özbilgin, Ahmet

    2014-01-01

    Flagellated protozoa that cause bronchopulmonary symptoms in humans are commonly neglected. These protozoal forms which were presumed to be “flagellated protozoa” have been previously identified in immunosuppressed patients in a number of studies, but have not been certainly classified so far. Since no human cases of bronchopulmonary flagellated protozoa were reported from Turkey, we aimed to investigate these putative protozoa in immunosuppressed patients who are particularly at risk of infectious diseases. Bronchoalveolar lavage fluid samples of 110 immunosuppressed adult patients who were admitted to the Department of Chest Diseases, Hafsa Sultan Hospital of Celal Bayar University, Manisa, Turkey, were examined in terms of parasites by light microscopy. Flagellated protozoal forms were detected in nine (8.2%) of 110 cases. Metronidazole (500 mg b.i.d. for 30 days) was given to all positive cases and a second bronchoscopy was performed at the end of the treatment, which revealed no parasites. In conclusion, immunosuppressed patients with bronchopulmonary symptoms should attentively be examined with regard to flagellated protozoa which can easily be misidentified as epithelial cells. PMID:24804259

  1. Longitudinal dose and type of immunosuppression in a national cohort of Australian liver, heart, and lung transplant recipients, 1984-2006.

    PubMed

    Na, Renhua; Laaksonen, Maarit A; Grulich, Andrew E; Webster, Angela C; Meagher, Nicola S; McCaughan, Geoffrey W; Keogh, Anne M; Vajdic, Claire M

    2015-11-01

    Unconfounded comparative data on the type and dose of immunosuppressive agents among solid organ transplant recipients are sparse, as are data on longitudinal immunosuppressive therapy since transplantation. We addressed this issue in a population-based cohort of Australian liver (n = 1895), heart (n = 1220), and lung (n = 1059) transplant recipients, 1984-2006. Data on immunosuppressive therapy were retrospectively collected at discharge, three months, and one, five, 10, and 15 yr after first transplant. We computed unadjusted and adjusted estimates for the association between the type and dose of immunosuppressive therapy and organ type. After adjustment for confounders, use of induction antibody and maintenance corticosteroids was more common in heart and lung compared to liver recipients (p < 0.001), and antibody therapy for rejection more common in liver recipients (p < 0.001). Liver recipients were more likely to receive calcineurin inhibitor monotherapy, with or without corticosteroids, compared to heart and lung recipients (p < 0.001). Liver recipients consistently received lower doses of azathioprine than heart and lung recipients (p < 0.001). These differences in immunosuppression may partly explain variations in immunosuppression-related morbidity by transplanted organ, for example, malignancy risk. Longitudinal changes in the type and the dose of immunosuppressive therapy over time since transplantation also demonstrate the need for time-dependent data in observational research.

  2. Manual ventilation therapy and aggressive potassium supplementation in the management of respiratory failure secondary to severe hypokalaemia in a cat with exocrine pancreatic insufficiency.

    PubMed

    Daste, Thomas; Dossin, Olivier; Reynolds, Brice S; Aumann, Marcel

    2014-04-01

    A domestic shorthair cat was referred for progressive muscle weakness and dyspnoea. The cat had a 2-month history of severe weight loss, small intestinal diarrhoea, polyphagia and polyuria/polydipsia. Biochemical analysis and venous blood gas evaluation revealed severe hypokalaemia [1.7 mmol/l; reference interval (RI): 3.5-5.1 mmol/l] and hypoventilation (partial pressure of carbon dioxide = 68 mmHg; RI: 34-38 mmHg). Aggressive potassium supplementation was initiated. The cat was manually ventilated until serum potassium increased to 3 mmol/l. A diagnosis of exocrine pancreatic insufficiency (EPI) was made based on clinical signs and serum feline trypsin-like immunoreactivity (0.1 μg/l; RI: 12-82 μg/l). Medical management of the EPI resulted in clinical recovery.

  3. Immunosuppressive effect induced by intraperitoneal and rectal administration of boar seminal immunosuppressive factor.

    PubMed

    Dostál, J; Veselský, L; Drahorád, J; Jonáková, V

    1995-06-01

    The immunosuppressive component was isolated from boar seminal vesicle secretion and administered i.p. or rectally to male mice. By means of the immunofluorescent method, the seminal immunosuppressive component was found on the membranes of 50-70% of white blood cells of treated mice the first day after i.p. and the third day after rectal administration. The immunosuppressive component was observed on the membranes of 10-20% of white cells even at the 17th day after treatment. Intraperitoneal or rectal administration of the immunosuppressive component led to a decrease in the white cell concentration in blood of treated mice. These findings indicate that rectal deposition of semen may compromise some aspects of the immune system and may be an important cofactor in the development of viral or bacterial infections among homosexual men.

  4. Alternative matrices for therapeutic drug monitoring of immunosuppressive agents using LC-MS/MS.

    PubMed

    Ghareeb, Mwlod; Akhlaghi, Fatemeh

    2015-01-01

    Immunosuppressive drugs used in solid organ transplants typically have narrow therapeutic windows and high intra- and intersubject variability. To ensure satisfactory exposure, therapeutic drug monitoring (TDM) plays a pivotal role in any successful posttransplant maintenance therapy. Currently, recommendations for optimum immunosuppressant concentrations are based on blood/plasma measurements. However, they introduce many disadvantages, including poor prediction of allograft survival and toxicity, a weak correlation with drug concentrations at the site of action and the invasive nature of the sample collection. Thus, alternative matrices have been investigated. This paper reviews tandem-mass spectrometry (LC-MS/MS) methods used for the quantification of immunosuppressant drugs utilizing nonconventional matrices, namely oral fluids, fingerprick blood and intracellular and intratissue sampling. The advantages, disadvantages and clinical application of such alternative mediums are discussed. Additionally, sample extraction techniques and basic chromatography information regarding these methods are presented in tabulated form.

  5. Histological spectrum of pulmonary manifestations in kidney transplant recipients on sirolimus inclusive immunosuppressive regimens

    PubMed Central

    2012-01-01

    Background After the introduction of novel effective immunosuppressive therapies, kidney transplantation became the treatment of choice for end stage renal disease. While these new therapies lead to better graft survival, they can also cause a variety of complications. Only small series or case reports describe pulmonary pathology in renal allograft recipients on mTOR inhibitor inclusive therapies. The goal of this study was to provide a systematic review of thoracic biopsies in kidney transplant recipients for possible association between a type of immunosuppressive regimen and pulmonary complications. Methods A laboratory database search revealed 28 of 2140 renal allograft recipients (18 males and 10 females, 25 to 77 years old, mean age 53 years) who required a biopsy for respiratory symptoms. The histological features were correlated with clinical findings including immunosuppressive medications. Results The incidence of neoplasia on lung biopsy was 0.4% (9 cases), which included 3 squamous cell carcinomas, 2 adenocarcinomas, 1 diffuse large B-cell lymphoma, 1 lymphomatoid granulomatosis, and 2 post transplant B-cell lymphoproliferative disorders. Diffuse parenchymal lung disease was identified in 0.4% (9 cases), and included 5 cases of pulmonary hemorrhage, 3 cases of organizing pneumonia and 1 case of pulmonary alveolar proteinosis. Five (0.2%) cases showed histological features indicative of a localized infectious process. Patients on sirolimus had neoplasia less frequently than patients on other immunosuppressive combinations (12.5% vs. 58.3%, p = 0.03). Lung biopsies in 4 of 5 patients with clinically suspected sirolimus toxicity revealed pulmonary hemorrhage as the sole histological finding or in combination with other patterns. Conclusions Our study documents a spectrum of neoplastic and non-neoplastic lesions in renal allograft recipients on current immunosuppressive therapies. Sirolimus inclusive regimens are associated with increased risk of pulmonary

  6. Immunosuppression Enhances Oncolytic Adenovirus Replication and Antitumor Efficacy in the Syrian Hamster Model

    PubMed Central

    Thomas, Maria A; Spencer, Jacqueline F; Toth, Karoly; Sagartz, John E; Phillips, Nancy J; Wold, William SM

    2012-01-01

    We recently described an immunocompetent Syrian hamster model for oncolytic adenoviruses (Ads) that permits virus replication in tumor cells as well as some normal tissues. This model allows exploration of interactions between the virus, tumor, normal organs, and host immune system that could not be examined in the immunodeficient or nonpermissive animal models previously used in the oncolytic Ad field. Here we asked whether the immune response to oncolytic Ad enhances or limits antitumor efficacy. We first determined that cyclophosphamide (CP) is a potent immunosuppressive agent in the Syrian hamster and that CP alone had no effect on tumor growth. Importantly, we found that the antitumor efficacy of oncolytic Ads was significantly enhanced in immunosuppressed animals. In animals that received virus therapy plus immunosuppression, significant differences were observed in tumor histology, and in many cases little viable tumor remained. Notably, we also determined that immunosuppression allowed intratumoral virus levels to remain elevated for prolonged periods. Although favorable tumor responses can be achieved in immunocompetent animals, the rate of virus clearance from the tumor may lead to varied antitumor efficacy. Immunosuppression, therefore, allows sustained Ad replication and oncolysis, which leads to substantially improved suppression of tumor growth. PMID:18665155

  7. Immunosuppression enhances oncolytic adenovirus replication and antitumor efficacy in the Syrian hamster model.

    PubMed

    Thomas, Maria A; Spencer, Jacqueline F; Toth, Karoly; Sagartz, John E; Phillips, Nancy J; Wold, William S M

    2008-10-01

    We recently described an immunocompetent Syrian hamster model for oncolytic adenoviruses (Ads) that permits virus replication in tumor cells as well as some normal tissues. This model allows exploration of interactions between the virus, tumor, normal organs, and host immune system that could not be examined in the immunodeficient or nonpermissive animal models previously used in the oncolytic Ad field. Here we asked whether the immune response to oncolytic Ad enhances or limits antitumor efficacy. We first determined that cyclophosphamide (CP) is a potent immunosuppressive agent in the Syrian hamster and that CP alone had no effect on tumor growth. Importantly, we found that the antitumor efficacy of oncolytic Ads was significantly enhanced in immunosuppressed animals. In animals that received virus therapy plus immunosuppression, significant differences were observed in tumor histology, and in many cases little viable tumor remained. Notably, we also determined that immunosuppression allowed intratumoral virus levels to remain elevated for prolonged periods. Although favorable tumor responses can be achieved in immunocompetent animals, the rate of virus clearance from the tumor may lead to varied antitumor efficacy. Immunosuppression, therefore, allows sustained Ad replication and oncolysis, which leads to substantially improved suppression of tumor growth.

  8. Dynamic Immune Cell Recruitment After Murine Pulmonary Aspergillus fumigatus Infection under Different Immunosuppressive Regimens

    PubMed Central

    Kalleda, Natarajaswamy; Amich, Jorge; Arslan, Berkan; Poreddy, Spoorthi; Mattenheimer, Katharina; Mokhtari, Zeinab; Einsele, Hermann; Brock, Matthias; Heinze, Katrin Gertrud; Beilhack, Andreas

    2016-01-01

    Humans are continuously exposed to airborne spores of the saprophytic fungus Aspergillus fumigatus. However, in healthy individuals pulmonary host defense mechanisms efficiently eliminate the fungus. In contrast, A. fumigatus causes devastating infections in immunocompromised patients. Host immune responses against A. fumigatus lung infections in immunocompromised conditions have remained largely elusive. Given the dynamic changes in immune cell subsets within tissues upon immunosuppressive therapy, we dissected the spatiotemporal pulmonary immune response after A. fumigatus infection to reveal basic immunological events that fail to effectively control invasive fungal disease. In different immunocompromised murine models, myeloid, notably neutrophils, and macrophages, but not lymphoid cells were strongly recruited to the lungs upon infection. Other myeloid cells, particularly dendritic cells and monocytes, were only recruited to lungs of corticosteroid treated mice, which developed a strong pulmonary inflammation after infection. Lymphoid cells, particularly CD4+ or CD8+ T-cells and NK cells were highly reduced upon immunosuppression and not recruited after A. fumigatus infection. Moreover, adoptive CD11b+ myeloid cell transfer rescued cyclophosphamide immunosuppressed mice from lethal A. fumigatus infection but not cortisone and cyclophosphamide immunosuppressed mice. Our findings illustrate that CD11b+ myeloid cells are critical for anti-A. fumigatus defense under cyclophosphamide immunosuppressed conditions. PMID:27468286

  9. Clinical Trials for Immunosuppression in Transplantation; The Case for Reform and Change in Direction.

    PubMed

    O'Connell, Philip J; Kuypers, Dirk; Mannon, Roslyn R; Abecassis, Michael; Chadban, Stephen; Gill, John S; Murphy, Barbara; Nickerson, Peter W; Schold, Jesse D; Stock, Peter; Seron, Daniel; Alloway, Rita; Bromberg, Jonathan; Budde, Klemens; Jordan, Stanley; Legendre, Christophe; Lefaucheur, Carmen; Sarwall, Minnie; Segev, Dorry; Stegall, Mark D; Tullius, Stefan G; Wong, Germaine; Woodle, E Steve; Ascher, Nancy; Morris, Randall E

    2017-02-15

    Currently trials of immunosuppression in transplantation are in decline because their objectives remain focused on improving acute rejection rates and graft survival in the first 12 months. With 1 year renal graft survival rates of greater than 90% the best that can be hoped for is noninferiority trial outcomes compared to current standard of care. Current trial design is not leading to novel therapies improving long term outcomes and safety, and hence important unmet clinical needs in transplantation remain unanswered. Issues that need to be addressed include but are not limited to: prevention of subclinical rejection in the first year, better 5 and 10 year graft outcomes, more effective treatment for high immunological risk and sensitized (including DSA) patients, immunosuppressive combinations that are better tolerated by patients with fewer side effects and less morbidity and mortality. In September 2015 the Transplantation Society convened a group of transplant clinical trial experts to address these problems. The aims were to substantially realign the priorities of clinical trials for renal transplant immunosuppression with the current unmet needs and to propose new designs for clinical trials for transplant immunosuppression. Moving forward, the transplant community needs to provide trial data that will identify superior treatment options for patient subgroups and allow new agents to be evaluated for efficacy and safety and achieve timely regulatory approval. Trial designs for new transplant immunosuppression must be intelligently restructured in order to ensure that short- and long-term clinical outcomes continue to improve.

  10. Successful administration of aggressive chemotherapy concomitant to tuberculostatic and highly active antiretroviral therapy in a patient with AIDS-related Burkitt's lymphoma.

    PubMed

    Lehmann, C; Wyen, C; Hoffmann, C; Fätkenheuer, G

    2005-01-01

    Treatment of AIDS-related malignant lymphoma (ARL) remains a therapeutic challenge. There are concerns not only about infectious and haematological complications in HIV-infected patients during intensive chemotherapy, but also about potential interactions between chemotherapy and highly active antiretroviral therapy (HAART). Current data on patients treated concomitantly with intensive chemotherapy and HAART are limited, and no data exist on patients with ARL suffering from active opportunistic infections. We report the case of a 38-year-old man with advanced HIV-1 infection, pulmonary tuberculosis and Burkitt's lymphoma. Intensive chemotherapy was administered in parallel with tuberculostatic therapy and HAART. Six months later, the patient achieved not only a complete remission of Burkitt's lymphoma and sustained viral suppression, but also a full recovery from tuberculosis. This case report provides some useful observations on the successful application of intensive chemotherapy in addition to tuberculostatic therapy and HAART in HIV-infected patients.

  11. Aggressive local therapy combined with systemic chemotherapy provides long-term control in grade II stage 2 canine mast cell tumour: 21 cases (1999-2012).

    PubMed

    Lejeune, A; Skorupski, K; Frazier, S; Vanhaezebrouck, I; Rebhun, R B; Reilly, C M; Rodriguez, C O

    2015-09-01

    This retrospective case series evaluates the outcome of 21 dogs with grade II stage 2 mast cell tumour (MCT) treated with adequate local therapy and adjuvant systemic chemotherapy (prednisone, vinblastine and CCNU). The median survival for all dogs was 1359 days (range, 188-2340). Median disease-free interval was 2120 days (149-2325 days). Dogs treated with surgery and chemotherapy had shorter survival (median, 1103 days; 188-2010 days) than those that underwent surgery, radiation therapy and chemotherapy as part of their treatment (median, 2056 days; 300-2340 days). Two patients had local recurrence in the radiation field and four patients had de novo MCT. Distant metastasis was not observed in any dogs. The results of this study suggest that, in the presence of loco-regional lymph node metastasis in grade II MCT, the use of prednisone, vinblastine and CCNU after adequate local-regional therapy can provide a median survival in excess of 40 months.

  12. Addressing canine and feline aggression in the veterinary clinic.

    PubMed

    Moffat, Kelly

    2008-09-01

    Handling aggressive dogs and cats in the veterinary clinic can be frustrating, time consuming, and injurious for both employee and animal. This article discusses the etiology of the aggressive dog and cat patient and how best to approach these cases. A variety of handling techniques, safety products, and drug therapy are reviewed.

  13. Circulating and thymic CD4 CD25 T regulatory cells in myasthenia gravis: effect of immunosuppressive treatment.

    PubMed

    Fattorossi, Andrea; Battaglia, Alessandra; Buzzonetti, Alexia; Ciaraffa, Francesca; Scambia, Giovanni; Evoli, Amelia

    2005-09-01

    Accumulating evidence indicates an immunosuppressive role of the thymus-derived CD4+ T-cell population constitutively expressing high level of CD25, T regulatory (Treg) cells, in autoimmune diseases. Here we show that the number of Treg cells in the blood is significantly lower in untreated myasthenia gravis patients than in age-matched healthy subjects, whereas it is normal or elevated in patients on immunosuppressive therapy (prednisone frequently associated with azathioprine). Therapeutic thymectomy (Tx) for either the thymoma or non-neoplastic thymic alterations that are often associated with myasthenia gravis provided unique material for studying intrathymic Treg cells and correlating them with their peripheral counterparts. We observed that Tx prevents the increase of Treg cells in the circulation that follows immunosuppressive therapy (particularly evident if the thymus is not neoplastic), indicating that the thymus contributes to Treg-cell normalization. However, thymic Treg cells are not modulated by immunosuppressive therapy and even in thymectomized patients Treg-cell numbers in the blood eventually recover. The present findings suggest that a deficiency in Treg cells favours the development of myasthenia gravis and that their normalization is an important clinical benefit of immunosuppressive therapy. Treg normalization appears to be largely thymus independent and possibly reflects the reported capacity of corticosteroids to promote Treg-cell development.

  14. Testosterone and Aggression.

    ERIC Educational Resources Information Center

    Archer, John

    1994-01-01

    Studies comparing aggressive and nonaggressive prisoners show higher testosterone levels among the former. While there is limited evidence for a strong association between aggressiveness and testosterone during adolescence, other studies indicate that testosterone levels are responsive to influences from the social environment, particularly those…

  15. Social Aggression among Girls.

    ERIC Educational Resources Information Center

    Underwood, Marion K.

    Noting recent interest in girls' social or "relational" aggression, this volume offers a balanced, scholarly analysis of scientific knowledge in this area. The book integrates current research on emotion regulation, gender, and peer relations, to examine how girls are socialized to experience and express anger and aggression from infancy…

  16. Neuropsychiatry of Aggression

    PubMed Central

    Lane, Scott D.; Kjome, Kimberly L.; Moeller, F. Gerard

    2010-01-01

    Synopsis Aggression is a serious medical problem that can place both the patient and the health care provider at risk. Aggression can result from medical, neurologic and or psychiatric disorders. A comprehensive patient evaluation is needed. Treatment options include pharmacotherapy as well as non-pharmacologic interventions, both need to be individualized to the patient. PMID:21172570

  17. Humor, Aggression, and Aging.

    ERIC Educational Resources Information Center

    Barrick, Ann Louise; And Others

    Although humor is an important phenomenon in human interactions, it has rarely been studied in the elderly. An understanding of responses to humor in aggressive cartoons as a function of advancing age would provide information regarding both the development of humor and the negative (aggressive) emotional experiences of the elderly. This study was…

  18. Serotonin and Aggression.

    ERIC Educational Resources Information Center

    Brown, Serena-Lynn; And Others

    1994-01-01

    Decreased serotonin function has consistently been shown to be highly correlated with impulsive aggression across a number of different experimental paradigms. Such lowered serotonergic indices appear to correlate with the dimension of aggression dyscontrol and/or impulsivity rather than with psychiatric diagnostic categories per se. Implications…

  19. Training Aggressive Adolescents in Prosocial Behavior

    ERIC Educational Resources Information Center

    Goldstein, Arnold P.; And Others

    1978-01-01

    Structured Learning Therapy (SLT) teaches aggressive adolescents prosocial skills (negotiation, self-relaxation, and anger control) by modeling, role playing, social reinforcement, and transfer of training. This article summarizes initial application of SLT with psychiatric clients, includes guidelines for improving trainee-trainer-treatment…

  20. Reversal of tumor-mediated immunosuppression.

    PubMed

    Vieweg, Johannes; Su, Zhen; Dahm, Philipp; Kusmartsev, Sergei

    2007-01-15

    Therapeutic cancer vaccines, one form of active immunotherapy, have long been under investigation; consequently, several vaccine-based strategies have now moved from the bench to the clinical arena. Despite their tremendous promise, current vaccine strategies have shown only limited success in clinical settings, even in renal cell carcinoma (RCC), a prototypical malignancy for the application of immunotherapy. There is ample evidence that, especially in RCC, multiple immunosuppressive mechanisms exist that considerably dampen antitumor responses and weaken the activity of current immunotherapeutic regimens. Therefore, it will be necessary to reverse tumor-mediated immunosuppression before immunotherapies can successfully be applied. Recent insights into the nature and characteristics of the regulatory elements of the immune system have provided new opportunities to enhance vaccine-mediated antitumor immunity and, thereby, increase the chance for improving patient outcome. These new insights represent important considerations for the future design and application of more effective cancer vaccines against RCC and other cancers.

  1. Brief Report: Comparative Effects of Antecedent Exercise and Lorazepam on the Aggressive Behavior of an Autistic Man.

    ERIC Educational Resources Information Center

    Allison, David B.; And Others

    1991-01-01

    This case study of a 24-year-old man with autistic disorder and mental retardation who exhibited aggression found that antecedent exercise significantly decreased aggression; drug therapy with an anxiolytic (lorazepam) alone had no significant effect on aggression; and exercise plus medication decreased aggression to a somewhat lesser degree than…

  2. Immunosuppressive lignans isolated from Saururus chinensis.

    PubMed

    Park, Shin-Young; Lee, Sung Hak; Choi, Woo Hyuck; Koh, Eun Mi; Seo, Jee Hee; Ryu, Shi Yong; Kim, Young Sup; Kwon, Dae Young; Koh, Woo Suk

    2007-06-01

    Bioactivity-guided fractionation of Saururus chinensis (Saururaceae) using a lymphoproliferation assay led us to isolate 5 lignans (compounds 1 - 5). Compounds 1 - 5 were identified as sauchinone, (-)-saucerneol, saucerneol C, manassantin A, and manassantin B, respectively, by spectroscopic analyses. The immunosuppressive activities of the active compounds were evaluated using lymphoproliferation, mixed leukocyte response, and Th1/Th2 cytokine assays. The relative potency was in the order: manassantin A, B > (-)-saucerneol > saucerneol C > sauchinone.

  3. Natalizumab in aggressive multiple sclerosis after haematopoietic stem cell transplantation.

    PubMed

    Capobianco, Marco; Motuzova, Y; Frau, J; Cocco, E; Mamusa, E; Marrosu, M G; Bertolotto, A

    2012-08-01

    High-dose cyclophosphamide followed by autologous haematopoietic stem cell transplantation (HDC-AHSCT) is a treatment option for aggressive and refractory multiple sclerosis (MS). Natalizumab is a monoclonal antibody approved for relapsing-remitting (RR) MS unresponsive to immunomodulating drugs. Nothing is known about the use of natalizumab in patients after HDC-AHSCT. We describe five female RR-MS patients with incomplete response to HDC-AHSCT. Natalizumab was then administered with abolition of both MRI and clinical activity. No severe adverse events, in particular opportunistic infections such as Progressive Multifocal Leukoencephalopathy (PML), were observed. Our results suggest that the use of natalizumab in aggressive RR-MS after HDC-AHSCT could be effective and safe. The very long-term risk of adverse events due to sequential aggressive immunosuppression has to be established.

  4. Ceramide structure predicts tumor ganglioside immunosuppressive activity.

    PubMed Central

    Ladisch, S; Li, R; Olson, E

    1994-01-01

    Molecular determinants of biological activity of gangliosides are generally believed to be carbohydrate in nature. However, our studies of immunomodulation by highly purified naturally occurring tumor gangliosides provide another perspective: while the immunosuppressive activity of gangliosides requires the intact molecule (both carbohydrate and ceramide moieties), ceramide structure strikingly influences ganglioside immunosuppressive activity. Molecular species of human neuroblastoma GD2 ganglioside in which the ceramide contains a shorter fatty acyl chain (C16:0, C18:0) were 6- to 10-fold more active than those with a longer fatty acyl chain (C22:0/C24:1, C24:0). These findings were confirmed in studies of ceramide species of human leukemia sialosylparagloboside and murine lymphoma GalNAcGM1b. Gangliosides that contain shorter-chain fatty acids (and are most immunosuppressive) are known to be preferentially shed by tumor cells. Therefore, the results suggest that the tumor cell is optimized to protect itself from host immune destruction by selective shedding of highly active ceramide species of gangliosides. Images PMID:8127917

  5. Immunosuppression associated with chronic inflammation in the tumor microenvironment

    PubMed Central

    Wang, Dingzhi; DuBois, Raymond N.

    2015-01-01

    Chronic inflammation contributes to cancer development via multiple mechanisms. One potential mechanism is that chronic inflammation can generate an immunosuppressive microenvironment that allows advantages for tumor formation and progression. The immunosuppressive environment in certain chronic inflammatory diseases and solid cancers is characterized by accumulation of proinflammatory mediators, infiltration of immune suppressor cells and activation of immune checkpoint pathways in effector T cells. In this review, we highlight recent advances in our understanding of how immunosuppression contributes to cancer and how proinflammatory mediators induce the immunosuppressive microenvironment via induction of immunosuppressive cells and activation of immune checkpoint pathways. PMID:26354776

  6. Toxicity of aggressive multimodality therapy including cisplatinum, bleomycin and methotrexate with radiation and/or surgery for advanced head and neck cancer

    SciTech Connect

    Weichselbaum, R.R.; Posner, M.R.; Ervin, T.J.; Fabian, R.L.; Miller, D.

    1982-05-01

    A combined modality regimen employing induction chemotherapy with cisplatinum, bleomycin and methotrexate followed by surgery and/or radiation therapy was initiated in patients with advanced squamous cell carcinoma of the head and neck. In the first 23 patients treated with this program there was a 90% response rate to induction chemotherapy (9% CR and 81% PR). Toxicity associated with radiotherapy, but not surgery, was increased with 11 of 23 patients (48%) who experienced some toxicity during or immediately after radiotherapy. Mucositis was worse than expected and severe delayed mucositis was seen in 2 patients, one of whom required hospitalization. Late complications, possibly related to therapy included one myocardial infarction and one episode of hypoglycemia, both of which were fatal. One other patient voluntarily failed to take prescribed oral leucovorin, dying of unrescued methotrexate toxicity during adjuvant therapy, a questionable suicide. Further follow-up analysis of failure will be necessary to determine if the value of a combined modality regimen in producing an increased cure rate and long term survival will out weigh increased toxicity.

  7. A case of disseminated sporotrichosis treated with prednisolone, immunosuppressants, and tocilizumab under the diagnosis of rheumatoid arthritis.

    PubMed

    Yamaguchi, Tetsuto; Ito, Satoshi; Takano, Yohei; Umeda, Naoto; Goto, Mizue; Horikoshi, Masanobu; Hayashi, Taichi; Goto, Daisuke; Matsumoto, Isao; Sumida, Takayuki

    2012-01-01

    We encountered a disseminated sporotrichosis patient with polyarthritis and progressive skin ulcers, who had been previously treated with prednisolone, tocilizmab, tacrolims, and cyclophosphamide under the diagnosis of rheumatoid arthritis in another hospital. Making the diagnosis of leukocytoclasticvasculitis based on the clinical observation of skin ulcers, we intensified immunosuppressive therapy. Unfortunately, the patient developed septic shock. Blood culture revealed that the pathogenic organism was sporothrixschenckii. Any case of intractable arthritis or skin ulcers, which does not improve, despite adequate immunosuppressive therapy, is likely to be suspicious of sporotrichosis.

  8. Management of immunosuppressant agents following liver transplantation: Less is more

    PubMed Central

    Ascha, Mustafa S; Ascha, Mona L; Hanouneh, Ibrahim A

    2016-01-01

    Immunosuppression in organ transplantation was revolutionary for its time, but technological and population changes cast new light on its use. First, metabolic syndrome (MS) is increasing as a public health issue, concomitantly increasing as an issue for post-orthotopic liver transplantation patients; yet the medications regularly used for immunosuppression contribute to dysfunctional metabolism. Current mainstay immunosuppression involves the use of calcineurin inhibitors; these are potent, but nonspecifically disrupt intracellular signaling in such a way as to exacerbate the impact of MS on the liver. Second, the impacts of acute cellular rejection and malignancy are reviewed in terms of their severity and possible interactions with immunosuppressive medications. Finally, immunosuppressive agents must be considered in terms of new developments in hepatitis C virus treatment, which undercut what used to be inevitable viral recurrence. Overall, while traditional immunosuppressive agents remain the most used, the specific side-effect profiles of all immunosuppressants must be weighed in light of the individual patient. PMID:26839639

  9. Evidence-based guidelines for laboratory screening for infectious diseases before initiation of systemic immunosuppressive agents in patients with autoimmune bullous dermatoses.

    PubMed

    Keith, P J; Wetter, D A; Wilson, J W; Lehman, J S

    2014-12-01

    Autoimmune bullous dermatoses (ABD) compromise the skin's innate barrier function for preventing infection. Treating patients with ABD frequently requires systemic immunosuppressive therapy, often with multiple agents. Currently, no pretreatment infection testing guidelines are available for clinicians caring for patients with ABD. We performed a systematic literature review in other medical disciplines that use similar iatrogenic immunosuppressive medications to treat various diseases and conditions and developed infection-testing recommendations for patients with ABD before initiating immunosuppressive therapy. Assessing individual patient risk factors for latent infection and preventable communicable diseases can direct testing for select infections before starting immunosuppressive therapy. Testing patients for hepatitis B virus, hepatitis C virus, and Mycobacterium tuberculosis infection is recommended before initiating rituximab treatment.

  10. Aggression and sport.

    PubMed

    Burton, Robert W

    2005-10-01

    Viewing aggression in its healthy form, in contrast to its extreme and inappropriate versions, and sport as a health-promoting exercise in psychological development and maturation may allow participants and spectators alike to retain an interest in aggression and sport and derive further enjoyment from them. In addition, it will benefit all involved with sport to have a broader understanding of human aggression. Physicians, mental health professionals, and other health care providers can be influential in this process, and should be willing to get involved and speak out when issues and problems arise.

  11. Evaluation of Two Treatments for Reactive and Proactive Aggression in Preschool

    ERIC Educational Resources Information Center

    Whitaker, Regina Navonne

    2010-01-01

    Previous research has indicated that preschoolers identified for aggressive behavior would benefit from family, group, or individual therapy. However, there remains an important gap in the current literature regarding treatments for aggressive behavior based on the subtype of aggression. The purpose of this pilot study was to examine if 2…

  12. Aggression in Pretend Play and Aggressive Behavior in the Classroom

    ERIC Educational Resources Information Center

    Fehr, Karla K.; Russ, Sandra W.

    2013-01-01

    Research Findings: Pretend play is an essential part of child development and adjustment. However, parents, teachers, and researchers debate the function of aggression in pretend play. Different models of aggression predict that the expression of aggression in play could either increase or decrease actual aggressive behavior. The current study…

  13. Future of Medicare Immunosuppressive Drug Coverage for Kidney Transplant Recipients in the United States

    PubMed Central

    Stone, Patricia W.; Mohan, Sumit; Cohen, David J.; Gaston, Robert S.

    2013-01-01

    Summary Kidney transplantation is the preferred treatment for patients with ESRD. It improves the quality of life in recipients, increases patient survival, and is also substantially less costly than maintenance dialysis. Long-term transplant success requires immunosuppressant drug therapy for the life of the allograft. Under current law, Medicare coverage for most recipients (except for those recipients over 65 years of age or with nonkidney-related disabilities) lasts only 3 years, leaving many recipients unable to afford these medications. Lack of drug therapy often leads to allograft rejection, resulting in premature graft failure, return to dialysis, or death. This article reviews the current policy for Medicare immunosuppressive drug coverage and analyzes the potential impact of pending legislative proposals H.R. 2969 and S. 1454 and the Patient Protection and Affordable Care Act. PMID:23559679

  14. Impact of immunosuppressive drugs on the therapeutic efficacy of ex vivo expanded human regulatory T cells

    PubMed Central

    Scottà, Cristiano; Fanelli, Giorgia; Hoong, Sec Julie; Romano, Marco; Lamperti, Estefania Nova; Sukthankar, Mitalee; Guggino, Giuliana; Fazekasova, Henrieta; Ratnasothy, Kulachelvy; Becker, Pablo D.; Afzali, Behdad; Lechler, Robert I.; Lombardi, Giovanna

    2016-01-01

    Immunosuppressive drugs in clinical transplantation are necessary to inhibit the immune response to donor antigens. Although they are effective in controlling acute rejection, they do not prevent long-term transplant loss from chronic rejection. In addition, immunosuppressive drugs have adverse side effects, including increased rate of infections and malignancies. Adoptive cell therapy with human Tregs represents a promising strategy for the induction of transplantation tolerance. Phase I/II clinical trials in transplanted patients are already underway, involving the infusion of Tregs alongside concurrent immunosuppressive drugs. However, it remains to be determined whether the presence of immunosuppressive drugs negatively impacts Treg function and stability. We tested in vitro and in vivo the effects of tacrolimus, mycophenolate and methylprednisolone (major ISDs used in transplantation) on ex vivo expanded, rapamycin-treated human Tregs. The in vitro results showed that these drugs had no effect on phenotype, function and stability of Tregs, although tacrolimus affected the expression of chemokine receptors and IL-10 production. However, viability and proliferative capacity were reduced in a dose-dependent manner by all the three drugs. The in vivo experiments using a humanized mouse model confirmed the in vitro results. However, treatment of mice with only rapamycin maintained the viability, function and proliferative ability of adoptively transferred Tregs. Taken together, our results suggest that the key functions of ex vivo expanded Tregs are not affected by a concurrent immunosuppressive therapy. However, the choice of the drug combination and their timing and dosing should be considered as an essential component to induce and maintain tolerance by Treg. PMID:26471483

  15. Impact of cyclosporine in the development of immunosuppressive therapy.

    PubMed

    Chaverri, C

    2004-03-01

    Cyclosporine has been of great interest to the transplant community during the last 20 years. It has permitted an evolution of knowledge through the changes in its original galenic formulation of Sandimmune to Neoral, and now through the recent application of the knowledge of pharmacodynamics and pharmacokinetics to tailor drug doses to each individual. The achievements of cyclosporine are still valid and possibly will be for the next years.

  16. Metabolic consequences of modern immunosuppressive agents in solid organ transplantation

    PubMed Central

    Bamgbola, Oluwatoyin

    2016-01-01

    Among other factors, sophistication of immunosuppressive (IS) regimen accounts for the remarkable success attained in the short- and medium-term solid organ transplant (SOT) survival. The use of steroids, mycophenolate mofetil and calcineurin inhibitors (CNI) have led to annual renal graft survival rates exceeding 90% in the last six decades. On the other hand, attrition rates of the allograft beyond the first year have remained unchanged. In addition, there is a persistent high cardiovascular (CV) mortality rate among transplant recipients with functioning grafts. These shortcomings are in part due to the metabolic effects of steroids, CNI and sirolimus (SRL), all of which are implicated in hypertension, new onset diabetes after transplant (NODAT), and dyslipidemia. In a bid to reduce the required amount of harmful maintenance agents, T-cell-depleting antibodies are increasingly used for induction therapy. The downsides to their use are greater incidence of opportunistic viral infections and malignancy. On the other hand, inadequate immunosuppression causes recurrent rejection episodes and therefore early-onset chronic allograft dysfunction. In addition to the adverse metabolic effects of the steroid rescue needed in these settings, the generated proinflammatory milieu may promote accelerated atherosclerotic disorders, thus setting up a vicious cycle. The recent availability of newer agent, belatacept holds a promise in reducing the incidence of metabolic disorders and hopefully its long-term CV consequences. Although therapeutic drug monitoring as applied to CNI may be helpful, pharmacodynamic tools are needed to promote a customized selection of IS agents that offer the most benefit to an individual without jeopardizing the allograft survival. PMID:27293540

  17. Everolimus immunosuppression in kidney transplantation: What is the optimal strategy?

    PubMed

    Witzke, Oliver; Sommerer, Claudia; Arns, Wolfgang

    2016-01-01

    Two main everolimus-based strategies have been pursued to facilitate calcineurin inhibitor (CNI) reduction after kidney transplantation: (i) everolimus with reduced CNI exposure from time of transplant and (ii) pre-emptive introduction of everolimus with CNI reduction or withdrawal at some point post-transplant. Randomized trials have shown no loss of immunosuppressive efficacy for everolimus (targeting 3-8 ng/mL) with reduced-exposure CNI versus standard-exposure CNI and mycophenolic acid (MPA) in low-to-moderate risk patients. Renal function has tended to be numerically, but not significantly, higher with everolimus and reduced-CNI versus MPA and standard-CNI. One study which used very low CsA exposure in everolimus-treated patients reported a substantial improvement in estimated GFR compared to controls, but this requires confirmation. Pre-emptive conversion to everolimus at three to six months after kidney transplantation significantly improves long-term renal function, but with an increased rate of mild acute rejection. Earlier conversion (up to two months post-transplant) can lead to an increase in rejection risk, while later conversion (more than six months post-transplant) is unproductive unless baseline renal function is good. This article considers the risks and benefits associated with either strategy, and reviews specific clinical situations that influence the optimal approach in individual patients. The balance of evidence suggests two options. De novo everolimus with reduced CNI, steroids and induction therapy ensures immunosuppressive efficacy in low- or standard-risk populations, and investigations into this strategy are ongoing. Conversion to everolimus with CNI withdrawal between three and six months post-transplant offers a long-term renoprotective effect if baseline graft function is good.

  18. Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2).

    PubMed

    Collins, Peter; Baudo, Francesco; Knoebl, Paul; Lévesque, Hervé; Nemes, László; Pellegrini, Fabio; Marco, Pascual; Tengborn, Lilian; Huth-Kühne, Angela

    2012-07-05

    Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level.

  19. Local brain heavy ion irradiation induced Immunosuppression

    NASA Astrophysics Data System (ADS)

    Lei, Runhong; Deng, Yulin; Huiyang Zhu, Bitlife.; Zhao, Tuo; Wang, Hailong; Yu, Yingqi; Ma, Hong; Wang, Xiao; Zhuang, Fengyuan; Qing, Hong

    Purpose: To investigate the long term effect of acute local brain heavy ion irradiation on the peripheral immune system in rat model. Methodology: Only the brain of adult male Wistar rats were radiated by heavy ions at the dose of 15 Gy. One, two and three months after irradiation, thymus and spleen were analyzed by four ways. Tunel assay was performed to evaluate the percentage of apoptotic cells in thymus and spleen, level of Inflammatory cytokines (IL-2, IL-6, SSAO, and TNF-α) was detected by ELISA assay, the differentiation of thymus T lymphocyte subsets were measured by flow cytometry and the relative expression levels of genes related to thymus immune cell development were measured by using quantitative real-time PCR. Results: Thymus and spleen showed significant atrophy from one month to three months after irradiation. A high level of apoptosis in thymus and spleen were obtained and the latter was more vulnerable, also, high level of inflammatory cytokines were found. Genes (c-kit, Rag1, Rag2 and Sca1) related to thymus lymphocytes’ development were down-regulated. Conclusion: Local area radiation in the rat brain would cause the immunosuppression, especially, the losing of cell-mediated immune functions. In this model, radiation caused inflammation and then induced apoptosis of cells in the immune organs, which contributed to immunosuppression.

  20. Distinct immunosuppressive effect by Isodon serra extracts.

    PubMed

    Zhang, Yan; Liu, Jianwen; Jia, Wei; Zhao, Aihua; Li, Ting

    2005-12-01

    Distinct effect of ent-Kaurene Diterpenoids from Isodon serra on abnormal proliferation of murine lymphocytes was examined with MTT assay and Flow Cytometry Analyses (FCAS). After choosing the most appropriate monomer from these Diterpenoids, we introduced mouse tumescence model to investigate whether it could impact cytokine production in vivo with ELISA assay. The result of MTT assay showed that four ent-Kaurene Diterpenoids could effectively suppress the murine splenic T lymphocytes overproduction stimulated by Concanavalin A, while inhibitive effect was softer on normal sleep lymphocytes than the stimulated ones. Among four ent-Kaurene Diterpenoids, Enmein was the most sensitive one with IC50/EC50 equaling to 1.55. This inhibitive activity was due to interfering DNA replication in G1-S stage and to regulating cell cycle according to flow cytometry analyses (FCAS) result. Xylene-induced mouse tumescence model result further suggested that Enmein depressed the murine ear swelling extent and the level of Interleukin-2 in blood serum in a dose-dependent manner. In conclusion, it demonstrated that four ent-Kaurene Diterpenoids from I. serra had distinct immunosuppressive effect in vitro and in vivo systems, which primarily differentiated Enmein from the others. The experimental results provided insight into a potential immunosuppressive action of Enmein as a promising drug, though profound mechanism remained to be further studied.

  1. Effects of age, gender, and immunosuppressive agents on in vivo toll-like receptor pathway responses.

    PubMed

    Khan, Niamat; Summers, Colin W; Helbert, Matthew R; Arkwright, Peter D

    2010-04-01

    Toll-like receptors (TLRs) are important in the initiation of immune responses in both health and disease. How TLR activity alters with age, gender, and also with immunosuppressive agents is still largely unexplored. We studied TLR activity in 49 healthy individuals as well as in 26 patients receiving immunosuppressive drugs. TLR activity did not alter significantly between the ages of 2 and 67 years. However, females had twice the TLR7 ligand-induced interferon-I response of males (OR [95% CI] 2.7 [1.4-5.1]), whereas TLR3 and four activities were not significantly different between the sexes. The T-cell immunosuppressant agents cyclosporine, tacrolimus, and azathioprine, as well as low dose glucocorticosteroids did not significantly alter TLR pathway responses. In contrast, high dose glucocorticosteroids reduced in vivo TLR responses by 70%-90%. We suggest that gender differences in TLR responses may help to explain the female preponderance of some autoimmune disorders. Furthermore, an understanding the effects of immunosuppressive agents on TLR-pathway activity should allow more focused therapy for autoimmune disorders.

  2. Differential potency of regulatory T cell-mediated immunosuppression in kidney tumors compared to subcutaneous tumors

    PubMed Central

    Devaud, Christel; Westwood, Jennifer A; Teng, Michele WL; John, Liza B; Yong, Carmen SM; Duong, Connie PM; Smyth, Mark J; Darcy, Phillip K; Kershaw, Michael H

    2014-01-01

    In many cancers, regulatory T cells (Treg) play a crucial role in suppressing the effector immune response thereby permitting tumor development. Indeed, in mouse models, their depletion can promote the regression of tumors of various origins, including renal cell carcinoma when located subcutaneous (SC). In the present study, we aimed to assess the importance of Treg immunosuppression in the physiologic context of metastatic renal carcinoma (Renca) disease. To that purpose we inoculated renal tumors orthotopically, intra-kidney (IK), in mice. Treg depletions were performed using anti-CD4 antibody in wild type mice or diphtheria toxin (DT) in Foxp3DTR transgenic mice. Our main observation was that Treg were not the key immunosuppressive component of the IK tumoral microenvironment, compared to the same tumors located SC. We demonstrated that the CD8+ effector immune response was still suppressed in IK tumors when compared to SC tumors, following Treg depletion. Furthermore, the level of program cell death protein (PD)-1 was increased on the surface of CD4+ T cells infiltrating IK tumors compared to SC tumors. Finally, the Treg-independent immunosuppression, occurring in IK tumors, was potent enough to inhibit regression of concomitant SC tumors, normally responsive to Treg depletion. Our findings provide further insight into the immunosuppressive nature of the immune response generated in the kidney microenvironment, suggesting that it can have additional mechanisms in addition to Treg. These observations might help to identify better targets from the kidney tumor microenvironment for future cancer therapies. PMID:25941590

  3. Differential potency of regulatory T cell-mediated immunosuppression in kidney tumors compared to subcutaneous tumors.

    PubMed

    Devaud, Christel; Westwood, Jennifer A; Teng, Michele Wl; John, Liza B; Yong, Carmen Sm; Duong, Connie Pm; Smyth, Mark J; Darcy, Phillip K; Kershaw, Michael H

    2014-11-01

    In many cancers, regulatory T cells (Treg) play a crucial role in suppressing the effector immune response thereby permitting tumor development. Indeed, in mouse models, their depletion can promote the regression of tumors of various origins, including renal cell carcinoma when located subcutaneous (SC). In the present study, we aimed to assess the importance of Treg immunosuppression in the physiologic context of metastatic renal carcinoma (Renca) disease. To that purpose we inoculated renal tumors orthotopically, intra-kidney (IK), in mice. Treg depletions were performed using anti-CD4 antibody in wild type mice or diphtheria toxin (DT) in Foxp3(DTR) transgenic mice. Our main observation was that Treg were not the key immunosuppressive component of the IK tumoral microenvironment, compared to the same tumors located SC. We demonstrated that the CD8(+) effector immune response was still suppressed in IK tumors when compared to SC tumors, following Treg depletion. Furthermore, the level of program cell death protein (PD)-1 was increased on the surface of CD4(+) T cells infiltrating IK tumors compared to SC tumors. Finally, the Treg-independent immunosuppression, occurring in IK tumors, was potent enough to inhibit regression of concomitant SC tumors, normally responsive to Treg depletion. Our findings provide further insight into the immunosuppressive nature of the immune response generated in the kidney microenvironment, suggesting that it can have additional mechanisms in addition to Treg. These observations might help to identify better targets from the kidney tumor microenvironment for future cancer therapies.

  4. How to treat splenic marginal zone lymphoma (SMZL) in patients unfit for surgery or more aggressive therapies: experience in 30 cases.

    PubMed

    Cervetti, Giulia; Ghio, Francesco; Cecconi, Nadia; Morganti, Riccardo; Galimberti, Sara; Petrini, Mario

    2017-04-01

    Splenic marginal zone lymphoma (SMZL) is an indolent disease that typically affects elderly patients. Thanks to its outcome, most patients don't need any specific therapy and 'a watch and wait' policy is frequently employed. Treatment is required in symptomatic cases. Splenectomy remains one of the first line options in patients fit for surgery. The best pharmacological strategy has not yet been identified for poor surgical risk cases. Amongst different possible chemotherapeutic approaches, alkylating agents, alone or in association with Rituximab, could employ in 'frail' patients. In the present study, the role of oral cyclophosphamide (100 mg per day for 15 consecutive days, every 30 for a total of six cycles) associated with anti-CD20 monoclonal antibody has been evaluated in 30 newly diagnosed SMZL patients, not fit for splenectomy or more toxic chemotherapic regimens. Overall response rate was 87% (CR 70%; PR 17%). Median PFS was 20 months (range, 1-53), with better outcome for low-risk cases according to IIL score prognostic index. Toxicity profile resulted mild.

  5. Immunosuppression in pediatric liver transplant recipients: Unique aspects.

    PubMed

    Miloh, Tamir; Barton, Andrea; Wheeler, Justin; Pham, Yen; Hewitt, Winston; Keegan, Tara; Sanchez, Christine; Bulut, Pinar; Goss, John

    2017-02-01

    Pediatric liver transplantation has experienced improved outcomes over the last 50 years. This can be attributed in part to establishing optimal use of immunosuppressive agents to achieve a balance between minimizing the risks of allograft rejection and infection. The management of immunosuppression in children is generally more complex and can be challenging when compared with the use of these agents in adult liver transplant patients. Physiologic differences in children alter the pharmacokinetics of immunosuppressive agents, which affects absorption, distribution, metabolism, and drug excretion. Children also have a longer expected period of exposure to immunosuppression, which can impact growth, risk of infection (bacterial, viral, and fungal), carcinogenesis, and likelihood of nonadherence. This review discusses immunosuppressive options for pediatric liver transplant recipients and the unique issues that must be addressed when managing this population. Further advances in the field of tolerance and accommodation are needed to relieve the acute and cumulative burden of chronic immunosuppression in children. Liver Transplantation 23 244-256 2017 AASLD.

  6. Immunosuppression of Allogenic Mesenchymal Stem Cells Transplantation after Spinal Cord Injury Improves Graft Survival and Beneficial Outcomes

    PubMed Central

    Torres-Espín, Abel; Redondo-Castro, Elena; Hernandez, Joaquim

    2015-01-01

    Abstract Cell therapy for spinal cord injury (SCI) is a promising strategy for clinical application. Mesenchymal stem cells (MSC) have demonstrated beneficial effects following transplantation in animal models of SCI. However, despite the immunoprivilege properties of the MSC, their survival in the injured spinal cord is reduced due to the detrimental milieu in the damaged tissue and immune rejection of the cells. The limited survival of the engrafted cells may determine the therapy success. Therefore, we compared two strategies to increase the presence of the cells in the injured spinal cord in rats: increasing the amount of MSC transplants and using immunosuppressive treatment with FK506 after transplantation. Functional outcomes for locomotion and electrophysiological responses were assessed. The grafted cells survival and the amount of cavity and spared tissue were studied. The findings indicate that immunosuppression improved grafted cells survival. A cell–dose effect was found regarding locomotion recovery and tissue protection independent of immunosuppression. Nevertheless, immunosuppression enhanced the electrophysiological outcomes and allowed filling of the cavity formed after injury by new regenerative tissue and axons. These results indicate that MSC transplantation combined with immunosuppression prolongs the survival of engrafted cells and improves functional and morphological outcomes after SCI. PMID:25203134

  7. Aggressive lymphoma in the elderly.

    PubMed

    Lichtman, S M

    2000-02-01

    Persons 65 years of age and older are the fastest growing segment of the United States population. Over the next 30 years they will comprise approximately 20% of the population. There will be a parallel rise in the number of patients with non-Hodgkin's lymphoma. Age has long been known to be an adverse prognostic factor. Clinical trials of older patients are complicated by the effect of comorbid illness, particularly its effect on overall survival. CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone) remains the standard therapy for all patients with aggressive non-Hodgkin's lymphoma. There are a number of regimens which may be beneficial for older patients with significant comorbidity and poor performance status. The randomized trials in the elderly has reaffirmed CHOP and emphasize the need for adequate dosing, maintaining schedule and anthracyclines. Relapsed patients have a poor prognosis but selected fit older patients may benefit from aggressive reinduction regimens and possibly bone marrow transplantation. Future research should include defining the role of comorbidity, measurement of organ dysfunction and assessment of performance status with geriatric functional scales. New drug treatments should also be explored.

  8. Response-adapted therapy for aggressive non-Hodgkin's lymphomas based on early [18F] FDG-PET scanning: ECOG-ACRIN Cancer Research Group study (E3404).

    PubMed

    Swinnen, Lode J; Li, Hailun; Quon, Andrew; Gascoyne, Randy; Hong, Fangxin; Ranheim, Erik A; Habermann, Thomas M; Kahl, Brad S; Horning, Sandra J; Advani, Ranjana H

    2015-07-01

    A persistently positive positron emission tomography (PET) scan during therapy for diffuse large B-cell lymphoma (DLBCL) is predictive of treatment failure. A response-adapted strategy consisting of an early treatment change to four cycles of R-ICE (rituximab, ifosfamide, carboplatin, etoposide) was studied in the Eastern Cooperative Oncology Group E3404 trial. Previously untreated patients with DLBCL stage III, IV, or bulky II, were eligible. PET scan was performed after three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and scored as positive or negative by central review during the fourth cycle. PET-positive patients received four cycles of R-ICE, PET-negative patients received two more cycles of R-CHOP. A ≥ 45% 2-year progression-free survival (PFS) for mid-treatment PET-positive patients was viewed as promising. Of 74 patients, 16% were PET positive, 79% negative. The PET positivity rate was much lower than the 33% expected. Two-year PFS was 70%; 42% [90% confidence interval (CI), 19-63%] for PET-positives and 76% (90% CI 65-84%) for PET-negatives. Three-year overall survival (OS) was 69% (90% CI 43-85%) and 93% (90% CI 86-97%) for PET-positive and -negative cases, respectively. The 2-year PFS for mid-treatment PET-positive patients intensified to R-ICE was 42%, with a wide confidence interval due to the low proportion of positive mid-treatment PET scans. Treatment modification based on early PET scanning should remain confined to clinical trials.

  9. [Infections and immunosuppressive agents in rheumatology].

    PubMed

    Kahn, M F; Vitale, C; Grimaldi, A

    The authors review the problem of infection occurring in patients with chronic inflammatory rheumatism, e.g. rheumatoid arthritis, and lupus erythematosus, treated with cytolytic drugs for immunodepressive reasons. From their investigation, it seems that there is a high frequency of bacterial and mycotic and viral infections in these patients, but controlled investigations seem to show quite definitely that the frequency of these infections depends on the disease itself. The risk does not seem to be increased by cytolytic drugs. The only exception is herpes which appears in 10 to 20% of patients treated with immunosuppressive agents, as against 2% in a controll series. The other virus diseases did not have an abnormally high frequency. The conclusions are, of course, only of value for the types of treatment used in rheumatology.

  10. Photodynamic therapy for treatment of AIDS-related mucocutaneous Kaposi's sarcoma (Invited Paper)

    NASA Astrophysics Data System (ADS)

    Schweitzer, Vanessa G.

    1992-06-01

    Since 1975, Phase I/II studies have demonstrated the successfulness of hematoporphyrin derivative photodynamic therapy (PDT) in the treatment of various malignancies of the skin, eye, bladder, lung, and head and neck. Moreover, in 1981 two cases of traditional Western cutaneous Kaposi's sarcoma (TKS) have been treated with photodynamic therapy with both early and late complete response. To date, attempts to cure and palliation of the more aggressive AIDS-related oral Kaposi's sarcoma with conventional radiation, chemotherapy or immunotherapy, or surgical excision have been limited and often associated with debilitating mucositis and further immunosuppression. Certain aspects of photodynamic therapy may be efficacious for treatment of mucocutaneous Kaposi's sarcoma: (1) the selective retention of hematoporphyrin derivative by neoplastic lesions (endothelial cell tumors); (2) a tumor- specific cytotoxic agent (i.e., free oxygen radical); (3) absence of systemic toxicity from immunosuppression; (4) the potential for retreatment without increasing side effects; and (5) porphyrin-mediated photoinactivation of enveloped viruses. Herein presented are seven cases of AIDS-related KS (EKS) with diffuse, superficial, and nodular mucocutaneous lesions treated with dihematoporphyrin derivative and photodynamic therapy with subsequent dramatic early partial and complete responses.

  11. Posterior Reversible Encephalopathy Syndrome and Fatal Cryptococcal Meningitis After Immunosuppression in a Patient With Elderly Onset Inflammatory Bowel Disease

    PubMed Central

    Vasant, Dipesh H.; Limdi, Jimmy K.; Borg-Bartolo, Simon P.; Bonington, Alec

    2016-01-01

    Advanced age and associated comorbidities are-recognized predictors of life-threatening adverse outcomes, such as opportunistic infection following immunosuppressive therapy. We describe the case of an elderly patient with stricturing colonic Crohn’s disease and significant clinical comorbidities, initially controlled with corticosteroid induction followed by infliximab, whose course was complicated by fatal disseminated cryptococcal infection and posterior reversible encephalopathy syndrome. Our patient’s case highlights rare, but serious, complications of immunosuppression. In applying modern treatment paradigms to the elderly, the clinician must consider the potential for more pronounced adverse effects in this potentially vulnerable group, maximizing benefit and minimizing harm. PMID:27807560

  12. Stability of Aggressive Behavior.

    ERIC Educational Resources Information Center

    Eron, Leonard D.; Huesmann, L. Rowell

    As indicated by multiple measures (including overt criminal behavior), stability of aggressive behavior was investigated across 22 years for males and females in a variety of situations. Originally, subjects included the entire population enrolled in the third grade in a semi-rural county in New York State. The sample included approximately 870…

  13. Aggressiveness and Disobedience

    ERIC Educational Resources Information Center

    Vaaland, Grete Sorensen; Idsoe, Thormod; Roland, Erling

    2011-01-01

    This study aims to conceptualize disobedient pupil behavior within the more general framework of antisocial behavior and to reveal how two forms of aggressiveness are related to disobedience. Disobedience, in the context of this article, covers disruptive pupil behavior or discipline problems when the pupil is aware of breaking a standard set by…

  14. Intellectual Competence and Aggression.

    ERIC Educational Resources Information Center

    Huesmann, L. Rowell; Yarmel, Patty Warnick

    Using data from a broader longitudinal study, this investigation explores within-subject and cross-generational stability of intellectual competence and the relationship of such stability to aggressive behavior. Data were gathered three times (when subjects' modal age was 8, 19, and 30 years). Initially, subjects included the entire population…

  15. Relational Aggression among Students

    ERIC Educational Resources Information Center

    Young, Ellie L.; Nelson, David A.; Hottle, America B.; Warburton, Brittney; Young, Bryan K.

    2011-01-01

    "Relational aggression" refers to harm within relationships caused by covert bullying or manipulative behavior. Examples include isolating a youth from his or her group of friends (social exclusion), threatening to stop talking to a friend (the silent treatment), or spreading gossip and rumors by email. This type of bullying tends to be…

  16. Neuroimaging and Aggression.

    ERIC Educational Resources Information Center

    Mills, Shari; Raine, Adrian

    1994-01-01

    Brain imaging research allows direct assessment of structural and functional brain abnormalities, and thereby provides an improved methodology for studying neurobiological factors predisposing to violent and aggressive behavior. This paper reviews 20 brain imaging studies using four different types of neuroimaging techniques that were conducted in…

  17. Human Aggression and Suicide

    ERIC Educational Resources Information Center

    Brown, Gerald L.; Goodwin, Frederick K

    1986-01-01

    The central nervous system transmitter serontonin may be altered in aggressive/impulsive and suicidal behaviors in humans. These reports are largely consistent with animal data, and constitute one of the most highly replicated set of findings in biological psychiatry. Suggests that some suicidal behavior may be a special kind of aggressive…

  18. Parents' Aggressive Influences and Children's Aggressive Problem Solutions with Peers

    ERIC Educational Resources Information Center

    Duman, Sarah; Margolin, Gayla

    2007-01-01

    This study examined children's aggressive and assertive solutions to hypothetical peer scenarios in relation to parents' responses to similar hypothetical social scenarios and parents' actual marital aggression. The study included 118 children ages 9 to 10 years old and their mothers and fathers. Children's aggressive solutions correlated with…

  19. Relational Aggression and Physical Aggression among Adolescent Cook Islands Students

    ERIC Educational Resources Information Center

    Page, Angela; Smith, Lisa F.

    2016-01-01

    Both physical and relational aggression are characterised by the intent to harm another. Physical aggression includes direct behaviours such as hitting or kicking; relational aggression involves behaviours designed to damage relationships, such as excluding others, spreading rumours, and delivering threats and verbal abuse. This study extended…

  20. Food safety for the solid organ transplant patient: preventing foodborne illness while on chronic immunosuppressive drugs.

    PubMed

    Obayashi, Patricia A C

    2012-12-01

    Issues regarding food safety are seen increasingly in the news; outbreaks of foodborne illness have been associated with public health concerns ranging from mild illness to death. For the solid organ transplant patient, immunosuppressive and antibacterial drugs, which maintain transplant organ function, can expose the transplant patient to increased risk of foodborne illness from bacteria, viruses, fungi, and parasites. This review article describes the clinical consequences, sources of foodborne illness, and food safety practices needed to minimize risks to the solid organ transplant patient who must take lifelong immunosuppressive drugs. All members of the transplant team share responsibility for education of the solid organ transplant patient in preventing infections. The registered dietitian, as part of the transplant team, is the recognized expert in providing food safety education in the context of medical nutrition therapy to solid organ transplant patients, the patients' caregivers, and other healthcare providers.

  1. Differential modulation of apoptosis and necrosis by antioxidants in immunosuppressed human lymphocytes.

    PubMed

    Rojas, Mauricio; Rugeles, María Teresa; Gil, Diana Patricia; Patiño, Pablo

    2002-04-15

    In the present study, we explored whether mitogenic stimulation of dexamethasone (DXM)- and cyclosporine A (CsA)-immunosuppressed peripheral blood lymphocytes (PBML) induced apoptosis or necrosis and their relation with the production of reactive oxygen intermediates. Our results indicate that both phenomena can occur in these cells and that antioxidants such as N-acetyl cysteine (NAC) and ascorbic acid (AA) can modulate them. However, DXM-induced apoptosis was only partially inhibited by NAC and AA, suggesting that DXM-treated PBMC had an additional apoptotic pathway independent of ROIs. Furthermore, we observed that the inhibition of apoptosis by antioxidants correlated with an increased cell proliferation, suggesting that the immunomodulation of both DXM and CsA may be related to induction of apoptosis. The ability to differentially modulate apoptosis and necrosis by antioxidants opens new possibilities in the management of immunosuppressive therapy, since the inhibition of necrosis may avoid inflammation and the tissue damage associated with immunosuppressors.

  2. Therapeutic efficacies of chitosan against Pneumocystis pneumonia of immunosuppressed rat.

    PubMed

    Liu, A-B; Pu, Y; Zheng, Y-Q; Cai, H; Ye, B

    2014-07-01

    This study was designed to investigate the therapeutic efficacy of chitosan on Pneumocystis pneumonia (PCP) in immunosuppressed rats. The PCP rat model was established using intramuscular injections of dexamethasone sodium phosphate. To estimate treatment effects of chitosan on rat PCP, weight gain, lung weight, lung weight/body weight (LW/BW) ratio and per cent survival were measured and the HSP70 mRNA expression of Pneumocystis carinii was detected using real-time PCR analysis. Rat lung tissues were stained with HE, and their pathological changes, inflammatory cells and alveolar macrophages were observed by light microscopy. Rat lymphocyte numbers and the concentrations of IL-10, IFN-γ and TNF-α were measured by flow cytometry and ELISA analysis. Additionally, the ultrastructure of P. carinii was examined by electron microscopy to evaluate the effects of chitosan on the protist. Our results demonstrated that chitosan has some apparent treatment effects on rat PCP by reducing HSP70 mRNA expression and lung inflammation, increasing the concentrations of IL-10 and IFN-γ as well as CD4(+) T-lymphocyte numbers, reducing the CD8(+) T-lymphocyte numbers and the concentration of TNF-α and inducing significant ultrastructural damage to P. carinii. Although its precise therapeutic mechanism has yet to be determined, these results lay a theoretical foundation for PCP chitosan therapy.

  3. Impulsive Aggression as a Comorbidity of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents

    PubMed Central

    Amann, Birgit H.

    2016-01-01

    Abstract Objective: This article examines the characteristics of impulsive aggression (IA) as a comorbidity in children and adolescents with attention-deficit/hyperactivity disorder (ADHD), focusing on its incidence, impact on ADHD outcomes, need for timely intervention, and limitations of current treatment practices. Methods: Relevant literature was retrieved with electronic searches in PubMed and PsycINFO using the search strategy of “ADHD OR attention deficit hyperactivity disorder” AND “impulsive aggression OR reactive aggression OR hostile aggression OR overt aggression” AND “pediatric OR childhood OR children OR pre-adolescent OR adolescent” with separate searches using review OR clinical trial as search limits. Key articles published before the 2007 Expert Consensus Report on IA were identified using citation analysis. Results: More than 50% of preadolescents with ADHD combined subtype reportedly display clinically significant aggression, with impulsive aggression being the predominant subtype. Impulsive aggression is strongly predictive of a highly unfavorable developmental trajectory characterized by the potential for persistent ADHD, increasing psychosocial burden, accumulating comorbidities, serious lifelong functional deficits across a broad range of domains, delinquency/criminality, and adult antisocial behavior. Impulsive aggression, which triggers peer rejection and a vicious cycle of escalating dysfunction, may be a key factor in unfavorable psychosocial outcomes attributed to ADHD. Because severe aggressive behavior does not remit in many children when treated with primary ADHD therapy (i.e., stimulants and behavioral therapy), a common practice is to add medication of a different class to specifically target aggressive behavior. Conclusions: Impulsive aggression in children and adolescents with ADHD is a serious clinical and public health problem. Although adjunctive therapy with an aggression-targeted agent is widely recommended when

  4. Immunosuppression for progressive membranous nephropathy: a UK randomised controlled trial

    PubMed Central

    Howman, Andrew; Chapman, Tracey L; Langdon, Maria M; Ferguson, Caroline; Adu, Dwomoa; Feehally, John; Gaskin, Gillian J; Jayne, David RW; O'Donoghue, Donal; Boulton-Jones, Michael; Mathieson, Peter W

    2013-01-01

    Summary Background Membranous nephropathy leads to end-stage renal disease in more than 20% of patients. Although immunosuppressive therapy benefits some patients, trial evidence for the subset of patients with declining renal function is not available. We aimed to assess whether immunosuppression preserves renal function in patients with idiopathic membranous nephropathy with declining renal function. Methods This randomised controlled trial was undertaken in 37 renal units across the UK. We recruited patients (18–75 years) with biopsy-proven idiopathic membranous nephropathy, a plasma creatinine concentration of less than 300 μmol/L, and at least a 20% decline in excretory renal function measured in the 2 years before study entry, based on at least three measurements over a period of 3 months or longer. Patients were randomly assigned (1:1:1) by a random number table to receive supportive treatment only, supportive treatment plus 6 months of alternating cycles of prednisolone and chlorambucil, or supportive treatment plus 12 months of ciclosporin. The primary outcome was a further 20% decline in renal function from baseline, analysed by intention to treat. The trial is registered as an International Standard Randomised Controlled Trial, number 99959692. Findings We randomly assigned 108 patients, 33 of whom received prednisolone and chlorambucil, 37 ciclosporin, and 38 supportive therapy alone. Two patients (one who received ciclosporin and one who received supportive therapy) were ineligible, so were not included in the intention-to-treat analysis, and 45 patients deviated from protocol before study end, mostly as a result of minor dose adjustments. Follow up was until primary endpoint or for minimum of 3 years if primary endpoint was not reached. Risk of further 20% decline in renal function was significantly lower in the prednisolone and chlorambucil group than in the supportive care group (19 [58%] of 33 patients reached endpoint vs 31 [84%] of 37, hazard

  5. Prevention of infection in immunosuppressive patients with autoimmune nephrosis by using an immunostimulating bacterial lysate Broncho-vaxom

    PubMed Central

    Zhang, Miao; Luan, Hong; Zhang, Qian; Wang, Le; Lv, Yong-Man; He, Fan; Chen, Yan; Zeng, Hong-Bing; Yao, Ying; Liu, Qin

    2012-01-01

    The utilization of immunosuppressive agents presents patients with autoimmune nephrosis at a high risk of infection. The present trial was to investigate the efficacy and safety of Broncho-Vaxom on preventing infection in immunosuppressive patients with autoimmune nephrosis. Methods: 40 patients with autoimmune nephrosis were randomly divided into two groups. The control group (20 cases) routinely received corticosteroid and (or) immunosuppressive therapy, while the treatment group (20 cases) received a capsule containing 7 mg Broncho-Vaxom daily for the first 10 d of each month for 3 consecutive months on the basis of conventional corticosteroid and (or) immunosuppressive therapy. The condition of infection and blood lymphocyte were assessed. Results: 4 patients in the treatment group and 5 patients in the control group were lost during the follow-up period. 25% of patients in the treatment group and 40% of patients in the control group suffered infection. There was no difference in the incidence of infection between the two groups (p > 0.05), while Broncho-Vaxom treated patients suffered a shorter infection period and of which fewer patients need to receive antibiotics therapy (p < 0.05). After the treatment with Broncho-Vaxom, the total number of blood T lymphocyte, proportion of CD4+ T lymphocyte, CD4+/CD8+ reduced less and the serum IgG rose more obviously (p < 0.05), but the blood lymphocyte, B lymphocyte, CD8+ T lymphocyte, IgA and IgM have no differences between the two groups (p > 0.05). Conclusion: Broncho-Vaxom might be a good choice for preventing the respiratory infection in nephrosis, especially in the patients under the therapy of immunosuppressive agents. PMID:22922768

  6. Serotonin and Aggressiveness in Chickens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Serotonin (5-HT) regulates aggressive behavior in animals. This study examined if 5-HT regulation of aggressiveness is gene-dependent. Chickens from two divergently selected lines KGB and MBB (Kind Gentle Birds and Mean Bad Birds displaying low and high aggressiveness, respectively) and DXL (Dekalb ...

  7. Immunosuppression during Rhizobium-legume symbiosis.

    PubMed

    Luo, Li; Lu, Dawei

    2014-01-01

    Rhizobium infects host legumes to elicit new plant organs, nodules where dinitrogen is fixed as ammonia that can be directly utilized by plants. The nodulation factor (NF) produced by Rhizobium is one of the determinant signals for rhizobial infection and nodule development. Recently, it was found to suppress the innate immunity on host and nonhost plants as well as its analogs, chitins. Therefore, NF can be recognized as a microbe/pathogen-associated molecular pattern (M/PAMP) like chitin to induce the M/PAMP triggered susceptibility (M/PTS) of host plants to rhizobia. Whether the NF signaling pathway is directly associated with the innate immunity is not clear till now. In fact, other MAMPs such as lipopolysaccharide (LPS), exopolysaccharide (EPS) and cyclic-β-glucan, together with type III secretion system (T3SS) effectors are also required for rhizobial infection or survival in leguminous nodule cells. Interestingly, most of them play similarly negative roles in the innate immunity of host plants, though their signaling is not completely elucidated. Taken together, we believe that the local immunosuppression on host plants induced by Rhizobium is essential for the establishment of their symbiosis.

  8. Immunosuppression and human cancer: role of prostaglandins.

    PubMed

    Harvey, H A; Allegra, J C; Demers, L M; Luderer, J R; Brenner, D E; Trautlein, J J; White, D S; Gillin, M A; Lipton, A

    1977-06-01

    Prostaglandins, unsaturated fatty acid derivatives with diversified pharmacologic activity, have been implicated in the pathophysiology of many diseases. Prostaglandin E (PGE) levels were measured by radioimmunoassay in the plasma of 41 normocalcemic patients with various stages of malignancies. Delayed hypersensitivity was assessed by a battery of six recall skin test antigens (ST) and by Dinitrochlorobenzene (DNCB) sensitization and challenge. Twenty-five patients with one or more positive skin tests had a mean PGE level of 87+/-8 pg/ml, whereas 16 patients with negative ST had a mean PGE level of 96+/-12 pg/ml. Twenty-one DNCB negative patients had a mean PGE level of 98+/-12 pg/ml and eight totally anergic patients had a mean PGE of 96+/-12 pg/ml. All PGE values were within the normal range and there was no statistical difference between the four groups. (p less than 0.1). We concluded that circulating PGE does not correlate with the non-specific immunosuppression seen in cancer patients.

  9. Immunosuppressive mechanisms in protein-calorie malnutrition

    SciTech Connect

    Redmond, H.P.; Shou, J.; Kelly, C.J.; Schreiber, S.; Miller, E.; Leon, P.; Daly, J.M. )

    1991-08-01

    Protein-calorie malnutrition (PCM) induces immunosuppression leading to increased mortality rates. Impaired macrophage respiratory burst activity (superoxide anion (O2-) generation) occurs in PCM, but cellular mechanisms are unclear. The major pathway resulting in O2- production involves inositol lipid-dependent signal transduction. This study examined the effect of mild versus severe PCM on macrophage O2- generating signal transduction pathways specific for responses to Candida albicans. Mice (CFW/Swiss Webster: n = 300) were randomized to either control or low protein diets for 3 or 8 weeks. Peritoneal macrophages were harvested for O2- production, mannose-fucose receptor (MFR) expression, membrane phospholipid analysis, arachidonic acid (AA) content, prostaglandin E2 (PGE2) production, and protein kinase C levels. O2- release was impaired in both mild and severe PCM. MFR expression was also decreased at these time points. Inositol lipid content was significantly lower at the 8-week time point only, although PGE2 and AA were significantly higher in the low protein diet group at 3 weeks. Protein kinase C levels were unchanged by PCM. Thus, mild PCM significantly increases macrophage-PGE2 production secondary to increased AA phospholipid content, with subsequent inhibition of O2- and MFR expression. Severe PCM inhibits macrophage (O2-) through depletion of critical membrane phospholipid components with subsequent impairment in signal transduction.

  10. Renoprotective strategies in lupus nephritis: beyond immunosuppression.

    PubMed

    Griffin, B; Lightstone, L

    2013-10-01

    Lupus nephritis needs to be diagnosed promptly and treated specifically with appropriate immunosuppression. However, all patients with lupus nephritis have by definition chronic kidney disease (CKD) as they will have proteinuria with varying degrees of renal impairment. CKD requires careful additional management, not only to reduce the risk of progression to end-stage renal disease but also because it is probably the strongest risk for cardiovascular morbidity and mortality. This review focuses on the evidence underscoring strategies to prevent progression of CKD beyond the "simple" treatment of the lupus nephritis. The strategies include immaculate control of blood pressure, inhibition of the renin-angiotensin system to reduce blood pressure and proteinuria, and the benefits of lifestyle modifications such as tackling smoking, obesity and exercise. We also review the literature on control of dyslipidaemias which, although clearly of cardiovascular benefit, provide less compelling data for offering renoprotection. We touch on the emerging area of the importance of controlling urate levels in protecting against progressive renal impairment. Finally, there is a reminder about the importance of considering the nephrotoxicity of all medications prescribed for patients with lupus nephritis - above all the need to avoid the use of non-steroidal anti-inflammatory drugs. Overall, the theme is that there is much more to the management of patients with lupus nephritis than "just" the nephritis - a multidisciplinary approach involving nephrologists as well as rheumatologists is more likely to provide the appropriate wider care required for all patients with lupus nephritis.

  11. Chemotherapy-Induced IL34 Enhances Immunosuppression by Tumor-Associated Macrophages and Mediates Survival of Chemoresistant Lung Cancer Cells.

    PubMed

    Baghdadi, Muhammad; Wada, Haruka; Nakanishi, Sayaka; Abe, Hirotake; Han, Nanumi; Putra, Wira Eka; Endo, Daisuke; Watari, Hidemichi; Sakuragi, Noriaki; Hida, Yasuhiro; Kaga, Kichizo; Miyagi, Yohei; Yokose, Tomoyuki; Takano, Atsushi; Daigo, Yataro; Seino, Ken-Ichiro

    2016-10-15

    The ability of tumor cells to escape immune destruction and their acquired resistance to chemotherapy are major obstacles to effective cancer therapy. Although immune checkpoint therapies such as anti-PD-1 address these issues in part, clinical responses remain limited to a subpopulation of patients. In this report, we identified IL34 produced by cancer cells as a driver of chemoresistance. In particular, we found that IL34 modulated the functions of tumor-associated macrophages to enhance local immunosuppression and to promote the survival of chemoresistant cancer cells by activating AKT signaling. Targeting IL34 in chemoresistant tumors resulted in a remarkable inhibition of tumor growth when accompanied with chemotherapy. Our results define a pathogenic role for IL34 in mediating immunosuppression and chemoresistance and identify it as a tractable target for anticancer therapy. Cancer Res; 76(20); 6030-42. ©2016 AACR.

  12. Group Music Intervention Reduces Aggression and Improves Self-esteem in Children with Highly Aggressive Behavior: A Pilot Controlled Trial

    PubMed Central

    Lee, Myeong Soo; Lee, Jung-Sook

    2010-01-01

    We investigated the effects of group music intervention on aggression and self-esteem in children with highly aggressive behavior. Forty-eight children were allocated to either a music intervention group or an untreated control group. The music intervention group received 50 min of music intervention twice weekly for 15 consecutive weeks. The outcome measures were Child Behavior Checklist Aggression Problems Scale (Parents), Child Aggression Assessment Inventory (Teachers) and Rosenberg Self-esteem Scale. After 15 weeks, the music intervention group showed significant reduction of aggression and improvement of self-esteem compared with the control group. All outcome measures were significantly lower in the music intervention group than prior to treatment, while there was no change in the control group. These findings suggest that music can reduce aggressive behavior and improve self-esteem in children with highly aggressive behavior. Music intervention is an easily accessible therapy for children and as such may be an effective intervention for aggressive behavior. Further more, objective and replicable measures are required from a randomized controlled trial with a larger sample size and active comparable control. PMID:18955314

  13. Two Cases of Cutaneous Squamous Cell Carcinoma Arising in Immunosuppressed Patients with Chronic Human Papillomavirus Infection

    PubMed Central

    Kuma, Yuki; Ito, Takamichi; Nagae, Konosuke; Mizote, Yukihiro; Nakahara, Takeshi; Uchi, Hiroshi; Yamada, Yuichi; Okura, Masae; Oda, Yoshinao; Yamashita, Toshiharu; Furue, Masutaka

    2015-01-01

    Increasing evidence has suggested that human papillomaviruses (HPVs) are linked to a large subset of numerous malignant tumors, including mucosal squamous cell carcinoma (SCC); however, its involvement in cutaneous SCC has not fully been elucidated. Cutaneous SCC is the second most common type of skin cancer and is increasing in frequency every year. Since we have no satisfactory treatment for advanced SCC, it is important to provide a definitive diagnosis and appropriate therapeutic intervention at an early stage. Here, we present two cases of SCC arising in immunosuppressed patients. In these cases, we suspected the association between SCC and HPV infection histopathologically and succeeded in proving the presence of high-risk type HPV by PCR analysis (HPV 14 in case 1 and HPV 23 and 38 in case 2). Although it is unclear whether HPV actually induced SCC in our cases, our cases showed rapid progression comparing to typical courses of actinic keratosis (AK)/SCC. SCC and AK are common diseases; in daily practice, dermatologists examine many patients with immunosuppression of various causes. We should apply increased oncological vigilance to these patients to prevent an aggressive course of SCC/AK. PMID:26351427

  14. Septic arthritis in immunocompetent and immunosuppressed hosts.

    PubMed

    Wang, Dingyuan Alvin; Tambyah, Paul Anantharajah

    2015-04-01

    Septic arthritis has long been considered an orthopedic emergency. Historically, Neisseria gonorrhoeae and Staphylococcus aureus have been the most common causes of septic arthritis worldwide but in the modern era of biological therapy and extensive use of prosthetic joint replacements, the spectrum of microbiological causes of septic arthritis has widened considerably. There are also new approaches to diagnosis but therapy remains a challenge, with a need for careful consideration of a combined medical and surgical approach in most cases.

  15. A RANDOMIZED PILOT STUDY OF SYSTEMIC IMMUNOSUPPRESSION IN THE TREATMENT OF AGE-RELATED MACULAR DEGENERATION WITH CHOROIDAL NEOVASCULARIZATION

    PubMed Central

    Nussenblatt, Robert B.; Byrnes, Gordon; Sen, H. Nida; Yeh, Steven; Faia, Lisa; Meyerle, Catherine; Wroblewski, Keith; Li, Zhuqing; Liu, Baoying; Chew, Emily; Sherry, Patti R.; Friedman, Penelope; Ferris, Frederick

    2011-01-01

    Background Age-related macular degeneration remains the leading cause of irreversible blindness in the United States and the developed world. Intravitreal injections of anti–vascular endothelial growth factor (VEGF) medications have become standard of care for the treatment of the wet form of the disease. Recent reports have demonstrated an association with various immune factors. We aimed to investigate the effect of immunosuppressive therapy in the clinical course of the wet form of the disease. We compared anti-VEGF therapy plus one of three systemic immunosuppressive therapies versus anti-VEGF therapy alone for recurrent choroidal neovascularization associated with age-related macular degeneration. Methods This was a pilot, Phase I/II, prospective, randomized, unmasked, single-center trial. Patients with subretinal exudation secondary to recurrent choroidal neovascularization associated with age-related macular degeneration were included in the study. Patients were randomized to 1 of 3 systemic arms immunosuppressive agents (daclizumab, rapamycin, or infliximab) for 6 months plus intraocular anti-VEGF therapy if indicated, compared with a group who received only anti-VEGF therapy if indicated. Results The number of anti-VEGF injections per group, visual acuity, retinal thickness, and safety measures were assessed in all groups. Thirteen patients were randomized; comparing anti-VEGF injections before and during the study, a decrease in the number of injections from 0.73 injections per month to 0.42 for daclizumab and from 0.67 to 0.34 for sirolimus was seen, while no apparent decrease was seen for either infliximab or observation. Visual acuities were maintained in all groups. Conclusion These preliminary data suggest that some immunosuppressive agents given systemically can alter the clinical course of the wet form of the disease and support the notion that more definitive clinical trials of immune mediation of age-related macular degeneration are indicated

  16. Motives in Sexual Aggression: The Chinese Context.

    ERIC Educational Resources Information Center

    Tang, Catherine So-Kum; And Others

    1993-01-01

    Compared sexual and aggressive motives for sexual aggression in Chinese college students. Male undergraduates (N=146) completed self-report measures. Results suggest that sex guilt and aggressive guilt acted as inhibitors for their respective drives and sexual aggression resulted from aggressive, rather than sexual, motives. Sexual aggression may…

  17. Synthesis of novel cinnamanilides as potential immunosuppressive agents.

    PubMed

    Shi, Lei; Wang, Lu; Wang, Zhi; Zhu, Hai-Liang; Song, Qiao

    2012-01-01

    A series of new cinnamanilides (6-40) were synthesized and their immunosuppressive activity and cytotoxicity were evaluated. Most of the cinnamanilides showed good immunosuppressive activity. Among the synthesized compounds, (Z)-N-(4-bromophenyl)-2-methoxy-3-(4-methoxyphenyl)acrylamide (37) and (Z)-2-methoxy-3-(4-methoxyphenyl)-N-p-tolylacrylamide (38) exhibited potent immunosuppressive activity (IC(50) = 1.77 ± 0.33 and 0.94 ± 0.13 μM) without significant cytotoxicity.

  18. [Current status of oral immunomodulatory and immunosuppressive agents].

    PubMed

    Meller, S; Baran, A M; Braun, S A; Klossowski, N; Homey, B

    2014-02-01

    Various dermatological disorders require treatments with immunosuppressive or immunomodulatory agents. Nevertheless, several studies demonstrate low prescription rates for systemic treatments. This low usage may be a result of physicians' low levels of confidence in administering systemic treatments. However, immunosuppressive treatments represent safe options when potential side effects as well as pharmacological interactions are considered. This review overviews the most important oral immunosuppressive or immunomodulatory agents and summarizes their mode of actions, indications, and adverse effects. Biologics that require intravenous or subcutaneous application are not included, but novel and new agents likely to be released soon are considered.

  19. Skin cancer in solid organ transplant recipients: advances in therapy and management: part II. Management of skin cancer in solid organ transplant recipients.

    PubMed

    Zwald, Fiona O'Reilly; Brown, Marc

    2011-08-01

    The management of skin cancer in solid organ transplant recipients is a challenge to both the dermatologist and transplant physician. Part II of this continuing medical education review offers an approach to the management of this increasing problem. The importance of specialty dermatology clinics providing access to transplant patients, frequent skin cancer screening, patient education, and multidisciplinary care is discussed. The management of low risk squamous cell carcinoma with topical therapies, photodynamic therapy, systemic retinoids, and capecitabine is reviewed. Revision of immunosuppression in the management of high-risk patients is discussed in association with the potential role of sentinel lymph node biopsy for aggressive disease. Finally, management of in-transit and metastatic squamous cell carcinoma is reviewed, with a discussion of the role of more recent innovative therapies, including epidermal growth factor receptor inhibitors in advanced squamous cell carcinoma in solid organ transplant recipients.

  20. Hepatitis B reactivation in the setting of chemotherapy and immunosuppression - prevention is better than cure

    PubMed Central

    Pattullo, Venessa

    2015-01-01

    Due to the inherent relationship between the immune system and the hepatitis B virus (HBV) in exposed and infected individuals, immunomodulation associated with the treatment of solid tumours, haematological malignancies and inflammatory disorders has been linked to HBV reactivation (HBVr). Reactivation of HBV infection in the setting of chemotherapy and immunosuppression may lead to fulminant liver failure and death, but there is a cumulative body of evidence that these are potentially preventable adverse outcomes. As chronic hepatitis B is largely asymptomatic but also endemic worldwide, clinicians caring for patients requiring chemotherapy or immunosuppression need to be vigilant of the potential for HBVr in susceptible individuals. Serological screening and prophylactic and pre-emptive antiviral treatment with a nucleos(t)ide analogue should be considered in appropriate settings. Hepatitis B prevalence is examined in this review article, as are the risks of HBVr in patients receiving chemo- and immunosuppressive therapy. Recommendations regarding screening, monitoring and the role of antiviral prophylaxis are outlined with reference to current international associations’ guidelines and the best available evidence to date. PMID:25954478

  1. From Leflunomide to Teriflunomide: Drug development and Immunosuppressive Oral Drugs in the Treatment of Multiple Sclerosis.

    PubMed

    Aly, Lilian; Hemmer, Bernhard; Korn, Thomas

    2016-12-08

    Immunosuppressive drugs have been used in the treatment of multiple sclerosis (MS) for a long time. Today, the increased number of approved substances and the possibility of an oral availability of some immunomodulators improve the therapeutic repertory and increase patient satisfaction and compliance. Teriflunomide is indicated as first line oral disease modifying therapy (DMT) in relapsing-remitting MS (RRMS). Its immunosuppressive capacity results from an inhibition of de novo pyrimidine synthesis in rapidly proliferating lymphocytes. While Teriflunomide has been approved for the treatment of RRMS only since 2012, there is substantial therapeutic experience with its prodrug Leflunomide used in the treatment of rheumatoid arthritis (RA). In MS, a daily dose of 14 mg Teriflunomide reduces the annualized relapse rate (ARR) by more than 30% and disability progression by 30% compared to placebo while it provides a reasonable safety profile. This review presents an overview on oral immunosuppressants used in the treatment of MS. With an emphasis on Teriflunomide it summarizes discovery, mechanism of action and clinical effectiveness in phase II and III trials as well as important aspects for treating physicians.

  2. Intensive Insulin Therapy: Tight Blood Sugar Control

    MedlinePlus

    ... insulin therapy can help you achieve desired blood sugar control and what intensive insulin therapy requires of ... aggressive treatment approach designed to control your blood sugar levels. Intensive insulin therapy requires close monitoring of ...

  3. Synthesis, biological evaluation of chrysin derivatives as potential immunosuppressive agents.

    PubMed

    Lv, Peng-Cheng; Cai, Tian-Tian; Qian, Yong; Sun, Juan; Zhu, Hai-Liang

    2011-01-01

    A series of novel chrysin derivatives was firstly synthesized and evaluated on their immunosuppressive activity in the search for potential immunosuppressive agents. Among them, compounds 5c displayed the most potent immunosuppressive inhibitory activity with IC(50) of 0.78 μM, which was comparable to that of cyclosporin A (IC(50) = 0.06 μM). The preliminary mechanism of compound 5c inhibition effects was also detected by flow cytometry (FCM), and the compound exerted immunosuppressive activity via inducing the apoptosis of activated lymph node cells in a dose dependent manner. Furthermore, the estimated LD(50) (in mg/kg) in vivo of compound 5c is 738.2, which indicated that compound 5c was low toxic.

  4. Immunosuppressive and anti-inflammatory properties of engineered nanomaterials.

    PubMed

    Ilinskaya, A N; Dobrovolskaia, M A

    2014-09-01

    Nanoparticle interactions with various components of the immune system are determined by their physicochemical properties such as size, charge, hydrophobicity and shape. Nanoparticles can be engineered to either specifically target the immune system or to avoid immune recognition. Nevertheless, identifying their unintended impacts on the immune system and understanding the mechanisms of such accidental effects are essential for establishing a nanoparticle's safety profile. While immunostimulatory properties have been reviewed before, little attention in the literature has been given to immunosuppressive and anti-inflammatory properties. The purpose of this review is to fill this gap. We will discuss intended immunosuppression achieved by either nanoparticle engineering, or the use of nanoparticles to carry immunosuppressive or anti-inflammatory drugs. We will also review unintended immunosuppressive properties of nanoparticles per se and consider how such properties could be either beneficial or adverse.

  5. Neoplasia in immunosuppressed renal transplant patients: a 20-year experience

    SciTech Connect

    Krueger, T.C.; Tallent, M.B. Jr.; Richie, R.E.; Johnson, H.K.; MacDonell, R.C.; Turner, B.

    1985-05-01

    This review examines a 20-year experience in renal transplantation at our center to determine the effects of immunosuppression on the subsequent development of malignancies. Twenty patients had 21 malignancies from primary sites other than skin, yielding an incidence of 2.5%. There were 0.65 malignancies for each 100 cumulative patient years of immunosuppression. Suppression of the host immune response is associated with an increased incidence of malignancies.

  6. Lung transplant immunosuppression – time for a new approach?

    PubMed Central

    Witt, CA; Puri, V; Gelman, AE; Krupnick, AS; Kreisel, D

    2015-01-01

    Summary Outcomes after lung transplantation remain worse compared to other solid organ transplants, which is in large part due to high rates of graft rejection. Despite emerging data that immune responses to lungs differ from other organs, immunosuppression for lung transplant recipients is still based on strategies established for recipients of other grafts. There exists an urgent need to develop immunosuppressive strategies for lung transplant recipients that take the unique immunological features of this organ into account. PMID:25220652

  7. Highly Aggressive Women in a Forensic Psychiatric Hospital.

    PubMed

    Beck, Niels C; Hammer, Joseph H; Robbins, Sharon; Tubbesing, Tara; Menditto, Anthony; Pardee, Alicia

    2017-03-01

    In this study, we compared three groups of women admitted to a public forensic inpatient facility over the course of a two-year period. Detailed and systematic examination of social and psychiatric histories revealed that the group with the most persistent levels of aggression differed from the other two groups with respect to frequency of self-harming behavior, intellectual impairment, hypothyroidism, a childhood diagnosis of attention deficit-hyperactivity disorder (ADHD), and age of onset of psychiatric and behavioral symptoms. The high-aggression group also had the highest rate of childhood physical and sexual abuse, but the difference between that group and the two lower aggression groups did not achieve statistical significance. From the standpoint of childhood adversity, 94 percent of those in the high-aggression group had been placed outside of the original home by age 11. Eighty-nine percent were intellectually impaired. At admission, physical examinations revealed that 50 percent had a history of hypothyroidism and two-thirds were obese. Before admission, most had manifested severe aggression and emotional dysregulation, as evinced by high levels of self-harm, suicide attempts, and aggressive behavior in previous institutional settings that was both frequent and intense. Patients who share these characteristics are currently placed on a ward at the hospital with a milieu and individual therapy programs that are based on a dialectical behavior therapy approach that targets key symptoms of emotional and behavioral dysregulation.

  8. Low-dose allopurinol plus azathioprine/cyclosporin/prednisolone, a novel immunosuppressive regimen.

    PubMed

    Chocair, P; Duley, J; Simmonds, H A; Cameron, J S; Ianhez, L; Arap, S; Sabbaga, E

    1993-07-10

    Early rejection can still complicate renal transplantation even with cyclosporin. We added low-dose allopurinol (25 mg on alternative days) to "triple" immunosuppression with cyclosporin, prednisolone, and azathioprine for twelve recipients of cadaver renal grafts. The controls were fifteen patients on triple therapy alone. Only one rejection episode occurred among the allopurinol-treated patients, whereas eleven controls had rejections (seven with more than one episode). Allopurinol may be toxic when combined with azathioprine, yet the bone marrow tolerated the new regimen well. As expected, reduction of the azathioprine dose was necessary in the treated group.

  9. Effect of Increased Immunosuppression on Developmental Outcome of Opsoclonus Myoclonus Syndrome (OMS).

    PubMed

    Mitchell, Wendy G; Wooten, Amelia A; O'Neil, Sharon H; Rodriguez, Jenny G; Cruz, Rosa E; Wittern, Rachael

    2015-07-01

    Opsoclonus myoclonus syndrome (OMS) produces long-term cognitive, behavioral, and motor deficits. Objective was to see if more aggressive treatment improved outcome. Assessment included opsoclonus myoclonus syndrome rating, developmental/cognitive and motor assessment, and adaptive behavior. Fourteen subjects completed testing. Nine had neuroblastoma. Onset was at 10 to 35 months; onset to diagnosis: 2 days to 14 months, and onset to first treatment: 5 days to 15 months. Initial treatment was corticotropin (12), oral steroids (3), plus intravenous immunoglobulin in all. Ten received rituximab, 5 cyclophosphamide. Age at testing ranged from 2.5 to 10.3 years. Adaptive Behavior Score (11 subjects), mean 93.5; estimated Intelligence Quotient/Developmental Quotient mean 93.5; Motor: mean 92.8. Residual opsoclonus myoclonus syndrome symptoms at the time of the evaluation were generally minor; opsoclonus myoclonus syndrome scores ranged from 0 to 6. Comparison to previously reported opsoclonus myoclonus syndrome subjects showed improved outcomes: Adaptive behavior, cognitive and motor scores were significantly higher (P < .001) in new subjects. Outcomes have improved with more aggressive immunosuppression, with most opsoclonus myoclonus syndrome survivors now functioning at or near normal.

  10. Transperineal aggressive angiomyxoma.

    PubMed

    Pereira, Pedro; Melo Abreu, Elisa; Cunha, Teresa Margarida; Rolim, Inês

    2017-04-11

    A 45-year-old woman with a history of total hysterectomy with adnexal preservation for uterine leiomyomas presented to our hospital with a right gluteal palpable mass, which she first noticed 6 months before and had progressively enlarged since then.Radiological studies revealed a 14 cm lesion with translevator growth that displaced rather than invaded adjacent structures, with a peculiar whorled pattern on T2-weighted MRI, which enhanced following gadolinium administration. CT-guided biopsy was performed, and in conjunction with imaging features the diagnosis of an aggressive angiomyxoma was assumed and confirmed following surgical excision.

  11. Effects of dexamethasone immunosuppression on turkey clostridial dermatitis.

    PubMed

    Thachil, Anil J; Shaw, Daniel P; Nagaraja, Kakambi V

    2014-09-01

    Clostridia represents a group of anaerobic spore-forming bacteria ubiquitous in the poultry environment. They are widely distributed in soil and survive for many years as highly resistant, inactive spores. They enter the body through wounds and contaminated feed as active bacteria or spores. Multiplication of clostridial bacteria occurs only in the absence of oxygen or in environments with very low concentrations of oxygen. During active multiplication, the clostridial organisms produce several toxins that are responsible for most of the clinical signs seen in clostridial diseases. Immunosuppression is a problem for the poultry industry. In modern, intensive poultry-rearing conditions, stress due to high population densities pose a considerable challenge for the immune system, and infectious agents can exploit this situation to cause disease. Immunosuppression may predispose turkeys to clostridial infection, resulting in clostridial dermatitis and mortality. The purpose of this study was to determine whether immunosuppression predisposes turkeys to clostridial infection and causes clostridial dermatitis. We immunosuppressed 10-wk-old turkey poults with dexamethasone. The birds immunosuppressed and not immunosuppressed were then challenged with Clostridium perfringens, Clostridium septicum, or both and examined for the development of clostridial dermatitis. The dexamethasone-treated birds were found to be more susceptible to C. peifingens/C. septicum challenge and developed clostridial dermatitis than the no-dexamethasone-treated birds through the subcutaneous route. However, oral inoculation of the same agents did not cause any dermatitis lesions in either of the groups.

  12. The nature of human aggression.

    PubMed

    Archer, John

    2009-01-01

    Human aggression is viewed from four explanatory perspectives, derived from the ethological tradition. The first consists of its adaptive value, which can be seen throughout the animal kingdom, involving resource competition and protection of the self and offspring, which has been viewed from a cost-benefit perspective. The second concerns the phylogenetic origin of aggression, which in humans involves brain mechanisms that are associated with anger and inhibition, the emotional expression of anger, and how aggressive actions are manifest. The third concerns the origin of aggression in development and its subsequent modification through experience. An evolutionary approach to development yields conclusions that are contrary to the influential social learning perspective, notably that physical aggression occurs early in life, and its subsequent development is characterized by learned inhibition. The fourth explanation concerns the motivational mechanisms controlling aggression: approached from an evolutionary background, these mechanisms range from the inflexible reflex-like responses to those incorporating rational decision-making.

  13. Refractory heparin induced thrombocytopenia with thrombosis (HITT) treated with therapeutic plasma exchange and rituximab as adjuvant therapy.

    PubMed

    Schell, Amy M; Petras, Melissa; Szczepiorkowski, Zbigniew M; Ornstein, Deborah L

    2013-10-01

    We report a case of refractory heparin-induced thrombocytopenia with thrombosis (HITT) with prolonged thrombocytopenia and multiple thrombotic complications that failed to improve despite aggressive treatment. A 60 year old female with a prior history of venous thromboembolism was admitted with an acute pulmonary embolism, and developed HITT after several days on heparin therapy. She suffered multiple complications including bilateral venous limb gangrene, acute renal failure, and refractory thrombocytopenia, leading us to use multimodality therapy including therapeutic plasma exchange (TPE) and rituximab immunosuppression. The patient had transient improvements in her thrombocytopenia with TPE, and rituximab was added in an attempt to reduce antibody production. She eventually required bilateral limb amputation, and only after removal of the gangrenous limbs did her platelet count show sustained improvement. We discuss the possible contribution of infection to her prolonged course.

  14. Aggression can be contagious: Longitudinal associations between proactive aggression and reactive aggression among young twins.

    PubMed

    Dickson, Daniel J; Richmond, Ashley D; Brendgen, Mara; Vitaro, Frank; Laursen, Brett; Dionne, Ginette; Boivin, Michel

    2015-01-01

    The present study examined sibling influence over reactive and proactive aggression in a sample of 452 same-sex twins (113 male dyads, 113 female dyads). Between and within siblings influence processes were examined as a function of relative levels of parental coercion and hostility to test the hypothesis that aggression contagion between twins occurs only among dyads who experience parental coerciveness. Teacher reports of reactive and proactive aggression were collected for each twin in kindergarten (M = 6.04 years; SD = 0.27) and in first grade (M = 7.08 years; SD = 0.27). Families were divided into relatively low, average, and relatively high parental coercion-hostility groups on the basis of maternal reports collected when the children were 5 years old. In families with relatively high levels of parental coercion-hostility, there was evidence of between-sibling influence, such that one twin's reactive aggression at age 6 predicted increases in the other twin's reactive aggression from ages 6 to 7, and one twin's proactive aggression at age 6 predicted increases in the other twin's proactive aggression from ages 6 to 7. There was also evidence of within-sibling influence such that a child's level of reactive aggression at age 6 predicted increases in the same child's proactive aggression at age 7, regardless of parental coercion-hostility. The findings provide new information about the etiology of reactive and proactive aggression and individual differences in their developmental interplay.

  15. Television viewing, aggression, and ethnicity.

    PubMed

    Harris, M B

    1992-02-01

    For 416 college students, questioned about their experiences with aggression and television viewing, only very weak correlations between preference for violent shows and aggression were observed. Black males watched significantly more television than other respondents. These findings suggest that the frequently reported correlation between viewing televised violence and aggression may not appear when sex, ethnicity, and education are controlled in a sample of young adults.

  16. Reduction of Aggressive Behavior in the School.

    ERIC Educational Resources Information Center

    Petermann, Ulrike

    1988-01-01

    Discusses what may be considered aggressive behavior, what motivates aggressive students, and possible teacher responses to aggressive behavior. Describes four points on which teachers can focus to diminish the attractiveness of aggression and ensure that it is not rewarded. Identifies learning activities which provide aggressive students with the…

  17. The Effects of Pornography on Aggressive Behavior.

    ERIC Educational Resources Information Center

    Stacy, Lauri L.

    This document reviews existing empirical research on the effect of pornography on aggressive behavior. Two types of pornography are distinguished: aggressive pornography and non-aggressive pornography. Conclusions drawn from the research review are presented, including: (1) aggressive pornograpy consistently increases aggressive attitudes and…

  18. Feasibility of localized immunosuppression: 1. Exploratory studies with glucocorticoids in a biohybrid device designed for cell transplantation.

    PubMed

    Buchwald, P; Bocca, N; Marzorati, S; Hochhaus, G; Bodor, N; Stabler, C; Kenyon, N S; Inverardi, L; Molano, R D; Ricordi, C; Pileggi, A

    2010-06-01

    Emerging biotechnologies, such as the use of biohybrid devices for cellular therapies, are showing increasing therapeutic promise for the treatment of various diseases, including type 1 diabetes mellitus. The functionality of such devices could be greatly enhanced if successful localized immunosuppression regimens could be established, since they would eliminate the many otherwise unavoidable side effects of currently used systemic immunosuppressive therapies. The existence of local immune privilege at some specialized tissues, such as the eye, CNS, or pregnant uterus, supports the feasibility of localized immunomodulation, and such an approach is particularly well-suited for cell transplant therapies where all transplanted tissue is localized within a device. Following the success of syngeneic transplantation in a subcutaneous prevascularized device as a bioartificial pancreas in a rodent model, we now report the first results of exploratory in vivo islet allograft studies in rats using locally delivered glucocorticoids (dexamethasone phosphate and the soft steroid loteprednol etabonate). Following in vitro assessments, in silico drug distribution models were used to establish tentative therapeutic dose ranges. Sustained local delivery was achieved via implantable osmotic mini-pumps through a central sprinkler, as well as with a sustained-delivery formulation for loteprednol etabonate using poly(D,L-lactic) acid (PLA) microspheres. Doses delivered locally were approximately hundred-fold smaller than those typically used in systemic treatments. While several solubility, stability, and implantation problems still remain to be addressed, both compounds showed promise in their ability to prolong graft survival after tapering of systemic immunosuppression, compared to control groups.

  19. Differentiation of cellular reaction to alloantigens and bacterial infection in human skin graft--immunosuppressive drugs or antibiotics.

    PubMed

    Moscicka-Wesolowska, M; Olszewski, W L; Zolich, D; Stelmach, E

    2002-01-01

    The human hand transplantations prompted revival of interest in evaluation of the rejection process of the grafted skin and its control with the antirejection drugs [1-3]. In case of first hand transplantation a combined immunosuppressive regimen was applied with currently available drugs resulting in acceptance of the entire composite graft. No major untoward systemic effects of antirejection therapy were observed. The most important clinical conclusion was that allogeneic skin can be accepted and function as in a normal extremity, although the attack of host cells on the graft can not be totally eliminated. Chronic perivascular and subepidermal infiltrates with recipient cells could be seen [4]. Another problem connected with skin transplantation is graft infection. Skin is inhabited by a specific spectrum of bacteria [5]. Allografted skin is more sensitive to bacterial penetration than normal skin due to local damage by the host-versus-graft cellular reaction and compromised immune reactivity to bacterial antigens by the immunosuppressive therapy. The histological pictures of rejecting skin represent a mixture of cellular reaction against the graft and penetrating microbes. Alloreaction requires modification of immunosuppressive regimen and infection is an indication for prolonged antibiotic therapy against skin bacterial flora. The question arises how to discriminate the alloreactive and bacterial changes in the skin graft. We studied the histological pictures of rejecting and infected human skin after transplantion to scid mice.

  20. Immunosuppressive properties of mesenchymal stem cells: advances and applications.

    PubMed

    De Miguel, M P; Fuentes-Julián, S; Blázquez-Martínez, A; Pascual, C Y; Aller, M A; Arias, J; Arnalich-Montiel, F

    2012-06-01

    Mesenchymal stem cells (MSCs) have been isolated from a variety of tissues, such as bone marrow, skeletal muscle, dental pulp, bone, umbilical cord and adipose tissue. MSCs are used in regenerative medicine mainly based on their capacity to differentiate into specific cell types and also as bioreactors of soluble factors that will promote tissue regeneration from the damaged tissue cellular progenitors. In addition to these regenerative properties, MSCs hold an immunoregulatory capacity, and elicit immunosuppressive effects in a number of situations. Not only are they immunoprivileged cells, due to the low expression of class II Major Histocompatibilty Complex (MHC-II) and costimulatory molecules in their cell surface, but they also interfere with different pathways of the immune response by means of direct cell-to-cell interactions and soluble factor secretion. In vitro, MSCs inhibit cell proliferation of T cells, B-cells, natural killer cells (NK) and dendritic cells (DC), producing what is known as division arrest anergy. Moreover, MSCs can stop a variety of immune cell functions: cytokine secretion and cytotoxicity of T and NK cells; B cell maturation and antibody secretion; DC maturation and activation; as well as antigen presentation. It is thought that MSCs need to be activated to exert their immunomodulation skills. In this scenario, an inflammatory environment seems to be necessary to promote their effect and some inflammation-related molecules such as tumor necrosis factor-α and interferon-γ might be implicated. It has been observed that MSCs recruit T-regulatory lymphocytes (Tregs) to both lymphoid organs and graft. There is great controversy concerning the mechanisms and molecules involved in the immunosuppressive effect of MSCs. Prostaglandin E2, transforming growth factor-β, interleukins- 6 and 10, human leukocyte antigen-G5, matrix metalloproteinases, indoleamine-2,3-dioxygenase and nitric oxide are all candidates under investigation. In vivo

  1. Lunar Influences on Human Aggression.

    ERIC Educational Resources Information Center

    Russell, Gordon W.; Dua, Manjula

    1983-01-01

    Used league records of all Canadian hockey games (N=426) played during a season to test a lunar-aggression hypothesis. Despite the use of multiple measures of lunar phase and interpersonal aggression, support for lunar influence was not forthcoming. Supplemental data revealed that beliefs in lunar influence are fairly common. (JAC)

  2. Traumatic Brain Injury and Aggression.

    ERIC Educational Resources Information Center

    Miller, Laurence

    1994-01-01

    Persons who have suffered traumatic injury to the brain may subsequently display aggressive behavior. Three main syndromes of aggression following traumatic brain injury are described: (1) episodic dyscontrol; (2) frontal lobe disinhibition; and (3) exacerbation of premorbid antisociality. The neuropsychological substrates of these syndromes are…

  3. Tumor-related gene changes in immunosuppressive Syrian hamster cholangiocarcinoma.

    PubMed

    Juasook, Amornrat; Aukkanimart, Ratchadawan; Boonmars, Thidarut; Sudsarn, Pakkayanee; Wonkchalee, Nadchanan; Laummaunwai, Porntip; Sriraj, Pranee

    2013-10-01

    The results of a previous study demonstrated that prednisolone enhanced cholangiocarcinogenesis. Therefore, to clarify molecular changes during immunosuppressive cholangiocarcinogenesis, Syrian hamsters were divided into 8 groups: uninfected controls; immunosuppressed Syrian hamsters using prednisolone (P); normal Syrian hamsters administered N-nitrosodimethylamine (ND); immunosuppressed Syrian hamsters administered N-nitrosodimethylamine (NDis); normal Syrian hamsters infected with Opisthorchis viverrini (OV); immunosuppressed Syrian hamsters infected with O. viverrini (OVis); normal Syrian hamsters infected with O. viverrini and administered N-nitrosodimethylamine (CCA); and immunosuppressed Syrian hamsters infected with O. viverrini and administered N-nitrosodimethylamine (CCAis). Syrian hamster livers were used for analysis of tumor-related gene expression and immunohistochemistry through cytokeratin 19 (CK19) and proliferating cell nuclear antigen (PCNA) staining. The tumor-related gene expression results show that CCAis groups at all time points exhibited upregulation of COX-2, IL-6, SOD1, CAT and iNOS and downregulation of p53, which correlated with the predominant expression of CK19 and PCNA in liver tissue. These results suggest that prednisolone enhances cholangiocarcinoma development, which was confirmed by molecular changes.

  4. The influence of immunosuppressive agents on BK virus risk following kidney transplantation, and implications for choice of regimen.

    PubMed

    Suwelack, Barbara; Malyar, Viola; Koch, Martina; Sester, Martina; Sommerer, Claudia

    2012-07-01

    The increasing incidence of BK-associated nephropathy following kidney transplantation has prompted an examination of strategies for risk reduction and management through immunosuppression manipulation. Evidence from retrospective and prospective studies suggests that BK viruria and viremia, and the need for BK virus treatment, are higher with tacrolimus than cyclosporine. Combined therapy with tacrolimus and mycophenolic acid may be associated with a particularly higher risk of BK infection, but data are conflicting as to whether mycophenolic acid per se is an independent risk factor. The incidence of BK-related events may be reduced in patients receiving mTOR inhibitors (everolimus or sirolimus) with cyclosporine vs a calcineurin inhibitor with mycophenolic acid. De novo immunosuppression regimens that avoid rabbit antithymocyte globulin and tacrolimus, particularly tacrolimus with mycophenolic acid, may be advantageous, whereas low-exposure cyclosporine with an mTOR inhibitor appears a favorable option. Routine screening for BK infection during the first 2 years posttransplant is recommended to allow preemptive modification of the immunosuppressive regimen. In patients at high risk of BK virus infection, appropriate de novo immunosuppression or very early conversion to an mTOR inhibitor to facilitate reduction or discontinuation of calcineurin inhibitors or antimetabolites should be considered. Extensive further research into optimal avoidance, screening, and treatment strategies is required.

  5. The Neurobiology of Impulsive Aggression.

    PubMed

    Blair, Robert J R

    2016-02-01

    This selective review provides a model of the neurobiology of impulsive aggression from a cognitive neuroscience perspective. It is argued that prototypical cases of impulsive aggression, those associated with anger, involve the recruitment of the acute threat response system structures; that is, the amygdala, hypothalamus, and periaqueductal gray. It is argued that whether the recruitment of these structures results in impulsive aggression or not reflects the functional roles of ventromedial frontal cortex and dorsomedial frontal and anterior insula cortex in response selection. It is also argued that impulsive aggression may occur because of impaired decision making. The aggression may not be accompanied by anger, but it will reflect disrupted evaluation of the rewards/benefits of the action.

  6. The Neurobiology of Impulsive Aggression

    PubMed Central

    2016-01-01

    Abstract This selective review provides a model of the neurobiology of impulsive aggression from a cognitive neuroscience perspective. It is argued that prototypical cases of impulsive aggression, those associated with anger, involve the recruitment of the acute threat response system structures; that is, the amygdala, hypothalamus, and periaqueductal gray. It is argued that whether the recruitment of these structures results in impulsive aggression or not reflects the functional roles of ventromedial frontal cortex and dorsomedial frontal and anterior insula cortex in response selection. It is also argued that impulsive aggression may occur because of impaired decision making. The aggression may not be accompanied by anger, but it will reflect disrupted evaluation of the rewards/benefits of the action. PMID:26465707

  7. False memories for aggressive acts.

    PubMed

    Laney, Cara; Takarangi, Melanie K T

    2013-06-01

    Can people develop false memories for committing aggressive acts? How does this process compare to developing false memories for victimhood? In the current research we used a simple false feedback procedure to implant false memories for committing aggressive acts (causing a black eye or spreading malicious gossip) or for victimhood (receiving a black eye). We then compared these false memories to other subjects' true memories for equivalent events. False aggressive memories were all too easy to implant, particularly in the minds of individuals with a proclivity towards aggression. Once implanted, the false memories were indistinguishable from true memories for the same events, on several dimensions, including emotional content. Implications for aggression-related memory more generally as well as false confessions are discussed.

  8. Beliefs about aggression moderate alcohol's effects on aggression.

    PubMed

    Levinson, Cheri A; Giancola, Peter R; Parrott, Dominic J

    2011-02-01

    The goal of this investigation was to determine whether permissive beliefs about aggression moderate the relation between acute alcohol intoxication and aggression in two large experiments. Participants in Study 1 were 328 (163 men and 165 women) social drinkers and those in Study 2 were 518 (252 men and 266 women) social drinkers. Beliefs about aggression were assessed using a well-validated self-report measure. Following the consumption of either an alcohol or a placebo beverage, participants were tested on a laboratory task in which electric shocks were received from, and administered to, a fictitious opponent under the guise of a competitive reaction-time task. Aggression was operationalized as the combined mean responses for shock intensity and duration across all trials. Our central finding was that alcohol increased aggression in persons with more approving beliefs about aggression than in those who did not hold such beliefs. Our results are discussed within the context of Huesmann's (1988) cognitive script model of aggression. Suggestions for violence prevention efforts are put forth as well.

  9. Persistent inflammatory, immunosuppressed, catabolic syndrome (PICS): A new phenotype of multiple organ failure

    PubMed Central

    Rosenthal, Martin D.; Moore, Frederick A.

    2015-01-01

    A new phenotype of multiple organ failure has appeared: Persistent Inflammatory, Immunosuppressed, Catabolic Syndrome (PICS). Comorbidities and age >65 years have been established as the leading risk factors for PICS. As the percentage of elderly people continues to increase the prevalence of PICS in our ICUs will surely grow. Malnutrition (despite appropriate supplementation), recurrent nosocomial infections, frailty, ventilator dependence, and an indolent death depicts the central theme that plagues PICS patients. Aligned with the recently awarded P50 grant by NIGMS entitled, “PICS: A New Horizon for Surgical Critical Care”, and the University Of Florida’s Sepsis and Critical Illness Research Center will investigate the genetic make-up of PICS patients, better understand frailty and the implication in trauma patients, and hopefully elucidate new therapies. Currently, there are no therapies to combat PICS aside from nutritional inference elaborated after reviewing the literature on Burns, Cachexia, and Sarcopenia. PMID:26086042

  10. Aggressive Erotica and Violence against Women.

    ERIC Educational Resources Information Center

    Donnerstein, Edward

    1980-01-01

    Examines the effects of aggressive-erotic stimuli on male aggression toward females. Male subjects' deliveries of electric shocks to males or females after viewing either a neutral, erotic, or aggressive-erotic film were measured. (Author/SS)

  11. New Immunosuppressive Sphingoid Base and Ceramide Analogues in Wild Cordyceps

    PubMed Central

    Mi, Jia-Ning; Han, Yuwei; Xu, Yingqiong; Kou, Junping; Wang, Jing-Rong; Jiang, Zhi-Hong

    2016-01-01

    A comprehensive identification of sphingoid bases and ceramides in wild Cordyceps was performed by integrating a sequential chromatographic enrichment procedure and an UHPLC-ultrahigh definition-Q-TOF-MS based sphingolipidomic approach. A total of 43 sphingoid bases and 303 ceramides were identified from wild Cordyceps, including 12 new sphingoid base analogues and 159 new ceramide analogues based on high-resolution MS and MS/MS data, isotope distribution, matching with the comprehensive personal sphingolipid database, confirmation by sphingolipid standards and chromatographic retention time rule. The immunosuppressive bioassay results demonstrated that Cordyceps sphingoid base fraction exhibits more potent immunosuppressive activity than ceramide fraction, elucidating the immunosuppressive ingredients of wild Cordyceps. This study represented the most comprehensive identification of sphingoid bases and ceramides from a natural source. The findings of this study provided an insight into therapeutic application of wild Cordyceps. PMID:27966660

  12. [Synthesis and immunosuppressive effects of novel phthalazine ketone derivatives].

    PubMed

    Wang, Ya-Li; Wang, Qing-He; Yang, Hong-Guang; Hao, Bo-Jun; Liang, Guo-Dong; Jiang, Chong-Guo; Cheng, Mao-Sheng

    2013-10-01

    A series of phthalazine ketone compounds were synthesized and the structures were confirmed by H NMR and HR-MS spectrum. All target compounds were obtained through 7 steps, including selective reduction, nitration, bromination, ring enlargement, reduction, Knoevenagel and acylated reaction. The compounds were evaluated for their immunosuppressive effects of T-cell proliferation and inhibitory activity of IMPDH type II in vitro, as well as their structure-activity relationship were assessed. Several compounds exhibited strong immunosuppressive properties, especially compounds 7f and 7h, with IC50 values of 0.093 micromol x L(-1) and 0.14 micromol x L(-1) respectively, which were superior to mycophenolic acid. The information obtained from the studies may be useful for further research on the immunosuppressive agents.

  13. New Immunosuppressive Sphingoid Base and Ceramide Analogues in Wild Cordyceps.

    PubMed

    Mi, Jia-Ning; Han, Yuwei; Xu, Yingqiong; Kou, Junping; Wang, Jing-Rong; Jiang, Zhi-Hong

    2016-12-14

    A comprehensive identification of sphingoid bases and ceramides in wild Cordyceps was performed by integrating a sequential chromatographic enrichment procedure and an UHPLC-ultrahigh definition-Q-TOF-MS based sphingolipidomic approach. A total of 43 sphingoid bases and 303 ceramides were identified from wild Cordyceps, including 12 new sphingoid base analogues and 159 new ceramide analogues based on high-resolution MS and MS/MS data, isotope distribution, matching with the comprehensive personal sphingolipid database, confirmation by sphingolipid standards and chromatographic retention time rule. The immunosuppressive bioassay results demonstrated that Cordyceps sphingoid base fraction exhibits more potent immunosuppressive activity than ceramide fraction, elucidating the immunosuppressive ingredients of wild Cordyceps. This study represented the most comprehensive identification of sphingoid bases and ceramides from a natural source. The findings of this study provided an insight into therapeutic application of wild Cordyceps.

  14. Differential diagnosis and management of human-directed aggression in dogs.

    PubMed

    Reisner, Ilana R

    2003-03-01

    Canine aggression directed to human beings is a common presenting complaint and requires attention to safety issues and behavior modification to minimize the risks of future aggression. Dogs may bite familiar people, including family members, or unfamiliar people for a variety of reasons. Anxiety plays an important role in aggression regardless of its target or circumstances. Effective management of aggression may include education and safety counseling for owners, lifestyle changes for dogs and owners, avoidance of provocations when possible, and behavior modification to minimize the risk of future bites. Drug therapy may be indicated to facilitate behavior modification or to reduce reactivity in the dog.

  15. Beyond cyclosporine: a systematic review of limited sampling strategies for other immunosuppressants.

    PubMed

    Ting, Lillian S L; Villeneuve, Eric; Ensom, Mary H H

    2006-06-01

    Therapeutic drug monitoring has gained much attention in the management of immunosuppressive therapy. Area under the plasma drug concentration-time curve (AUC) is the pharmacokinetic (PK) parameter most commonly used to assess total exposure to a drug. However, estimation of AUC requires multiple blood samples throughout the dosing period, which is often inconvenient and expensive. Limited sampling strategies (LSSs) are therefore developed to estimate AUC and other PK parameters accurately and precisely while minimizing the number of blood samples needed. This greatly reduces costs, labor and inconvenience for both patients and clinical staff. In the therapeutic management of solid organ transplantation, LSSs for cyclosporine are commonplace and have been extensively reviewed. Thus, this systematic review paper focuses on other immunosuppressive agents and categorizes the 24 pertinent citations according to the U.S. Preventive Services Task Force rating scale. Thirteen articles (3 level I, 1 level II-1, 2 level II-2, and 7 level III) involved LSSs for mycophenolate, 7 citations (1 level I and 6 level III) for tacrolimus (TAC), and 3 citations (all level III) for other drugs (sirolimus) or multiple drugs. The 2 main approaches to establishing LSSs, multiple regression and Bayesian analyses, are also reviewed. Important elements to consider for future LSS studies, including proper validation of LSSs, convenient sampling times, and application of LSSs to the appropriate patient population and drug formulation are discussed. Limited sampling strategies are a useful tool to help clinicians make decisions on drug therapy. However, patients' pathophysiology, environmental and genetic factors, and pharmacologic response to therapy, in conjunction with PK profiling tools such as LSSs, should be considered collectively for optimal therapy management.

  16. [The effect of media violence on aggression: is aggressive behavior mediated by aggressive cognitions and emotions?].

    PubMed

    Yukawa, S; Yoshida, F

    1999-06-01

    This study investigated whether cognitions and emotions elicited by media violence mediate aggressive behavior. Eighty undergraduates, 40 men and 40 women, participated in the experiment. First, subjects were exposed to one of four violent videos which varied in levels of violence and entertainment. Subjects' heart rate and eyeblink rate were continuously recorded while they watched the video. After watching it, subjects described their thoughts which occurred while watching it and rated their affective reactions to it. Finally, their aggressive behavior was measured. Results showed that (1) videos high in violence elicited more aggressive thoughts, more thoughts of negative affect, stronger negative affects, and stronger empty-powerless affects, whereas videos high in entertainment elicited stronger positive affects; (2) no significant differences were found among the videos in terms of physiological reactions and aggressive behavior; and (3) cognitions and emotions elicited by media violence did not mediate aggressive behavior.

  17. [Rapamycin: a new immunosuppressive agent capable of inhibiting chronic rejection?].

    PubMed

    Viklický, O; Matl, I

    2001-01-19

    Chronic rejection represents the most common cause of transplanted graft loss in the long term. Rapamycin (sirolimus), and it's derivate RAD, are new and potent, immunosuppressive drugs. They inhibit cell proliferation driven by various growth factors. These drugs were successfully tested in some experimental models of the chronic rejection. Results of the first clinical trials have defined rapamycin pharmacokinetics and proved immunosuppressive efficacy. Rapamycin acts synergistically with cyclosporin A. The side effects are a dose-dependent thrombocytopenia and leukopenia but the most frequent is hyperlipidemia. The question, if rapamycin and RAD inhibit development of chronic rejection in man, will be solved by the prospective clinical trials over years.

  18. Aggression Can be Contagious: Longitudinal Associations between Proactive Aggression and Reactive Aggression Among Young Twins

    PubMed Central

    Dickson, Daniel J.; Richmond, Ashley; Brendgen, Mara; Vitaro, Frank; Laursen, Brett; Dionne, Ginette; Boivin, Michel

    2015-01-01

    The present study examined sibling influence over reactive and proactive aggression in a sample of 452 same-sex twins (113 male dyads, 113 female dyads). Between and within siblings influence processes were examined as a function of relative levels of parental coercion and hostility to test the hypothesis that aggression contagion between twins occurs only among dyads who experience parental coerciveness. Teacher reports of reactive and proactive aggression were collected for each twin in kindergarten (M = 6.04 years; SD = 0.27) and in first grade (M = 7.08 years; SD = 0.27). Families were divided into relatively low, average, and relatively high parental coercion-hostility groups on the basis of maternal reports collected when the children were 5 years old. In families with relatively high levels of parental coercion-hostility, there was evidence of between-sibling influence, such that one twin’s reactive aggression at age 6 predicted increases in the other twin’s reactive aggression from ages 6 to 7, and one twin’s proactive aggression at age 6 predicted increases in the other twin’s proactive aggression from ages 6 to 7. There was also evidence of within-sibling influence such that a child’s level of reactive aggression at age 6 predicted increases in the same child’s proactive aggression at age 7, regardless of parental coercion-hostility. The findings provide new information about the etiology of reactive and proactive aggression and individual differences in their developmental interplay. PMID:25683448

  19. Predictors of aggressive clinical phenotype among immunohistochemically confirmed atypical adenomas.

    PubMed

    Zaidi, Hasan A; Cote, David J; Dunn, Ian F; Laws, Edward R

    2016-12-01

    Despite formal pathological criteria, not all atypical pituitary adenomas display clinically aggressive behavior. We set out to determine which factors predict a clinically aggressive phenotype among a cohort of atypical pituitary adenomas. Medical records were retrospectively reviewed from April 2008 to July 2015. Of 569 pituitary adenomas, 47 (8.3%) patients were surgically treated for atypical adenomas as defined by the WHO criteria. Clinically aggressive adenomas were defined as occurring in those patients who necessitated additional therapeutic intervention after the index (first) surgery, including additional surgery, medical therapy, or radiosurgery. Forty-seven patients with histopathological and immunohistochemical confirmation of atypical adenomas were identified and of these, 23 were noted to have a clinically aggressive course. Among the remaining 24 patients, the disease remained quiescent after the index surgery. On univariate analysis, clinically aggressive lesions were more likely to have a larger axial diameter on MRI (2.9±1.9cm vs. 1.9±0.7cm, p=0.02), greater incidence of cavernous sinus invasion (65.2% vs. 20.8%, p<0.01), and greater incidence of clival extension (60.9% vs. 0, p<0.01) on preoperative imaging. The two groups were equivalent with regard to immunohistochemical staining for ACTH, HGH, LH, FSH, PRL, and TSH. Clinically aggressive lesions, however, trended towards a greater average MIB-1 proliferative index (7.5%±4.9 vs. 6.0%±3.6, p=0.03). On multivariate analysis, the MIB-1 proliferative index trended towards statistical significance (p=0.06) as an independent predictor of clinical aggressiveness. Atypical pituitary adenomas are defined by a rigid set of immunohistochemical markers, but not all necessarily demonstrate an aggressive clinical phenotype.

  20. An Aggressive Retroperitoneal Fibromatosis

    PubMed Central

    Campara, Zoran; Spasic, Aleksandar; Aleksic, Predrag; Milev, Bosko

    2016-01-01

    Introduction: Aggressive fibromatosis (AF) is a heterogeneous group of mesenchymal tumors that have locally infiltrative growth and a tendency to relapse. The clinical picture is often conditioned by the obstruction of the ureter or small intestine. Diagnosis is based on clinical, radiological and histological parameters. A case report: We report a case of male patient, aged 35 years, with the retroperitoneal fibromatosis. He reported to the physician because of frequent urination with the feeling of pressure and pain. Computed tomography revealed the tumor mass on the front wall of the bladder with diameter of 70mm with signs of infiltration of the musculature of the anterior abdominal wall. Endoscopic transurethral biopsy showed proliferative lesion binders by type of fibromatosis. The tumor was surgically removed in a classical way. The patient feels well and has no recurrence thirty-six months after the operative procedure. Conclusion: The complete tumor resection is the therapeutic choice for the primary tumor as well as for a relapse. PMID:27147794

  1. From aggressiveness to creativity.

    PubMed

    Mrevlje, Gorazd V

    2004-02-01

    Psychology has a long tradition of considering human creativity as a distinct human characteristic and a special kind of human activity. After explaining the key motives for such an attitude, the author discusses those forms of healthy aggressiveness that stand out as necessary and constitutive elements of the creative process. Taking the well-known statement of C. G. Jung's 'The person who does not build (create), will demolish and destroy' as a starting point, the author compares the basic premises for understanding the process of human creativity, at the same time drawing on Freud's psychology of the individual and Jung's principle of the collective unconscious as well as his notion of 'complexes'. In doing so, the author somewhat boldly paraphrases Jung's dictum: 'In order to be creative, rather than just constructive, one must occasionally also destroy'. With reference to Wallas, Taylor and Neumann (Wallas 1926; Taylor 1959;;Neumann 2001), the author goes on to explore those concepts which help us to investigate the phenomenon of human creativity, drawing distinctions between emergent, expressive, productive, inventive and innovative creativity. The second part of the article discusses the importance of intelligence, originality, nonconformity, subversiveness and free-mindedness for the creative process of human beings. The author concludes with a further explanation of Erich Neumann's argument that human creativity cannot be understood solely as a result of sociogenetic factors, and argues that it is only by taking into consideration Jung's perception of creativity that a global ontological understanding of these processes can be achieved.

  2. More aggressive cartoons are funnier.

    PubMed

    McCauley, C; Woods, K; Coolidge, C; Kulick, W

    1983-04-01

    Independent rankings of humor and aggressiveness were obtained for sets of cartoons drawn randomly from two different magazines. The correlation of median humor and median aggressiveness rankings ranged from .49 to .90 in six studies involving six different sets of cartoons and six different groups of subjects, including children and adults, high and low socioeconomic status (SES) individuals, and native- and foreign-born individuals. This correlation is consistent with Freudian, arousal, and superiority theories of humor. Another prediction of Freudian theory, that high-SES subjects should be more appreciative of aggressive humor than low-SES subjects, was not supported.

  3. Predicting workplace aggression and violence.

    PubMed

    Barling, Julian; Dupré, Kathryne E; Kelloway, E Kevin

    2009-01-01

    Consistent with the relative recency of research on workplace aggression and the considerable media attention given to high-profile incidents, numerous myths about the nature of workplace aggression have emerged. In this review, we examine these myths from an evidence-based perspective, bringing greater clarity to our understanding of the predictors of workplace aggression. We conclude by pointing to the need for more research focusing on construct validity and prevention issues as well as for methodologies that minimize the likelihood of mono-method bias and that strengthen the ability to make causal inferences.

  4. [The BCTRIMS Expanded Consensus on treatment of multiple sclerosis: I. The evidences for the use of immunosuppressive agents, plasma exchange and autologous hematopoietic stem cell transplantation].

    PubMed

    Callegaro, Dagoberto; Lana-Peixoto, Marco Aurélio; Moreira, Marcos Aurélio; Marchiori, Paulo Eurípedes; Bacheschi, Luiz Alberto; Arruda, Walter Oleschko; Campos, Gilberto Belisário; Lino, Angelina Maria Martins; Melo, Aílton Souza; Rocha, Fernando Coronetti Gomes; Ferreira, Maria Lúcia Brito; Ataide, Luiz; Maciel, Damacio Ramón Kaimen

    2002-09-01

    Since the sixties immunosuppressive agents have been used in the treatment of multiple sclerosis as there was cumulating evidence of the inflammatory nature of the disease. Cyclophosphamide, azathioprine and methotrexate have been the most frequently employed drugs whereas other agents such as cyclosporine and cladribine have been recently tested for RRMS. Mithoxantrone, on the other hand, was approved by the FDA for treatment of aggressive forms of the disease. Other immunointerventions such as plasma exchange and autologous hematopoietic stem cell transplantation have recently been employed in some special circumstances. This paper analyses the most important published data on the use of the immunosuppressive agents, plasma exchange and autologous hematopoietic stem cell transplantation according to the classes of evidences and types of recommendations of these drugs and immunointerventions. It provides sufficient information to support the guidelines expressed in the BCTRIMS Expanded Consensus on Treatment of MS.

  5. [Pathophysiology of aggressive behavior: evaluation and management of pathological aggression].

    PubMed

    Pompili, E; Carlone, C; Silvestrini, C; Nicolò, G

    2016-01-01

    This work aims to define the aggression in all its forms, with notes on management and rapid tranquilization. The pathological aggression is described as a non-homogeneous phenomenon, it is variable in according to social, psychological and biological agents. The distinction of violence between affective aggression and predatory aggression can be functional to the prediction of outcome of any treatment. In general, a pattern of predatory violence tend to match with patients unresponsive and not compliant to treatment, a low probability to predict future violence and, therefore, a difficulty in managing risk. The affective aggressor, however, shows increased probability of treatment response, with more predictability of violent actions in reaction to situations perceived as threatening and, therefore, greater management of future violence risk. Those who act affective violence tend to show a wide range of emotional and cognitive problems, while those who act with predatory patterns show greater inclination to aggression and antisocial behavior. Aggression that occurs in psychiatry mostly appears to be affective, therefore susceptible to modulation through treatments.

  6. Parameter on aggressive periodontitis. American Academy of Periodontology.

    PubMed

    2000-05-01

    The American Academy of Periodontology has developed the following parameter on the treatment of aggressive periodontitis. Patients should be informed of the disease process, therapeutic alternatives, potential complications, expected results, and their responsibility in treatment. Consequences of no treatment should be explained. Failure to treat aggressive periodontitis appropriately can result in progressive and often rapid loss of periodontal supporting tissues. This may have an adverse effect upon prognosis and could result in tooth loss. Given this information, patients (or their parents or guardians, as appropriate) should then be able to make informed decisions regarding their periodontal therapy.

  7. Drug-drug interactions between antiretroviral and immunosuppressive agents in HIV-infected patients after solid organ transplantation: a review.

    PubMed

    van Maarseveen, Erik M; Rogers, Christin C; Trofe-Clark, Jennifer; van Zuilen, Arjan D; Mudrikova, Tania

    2012-10-01

    Since the introduction of combination antiretroviral therapy (cART) resulting in the prolonged survival of HIV-infected patients, HIV infection is no longer considered to be a contraindication for solid organ transplantation (SOT). The combined management of antiretroviral and immunosuppressive therapy proved to be extremely challenging, as witnessed by high rates of allograft rejection and drug toxicity, but the profound drug-drug interactions between immunosuppressants and cART, especially protease inhibitors (PIs) also play an important role. Caution and frequent drug level monitoring of calcineurin inhibitors, such as tacrolimus are necessary when PIs are (re)introduced or withdrawn in HIV-infected recipients. Furthermore, the pharmacokinetics of glucocorticoids and mTOR inhibitors are seriously affected by PIs. With the introduction of integrase inhibitors, CCR5-antagonists and fusion inhibitors which cause significantly less pharmacokinetic interactions, have minor overlapping toxicity, and offer the advantage of pharmacodynamic synergy, it is time to revaluate what may be considered the optimal antiretroviral regimen in SOT recipients. In this review we provide a brief overview of the recent success of SOT in the HIV population, and an update on the pharmacokinetic and pharmacodynamic interactions between currently available cART and immunosuppressants in HIV-infected patients, who underwent SOT.

  8. Surgical treatment of aggressive vertebral hemangiomas.

    PubMed

    Vasudeva, Viren S; Chi, John H; Groff, Michael W

    2016-08-01

    patient who underwent en bloc resection who continued to have back pain. CONCLUSIONS Gross-total resection or subtotal resection in combination with vertebroplasty or adjuvant radiation therapy to treat residual tumor seems sufficient in the treatment of aggressive vertebral hemangiomas. En bloc resection appears to provide a similar oncological benefit, but it carries higher morbidity to the patient.

  9. Prostaglandin E2 Mediates Immunosuppression in Acutely Decompensated Cirrhosis

    PubMed Central

    O’Brien, Alastair J.; Fullerton, James N.; Massey, Karen A.; Auld, Grace; Sewell, Gavin; James, Sarah; Newson, Justine; Karra, Effie; Winstanley, Alison; Alazawi, William; Garcia-Marquez, Rita; Cordoba, Juan; Nicolaou, Anna; Gilroy, Derek W.

    2017-01-01

    Patients with advanced cirrhosis experience frequent infections leading to sepsis, which carries high mortality. While innate immune dysfunction underlies this vulnerability, the precise cause remains elusive. We found prostaglandin (PGE2) elevated in acutely decompensated (AD) patients at immunosuppressive levels. Plasma from AD and end-stage liver disease (ESLD) patients suppressed macrophage cytokine secretion and bacteria killing in a PGE2 receptor-dependent manner, effects not seen in stable cirrhosis. Mouse models (bile duct ligation and CCL4-liver injury) also demonstrated elevated PGE2, which when inhibited completely restored immune competence and survival following infection. Importantly, albumin binds/inactivates PGE2 resulting in greater PGE2 bioavailability. This results in enhanced immunosuppressive effects of AD plasma in patients with low albumin levels. Administering albumin to AD patients reversed immunosuppressive properties of their plasma; protective effects recapitulated in rodent survival studies. Thus, elevated PGE2 combined with hypoalbuminemia mediates immunosuppression in AD and ESLD patients, which can be reversed with albumin. PMID:24728410

  10. [Immunosuppression in dogs and pigs infected with canine distemper virus].

    PubMed

    Sereda, A D; Nogina, I V

    2011-01-01

    Immunosuppression manifesting itself as leukopenia and a considerably lower lymphocyte proliferative response to T- and B-cell mitogens develops in pigs and dogs within 2-3 weeks after intramuscular or oral infection with canine distemper virus (CDV). CDV antigens are detectable in the oral secretions of the animals within 2-2.5 week after infection.

  11. Mortality from duck plague virus in immunosuppressed adult mallard ducks

    SciTech Connect

    Goldberg, D.R.; Yuill, T.M.; Burgess, E.C. )

    1990-07-01

    Environmental contaminants contain chemicals that, if ingested, could affect the immunological status of wild birds, and in particular, their resistance to infectious disease. Immunosuppression caused by environmental contaminants, could have a major impact on waterfowl populations, resulting in increased susceptibility to contagious disease agents. Duck plague virus has caused repeated outbreaks in waterfowl resulting in mortality. In this study, several doses of cyclophosphamide (CY), a known immunosuppressant, were administered to adult mallards (Anas platyrhynchos) to determine if a resultant decrease in resistance to a normally sub-lethal strain of duck plague virus would occur, and induce mortality in these birds. Death occurred in birds given CY only, and in birds given virus and CY, but not in those given virus only. There was significantly greater mortality and more rapid deaths in the duck plague virus-infected groups than in groups receiving only the immunosuppressant. A positively correlated dose-response effect was observed with CY mortalities, irrespective of virus exposure. A fuel oil and a crude oil, common environmental contaminants with immunosuppressive capabilities, were tested to determine if they could produce an effect similar to that of CY. Following 28 days of oral oil administration, the birds were challenged with a sub-lethal dose of duck plague virus. No alteration in resistance to the virus (as measured by mortality) was observed, except in the positive CY control group.

  12. Immunosuppressive and anti-inflammatory properties of engineered nanomaterials

    PubMed Central

    Ilinskaya, A N; Dobrovolskaia, M A

    2014-01-01

    Nanoparticle interactions with various components of the immune system are determined by their physicochemical properties such as size, charge, hydrophobicity and shape. Nanoparticles can be engineered to either specifically target the immune system or to avoid immune recognition. Nevertheless, identifying their unintended impacts on the immune system and understanding the mechanisms of such accidental effects are essential for establishing a nanoparticle's safety profile. While immunostimulatory properties have been reviewed before, little attention in the literature has been given to immunosuppressive and anti-inflammatory properties. The purpose of this review is to fill this gap. We will discuss intended immunosuppression achieved by either nanoparticle engineering, or the use of nanoparticles to carry immunosuppressive or anti-inflammatory drugs. We will also review unintended immunosuppressive properties of nanoparticles per se and consider how such properties could be either beneficial or adverse. Linked Articles This article is part of a themed section on Nanomedicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-17 PMID:24724793

  13. Mortality from duck plague virus in immunosuppressed adult mallard ducks

    USGS Publications Warehouse

    Goldberg, D.R.; Yuill, Thomas M.; Burgess, E.C.

    1990-01-01

    Environmental contaminants contain chemicals that, if ingested, could affect the immunological status of wild birds, and in particular, their resistance to infectious disease. Immunosuppression caused by environmental contaminants, could have a major impact on waterfowl populations, resulting in increased susceptibility to contagious disease agents. Duck plague virus has caused repeated outbreaks in waterfowl resulting in mortality. In this study, several doses of cyclophosphamide (CY), a known immunosuppressant, were administered to adult mallards (Anas platyrhynchos) to determine if a resultant decrease in resistance to a normally sub-lethal strain of duck plague virus would occur, and induce mortality in these birds. Death occurred in birds given CY only, and in birds given virus and CY, but not in those given virus only. There was significantly greater mortality and more rapid deaths in the duck plague virus-infected groups than in groups receiving only the immunosuppressant. A positively correlated dose-response effect was observed with CY mortalities, irrespective of virus exposure. A fuel oil and a crude oil, common environmental contaminants with immunosuppressive capabilities, were tested to determine if they could produce an effect similar to that of CY. Following 28 days of oral oil administration, the birds were challenged with a sub-lethal dose of duck plague virus. No alteration in resistance to the virus (as measured by mortality) was observed, except in the positive CY control group.

  14. Quantifying Aggressive Behavior in Zebrafish.

    PubMed

    Teles, Magda C; Oliveira, Rui F

    2016-01-01

    Aggression is a complex behavior that influences social relationships and can be seen as adaptive or maladaptive depending on the context and intensity of expression. A model organism suitable for genetic dissection of the underlying neural mechanisms of aggressive behavior is still needed. Zebrafish has already proven to be a powerful vertebrate model organism for the study of normal and pathological brain function. Despite the fact that zebrafish is a gregarious species that forms shoals, when allowed to interact in pairs, both males and females express aggressive behavior and establish dominance hierarchies. Here, we describe two protocols that can be used to quantify aggressive behavior in zebrafish, using two different paradigms: (1) staged fights between real opponents and (2) mirror-elicited fights. We also discuss the methodology for the behavior analysis, the expected results for both paradigms, and the advantages and disadvantages of each paradigm in face of the specific goals of the study.

  15. Vasopressin/oxytocin and aggression.

    PubMed

    Ferris, Craig F

    2005-01-01

    Vasopressin/oxytocin and related peptides comprise a phylogenetically old superfamily of chemical signals in both vertebrates and invertebrates. Each peptide isoform has its own distinct receptor subtype and specific cellular action. The conservation and dispersion of vasopressin/oxytocin signalling systems across the animal kingdom attests to their functional significance in evolution. Indeed, they are involved in the physiology of fluid balance, carbohydrate metabolism, thermoregulation, immunity and reproduction. In addition, these peptides evolved a role in social behaviours related to aggression and affiliation. The focus of this chapter is the role of vasopressin/oxytocin as chemical signals in the brain altering aggressive responding in a context- and species-dependent manner. There is compelling evidence from several mammalian species including humans that vasopressin enhances aggression. The activity of the vasopressin appears linked to the serotonin system providing a mechanism for enhancing and suppressing aggressive behaviour.

  16. Environmental factors and aggressive behavior

    SciTech Connect

    Anderson, A.C.

    1982-07-01

    This paper briefly reviews some of the research areas which indicate a correlation between environmental factors and initiation of aggressive behavior. Environmental factors including lunar influences, month of birth, climate and the effects of crowding and certain chemicals are discussed.

  17. Hyperkalemic distal renal tubular acidosis caused by immunosuppressant treatment with tacrolimus in a liver transplant patient: case report.

    PubMed

    Riveiro-Barciela, M; Campos-Varela, I; Tovar, J L; Vargas, V; Simón-Talero, M; Ventura-Cots, M; Crespo, M; Bilbao, I; Castells, L

    2011-12-01

    Nephrotoxicity is one of the most common side effects of long-term immunosuppressive therapy with calcineurin inhibitors. We describe a case of distal renal tubular acidosis secondary to tacrolimus administration. A 43-year-old man with end-stage liver disease due to hepatitis C and B virus infections and alcoholic cirrhosis received a liver transplantation under immunosuppressive treatment with tacrolimus and mycophenolate mofetil. In the postoperative period, the patient developed hyperkalemic hyperchloremic metabolic acidosis, with a normal serum anion gap and a positive urinary anion gap, suggesting distal renal tubular acidosis. We excluded other causes of hyperkalemia. Administration of intravenous bicarbonate, loop diuretics, and oral resin exchanger corrected the acidosis and potassium levels. Distal renal tubular acidosis is one of several types of nephrotoxicity induced by tacrolimus treatment, resulting from inhibition of potassium secretion in the collecting duct. Treatment to correct the acidosis and hyperkalemia should be promptly initiated, and the tacrolimus dose adjusted when possible.

  18. Expression and/or activity of the SVCT2 ascorbate transporter may be decreased in many aggressive cancers, suggesting potential utility for sodium bicarbonate and dehydroascorbic acid in cancer therapy.

    PubMed

    McCarty, Mark F

    2013-10-01

    Hypoxia-inducible factor-1 (HIF-1) is a heterodimer transcription factor whose elevated activity in many cancers helps them to survive under hypoxic conditions and enhances their capacity to grow invasively, establish metastases, and survive chemo- or radiotherapy. Optimal intracellular levels of ascorbate suppress the level and transcriptional activity of HIF-1under normoxic or mildly hypoxic conditions by supporting the activity of proly and asparagyl hydroxylases that target HIF-1alpha. High intracellular ascorbate can also work in various ways to down-regulate activation of NF-kappaB which, like HIF-1 is constitutively active in many cancers and promotes aggressive behavior - in part by promoting transcription of HIF-1alpha. Yet recent evidence suggests that, even in the context of adequate ascorbate nutrition, the intracellular ascorbate content of many aggressive cancers may be supoptimal for effective HIF-1 control. This likely reflects low expression or activity of the SVCT2 ascorbate transporter. The expression of SVCT2 in cancers has so far received little study; but the extracellular acidity characteristic of many tumors would be expected to reduce the activity of this transporter, which has a mildly alkaline pH optimum. Unfortunately, since SVCT2 has a high affinity for ascorbate, and its activity is nearly saturated at normal healthy serum levels of this vitamin, increased oral administration of ascorbate would be unlikely to have much impact on the intracellular ascorbate content of tumors. However, cancers in which HIF-1 is active express high levels of glucose transporters such as GLUT-1, and these transporters can promote influx of dehydroascorbic acid (DHA) via facilitated diffusion; once inside the cell, DHA is rapidly reduced to ascorbate, which effectively is "trapped" within the cell. Hence, episodic intravenous infusions of modest doses of DHA may have potential for optimizing the intracellular ascorbate content of cancers, potentially

  19. Generic immunosuppression in solid organ transplantation: a Canadian perspective.

    PubMed

    Harrison, Jennifer J; Schiff, Jeffrey R; Coursol, Christian J; Daley, Christopher J A; Dipchand, Anne I; Heywood, Norine M; Keough-Ryan, Tammy M; Keown, Paul A; Levy, Gary A; Lien, Dale C; Wichart, Jenny R; Cantarovich, Marcelo

    2012-04-15

    The introduction of generic immunosuppressant medications may present an opportunity for cost savings in solid organ transplantation if equivalent clinical outcomes to the branded counterparts can be achieved. An interprofessional working group of the Canadian Society of Transplantation was established to develop recommendations on the use of generic immunosuppression in solid organ transplant recipients (SOTR) based on a review of the available data. Under current Health Canada licensing requirements, a demonstration of bioequivalence with the branded formulation in healthy volunteers allows for bridging of clinical data. Cyclosporine, tacrolimus, and sirolimus are designated as "critical dose drugs" and are held to stricter criteria. However, whether this provides sufficient guarantee of therapeutic equivalence in SOTR remains controversial, and failure to maintain an appropriate balance of immunosuppression may have serious consequences, including rejection, graft loss, and death. Published evidence supporting therapeutic equivalence of generic formulations in SOTR is lacking. Moreover, in the setting of multiple generic formulations the potential for uncontrolled product switching is a major concern, since generic preparations are not required to demonstrate bioequivalence with each other. Although close monitoring is recommended with any change in formulation, drug product switches are likely to occur without prescriber knowledge and may pose a significant patient safety risk. The advent of generic immunosuppression will require new practices including more frequent therapeutic drug and clinical monitoring, and increased patient education. The additional workload placed on transplant centers without additional funding will create challenges and could ultimately jeopardize patient outcomes. Until more robust clinical data are available and adequate regulatory safeguards are instituted, caution in the use of generic immunosuppressive drugs in solid organ

  20. Progressive multifocal leukoencephalopathy in individuals with minimal or occult immunosuppression

    PubMed Central

    Gheuens, Sarah; Pierone, Gerald; Peeters, Patrick; Koralnik, Igor J.

    2010-01-01

    Background Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease of the brain, caused by reactivation of the polyomavirus JC (JCV). PML has classically been described in individuals with profound cellular immunosuppression such as patients with AIDS, hematological malignancies, organ transplant recipients or those treated with immunosuppressive or immunomodulatory medications for autoimmune diseases. Methods and case reports We describe five HIV seronegative patients with minimal or occult immunosuppression who developed PML including two patients with alcoholic cirrhosis, one with untreated dermatomyositis, and two with idiopathic CD4+ T cell lymphocytopenia. We performed a review of the literature to find similar cases. Results We found an additional 33 cases in the literature. Of a total of 38 cases, seven (18.4%) had hepatic cirrhosis, five (13.2%) had renal failure, including one with concomitant hepatic cirrhosis, two (5.2%) were pregnant women, two (5.2%) had concomitant dementia, one (2.6%) had dermatomyositis and 22 (57.9%) had no specific underlying diagnosis. Among these 22, five (22.7%) had low CD4+ T cell counts (0.080–0.294×109/L) and were diagnosed with idiopathic CD4+ lymphocytopenia, and one had borderline CD4+ T cell count of 0.308×109/L. The outcome was fatal in 27/38 (71.1%) cases within 1.5–120 months (median 8 months) from onset of symptoms, and 3/4 cases who harbored JCV-specific T cells in their peripheral blood had inactive disease with stable neurological deficits after 6–26 months of follow up. Discussion These results indicate that PML can occur in patients with minimal or occult immunosuppression and invite us to revisit the generally accepted notion that profound cellular immunosuppression is a prerequisite for the development of PML. PMID:19828476

  1. [Biology of aggression in dogs].

    PubMed

    Feddersen-Petersen, D U

    2001-03-01

    The science of ethology is concerned with the way external stimuli and internal events cause animals to fight in a particular way. The classification of dog breeds with respect to their relative danger to humans makes no sense, as both, the complex antecedent conditions in which aggressive behaviour occurs, and its ramifying consequences in the individual dog's ecological and social environment, are not considered. From a biological point of view, environmental and learning effects are always superimposed upon genetic influences. Based on the recent developments in the study of ethology, aggression of wolves (Canis lupus L.) and domesticated dogs (Canis lupus f. familiaris) was put into context with respect to other aspects of the lifestyle of wild and domestic canids. Aggressive behaviour does not occur in a biological vacuum. This is also true for domestic dogs and their relationship to human partners. Individual dogs can become highly aggressive and dangerous. Their development and social situation will be presented and discussed in case studies. Finally, there is the question about defining "normal aggression" versus symptoms for maladaptive aggression resp. danger to humans as conspecifics. It is possible to protect the safety of the public and at the the same time practise animal care. Effective animal control legislation must focus on responsible ownership and socialisation of pups f.e. Problems are not unique to some breeds.

  2. Music, Substance Use, and Aggression

    PubMed Central

    Chen, Meng-Jinn; Miller, Brenda A.; Grube, Joel W.; Waiters, Elizabeth D.

    2016-01-01

    Objective This study investigated whether young people’s substance use and aggressive behaviors are related to their listening to music containing messages of substance use and violence. Method Data were collected using self-administered questionnaires and from a sample of community college students aged 15-25 (N = 1056; 43% male). A structural equation modeling method was used to simultaneously assess the associations between listening to various genres of music, alcohol use, illicit drug use, and aggressive behaviors, taking into account respondents’ age, gender, race/ethnicity, and level of sensation seeking. Results Listening to rap music was significantly and positively associated with alcohol use, problematic alcohol use, illicit drug use, and aggressive behaviors when all other variables were controlled. Additionally, alcohol and illicit drug use were positively associated with listening to musical genres of techno and reggae. Control variables such as sensation seeking, age, gender and race/ethnicity were significantly related to substance use and aggressive behaviors. Conclusion The findings suggest that young people’s substance use and aggressive behaviors may be related to their frequent exposure to music containing references to substance use and violence. Conversely, music listening preference may reflect some personal predispositions or lifestyle preferences. Alternatively, substance use, aggression and music preference are independent constructs, but share common “third factors.” PMID:16608146

  3. Driver irritation and aggressive behaviour.

    PubMed

    Björklund, Gunilla M

    2008-05-01

    A sample of 98 drivers responded to a Swedish version of the UK Driving Anger Scale [UK DAS; [Lajunen, T., Parker, D., Stradling, S.G., 1998. Dimensions of driver anger, aggressive and highway code violations and their mediation by safety orientation in UK drivers. Transport. Res. Part F 1, 107-121]. The results indicated that the Swedish version, like the British original, measures three sources of driver irritation: "progress impeded", "reckless driving", and "direct hostility". Structural equation modelling was used to investigate the relationships between the three sources of self-reported driver irritation, aggressive actions, speed, sex, age, and annual mileage. The models suggested a positive relationship between the amount of driver irritation and frequency of aggressive actions for all three sources of irritation. Female drivers tended to become more irritated than male drivers, while the male drivers tended to act aggressively more often. Surprisingly, drivers who reported that they enjoy fast speeds did not become more irritated than slower drivers when obstructed. The important conclusions are that experienced irritation often leads to openly aggressively actions, and that expression of aggressive behaviours may be a cause of other drivers' feeling of irritation.

  4. Normative beliefs about aggression and cyber aggression among young adults: a longitudinal investigation.

    PubMed

    Wright, Michelle F; Li, Yan

    2013-01-01

    This longitudinal study examined normative beliefs about aggression (e.g., face-to-face, cyber) in relation to the engagement in cyber aggression 6 months later among 126 (69 women) young adults. Participants completed electronically administered measures assessing their normative beliefs, face-to-face and cyber aggression at Time 1, and cyber aggression 6 months later (Time 2). We found that men reported more cyber relational and verbal aggression when compared to women. After controlling for each other, Time 1 face-to-face relational aggression was positively related to Time 2 cyber relational aggression, whereas Time 1 face-to-face verbal aggression was positively related to Time 2 cyber verbal aggression. Normative beliefs regarding cyber aggression was positively related to both forms of cyber aggression 6 months later, after controlling for normative beliefs about face-to-face aggression. Furthermore, a significant two-way interaction between Time 1 cyber relational aggression and normative beliefs about cyber relational aggression was found. Follow-up analysis showed that Time 1 cyber relational aggression was more strongly related to Time 2 cyber relational aggression when young adults held higher normative beliefs about cyber relational aggression. A similar two-way interaction was found for cyber verbal aggression such that the association between Time 1 and Time 2 cyber verbal aggression was stronger at higher levels of normative beliefs about cyber verbal aggression. Results are discussed in terms of the social cognitive and behavioral mechanisms associated with the engagement of cyber aggression.

  5. Intratumoral oncolytic adenoviral treatment modulates the glioma microenvironment and facilitates systemic tumor-antigen-specific T cell therapy

    PubMed Central

    Qiao, Jian; Dey, Mahua; Chang, Alan L; Kim, Julius W; Miska, Jason; Ling, Alex; M Nettlebeck, Dirk; Han, Yu; Zhang, Lingjiao; Lesniak, Maciej S

    2015-01-01

    Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor and is associated with poor survival. Virotherapy is a promising candidate for the development of effective, novel treatments for GBM. Recent studies have underscored the potential of virotherapy in enhancing antitumor immunity despite the fact that its mechanisms remain largely unknown. Here, using a syngeneic GBM mouse model, we report that intratumoral virotherapy significantly modulates the tumor microenvironment. We found that intratumoral administration of an oncolytic adenovirus, AdCMVdelta24, decreased tumor-infiltrating CD4+ Foxp3+ regulatory T cells (Tregs) and increased IFNγ-producing CD8+ T cells in treated tumors, even in late stage disease in which a highly immunosuppressive tumor microenvironment is considered to be a significant barrier to immunotherapy. Importantly, intratumoral AdCMVdelta24 treatment augmented systemically transferred tumor-antigen-specific T cell therapy. Furthermore, mechanistic studies showed (1) downregulation of Foxp3 in Tregs that were incubated with media conditioned by virus-infected tumor cells, (2) downregulation of indoleamine 2,3 dioxygenase 1 (IDO) in glioma cells upon infection by AdCMVdelta24, and (3) reprograming of Tregs from an immunosuppressive to a stimulatory state. Taken together, our findings demonstrate the potency of intratumoral oncolytic adenoviral treatment in enhancing antitumor immunity through the regulation of multiple aspects of immune suppression in the context of glioma, supporting further clinical development of oncolytic adenovirus-based immune therapies for malignant brain cancer. PMID:26405578

  6. Do Teachers Misbehave? Aggression in School Teams

    ERIC Educational Resources Information Center

    Ben Sasson, Dvora; Somech, Anit

    2015-01-01

    Purpose: Despite growing research on school aggression, significant gaps remain in the authors' knowledge of team aggression, since most studies have mainly explored aggression on the part of students. The purpose of this paper is to focus on understanding the phenomenon of workplace aggression in school teams. Specifically, the purpose of the…

  7. Cyclosporine A-induced hyperactivity in rats: is it mediated by immunosuppression, neurotrophism, or both?

    PubMed

    Borlongan, C V; Stahl, C E; Fujisaki, T; Sanberg, P R; Watanabe, S

    1999-01-01

    Cyclosporine A (CsA) immunosuppressive treatment has become an adjunctive therapy in neural transplantation of dopamine-secreting cells for treatment of Parkinson's disease (PD). Recently, CsA and its analogues have been shown to promote trophic effects against neurodegenerative disorders, and therefore CsA may have direct beneficial effects on dopaminergic neurons and dopamine-mediated behaviors. The present study examined the interaction between the reported CsA-induced hyperactivity and the possible alterations in nigral tyrosine hydroxylase (TH)-immunoreactive neurons in rats with damaged blood-brain barrier. CsA was administered at a therapeutic dose (10 mg/kg/day, IP, for 9 days) used in neural transplantation protocol for PD animal models. CsA-treated animals displayed significantly higher general spontaneous locomotor activity than control animals at drug injection days 7 and 9. Histological assays at day 9 revealed that there was a significant increase in TH-immunoreactive neurons in the nigra of CsA-treated rats compared to that of the vehicle-treated rats. The nigral TH elevation was accompanied by suppressed calcium-phosphotase calcineurin activity, indicating an inhibition of host immune response. This is the first report of CsA exerting simultaneous immunosuppressive and neurotrophic effects, as well as increasing general spontaneous locomotor behavior. These results support the utility of CsA as a therapeutic agent for PD and other movement disorders.

  8. Successful Immunosuppressive Treatment of Mixed Connective Tissue Disease Complicated by Microscopic Polyangiitis.

    PubMed

    Sato, Shuzo; Yashiro, Makiko; Matsuoka, Naoki; Uematsu, Manabu; Asano, Tomoyuki; Kobayashi, Hiroko; Watanabe, Hiroshi; Ohira, Hiromasa

    2016-01-01

    Mixed connective tissue disease (MCTD) is characterized by a combination of clinical features of systemic lupus erythematosus, systemic sclerosis, and polymyositis with elevated antibodies to U1 small nuclear ribonucleoprotein (U1-RNP). MCTD is often accompanied by interstitial lung disease as pulmonary involvement. On the other hand, microscopic polyangiitis (MPA) is a systemic autoimmune disease characterized by the inflammation of small vessels (arterioles, capillaries, and venules) mainly affecting the lung and kidney. MPA is associated with elevated serum anti-neutrophil cytoplasmic antibody (ANCA). Complication of MPA in patients with MCTD is rare. So far, only nine case reports of MCTD complicated by MPA with serum myeloperoxidase-specific ANCA (MPO-ANCA) are available. Here, we describe a 64-year-old male suffering from MCTD with MPA. The patient developed interstitial pneumonia with alveolar hemorrhage accompanied by myositis, scleroderma, and elevated anti-U1-RNP antibody and MPO-ANCA levels with substantial systemic inflammation. Strong immunosuppressive therapy (corticosteroid, intravenous immunoglobulin, and cyclosporine A) ameliorated the myositis, interstitial lung disease, and inflammation, with the decrease of MPO-ANCA levels, despite that severe lung complications are often associated with poor outcomes. In conclusion, MCTD may be accompanied by MPA with alveolar hemorrhage. Severe lung complications may indicate a poor outcome, and therefore prompt immunosuppressive treatment should be performed in such patients.

  9. Prednisone withdrawal in pediatric kidney transplant recipients on tacrolimus-based immunosuppression: four-year data.

    PubMed

    Hamiwka, Lorraine A; Burns, Angela; Bell, Lorraine

    2006-05-01

    Corticosteroids have been used in renal transplant immunosuppression for over 40 yr. Despite their adverse effects, steroid therapy continues to be part of early as well as maintenance immunosuppression in most pediatric renal transplant centers. The association of steroids with growth retardation, weight gain, and acne may be particularly distressing during the critical years of adolescence and young adulthood, increasing the risk of medication non-adherence. This study reviews the outcomes of pediatric renal transplant patients treated with low-dose tacrolimus, mycophenolate mofetil, or azathioprine, and planned prednisone withdrawal. Thirty-seven pediatric renal transplant recipients were withdrawn from steroids. The mean follow-up after steroid withdrawal was 42+/-19 months. Graft and patient survival were 100%. The mean serum creatinine levels and calculated creatinine clearances remained stable throughout the period of observation. The mean creatinine clearance was 96+/-24 mL/min/1.73 m2 at steroid withdrawal and 93+/-20 mL/min/1.73 m2 at the latest follow-up. Five patients restarted prednisone; in four (11%) it was for suspected or confirmed acute rejection. Improvements were observed in serum lipid profiles, blood pressure, and body mass index. Most patients experienced catchup or stable growth after prednisone withdrawal. Four patients developed viral infections; all were successfully treated. The potential benefits of steroid withdrawal in pediatric renal transplantation are supported by our results.

  10. Risk Factors for Type 1 Diabetes Recurrence in Immunosuppressed Recipients of Simultaneous Pancreas–Kidney Transplants

    PubMed Central

    Vendrame, F.; Hopfner, Y‐Y.; Diamantopoulos, S.; Virdi, S. K.; Allende, G.; Snowhite, I. V.; Reijonen, H. K.; Chen, L.; Ruiz, P.; Ciancio, G.; Hutton, J. C.; Messinger, S.

    2015-01-01

    Patients with type 1 diabetes (T1D) who are recipients of pancreas transplants are believed to rarely develop T1D recurrence in the allograft if effectively immunosuppressed. We evaluated a cohort of 223 recipients of simultaneous pancreas–kidney allografts for T1D recurrence and its risk factors. With long‐term follow‐up, recurrence was observed in approximately 7% of patients. Comparing the therapeutic regimens employed in this cohort over time, lack of induction therapy was associated with recurrence, but this occurs even with the current regimen, which includes induction; there was no influence of maintenance regimens. Longitudinal testing for T1D‐associated autoantibodies identified autoantibody positivity, number of autoantibodies, and autoantibody conversion after transplantation as critical risk factors. Autoantibodies to the zinc transporter 8 had the strongest and closest temporal association with recurrence, which was not explained by genetically encoded amino acid sequence donor–recipient mismatches for this autoantigen. Genetic risk factors included the presence of the T1D‐predisposing HLA‐DR3/DR4 genotype in the recipient and donor–recipient sharing of HLA‐DR alleles, especially HLA‐DR3. Thus, T1D recurrence is not uncommon and is developing in patients treated with current immunosuppression. The risk factors identified in this study can be assessed in the transplant clinic to identify recurrent T1D and may lead to therapeutic advances. PMID:26317167

  11. Intensive pharmacological immunosuppression allows for repetitive liver gene transfer with recombinant adenovirus in nonhuman primates.

    PubMed

    Fontanellas, Antonio; Hervás-Stubbs, Sandra; Mauleón, Itsaso; Dubrot, Juan; Mancheño, Uxua; Collantes, María; Sampedro, Ana; Unzu, Carmen; Alfaro, Carlos; Palazón, Asis; Smerdou, Cristian; Benito, Alberto; Prieto, Jesús; Peñuelas, Iván; Melero, Ignacio

    2010-04-01

    Repeated administration of gene therapies is hampered by host immunity toward vectors and transgenes. Attempts to circumvent antivector immunity include pharmacological immunosuppression or alternating different vectors and vector serotypes with the same transgene. Our studies show that B-cell depletion with anti-CD20 monoclonal antibody and concomitant T-cell inhibition with clinically available drugs permits repeated liver gene transfer to a limited number of nonhuman primates with recombinant adenovirus. Adenoviral vector-mediated transfer of the herpes simplex virus type 1 thymidine kinase (HSV1-tk) reporter gene was visualized in vivo with a semiquantitative transgene-specific positron emission tomography (PET) technique, liver immunohistochemistry, and immunoblot for the reporter transgene in needle biopsies. Neutralizing antibody and T cell-mediated responses toward the viral capsids were sequentially monitored and found to be repressed by the drug combinations tested. Repeated liver transfer of the HSV1-tk reporter gene with the same recombinant adenoviral vector was achieved in macaques undergoing a clinically feasible immunosuppressive treatment that ablated humoral and cellular immune responses. This strategy allows measurable gene retransfer to the liver as late as 15 months following the first adenoviral exposure in a macaque, which has undergone a total of four treatments with the same adenoviral vector.

  12. Sensory modulation intervention and behaviour support modification for the treatment of severe aggression in Huntington's disease. A single case experimental design.

    PubMed

    Fisher, Caroline A; Brown, Anahita

    2015-10-13

    Aggression is common in Huntington's disease. However, at present there are no standard guidelines for managing aggression in Huntington's sufferers due to a lack of empirical research. This paper presents a case study of the treatment of very high levels of aggression with sensory modulation and behaviour support intervention in a Huntington's sufferer. The client exhibited a range of aggressive behaviours, including physical aggression to people, furniture and objects, and verbal aggression. Following an eight week baseline phase, five weeks of sensory modulation intervention were employed. A behaviour support plan was then implemented as an adjunct to the sensory intervention, with aggressive behaviour systematically audited for a further 11 weeks. The results indicate a significant reduction in reported levels of aggression during the combined sensory modulation and behaviour support phase, compared to both the baseline and the sensory modulation therapy alone phases. This case study highlights the efficacy non-pharmacological interventions may have for reducing aggression in HD.

  13. [Immunosuppressive acidic protein (IAP) in gynecologic malignant tumors and its relationship with other immunosuppressive substances and cell-mediated immunity].

    PubMed

    Takada, M

    1983-02-01

    We investigated the relationship between immunosuppressive acidic protein (IAP), an immunosuppressive substance determined in the body fluid from patients with cancer and the stages of cancer, and also its relationship with the progress of cancer during treatment and convalescence in 42 cases of ovary cancer, 47 cases of cancer of the uterine neck, 19 cases of cancer of the uterine body, and 5 cases of other of cancers. In addition, the relationship of IAP with other immunosuppressive substances and cell-mediated immunities was also investigated. The IAP level in the serum was not useful for early diagnosis of gynecologic malignant tumors, but it reflected on stages of cancer more accurately compared to levels of other immunosuppressive substances in the serum: alpha-antitripsine (alpha AT), alpha-glyco-protein (alpha AG), carcinoembrionic antigen (CEA), c-reactive protein (CRP), and serum ferritin (s-Fer), were useful as parameters showing progress of cancer during treatment and convalescence. The IAP level in the peritoneal fluid showed the same tendency. For the relationship with cell-mediated immunity, a stimulate index (SI) showed an inverse correlation from stage I; a T-cell count exhibited the same tendency; IgGFcR+ T-cell count showed a positive correlation in stage III; and ADCC exhibited an inverse correlation in stage III. However, immunosuppressive substances including IAP show high levels also in inflammatory diseases. Therefore, an appreciative value of IAP in the clinical area increases by being used for monitoring gynecologic cancer patients in combination with indicators of cell-mediated immunity, particularly, with SI.

  14. Longitudinal variation in hepatitis C virus (HCV) viraemia and early course of HCV infection after liver transplantation for HCV cirrhosis: the role of different immunosuppressive regimens

    PubMed Central

    Papatheodoridis, G; Barton, S; Andrew, D; Clewley, G; Davies, S; Dhillon, A; Dusheiko, G; Davidson, B; Rolles, K; Burroughs, A

    1999-01-01

    BACKGROUND—The role of the type of immunosuppression in the natural history of post-transplant hepatitis C virus (HCV) infection is unclear.
AIMS—To evaluate the fluctuation of HCV viraemia and the early course of infection, and their relation to the type of immunosuppression in HCV transplant patients.
METHODS—In 47 HCV transplant patients, serum HCV RNA levels were determined pretransplant and at one and two weeks, and three and 12 months after transplant. Initial immunosuppression was triple (cyclosporin, azathioprine, prednisolone) in 31, double (cyclosporin, prednisolone) in five, and single (cyclosporin or tacrolimus) in 11 patients. Prednisolone was withdrawn at a median of six months.
RESULTS—At three months, HCV RNA levels were higher in patients with single than with triple or double initial therapy. At 12 months, HCV RNA levels correlated only with duration of prednisolone treatment and were relatively higher in patients with triple compared with single initial immunosuppression. A higher necroinflammatory activity at 12 months post-transplant was found in patients with post-transplant acute hepatitis compared with those without. Extent of fibrosis at 12 months was associated with the 12 month HCV RNA level and occurrence of post-transplant acute hepatitis.
CONCLUSIONS—HCV RNA levels at three months after transplant are higher in patients treated with single initial immunosuppressive therapy, but at 12 months are higher in patients with longer duration of steroid treatment. HCV viraemia at 12 months seems to be particularly important, as its levels are strongly correlated with the severity of fibrosis.


Keywords: HCV RNA; HCV genotype; grading score; staging score; immunosuppression; liver transplantation PMID:10446114

  15. Therapy of Lies

    ERIC Educational Resources Information Center

    Price, Sean

    2012-01-01

    Conversion therapy comes in many forms, ranging from informal chats with counselors to aggressive physical coercion, but all are based on the belief that a gay male or a lesbian can be changed "back" to heterosexual behavior. It is not just alarmed parents who turn to this therapy. Many LGBT individuals seek out such treatment in an effort to…

  16. Massage Therapy Research

    ERIC Educational Resources Information Center

    Field, Tiffany; Diego, Miguel; Hernandez-Reif, Maria

    2007-01-01

    Massage therapy has been notably effective in preventing prematurity, enhancing growth of infants, increasing attentiveness, decreasing depression and aggression, alleviating motor problems, reducing pain, and enhancing immune function. This review covers massage therapy research from the last decade, as an update to the American Psychologist 1998…

  17. Kindergarten Children's Genetic Vulnerabilities Interact with Friends' Aggression to Promote Children's Own Aggression

    ERIC Educational Resources Information Center

    van Lier, Pol; Boivin, Michel; Dionne, Ginette; Vitaro, Frank; Brendgen, Mara; Koot, Hans; Tremblay, Richard E.; Perusse, Daniel

    2007-01-01

    Objective: To examine whether kindergarten children's genetic liability to physically aggress moderates the contribution of friends' aggression to their aggressive behaviors. Method: Teacher and peer reports of aggression were available for 359 6-year-old twin pairs (145 MZ, 212 DZ) as well as teacher and peer reports of aggression of the two best…

  18. Enhanced efficacy of cidofovir combined with vaccinia immune globulin in treating progressive cutaneous vaccinia virus infections in immunosuppressed hairless mice.

    PubMed

    Smee, Donald F; Dagley, Ashley; Downs, Brittney; Hagloch, Joseph; Tarbet, E Bart

    2015-01-01

    The treatment of progressive vaccinia in individuals has involved antiviral drugs, such as cidofovir (CDV), brincidofovir, and/or tecovirimat, combined with vaccinia immune globulin (VIG). VIG is costly, and its supply is limited, so sparing the use of VIG during treatment is an important objective. VIG sparing was modeled in immunosuppressed mice by maximizing the treatment benefits of CDV combined with VIG to determine the effective treatments that delayed the time to death, reduced cutaneous lesion severity, and/or decreased tissue viral titers. SKH-1 hairless mice immunosuppressed with cyclophosphamide and hairless SCID mice (SHO strain) were infected cutaneously with vaccinia virus. Monotherapy, dual combinations (CDV plus VIG), or triple therapy (topical CDV, parenteral CDV, and VIG) were initiated 2 days postinfection and were given every 3 to 4 days through day 11. The efficacy assessment included survival rate, cutaneous lesion severity, and viral titers. Delays in the time to death and the reduction in lesion severity occurred in the following order of efficacy: triple therapy had greater efficacy than double combinations (CDV plus VIG or topical plus parenteral CDV), which had greater efficacy than VIG alone. Parenteral administration of CDV or VIG was necessary to suppress virus titers in internal organs (liver, lung, and spleen). The skin viral titers were significantly reduced by triple therapy only. The greatest efficacy was achieved by triple therapy. In humans, this regimen should translate to a faster cure rate, thus sparing the amount of VIG used for treatment.

  19. Immunosuppression Induced by Chronic Inflammation and the Progression to Oral Squamous Cell Carcinoma

    PubMed Central

    Sun, Yujuan; Liu, Nan; Guan, Xiaobing; Wu, Hongru

    2016-01-01

    Oral squamous cell carcinoma (OSCC) is an aggressive, invasive malignancy of epithelial origin. The progression from premalignant lesions—oral leukoplakia (OLK) and oral lichen planus (OLP)—to OSCC involves complex inflammatory processes that have not been elucidated. We investigated the roles of inflammatory mediators and infiltrating immunocytes in the pathogenic progression of OLK and OLP to OSCC. The occurrence of regulatory T-cells (Tregs) and tumor-associated macrophages (TAMs) and the expression of anti-inflammatory cytokines and proinflammatory cytokines were investigated in OLK, OLP, and OSCC tissues. Immunohistochemical staining of CD4, FOXP3, CD68, TGF-β1, IL-10, IL-4, IFN-γ, and MCP-1 showed that the occurrence of Tregs and TAMs increased in parallel with disease progression in OLK and OSCC. IL-10 gradually increased during the early stages of OLK and in OSCC. Infiltrating IL-4+ macrophages were seen with increasing frequency in OLK tissue during the progression of oral dysplasia. Fewer TGF-β1+ macrophages were seen in OSCC than in OLK and OLP. The expression of IFN-γ decreased gradually with the OLK development and had the lowest expression in OSCC. MCP-1 expression did not change significantly during the development of OSCC. The results suggested that the immunosuppression induced by chronic inflammation promotes tumorigenesis in OSCC, rather than initiating it. PMID:28053372

  20. Mesenchymal stem cell secretome and regenerative therapy after cancer.

    PubMed

    Zimmerlin, Ludovic; Park, Tea Soon; Zambidis, Elias T; Donnenberg, Vera S; Donnenberg, Albert D

    2013-12-01

    Cancer treatment generally relies on tumor ablative techniques that can lead to major functional or disfiguring defects. These post-therapy impairments require the development of safe regenerative therapy strategies during cancer remission. Many current tissue repair approaches exploit paracrine (immunomodulatory, pro-angiogenic, anti-apoptotic and pro-survival effects) or restoring (functional or structural tissue repair) properties of mesenchymal stem/stromal cells (MSC). Yet, a major concern in the application of regenerative therapies during cancer remission remains the possible triggering of cancer recurrence. Tumor relapse implies the persistence of rare subsets of tumor-initiating cancer cells which can escape anti-cancer therapies and lie dormant in specific niches awaiting reactivation via unknown stimuli. Many of the components required for successful regenerative therapy (revascularization, immunosuppression, cellular homing, tissue growth promotion) are also critical for tumor progression and metastasis. While bi-directional crosstalk between tumorigenic cells (especially aggressive cancer cell lines) and MSC (including tumor stroma-resident populations) has been demonstrated in a variety of cancers, the effects of local or systemic MSC delivery for regenerative purposes on persisting cancer cells during remission remain controversial. Both pro- and anti-tumorigenic effects of MSC have been reported in the literature. Our own data using breast cancer clinical isolates have suggested that dormant-like tumor-initiating cells do not respond to MSC signals, unlike actively dividing cancer cells which benefited from the presence of supportive MSC. The secretome of MSC isolated from various tissues may partially diverge, but it includes a core of cytokines (i.e. CCL2, CCL5, IL-6, TGFβ, VEGF), which have been implicated in tumor growth and/or metastasis. This article reviews published models for studying interactions between MSC and cancer cells with a focus

  1. Molecular Pathways Associated with Aggressiveness of Papillary Thyroid Cancer

    PubMed Central

    Benvenga, Salvatore; Koch, Christian A

    2014-01-01

    The most common thyroid malignancy is papillary thyroid cancer (PTC). Mortality rates from PTC mainly depend on its aggressiveness. Geno- and phenotyping of aggressive PTC has advanced our understanding of treatment failures and of potential future therapies. Unraveling molecular signaling pathways of PTC including its aggressive forms will hopefully pave the road to reduce mortality but also morbidity from this cancer. The mitogen-activated protein kinase and the phosphatidylinositol 3-kinase signaling pathway as well as the family of RAS oncogenes and BRAF as a member of the RAF protein family and the aberrant expression of microRNAs miR-221, miR-222, and miR-146b all play major roles in tumor initiation and progression of aggressive PTC. Small molecule tyrosine kinase inhibitors targeting BRAF-mediated events, vascular endothelial growth factor receptors, RET/PTC rearrangements, and other molecular targets, show promising results to improve treatment of radioiodine resistant, recurrent, and aggressive PTC. PMID:24955023

  2. [Therapeutic Aggressiveness and Liquid Oncology].

    PubMed

    Barón Duarte, F J; Rodríguez Calvo, M S; Amor Pan, J R

    2017-01-01

    Aggressiveness criteria proposed in the scientific literature a decade ago provide a quality judgment and are a reference in the care of patients with advanced cancer, but their use is not generalized in the evaluation of Oncology Services. In this paper we analyze the therapeutic aggressiveness, according to standard criteria, in 1.001 patients with advanced cancer who died in our Institution between 2010 and 2013. The results seem to show that aggressiveness at the end of life is present more frequently than experts recommend. About 25% of patients fulfill at least one criterion of aggressiveness. This result could be explained by a liquid Oncology which does not prioritize the patient as a moral subject in the clinical appointment. Medical care is oriented to necessities and must be articulated in a model focused on dignity and communication. Its implementation through Advanced Care Planning, consideration of patient's values and preferences, and Limitation of therapeutic effort are ways to reduce aggressiveness and improve clinical practice at the end of life. We need to encourage synergic and proactive attitudes, adding the best of cancer research with the best clinical care for the benefit of human being, moral subject and main goal of Medicine.

  3. In silico tumor control induced via alternating immunostimulating and immunosuppressive phases

    PubMed Central

    Reppas, AI; Alfonso, JCL; Hatzikirou, H

    2016-01-01

    Despite recent advances in the field of Oncoimmunology, the success potential of immunomodulatory therapies against cancer remains to be elucidated. One of the reasons is the lack of understanding on the complex interplay between tumor growth dynamics and the associated immune system responses. Toward this goal, we consider a mathematical model of vascularized tumor growth and the corresponding effector cell recruitment dynamics. Bifurcation analysis allows for the exploration of model's dynamic behavior and the determination of these parameter regimes that result in immune-mediated tumor control. In this work, we focus on a particular tumor evasion regime that involves tumor and effector cell concentration oscillations of slowly increasing and decreasing amplitude, respectively. Considering a temporal multiscale analysis, we derive an analytically tractable mapping of model solutions onto a weakly negatively damped harmonic oscillator. Based on our analysis, we propose a theory-driven intervention strategy involving immunostimulating and immunosuppressive phases to induce long-term tumor control. PMID:26305801

  4. On the adaptive significance of stress-induced immunosuppression.

    PubMed Central

    Råberg, L; Grahn, M; Hasselquist, D; Svensson, E

    1998-01-01

    We approach the field of stress immunology from an ecological point of view and ask: why should a heavy physical workload, for example as a result of a high reproductive effort, compromise immune function? We argue that immunosuppression by neuroendocrine mechanisms, such as stress hormones, during heavy physical workload is adaptive, and consider two different ultimate explanations of such immunosuppression. First, several authors have suggested that the immune system is suppressed to reallocate resources to other metabolic demands. In our view, this hypothesis assumes that considerable amounts of energy or nutrients can be saved by suppressing the immune system; however, this assumption requires further investigation. Second, we suggest an alternative explanation based on the idea that the immune system is tightly regulated by neuroendocrine mechanisms to avoid hyperactivation and ensuing autoimmune responses. We hypothesize that the risk of autoimmune responses increases during heavy physical workload and that the immune system is suppressed to counteract this. PMID:9753786

  5. A Model for HCMV Infection in Immunosuppressed Patients

    PubMed Central

    Kepler, G.M.; Banks, H.T.; Davidian, M.; Rosenberg, E.S.

    2009-01-01

    We propose a model for HCMV infection in healthy and immunosuppressed patients. First, we present the biological model and formulate a system of ordinary differential equations to describe the pathogenesis of primary HCMV infection in immunocompetent and immunosuppressed individuals. We then investigate how clinical data can be applied to this model. Approximate parameter values for the model are derived from data available in the literature and from mathematical and physiological considerations. Simulations with the approximated parameter values demonstrates that the model is capable of describing primary, latent, and secondary (reactivated) HCMV infection. Reactivation simulations with this model provide a window into the dynamics of HCMV infection in (D-R+) transplant situations, where latently-infected recipients (R+) receive transplant tissue from HCMV-naive donors (D-). PMID:20161307

  6. Neurologic emergencies in HIV-negative immunosuppressed patients.

    PubMed

    Guzmán-De-Villoria, J A; Fernández-García, P; Borrego-Ruiz, P J

    HIV-negative immunosuppressed patients comprise a heterogeneous group including transplant patients, patients undergoing treatment with immunosuppressors, uremic patients, alcoholics, undernourished patients, diabetics, patients on dialysis, elderly patients, and those diagnosed with severe or neoplastic processes. Epileptic seizures, focal neurologic signs, and meningoencephalitis are neurologic syndromes that require urgent action. In most of these situations, neuroimaging tests are necessary, but the findings can be different from those observed in immunocompetent patients in function of the inflammatory response. Infectious disease is the first diagnostic suspicion, and the identification of an opportunistic pathogen should be oriented in function of the type and degree of immunosuppression. Other neurologic emergencies include ischemic stroke, cerebral hemorrhage, neoplastic processes, and pharmacological neurotoxicity. This article reviews the role of neuroimaging in HIV-negative immunodepressed patients with a neurologic complication that requires urgent management.

  7. Behavioral Interventions for Anger, Irritability, and Aggression in Children and Adolescents

    PubMed Central

    Smith, Stephanie D.; McCauley, Spencer A.; Ibrahim, Karim; Piasecka, Justyna B.

    2016-01-01

    Abstract Objective: Anger, irritability, and aggression are among the most common reasons for child mental health referrals. This review is focused on two forms of behavioral interventions for these behavioral problems: Parent management training (PMT) and cognitive-behavioral therapy (CBT). Methods: First, we provide an overview of anger/irritability and aggression as the treatment targets of behavioral interventions, followed by a discussion of the general principles and techniques of these treatment modalities. Then we discuss our current work concerning the transdiagnostic approach to CBT for anger, irritability, and aggression. Results: PMT is aimed at improving aversive patterns of family interactions that engender children's disruptive behavior. CBT targets deficits in emotion regulation and social problem-solving that are associated with aggressive behavior. Both forms of treatment have received extensive support in randomized controlled trials. Given that anger/irritability and aggressive behavior are common in children with a variety of psychiatric diagnoses, a transdiagnostic approach to CBT for anger and aggression is described in detail. Conclusions: PMT and CBT have been well studied in randomized controlled trials in children with disruptive behavior disorders, and studies of transdiagnostic approaches to CBT for anger and aggression are currently underway. More work is needed to develop treatments for other types of aggressive behavior (e.g., relational aggression) that have been relatively neglected in clinical research. The role of callous-unemotional traits in response to behavioral interventions and treatment of irritability in children with anxiety and mood disorders also warrants further investigation. PMID:26745682

  8. Immunosuppression by fractionated total lymphoid irradiation in collagen arthritis

    SciTech Connect

    McCune, W.J.; Buckley, J.A.; Belli, J.A.; Trentham, D.E.

    1982-05-01

    Treatments with fractionated total lymphoid irradiation (TLI) and cyclophosphamide were evaluated for rats injected with type II collagen. Preadministration of TLI and repeated injections of cyclophosphamide suppressed the severity of arthritis and lowered antibody titers to collagen significantly. TLI initiated at the onset of collagen arthritis decreased humoral and cellular responses to collagen but did not affect the severity of arthritis. These data demonstrate that both TLi and cyclophosphamide are immunosuppressive in an experimentally inducible autoimmune disease.

  9. Effects of immunosuppressive treatment on protein expression in rat kidney

    PubMed Central

    Kędzierska, Karolina; Sporniak-Tutak, Katarzyna; Sindrewicz, Krzysztof; Bober, Joanna; Domański, Leszek; Parafiniuk, Mirosław; Urasińska, Elżbieta; Ciechanowicz, Andrzej; Domański, Maciej; Smektała, Tomasz; Masiuk, Marek; Skrzypczak, Wiesław; Ożgo, Małgorzata; Kabat-Koperska, Joanna; Ciechanowski, Kazimierz

    2014-01-01

    The structural proteins of renal tubular epithelial cells may become a target for the toxic metabolites of immunosuppressants. These metabolites can modify the properties of the proteins, thereby affecting cell function, which is a possible explanation for the mechanism of immunosuppressive agents’ toxicity. In our study, we evaluated the effect of two immunosuppressive strategies on protein expression in the kidneys of Wistar rats. Fragments of the rat kidneys were homogenized after cooling in liquid nitrogen and then dissolved in lysis buffer. The protein concentration in the samples was determined using a protein assay kit, and the proteins were separated by two-dimensional electrophoresis. The obtained gels were then stained with Coomassie Brilliant Blue, and their images were analyzed to evaluate differences in protein expression. Identification of selected proteins was then performed using mass spectrometry. We found that the immunosuppressive drugs used in popular regimens induce a series of changes in protein expression in target organs. The expression of proteins involved in drug, glucose, amino acid, and lipid metabolism was pronounced. However, to a lesser extent, we also observed changes in nuclear, structural, and transport proteins’ synthesis. Very slight differences were observed between the group receiving cyclosporine, mycophenolate mofetil, and glucocorticoids (CMG) and the control group. In contrast, compared to the control group, animals receiving tacrolimus, mycophenolate mofetil, and glucocorticoids (TMG) exhibited higher expression of proteins responsible for renal drug metabolism and lower expression levels of cytoplasmic actin and the major urinary protein. In the TMG group, we observed higher expression of proteins responsible for drug metabolism and a decrease in the expression of respiratory chain enzymes (thioredoxin-2) and markers of distal renal tubular damage (heart fatty acid-binding protein) compared to expression in the CMG

  10. Exogenous surfactant restores lung function but not peripheral immunosuppression in ventilated surfactant-deficient rats.

    PubMed

    Vreugdenhil, Harriet A; Lachmann, Burkhard; Haitsma, Jack J; Zijlstra, Jitske; Heijnen, Cobi J; Jansen, Nicolaas J; van Vught, Adrianus J

    2006-01-01

    The authors have previously shown that mechanical ventilation can result in increased pulmonary inflammation and suppressed peripheral leukocyte function. In the present study the effect of surfactant therapy on pulmonary inflammation and peripheral immune function in ventilated surfactant-deficient rats was assessed. Surfactant deficiency was induced by repeated lung lavage, treated rats with surfactant or left them untreated, and ventilated the rats during 2 hours. Nonventilated rats served as healthy control group. Expression of macrophage inflammatory protein (MIP)-2 was measured in bronchoalveolar lavage (BAL), interleukin (IL)-1beta, and heat shock protein 70 (HSP70) were measured in total lung homogenates. Outside the lung phytohemagglutinin (PHA)-induced lymphocyte proliferation, interferon (IFN)-gamma and IL-10 production, and natural killer activity were measured in splenocytes. After 2 hours of mechanical ventilation, expression of MIP-2, IL-1beta, and HSP70 increased significantly in the lungs of surfactant-deficient rats. Outside the lung, mitogen-induced proliferation and production of IFN-gamma and IL-10 reduced significantly. Only natural killer cell activity remained unaffected. Surfactant treatment significantly improved lung function, but could not prevent increased pulmonary expression of MIP-2, IL-1beta, and HSP70 and decreased peripheral mitogen-induced lymphocyte proliferation and IFN-gamma and IL-10 production in vitro. In conclusion, 2 hours of mechanical ventilation resulted in increased lung inflammation and partial peripheral leukocyte suppression in surfactant-deficient rats. Surfactant therapy ameliorated lung function but could not prevent or restore peripheral immunosuppression. The authors postulate that peripheral immunosuppression may occur in ventilated surfactant deficient patients, which may enhance susceptibility for infections.

  11. The effect of immunosuppressants on experimental infection with Fasciola hepatica.

    PubMed

    Corba, J; Spaldonová, R

    1975-01-01

    Results are presented on the effect of immunosuppressive substances such as chlorambucil, cyclophosphamide, azathioprine, amethopterine and a cortizone derivate of betamethasone, on the development of Fasciola hepatica in the rat. The suppression of the immune response of the host to immunosuppressants was reflected in an earlier start of migration of the flukes to the common bile duct, and in an earlier onset of egg production as compared with that in the controls. Of the substances employed, cyclophosphamide and betamethasone were the most effective ones within the period from week 2--6 p.i., which is the time during which the migration of the flukes in the liver parenchyma is highest. Pathological changes in the liver of the animals were less marked than those of the infected controls. Evidence was obtained on an increased pathogenicity of infective larval flukes causing a higher mortality of the hosts in comparison with that of the control animals. On the other hand, the administration of immunosuppressants did neither influence the total number of developed flukes nor the appearance of eosinophilia in the peripheral blood of the treated animals.

  12. In Vivo Persistence of Human Rhinoviruses in Immunosuppressed Patients

    PubMed Central

    Engelmann, Ilka; Dewilde, Anny; Lazrek, Mouna; Batteux, Mathilde; Hamissi, Aminati; Yakoub-Agha, Ibrahim; Hober, Didier

    2017-01-01

    Several species of the genus Enterovirus cause persistent infections in humans. Human rhinovirus (HRV) infections are generally self-limiting but occasionally persistent infections have been described. This study aimed to identify persistent HRV infections and investigate the clinical and virologic characteristics of patients with persistent infections. From January 2012 to March 2015, 3714 respiratory specimens from 2608 patients were tested for respiratory viruses by using a multiplex reverse transcription–polymerase chain reaction. A retrospective study was performed. Patients with at least two specimens positive for HRV/enterovirus taken 45 days or longer apart were identified and the HRV/enteroviruses were typed. Patients with persistent infection were compared to patients with reinfection and patients with cleared infection. Phylogenetic analysis of the viral protein(VP)4/VP2 region was performed. 18 patients with persistent HRV/enterovirus infection were identified. Minimum median duration of persistence was 92 days (range 50–455 days). All but one patients with persistence were immunosuppressed. Immunosuppression and hematologic disorders were more frequent in patients with persistence (n = 18) than in patients with reinfection (n = 33) and with cleared infection (n = 25) (p = 0.003 and p = 0.001, respectively). In conclusion, this retrospective study identified HRV persistence in vivo which occurred mainly in immunosuppressed patients. PMID:28151988

  13. Anti-inflammatory and immunosuppressive agents in PAH.

    PubMed

    Meloche, Jolyane; Renard, Sébastien; Provencher, Steeve; Bonnet, Sébastien

    2013-01-01

    Pulmonary arterial hypertension (PAH) pathobiology involves a remodeling process in distal pulmonary arteries, as well as vasoconstriction and in situ thrombosis, leading to enhanced pulmonary vascular resistance and pressure, to right heart failure and death. The exact mechanisms accounting for PAH development remain unknown, but growing evidence demonstrate that inflammation plays a key role in triggering and maintaining pulmonary vascular remodeling. Not surprisingly, PAH is often associated with diverse inflammatory disorders. Furthermore, pathologic specimens from PAH patients reveal an accumulation of inflammatory cells in and around vascular lesions, including macrophages, T and B cells, dendritic cells, and mast cells. Circulating levels of autoantibodies, chemokines, and cytokines are also increased in PAH patients and some of these correlate with disease severity and patients' outcome. Moreover, preclinical experiments demonstrated the key role of inflammation in PAH pathobiology. Immunosuppressive agents have also demonstrated beneficial effects in animal PAH models. In humans, observational studies suggested that immunosuppressive drugs may be effective in treating some PAH subtypes associated with marked inflammation. The present chapter reviews experimental and clinical evidence suggesting that inflammation is involved in the pathogenesis of PAH, as well the therapeutic potential of immunosuppressive agents in PAH.

  14. Play Therapy

    PubMed Central

    Lawver, Timothy; Blankenship, Kelly

    2008-01-01

    Play therapy is a treatment modality in which the therapist engages in play with the child. Its use has been documented in a variety of settings and with a variety of diagnoses. Treating within the context of play brings the therapist and the therapy to the level of the child. By way of an introduction to this approach, a case is presented of a six-year-old boy with oppositional defiant disorder. The presentation focuses on the events and interactions of a typical session with an established patient. The primary issues of the session are aggression, self worth, and self efficacy. These themes manifest themselves through the content of the child’s play and narration of his actions. The therapist then reflects these back to the child while gently encouraging the child toward more positive play. Though the example is one of nondirective play therapy, a wide range of variation exists under the heading of play therapy. PMID:19724720

  15. Trends in the use of immunosuppressive agents by outpatients after renal transplantation at a medical center in southern Taiwan.

    PubMed

    Mao, P C-M; Lee, E K-L; Tseng, P-L

    2012-01-01

    Kidney transplantation has become an effective treatment for end-stage renal failure. This study analyzed trends in immunosuppressive agent use after renal transplantation at a medical center in southern Taiwan over a 9-year period (2000-2008) seeking to determine whether the trends were consistent with clinical trial outcomes and published guidelines. We identified adult outpatients who had diagnoses of renal transplantation and who had concurrent immunosuppressive drug claims. From 2000-2008, we discovered 39,189 prescriptions related to kidney transplantation. The overall medication consumption showed an increase from 4.9% to 31.9%. Cyclosporine was the main determinant of overall drug costs during these 9 years. The long-term prescribing trend for immunosuppressive use among renal transplantation outpatients showed a clear change during the course of the study. Tacrolimus and sodium mycophenolate/mycophenolate mofetil were used increasingly as combination therapy. However, our survey revealed that management of this transplantation population, especially regarding the use of either calcineurin inhibitor or corticosteroids, was based on potential long-term side effects.

  16. The influence of intrauterine exposure to immunosuppressive treatment on changes in the immune system in juvenile Wistar rats

    PubMed Central

    Kabat-Koperska, Joanna; Kolasa-Wołosiuk, Agnieszka; Wojciuk, Bartosz; Wojciechowska-Koszko, Iwona; Roszkowska, Paulina; Krasnodębska-Szponder, Barbara; Paczkowska, Edyta; Safranow, Krzysztof; Gołembiewska, Edyta; Machaliński, Bogusław; Ciechanowski, Kazimierz

    2016-01-01

    Background In our study, we assessed the impact of immunosuppressive drug combinations on changes in the immune system of juvenile Wistar rats exposed to these drugs during pregnancy. We primarily concentrated on changes in two organs of the immune system – the thymus and the spleen. Methods The study was conducted on 40 (32+8) female Wistar rats administered full and half dose of drugs, respectively, subjected to regimens commonly used in therapy of human kidney transplant recipients ([1] cyclosporine A, mycophenolate mofetil, and prednisone; [2] tacrolimus, mycophenolate mofetil, and prednisone; [3] cyclosporine A, everolimus, and prednisone). The animals received drugs by oral gavage 2 weeks before pregnancy and during 3 weeks of pregnancy. Results There were no statistically significant differences in the weight of the thymus and spleen, but changes were found in the results of blood hematology, cytometry from the spleen, and a histologic examination of the examined immune organs of juvenile Wistar rats. In the cytokine assay, changes in the level of interleukine 17 (IL-17) after increasing amounts of concanavaline A were dose-dependent; the increase of IL-17 was blocked after administration of higher doses of immunosuppressive drugs. However, after a reduction of doses, its increase resumed. Conclusion Qualitative, quantitative, and morphological changes in the immune system of infant rats born to pharmacologically immunosuppressed females were observed. Thymus structure, spleen composition, and splenocyte IL-17 production were mostly affected in a drug regimen–dependent manner. PMID:27471376

  17. Immunosuppression With CD40 Costimulatory Blockade Plus Rapamycin for Simultaneous Islet-Kidney Transplantation in Nonhuman Primates.

    PubMed

    Oura, T; Hotta, K; Lei, J; Markmann, J; Rosales, I; Dehnadi, A; Kawai, K; Ndishabandi, D; Smith, R-N; Cosimi, A B; Kawai, T

    2017-03-01

    The lack of a reliable immunosuppressive regimen that effectively suppresses both renal and islet allograft rejection without islet toxicity hampers a wider clinical application of simultaneous islet-kidney transplantation (SIK). Seven MHC-mismatched SIKs were performed in diabetic cynomolgus monkeys. Two recipients received rabbit antithymocyte globulin (ATG) induction followed by daily tacrolimus and rapamycin (ATG/Tac/Rapa), and five recipients were treated with anti-CD40 monoclonal antibody (mAb) and rapamycin (aCD40/Rapa). Anti-inflammatory therapy, including anti-interleukin-6 receptor mAb and anti-tumor necrosis factor-α mAb, was given in both groups. The ATG/Tac/Rapa recipients failed to achieve long-term islet allograft survival (19 and 26 days) due to poor islet engraftment and cytomegalovirus pneumonia. In contrast, the aCD40/Rapa regimen provided long-term islet and kidney allograft survival (90, 94, >120, >120, and >120 days), with only one recipient developing evidence of allograft rejection. The aCD40/Rapa regimen was also tested in four kidney-alone transplant recipients. All four recipients achieved long-term renal allograft survival (100% at day 120), which was superior to renal allograft survival (62.9% at day 120) with triple immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and steroids). The combination of anti-CD40 mAb and rapamycin is an effective and nontoxic immunosuppressive regimen that uses only clinically available agents for kidney and islet recipients.

  18. Long-term renal allograft function on a tacrolimus-based, pred-free maintenance immunosuppression comparing sirolimus vs. MMF.

    PubMed

    Gallon, L; Perico, N; Dimitrov, B D; Winoto, J; Remuzzi, G; Leventhal, J; Gaspari, F; Kaufman, D

    2006-07-01

    It is not known how different steroid-free immunosuppressive combinations affect renal graft survival and long-term kidney transplant function. Here we sought to compare the impact on graft survival and long-term graft function of two tacrolimus (Tac)-based, prednisone-free maintenance immunosuppressive protocols: Tac/Mycophenolate Mofetil (MMF) vs. Tac/Sirolimus (SRL). Renal transplant patients given induction therapy with IL2-RA and methylprednisolone on days 0, 1 and 2 post-transplant were prospectively randomized to two maintenance immunosuppressive regimens with Tac/MMF (n = 45) or Tac/SRL (n = 37). During the 3-year follow-up the following data were collected: patient survival, renal allograft survival, incidence of acute rejection and glomerular filtration rate (GFR) at different time-points post-transplant. Cumulative graft survival was significantly different in the two groups: one kidney loss in the Tac/MMF vs. six kidney losses in the Tac/SRL (log-rank test p = 0.04). GFR at different time-points post-transplant was consistently and statistically better in the Tac/MMF than in the Tac/SRL group. The slope of GFR decline per month was flatter in the Tac/MMF than in the Tac/SRL group. This study showed that renal graft survival and graft function were significantly lower in the combination of Tac/SRL than Tac/MMF.

  19. Personalization of the Immunosuppressive Treatment in Renal Transplant Recipients: The Great Challenge in “Omics” Medicine

    PubMed Central

    Zaza, Gianluigi; Granata, Simona; Tomei, Paola; Dalla Gassa, Alessandra; Lupo, Antonio

    2015-01-01

    Renal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed, in most cases, by a significant enhancement in patients’ quality of life. Significant improvements in one-year renal allograft and patients’ survival rates have been achieved over the last 10 years primarily as a result of newer immunosuppressive regimens. Despite these notable achievements in the short-term outcome, long-term graft function and survival rates remain less than optimal. Death with a functioning graft and chronic allograft dysfunction result in an annual rate of 3%–5%. In this context, drug toxicity and long-term chronic adverse effects of immunosuppressive medications have a pivotal role. Unfortunately, at the moment, except for the evaluation of trough drug levels, no clinically useful tools are available to correctly manage immunosuppressive therapy. The proper use of these drugs could potentiate therapeutic effects minimizing adverse drug reactions. For this purpose, in the future, “omics” techniques could represent powerful tools that may be employed in clinical practice to routinely aid the personalization of drug treatment according to each patient’s genetic makeup. However, it is unquestionable that additional studies and technological advances are needed to standardize and simplify these methodologies. PMID:25690039

  20. Relevance of maintenance triple-drug immunosuppression to bridle the amplification of rat cytomegalovirus infection after experimental lung transplantation.

    PubMed

    Lehle, K; von Suesskind-Schwendi, M; Diez, C; Michl, M; Geissler, E K; Wottge, H U; Schmid, C; Hirt, S W

    2012-12-01

    Immunosuppressive therapy required to treat rejection after lung transplantation (LTx) contributes significantly to the pathogenesis of cytomegalovirus (CMV) infection and disease. In a weak allogeneic left LTx model in the rat (Fisher 344 [F344] to Wistar Kyoto [WKY] rats) we analyzed the influence of acute CMV infection on postoperative day (POD) 3, with application of standard triple-drug immunosuppression (TD-IS) (cyclosporin A, azathioprine, prednisolone) on late outcome after LTx. Native right lungs and syngeneic grafts (WKY to WKY) served as controls. Rats were sacrificed on POD 15, 30, 60, and 100. TD-IS completely prevented acute and chronic rejection in non-infected rats. Allografts of CMV-infected rats treated with TD-IS showed only mild perivascular infiltrations in 6/10 rats (POD 15 and 30), which persisted up to POD 100 in 4/10 rats. In the long-term course, mild isolated interstitial and alveolar changes were found in 40% of these animals. In conclusion, rat CMV infection partially neutralized the immunosuppressive effect of TD-IS. However, an amplification of CMV infection under TD-IS can be controlled and does not result in fatal outcome.

  1. Hypocholesterolaemia in dogs with dominance aggression.

    PubMed

    Sentürk, S; Yalçin, E; Pentürk, S

    2003-09-01

    Serum lipids and lipoprotein concentrations have been associated with dominance aggression in humans. The aim of this study was to investigate the link between serum lipids, including cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC) to HDL-C ratio and dominance aggression in dogs. Levels of serum TC, triglyceride and HDL-C were significantly lower in dogs with dominance aggression compared with non-aggressive dogs (P < 0.001). These results suggest that a relationship exists between serum lipid profile and dominance aggression in dogs, and hypocholesterolaemia exists in dogs with dominance aggression.

  2. Genetics and neurobiology of aggression in Drosophila

    PubMed Central

    Zwarts, Liesbeth; Versteven, Marijke; Callaerts, Patrick

    2012-01-01

    Aggressive behavior is widely present throughout the animal kingdom and is crucial to ensure survival and reproduction. Aggressive actions serve to acquire territory, food, or mates and in defense against predators or rivals; while in some species these behaviors are involved in establishing a social hierarchy. Aggression is a complex behavior, influenced by a broad range of genetic and environmental factors. Recent studies in Drosophila provide insight into the genetic basis and control of aggression. The state of the art on aggression in Drosophila and the many opportunities provided by this model organism to unravel the genetic and neurobiological basis of aggression are reviewed. PMID:22513455

  3. Successful Orthotopic Heart Transplantation and Immunosuppressive Management in 2 Human Immunodeficiency Virus-Seropositive Patients.

    PubMed

    Conte, Antonio Hernandez; Kittleson, Michelle M; Dilibero, Deanna; Hardy, W David; Kobashigawa, Jon A; Esmailian, Fardad

    2016-02-01

    Few orthotopic heart transplantations have been performed in patients infected with the human immunodeficiency virus since the first such case was reported in 2001. Since that time, advances in highly active antiretroviral therapy have resulted in potent and durable suppression of the causative human immunodeficiency virus-accompanied by robust immune reconstitution, reversal of previous immunodeficiency, a marked decrease in opportunistic and other infections, and near-normal long-term survival. Although human immunodeficiency virus infection is not an absolute contraindication, few centers in the United States and Canada have performed heart transplantations in this patient population; these patients have been de facto excluded from this procedure in North America. Re-evaluation of the reasons for excluding these patients from cardiac transplantation is warranted in light of such significant advances in antiretroviral therapy. This case report documents successful orthotopic heart transplantation in 2 patients infected with human immunodeficiency virus, and we describe their antiretroviral therapy and immunosuppressive management challenges. Both patients were doing well without sequelae 43 and 38 months after transplantation.

  4. Successful Orthotopic Heart Transplantation and Immunosuppressive Management in 2 Human Immunodeficiency Virus–Seropositive Patients

    PubMed Central

    Kittleson, Michelle M.; Dilibero, Deanna; Hardy, W. David; Kobashigawa, Jon A.; Esmailian, Fardad

    2016-01-01

    Few orthotopic heart transplantations have been performed in patients infected with the human immunodeficiency virus since the first such case was reported in 2001. Since that time, advances in highly active antiretroviral therapy have resulted in potent and durable suppression of the causative human immunodeficiency virus—accompanied by robust immune reconstitution, reversal of previous immunodeficiency, a marked decrease in opportunistic and other infections, and near-normal long-term survival. Although human immunodeficiency virus infection is not an absolute contraindication, few centers in the United States and Canada have performed heart transplantations in this patient population; these patients have been de facto excluded from this procedure in North America. Re-evaluation of the reasons for excluding these patients from cardiac transplantation is warranted in light of such significant advances in antiretroviral therapy. This case report documents successful orthotopic heart transplantation in 2 patients infected with human immunodeficiency virus, and we describe their antiretroviral therapy and immunosuppressive management challenges. Both patients were doing well without sequelae 43 and 38 months after transplantation. PMID:27047290

  5. Comparison of the immunosuppressive effect of fractionated total lymphoid irradiation (TLI) vs conventional immunosuppression (CI) in renal cadaveric allotransplantation

    SciTech Connect

    Waer, M.; Vanrenterghem, Y.; Ang, K.K.; van der Schueren, E.; Michielsen, P.; Vandeputte, M.

    1984-02-01

    Beginning in November 1981, eight patients with end stage diabetic nephropathy underwent renal cadaveric transplantation after TLI. Transplantation was done between 2 to 11 days after the end of a fractionated TLI to a total dose of 20 to 30 Gy. During the same observation period, 60 nondiabetic patients with end stage renal disease of different origin also received a cadaveric kidney graft, with a conventional regimen of immunosuppression that consists of anti-lymphocyte-globulin, tapering high doses of prednisone, and azathioprine. Phytohemagglutinin (PHA)-, concanavalin A (con A)-, and pokeweed mitogen (PWM)-induced blastogenesis, as well as the mixed lymphocyte reaction (MLR) and the cell-mediated lympholysis (CML) decreased progressively during the first months after conventional immunosuppression to 50% of the pretransplantation level, and remained there for the first year after transplantation. These tests were much more impaired after TLI and again no recovery occurred during the first year. In the clinic, the more profound immunosuppression in TLI patients was more frequently associated with viral infections (cytomegalovirus and herpes zoster). The incidence of rejections, however, was somewhat less frequent in the TLI-treated group and occurred significantly later. After TLI, the mean cumulative dose of steroids needed for kidney transplantation during the first year after transplantation could be substantially reduced.

  6. Anti-TNF levels and anti-drug antibodies, immunosuppressants and clinical outcomes in inflammatory bowel disease.

    PubMed

    Ha, Christina; Mathur, Jagrati; Kornbluth, Asher

    2015-04-01

    The anti-tumor necrosis factor-α (TNF) antibodies have revolutionized the management of ulcerative colitis and Crohn's disease. The development of assays to allow for the measurements of serum drug levels and anti-drug antibodies have provided a more objective means of therapeutic decision making, particularly among patients losing response to treatment. Additionally, more evidence is emerging that indicates the relationship between drug levels and response to therapy including clinical response, mucosal healing and sustained remission. The use of combination therapies of the anti-TNF agents and the thiopurine immunosuppressants may also decrease immunogenicity to the anti-TNF agents and potentiate response to therapy. With more evidence emerging evidence of the importance of therapeutic drug levels and anti-drug antibodies, clinicians may be able to better optimize the current arsenal of inflammatory bowel disease therapeutics to achieve greater rates of durable remission and improved quality of life.

  7. Nonsurgical treatment of aggressive fibromatosis in the head and neck

    SciTech Connect

    West, C.B. Jr.; Shagets, F.W.; Mansfield, M.J. )

    1989-09-01

    Aggressive fibromatosis is a poorly defined, locally aggressive, yet histologically benign fibroblastic proliferative lesion that may occur in the head and neck. The lesion is highly cellular and locally infiltrative and has a propensity to invade and erode bone, compromising vital structures within the head and neck. However, it is not a true malignancy because it does not have malignant cytologic characteristics nor does it metastasize. We present two cases of aggressive fibromatosis occurring in young adult men. The first case involved a rapidly enlarging mass of the anterior maxilla that involved the upper lip, nasal alae, nasal septum, inferior turbinates, and hard palate. The patient underwent incisional biopsy to confirm the diagnosis. Because of difficulty in determining the actual margins of this extensive lesion and the significant morbidity that would have resulted from surgical resection, we elected to treat this patient with chemotherapy and radiation therapy. The second case was an extensive lesion involving the right temporal bone, pterygomaxillary space, and infratemporal, temporal, and middle cranial fossae. Incisional biopsy confirmed the diagnosis. Because of the lack of functional and cosmetic deficits and the unavoidable morbidity of a surgical resection, this patient was treated with radiation therapy. Although wide field resection is the most satisfactory form of treatment, in situations in which this modality would result in unacceptable morbidity or if surgical margins are positive, then radiation therapy and chemotherapy should be considered. Support for these therapeutic modalities is found in larger series of cases outside the head and neck.

  8. Aggressive periodontitis: The unsolved mystery.

    PubMed

    Clark, Danielle; Febbraio, Maria; Levin, Liran

    2017-01-01

    Aggressive periodontal disease is an oral health mystery. Our current understanding of this disease is that specific bacteria invade the oral cavity and the host reacts with an inflammatory response leading to mass destruction of the alveolar bone. Aggressive periodontal disease is typically observed in a population under the age of 30 and occurs so rapidly that it is difficult to treat. Unfortunately, the consequence of this disease frequently involves tooth extractions. As a result, the aftermath is chewing disability and damage to self-esteem due to an altered self-image. Furthermore, patients are encumbered by frequent dental appointments which have an economic impact in regards to both personal financial strain and absent days in the workplace. Aggressive periodontal disease has a tremendous effect on patients' overall quality of life and needs to be investigated more extensively in order to develop methods for earlier definitive diagnosis and effective treatments. One of the mysteries of aggressive periodontal disease is the relatively nominal amount of plaque present on the tooth surface in relation to the large amount of bone loss. There seems to be a hidden factor that lies between the response by the patient's immune system and the bacterial threat that is present. A better mechanistic understanding of this disease is essential to provide meaningful care and better outcomes for patients.

  9. Risperidone and Explosive Aggressive Autism.

    ERIC Educational Resources Information Center

    Horrigan, Joseph P.; Barnhill, L. Jarrett

    1997-01-01

    In this study, 11 males with autism and mental retardation were administered risperidone. Substantial clinical improvement was noted almost immediately; patients with aggression, self-injury, explosivity, and poor sleep hygiene were most improved. The modal dose for optimal response was 0.5 mg bid. Weight gain was a significant side effect.…

  10. School Athletics and Fan Aggression

    ERIC Educational Resources Information Center

    Bryan, Clifford; Horton, Robert

    1976-01-01

    Several hypotheses are developed regarding fans and their behavior based upon a review of the literature. An exploratory study is then described, in which participant observers at a university sports arena observed cases of aggressive behavior among the spectators. Based upon the literature review and the findings of the study, four…

  11. Biochemistry and Aggression: Psychohematological Model.

    ERIC Educational Resources Information Center

    Foster, Hilliard G., Jr.; Spitz, Reuben T.

    1994-01-01

    Examines biochemical measures in a population of forensic psychiatric inpatients. Regression equations utilizing chemical and biological variables were developed and evaluated to determine their value in predicting the severity and frequency of aggression. Findings strongly suggest the presence of specific biochemical alteration among those…

  12. Teachers' Reactions to Children's Aggression

    ERIC Educational Resources Information Center

    Nesdale, Drew; Pickering, Kaye

    2006-01-01

    Drawing on social schema theory (Fiske & Taylor, 1991) and social identity theory (Tajfel & Turner, 1979), this study examined the impact on teachers' reactions to children's aggression of three variables, two of which were related to the aggressors and one was related to the teachers. Experienced female elementary school teachers (N=90) each read…

  13. Personal standards for judging aggression by a relationship partner: How much aggression is too much?

    PubMed

    Arriaga, Ximena B; Capezza, Nicole M; Daly, Christine A

    2016-01-01

    What determines whether people tolerate partner aggression? This research examined how norms, relationship experiences, and commitment predict personal standards for judging aggressive acts by a partner. Studies 1a and 1b (n = 689) revealed that experiencing aggression in a current relationship and greater commitment predicted greater tolerance for common partner aggression. Study 2 longitudinally tracked individuals who had never experienced partner aggression (n = 52). Once aggression occurred, individuals adopted more tolerant standards, but only if they were highly committed. Study 3 involved experimentally manipulating the relevance of partner aggression among individuals who reported current partner aggression (n = 73); they were more tolerant of aggressive acts imagined to occur by their partner (vs. the same acts by a stranger), but only if they were highly committed. Personal standards for judging partner aggression are dynamic. They shift toward greater tolerance when committed people experience aggression in a current relationship.

  14. Implicit cognitive aggression among young male prisoners: Association with dispositional and current aggression.

    PubMed

    Ireland, Jane L; Adams, Christine

    2015-01-01

    The current study explores associations between implicit and explicit aggression in young adult male prisoners, seeking to apply the Reflection-Impulsive Model and indicate parity with elements of the General Aggression Model and social cognition. Implicit cognitive aggressive processing is not an area that has been examined among prisoners. Two hundred and sixty two prisoners completed an implicit cognitive aggression measure (Puzzle Test) and explicit aggression measures, covering current behaviour (DIPC-R) and aggression disposition (AQ). It was predicted that dispositional aggression would be predicted by implicit cognitive aggression, and that implicit cognitive aggression would predict current engagement in aggressive behaviour. It was also predicted that more impulsive implicit cognitive processing would associate with aggressive behaviour whereas cognitively effortful implicit cognitive processing would not. Implicit aggressive cognitive processing was associated with increased dispositional aggression but not current reports of aggressive behaviour. Impulsive implicit cognitive processing of an aggressive nature predicted increased dispositional aggression whereas more cognitively effortful implicit cognitive aggression did not. The article concludes by outlining the importance of accounting for implicit cognitive processing among prisoners and the need to separate such processing into facets (i.e. impulsive vs. cognitively effortful). Implications for future research and practice in this novel area of study are indicated.

  15. Predicting and preventing supervisory workplace aggression.

    PubMed

    Dupré, Kathryne E; Barling, Julian

    2006-01-01

    The authors examined factors that lead to and prevent aggression toward supervisors at work using two samples: doctoral students and correctional service guards. The results supported that perceived interpersonal injustice mediates the relationship between perceptions of supervisory control over work performance and psychological aggression directed at supervisors, and further that psychological aggression toward supervisors is positively associated with physical acts of aggression directed at supervisors, supporting the notion of an escalation of aggressive workplace behaviors. Moreover, employees' perceptions of organizational sanctions (i.e., negative consequences for disobeying organizational policies) against aggression appear to play an important role in the prevention of workplace aggression by moderating the relationship between injustice and aggression targeting supervisors.

  16. Personality and trait aggression profiles of male and female prison inmates.

    PubMed

    Falk, Örjan; Sfendla, Anis; Brändström, Sven; Anckarsäter, Henrik; Nilsson, Thomas; Kerekes, Nóra

    2017-04-01

    Gender specific personality profiles in association with the level of aggressive antisocial behavior in offenders have not been previously investigated. In the present study we analyzed data collected from 65 male and 50 female offenders using structured protocols regarding criminal history (by criminal register data), trait aggression (by the Life History of Aggression (LHA) questionnaire), and personality profiles (by the Temperament and Character Inventory (TCI)). Prison inmates differed significantly on several personality dimensions, most pronouncedly were they characterized with low character maturity (low scores in the Self-Directedness and Cooperativeness dimensions of TCI) when compared to gender and age matched controls of the general population. The majority of offenders scored distinctively high on trait aggression. There were moderate to strong associations between the personality dimensions and each of the subscales of LHA (Aggression, Self-directed Aggression and Antisocial behavior). These associations were stronger in the female offender sample. Trait aggression could be best explained by a model, which included male gender, younger age, high novelty seeking temperament and low character maturity. Our results suggest that therapies aiming at strengthening self-governance and increasing cooperativeness (focusing on character maturity) may alleviate aggressive antisocial behavior in offenders.

  17. Aggressive digital papillary adenoma-adenocarcinoma.

    PubMed

    Keramidas, Evangelos G; Miller, Gavin; Revelos, Kyriakos; Kitsanta, Panagiota; Page, Robert E

    2006-01-01

    Aggressive digital papillary adenocarcinoma and aggressive digital papillary adenoma are rare tumours of the sweat glands. They are most common in the most distal part of the fingers and are locally aggressive with a 50% local recurrence rate; 14% of tumours metastasize. We present two cases.

  18. Lunar Cycles and Human Aggression: A Replication.

    ERIC Educational Resources Information Center

    Russell, Gordon W.; de Graaf, Jane P.

    1985-01-01

    Tested lunar-aggression hypothesis using the aggressive penalties awarded in ice hockey over a season of competition. Interpersonal aggression was found to be unrelated to either the synodic or anomalistic cycles. Discussion centers on the persistence of lunar beliefs and their links to the literature on selective exposure and interpersonal…

  19. Effect of carnosine on the immunosuppressive effect of histamine

    SciTech Connect

    Sharpan, Yu. V.

    1985-04-01

    This paper studies the ability of carnosine (beta-imidazole-lactate) to affect histamine-induced immunosuppression of proliferative activity of various lymphocyte subpopulations and the realization of this effect through surface histamine receptors of the cells. The experiments were carried out on mice; lymphocytes were incubated with tritium-labeled thymidine for 4 h, after which their radioactivity was determined on a scintillation counter. The results show that histamine has an inhibitory action on antigen-induced proliferation of T suppressor lymphocytes through H-2 histamine receptors, for this effect was considerably inhibited by the H-2 histamine blockers metiamide, but not by the H-1 histamine blocker mepyramine.

  20. Anti-inflammatory and immunosuppressive drugs and reproduction

    PubMed Central

    Østensen, Monika; Khamashta, Munther; Lockshin, Michael; Parke, Ann; Brucato, Antonio; Carp, Howard; Doria, Andrea; Rai, Raj; Meroni, Pierluigi; Cetin, Irene; Derksen, Ronald; Branch, Ware; Motta, Mario; Gordon, Caroline; Ruiz-Irastorza, Guillermo; Spinillo, Arsenio; Friedman, Deborah; Cimaz, Rolando; Czeizel, Andrew; Piette, Jean Charles; Cervera, Ricard; Levy, Roger A; Clementi, Maurizio; De Carolis, Sara; Petri, Michelle; Shoenfeld, Yehuda; Faden, David; Valesini, Guido; Tincani, Angela

    2006-01-01

    Rheumatic diseases in women of childbearing years may necessitate drug treatment during a pregnancy, to control maternal disease activity and to ensure a successful pregnancy outcome. This survey is based on a consensus workshop of international experts discussing effects of anti-inflammatory, immunosuppressive and biological drugs during pregnancy and lactation. In addition, effects of these drugs on male and female fertility and possible long-term effects on infants exposed to drugs antenatally are discussed where data were available. Recommendations for drug treatment during pregnancy and lactation are given. PMID:16712713

  1. CLIPPERS and the need for long-term immunosuppression.

    PubMed

    Abkur, Tarig M; Kearney, Hugh; Hennessy, Michael J

    2017-02-01

    Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) is a rare chronic inflammatory disorder of the central nervous system. Herein, we describe the case of a 62-year-old female who presented with right sided facial tingling, gait ataxia and diplopia. Neuroimaging revealed pontine curvilinear enhancing lesions with extension into cerebellar peduncles, characteristic of CLIPPERS. This report discusses the differential diagnosis and the importance of prolonged immunomodulatory treatment for this rare neuro-inflammatory disorder. Long-term immunosuppression appears to be mandatory in order to achieve sustained remission and prevent disability related to atrophy of the structures involved in repeated attacks.

  2. Cervical necrotizing fasciitis as a complication of acute epiglottitis managed with minimally aggressive surgical intervention: Case report.

    PubMed

    Gollapalli, Rajesh Babu; Naiman, Ana Nusa; Merry, David

    2015-07-01

    Cervical necrotizing fasciitis secondary to epiglottitis is rare. The standard treatment of this severe condition has long been early and aggressive surgical debridement and adequate antimicrobial therapy. We report the case of an immunocompetent 59-year-old man who developed cervical necrotizing fasciitis as a complication of acute epiglottitis. We were able to successfully manage this patient with conservative surgical treatment (incision and drainage, in addition to antibiotic therapy) that did not involve aggressive debridement.

  3. Social Aggression on Television and Its Relationship to Children's Aggression in the Classroom

    ERIC Educational Resources Information Center

    Martins, Nicole; Wilson, Barbara J.

    2012-01-01

    A survey was conducted with over 500 children in grades K-5 to examine whether exposure to socially aggressive content was related to children's use of social aggression. The results of the survey revealed a significant relationship between exposure to televised social aggression and increased social aggression at school, but only for girls and…

  4. Examining the Mediating Effect of Self-Efficacy on Approval of Aggression and Proactive Aggression

    ERIC Educational Resources Information Center

    Hadley, Jade; Mowbray, Tony; Jacobs, Nicky

    2017-01-01

    Proactive aggression (PA) is goal-directed, hostile social behavior that has been linked to detrimental outcomes. It has been theorized that adolescents who believe aggression is a normal and acceptable social response (approval of aggression) are more likely to show PA. Confidence in one's ability to behave aggressively (self-efficacy about…

  5. Read anything mean lately? associations between reading aggression in books and aggressive behavior in adolescents.

    PubMed

    Stockdale, Laura A; Coyne, Sarah M; Nelson, David A; Padilla-Walker, Laura M

    2013-01-01

    Although there have been hundreds of studies on media violence, few have focused on literature, with none examining novels. Accordingly, the aim of the current study was to examine whether reading physical and relational aggression in books was associated with aggressive behavior in adolescents. Participants consisted of 223 adolescents who completed a variety of measures detailing their media use and aggressive behavior. A non-recursive structural equation model revealed that reading aggression in books was positively associated with aggressive behavior, even after controlling for exposure to aggression in other forms of media. Associations were only found for congruent forms of aggression. Implications regarding books as a form of media are discussed.

  6. UV radiation-induced immunosuppression is greater in men and prevented by topical nicotinamide.

    PubMed

    Damian, Diona L; Patterson, Clare R S; Stapelberg, Michael; Park, Joohong; Barnetson, Ross St C; Halliday, Gary M

    2008-02-01

    UV radiation-induced immunosuppression augments cutaneous carcinogenesis. The incidence of skin cancer continues to increase despite increased use of sunscreens, which are less effective at preventing immunosuppression than sunburn. Using the Mantoux reaction as a model of skin immunity, we investigated the effects of solar-simulated (ss) UV and its component UVA and UVB wavebands and tested the ability of topical nicotinamide to protect from UV-induced immunosuppression. Healthy, Mantoux-positive volunteers were UV-irradiated on their backs, with 5% nicotinamide or vehicle applied to different sites in a randomized, double-blinded manner. Subsequent Mantoux testing at irradiated and adjacent unirradiated sites enabled measurement of UV-induced immunosuppression with and without nicotinamide. Suberythemal ssUV caused significant immunosuppression, although component UVB and UVA doses delivered independently did not. Men were immunosuppressed by ssUV doses three times lower than those required to immunosuppress women. This may be an important cause of the higher skin cancer incidence and mortality observed in men. Topical nicotinamide prevented immunosuppression, with gene chip microarrays suggesting that the mechanisms of protection may include alterations in complement, energy metabolism and apoptosis pathways. Nicotinamide is a safe and inexpensive compound that could be added to sunscreens or after-sun lotions to improve protection from immunosuppression. immunosuppression.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://network.nature.com/group/jidclub

  7. Steroid withdrawal or steroid avoidance in renal transplant recipients: focus on tacrolimus-based immunosuppressive regimens.

    PubMed

    Krämer, B K; Krüger, B; Mack, M; Obed, A; Banas, B; Paczek, L; Schlitt, H J

    2005-05-01

    Steroid-induced adverse effects after transplantation include cosmetic, metabolic, and cardiovascular complications. Steroid withdrawal or avoidance with cyclosporine-based regimens have been hampered by an unacceptably high rate of acute rejections and increased rates of graft loss. Recently the results of several large, randomized trials of steroid withdrawal/avoidance with tacrolimus-based immunosuppression in renal transplant recipients became available. A review of these trials appeared to be of clinical interest. Data from the THOMAS trial clearly indicate that steroid withdrawal from a regimen of tacrolimus, mycophenolate mofetil (MMF), steroids after 3 months after transplantation is safe with regard to acute rejection rate and graft survival. If an induction therapy with daclizumab is used in combination with tacrolimus and MMF (CARMEN trial), even steroid avoidance is safe with regard to acute rejection rate and graft survival. Finally, in the ATLAS trial, steroid avoidance with basiliximab in combination with tacrolimus (resulting in tacrolimus monotherapy) or alternatively with tacrolimus and MMF both resulted in similar graft survival, but higher rates of acute rejection. In conclusion, steroid withdrawal is safe from a triple-drug regimen of tacrolimus, MMF, and steroids after 3 months after transplantation, and steroid use may completely be avoided with tacrolimus, and MMF combined with daclizumab induction. Tacrolimus monotherapy may be achieved using basiliximab induction at the price of higher rates of acute rejection, but with unaffected graft survival. Thus tacrolimus-based immunosuppression with or without interleukin-2 receptor antagonist induction has made steroid withdrawal or avoidance a realistic option in renal transplantation.

  8. Localized severe aggressive periodontitis. Disease progression and tooth preservation: a short case report over 14 years.

    PubMed

    Pelka, Matthias; Petschelt, Anselm

    2009-04-01

    A case of a 31-year-old female with aggressive periodontitis over 14 years is presented. From 1993 to 2000, no periodontal therapy occurred; disease development and progression could be reconstructed upon radiographic findings. In 2000, full-mouth disinfection therapy and antibiotic therapy was performed, as well as regenerative surgical treatments. Seven years after surgical treatment, stable periodontal conditions and clear bone regeneration in the surgical areas was evident.

  9. Workplace aggression: beginning a dialogue.

    PubMed

    McLemore, Monica R

    2006-08-01

    The June 2005 Clinical Journal of Oncology Nursing editorial titled "Communication: Whose Problem Is It?" (Griffin-Sobel, 2005) was written to begin a dialogue about a phenomenon frequently experienced yet rarely discussed: workplace aggression, also known as disruptive behavior. Prompted by a groundbreaking study published in the American Journal of Nursing by Rosenstein and O'Daniel (2005), the editorial challenged oncology nurses to begin to fix problems of communication. After reflecting on both of the articles and considering my own experience as a nurse manager, clinician, and scholar, I decided to explore the topic as it relates to nurse-to-nurse workplace aggression. The following is a summary of interviews with nurse managers, nurse practitioners, and nurse scientists about root causes and effective strategies to manage these sometimes complicated situations. This article is meant to continue the dialogue about the very sensitive issue. Confidentiality has been maintained, and I welcome your comments.

  10. Myeloablative chemotherapy for recurrent aggressive oligodendroglioma.

    PubMed Central

    Cairncross, G.; Swinnen, L.; Bayer, R.; Rosenfeld, S.; Salzman, D.; Paleologos, N.; Kaminer, L.; Forsyth, P.; Stewart, D.; Peterson, K.; Hu, W.; Macdonald, D.; Ramsay, D.; Smith, A.

    2000-01-01

    The objective of this study was to ascertain the duration of tumor control and the toxicities of dose-intense myeloablative chemotherapy for patients with recurrent oligodendrogliomas. Patients with previously irradiated oligodendrogliomas, either pure or mixed, that were contrast enhancing, measurable, and behaving aggressively at recurrence were eligible for this study. Only complete responders or major partial responders (75 % reduction in tumor size) to induction chemotherapy--either intensive-dose procarbazine, lomustine, and vincristine or cisplatin plus etoposide-could receive high-dose thiotepa (300 mg/m2/day for 3 days) followed by hematopoietic reconstitution using either bone marrow or peripheral blood stem cells. Thirty-eight patients began induction chemotherapy and 20 (10 men, 10 women; median age 46 years; median Karnofsky score 80) received high-dose thiotepa. For the high-dose group, the median event-free, progression-free, and overall survival times from recurrence were 17, 20, and 49 months, respectively. Tumor control in excess of 2 years was observed in 6 patients (30%). Four patients (20%) are alive and tumor free 27 to 77 months (median, 42 months) from the start of induction therapy; however, fatal treatment-related toxicities also occurred in 4 patients (20%). Three patients died as a result of a progressive encephalopathy which, in 2 instances, was accompanied by a wasting syndrome; 1 patient died as a consequence of an intracerebral (intratumoral) hemorrhage. Fatal toxicities occurred in patients with pretreatment Karnofsky scores of 60 or 70. High-dose thiotepa to consolidate response was a disappointing treatment strategy for patients with recurrent aggressive oligodendroglial neoplasms, although several patients had durable responses. Moreover, as prescribed, high-dose thiotepa had significant toxic effects in previously irradiated patients, especially those with poorer performance status. PMID:11303620

  11. Serologic response after vaccination against influenza (A/H1N1)pdm09 in children with renal disease receiving oral immunosuppressive drugs.

    PubMed

    Tanaka, Seiji; Saikusa, Tomoko; Katafuchi, Yuno; Ushijima, Kosuke; Ohtsu, Yasushi; Tsumura, Naoki; Ito, Yuhei

    2015-09-11

    A limited number of reports are available regarding the effect of the influenza vaccine in pediatric patients receiving steroid and immunosuppressant therapy. The influenza A(H1N1)pdm09 vaccine was administered to 15 children with renal disease who were receiving steroid and immunosuppressant therapy (treatment group) and 23 children with who were not receiving these drugs (non-treatment group). Titer transition of the hemagglutination inhibition antibody was compared between the 2 groups immediately before vaccination and 4 weeks and 6 months after vaccination. Multivariate analysis showed a significant correlation between geometric mean titer, SCR, and SPR with age, while no correlation was observed between treatment with immunosuppressant therapy and efficacy. No serious adverse reactions occurred after vaccination. This strain is not present in existing influenza vaccines, and A(H1N1)pdm09HA vaccination was administered alone in 2009. The children in this study had not previously been exposed to this strain. Therefore, we evaluated the effect of the A(H1N1)pdm09HA vaccine without the effects of vaccination or past infection with A(H1N1)pdm09HA or A(H3N2) vaccination in the previous year.

  12. Use of multiple immunosuppressive agents in recalcitrant ACANTHAMOEBA scleritis.

    PubMed

    Igras, Estera; Murphy, Conor

    2015-04-15

    A 48-year-old woman who is a contact lens wearer presented with unilateral ACANTHAMOEBA keratitis, confirmed by PCR, which responded initially to topical polyhexamethylene biguanide (PHMB) and brolene. Three months later, despite continued treatment, she developed diffuse anterior scleritis with severe pain and marked scleral injection but without evidence of recurrence keratitis. Oral non-steroidal anti-inflammatories and oral high-dose corticosteroids were added without success. Subsequent treatment with intravenous methylprednisolone and high-dose cyclosporine led to a temporary improvement. Re-presenting with signs of recurrent scleritis and severe pain, the antitumor necrosis factor monoclonal antibody adalimumab, and later oral cyclophosphamide, were added. This led to complete quiescence of the scleritis. Unfortunately, frequent recurrences of ACANTHAMOEBA keratitis and anterior uveitis occurred on immunosuppression requiring continued treatment with PHMB, brolene and topical corticosteroids. This is the first case of severe refractory ACANTHAMOEBA scleritis requiring the concomitant use of four immunosuppressive agents to achieve continued disease control. The challenges in managing this case are discussed.

  13. Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment

    PubMed Central

    Mussai, Francis; De Santo, Carmela; Abu-Dayyeh, Issa; Booth, Sarah; Quek, Lynn; McEwen-Smith, Rosanna M.; Qureshi, Amrana; Dazzi, Francesco; Vyas, Paresh

    2013-01-01

    Acute myeloid leukemia (AML) is the most common acute leukemia in adults and the second most common frequent leukemia of childhood. Patients may present with lymphopenia or pancytopenia at diagnosis. We investigated the mechanisms by which AML causes pancytopenia and suppresses patients’ immune response. This study identified for the first time that AML blasts alter the immune microenvironment through enhanced arginine metabolism. Arginase II is expressed and released from AML blasts and is present at high concentrations in the plasma of patients with AML, resulting in suppression of T-cell proliferation. We extended these results by demonstrating an arginase-dependent ability of AML blasts to polarize surrounding monocytes into a suppressive M2-like phenotype in vitro and in engrafted nonobese diabetic–severe combined immunodeficiency mice. In addition, AML blasts can suppress the proliferation and differentiation of murine granulocyte-monocyte progenitors and human CD34+ progenitors. Finally, the study showed that the immunosuppressive activity of AML blasts can be modulated through small-molecule inhibitors of arginase and inducible nitric oxide synthase, suggesting a novel therapeutic target in AML. The results strongly support the hypothesis that AML creates an immunosuppressive microenvironment that contributes to the pancytopenia observed at diagnosis. PMID:23733335

  14. An Immunosuppressant Peptide from the Hard Tick Amblyomma variegatum

    PubMed Central

    Tian, Yufeng; Chen, Wenlin; Mo, Guoxiang; Chen, Ran; Fang, Mingqian; Yedid, Gabriel; Yan, Xiuwen

    2016-01-01

    Ixodid ticks are well known for spreading transmitted tick-borne pathogens while being attached to their hosts for almost 1–2 weeks to obtain blood meals. Thus, they must secrete many immunosuppressant factors to combat the hosts’ immune system. In the present work, we investigated an immunosuppressant peptide of the hard tick Amblyomma variegatum. This peptide, named amregulin, is composed of 40 residues with an amino acid sequence of HLHMHGNGATQVFKPRLVLKCPNAAQLIQPGKLQRQLLLQ. A cDNA of the precursor peptide was obtained from the National Center for Biotechnology Information (NCBI, Bethesda, MD, USA). In rat splenocytes, amregulin exerts significant anti-inflammatory effects by inhibiting the secretion of inflammatory factors in vitro, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-8 (IL-8) and interferon-gamma (IFN-γ). In rat splenocytes, treated with amregulin, compared to lipopolysaccharide (LPS) alone, the inhibition of the above inflammatory factors was significant at all tested concentrations (2, 4 and 8 µg/mL). Amregulin shows strong free radical scavenging and antioxidant activities (5, 10 and 20 µg/mL) in vitro. Amregulin also significantly inhibits adjuvant-induced paw inflammation in mouse models in vivo. This peptide may facilitate the ticks’ successful blood feeding and may lead to host immunotolerance of the tick. These findings have important implications for the understanding of tick-host interactions and the co-evolution between ticks and the viruses that they bear. PMID:27153086

  15. Fungus dose-dependent primary pulmonary aspergillosis in immunosuppressed mice.

    PubMed Central

    Dixon, D M; Polak, A; Walsh, T J

    1989-01-01

    We report on a model of primary pulmonary aspergillosis occurring after intranasal instillation of concentrated suspensions of conidia of Aspergillus fumigatus in immunocompromised mice. Unconcentrated suspensions of inoculum contained ca. 2 x 10(7) conidia per ml (1x). These suspensions were concentrated by centrifugation, adjusted to give ca. 2 x 10(8) (10x) or 2 x 10(9) (100x) conidia per ml, and delivered in 30-microliters droplets to the nares of anesthetized mice. Mice were untreated or injected with cortisone acetate (CA) or cyclophosphamide (CY) in various dosage regimens. It was not possible to obtain mortality of more than 50% with sublethal immunosuppressive treatment and 1x fungus. In contrast, mortality followed a fungus dose response in mice receiving sublethal immunosuppression with either CA or CY. Mortality rates of up to 100% were obtained with 100x fungus and a single dose of CY (200 mg/kg) or CA (250 mg/kg) or three alternate doses (125 mg/kg per day) of CA prior to infection. This model is applicable to the study of acute, fatal primary pulmonary aspergillosis and chemotherapy trials. PMID:2651308

  16. Immunosuppression induced by talc granulomatosis in the rat.

    PubMed Central

    Radić, I; Vucak, I; Milosević, J; Marusić, A; Vukicević, S; Marusić, M

    1988-01-01

    Granulomatosis caused by four subcutaneous talc powder-suspension injections induced strong immunosuppression in rats. The disturbance included reduction of mononuclear white blood cell count in the peripheral blood, atrophy of the thymic cortex, spleen enlargement with predominance of red over the white pulp, increase in the number of lymph node germinal centres and a significant delay of the first-set and second-set allograft rejection. Neither phagocytic function of reticuloendothelial system nor erythrocyte count and humoral immune response were found to be altered. Indomethacin suppression of prostaglandin production did not normalize the allograft rejection dynamics. In contrast, splenectomy completely abolished the immunosuppressive effects of granulomatosis. In splenectomized, talc-treated animals WBC counts were not altered and the rejection of allografts was not delayed. Suppression of immune response to alloantigens was transferred to normal and splenectomized recipients by both serum and spleen cells of talc-injected animals. Also, in a cell mixture-transfer experiment, spleen cells from talc-granulomatosis-bearing donors suppressed the immune response induced by lymph node cells from immune donors in T cell-deficient rats. The inability of serum from splenectomized talc-injected rats to transfer the suppression suggested the crucial role of the spleen in the mechanisms leading to suppression in rats bearing talc-granulomatosis. PMID:3052948

  17. The macrolide immunosuppressants in dermatology: mechanisms of action.

    PubMed

    Marsland, Alexander M; Griffiths, Christopher E M

    2002-01-01

    Macrolides are xenobiotics, produced by soil fungi, which have immunosuppressant properties. They will probably revolutionise the treatment of inflammatory dermatoses. This article outlines the context and putative mechanisms of action of this novel class of drugs. Cyclosporin, and the structurally distinct macrolides tacrolimus and pimecrolimus (an ascomycin derivative), modulate immune-cell function by inhibiting calcineurin-dependent dephosphorylation-activation of specific nuclear factors, thus preventing transcription of pro-inflammatory cytokines. The macrolide rapamycin (sirolimus) acts by abrogating Target of Rapamycin, a key signalling protein that controls activation of a number of proteins which direct progression of the cell cycle in response to pro-inflammatory cytokines. Tacrolimus and pimecrolimus are small enough molecules to penetrate skin and are available in topical formulations. "Skin-specific" pimecrolimus seems not to cause systemic immunosuppression when given orally. Neither topical tacrolimus nor pimecrolimus are capable of producing skin atrophy. Sirolimus has anti-angiogenic properties that may be beneficial to the treatment of psoriasis and perhaps skin cancer.

  18. Rural neighborhoods and child aggression.

    PubMed

    Bowen, Natasha K; Wretman, Christopher J

    2014-12-01

    Structural equation modeling with latent variables was used to evaluate the direct and mediated effects of a neighborhood risk factor (negative teen behaviors) on the parent-report aggressive behavior of 213 students in grades 3 through 5 attending a school in a low-income, rural community. Contagion and social control hypotheses were examined as well as hypotheses about whether the neighborhood served as a microsystem or exosystem for rural pre-adolescents. Analyses took into account the clustering of students and ordinal nature of the data. Findings suggest that rural neighborhoods may operate as both a microsystem and exosystem for children, with direct contagion effects on their aggressive behaviors as well as indirect social control effects through parenting practices. Direct effects on aggression were also found for parenting practices and child reports of friends' negative behaviors. Pre-adolescence may be a transitional stage, when influences of the neighborhood on child behavior begin to compete with influences of caregivers. Findings can inform the timing and targets of violence prevention in rural communities.

  19. Understanding the use of immunosuppressive agents in the clinical management of IBD.

    PubMed

    Waters, O R; Lawrance, I C

    2011-08-01

    The advent of the biological era has seen many improvements in the management of inflammatory bowel disease (IBD). These agents, however, are not a ubiquitous panacea as they are neither universally available nor are they universally efficacious in the short or long-term. There is, therefore, still a need for other therapies and it is important to remember about the medications that have been effective in the past. The use of azathioprine and 6-mercoptopurine has been the mainstay of long-term therapy for many IBD patients for many years. Their role as steroid sparing agents and in the maintenance of remission is well recognized, and with the advent of metabolite testing their use has been refined. Methotrexate is a second line immunomodulator with less impressive data but still with observed benefits in Crohn's disease (CD) and two newer immunosuppressive agents, mycophenylate mofetil and tacrolimus have sparked some interest as they appear to be efficacious in some patients. As IBD is a chronic incurable condition that primarily presents in young patients, the treating clinician's goal is to induce and maintain long-term remission. So when one agent is ineffective, or unavailable, other agents need to be considered. This review aims to provide clinicians with practical and up to date knowledge about the use of the immunomodulators in the management of IBD, which is vital in order to offer the best management for their patients.

  20. Cruel intentions on television and in real life: can viewing indirect aggression increase viewers' subsequent indirect aggression?

    PubMed

    Coyne, Sarah M; Archer, John; Eslea, Mike

    2004-07-01

    Numerous studies have shown that viewing violence in the media can influence an individual's subsequent aggression, but none have examined the effect of viewing indirect aggression. This study examines the immediate effect of viewing indirect and direct aggression on subsequent indirect aggression among 199 children ages 11 to 14 years. They were shown an indirect, direct, or no-aggression video and their subsequent indirect aggression was measured by negative evaluation of a confederate and responses to a vignette. Participants viewing indirect or direct aggression gave a more negative evaluation of and less money to a confederate than participants viewing no-aggression. Participants viewing indirect aggression gave less money to the confederate than those viewing direct aggression. Participants viewing indirect aggression gave more indirectly aggressive responses to an ambiguous situation and participants viewing direct aggression gave more directly aggressive responses. This study provides the first evidence that viewing indirect aggression in the media can have an immediate impact on subsequent aggression.

  1. TLR2 limits development of hepatocellular carcinoma by reducing IL18-mediated immunosuppression.

    PubMed

    Li, Shinan; Sun, Rui; Chen, Yongyan; Wei, Haiming; Tian, Zhigang

    2015-03-15

    Immune mechanisms underlying hepatocellular carcinoma (HCC) are not well understood. Here, we show that the Toll-like receptor TLR2 inhibits production of the proinflammatory cytokine IL18 and protects mice from DEN-induced liver carcinogenesis. On this protocol, Tlr2(-/-) mice exhibited more aggressive HCC development associated with impaired CD8(+) T-cell function. Furthermore, Ly6C(high)IL18Rα(+) myeloid-derived suppressor cells (MDSC) were increased in number in the livers of Tlr2(-/-) mice before tumor onset. MDSC in this setting exhibited higher iNOS levels that could inhibit IFNγ production and CD8(+) T-cell proliferation in vitro. Notably, Tlr2(-/-) hepatocytes produced more mature IL18 after DEN treatment that was sufficient to drive MDSC accumulation there. IL18 administration was sufficient to induce accumulation of MDSC, whereas hepatocyte-specific silencing of IL18 in Tlr2(-/-) mice decreased the proportion of MDSC, increased the proportion of functional CD8(+) T cells, and alleviated HCC progression. IL18 production was mediated by caspase-8 insofar as the decrease in its silencing was sufficient to attenuate levels of mature IL18 in Tlr2(-/-) mice. Furthermore, the TLR2 agonist Pam3CSK4 inhibited both caspase-8 and IL18 expression, decreasing MDSC, increasing CD8(+) T-cell function, and promoting HCC regression. Overall, our findings show how TLR2 deficiency accelerates IL18-mediated immunosuppression during liver carcinogenesis, providing new insights into immune control that may assist the design of effective immunotherapies to treat HCC.

  2. Human Mesenchymal Stromal Cells from Adult and Neonatal Sources: A Comparative In Vitro Analysis of Their Immunosuppressive Properties Against T Cells

    PubMed Central

    Castro-Manrreza, Marta E.; Mayani, Hector; Monroy-García, Alberto; Flores-Figueroa, Eugenia; Chávez-Rueda, Karina; Legorreta-Haquet, Victoria; Santiago-Osorio, Edelmiro

    2014-01-01

    Bone marrow-mesenchymal stromal cells (BM-MSCs) have immunosuppressive properties and have been used in cell therapies as immune regulators for the treatment of graft-versus-host disease. We have previously characterized several biological properties of MSCs from placenta (PL) and umbilical cord blood (UCB), and compared them to those of BM—the gold standard. In the present study, we have compared MSCs from BM, UCB, and PL in terms of their immunosuppressive properties against lymphoid cell populations enriched for CD3+ T cells. Our results confirm the immunosuppressive potential of BM-MSCs, and demonstrate that MSCs from UCB and, to a lesser extent PL, also have immunosuppressive potential. In contrast to PL-MSCs, BM-MSCs and UCB-MSCs significantly inhibited the proliferation of both CD4+ and CD8+ activated T cells in a cell–cell contact-dependent manner. Such a reduced proliferation in cell cocultures correlated with upregulation of programmed death ligand 1 on MSCs and cytotoxic T lymphocyte-associated Ag-4 (CTLA-4) on T cells, and increased production of interferon-γ, interleukin-10, and prostaglandin E2. Importantly, and in contrast to PL-MSCs, both BM-MSCs and UCB-MSCs favored the generation of T-cell subsets displaying a regulatory phenotype CD4+CD25+CTLA-4+. Our results indicate that, besides BM-MSCs, UCB-MSCs might be a potent and reliable candidate for future therapeutic applications. PMID:24428376

  3. Men and women, alcohol and aggression.

    PubMed

    Giancola, Peter R; Levinson, Cheri A; Corman, Michelle D; Godlaski, Aaron J; Morris, David H; Phillips, Joshua P; Holt, Jerred C D

    2009-06-01

    The purpose of this study was to examine the acute effects of alcohol on aggressive behavior in men and women in a laboratory setting. Participants were 526 (261 men and 265 women) healthy social drinkers between 21 and 35 years of age. They were randomly assigned to either an alcohol or a placebo group. Aggression was measured using a modified version of the Taylor Aggression Paradigm in which electric shocks are received from, and delivered to, a same gender fictitious opponent during a supposed competitive interpersonal task. Aggression was operationalized as the intensity and duration of shocks that participants administered to their "opponent." Overall, men were more aggressive than women. Alcohol increased aggression for both men and women but this effect was stronger for men. This is one of the first laboratory studies to demonstrate that alcohol increases aggression in women.

  4. [Pharmacological treatment of syndromes of aggressivity].

    PubMed

    Itil, T M

    1978-01-01

    In the treatment of violent-aggressive behavior, four major groups of drugs emerged: 1. Major tranquilizers in the treatment of aggressive-violent behavior associated with psychotic syndromes. 2. Anti-epileptic drugs such as diphenylhydantoin and barbiturates in the treatment of aggressive-violent behavior within the epileptic syndrome. 3. Psychostimulants in the treatment of aggressive behavior of adolescents and children within behavior disturbances. 4. Anti-male hormones such as cyproterone acetate in the treatment of violent-aggressive behavior associated with pathological sexual hyperactivity. Whereas each category of drug is predominantly effective in one type of aggressive syndrome, it may also be effective in other conditions as well. Aggression as a result of a personality disorder is most difficult to treat with drugs.

  5. Intergenerational Transmission of Aggression: Physiological Regulatory Processes

    PubMed Central

    Margolin, Gayla; Ramos, Michelle C.; Timmons, Adela C.; Miller, Kelly F.; Han, Sohyun C.

    2015-01-01

    Children who grow up in aggressive households are at risk of having problems with physiological regulation, but researchers have not investigated physiology as a mechanism in the intergenerational transmission of aggression. In this article, we posit that physiological regulation, particularly during stressful interpersonal interactions, may shed light on sensitivity to conflict, It can also inform our understanding of associations between childhood exposure to aggression in families of origin and aggression against partners in adolescence or adulthood. In support of this model, we highlight findings showing that childhood exposure to family aggression relates to physiological regulation across the life span, and that reactions to physiological stress concurrently relate to aggression against intimate partners. Emerging evidence from research on biological processes during stressful interpersonal interactions raises questions about what is adaptive for individuals from aggressive families, particularly as past family experiences intersect with the challenges of new relationships. PMID:26929773

  6. Emerging and Mechanism-Based Therapies for Recurrent or Metastatic Merkel Cell Carcinoma

    PubMed Central

    Miller, Natalie J.; Bhatia, Shailender; Parvathaneni, Upendra; Iyer, Jayasri G.; Nghiem, Paul

    2013-01-01

    Opinion statement Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer with a disease-specific mortality of approximately 40 %. The association of MCC with a recently discovered polyomavirus, combined with the increased incidence and mortality of MCC among immunocompromised patients, highlight the importance of the immune system in controlling this cancer. Initial management of MCC is summarized within the NCCN guidelines and in recently published reviews. The high rate of recurrent and metastatic disease progression in MCC, however, presents a major challenge in a cancer that lacks mechanism-based, disease-specific therapies. Traditional treatment approaches have focused on cytotoxic chemotherapy that, despite frequent initial efficacy, rarely provides durable responses and has high morbidity among the elderly. In addition, the immunosuppressive nature of chemotherapy is of concern when treating a virus-associated cancer for which survival is unusually tightly linked to immune function. With a median survival of 9.6 months after development of an initial metastasis (n=179, described herein), and no FDA-approved agents for this cancer, there is an urgent need for more effective treatments. We review diverse management options for patients with advanced MCC, with a focus on emerging and mechanism-based therapies, some of which specifically target persistently expressed viral antigens. These treatments include single-dose radiation and novel immunotherapies, some of which are in clinical trials. Due to their encouraging efficacy, low toxicity, and lack of immune suppression, these therapies may offer viable alternatives to traditional cytotoxic chemotherapy. PMID:23436166

  7. Successful Treatment of Plasma Cell-Rich Acute Rejection Using Pulse Steroid Therapy Alone: A Case Report

    PubMed Central

    Nakada, Yasuyuki; Yamamoto, Izumi; Kawabe, Mayuko; Yamakawa, Takafumi; Katsuma, Ai; Katsumata, Haruki; Mafune, Aki; Kobayashi, Akimitsu; Koike, Yusuke; Yamada, Hiroki; Miki, Jun; Tanno, Yudo; Ohkido, Ichiro; Tsuboi, Nobuo; Yokoyama, Keitaro; Yamamoto, Hiroyasu; Yokoo, Takashi

    2017-01-01

    Despite the recent development of immunosuppressive agents, plasma cell-rich acute rejection (PCAR) has remained refractory to treatment. Herein, we report an unusual case of PCAR that responded well to pulse steroid therapy alone. A 47-year-old man was admitted for a protocol biopsy three months after kidney transplantation, with a stable serum creatinine level of 1.6 mg/dL. Histological examination showed focal aggressive tubulointerstitial inflammatory cell infiltration of predominantly polyclonal mature plasma cells, leading to our diagnosis of PCAR. Three months following three consecutive days of high-dose methylprednisolone (mPSL) therapy, an allograft biopsy performed for therapy evaluation showed persistent PCAR. We readministered mPSL therapy and successfully resolved the PCAR. Although PCAR generally develops more than six months after transplantation, we diagnosed this case early, at three months after transplantation, with focally infiltrated PCAR. This case demonstrates the importance of early diagnosis and prompt treatment of PCAR to manage the development and severity of allograft rejection. PMID:28168079

  8. Endogenous Nocardial Endophthalmitis in an Immunosuppressed Patient: A Serious Warning of an Underlying Life Threatening and Blinding Disorder

    PubMed Central

    Trehan, Hemant; Kaushik, Jaya; Jain, Vaibhav Kumar; Parihar, Jitendra Kumar Singh; Avasthi, Abhijit

    2017-01-01

    Purpose: To report a case of bilateral endogenous nocardial endophthalmitis with central nervous system involvement in an immunocompromised individual with an extremely poor outcome. Case Report: A 35-year-old man with a history of long-term, prescribed oral steroid use for membranoproliferative glomerulonephritis presented with profound bilateral vision loss. Patient's diagnosis of bilateral endogenous nocardial endophthalmitis was delayed. Nocardia was finally isolated from a brain biopsy after a repeat magnetic resonance imaging revealed a brain abscess. With anti-nocardia therapy, patient improved systemically, but the visual outcome was poor, with no light perception in both eyes. Conclusion: Ocular nocardiosis is a serious vision and life threatening disorder, particularly in patients on immunosuppressive therapy. A high index of suspicion is required for successful treatment. PMID:28299015

  9. Bibliotherapy: an indirect approach to treatment of childhood aggression.

    PubMed

    Shechtman, Z

    1999-01-01

    The process of group therapy with five aggressive young boys, utilizing bibliotherapy as its primary mode of intervention, was investigated and is illustrated in this paper. The rationale for using affective bibliotherapy in a group context is given, the content of the program is described, and the process is fully displayed. The effectiveness of the treatment was studied in a single-subject design, comparing treatment children with their matched counterparts. Results pointed to reduced aggression of all the five treatment students, compared with no change in the control children, by self- and teacher report. In addition, results based on an analysis of transcripts showed increased constructive behavior in group for all participants. Although these results should not be generalized, they suggest an interesting line of research for future investigation.

  10. Brachytherapy in the treatment of recurrent aggressive falcine meningiomas.

    PubMed

    Abou Al-Shaar, Hussam; Almefty, Kaith K; Abolfotoh, Mohammad; Arvold, Nils D; Devlin, Phillip M; Reardon, David A; Loeffler, Jay S; Al-Mefty, Ossama

    2015-09-01

    Recurrent aggressive falcine meningiomas are uncommon tumors that recur despite receiving extensive surgery and radiation therapy (RT). We have utilized brachytherapy as a salvage treatment in two such patients with a unique implantation technique. Both patients had recurrence of WHO Grade II falcine meningiomas despite multiple prior surgical and RT treatments. Radioactive I-125 seeds were made into strands and sutured into a mesh implant, with 1 cm spacing, in a size appropriate to cover the cavity and region of susceptible falcine dura. Following resection the vicryl mesh was implanted and fixed to the margins of the falx. Implantation in this interhemispheric space provides good dose conformality with targeting of at-risk tissue and minimal radiation exposure to normal neural tissues. The patients are recurrence free 31 and 10 months after brachytherapy treatment. Brachytherapy was an effective salvage treatment for the recurrent aggressive falcine meningiomas in our two patients.

  11. Synthesis and biological evaluation of pseudolaric acid B derivatives as potential immunosuppressive agents.

    PubMed

    Chen, Shou-Qiang; Wang, Jie; Zhao, Chuan; Sun, Qiang-Wen; Wang, Yi-Teng; Ai, Ting; Li, Tan; Gao, Ying; Wang, Huo; Chen, Hong

    2015-01-01

    Pseudolaric acid B (PB) derivatives with immunosuppressive activity were found by our group. In order to find potential immunosuppressive agents with high efficacy and low toxicity, a series of novel PB derivatives were synthesized and evaluated on their immunosuppressive activities. Most of the synthesized compounds were tested in vitro on murine T and B proliferation. In particular, compound 11 exhibited excellent inhibitory activity toward murine T cells (up to 19-fold enhancement compared to that of mycophenolatemofetil) and little cytotoxicity toward normal murine spleen cells. These experimental data demonstrated that some of these PB derivatives have great potential for future immunosuppressive studies.

  12. Rituximab Maintenance Therapy After Autologous Stem-Cell Transplantation in Patients With Relapsed CD20+ Diffuse Large B-Cell Lymphoma: Final Analysis of the Collaborative Trial in Relapsed Aggressive Lymphoma

    PubMed Central

    Gisselbrecht, Christian; Schmitz, Norbert; Mounier, Nicolas; Singh Gill, Devinder; Linch, David C.; Trneny, Marek; Bosly, Andre; Milpied, Noel J.; Radford, John; Ketterer, Nicolas; Shpilberg, Ofer; Dührsen, Ulrich; Hagberg, Hans; Ma, David D.; Viardot, Andreas; Lowenthal, Ray; Brière, Josette; Salles, Gilles; Moskowitz, Craig H.; Glass, Bertram

    2012-01-01

    Purpose The standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL) is salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT). The impact of maintenance rituximab after ASCT is not known. Patients and Methods In total, 477 patients with CD20+ DLBCL who were in their first relapse or refractory to initial therapy were randomly assigned to one of two salvage regimens. After three cycles of salvage chemotherapy, the responding patients received high-dose chemotherapy followed by ASCT. Then, 242 patients were randomly assigned to either rituximab every 2 months for 1 year or observation. Results After ASCT, 122 patients received rituximab, and 120 patients were observed only. The median follow-up time was 44 months. The 4-year event-free survival (EFS) rates after ASCT were 52% and 53% for the rituximab and observation groups, respectively (P = .7). Treatment with rituximab was associated with a 15% attributable risk of serious adverse events after day 100, with more deaths (six deaths v three deaths in the observation arm). Several factors affected EFS after ASCT (P < .05), including relapsed disease within 12 months (EFS: 46% v 56% for relapsed disease after 12 months), secondary age-adjusted International Prognostic Index (saaIPI) more than 1 (EFS: 37% v 61% for saaIPI < 1), and prior treatment with rituximab (EFS: 47% v 59% for no prior rituximab). A significant difference in EFS between women (63%) and men (46%) was also observed in the rituximab group. In the Cox model for maintenance, the saaIPI was a significant prognostic factor (P < .001), as was male sex (P = .01). Conclusion In relapsed DLBCL, we observed no difference between the control group and the rituximab maintenance group and do not recommend rituximab after ASCT. PMID:23091101

  13. Nitric oxide-mediated immunosuppression following murine Echinococcus multilocularis infection

    PubMed Central

    DAI, W J; GOTTSTEIN, B

    1999-01-01

    In some parasitic infections immunosuppression is a prominent characteristic of the host–parasite interplay. We have used a murine alveolar echinococcosis (AE) model in susceptible C57BL/6 mice to document a suppressed splenocyte proliferative response to concanavalin A (Con A) at the early (1-month) stage and to Echinococcus multilocularis-crude antigen (Emc-antigen) at the late (4–6-month) stage of chronic infection. Despite proliferative suppression, splenic cytokine production [interleukin-2 (IL-2), IL-4 and interferon-γ (IFN-γ)] in response to Con A or Emc-antigen stimulation was not suppressed at 1 month postinfection (p.i.). Infection resulted in a strong Mac-1+ cell infiltration of the peritoneal cavity and spleen. Peritoneal cells (PEC) from mice infected at the 1-month stage were rich in macrophages and expressed significantly higher levels of transcripts for the inflammatory cytokine IL-1β and for tumour necrosis factor-α and inducible nitric oxide synthase (iNOS), when compared with PEC from non-infected control mice. Conversely, the IL-10 transcript level remained low and did not change during infection. Spleen cells supplemented with PEC from infected mice induced a marked increase in the levels of nitrite in response to Con A and Emc-antigen stimulation, and also a complete suppression of splenic proliferation. The spleen cells from late-stage infected mice expressed only background levels of IL-10 but greatly increased levels of iNOS, when compared with normal spleen cells. This observation correlated with the immunosuppression demonstrated at the late stage of murine AE. Furthermore, the suppressed splenic proliferative responses observed at the early and late stage were reversed to a large extent by the addition of NG-monomethyl-l-arginine and partially by anti-IFN-γ. Thus, our results demonstrated that the immunosuppression observed in chronic AE was not primarily dependent on IL-10 but rather on nitric oxide production by macrophages

  14. Female alcohol consumption, motivations for aggression and aggressive incidents in licensed premises.

    PubMed

    Newberry, Michelle; Williams, Nikki; Caulfield, Laura

    2013-03-01

    Research into the relationship between alcohol and aggression has previously focused on men. However, in recent years there has been an increase in binge drinking and violent crime among women, behaviours which have been labelled 'ladette' culture in the UK. The current study advances the literature in this area by investigating the relationship between alcohol consumption and aggressive behaviour of females in licensed premises, including the type of aggression and motivations for aggressive incidents. Ninety-three female university students completed the Student Alcohol Questionnaire (SAQ; Engs, 2002), the Aggression Questionnaire (Buss & Perry, 1992) and a questionnaire developed to measure self-reported aggressive incidents. Females who had been involved in an aggressive incident reported spending more time on average in licensed premises per week and higher levels of aggression as well as consuming significantly more alcohol on the day of the incident than females who had not been involved in an aggressive incident. Contrary to expectations, however, those who had been involved in an aggressive incident did not report drinking more beer (a male-orientated drink) than those who had not. Verbally aggressive incidents were reported more than physically aggressive incidents, and aggression was commonly motivated by an emotional reaction or to address a grievance. The finding that average alcohol consumption per week was significantly associated with female aggression in licensed premises highlights the importance of developing interventions to reduce alcohol consumption among young females.

  15. Intergroup Biases in Fear-induced Aggression

    PubMed Central

    Mifune, Nobuhiro; Simunovic, Dora; Yamagishi, Toshio

    2017-01-01

    Using a recently created preemptive strike game (PSG) with 176 participants, we investigated if the motivations of spite and/or fear promotes aggression that requires a small cost to the aggressor and imposes a larger cost on the opponent, and confirmed the earlier finding that fear does but spite does not promote intergroup aggression when the groups are characterized as minimal groups; additionally, the rate of intergroup aggression did not vary according to the group membership of the opponent. The PSG represents a situation in which both the motivations of spite and of fear can logically drive players to choose an option of aggression against an opponent. Participants decide whether or not to attack another participant, who also has the same capability. The decision is made in real time, using a computer. We discuss theoretical implications of our findings on the evolutionary foundations of intragroup cooperation and intergroup aggression. The evolutionary model of intergroup aggression, or the parochial altruism model, posits that intragroup cooperation and intergroup aggression have co-evolved, and thus it predicts both intragroup cooperation and intergroup aggression to emerge even in a minimal group devoid of a history of intergroup relationships. The finding that only intragroup cooperation but not intergroup aggression emerged in the minimal group experiments strongly suggests that intergroup aggression involves a psychological mechanism that is independent from that of intragroup cooperation. We further discuss the implications of these findings on real-world politics and military strategy. PMID:28174553

  16. Secretory pathways generating immunosuppressive NKG2D ligands

    PubMed Central

    Baragaño Raneros, Aroa; Suarez-Álvarez, Beatriz; López-Larrea, Carlos

    2014-01-01

    Natural Killer Group 2 member D (NKG2D) activating receptor, present on the surface of various immune cells, plays an important role in activating the anticancer immune response by their interaction with stress-inducible NKG2D ligands (NKG2DL) on transformed cells. However, cancer cells have developed numerous mechanisms to evade the immune system via the downregulation of NKG2DL from the cell surface, including the release of NKG2DL from the cell surface in a soluble form. Here, we review the mechanisms involved in the production of soluble NKG2DL (sNKG2DL) and the potential therapeutic strategies aiming to block the release of these immunosuppressive ligands. Therapeutically enabling the NKG2D-NKG2DL interaction would promote immunorecognition of malignant cells, thus abrogating disease progression. PMID:25050215

  17. Immunosuppression-free transplantation reconsidered from a regenerative medicine perspective.

    PubMed

    Orlando, Giuseppe

    2012-02-01

    Recent groundbreaking progress in regenerative medicine has shown its potential to meet the two major needs of solid organ transplantation, namely the achievement of an immunosuppression-free state (IFS) and the identification of a new, potentially inexhaustible source of organs. This review illustrates how regenerative medicine technology may contribute to the achievement of IFS. There are three possible strategies: organ bioengineering, immuno-isolation and thymus bioengineering. The goal of organ bioengineering is to manufacture organs ex vivo from autologous cells. Immuno-isolation technology implements strategies aiming to prevent recognition of nonself antigens by the host immune system. Thymus organoids have been bioengineered with scaffold-seeding methods to allow deletion of T-cell clones responsible for allograft rejection. Despite the several hurdles that must be overcome, regenerative medicine technologies offer alternative strategies aimed at establishing immediate, stable and durable IFS in solid organ graft recipients.

  18. Nutrition Support for Persistent Inflammation, Immunosuppression, and Catabolism Syndrome.

    PubMed

    Moore, Frederick A; Phillips, Stuart M; McClain, Craig J; Patel, Jayshil J; Martindale, Robert G

    2017-04-01

    Despite tremendous advances in critical care, multiple-organ failure continues to be a significant problem. However, in recent years, far fewer patients with multiple-organ failure die early, but many experience ongoing immune dysregulation and are developing persistent inflammation, immunosuppression, and catabolism syndrome (PICS). Most PICS patients are discharged to nonhome destinations, fail to rehabilitate, and succumb to indolent death. From a nutrition perspective, patients with PICS experience persistent inflammation-induced cachexia despite evidenced-based recommended intensive care unit nutrition support. Recent basic and translational research indicates that prolonged expansion of myeloid-derived suppressor cells plays a central role in the pathogenesis of PICS. Myeloid-derived suppressor cells express arginase 1, which depletes arginine, causing immunosuppression and impaired wound healing. This is the rationale for arginine supplementation in PICS. Other nutrition support recommendations for PICS are based on inferences made from other patient populations who experience similar persistent inflammation-induced cachexia. These include patients with established cancers, major burns, and sarcopenia. These patients experience anabolic resistance, but studies show that this can be overcome by providing higher levels of protein and certain specific amino acids. Nutrition support guidelines recommend provision of >1.5 g/kg/d of protein and indicate that higher levels may be needed. Protein composition is also important. There is good evidence that leucine can promote anabolism in patients with cancer and sarcopenia. Finally, anabolic interventions-including intensive insulin, oxandrolone, propranolol, and resistance exercise-have proven to be effective in patients with major burns and are likely relevant in combating PICS cachexia.

  19. Mapping the immunosuppressive environment in uterine tumors: implications for immunotherapy.

    PubMed

    Vanderstraeten, Anke; Luyten, Catherine; Verbist, Godelieve; Tuyaerts, Sandra; Amant, Frederic

    2014-06-01

    The major hurdle for cancer vaccines to be effective is posed by tumor immune evasion. Several common immune mechanisms and mediators are exploited by tumors to avoid immune destruction. In an attempt to shed more light on the immunosuppressive environment in uterine tumors, we analyzed the presence of PD-L1, PDL2, B7-H4, indoleamine 2,3-dioxygenase (IDO), galectin- 1, galectin-3, arginase-1 activity and myeloid-derived suppressor cell (MDSC) infiltration. IDO, PD-L1, PD-L2 and B7-H4 were analyzed by immunohistochemistry. PDL2 was mostly expressed at low levels in these tumors. We found high IDO expression in 21 % of endometrial carcinoma samples and in 14 % of uterine sarcoma samples. For PD-L1 and B7-H4, we found high expression in 92 and 90 % of endometrial cancers, respectively, and in 100 and 92 % of the sarcomas. Galectin-1 and 3 were analyzed in tissue lysates by ELISA, but we did not find an increase in both molecules in tumor lysates compared with benign tissues. We detected expression of galectin-3 by fibroblasts, immune cells and tumor cells in single-cell tumor suspensions. In addition, we noted a highly significant increase in arginase-1 activity in endometrial carcinomas compared with normal endometria, which was not the case for uterine sarcomas. Finally, we could demonstrate MDSC infiltration in fresh tumor suspensions from uterine tumors. These results indicate that the PD-1/PD-L1 interaction and B7-H4 could be possible targets for immune intervention in uterine cancer patients as well as mediation of MDSC function. These observations are another step toward the implementation of inhibitors of immunosuppression in the treatment of uterine cancer patients.

  20. Cell source-dependent in vivo immunosuppressive properties of mesenchymal stem cells derived from the bone marrow and synovial fluid of minipigs

    SciTech Connect

    Lee, Won-Jae; Hah, Young-Sool; Ock, Sun-A.; Lee, Jae-Hoon; Jeon, Ryong-Hoon; Park, Ji-Sung; Lee, Sang-Il; Rho, Na-Young; Rho, Gyu-Jin; Lee, Sung-Lim

    2015-05-01

    The in vitro differentiation and immunosuppressive capacity of mesenchymal stem cells (MSCs) derived from synovial fluid (SF-MSCs) and bone marrow extract (BM-MSCs) in an isogenic background of minipigs were comparatively analyzed in a collagen-induced arthritis (CIA) mouse model of rheumatoid arthritis (RA). The proliferation capacity and expression of pluripotent transcription factors (Oct3/4 and Sox2) were significantly (P<0.05) higher in SF-MSCs than in BM-MSCs. The differentiation capacity of SF-MSCs into adipocytes, osteocytes and neurocytes was significantly (P<0.05) lower than that of BM-MSCs, and the differentiation capacity of SF-MSCs into chondrocytes was significantly (P<0.05) higher than that of BM-MSCs. Systemic injection of BM- and SF-MSCs significantly (P<0.05) ameliorated the clinical symptoms of CIA mice, with SF-MSCs having significantly (P<0.05) higher clinical and histopathological recovery scores than BM-MSCs. Furthermore, the immunosuppressive properties of SF-MSCs in CIA mice were associated with increased levels of the anti-inflammatory cytokine interleukin (IL)-10, and decreased levels of the pro-inflammatory cytokine IL-1β and osteoclast-related sRANKL. In conclusion, SF-MSCs exhibited eminent pluripotency and differentiation capacity into chondrocytes, addition to substantial in vivo immunosuppressive capacity by elevating IL-10 and reducing IL-1β levels in CIA mice. - Highlights: • Immunosuppressive capacity of BM-, SM-, and SF-MSCs was evaluated in an RA model. • Proliferation, pluripotency and chondrogenic differentiation capacity were higher in SF-MSCs. • SF-MSCs exhibited improved therapeutic effects than BM-MSCs. • SF-MSCs may have applications as immunosuppressive therapy in autoimmune diseases.

  1. Sleep deprivation suppresses aggression in Drosophila

    PubMed Central

    Kayser, Matthew S; Mainwaring, Benjamin; Yue, Zhifeng; Sehgal, Amita

    2015-01-01

    Sleep disturbances negatively impact numerous functions and have been linked to aggression and violence. However, a clear effect of sleep deprivation on aggressive behaviors remains unclear. We find that acute sleep deprivation profoundly suppresses aggressive behaviors in the fruit fly, while other social behaviors are unaffected. This suppression is recovered following post-deprivation sleep rebound, and occurs regardless of the approach to achieve sleep loss. Genetic and pharmacologic approaches suggest octopamine signaling transmits changes in aggression upon sleep deprivation, and reduced aggression places sleep-deprived flies at a competitive disadvantage for obtaining a reproductive partner. These findings demonstrate an interaction between two phylogenetically conserved behaviors, and suggest that previous sleep experiences strongly modulate aggression with consequences for reproductive fitness. DOI: http://dx.doi.org/10.7554/eLife.07643.001 PMID:26216041

  2. Executive functioning and alcohol-related aggression.

    PubMed

    Giancola, Peter R

    2004-11-01

    The primary goal of this investigation was to determine whether executive functioning (EF) would moderate the alcohol-aggression relation. Participants were 310 (152 men and 158 women) healthy social drinkers between 21 and 35 years of age. EF as well as non-EF skills were measured with 13 validated neuropsychological tests. Following the consumption of either an alcoholic or a placebo beverage, participants were tested on a modified version of the Taylor Aggression Paradigm (S. Taylor, 1967), in which mild electric shocks were received from, and administered to, a fictitious opponent. Aggressive behavior was operationalized as the shock intensities administered to the fictitious opponent. EF was negatively related to aggressive behavior for men, regardless of beverage group, even when controlling for non-EF skills. Furthermore, alcohol increased aggression only for men with lower EF scores. Finally, the mere belief that alcohol was consumed suppressed aggression for women but not for men.

  3. Sense of control and adolescents' aggression: The role of aggressive cues.

    PubMed

    Guo, Xucheng; Egan, Vincent; Zhang, Jianxin

    2016-12-01

    The misperception of aggressive cues is considered a risk factor for inducing adolescent aggression. Poor coping with life stress is also considered a major influence on aggression. The current study examined the relationship between subjective sense of control and adolescent aggression, considering influences upon the perception of these aggressive cues. In Study 1, 60 participants took part in a 2 (sense of control: high sense of control vs. low sense of control) × 2 (aggressive cue: aggressive vs. neutral) between-subjects contextual experiment. The result found that a lower sense of control led to an increase in adolescents' aggression; only in the low-sense-of-control condition did exposure to aggressive cues boost aggression. In Study 2, the catalytic effect of aggressive cues was further explored by an experiment in which 40 adolescents were randomly assigned to a low- or high-sense-of-control condition to test the importance of aggressive cues. The results suggest that adolescents in the low-sense-of-control condition show a higher salience for aggressive cues.

  4. Do competitive martial arts attract aggressive children?

    PubMed

    Reynes, E; Lorant, J

    2001-10-01

    The purpose of the present study was to ascertain whether children beginning martial arts training were more aggressive than their peers. 150 8-yr.-old children were administered the Buss-Perry Aggression Questionnaire. Analysis showed that children beginning martial arts training did not score more aggressive than their peers but scored higher on the Anger scale. This difference, however, appeared only in children practicing judo.

  5. The immunosuppressive signature of menstrual blood mesenchymal stem cells entails opposite effects on experimental arthritis and graft versus host diseases.

    PubMed

    Luz-Crawford, Patricia; Torres, Maria J; Noël, Daniele; Fernandez, Ainoa; Toupet, Karine; Alcayaga-Miranda, Francisca; Tejedor, Gautier; Jorgensen, Christian; Illanes, Sebastian E; Figueroa, Fernando E; Djouad, Farida; Khoury, Maroun

    2016-02-01

    Recently, a noninvasive and highly proliferative stem cell population from menstrual blood called MenSCs has been identified. Despite their use in clinical studies, their immunomodulatory properties have not yet been investigated. In this context, we studied the immunosuppressive properties of MenSCs in comparison with the well-characterized bone marrow derived-MSCs (BM-MSCs). Using an in vitro proliferation assays, we showed that MenSCs displayed a lower suppressive effect on peripheral blood mononuclear cells and in particular on the proinflammatory CD4(+) IFN-γ(+) and CD8(+) IFNγ(+) cells than BM-MSCs. Moreover, compared to BM-MSCs, MenSCs activated with IFN-γ and IL-1β produced lower amounts of immunosuppressive factors such as IDO, PDL-1, PGE2, and Activin A and exhibited a substantial lower expression level of IFN-γ receptor subunits. In the collagen induced arthritis model, while BM-MSCs administration resulted in a potent therapeutic effect associated with a significant decrease of proinflammatory T cell frequency in the lymph nodes, MenSCs injection did not. In contrast, in the xeno-GVHD model, only MenSCs administration significantly increased the survival of mice. This beneficial effect mediated by MenSCs was associated with a higher capacity to migrate into the intestine and liver and not to their anti-inflammatory capacities. All together our results demonstrate for the first time that the therapeutic potential of MSC in the experimental xeno-GVHD model is independent of their immunosuppressive properties. These findings should be taken into consideration for the development of safe and effective cell therapies.

  6. Oxidative and Nitrosative Stress in Stable Renal Transplant Recipients with Respect to the Immunosuppression Protocol – Differences or Similarities?

    PubMed Central

    Cvetković, Tatjana; Veličković-Radovanović, Radmila; Stojanović, Dijana; Stefanović, Nikola; Ignjatović, Aleksandra; Stojanović, Ivana; Sladojević, Nikola; Pavlović, Dušica

    2015-01-01

    Summary Background The aim of the study was to evaluate parameters of oxidative and nitrosative stress as well as antioxidative parameters in a group of renal transplant recipients with stable graft function and no clinical signs of cardiovascular disease. We also aimed to determine the correlations among these parameters and to evaluate potential differences in all the biomarkers with regard to the immunosuppression protocol. Methods We enrolled 57 renal transplant recipients and 31 controls who were age and sex matched with the renal transplant recipients. All of the patients included in this study had post-renal transplant surgery at least 12 months earlier and were on standard immunosuppressive therapy. In this study, we determined thiobarbituric acid-reactive substances in plasma and red blood cells and advanced oxidation protein products, nitrosative stress parameters (asymmetric and symmetric dimethylarginine – ADMA and SDMA), and antioxidative parameters (total SH groups and catalase activity). Results The results of our study demonstrated that the levels of oxidative and nitrosative stress were significantly increased compared to the healthy population (p<0.01 except for plasma catalase activity p<0.05). Correlation analysis showed significant positive correlations between: ADMA and SDMA (p<0.01); ADMA and nitrates (p<0.05); SDMA and nitrates (p<0.05); between OS parameters in the experimental group; AOPP and SH groups (p<0.05) and TBARS in plasma and SH groups (p<0.01), SDMA and AOPP (p< 0.05); SDMA and TBARS in plasma (p<0.05); SDMA and SH groups (p<0.01); nitrates and SH groups (p<0.05). Conclusion There was no significant difference in oxidative and nitrosative stress parameters with respect to the immunosuppressive protocol. PMID:28356840

  7. Genetics of human aggressive behaviour.

    PubMed

    Craig, Ian W; Halton, Kelly E

    2009-07-01

    A consideration of the evolutionary, physiological and anthropological aspects of aggression suggests that individual differences in such behaviour will have important genetic as well as environmental underpinning. Surveys of the likely pathways controlling the physiological and neuronal processes involved highlight, as obvious targets to investigate, genes implicated in sexual differentiation, anxiety, stress response and the serotonin neurotransmitter pathway. To date, however, association studies on single candidates have provided little evidence for any such loci with a major effect size. This may be because genes do not operate independently, but function against a background in which other genetic and environmental factors are crucial. Indeed, a series of recent studies, particularly concentrating on the serotonin and norepinephrine metabolising enzyme, monoamine oxidase A, has emphasised the necessity of examining gene by environmental interactions if the contributions of individual loci are to be understood. These findings will have major significance for the interpretation and analysis of data from detailed whole genome association studies. Functional imaging studies of genetic variants affecting serotonin pathways have also provided valuable insights into potential links between genes, brain and aggressive behaviour.

  8. Targeting Aggressive Cancer Stem Cells in Glioblastoma

    PubMed Central

    Seymour, Tracy; Nowak, Anna; Kakulas, Foteini

    2015-01-01

    Glioblastoma (GBM) is the most common and fatal type of primary brain tumor. Gliosarcoma (GSM) is a rarer and more aggressive variant of GBM that has recently been considered a potentially different disease. Current clinical treatment for both GBM and GSM includes maximal surgical resection followed by post-operative radiotherapy and concomitant and adjuvant chemotherapy. Despite recent advances in treating other solid tumors, treatment for GBM and GSM still remains palliative, with a very poor prognosis and a median survival rate of 12–15 months. Treatment failure is a result of a number of causes, including resistance to radiotherapy and chemotherapy. Recent research has applied the cancer stem cells theory of carcinogenesis to these tumors, suggesting the existence of a small subpopulation of glioma stem-like cells (GSCs) within these tumors. GSCs are thought to contribute to tumor progression, treatment resistance, and tumor recapitulation post-treatment and have become the focus of novel therapy strategies. Their isolation and investigation suggest that GSCs share critical signaling pathways with normal embryonic and somatic stem cells, but with distinct alterations. Research must focus on identifying these variations as they may present novel therapeutic targets. Targeting pluripotency transcription factors, SOX2, OCT4, and Nanog homeobox, demonstrates promising therapeutic potential that if applied in isolation or together with current treatments may improve overall survival, reduce tumor relapse, and achieve a cure for these patients. PMID:26258069

  9. Quality of life-adjusted survival analysis of high-dose therapy with autologous bone marrow transplantation versus sequential chemotherapy for patients with aggressive lymphoma in first complete remission. Groupe d'Etude les Lymphomes de l'Adulte (GELA).

    PubMed

    Mounier, N; Haioun, C; Cole, B F; Gisselbrecht, C; Sebban, C; Morel, P; Marit, G; Bouabdallah, R; Ravoet, C; Salles, G; Reyes, F; Lepage, E

    2000-06-15

    Evaluating high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) in term of both duration and quality of life (QOL) presents major interests for patients with non-Hodgkin lymphoma. The quality-adjusted time without symptom and toxicity (Q-TWiST) methodology was applied to the LNH87-2 trial comparing HDT with ASCT versus sequential chemotherapy in 541 patients in first complete remission (CR). Overall survival (OS) and disease-free survival (DFS) curves were used to estimate duration of 4 health states: acute short-term toxicity (Tox1), secondary toxicity (Tox2), time without symptom and toxicity (TWiST), and relapse (Rel). Areas under survival curves (AUC) were retrospectively weighted according to QOL coefficients. HDT increased, but not significantly, TWiST (+2. 4 months in AUC, P =.17) and decreased Rel (-3 months, P <.01). Survival estimates did not differ between the 2 treatments (AUC 47.7 months for OS, 39.7 months for DFS). High-risk patients treated by HDT versus chemotherapy had a significant benefit in DFS (AUC 28.8 versus 24.9 months, P <.01) but not in OS (AUC 37.3 versus 36 months, P =.27). Sensitivity analysis, performed by varying QOL coefficients, demonstrated significant quality-adjusted survival gain in high-risk patients treated by HDT. In low-risk patients, a diagram provided an aid to clinical decision-making. This analysis supports the use of HDT in these patients with adverse prognostic factors in the first CR, even after adjusting for QOL using the Q-TWiST method. (Blood. 2000;95:3687-3692)

  10. Photodynamic Therapy and Non-Melanoma Skin Cancer

    PubMed Central

    Griffin, Liezel L.; Lear, John T.

    2016-01-01

    Non-melanoma skin cancer (NMSC) is the most common malignancy among the Caucasian population. Photodynamic therapy<