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  1. Advances in predicting acute GVHD

    PubMed Central

    Harris, Andrew C.; Ferrara, James L.M.; Levine, John E.

    2012-01-01

    Summary Acute graft-versus-host disease (GVHD) is a leading cause of non-relapse mortality following allogeneic haematopoietic cell transplantation. Attempts to improve treatment response in clinically-established GVHD have not improved overall survival, often due to the increased risk of infectious complications. Alternative approaches to decrease GVHD-related morbidity and mortality have focused on the ability to predict GVHD prior to clinical manifestation in an effort to provide an opportunity to abort GVHD development, and to gain new insights into GVHD pathophysiology. This review outlines the research efforts to date that have identified clinical and laboratory-based factors that are predictive of acute GVHD and describes future directions in developing algorithms that will improve the ability to predict the development of clinically relevant GVHD. PMID:23205489

  2. Extracorporeal photopheresis in prevention and treatment of acute GVHD.

    PubMed

    Kitko, Carrie L; Levine, John E

    2015-04-01

    Acute graft versus host disease (GVHD), a common complication after allogeneic hematopoietic cell transplantation (HCT), occurs in as many as 70% of recipients of this life saving treatment. Front line therapy for GVHD with corticosteroids will fail in up to 40% of patients, which leads to high morbidity and mortality. Traditional prevention and treatment strategies have focused on reducing alloreactivity, typically with therapy to reduce cytotoxic T-cell function. Emerging evidence exists that promotion of regularly T-cell function, through treatments such as extracorporeal photopheresis, is effective for GVHD treatment and has potential for prevention as well. This review will focus on literature reporting the success of ECP for steroid refractory acute GVHD and the potential for delivery of ECP in the early pre and post-transplant periods that shows promise as a less immunosuppressive strategy to reduce rates of acute GVHD. PMID:25748231

  3. Corruption of dendritic cell antigen presentation during acute GVHD leads to regulatory T-cell failure and chronic GVHD.

    PubMed

    Leveque-El Mouttie, Lucie; Koyama, Motoko; Le Texier, Laetitia; Markey, Kate A; Cheong, Melody; Kuns, Rachel D; Lineburg, Katie E; Teal, Bianca E; Alexander, Kylie A; Clouston, Andrew D; Blazar, Bruce R; Hill, Geoffrey R; MacDonald, Kelli P A

    2016-08-11

    Chronic graft-versus-host disease (cGVHD) is a major cause of late mortality following allogeneic bone marrow transplantation (BMT) and is characterized by tissue fibrosis manifesting as scleroderma and bronchiolitis obliterans. The development of acute GVHD (aGVHD) is a powerful clinical predictor of subsequent cGVHD, suggesting that aGVHD may invoke the immunologic pathways responsible for cGVHD. In preclinical models in which sclerodermatous cGVHD develops after a preceding period of mild aGVHD, we show that antigen presentation within major histocompatibility complex (MHC) class II of donor dendritic cells (DCs) is markedly impaired early after BMT. This is associated with a failure of regulatory T-cell (Treg) homeostasis and cGVHD. Donor DC-restricted deletion of MHC class II phenocopied this Treg deficiency and cGVHD. Moreover, specific depletion of donor Tregs after BMT also induced cGVHD, whereas adoptive transfer of Tregs ameliorated it. These data demonstrate that the defect in Treg homeostasis seen in cGVHD is a causative lesion and is downstream of defective antigen presentation within MHC class II that is induced by aGVHD. PMID:27338097

  4. Extracorporeal photopheresis for the treatment of steroid refractory acute GVHD.

    PubMed

    Perfetti, P; Carlier, P; Strada, P; Gualandi, F; Occhini, D; Van Lint, M T; Ibatici, A; Lamparelli, T; Bruno, B; Raiola, A M; Dominietto, A; Di Grazia, C; Bregante, S; Zia, S; Ferrari, G M; Stura, P; Pogliani, E; Bacigalupo, A

    2008-11-01

    Extracorporeal photopheresis (ECP) was given to 23 patients with steroid-refractory acute GVHD (aGVHD, grade II (n=10), III (n=7) or IV (n=6)). The median duration of ECP was 7 months (1-33) and the median number of ECP cycles in each patient was 10. Twelve patients (52%) had complete responses. Eleven patients (48%) survived and 12 died, 10 of GVHD with or without infections and two of leukaemia relapse. The average grade of GVHD was reduced from 2.8 (on the first day of ECP) to 1.4 (on day +90 from ECP) (P=0.08), and the average dose of i.v. methylprednisolone from 2.17 to 0.2 mg/kg/d (P=0.004). Complete responses were obtained in 70, 42 and 0% of patients, respectively, with grades II, III and IV aGVHD; complete responses in the skin, liver and gut were 66, 27 and 40%. Patients treated within 35 days from onset of aGVHD had higher responses (83 vs 47%; P=0.1). A trend for improved survival was seen in grade III-IV aGVHD treated with ECP as compared to matched controls (38 vs 16%; P 0.08). ECP is a treatment option for patients with steroid refractory aGVHD and should be considered early in the course of the disease. PMID:18660840

  5. Evaluation of published single nucleotide polymorphisms associated with acute GVHD.

    PubMed

    Chien, Jason W; Zhang, Xinyi Cindy; Fan, Wenhong; Wang, Hongwei; Zhao, Lue Ping; Martin, Paul J; Storer, Barry E; Boeckh, Michael; Warren, Edus H; Hansen, John A

    2012-05-31

    Candidate genetic associations with acute GVHD (aGVHD) were evaluated with the use of genotyped and imputed single-nucleotide polymorphism data from genome-wide scans of 1298 allogeneic hematopoietic cell transplantation (HCT) donors and recipients. Of 40 previously reported candidate SNPs, 6 were successfully genotyped, and 10 were imputed and passed criteria for analysis. Patient and donor genotypes were assessed for association with grades IIb-IV and III-IV aGVHD, stratified by donor type, in univariate and multivariate allelic, recessive and dominant models. Use of imputed genotypes to replicate previous IL10 associations was validated. Similar to previous publications, the IL6 donor genotype for rs1800795 was associated with a 20%-50% increased risk for grade IIb-IV aGVHD after unrelated HCT in the allelic (adjusted P = .011) and recessive (adjusted P = .0013) models. The donor genotype was associated with a 60% increase in risk for grade III-IV aGVHD after related HCT (adjusted P = .028). Other associations were found for IL2, CTLA4, HPSE, and MTHFR but were inconsistent with original publications. These results illustrate the advantages of using imputed single-nucleotide polymorphism data in genetic analyses and demonstrate the importance of validation in genetic association studies. PMID:22282500

  6. Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD.

    PubMed

    Hechinger, Anne-Kathrin; Smith, Benjamin A H; Flynn, Ryan; Hanke, Kathrin; McDonald-Hyman, Cameron; Taylor, Patricia A; Pfeifer, Dietmar; Hackanson, Björn; Leonhardt, Franziska; Prinz, Gabriele; Dierbach, Heide; Schmitt-Graeff, Annette; Kovarik, Jiri; Blazar, Bruce R; Zeiser, Robert

    2015-01-15

    The common γ chain (CD132) is a subunit of the interleukin (IL) receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Because levels of several of these cytokines were shown to be increased in the serum of patients developing acute and chronic graft-versus-host disease (GVHD), we reasoned that inhibition of CD132 could have a profound effect on GVHD. We observed that anti-CD132 monoclonal antibody (mAb) reduced acute GVHD potently with respect to survival, production of tumor necrosis factor, interferon-γ, and IL-6, and GVHD histopathology. Anti-CD132 mAb afforded protection from GVHD partly via inhibition of granzyme B production in CD8 T cells, whereas exposure of CD8 T cells to IL-2, IL-7, IL-15, and IL-21 increased granzyme B production. Also, T cells exposed to anti-CD132 mAb displayed a more naive phenotype in microarray-based analyses and showed reduced Janus kinase 3 (JAK3) phosphorylation upon activation. Consistent with a role of JAK3 in GVHD, Jak3(-/-) T cells caused less severe GVHD. Additionally, anti-CD132 mAb treatment of established chronic GVHD reversed liver and lung fibrosis, and pulmonary dysfunction characteristic of bronchiolitis obliterans. We conclude that acute GVHD and chronic GVHD, caused by T cells activated by common γ-chain cytokines, each represent therapeutic targets for anti-CD132 mAb immunomodulation. PMID:25352130

  7. Six-month freedom from treatment failure is an important end point for acute GVHD clinical trials.

    PubMed

    Sengsayadeth, S; Savani, B N; Jagasia, M; Goodman, S; Greer, J P; Chen, H; Chinratanalab, W; Kassim, A A; Engelhardt, B G

    2014-02-01

    We studied the American Society for Blood and Marrow Transplantation (ASBMT) 6-month (m) freedom from treatment failure (FFTF) as a predictor of survival for patients with acute GVHD (aGVHD) requiring treatment. Adult patients undergoing allogeneic hematopoietic cell transplant (HCT) from February 2007 to March 2009 who were enrolled in a prospective biomarker clinical trial and developed aGVHD requiring systemic corticosteroids by day +100 were included (N=44). Six-month FFTF was defined as per the ASBMT guidelines (absence of death, malignancy relapse/progression or systemic immunosuppression change within 6 months of starting steroids and before chronic GVHD development). aGVHD was treated with systemic corticosteroids in 44 patients. Day 28 response after steroid initiation (complete response+very good partial response+partial response) occurred in 38 (87%) patients, but only 28 (64%) HCT recipients met the 6-m FFTF end point. Day 28 response predicted 6-m FFTF. Achieving 6-m FFTF was associated with improved 2-year (y) OS (81% vs 48%; P=0.03) and decreased 2-y non-relapse mortality (8% vs 49%; P=0.01). In multivariate analysis, 6-m FFTF continued to predict improved OS (hazard ratio, 0.27; P=0.03). The 6-m FFTF end point measures fixed outcomes, predicts long-term therapeutic success and could be less prone to measurement error than aGVHD clinical response at day 28. PMID:24096824

  8. CD4+ T cell STAT3 phosphorylation precedes acute GVHD, and subsequent Th17 tissue invasion correlates with GVHD severity and therapeutic response

    PubMed Central

    Betts, Brian C.; Sagatys, Elizabeth M.; Veerapathran, Anandharaman; Lloyd, Mark C.; Beato, Francisca; Lawrence, Harshani R.; Yue, Binglin; Kim, Jongphil; Sebti, Said M.; Anasetti, Claudio; Pidala, Joseph

    2015-01-01

    Th17 cells contribute to severe GVHD in murine bone marrow transplantation. Targeted deletion of the RORγt transcription factor or blockade of the JAK2-STAT3 axis suppresses IL-17 production and alloreactivity by Th17 cells. Here, we show that pSTAT3 Y705 is increased significantly in CD4+ T cells among human recipients of allogeneic HCT before the onset of Grade II–IV acute GVHD. Examination of target-organ tissues at the time of GVHD diagnosis indicates that the amount of RORγt + Th17 cells is significantly higher in severe GVHD. Greater accumulation of tissue-resident Th17 cells also correlates with the use of MTX- compared with Rapa-based GVHD prophylaxis, as well as a poor therapeutic response to glucocorticoids. RORγt is optimally suppressed by concurrent neutralization of TORC1 with Rapa and inhibition of STAT3 activation with S3I-201, supporting that mTOR- and STAT3-dependent pathways converge upon RORγt gene expression. Rapa-resistant T cell proliferation can be totally inhibited by STAT3 blockade during initial allosensitization. We conclude that STAT3 signaling and resultant Th17 tissue accumulation are closely associated with acute GVHD onset, severity, and treatment outcome. Future studies are needed to validate the association of STAT3 activity in acute GVHD. Novel GVHD prevention strategies that incorporate dual STAT3 and mTOR inhibition merit investigation. PMID:25663681

  9. Prophylaxis of acute GVHD: manipulate the graft or the environment?

    PubMed Central

    Barrett, John; Le Blanc, Katarina

    2013-01-01

    Graft-versus-host disease (GVHD) is the immune response of donor T lymphocytes responding to the recipient’s alloantigens. The cellular and cytokine mechanisms driving GVHD are now well defined and have led to several prophylactic approaches. Selective allodepletion techniques promise to prevent GVHD without causing immune deficiency provoked by global T-cell depletion. Targeted dosing other (non-T-cells) cells in the graft – such as CD34+ progenitors, regulatory T cells, natural killer cells and mesenchymal stromal cells – can also lead to transplants designed to retain immune capability without causing GVHD. Immunosuppressive drugs such as methotrexate, cyclosporine and anti-lymphocyte antibodies are the mainstay in the prevention of GVHD and can be used in conjunction with engineered grafts to eliminate GVHD. In future it is anticipated that further refinements in targeting the elimination or suppression of GVHD reacting T cells should be selective enough to preserve the important graft-versus-leukemia effect which contributes to the cure of malignant diseases by allogeneic stem-cell transplantation. PMID:18503984

  10. Biomarker profiling of steroid-resistant acute GVHD in patients after infusion of mesenchymal stromal cells.

    PubMed

    Te Boome, L C J; Mansilla, C; van der Wagen, L E; Lindemans, C A; Petersen, E J; Spierings, E; Thus, K A; Westinga, K; Plantinga, M; Bierings, M; Broers, A E C; Cuijpers, M L H; van Imhoff, G W; Janssen, J J; Huisman, C; Zeerleder, S; Huls, G; Boelens, J J; Wulffraat, N M; Slaper-Cortenbach, I C M; Kuball, J

    2015-09-01

    We performed a prospective phase II study to evaluate clinical safety and outcome in 48 patients with steroid-refractory grade II-IV acute graft-versus-host disease (aGVHD) treated with mesenchymal stromal cells (MSCs). Clinical outcomes were correlated to comprehensive analyses of soluble and cellular biomarkers. Complete resolution (CR) of aGVHD at day 28 (CR-28) occurred in 12 (25%) patients, CR lasting >1 month (CR-B) occurred in 24 (50%) patients. One-year overall survival was significantly improved in CR-28 (75 versus 33%, P=0.020) and CR-B (79 versus 8%, P<0.001) versus non-CR patients. A six soluble biomarker-panel was predictive for mortality (HR 2.924; CI 1.485-5.758) when measured before MSC-administration. Suppression of tumorigenicity 2 (ST2) was only predictive for mortality 2 weeks after but not before MSC-administration (HR 2.389; CI 1.144-4.989). In addition, an increase in immature myeloid dendritic cells associated with decreased mortality (HR 0.554, CI 0.389-0.790). Patients had persisting T-cell responses against defined virus- and leukemia-associated antigens. In conclusion, our data emphasize the need to carefully assess biomarkers in cohorts with homogeneous GVHD treatments. Biomarkers might become an additional valuable component of composite end points for the rapid and efficient testing of novel compounds to decrease lifecycle of clinical testing and improve the success rate of phase II/III trials. PMID:25836589

  11. A refined risk score for acute GVHD that predicts response to initial therapy, survival and transplant-related mortality

    PubMed Central

    MacMillan, Margaret L.; Robin, Marie; Harris, Andrew C.; DeFor, Todd E.; Martin, Paul J.; Alousi, Amin; Ho, Vincent T.; Bolaños-Meade, Javier; Ferrara, James L.M.; Jones, Richard; Arora, Mukta; Blazar, Bruce R.; Holtan, Shernan G.; Jacobsohn, David; Pasquini, Marcelo; Socie, Gerard; Antin, Joseph H.; Levine, John E.; Weisdorf, Daniel J.

    2015-01-01

    To develop a novel acute graft-versus-host disease (GVHD) Risk Score, we examined the GVHD clinical stage and grade of 1723 patients at the onset of treatment with systemic steroids. Using clinical grouping, descriptive statistics and recursive partitioning, we identified poorly responsive, high-risk (HR) acute GVHD by the number of involved organs and severity of GVHD at onset. The overall response [(complete response/partial response (CR/PR)] rate 28 days after initiation of steroid therapy for acute GVHD was lower in the 269 patients with HR-GVHD than in the 1454 patients with standard risk (SR)-GVHD [44% (95% CI 38–50%) vs. 68% (95% CI 66–70%), p<0.001. Patients with HR-GVHD were less likely to respond at day 28 [odds ratio (OR), 0.3, 95% CI 0.2–0.4, p<0.001], and had higher risks of mortality [relative risk (RR) 2.1, 95% CI 1.7–2.6, P<0.001] and transplant-related mortality (RR 2.5, 95% CI 2.0–3.2%, p<0.001) compared to patients with SR-GVHD. This refined definition of acute GVHD risk is a better predictor of response, survival and transplant-related mortality than other published acute GVHD risk scores. Patients with HR-GVHD are candidates for studies investigating new treatment approaches. Likewise, patients with SR-GVHD are candidates for studies investigating less toxic therapy. PMID:25585275

  12. International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium.

    PubMed

    Harris, Andrew C; Young, Rachel; Devine, Steven; Hogan, William J; Ayuk, Francis; Bunworasate, Udomsak; Chanswangphuwana, Chantiya; Efebera, Yvonne A; Holler, Ernst; Litzow, Mark; Ordemann, Rainer; Qayed, Muna; Renteria, Anne S; Reshef, Ran; Wölfl, Matthias; Chen, Yi-Bin; Goldstein, Steven; Jagasia, Madan; Locatelli, Franco; Mielke, Stephan; Porter, David; Schechter, Tal; Shekhovtsova, Zhanna; Ferrara, James L M; Levine, John E

    2016-01-01

    Acute graft-versus-host disease (GVHD) remains a leading cause of morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation. The clinical staging of GVHD varies greatly between transplant centers and is frequently not agreed on by independent reviewers. The lack of standardized approaches to handle common sources of discrepancy in GVHD grading likely contributes to why promising GVHD treatments reported from single centers have failed to show benefit in randomized multicenter clinical trials. We developed guidelines through international expert consensus opinion to standardize the diagnosis and clinical staging of GVHD for use in a large international GVHD research consortium. During the first year of use, the guidance followed discussion of complex clinical phenotypes by experienced transplant physicians and data managers. These guidelines increase the uniformity of GVHD symptom capture, which may improve the reproducibility of GVHD clinical trials after further prospective validation. PMID:26386318

  13. Plasma biomarkers of acute GVHD and nonrelapse mortality: predictive value of measurements before GVHD onset and treatment.

    PubMed

    McDonald, George B; Tabellini, Laura; Storer, Barry E; Lawler, Richard L; Martin, Paul J; Hansen, John A

    2015-07-01

    We identified plasma biomarkers that presaged outcomes in patients with gastrointestinal graft-versus-host disease (GVHD) by measuring 23 biomarkers in samples collected before initiation of treatment. Six analytes with the greatest accuracy in predicting grade 3-4 GVHD in the first cohort (74 patients) were then tested in a second cohort (76 patients). The same 6 analytes were also tested in samples collected at day 14 ± 3 from 167 patients free of GVHD at the time. Logistic regression and calculation of an area under a receiver-operating characteristic (ROC) curve for each analyte were used to determine associations with outcome. Best models in the GVHD onset and landmark analyses were determined by forward selection. In samples from the second cohort, collected a median of 4 days before start of treatment, levels of TIM3, IL6, and sTNFR1 had utility in predicting development of peak grade 3-4 GVHD (area under ROC curve, 0.88). Plasma ST2 and sTNFR1 predicted nonrelapse mortality within 1 year after transplantation (area under ROC curve, 0.90). In the landmark analysis, plasma TIM3 predicted subsequent grade 3-4 GVHD (area under ROC curve, 0.76). We conclude that plasma levels of TIM3, sTNFR1, ST2, and IL6 are informative in predicting more severe GVHD and nonrelapse mortality. PMID:25987657

  14. Response of Steroid-Refractory Acute GVHD to α1-Antitrypsin.

    PubMed

    Marcondes, A Mario; Hockenbery, David; Lesnikova, Marina; Dinarello, Charles A; Woolfrey, Ann; Gernsheimer, Terry; Loghman-Adham, Mahmoud; Gelmont, David; Storer, Barry; Hansen, John A; Deeg, H Joachim

    2016-09-01

    α1-Antitrypsin (AAT) is a serine protease inhibitor with anti-inflammatory, antiapoptotic, and immunomodulatory properties. It has therapeutic efficacy in animal models of autoimmune diseases, inflammatory disorders, and transplantation. In a phase I/II open-label single-center study, we administered AAT (Glassia; Baxalta/Kamada, New Ziona, Israel) as salvage therapy to 12 patients with steroid-refractory acute graft-versus-host disease (GVHD). AAT was given i.v. at 2 dose levels over a 15-day course. All patients had grades III or IV GVHD with stage 4 gut involvement. After treatment, plasma AAT levels increased in both cohorts and remained within 2 to 4 mg/mL for the duration of treatment. No clinically relevant toxicities attributable to AAT were observed. GVHD manifestations improved in 8 of 12 patients, and 4 responses were complete. Six patients (50%) were alive at last follow-up (>104 to >820 days). These findings show that AAT is well tolerated and has efficacy in the treatment of steroid-refractory severe acute GVHD. Further studies are warranted. PMID:27223109

  15. Extracorporeal photopheresis for treatment of adults and children with acute GVHD: UK consensus statement and review of published literature.

    PubMed

    Das-Gupta, E; Dignan, F; Shaw, B; Raj, K; Malladi, R; Gennery, A; Bonney, D; Taylor, P; Scarisbrick, J

    2014-10-01

    Extracorporeal photopheresis (ECP) has been used for over 20 years to treat acute GVHD (aGVHD) and chronic GVHD. Evidence on the efficacy of response in aGVHD has continued to accrue and data suggest that there is a good response and prolonged survival in both children and adults with grade II-IV aGVHD. Unlike chronic GVHD where treatment schedules are typically one or two times monthly for 12-18 months, patients with aGVHD respond rapidly to an intense weekly treatment schedule for 8 weeks, typically allowing steroids to be discontinued without flare-ups of aGVHD. Maintenance ECP therapy is generally not required. Many centres across Europe and United States treat aGVHD with ECP as second-line therapy and responses are excellent in a subset of patients. Unlike other second-line therapies, ECP is not immunosuppressive and has no reported drug interactions. Importantly, ECP does not have a negative impact on the graft-versus-malignancy effect of the transplant. This statement aims to select those patients most likely to respond to treatment and summarises treatment and monitoring schedules for the management of aGVHD in adult and paediatric patients to ensure the correct patients are treated with the optimal protocol for efficacy. PMID:24887389

  16. Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion.

    PubMed

    Chopra, Martin; Biehl, Marlene; Steinfatt, Tim; Brandl, Andreas; Kums, Juliane; Amich, Jorge; Vaeth, Martin; Kuen, Janina; Holtappels, Rafaela; Podlech, Jürgen; Mottok, Anja; Kraus, Sabrina; Jordán-Garrote, Ana-Laura; Bäuerlein, Carina A; Brede, Christian; Ribechini, Eliana; Fick, Andrea; Seher, Axel; Polz, Johannes; Ottmüller, Katja J; Baker, Jeanette; Nishikii, Hidekazu; Ritz, Miriam; Mattenheimer, Katharina; Schwinn, Stefanie; Winter, Thorsten; Schäfer, Viktoria; Krappmann, Sven; Einsele, Hermann; Müller, Thomas D; Reddehase, Matthias J; Lutz, Manfred B; Männel, Daniela N; Berberich-Siebelt, Friederike; Wajant, Harald; Beilhack, Andreas

    2016-08-22

    Donor CD4(+)Foxp3(+) regulatory T cells (T reg cells) suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HCT [allo-HCT]). Current clinical study protocols rely on the ex vivo expansion of donor T reg cells and their infusion in high numbers. In this study, we present a novel strategy for inhibiting GvHD that is based on the in vivo expansion of recipient T reg cells before allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in T reg cell biology. Expanding radiation-resistant host T reg cells in recipient mice using a mouse TNFR2-selective agonist before allo-HCT significantly prolonged survival and reduced GvHD severity in a TNFR2- and T reg cell-dependent manner. The beneficial effects of transplanted T cells against leukemia cells and infectious pathogens remained unaffected. A corresponding human TNFR2-specific agonist expanded human T reg cells in vitro. These observations indicate the potential of our strategy to protect allo-HCT patients from acute GvHD by expanding T reg cells via selective TNFR2 activation in vivo. PMID:27526711

  17. Systematic review and meta-analysis of prospective studies for ECP treatment in patients with steroid-refractory acute GVHD

    PubMed Central

    Zhang, Hongming; Chen, Runzhe; Cheng, Jian; Jin, Nan; Chen, Baoan

    2015-01-01

    Purpose The aim of this systematic review was to evaluate the efficacy and safety of extracorporeal photopheresis (ECP) treatment in patients with steroid-refractory acute graft-versus-host disease (SR-aGVHD). Methods An electronic search was carried out on the MEDLINE, EMBASE, Science Citation Index (SCI), and Cochrane Library databases. We included prospective clinical trials in SR-aGVHD treated by ECP. The main endpoints consisted of mortality, exacerbation, or response. Results Only seven studies involving 121 patients met the inclusion criteria for further review. Our analysis showed positive results of ECP for aGVHD. The overall response rate (ORR) was 0.71 and the complete response rate (CRR) was 0.71. The efficacy of ECP for skin aGVHD, liver aGVHD, and gut aGVHD were 0.86, 0.60, and 0.68, respectively. However, no sufficient evidence verifies the exact benefit in this review, because the number of patients enrolled in trials is limited and publish bias exists. Conclusion ECP is an effective therapy for skin, liver, and gut aGVHD, and large double-blind clinical trials are required to prove the outcome of this meta-analysis. PMID:25653504

  18. Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD.

    PubMed

    Matta, Benjamin M; Reichenbach, Dawn K; Zhang, Xiaoli; Mathews, Lisa; Koehn, Brent H; Dwyer, Gaelen K; Lott, Jeremy M; Uhl, Franziska M; Pfeifer, Dietmar; Feser, Colby J; Smith, Michelle J; Liu, Quan; Zeiser, Robert; Blazar, Bruce R; Turnquist, Hēth R

    2016-07-21

    During allogeneic hematopoietic cell transplantation (alloHCT), nonhematopoietic cell interleukin-33 (IL-33) is augmented and released by recipient conditioning to promote type 1 alloimmunity and lethal acute graft-versus-host disease (GVHD). Yet, IL-33 is highly pleiotropic and exhibits potent immunoregulatory properties in the absence of coincident proinflammatory stimuli. We tested whether peri-alloHCT IL-33 delivery can protect against development of GVHD by augmenting IL-33-associated regulatory mechanisms. IL-33 administration augmented the frequency of regulatory T cells (Tregs) expressing the IL-33 receptor, suppression of tumorigenicity-2 (ST2), which persist following total body irradiation. ST2 expression is not exclusive to Tregs and IL-33 expands innate immune cells with regulatory or reparative properties. However, selective depletion of recipient Foxp3(+) cells concurrent with peri-alloHCT IL-33 administration accelerated acute GVHD lethality. IL-33-expanded Tregs protected recipients from GVHD by controlling macrophage activation and preventing accumulation of effector T cells in GVHD-target tissue. IL-33 stimulation of ST2 on Tregs activates p38 MAPK, which drives expansion of the ST2(+) Treg subset. Associated mechanistic studies revealed that proliferating Tregs exhibit IL-33-independent upregulation of ST2 and the adoptive transfer of st2(+) but not st2(-) Tregs mediated GVHD protection. In total, these data demonstrate the protective capacity of peri-alloHCT administration of IL-33 and IL-33-responsive Tregs in mouse models of acute GVHD. These findings provide strong support that the immunoregulatory relationship between IL-33 and Tregs can be harnessed therapeutically to prevent GVHD after alloHCT for treatment of malignancy or as a means for tolerance induction in solid organ transplantation. PMID:27222477

  19. Risk factors and prognosis of hepatic acute GvHD after allogeneic hematopoietic cell transplantation.

    PubMed

    Arai, Y; Kanda, J; Nakasone, H; Kondo, T; Uchida, N; Fukuda, T; Ohashi, K; Kaida, K; Iwato, K; Eto, T; Kanda, Y; Nakamae, H; Nagamura-Inoue, T; Morishima, Y; Hirokawa, M; Atsuta, Y; Murata, M

    2016-01-01

    Hepatic acute GvHD (aGvHD) is associated with high mortality owing to poor response to immunosuppressive therapy. The pathogenesis of hepatic aGvHD differs from that of other lesions, and specific risk factors related to pre-transplant liver conditions should be determined. We conducted a cohort study by using a Japanese transplant registry database (N=8378). Of these subjects, 1.5% had hepatitis C virus Ab (HCV-Ab) and 9.4% had liver dysfunction (elevated transaminase or bilirubin levels) before hematopoietic cell transplantation (HCT). After HCT, the cumulative incidence of hepatic aGvHD was 6.7%. On multivariate analyses, HCV-Ab positivity (hazard ratio (HR), 1.93; P=0.02) and pre-transplant liver dysfunction (HR, 1.85; P<0.01), as well as advanced HCT risk, unrelated donors, HLA mismatch and cyclosporine as GvHD prophylaxis, were significant risk factors for hepatic aGvHD, whereas hepatitis B virus surface Ag was not. Hepatic aGvHD was a significant risk factor for low overall survival and high transplant-related mortality in all aGvHD grades (P<0.01). This study is the first to show the relationship between pre-transplant liver conditions and hepatic aGvHD. A prospective study is awaited to validate the results of this study and establish a new strategy especially for high-risk patients. PMID:26367230

  20. Alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following alemtuzumab, fludarabine, and melphalan RIC HCT.

    PubMed

    Marsh, Rebecca A; Lane, Adam; Mehta, Parinda A; Neumeier, Lisa; Jodele, Sonata; Davies, Stella M; Filipovich, Alexandra H

    2016-01-28

    Reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) with alemtuzumab, fludarabine, and melphalan is an effective approach for patients with nonmalignant disorders. Mixed chimerism and graft-versus-host-disease (GVHD) remain limitations on success. We hypothesized that higher levels of alemtuzumab at day 0 would result in a low risk of acute GVHD, a higher risk of mixed chimerism, and delayed early lymphocyte recovery and that alemtuzumab level thresholds for increased risks of these outcomes would be definable. We collected data from 105 patients to examine the influence of peritransplant alemtuzumab levels on acute GVHD, mixed chimerism, and lymphocyte recovery. The cumulative incidences of initial grades I-IV, II-IV, and III-IV acute GVHD in patients with alemtuzumab levels ≤0.15 vs ≥0.16 μg/mL were 68% vs 18% (P < .0001), 47% vs 13% (P = .0002), and 32% vs 8%, respectively (P = .005). The cumulative incidence of mixed chimerism in patients with an alemtuzumab level ≤0.15 μg/mL was 21%, vs 42% with levels of 0.16 to 4.35 μg/mL, and 100% with levels >4.35 μg/mL (P = .003). Patients with alemtuzumab levels ≤0.15 or 0.16 to 0.56 μg/mL had higher lymphocyte counts at day +30 and higher T-cell counts at day +100 compared with patients with levels ≥0.57 μg/mL (all P < .05). We conclude that peritransplant alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following RIC HCT with alemtuzumab, fludarabine, and melphalan. Precision dosing trials are warranted. We recommend a day 0 therapeutic range of 0.2 to 0.4 μg/mL. PMID:26644451

  1. Numerical impairment of nestin(+) bone marrow niches in acute GvHD after allogeneic hematopoietic stem cell transplantation for AML.

    PubMed

    Medinger, M; Krenger, W; Jakab, A; Halter, J; Buser, A; Bucher, C; Passweg, J; Tzankov, A

    2015-11-01

    The nestin(+) perivascular bone marrow (BM) stem cell niche (N(+)SCN) may be involved in GvHD. To investigate whether acute GvHD (aGvHD) reduces the number of N(+)SCN, we examined patients with AML who had undergone allogeneic hematopoietic stem cell transplantation. In the test cohort (n=8), the number of N(+)SCN per mm(2) in BM biopsies was significantly reduced in aGvHD patients at the time of aGvHD compared with patients who did not have aGvHD (1.2±0.78 versus 2.6±0.93, P=0.04). In the validation cohort (n=40), the number of N(+)SCN was reduced (1.9±0.99 versus 2.6±0.90 N(+)SCN/mm(2), P=0.05) in aGvHD patients. Receiver operating curves suggested that the cutoff score that best discriminated between patients with and without aGvHD was 2.29 N(+)SCN/mm(2). Applying this cutoff score, 9/11 patients with clinically relevant aGvHD (⩾grade 2) and 13/20 with any type of GvHD had decreased N(+)SCN numbers compared with only 10/29 patients without clinically relevant aGvHD (P=0.007) and 6/20 patients without any type of GvHD (P=0.028). In patients tracked over time, N(+)SCN density returned to normal after aGvHD resolved or remained stable in patients who did not have aGvHD. Our results show a decrease in the number of N(+)SCN in aGvHD. PMID:26301968

  2. Amino acid substitution at peptide-binding pockets of HLA class I molecules increases risk of severe acute GVHD and mortality

    PubMed Central

    Wang, Tao; Haagenson, Michael; Spellman, Stephen R.; Askar, Medhat; Battiwalla, Minoo; Baxter-Lowe, Lee Ann; Bitan, Menachem; Fernandez-Viña, Marcelo; Gandhi, Manish; Jakubowski, Ann A.; Maiers, Martin; Marino, Susana R.; Marsh, Steven G. E.; Oudshoorn, Machteld; Palmer, Jeanne; Prasad, Vinod K.; Reddy, Vijay; Ringden, Olle; Saber, Wael; Santarone, Stella; Schultz, Kirk R.; Setterholm, Michelle; Trachtenberg, Elizabeth; Turner, E. Victoria; Woolfrey, Ann E.; Lee, Stephanie J.; Anasetti, Claudio

    2013-01-01

    HLA disparity has a negative impact on the outcomes of hematopoietic cell transplantation (HCT). We studied the independent impact of amino acid substitution (AAS) at peptide-binding positions 9, 99, 116, and 156, and killer immunoglobulin-like receptor binding position 77 of HLA-A, B, or C, on the risks for grade 3-4 acute graft-versus-host disease (GVHD), chronic GVHD, treatment-related mortality (TRM), relapse, and overall survival. In multivariate analysis, a mismatch at HLA-C position 116 was associated with increased risk for severe acute GVHD (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.15-1.82, P = .0016). Mismatch at HLA-C position 99 was associated with increased transplant-related mortality (HR = 1.37, 95% CI = 1.1-1.69, P = .0038). Mismatch at HLA-B position 9 was associated with increased chronic GVHD (HR = 2.28, 95% CI = 1.36-3.82, P = .0018). No AAS were significantly associated with outcome at HLA-A. Specific AAS pair combinations with a frequency >30 were tested for association with HCT outcomes. Cysteine to tyrosine substitution at position 99 of HLA-C was associated with increased TRM (HR = 1.78, 95% = CI 1.27-2.51, P = .0009). These results demonstrate that donor-recipient mismatch for certain peptide-binding residues of the HLA class I molecule is associated with increased risk for acute and chronic GVHD and death. PMID:23982174

  3. Co-infusion of ex vivo-expanded, parental MSCs prevents life-threatening acute GVHD, but does not reduce the risk of graft failure in pediatric patients undergoing allogeneic umbilical cord blood transplantation.

    PubMed

    Bernardo, M E; Ball, L M; Cometa, A M; Roelofs, H; Zecca, M; Avanzini, M A; Bertaina, A; Vinti, L; Lankester, A; Maccario, R; Ringden, O; Le Blanc, K; Egeler, R M; Fibbe, W E; Locatelli, F

    2011-02-01

    When compared with BMT, umbilical cord blood transplantation (UCBT) is associated with a lower rate of engraftment and delayed hematological/immunological recovery. This leads to increased risk of TRM in the early post transplantation period due to infection. Acute GVHD, although occurring less frequently in UCBT compared with BMT, is also significantly associated with increased rate of early TRM. BM MSCs are known to support normal in vivo hematopoiesis, and co-transplantation of MSCs has been shown to enhance engraftment of human cord blood hematopoietic cells in nonobese diabetic/SCID mice. In 13 children with hematological disorders (median age 2 years) undergoing UCBT, we co-transplanted paternal, HLA-disparate MSCs with the aim of improving hematological recovery and reducing rejection. We observed no differences in hematological recovery or rejection rates compared with 39 matched historical controls, most of whom received G-CSF after UCBT. However, the rate of grade III and IV acute GVHD was significantly decreased in the study cohort when compared with controls (P=0.05), thus resulting in reduced early TRM. Although these data do not support the use of MSCs in UCBT to support hematopoietic engraftment, they suggest that MSCs, possibly because of their immunosuppressive effect, may abrogate life-threatening acute GVHD and reduce early TRM. PMID:20400983

  4. Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell–depleted stem cell transplantation

    PubMed Central

    Shah, Nirali N.; Baird, Kristin; Delbrook, Cynthia P.; Fleisher, Thomas A.; Kohler, Mark E.; Rampertaap, Shakuntala; Lemberg, Kimberly; Hurley, Carolyn K.; Kleiner, David E.; Merchant, Melinda S.; Pittaluga, Stefania; Sabatino, Marianna; Stroncek, David F.; Wayne, Alan S.; Zhang, Hua; Fry, Terry J.

    2015-01-01

    Natural killer (NK) cells can enhance engraftment and mediate graft-versus-leukemia following allogeneic hematopoietic stem cell transplantation (HSCT), but the potency of graft-versus-leukemia mediated by naturally reconstituting NK cells following HSCT is limited. Preclinical studies demonstrate that activation of NK cells using interleukin-15 (IL-15) plus 4-1BBL upregulates activating receptor expression and augments killing capacity. In an effort to amplify the beneficial effects of NK cells post-HSCT, we conducted a first-in-human trial of adoptive transfer of donor-derived IL-15/4-1BBL–activated NK cells (aNK-DLI) following HLA-matched, T-cell–depleted (1-2 × 104 T cells/kg) nonmyeloablative peripheral blood stem cell transplantation in children and young adults with ultra-high-risk solid tumors. aNK-DLI were CD3+-depleted, CD56+-selected lymphocytes, cultured for 9 to 11 days with recombinant human IL-15 plus 4-1BBL+IL-15Rα+ artificial antigen-presenting cells. aNK-DLI demonstrated potent killing capacity and displayed high levels of activating receptor expression. Five of 9 transplant recipients experienced acute graft-versus-host disease (GVHD) following aNK-DLI, with grade 4 GVHD observed in 3 subjects. GVHD was more common in matched unrelated donor vs matched sibling donor recipients and was associated with higher donor CD3 chimerism. Given that the T-cell dose was below the threshold required for GVHD in this setting, we conclude that aNK-DLI contributed to the acute GVHD observed, likely by augmenting underlying T-cell alloreactivity. This trial was registered at www.clinicaltrials.gov as #NCT01287104. PMID:25452614

  5. Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation.

    PubMed

    Shah, Nirali N; Baird, Kristin; Delbrook, Cynthia P; Fleisher, Thomas A; Kohler, Mark E; Rampertaap, Shakuntala; Lemberg, Kimberly; Hurley, Carolyn K; Kleiner, David E; Merchant, Melinda S; Pittaluga, Stefania; Sabatino, Marianna; Stroncek, David F; Wayne, Alan S; Zhang, Hua; Fry, Terry J; Mackall, Crystal L

    2015-01-29

    Natural killer (NK) cells can enhance engraftment and mediate graft-versus-leukemia following allogeneic hematopoietic stem cell transplantation (HSCT), but the potency of graft-versus-leukemia mediated by naturally reconstituting NK cells following HSCT is limited. Preclinical studies demonstrate that activation of NK cells using interleukin-15 (IL-15) plus 4-1BBL upregulates activating receptor expression and augments killing capacity. In an effort to amplify the beneficial effects of NK cells post-HSCT, we conducted a first-in-human trial of adoptive transfer of donor-derived IL-15/4-1BBL-activated NK cells (aNK-DLI) following HLA-matched, T-cell-depleted (1-2 × 10(4) T cells/kg) nonmyeloablative peripheral blood stem cell transplantation in children and young adults with ultra-high-risk solid tumors. aNK-DLI were CD3(+)-depleted, CD56(+)-selected lymphocytes, cultured for 9 to 11 days with recombinant human IL-15 plus 4-1BBL(+)IL-15Rα(+) artificial antigen-presenting cells. aNK-DLI demonstrated potent killing capacity and displayed high levels of activating receptor expression. Five of 9 transplant recipients experienced acute graft-versus-host disease (GVHD) following aNK-DLI, with grade 4 GVHD observed in 3 subjects. GVHD was more common in matched unrelated donor vs matched sibling donor recipients and was associated with higher donor CD3 chimerism. Given that the T-cell dose was below the threshold required for GVHD in this setting, we conclude that aNK-DLI contributed to the acute GVHD observed, likely by augmenting underlying T-cell alloreactivity. This trial was registered at www.clinicaltrials.gov as #NCT01287104. PMID:25452614

  6. Extracorporeal Photopheresis for the Prevention of Acute GVHD in Patients Undergoing Standard Myeloablative Conditioning and Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Shaughnessy, Paul J; Bolwell, Brian J; van Besien, Koen; Mistrik, Martin; Grigg, Andrew; Dodds, Anthony; Prince, H Miles; Durrant, Simon; Ilhan, Osman; Parenti, Dennis; Rogers, Jon; Gallo, Jose; Foss, Francine; Apperley, Jane; Zhang, Mei-Jie; Horowitz, Mary M; Abhyankar, Sunil

    2012-01-01

    Summary Graft-versus-host disease (GVHD) is partly mediated by host antigen presenting cells (APCs) that activate donor T-cells. Extracorporeal photopheresis (ECP) can modulate APC function and benefit some patients with GVHD. We report the results of a study using ECP administered prior to a standard myeloablative preparative regimen intended to prevent GVHD. Grade II-IV aGVHD developed in 9 (30%) of 30 recipients of HLA-matched related transplants and 13 (42%) of 31 recipients of HLA-matched unrelated or HLA-mismatched related donor transplants. Actuarial estimates of overall survival (OS) at day 100 and 1 year post transplant were 89% (95% CI, 78%-94%) and 77% (95% CI, 64%-86%), respectively. There were no unexpected adverse effects of ECP. Historical controls receiving similar conditioning and GVHD prophylaxis regimens but no ECP were identified from the database of the Center for International Blood and Marrow Transplant Research and multivariate analysis indicated a lower risk of grade II-IV aGVHD in patients receiving ECP (p=0.04). Adjusted OS at one year was 83% in the ECP study group and 67% in the historical control group (relative risk 0.44, 95% CI, 0.24-0.80) (p= 0.007). These preliminary data may indicate a potential survival advantage with ECP for transplant recipients undergoing standard myeloablative hematopoietic cell transplantation. PMID:19915634

  7. Donor Atorvastatin Treatment in Preventing Severe Acute GVHD After Nonmyeloablative Peripheral Blood Stem Cell Transplant in Patients With Hematological Malignancies

    ClinicalTrials.gov

    2016-04-28

    Aggressive Non-Hodgkin Lymphoma; Myelodysplastic/Myeloproliferative Neoplasm; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Aggressive Adult Non-Hodgkin Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Hodgkin Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Plasma Cell Myeloma; Waldenstrom Macroglobulinemia

  8. Reduced incidence of acute graft versus host disease (GVHD) of the gut in Chinese carriers of Helicobacter pylori during allogeneic bone marrow transplantation.

    PubMed

    Au, W Y; Wong, R W M; Wong, B C Y; Lie, A K W; Liang, R; Leung, A Y H; Kwong, Y-L

    2004-01-01

    Helicobacter pylori ( H. Pylori) infection is associated with gastritis and peptic ulcer, but its relationship with gut graft versus host disease (GVHD) is unknown. We investigated the association between H. Pylori carriage and incidence and severity of mucosal toxicity and GVHD in 128 consecutive matched sibling stem cell transplantation (SCT) recipients. Using a verified enzyme linked immunosorbant assay (ELISA), 43.5% of patients had H. Pylori exposure before SCT. There was absolute concordance between serological and breath test data in 40 prospective cases. There was no increased risk in WHO grade 3 or 4 mucositis in H. Pylori carriers. Significant (grade II or above) overall GVHD was only predicted by preceding mucositis (p<0.001), while gut GVHD was associated with increased age (p=0.001) and mucositis (p=0.022). Despite increased incidence with age, H. Pylori carriage was associated with significantly reduced risk of gut GVHD (p=0.04) but not overall GVHD. The reduced risk of immune-mediated gut inflammation in H. Pylori carriers after SCT may be related to the known reduced incidence of inflammatory bowel disease in chronic H. Pylori carriers. PMID:14551739

  9. Very low-dose methotrexate in the treatment of GVHD in children.

    PubMed

    Vettenranta, K; Hovi, L; Parto, K; Saarinen-Pihkala, U M

    1997-07-01

    Acute GVHD is an important clinical problem frequently encountered in relation to stem cell transplantation. In its initial treatment glucocorticoids remain the established drug of choice. In the face of the side-effects related to therapy with glucocorticoids other, possibly less toxic, options for the initial treatment of acute GVHD might be of use. We report the successful treatment of progressive cutaneous acute GVHD up to grade II in five pediatric recipients of unrelated marrow grafts. PMID:9232262

  10. Extracorporeal Photopheresis for Non-skin GvHD.

    PubMed

    Bittenbring, Joerg; Reichrath, Joerg

    2016-03-01

    Graft versus host disease (GvHD) is one of the most feared adverse events of allogeneic hematopoietic stem cell transplantation. In severe grades of GvHD patients die from infections due to impairment of their immune defense or therapy-refractory involvement of intestines, liver and lung. Extracorporeal photopheresis is an effective treatment for acute and chronic graft versus host disease without severe impairment of the recipient's immune system. It is generally better known for its effect on skin GvHD but all other manifestations of GvHD can respond as well. Herein we report a brief review of its history and give an overview of the current knowledge of extracorporeal photopheresis in non-skin GvHD. PMID:26977041

  11. Acute graft-vs-host disease: pathobiology and management.

    PubMed

    Goker, H; Haznedaroglu, I C; Chao, N J

    2001-03-01

    Acute graft-vs-host disease (GVHD) is a major obstacle to safe allogeneic hematopoietic stem cell transplantation (HSCT), leading to a significant morbidity and mortality. GVHD occurs when transplanted donor T lymphocytes react to foreign host cells. It causes a wide variety of host tissue injuries. This review focuses on the pathobiological basis, clinical aspects, and current management strategies of acute GVHD. Afferent phase of acute GVHD starts with myeloablative conditioning, i.e., before the infusion of the graft. Total-body irradiation (TBI) or high-dose chemotherapy regimens cause extensive damage and activation in host tissues, which release inflammatory cytokines and enhance recipient major histocompatibility complex (MHC) antigens. Recognition of the foreign host antigens by donor T cells and activation, stimulation, and proliferation of T cells is crucial in the afferent phase. Effector phase of acute GVHD results in direct and indirect damage to host cells. The skin, gastrointestinal tract, and liver are major target organs of acute GVHD. Combination drug prophylaxis in GVHD is essential in all patients undergoing allogeneic HSCT. Steroids have remained the standard for the treatment of acute GVHD. Several clinical trials have evaluated monoclonal antibodies or receptor antagonist therapy for steroid-resistant acute GVHD, with different successes in a variety of settings. There are some newer promising agents like mycophenolate mofetil, glutamic acid-lysine-alanine-tyrosine (GLAT), rapamycin, and trimetrexate currently entering in the clinical studies, and other agents are in development. Future experimental and clinical studies on GVHD will shed further light on the better understanding of the disease pathobiology and generate the tools to treat malignant disorders with allogeneic HSCT with specific graft-vs-tumor effects devoid of GVHD. PMID:11274753

  12. Advances in the treatment of acute graft-versus-host disease

    PubMed Central

    Qian, Liren; Wu, Zhengcheng; Shen, Jianliang

    2013-01-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) has been widely used for the treatment of hematologic malignant and non-malignant hematologic diseases and other diseases. However, acute graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic transplantation. Acute GVHD may occur in 30% of transplant recipients, which is a syndrome of erythematous skin eruption, cholestatic liver disease and intestinal dysfunction, resulting from the activation of donor T lymphocytes by host antigen-presenting cells, resulting in an immune-mediated inflammatory response. Recent scientific advances in the understanding of the pathogenesis involved in the development of acute GVHD and clinical investigation have provided more effective therapeutic strategies for acute GVHD. This review focuses on major scientific and clinical advances in the treatment of acute GVHD. PMID:23802653

  13. Improved outcome of children transplanted for high-risk leukemia by using a new strategy of cyclosporine-based GVHD prophylaxis.

    PubMed

    Bleyzac, N; Cuzzubbo, D; Rénard, C; Garnier, N; Dubois, V; Domenech, C; Goutagny, M-P; Plesa, A; Grardel, N; Goutelle, S; Janoly-Duménil, A; Bertrand, Y

    2016-05-01

    There is currently a major concern regarding the optimal immunosuppression therapy to be administered after hematopoietic stem cell transplantation (HSCT) to reduce both the toxicity of GvHD and the rate of relapse. We report the outcome of high-risk leukemia children transplanted with a new way of managing cyclosporine (CsA)-based GvHD prophylaxis. A total of 110 HSCT in 109 ALL or AML children who received CsA without mycophenolate or methotrexate in matched related as well as in matched or mismatched unrelated stem cell transplantation were included. CsA dosage regimens were individualized to obtain specific trough blood concentrations values. The incidences of grade I-II and III-IV acute GvHD were 69.1% and 1.8%, respectively, and 8.4% for chronic GvHD. GvHD was neither more frequent nor severe in unrelated than in related HSCT. GvHD occurred in 87% of patients with a mean CsA trough concentration ⩽120 ng/mL versus 43% with concentration >120 ng/mL (P<0.0001). Five-year disease-free survival (DFS) and overall survival were 78% and 83.6%, respectively. DFS was 76.9% for ALL and 80.4% for AML patients. There was no difference in DFS between matched siblings and matched unrelated or mismatched unrelated HSCT. DFS in patients with minimal residual disease (MRD) ⩾10(-3) and in those with MRD <10(-3) before SCT was comparable. Our results indicate that a GvHD prophylaxis regimen based on CsA without mycophenolate or methotrexate is safe and effective whatever the donor compatibility is. These results suggest that GvL effect may be enhanced by this strategy of GvHD prophylaxis. PMID:26808568

  14. Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation

    PubMed Central

    Hashimoto, Daigo; Chow, Andrew; Greter, Melanie; Saenger, Yvonne; Kwan, Wing-Hong; Leboeuf, Marylene; Ginhoux, Florent; Ochando, Jordi C.; Kunisaki, Yuya; van Rooijen, Nico; Liu, Chen; Teshima, Takanori; Heeger, Peter S.; Stanley, E. Richard; Frenette, Paul S.

    2011-01-01

    Acute graft-versus-host disease (GVHD) results from the attack of host tissues by donor allogeneic T cells and is the most serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Host antigen-presenting cells are thought to control the priming of alloreactive T cells and the induction of acute GVHD after allo-HCT. However, whereas the role of host DC in GVHD has been established, the contribution of host macrophages to GVHD has not been clearly addressed. We show that, in contrast to DC, reducing of the host macrophage pool in recipient mice increased donor T cell expansion and aggravated GVHD mortality after allo-HCT. We also show that host macrophages that persist after allo-HCT engulf donor allogeneic T cells and inhibit their proliferation. Conversely, administration of the cytokine CSF-1 before transplant expanded the host macrophage pool, reduced donor T cell expansion, and improved GVHD morbidity and mortality after allo-HCT. This study establishes the unexpected key role of host macrophages in inhibiting GVHD and identifies CSF-1 as a potential prophylactic therapy to limit acute GVHD after allo-HCT in the clinic. PMID:21536742

  15. Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner.

    PubMed

    McDonald-Hyman, Cameron; Flynn, Ryan; Panoskaltsis-Mortari, Angela; Peterson, Nicholas; MacDonald, Kelli P A; Hill, Geoffrey R; Luznik, Leo; Serody, Jonathan S; Murphy, William J; Maillard, Ivan; Munn, David H; Turka, Laurence A; Koreth, John; Cutler, Corey S; Soiffer, Robert J; Antin, Joseph H; Ritz, Jerome; Blazar, Bruce R

    2016-08-18

    Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation. In cGVHD, alloreactive T cells and germinal center (GC) B cells often participate in GC reactions to produce pathogenic antibodies. Although regulatory T cells (Tregs) can inhibit GC reactions, Treg numbers are reduced in cGVHD, contributing to cGVHD pathogenesis. Here, we explored 2 means to increase Tregs in cGVHD: interleukin-2/monoclonal antibody (IL-2/mAb) complexes and donor Treg infusions. IL-2/mAb complexes given over 1 month were efficacious in expanding Tregs and treating established cGVHD in a multi-organ-system disease mouse model characterized by GC reactions, antibody deposition, and lung dysfunction. In an acute GVHD (aGVHD) model, IL-2/mAb complexes given for only 4 days resulted in rapid mortality, indicating IL-2/mAb complexes can drive conventional T-cell (Tcon)-mediated injury. In contrast, Treg infusions, which uniformly suppress aGVHD, increased Treg frequency and were effective in preventing the onset of, and treating, established cGVHD. Efficacy was dependent upon CXCR5-sufficient Tregs homing to, and inhibiting, GC reactions. These studies indicate that the infusion of Tregs, especially ones enriched for GC homing, may be desirable for cGVHD therapy. Although IL-2/mAb complexes can be efficacious in cGVHD, a cautious approach needs to be taken in settings in which aGVHD elements, and associated Tcon, are present. PMID:27385791

  16. Estimation of the prevalence and rate of acute transfusion reactions occurring in Windhoek, Namibia

    PubMed Central

    Meza, Benjamin P.L.; Lohrke, Britta; Wilkinson, Robert; Pitman, John P.; Shiraishi, Ray W.; Bock, Naomi; Lowrance, David W.; Kuehnert, Matthew J.; Mataranyika, Mary; Basavaraju, Sridhar V.

    2014-01-01

    Background Acute transfusion reactions are probably common in sub-Saharan Africa, but transfusion reaction surveillance systems have not been widely established. In 2008, the Blood Transfusion Service of Namibia implemented a national acute transfusion reaction surveillance system, but substantial under-reporting was suspected. We estimated the actual prevalence and rate of acute transfusion reactions occurring in Windhoek, Namibia. Methods The percentage of transfusion events resulting in a reported acute transfusion reaction was calculated. Actual percentage and rates of acute transfusion reactions per 1,000 transfused units were estimated by reviewing patients’ records from six hospitals, which transfuse >99% of all blood in Windhoek. Patients’ records for 1,162 transfusion events occurring between 1st January – 31st December 2011 were randomly selected. Clinical and demographic information were abstracted and Centers for Disease Control and Prevention National Healthcare Safety Network criteria were applied to categorize acute transfusion reactions1. Results From January 1 – December 31, 2011, there were 3,697 transfusion events (involving 10,338 blood units) in the selected hospitals. Eight (0.2%) acute transfusion reactions were reported to the surveillance system. Of the 1,162 transfusion events selected, medical records for 785 transfusion events were analysed, and 28 acute transfusion reactions were detected, of which only one had also been reported to the surveillance system. An estimated 3.4% (95% confidence interval [CI]: 2.3–4.4) of transfusion events in Windhoek resulted in an acute transfusion reaction, with an estimated rate of 11.5 (95% CI: 7.6–14.5) acute transfusion reactions per 1,000 transfused units. Conclusion The estimated actual rate of acute transfusion reactions is higher than the rate reported to the national haemovigilance system. Improved surveillance and interventions to reduce transfusion-related morbidity and mortality

  17. Potential protective effect of Helicobacter pylori on the development of gastrointestinal GvHD.

    PubMed

    Velasco-Guardado, A; Mora-Soler, A; López-Corral, L; López-Godino, O; Vázquez-López, L; Blanco-Muñez, O; Pérez-López, E; Rodríguez-Pérez, A; Caballero-Barrigón, D

    2016-06-01

    Previous reports ascribe a modulating capacity of the immune response to Helicobacter pylori (HP). Our hypothesis was to demonstrate in a prospective study that HP infection could have a protective effect against development of gastrointestinal GvHD in patients receiving allogeneic hematopoietic cell transplantation (HCT). Presence of HP before transplant was determined using C(13) urea breath test. Seventy-nine patients receiving an allogeneic HCT were included and 93.7% of them received PBSC; in 51.9%, the donor was unrelated. Acute gastrointestinal GvHD was diagnosed in 51.9% (n=41). In the multivariable analysis, HP infection was associated with a lower frequency of gastrointestinal GvHD (odds ratio (OR)=0.19 (95% confidence interval (CI): 0.05-0.67); in contrast, an unrelated donor was associated with a higher frequency of gastrointestinal GvHD (odds ratio=5.4 (95% confidence interval: 1.6-18.2). One year overall survival (OS) was 74%. In the multivariate Cox proportional-hazards regression analysis, stages 0-II gastrointestinal GvHD (hazards ratio (HR)=0.19), reduced intensity conditioning (HR=0.04) and tacrolimus-sirolimus GvHD prophylaxis (HR=0.06) were all associated with a better OS. In summary, HP infection could have a role in decreasing gastrointestinal GvHD in patients receiving allogeneic HCT from peripheral blood including related and unrelated donors. PMID:26950379

  18. 18F-FDG PET/CT for the assessment of gastrointestinal GVHD: results of a pilot study.

    PubMed

    Bodet-Milin, C; Lacombe, M; Malard, F; Lestang, E; Cahu, X; Chevallier, P; Guillaume, T; Delaunay, J; Brissot, E; Moreau, P; Kraeber-Bodere, F; Mohty, M

    2014-01-01

    This prospective pilot study aimed to evaluate the predictive value of (18)F-FDG PET/CT for early diagnosis of acute gastrointestinal GVHD (GI-GVHD). In all, 42 consecutive patients who received allo-SCT were included. (18)F-FDG PET/CT was systematically performed at a median of 28 (range, 24-38) days after allo-SCT. (18)F-FDG PET/CT data review was positive in 15 cases (36%) (9 true positive (TP) cases and 6 false positive (FP) cases) and negative in 27 cases (64%; 26 true negative (TN) cases and 1 false negative (FN) case) at visual analysis. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of (18)F-FDG PET/CT for the diagnosis of acute GI-GVHD were, respectively, 81%, 90%, 60%, 96% and 83%. There were no significant differences of SUVmax values between grade 1-2 GI-GVHD and severe grade 3-4 GI-GVHD. Overall, these preliminary findings suggested that the inflammatory activity of the gastrointestinal tract associated with acute GI-GVHD could be assessed by (18)F-FDG PET/CT suggesting that noninvasive (18)F-FDG PET/CT could become a valuable examination to be performed shortly before endoscopy to map acute GI-GVHD lesions, guide the biopsy sites and choose the appropriate endoscopic procedure, especially in those asymptomatic patients with a positive (18)F-FDG PET/CT. PMID:24076550

  19. Dermoscopic Follow-Up of the Skin towards Acute Graft-versus-Host-Disease in Patients after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Kaminska-Winciorek, Grazyna; Czerw, Tomasz; Kruzel, Tomasz; Giebel, Sebastian

    2016-01-01

    Background. Acute graft-versus-host disease (aGVHD) involving skin is one of the most frequent complications of allogeneic hematopoietic stem cell transplantation (alloHSCT), usually diagnosed based on clinical manifestations. So far, skin biopsy with histopathological evaluation is the only method to confirm the diagnosis. Objective. In this prospective study we monitored alloHSCT recipients by dermoscopy in order to assess its utility as an alternative noninvasive tool to early diagnose acute GVHD. Methods. Thirteen consecutive patients who received alloHSCT were examined clinically and dermoscopically towards aGVHD [days 28 (±7), 56 (±7), and 100 (±7)], as well as in each patient who developed cutaneous aGVHD diagnosed according to clinical criteria (Glucksberg scale). Results. Six patients (46%) developed symptoms of cutaneous acute GVHD (grade 1, n = 3; grade 2, n = 3). Dermoscopic evaluation revealed pinkish or reddish background and well-visible, multiple thin telangiectasias. Conclusion. To our knowledge, this is the first report on the use of dermoscopy to evaluate skin involvement in the course of acute GVHD suggesting its role as a diagnostic tool in follow-up of GVHD, which can be also used before clinical symptoms occur. PMID:27446950

  20. Selective NFAT targeting in T cells ameliorates GvHD while maintaining antitumor activity.

    PubMed

    Vaeth, Martin; Bäuerlein, Carina A; Pusch, Tobias; Findeis, Janina; Chopra, Martin; Mottok, Anja; Rosenwald, Andreas; Beilhack, Andreas; Berberich-Siebelt, Friederike

    2015-01-27

    Graft-versus-host disease (GvHD) is a life-threatening immunological complication after allogenic hematopoietic stem cell transplantation (allo-HCT). The intrinsic graft-versus-leukemia (GvL) effect, however, is the desirable curative benefit. Patients with acute GvHD are treated with cyclosporine A (CsA) or tacrolimus (FK506), which not only often causes severe adverse effects, but also interferes with the anticipated GvL. Both drugs inhibit calcineurin, thus at first suppressing activation of the nuclear factor of activated T cells (NFAT). Therefore, we explored the specific contribution of individual NFAT factors in donor T cells in animal models of GvHD and GvL. Ablation of NFAT1, NFAT2, or a combination of both resulted in ameliorated GvHD, due to reduced proliferation, target tissue homing, and impaired effector function of allogenic donor T cells. In contrast, the frequency of Foxp3(+) regulatory T (Treg) cells was increased and NFAT-deficient Tregs were fully protective in GvHD. CD8(+) T-cell recall response and, importantly, the beneficial antitumor activity were largely preserved in NFAT-deficient effector T cells. Thus, specific inhibition of NFAT opens an avenue for an advanced therapy of GvHD maintaining protective GvL. PMID:25583478

  1. Acute esophageal necrosis occurring in a patient undergoing percutaneous coronary intervention.

    PubMed

    Kwon, Hyung-Jin; Park, Sang-Ho; Ahn, Ji-Hoon; Lee, Tae-Hoon; Lee, Chang-Kyun

    2014-05-01

    Acute esophageal necrosis is uncommon in the literature. Its etiology is unknown, although cardiovascular disease, hemodynamic compromise, gastric outlet obstruction, alcohol ingestion, hypoxemia, hypercoagulable state, infection, and trauma have all been suggested as possible causes. A 67-year-old female underwent a coronary angiography (CAG) for evaluation of chest pain. CAG findings showed coronary three-vessel disease. We planned percutaneous coronary intervention (PCI). Coronary arterial dissection during the PCI led to sudden hypotension. Six hours after the index procedure, the patient experienced a large amount of hematemesis. Emergency gastrofibroscopy was performed and showed mucosal necrosis with a huge adherent blood clot in the esophagus. After conservative treatment for 3 months, the esophageal lesion was completely improved. She was diagnosed with acute esophageal necrosis. We report herein a case of acute esophageal necrosis occurring in a patient undergoing percutaneous coronary intervention. PMID:24851074

  2. Control of GVHD: it's in our DNA!

    PubMed

    Chao, Nelson

    2012-02-01

    Selective depletion of the alloreactive T cells causing graft-versus-host disease (GVHD) without loss of the graft-versus-leukemia (GVL) effect is the holy grail of hematopoietic cell transplantation (HCT). In this issue of Blood, He et al demonstrate that inhibition of histone methylation leads to selective apoptosis of the alloreactive effector cells. Moreover, they demonstrate that this inhibition of histone methylation remarkably stops ongoing GVHD. PMID:22308280

  3. The Genotype of the Donor for the (GT)n Polymorphism in the Promoter/Enhancer of FOXP3 Is Associated with the Development of Severe Acute GVHD but Does Not Affect the GVL Effect after Myeloablative HLA-Identical Allogeneic Stem Cell Transplantation.

    PubMed

    Noriega, Víctor; Martínez-Laperche, Carolina; Buces, Elena; Pion, Marjorie; Sánchez-Hernández, Noemí; Martín-Antonio, Beatriz; Guillem, Vicent; Bosch-Vizcaya, Anna; Bento, Leyre; González-Rivera, Milagros; Balsalobre, Pascual; Kwon, Mi; Serrano, David; Gayoso, Jorge; de la Cámara, Rafael; Brunet, Salut; Rojas-Contreras, Rafael; Nieto, José B; Martínez, Carmen; Gónzalez, Marcos; Espigado, Ildefonso; Vallejo, Juan C; Sampol, Antonia; Jiménez-Velasco, Antonio; Urbano-Ispizua, Alvaro; Solano, Carlos; Gallardo, David; Díez-Martín, José L; Buño, Ismael

    2015-01-01

    The FOXP3 gene encodes for a protein (Foxp3) involved in the development and functional activity of regulatory T cells (CD4+/CD25+/Foxp3+), which exert regulatory and suppressive roles over the immune system. After allogeneic stem cell transplantation, regulatory T cells are known to mitigate graft versus host disease while probably maintaining a graft versus leukemia effect. Short alleles (≤(GT)15) for the (GT)n polymorphism in the promoter/enhancer of FOXP3 are associated with a higher expression of FOXP3, and hypothetically with an increase of regulatory T cell activity. This polymorphism has been related to the development of auto- or alloimmune conditions including type 1 diabetes or graft rejection in renal transplant recipients. However, its impact in the allo-transplant setting has not been analyzed. In the present study, which includes 252 myeloablative HLA-identical allo-transplants, multivariate analysis revealed a lower incidence of grade III-IV acute graft versus host disease (GVHD) in patients transplanted from donors harboring short alleles (OR = 0.26, CI 0.08-0.82, p = 0.021); without affecting chronic GVHD or graft versus leukemia effect, since cumulative incidence of relapse, event free survival and overall survival rates are similar in both groups of patients. PMID:26473355

  4. The Genotype of the Donor for the (GT)n Polymorphism in the Promoter/Enhancer of FOXP3 Is Associated with the Development of Severe Acute GVHD but Does Not Affect the GVL Effect after Myeloablative HLA-Identical Allogeneic Stem Cell Transplantation

    PubMed Central

    Buces, Elena; Pion, Marjorie; Sánchez-Hernández, Noemí; Martín-Antonio, Beatriz; Guillem, Vicent; Bosch-Vizcaya, Anna; Bento, Leyre; González-Rivera, Milagros; Balsalobre, Pascual; Kwon, Mi; Serrano, David; Gayoso, Jorge; de la Cámara, Rafael; Brunet, Salut; Rojas-Contreras, Rafael; Nieto, José B.; Martínez, Carmen; Gónzalez, Marcos; Espigado, Ildefonso; Vallejo, Juan C.; Sampol, Antonia; Jiménez-Velasco, Antonio; Urbano-Ispizua, Alvaro; Solano, Carlos; Gallardo, David; Díez-Martín, José L.; Buño, Ismael

    2015-01-01

    The FOXP3 gene encodes for a protein (Foxp3) involved in the development and functional activity of regulatory T cells (CD4+/CD25+/Foxp3+), which exert regulatory and suppressive roles over the immune system. After allogeneic stem cell transplantation, regulatory T cells are known to mitigate graft versus host disease while probably maintaining a graft versus leukemia effect. Short alleles (≤(GT)15) for the (GT)n polymorphism in the promoter/enhancer of FOXP3 are associated with a higher expression of FOXP3, and hypothetically with an increase of regulatory T cell activity. This polymorphism has been related to the development of auto- or alloimmune conditions including type 1 diabetes or graft rejection in renal transplant recipients. However, its impact in the allo-transplant setting has not been analyzed. In the present study, which includes 252 myeloablative HLA-identical allo-transplants, multivariate analysis revealed a lower incidence of grade III-IV acute graft versus host disease (GVHD) in patients transplanted from donors harboring short alleles (OR = 0.26, CI 0.08–0.82, p = 0.021); without affecting chronic GVHD or graft versus leukemia effect, since cumulative incidence of relapse, event free survival and overall survival rates are similar in both groups of patients. PMID:26473355

  5. GVHD (Graft-Versus-Host Disease): A Guide for Patients and Families After Stem Cell Transplant

    MedlinePlus

    ... the first 100 days after your transplant or infusion of T-cells (in a donor lymphocyte infusion, or DLI). Acute GVHD commonly affects your skin, ... mouth or put on your skin or an infusion through a vascular access device. Also, treatment may ...

  6. Efficacy of enrofloxacin in the treatment of naturally occurring acute clinical Escherichia coli mastitis.

    PubMed

    Suojala, L; Simojoki, H; Mustonen, K; Kaartinen, L; Pyörälä, S

    2010-05-01

    The efficacy of the combination of systemic enrofloxacin (5mg/kg twice with a 24-h interval, first dose i.v., second dose s.c.) and the nonsteroidal antiinflammatory agent ketoprofen (3mg/kg i.m. or 4 mg/kg per os daily for 1 to 3 d) treatment was compared with antiinflammatory treatment only in dairy cows with naturally occurring acute clinical Escherichia coli mastitis. A total of 132 cows with acute clinical mastitis and with confirmed growth of E. coli in a pretreatment milk sample were randomly allocated to 1 of 2 treatment groups. Response to treatment was evaluated clinically and by bacteriological culturing and determination of N-acetyl-beta-d-glucosaminidase (NAGase) activity on d 2 and 21 posttreatment. Enrofloxacin treatment did not increase bacteriological (90.5% of treated vs. 86.8% of nontreated cured) or clinical cure (46.7% of treated vs. 57.1% of nontreated cured), cow survival (95.3% of treated vs. 92.7% of nontreated), or quarter milk production assessed 21 d posttreatment (21.8 vs. 29.3% return to preinfection level for nontreated cows), nor did it decrease mammary gland tissue damage estimated using determination of milk NAGase activity (24.0+/-0.3 vs. 18.3+/-1.3 pmol of 4-methylumbelliferone per min per microL for nontreated cows). Treatment did not influence the number of study cows remaining in the herd after 6 mo (71.9% of treated vs. 80.6% of nontreated). The only significant effects of enrofloxacin were enhancing the bacteriological cure (odds ratio=3.32 for treated cows) and decreasing the clinical cure (odds ratio=0.05 for treated cows) on d 2 posttreatment. Our results did not support the use of enrofloxacin to treat acute clinical E. coli mastitis. PMID:20412909

  7. Diagnostic features in 10 naturally occurring cases of acute fatal canine leptospirosis.

    PubMed

    Rissi, Daniel R; Brown, Cathy A

    2014-11-01

    The current report describes the diagnostic features in 10 cases of acute fatal canine leptospirosis with minimal renal and hepatic changes that may present a diagnostic challenge for the pathologist. Most affected dogs were less than 6 months of age and had a biochemical profile consistent with hepatorenal dysfunction. Clinical signs consisted of vomiting, depression, icterus, dehydration, diarrhea, and anorexia. All dogs died or were humanely euthanized within 3-7 days after the onset of clinical disease. Necropsy findings included pulmonary edema with hemorrhages, icterus, renal and hepatic pallor and swelling, and gastric edema with hemorrhage. Despite severe azotemia, histological changes in the kidneys were subtle in all dogs, and included mild renal tubular simplification, with single-cell necrosis and attenuation, along with minimal interstitial lymphoplasmacytic inflammation, edema, and hemorrhage. Hepatic lesions included scattered hepatocellular single-cell necrosis and hepatocellular dissociation. Prominent extrarenal lesions typically associated with uremia including vascular fibrinoid necrosis in multiple organs, pulmonary mineralization with occasional fibrinosuppurative exudation, and gastric mineralization were also present. Postmortem diagnostic confirmation was based on the detection of leptospiral antigen on fresh renal samples by fluorescent antibody test and on the demonstration of intact spirochetes in sections of kidneys using immunohistochemical staining. Acute fatal canine leptospirosis occurred as a fulminant hepatorenal disease affecting mainly young dogs, and the diagnosis was dependent on the recognition of the subtle renal changes with confirmation via fluorescent antibody testing or immunohistochemical staining. PMID:25274745

  8. Periodic synchronous discharge occurred in an elderly with acute valacyclovir-associated encephalopathy.

    PubMed

    Nakatani, Mitsuyoshi; Tsukino, Mitsuhiro; Takahashi, Ryosuke; Ikeda, Akio

    2016-07-28

    An 81-year-old woman suffering from sarcoidosis, chronic renal failure caused by hypertention was treated by valacyclovir 500 mg/day, for the diagnosis of herpes zoster of her right back. Her consciousness gradually became worse, and 3 days after taking the drug, she was sent to the emergency department of the hospital. Her conscious level was E2V2M5 (Glasgow Coma Scale) and myoclonus especially in her lower extremities occurred. Head CT and MRI show no obvious, acute abnormal findings other than chronic ischemic lesions, while an electroencephalogram (EEG) shows periodic synchronous discharges (PSDs) and disorganized background activity. Based on these findings, she was diagnosed as valacyclovir-associated acute encephalopathy. After conservative therapy of maintenance hemodialysis, her consciousness gradually improved, and PSDs disappeared accordingly and background activity of EEG became improved. In this case report, we presented valacyclovir-associated neurotoxicity with PSDs in EEG as potentially a surrogate marker. We should be cautious to use valaciclovir which may cause drug-induced encephalopathy especially in elderly or patients with renal failure even though the dose was adjusted in advance. PMID:27356736

  9. Acute Herpes Simplex Viral Esophagitis Occurring in 5 Immunocompetent Individuals With Eosinophilic Esophagitis

    PubMed Central

    Criblez, Dominique H.; Dellon, Evan S.; Bussmann, Christian; Pfeifer, David; Froh, Matthias; Straumann, Alex

    2016-01-01

    Herpes simplex esophagitis (HSE) is an acute, severe viral infection of the esophagus, rarely occurring in immunocompetent individuals. Eosinophilic esophagitis (EoE) is a rare immune-mediated esophageal disorder. We recently observed 5 severe HSE cases in diagnosed EoE patients. Four of the 5 patients had active, untreated EoE at the time of infection, so HSE is not likely a side effect of swallowed topical corticosteroids, the first-line medical treatment of EoE. However, this coincidence of these 2 rare conditions raises the question of a causal relationship between these 2 forms of esophagitis, and whether active EoE might predispose to HSE infection. PMID:27144193

  10. Acute Herpes Simplex Viral Esophagitis Occurring in 5 Immunocompetent Individuals With Eosinophilic Esophagitis.

    PubMed

    Zimmermann, Dorothee; Criblez, Dominique H; Dellon, Evan S; Bussmann, Christian; Pfeifer, David; Froh, Matthias; Straumann, Alex

    2016-04-01

    Herpes simplex esophagitis (HSE) is an acute, severe viral infection of the esophagus, rarely occurring in immunocompetent individuals. Eosinophilic esophagitis (EoE) is a rare immune-mediated esophageal disorder. We recently observed 5 severe HSE cases in diagnosed EoE patients. Four of the 5 patients had active, untreated EoE at the time of infection, so HSE is not likely a side effect of swallowed topical corticosteroids, the first-line medical treatment of EoE. However, this coincidence of these 2 rare conditions raises the question of a causal relationship between these 2 forms of esophagitis, and whether active EoE might predispose to HSE infection. PMID:27144193

  11. Glycosphingolipid analysis in a naturally occurring ovine model of acute neuronopathic Gaucher disease.

    PubMed

    Karageorgos, Litsa; Hein, Leanne; Rozaklis, Tina; Adams, Melissa; Duplock, Stephen; Snel, Marten; Hemsley, Kim; Kuchel, Tim; Smith, Nicholas; Hopwood, John J

    2016-07-01

    Gaucher disease arises from mutations in the β-glucocerebrosidase gene which encodes an enzyme required for the lysosomal catabolism of glucosylceramide. We have identified a naturally occurring mutation in the β-glucocerebrosidase gene in sheep that leads to Gaucher disease with acute neurological symptoms. Here we have examined the clinical phenotype at birth and subsequently quantified lipids in Gaucher lamb brain, in order to characterise the disorder. Enzyme activity assessments showed that a reduction in β-glucocerebrosidase activity to 1-5% of wild-type occurs consistently across newborn Gaucher lamb brain regions. We analyzed glucosylceramide, glucosylsphingosine, bis(monoacylglycero)phosphate and ganglioside profiles in brain, liver, and spleen, and observed 30- to 130-fold higher glucosylceramide, and 500- to 2000-fold higher glucosylsphingosine concentrations in Gaucher diseased lambs compared to wild-type. Significant increases of bis(monoacylglycero)phosphate and gangliosides [GM1, GM2, GM3] concentrations were also detected in the brain. As these glycosphingolipids are involved in many cellular events, an imbalance or disruption of the cell membrane lipid homeostasis would be expected to impair normal neuronal function. To our knowledge, this is the first detailed analysis of glycosphingolipids in various brain regions in a large animal model of neuronal disease, which permits the mechanistic investigation of lipid deregulation and their contribution to neurodegenerative process. PMID:26976737

  12. Murine allogeneic CD19 CAR T cells harbor potent antileukemic activity but have the potential to mediate lethal GVHD.

    PubMed

    Jacoby, Elad; Yang, Yinmeng; Qin, Haiying; Chien, Christopher D; Kochenderfer, James N; Fry, Terry J

    2016-03-10

    Acute lymphoblastic leukemia (ALL) persisting or relapsing following bone marrow transplantation (BMT) has a dismal prognosis. Success with chimeric antigen receptor (CAR) T cells offers an opportunity to treat these patients with leukemia-redirected donor-derived T cells, which may be more functional than T cells derived from patients with leukemia but have the potential to mediate graft-versus-host disease (GVHD). We, together with others, have previously demonstrated tumor-specific T-cell dysfunction in the allogeneic environment. Here, we studied CAR T-cell function following BMT using an immunocompetent murine model of minor mismatched allogeneic transplantation followed by donor-derived CD19-CAR T cells. Allogeneic donor-derived CD19-CAR T cells eliminated residual ALL with equal potency to those administered after syngeneic BMT. Surprisingly, allogeneic CAR T cells mediated lethal acute GVHD with early mortality, which is atypical for this minor mismatch model. We demonstrated that both allogeneic and syngeneic CAR T cells show initial expansion as effector T cells, with a higher peak but rapid deletion of allogeneic CAR T cells. Interestingly, CAR-mediated acute GVHD was only seen in the presence of leukemia, suggesting CAR-target interactions induced GVHD. Indeed, serum interleukin (IL)-6 was elevated only in the presence of both leukemia and CAR T cells, and IL-6 neutralization ameliorated the severity of GVHD in a delayed donor lymphocyte infusion model. Finally, allogeneic CD4(+) CAR T cells were responsible for GVHD, which correlated with their ability to produce IL-6 upon CAR stimulation. Altogether, we demonstrate that donor-derived allogeneic CAR T cells are active but have the capacity to drive GVHD. PMID:26660684

  13. Single-agent GVHD prophylaxis with posttransplantation cyclophosphamide after myeloablative, HLA-matched BMT for AML, ALL, and MDS

    PubMed Central

    Kanakry, Christopher G.; Tsai, Hua-Ling; Bolaños-Meade, Javier; Smith, B. Douglas; Gojo, Ivana; Kanakry, Jennifer A.; Kasamon, Yvette L.; Gladstone, Douglas E.; Matsui, William; Borrello, Ivan; Huff, Carol Ann; Swinnen, Lode J.; Powell, Jonathan D.; Pratz, Keith W.; DeZern, Amy E.; Showel, Margaret M.; McDevitt, Michael A.; Brodsky, Robert A.; Levis, Mark J.; Ambinder, Richard F.; Fuchs, Ephraim J.; Rosner, Gary L.; Jones, Richard J.

    2014-01-01

    High-dose, posttransplantation cyclophosphamide (PTCy) reduces severe graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT), but the impact of PTCy on long-term, disease-specific outcomes is unclear. We conducted a retrospective study of 209 consecutive adult patients transplanted for acute myeloid leukemia (AML, n = 138), myelodysplastic syndrome (n = 28), or acute lymphoblastic leukemia (ALL, n = 43) using PTCy as sole GVHD prophylaxis after myeloablative conditioning and HLA-matched–related or –unrelated T-cell–replete allografting. At alloBMT, 30% of patients were not in morphologic complete remission. The cumulative incidences of grades II to IV and III to IV acute GVHD at 100 days and chronic GVHD at 2 years were 45%, 11%, and 13%, respectively. Forty-three percent of patients did not require immunosuppression for any reason beyond PTCy. At 3 years, relapse cumulative incidence was 36%, disease-free survival was 46%, survival free of disease and chronic GVHD was 39%, and overall survival was 58%. Lack of remission at alloBMT, adverse cytogenetics, and low allograft nucleated cell dose were associated with inferior survival for AML patients. Minimal residual disease but not t(9;22) was associated with inferior outcomes for ALL patients. The ability to limit posttransplantation immunosuppression makes PTCy a promising transplantation platform for the integration of postgrafting strategies to prevent relapse. PMID:25316679

  14. Acute phase proteins in naturally occurring respiratory disease of feedlot cattle.

    PubMed

    Idoate, Ignacio; Vander Ley, Brian; Schultz, Loren; Heller, Meera

    2015-02-15

    The aim of this study was to evaluate three acute phase proteins (APP) [haptoglobin (HPT), lipopolysaccharide binding protein (LBP) and transferrin (Tf)] in feedlot cattle with naturally occurring respiratory disease diagnosed by a calf health scoring chart (CHSC). Seventy-seven beef calves were observed for signs of Bovine Respiratory Disease (BRD) during the first 28 days after arrival at the feedlot. Fourteen cases and pen matched controls were selected based on the CHSC. BRD cases were defined as a score of ≥ 5, while controls were defined as a score ≤ 4. The mean CHSC score in cases was 6.9 which was significantly greater than the controls 2.8 (P < 0.01). Mean plasma LBP and HPT concentrations were significantly greater in cases than controls (P < 0.01). Our study results show that measurement of HPT and LBP could be useful in detecting respiratory disease in feedlot conditions. Transferrin concentrations between the two groups were not statistically different. PMID:25599608

  15. Oral hairy leukoplakia which occurred as a presenting sign of acute myeloid leukemia in a child.

    PubMed

    Cho, Hyun-Ho; Kim, Su-Han; Seo, Sang-Hee; Jung, Do-Sang; Ko, Hyun-Chang; Kim, Moon-Bum; Kwon, Kyung-Sool

    2010-02-01

    Oral hairy leukoplakia (OHL) is caused by the reactivation of a previous Epstein-Barr virus (EBV) infection in the epithelium of the tongue. Most lesions are characterized by corrugated whitish patches on the lateral border of the tongue. It is frequently associated with AIDS, but cases in patients with other immunosuppressed states have also been reported. In leukemia patients, OHL is rarely encountered, and appears only after chemotherapy. We report a case of OHL which occurred as a presenting sign of acute myeloid leukemia (AML) in a previously healthy 15-year-old child. A 15-year-old boy presented with a whitish patch on the left lateral border of the tongue. The biopsy specimen revealed papillomatosis, hyperkeratosis, acanthosis and ballooning degeneration in the stratum spinosum. The patient was EBV seropositive, and PCR analysis of EBV DNA in the lesional tissue was positive. After the diagnosis of OHL in dermatologic department, the patient was referred to pediatrics due to the abnormal peripheral blood smear, and was diagnosed with AML. PMID:20548888

  16. Acute lethal graft-versus-host disease stimulates cellular proliferation in the adult rat liver.

    PubMed

    Klein, R M; Clancy, J; Stuart, S

    1982-11-01

    The present investigation was designed to analyse the effects of acute lethal graft-versus-host disease (GVHD) in adult (DA x LEW)F1 rats on cellular proliferation within the liver. The influence of the host thymus on GVHD-induced proliferation was also assessed. From 1-28 days after initiation of GVHD [3H]thymidine ([3H]-TdR) was injected i.v. and rats were killed one hour later. Percentage labelled cells (LI) of periportal infiltrating cells (PIC), hepatocytes (H), and sinusoidal lining cells (SC) were counted. Mean values for control rats were 0.3 +/- 0.1% (H), 0.4 +/- 0.1% (SC) and 0.2 +/- 0.1% (PIC). GVHD rats demonstrated a significant increase in LI of PIC (days 1-21), SC (days 2-17) and H (days 2-17). Most labelled cells in PIC were large lymphocytes. Peak LI values were 7.0 +/- 1.0% PIC (day 17), 6.8 +/- 0.9% SC (day 17), and 5.2 +/- 0.9% H (day 7), with all cellular compartments returning to near normal LI values by day 28. Stimulation of cellular proliferation occurred in all three liver cell compartments in neonatally thymectomized (TXM) rats. The intensity of GVHD-induced cell proliferation was significantly decreased at day 7 in all compartments and PIC was dramatically decreased at day 21 in TXM-GVHD rats as compared to non-TXM-GVHD rats. It is hypothesized that the general stimulation of hepatocyte cell proliferation in GVHD is related to the secretion of lymphokines by primarily donor and secondarily host T cells in the periportal infiltrate. PMID:7172201

  17. PHASE II TRIAL OF GVHD PROPHYLAXIS WITH POST-TRANSPLANTATION CYCLOPHOSPHAMIDE FOLLOWING REDUCED-INTENSITY BUSULFAN/FLUDARABINE (BU/FLU) CONDITIONING FOR HEMATOLOGICAL MALIGNANCIES

    PubMed Central

    Alousi, Amin M.; Brammer, Jonathan E.; Saliba, Rima M.; Andersson, Borje; Popat, Uday; Hosing, Chitra; Jones, Roy; Shpall, Elizabeth J; Khouri, Issa; Qazilbash, Muzaffar; Nieto, Yago; Shah, Nina; Ahmed, Sairah; Oran, Betul; Atrash, Gheath Al; Ciurea, Stefan; Kebriaei, Partow; Chen, Julianne; Rondon, Gabriela; Champlin, Richard

    2016-01-01

    GVHD-prophylaxis with post-transplant cyclophosphamide (CY) following ablative HLA-matched bone marrow (BM) transplantation has been reported to have comparable rates of acute GVHD with an apparent reduction in chronic GVHD and infections. We conducted a phase II trial of post-CY following reduced-intensity conditioning (RIC) using intravenous busulfan (AUC of 4,000 micromolar-minutes), Fludarabine (40mg/m2) for 4 days and CY 50mg/kg on days +3 and +4 following BM or peripheral blood (PB) transplants from matched related (MRD) or unrelated donors (MUD). MUD- recipients received anti-thymocyte globulin (ATG); however, a later amendment removed ATG. 49 patients were treated (AML/MDS: 82%). Median age was 62 years (range, 39–72). Fifteen patients received a MRD (9 PB/6 BM); 34 had a MUD (2 PB/32 BM). The cumulative incidence of grade II–IV, III–IV acute and chronic GVHD was 58%, 22% and 18%. A matched-cohort analysis compared outcomes to tacrolimus/methotrexate GVHD prophylaxis and indicated higher rates of acute GVHD grade II–IV (46% versus 19%, HR=2.8, p=0.02) and treatment-related mortality (HR 3.3, p=0.035) and worse overall survival (HR=1.9, p=0.04) with post-Cy. The incidence of chronic GVHD and CMV reactivation did not differ. This study suggests that post-transplant CY should not be used as sole GVHD-prophylaxis following a RIC transplant from HLA matched donors. PMID:25667989

  18. Successful salvage treatment of acute graft-versus-host disease after liver transplantation by withdrawal of immunosuppression: a case report

    PubMed Central

    Qiu, Wei; Lv, Guo-Yue; Jiang, Chao; Zhang, Ping; Sun, Xiao-Dong; Shi, Xiao-Ju; Liu, Xue-Yan

    2016-01-01

    Acute graft-versus-host disease (GVHD) following liver transplantation is a rare but fatal complication. The correct diagnosis and management of GVHD after liver transplantation are still major challenges. Herein, we reported successful salvage treatment of acute GVHD by withdrawal of immunosuppression in a patient who presented with fever, skin rashes, and decreased blood cell counts after liver transplantation. This case highlights the need for awareness of drug-induced liver injury if liver function tests are elevated during treatment, especially in patients taking multiple potentially hepatotoxic drugs, such as broad-spectrum antibiotics. When occurs, an artificial liver support system is a useful tool to provide temporary support of liver function for the patient in the event of drug-induced liver injury. PMID:26925149

  19. Topical Tacrolimus and Periodontal Therapy in the Management of a Case of Oral Chronic GVHD Characterized by Specific Gingival Localization

    PubMed Central

    Conrotto, Davide; Broccoletti, Roberto; Carcieri, Paola; Giaccone, Luisa; Arduino, Paolo G.

    2014-01-01

    Background. Chronic graft versus host disease (cGVHD) is a complication following bone marrow transplantation. The oral lesions are difficult to control with a systemic pharmacological therapy. Case Description. A 63-year-old female patient, who underwent an allogeniec transplantation for acute myeloid leukemia, developed a chronic oral and cutaneous GVHD. The patient was treated with topical tacrolimus 0.1%, twice daily for two months, and underwent a protocol of oral hygiene characterized by 3 appointments of scaling, root planning, and daily oral hygiene instructions. The patient showed marked resolution of gingival lesions and a significant improvement of related pain and gingival inflammatory indexes. Clinical Implications. This case report suggests that treatment with topical tacrolimus and professional oral hygiene may be helpful in the management of chronic oral GVHD with severe gingival involvement. PMID:24639902

  20. Tc17 cells are a proinflammatory, plastic lineage of pathogenic CD8+ T cells that induce GVHD without antileukemic effects.

    PubMed

    Gartlan, Kate H; Markey, Kate A; Varelias, Antiopi; Bunting, Mark D; Koyama, Motoko; Kuns, Rachel D; Raffelt, Neil C; Olver, Stuart D; Lineburg, Katie E; Cheong, Melody; Teal, Bianca E; Lor, Mary; Comerford, Iain; Teng, Michele W L; Smyth, Mark J; McCluskey, James; Rossjohn, Jamie; Stockinger, Brigitta; Boyle, Glen M; Lane, Steven W; Clouston, Andrew D; McColl, Shaun R; MacDonald, Kelli P A; Hill, Geoffrey R

    2015-09-24

    IL-17-producing cells are important mediators of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Here we demonstrate that a distinct CD8(+) Tc17 population develops rapidly after SCT but fails to maintain lineage fidelity such that they are unrecognizable in the absence of a fate reporter. Tc17 differentiation is dependent on alloantigen presentation by host dendritic cells (DCs) together with IL-6. Tc17 cells express high levels of multiple prototypic lineage-defining transcription factors (eg, RORγt, T-bet) and cytokines (eg, IL-17A, IL-22, interferon-γ, granulocyte macrophage colony-stimulating factor, IL-13). Targeted depletion of Tc17 early after transplant protects from lethal acute GVHD; however, Tc17 cells are noncytolytic and fail to mediate graft-versus-leukemia (GVL) effects. Thus, the Tc17 differentiation program during GVHD culminates in a highly plastic, hyperinflammatory, poorly cytolytic effector population, which we term "inflammatory iTc17" (iTc17). Because iTc17 cells mediate GVHD without contributing to GVL, therapeutic inhibition of iTc17 development in a clinical setting represents an attractive approach for separating GVHD and GVL. PMID:26206951

  1. Factors associated with marketable milk production recovery after treatment of naturally occurring acute coliform mastitis.

    PubMed

    Shinozuka, Yasunori; Kaneko, Sohei; Kurose, Tomoyasu; Watanabe, Aiko; Kuruhara, Kana; Kawai, Kazuhiro

    2016-06-01

    Milk production loss after recovery from acute coliform mastitis causes major economic losses for dairy industries. Declines in milk production and composition are caused by multiple factors, including cow factors, microorganisms and treatments, but the influence of each factor has not been determined. To investigate risk factors for milk loss after treatment for acute coliform mastitis, multiple logistic regression analyses were conducted in 53 clinical cases. Systemic administration of fluoroquinolone was significantly associated with recovery of marketable milk production. The time to slaughter was significantly shorter in cows with complete loss of quarter milk production than in cows that produced marketable milk. In this study, we identified factors associated with increased risk of milk production loss. PMID:26860356

  2. Contralateral acute subdural hematoma occurring after evacuation of subdural hematoma with coexistent contralateral subdural hygroma.

    PubMed

    Sun, Hsiao-Lun; Chang, Chih-Ju; Hsieh, Cheng-Ta

    2014-07-01

    Burr-hole craniostomy with closed-system drainage is a safe and effective method for the management of chronic subdural hematoma. However, contralateral acute subdural hematoma has been reported to be a rare and devastating complication. Only 3 cases have been described in the literature. Herein, we reported an 80-year-old male with chronic subdural hematoma and contralateral subdural hygroma. The burr-hole craniostomy with closed-system drainage was initially performed to treat the chronic subdural hematoma. Three days after surgery, weakness of the extremities developed, and contralateral acute subdural bleeding within the previous subdural hygroma was diagnosed by CT scan of the brain. The pathophysiological mechanism of this rare complication was discussed, and the relevant literature was also reviewed. PMID:24983286

  3. Contralateral acute subdural hematoma occurring after evacuation of subdural hematoma with coexistent contralateral subdural hygroma

    PubMed Central

    Sun, Hsiao-Lun; Chang, Chih-Ju; Hsieh, Cheng-Ta

    2014-01-01

    Burr-hole craniostomy with closed-system drainage is a safe and effective method for the management of chronic subdural hematoma. However, contralateral acute subdural hematoma has been reported to be a rare and devastating complication. Only 3 cases have been described in the literature. Herein, we reported an 80-year-old male with chronic subdural hematoma and contralateral subdural hygroma. The burr-hole craniostomy with closed-system drainage was initially performed to treat the chronic subdural hematoma. Three days after surgery, weakness of the extremities developed, and contralateral acute subdural bleeding within the previous subdural hygroma was diagnosed by CT scan of the brain. The pathophysiological mechanism of this rare complication was discussed, and the relevant literature was also reviewed. PMID:24983286

  4. Factors associated with marketable milk production recovery after treatment of naturally occurring acute coliform mastitis

    PubMed Central

    SHINOZUKA, Yasunori; KANEKO, Sohei; KUROSE, Tomoyasu; WATANABE, Aiko; KURUHARA, Kana; KAWAI, Kazuhiro

    2016-01-01

    Milk production loss after recovery from acute coliform mastitis causes major economic losses for dairy industries. Declines in milk production and composition are caused by multiple factors, including cow factors, microorganisms and treatments, but the influence of each factor has not been determined. To investigate risk factors for milk loss after treatment for acute coliform mastitis, multiple logistic regression analyses were conducted in 53 clinical cases. Systemic administration of fluoroquinolone was significantly associated with recovery of marketable milk production. The time to slaughter was significantly shorter in cows with complete loss of quarter milk production than in cows that produced marketable milk. In this study, we identified factors associated with increased risk of milk production loss. PMID:26860356

  5. All pain, no gain: Tc17 phantoms in GVHD.

    PubMed

    Ferrara, James

    2015-09-24

    Elusive CD8+ T cells that transiently secrete interleukin (IL)-17 cause graft-versus-host disease (GVHD) but do not contribute to beneficial graft-versus-leukemia (GVL) responses, as reported by Gartlan et al in this issue of Blood. GVHD remains a lethal and morbid complication of allogeneic bone marrow transplantation, but GVHD is tightly linked to beneficial GVL effects, and removal of donor T cells that cause GVHD also diminish GVL, leading to greater relapse after bone marrow transplantation (BMT). This elegant paper from the laboratory of Geoffrey Hill has identified a rare “night fury” T-cell subset that causes much pain with no gain, a finding that may take us one large step closer to the long sought after goal of separating GVL and GVHD. PMID:26405216

  6. Exercise-induced acute compartment syndrome in a young man, occurring after a short race.

    PubMed

    Basnet, Bibhusan; Matar, Mousa; Vaitilingham, Siddharthan; Chalise, Shyam; Irooegbu, Nkem; Bang, Jane

    2016-04-01

    We describe a case of exercise-induced acute compartment syndrome (ACS) in a 23-year-old man who presented to his primary care physician 48 hours after he attempted to run a 5K race. He noticed searing pain in his left leg after the first half mile but had no other symptoms. He was referred to the emergency department and diagnosed with ACS, and a fasciotomy was done. A presentation of limb pain that is out of proportion to a known or suspected injury should prompt consideration of ACS. Early recognition and surgical management are essential to achieving the best possible outcome. PMID:27034546

  7. Acute compartment syndrome occurring in forearm with relatively small amount of hematoma following transradial coronary intervention.

    PubMed

    Sugimoto, Atsuhiko; Iwamoto, Jotaro; Tsumuraya, Naoko; Nagaoka, Masakazu; Ikari, Yuji

    2016-04-01

    A 59-year-old female with angina pectoris successfully underwent percutaneous coronary intervention via the right radial artery. She complained of right forearm pain and numbness 4.5 h after the procedure. Though the swelling in her right arm seemed relatively mild, pressure measurement showed significant increase of internal forearm pressure. She developed acute compartment syndrome in the right forearm, and fasciotomy was performed immediately. The weight of subcutaneous hematoma in her right arm was approximately 100 g. Symptoms of paralysis and the impairment of perception remained for some time, but had completely recovered 4 months post-surgery. PMID:25855327

  8. Exercise-induced acute compartment syndrome in a young man, occurring after a short race

    PubMed Central

    Matar, Mousa; Vaitilingham, Siddharthan; Chalise, Shyam; Irooegbu, Nkem; Bang, Jane

    2016-01-01

    We describe a case of exercise-induced acute compartment syndrome (ACS) in a 23-year-old man who presented to his primary care physician 48 hours after he attempted to run a 5K race. He noticed searing pain in his left leg after the first half mile but had no other symptoms. He was referred to the emergency department and diagnosed with ACS, and a fasciotomy was done. A presentation of limb pain that is out of proportion to a known or suspected injury should prompt consideration of ACS. Early recognition and surgical management are essential to achieving the best possible outcome. PMID:27034546

  9. Acute and chronic disease associated with naturally occurring T-2 mycotoxicosis in sheep.

    PubMed

    Ferreras, M C; Benavides, J; García-Pariente, C; Delgado, L; Fuertes, M; Muñoz, M; García-Marín, J F; Pérez, V

    2013-02-01

    A flock of approximately 1,000 sheep were exposed intermittently to food contaminated with T-2 toxin (T-2), a potent type-A trichothecene mycotoxin produced primarily by Fusarium sporotrichioides and Fusarium poae. In the acute stage of the intoxication, affected sheep developed anorexia, decreased water consumption, ruminal atony, soft faeces and apathy. One hundred and ninety of the exposed sheep died. The main gross lesions observed in animals dying during the acute disease were rumenitis and ulcerative abomasitis, depletion of lymphocytes in lymphoid organs, necrosis of the exocrine pancreas, myocarditis and intense oedema of the skin and brain. Sheep developing the chronic stage of disease showed weight loss and reproductive inefficiency and the main pathological features observed in animals dying during this stage were gastrointestinal inflammation, myocardial fibrosis and necrotic and suppurative lesions in the oral cavity. Opportunistic infections (e.g. mycotic mastitis or parasitic pneumonia) were also identified in these animals. Increased serum concentrations of lactate dehydrogenase and creatine kinase were observed, most likely related to heart lesions. T-2 toxins were detected in all samples of the diet of these animals that were analyzed. The changes in the sheep reported here are similar to those described previously in experimental studies. Lesions observed in the present animals suggest an additional cardiotoxic effect of T-2 in sheep. PMID:22819015

  10. Bone marrow transplantation for acute myelogenous leukemia: factors associated with early mortality

    SciTech Connect

    Bortin, M.M.; Gale, R.P.; Kay, H.E.; Rimm, A.A.

    1983-03-04

    Comprehensive data were reported to the International Bone Marrow Transplant Registry, Milwaukee, regarding 156 patients with acute myelogenous leukemia who were treated with allogeneic bone marrow transplantation between 1978 and 1980. The minimum observation period was 15 months after transplant and most deaths occurred within the first six months. Prognostic factors were evaluated for associations with early mortality or life-threatening complications. Most early deaths were due to infections, interstitial pneumonitis, and graft-v-host disease (GVHD). Multivariate analyses disclosed five factors with significant associations with early death or a major cause of early death: (1) disease status; (2) dose-rate of irradiation; (3) drug used to prevent GVHD; (4) severity of GVHD; and (5) dose of marrow cells.It is emphasized that several of the important prognostic factors are within the control of the referring physician or the transplant team.

  11. Antibody- and aptamer-strategies for GvHD prevention

    PubMed Central

    Oelkrug, Christopher; Sack, Ulrich; Boldt, Andreas; Nascimento, Isis C; Ulrich, Henning; Fricke, Stephan

    2015-01-01

    Prevention of Graft-versus-Host-Disease (GvHD) by preserved Graft-versus-Leukaemia (GvL) effect is one of the major obstacles following allogeneic haematopoietic stem cell transplantation. Currently used drugs are associated with side effects and were not able to separate GvHD from the GvL-effect because of general T-cell suppression. This review focuses on murine models for GvHD and currently available treatment options involving antibodies and applications for the therapeutic use of aptamers as well as strategies for targeting immune responses by allogenic antigens. PMID:25353670

  12. Antibody- and aptamer-strategies for GvHD prevention.

    PubMed

    Oelkrug, Christopher; Sack, Ulrich; Boldt, Andreas; Nascimento, Isis C; Ulrich, Henning; Fricke, Stephan

    2015-01-01

    Prevention of Graft-versus-Host-Disease (GvHD) by preserved Graft-versus-Leukaemia (GvL) effect is one of the major obstacles following allogeneic haematopoietic stem cell transplantation. Currently used drugs are associated with side effects and were not able to separate GvHD from the GvL-effect because of general T-cell suppression. This review focuses on murine models for GvHD and currently available treatment options involving antibodies and applications for the therapeutic use of aptamers as well as strategies for targeting immune responses by allogenic antigens. PMID:25353670

  13. Cell-autonomous role of TGFβ and IL-2 receptors in CD4+ and CD8+ inducible regulatory T-cell generation during GVHD

    PubMed Central

    Sawamukai, Norifumi; Satake, Atsushi; Schmidt, Amanda M.; Lamborn, Ian T.; Ojha, Priti; Tanaka, Yoshiya

    2012-01-01

    FoxP3+ regulatory T cells (Tregs) suppress GVHD while preserving graft-versus-tumor effects, making them an attractive target for GVHD therapy. The donor-derived Treg pool can potentially be derived from the expansion of preexisting natural Tregs (nTregs) or from de novo generation of inducible Tregs (iTregs) from donor Tconvs in the transplantation recipient. Using an MHC-mismatched model of acute GVHD, in the present study we found that the Treg pool was comprised equally of donor-derived nTregs and iTregs. Experiments using various combinations of T cells from wild-type and FoxP3-deficient mice suggested that both preexisting donor nTregs and the generation of iTregs in the recipient mice contribute to protection against GVHD. Surprisingly, CD8+FoxP3+ T cells represented approximately 70% of the iTreg pool. These CD8+FoxP3+ T cells shared phenotypic markers with their CD4+ counterparts and displayed suppressive activity, suggesting that they were bona fide iTregs. Both CD4+ and CD8+ Tregs appeared to be protective against GVHD-induced lethality and required IL-2 and TGFβ receptor expression for their generation. These data illustrate the complex makeup of the donor-derived FoxP3+ Treg pool in allogeneic recipients and their potential role in protection against GVHD. PMID:22496155

  14. Cell-autonomous role of TGFβ and IL-2 receptors in CD4+ and CD8+ inducible regulatory T-cell generation during GVHD.

    PubMed

    Sawamukai, Norifumi; Satake, Atsushi; Schmidt, Amanda M; Lamborn, Ian T; Ojha, Priti; Tanaka, Yoshiya; Kambayashi, Taku

    2012-06-01

    FoxP3(+) regulatory T cells (Tregs) suppress GVHD while preserving graft-versus-tumor effects, making them an attractive target for GVHD therapy. The donor-derived Treg pool can potentially be derived from the expansion of preexisting natural Tregs (nTregs) or from de novo generation of inducible Tregs (iTregs) from donor Tconvs in the transplantation recipient. Using an MHC-mismatched model of acute GVHD, in the present study we found that the Treg pool was comprised equally of donor-derived nTregs and iTregs. Experiments using various combinations of T cells from wild-type and FoxP3-deficient mice suggested that both preexisting donor nTregs and the generation of iTregs in the recipient mice contribute to protection against GVHD. Surprisingly, CD8(+)FoxP3(+) T cells represented approximately 70% of the iTreg pool. These CD8(+)FoxP3(+) T cells shared phenotypic markers with their CD4(+) counterparts and displayed suppressive activity, suggesting that they were bona fide iTregs. Both CD4(+) and CD8(+) Tregs appeared to be protective against GVHD-induced lethality and required IL-2 and TGFβ receptor expression for their generation. These data illustrate the complex makeup of the donor-derived FoxP3(+) Treg pool in allogeneic recipients and their potential role in protection against GVHD. PMID:22496155

  15. Analysis of gastrointestinal and hepatic chronic GVHD manifestations on major outcomes: A Chronic GVHD Consortium study

    PubMed Central

    Pidala, Joseph; Chai, Xiaoyu; Kurland, Brenda F.; Inamoto, Yoshihiro; Flowers, Mary E.D.; Palmer, Jeanne; Khera, Nandita; Jagasia, Madan; Cutler, Corey; Arora, Mukta; Vogelsang, Georgia; Lee, Stephanie J.

    2013-01-01

    While data support adverse prognosis of overlap subtype of chronic GVHD, the importance of site of gastrointestinal (GI) and type of hepatic involvement is not known. Using data from the Chronic GVHD Consortium observational cohort study (n=567, total of 2115 visits), we examined whether the site of GI (esophageal, upper GI, lower GI) and type of hepatic (bilirubin, alkaline phosphatase (AP), alanine aminotransferase (ALT)) involvement are associated with overall survival (OS)and non-relapse mortality (NRM), symptoms, quality of life (QOL) and functional status measures. In multivariate analysis utilizing data from enrollment visits only, lower GI involvement (HR 1.67, p=0.05) and elevated bilirubin (HR 2.46, p=0.001) were associated with OS; both were also associated with NRM. In multivariable analysis using all visits (time-dependent covariates), GI score greater than zero (HR 1.69, p=0.02) and elevated bilirubin (HR 3.73, p<0.001) were associated with OS; results were similar for NRM. Any esophageal involvement and GI score greater than zero were associated with both symptoms and QOL while elevated bilirubin was associated with QOL. We found no consistent evidence that upper GI involvement, AP, ALT, or NIH liver score add prognostic value for survival, overall symptom burden, or quality of life. These data support important differences in patient-reported outcomes according to GI and hepatic involvement among chronic GVHD affected patients, and identify those with elevated bilirubin or higher GI score at any time, or lower GI involvement at cohort enrollment, as patients at greater risk for mortality under current treatment approaches. PMID:23395601

  16. α-1-Antitrypsin (AAT)-modified donor cells suppress GVHD but enhance the GVL effect: a role for mitochondrial bioenergetics.

    PubMed

    Marcondes, A Mario; Karoopongse, Ekapun; Lesnikova, Marina; Margineantu, Daciana; Welte, Tobias; Dinarello, Charles A; Hockenbery, David; Janciauskiene, Sabina; Deeg, H Joachim

    2014-10-30

    Hematopoietic cell transplantation is curative in many patients. However, graft-versus-host disease (GVHD), triggered by alloreactive donor cells, has remained a major complication. Here, we show an inverse correlation between plasma α-1-antitrypsin (AAT) levels in human donors and the development of acute GVHD in the recipients (n = 111; P = .0006). In murine models, treatment of transplant donors with human AAT resulted in an increase in interleukin-10 messenger RNA and CD8(+)CD11c(+)CD205(+) major histocompatibility complex class II(+) dendritic cells (DCs), and the prevention or attenuation of acute GVHD in the recipients. Ablation of DCs (in AAT-treated CD11c-DTR donors) decreased CD4(+)CD25(+)FoxP3(+) regulatory T cells to one-third and abrogated the anti-GVHD effect. The graft-versus-leukemia (GVL) effect of donor cells (against A20 tumor cells) was maintained or even enhanced with AAT treatment of the donor, mediated by an expanded population of NK1.1(+), CD49B(+), CD122(+), CD335(+) NKG2D-expressing natural killer (NK) cells. Blockade of NKG2D significantly suppressed the GVL effect. Metabolic analysis showed a high glycolysis-high oxidative phosphorylation profile for NK1.1(+) cells, CD4(+)CD25(+)FoxP3(+) T cells, and CD11c(+) DCs but not for effector T cells, suggesting a cell type-specific effect of AAT. Thus, via altered metabolism, AAT exerts effective GVHD protection while enhancing GVL effects. PMID:25224412

  17. Reduced-dose methotrexate in combination with tacrolimus was associated with rapid engraftment and recovery from oral mucositis without affecting the incidence of GVHD.

    PubMed

    Matsukawa, Toshihiro; Hashimoto, Daigo; Sugita, Junichi; Nakazawa, Seitarou; Matsushita, Takae; Kashiwazaki, Haruhiko; Goto, Hideki; Onozawa, Masahiro; Kahata, Kaoru; Fujimoto, Katsuya; Endo, Tomoyuki; Kondo, Takeshi; Hashino, Satoshi; Yamazaki, Yutaka; Teshima, Takanori

    2016-07-01

    Allogeneic hematopoietic stem cell transplantation is a curable treatment for hematological diseases. Graft-versus-host disease (GVHD) causes morbidity and mortality after HSCT. Methotrexate (MTX) is used for GVHD prophylaxis, but its appropriate dose remains unclear. In the present study, we compared the efficacy and toxicity of 15-10-10 MTX (day +1: 15 mg/m(2); days +3 and +6: 10 mg/m(2)) with 10-7-7 MTX (day +1: 10 mg/m(2); day +3 and +6: 7 mg/m(2)) in combination with tacrolimus. The cumulative incidence rates of grades II-IV acute GVHD, grades III-IV acute GVHD and chronic GVHD in the 15-10-10 MTX and 10-7-7 MTX groups did not differ to a statistically significant extent. The median time for neutrophil engraftment in the 15-10-10 MTX group was 16 days (range, 11-31 days), while that in the 10-7-7 group was 15 days (range, 12-19 days) (P = 0.024). Moreover, the median time for platelet recovery was significantly shorter in the 10-7-7 MTX group (22 days; range, 13-49 days) than that in the 15-10-10 MTX group (27 days; range, 9-405 days) (P = 0.027). The duration of oral mucositis was significantly shorter in the patients who received a reduced dose of MTX (median, 4.5 vs 13.0 days; P = 0.013). In conclusion, GVHD prophylaxis with a reduced dose of MTX was associated with earlier engraftment and earlier recovery from mucositis in comparison to a standard dose of MTX, without affecting the incidence of GVHD. PMID:27119977

  18. Extracorporeal photopheresis combined with pentostatin in the conditioning regimen for canine hematopoietic cell transplantation does not prevent GVHD.

    PubMed

    Bethge, W A; Kerbauy, F R; Santos, E B; Gooley, T; Storb, R; Sandmaier, B M

    2014-09-01

    Extracorporeal photopheresis (ECP) and the purine analog pentostatin exert potent immunomodulatory effects. We evaluated the use of these treatment modalities to prevent GVHD in a canine model of unrelated dog leukocyte Ag-mismatched hematopoietic cell transplantation, after conditioning with 920 cGy TBI. We have shown previously in this model that 36/40 dogs given MTX alone as postgrafting immunosuppression engrafted and that 25 of 40 dogs had severe GVHD and median survival of 21 days. In the current study, nine dogs received conditioning with 920 cGy TBI and postgrafting MTX either with ECP on days -2 to -1 alone (n=5) or ECP on days -6 and -5 combined with two doses of pentostatin (days -4 to -3) (n=4). Seven of nine dogs achieved engraftment. Six dogs developed severe acute GVHD (four in the group with ECP alone and two with pentostatin and ECP). We failed to demonstrate a positive impact of ECP and pentostatin for the prevention of GVHD compared with historical control dogs. PMID:25046213

  19. How I treat acute graft-versus-host disease of the gastrointestinal tract and the liver

    PubMed Central

    2016-01-01

    Treatment of acute graft-versus-host disease (GVHD) has evolved from a one-size-fits-all approach to a more nuanced strategy based on predicted outcomes. Lower and time-limited doses of immune suppression for patients predicted to have low-risk GVHD are safe and effective. In more severe GVHD, prolonged exposure to immunosuppressive therapies, failure to achieve tolerance, and inadequate clinical responses are the proximate causes of GVHD-related deaths. This article presents acute GVHD-related scenarios representing, respectively, certainty of diagnosis, multiple causes of symptoms, jaundice, an initial therapy algorithm, secondary therapy, and defining futility of treatment. PMID:26729898

  20. Six Month Freedom from Treatment Failure is an Important Endpoint for Acute Graft-Versus-Host Disease Clinical Trials

    PubMed Central

    Sengsayadeth, Salyka; Savani, Bipin N.; Jagasia, Madan; Goodman, Stacey; Greer, John P.; Chen, Heidi; Chinratanalab, Wichai; Kassim, Adetola A.; Engelhardt, Brian G.

    2013-01-01

    We studied the ASBMT 6 month (m) freedom from treatment failure (FFTF) as a predictor of survival for patients with acute graft-versus-host disease (aGVHD) requiring treatment. Adult patients undergoing allogeneic hematopoietic cell transplant (HCT) from February 2007 to March 2009 who were enrolled in a prospective biomarker clinical trial and developed aGVHD requiring systemic corticosteroids by day +100 were included (N=44). Six month FFTF was defined per ASBMT guidelines [absence of death, malignancy relapse/progression, or systemic immunosuppression change within 6 months of starting steroids and before chronic GVHD development]. aGVHD was treated with systemic corticosteroids in 44 patients. Day 28 response after steroid initiation (CR+VGPR+PR) occurred in 38 (87%) patients, but only 28 (64%) HCT recipients met the 6 m FFTF endpoint. Day 28 response predicted 6 m FFTF. Achieving 6 m FFTF was associated with improved 2 year (y) overall survival (OS) [81% vs. 48%, P= 0.03)] and decreased 2 y non-relapse mortality [8% vs. 49% (P= 0.01)]. In multivariate analysis, 6 m FFTF continued to predict improved OS (HR, 0.27; P=0.03). The 6 m FFTF endpoint measures fixed outcomes, predicts long-term therapeutic success, and could be less prone to measurement error than aGVHD clinical response at day 28. PMID:24096824

  1. p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells

    PubMed Central

    Trocoli, A; Bensadoun, P; Richard, E; Labrunie, G; Merhi, F; Schläfli, A M; Brigger, D; Souquere, S; Pierron, G; Pasquet, J-M; Soubeyran, P; Reiffers, J; Ségal-Bendirdjian, E; Tschan, M P; Djavaheri-Mergny, M

    2014-01-01

    The p62/SQSTM1 adapter protein has an important role in the regulation of several key signaling pathways and helps transport ubiquitinated proteins to the autophagosomes and proteasome for degradation. Here, we investigate the regulation and roles of p62/SQSTM1 during acute myeloid leukemia (AML) cell maturation into granulocytes. Levels of p62/SQSTM1 mRNA and protein were both significantly increased during all-trans retinoic acid (ATRA)-induced differentiation of AML cells through a mechanism that depends on NF-κB activation. We show that this response constitutes a survival mechanism that prolongs the life span of mature AML cells and mitigates the effects of accumulation of aggregated proteins that occurs during granulocytic differentiation. Interestingly, ATRA-induced p62/SQSTM1 upregulation was impaired in maturation-resistant AML cells but was reactivated when differentiation was restored in these cells. Primary blast cells of AML patients and CD34+ progenitors exhibited significantly lower p62/SQSTM1 mRNA levels than did mature granulocytes from healthy donors. Our results demonstrate that p62/SQSTM1 expression is upregulated in mature compared with immature myeloid cells and reveal a pro-survival function of the NF-κB/SQSTM1 signaling axis during granulocytic differentiation of AML cells. These findings may help our understanding of neutrophil/granulocyte development and will guide the development of novel therapeutic strategies for refractory and relapsed AML patients with previous exposure to ATRA. PMID:25034783

  2. Syk and tired of current chronic GVHD therapies.

    PubMed

    Fowler, Daniel H; Pavletic, Steven Z

    2015-06-25

    In this issue of Blood, Flynn et al1 provide key data that lend further support to the development of clinical trials of spleen tyrosine kinase (Syk) inhibition for more effective chronic graft-versus-host disease (cGVHD) treatment. PMID:26113534

  3. Chronic GVHD induced GVL effect after unmanipulated haploidentical hematopoietic SCT for AML and myelodysplastic syndrome.

    PubMed

    Mo, X-D; Xu, L-P; Zhang, X-H; Liu, D-H; Wang, Y; Chen, H; Yan, C-H; Chen, Y-H; Han, W; Wang, F-R; Wang, J-Z; Liu, K-Y; Huang, X-J

    2015-01-01

    The aim of this study was to investigate the impact of occurrence of chronic GVHD (cGVHD) and its severity on transplantation outcomes in a consecutive cohort of AML and myelodysplastic syndrome (MDS) patients who received unmanipulated haploidentical hematopoietic SCT (haplo-HSCT; n=324). The cumulative incidence of relapse was significantly decreased in patients with cGVHD compared with the non-cGVHD group (1 year: 3.2% vs 11.9%, P=0.002; 3 years: 6.0% vs 16.3%, P=0.002), particularly in those with mild cGVHD. The cumulative incidence of non-relapse mortality was comparable between patients with and without cGVHD. The probabilities of disease-free survival (DFS) were significantly better in patients with cGVHD than in those in the non-cGVHD group (1 year: 90.5% vs 78.5%, P=0.002; 3 years: 86.5% vs 71.5%, P<0.001), particularly in those with mild or moderate cGVHD; however, no significant impact of severe cGVHD on DFS was seen. Our findings highlight the close relationship between cGVHD and the immune-mediated GVL effect in patients with AML and MDS receiving unmanipulated haplo-HSCT; however, only mild or moderate cGVHD was associated with a lower risk of relapse translating into improved DFS. PMID:25387095

  4. Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation

    PubMed Central

    Faridi, Rehan Mujeeb; Kemp, Taylor J.; Dharmani-Khan, Poonam; Lewis, Victor; Rajalingam, Raja; Berka, Noureddine; Storek, Jan; Masood Khan, Faisal

    2016-01-01

    Background Allogeneic hematopoietic cell transplantation (HCT) can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD) and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR)-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG) is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCT Methods and Findings The study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into ‘discovery’ (135 pairs) and ‘validation’ (146 pairs) cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD), chronic GVHD needing systemic therapy (cGVHD) and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS), cGVHD & relapse free survival (cGRFS) and overall survival (OS)] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa) and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50–5.17) and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33–5.11). High incidence of cGVHD associated

  5. α-1-Antitrypsin (AAT)–modified donor cells suppress GVHD but enhance the GVL effect: a role for mitochondrial bioenergetics

    PubMed Central

    Karoopongse, Ekapun; Lesnikova, Marina; Margineantu, Daciana; Welte, Tobias; Dinarello, Charles A.; Hockenbery, David; Janciauskiene, Sabina; Deeg, H. Joachim

    2014-01-01

    Hematopoietic cell transplantation is curative in many patients. However, graft-versus-host disease (GVHD), triggered by alloreactive donor cells, has remained a major complication. Here, we show an inverse correlation between plasma α-1-antitrypsin (AAT) levels in human donors and the development of acute GVHD in the recipients (n = 111; P = .0006). In murine models, treatment of transplant donors with human AAT resulted in an increase in interleukin-10 messenger RNA and CD8+CD11c+CD205+ major histocompatibility complex class II+ dendritic cells (DCs), and the prevention or attenuation of acute GVHD in the recipients. Ablation of DCs (in AAT-treated CD11c-DTR donors) decreased CD4+CD25+FoxP3+ regulatory T cells to one-third and abrogated the anti-GVHD effect. The graft-versus-leukemia (GVL) effect of donor cells (against A20 tumor cells) was maintained or even enhanced with AAT treatment of the donor, mediated by an expanded population of NK1.1+, CD49B+, CD122+, CD335+ NKG2D-expressing natural killer (NK) cells. Blockade of NKG2D significantly suppressed the GVL effect. Metabolic analysis showed a high glycolysis–high oxidative phosphorylation profile for NK1.1+ cells, CD4+CD25+FoxP3+ T cells, and CD11c+ DCs but not for effector T cells, suggesting a cell type–specific effect of AAT. Thus, via altered metabolism, AAT exerts effective GVHD protection while enhancing GVL effects. PMID:25224412

  6. First Generation Gene Expression Signature for Early Prediction of Late Occurring Hematological Acute Radiation Syndrome in Baboons.

    PubMed

    Port, M; Herodin, F; Valente, M; Drouet, M; Lamkowski, A; Majewski, M; Abend, M

    2016-07-01

    We implemented a two-stage study to predict late occurring hematologic acute radiation syndrome (HARS) in a baboon model based on gene expression changes measured in peripheral blood within the first two days after irradiation. Eighteen baboons were irradiated to simulate different patterns of partial-body and total-body exposure, which corresponded to an equivalent dose of 2.5 or 5 Gy. According to changes in blood cell counts the surviving baboons (n = 17) exhibited mild (H1-2, n = 4) or more severe (H2-3, n = 13) HARS. Blood samples taken before irradiation served as unexposed control (H0, n = 17). For stage I of this study, a whole genome screen (mRNA microarrays) was performed using a portion of the samples (H0, n = 5; H1-2, n = 4; H2-3, n = 5). For stage II, using the remaining samples and the more sensitive methodology, qRT-PCR, validation was performed on candidate genes that were differentially up- or down-regulated during the first two days after irradiation. Differential gene expression was defined as significant (P < 0.05) and greater than or equal to a twofold difference above a H0 classification. From approximately 20,000 genes, on average 46% appeared to be expressed. On day 1 postirradiation for H2-3, approximately 2-3 times more genes appeared up-regulated (1,418 vs. 550) or down-regulated (1,603 vs. 735) compared to H1-2. This pattern became more pronounced at day 2 while the number of differentially expressed genes decreased. The specific genes showed an enrichment of biological processes coding for immune system processes, natural killer cell activation and immune response (P = 1 × E-06 up to 9 × E-14). Based on the P values, magnitude and sustained differential gene expression over time, we selected 89 candidate genes for validation using qRT-PCR. Ultimately, 22 genes were confirmed for identification of H1-3 classifications and seven genes for identification of H2-3 classifications using qRT-PCR. For H1-3 classifications, most genes were

  7. Acute Toxicological Responses of Fischer Rats to Naturally Occurring Asbestos from theUnited States and Canada

    EPA Science Inventory

    This study was designed to provide understanding of the toxicity of naturally occurring asbestos (NOA) including Libby amphibole (LA), Sumas Mountain chrysotile (SM), EI Dorado Hills tremolite (ED) and Ontario actinolite/ferroactinolite cleavage fragments (ON). Ratrespirable fra...

  8. AcuteToxicological Responses of Fischer Rats to Naturally Occurring Asbestos Samples from the United States and Canada

    EPA Science Inventory

    The potential public health issues related to exposure to natural asbestos deposits (commonly termed naturally occurring asbestos, NO A) has gained the regulatory and media spotlight in recent years. Arguably the most well known example is Libby, Montana, the site of the largest ...

  9. IL-6 cytoprotection in hyperoxic acute lung injury occurs via PI3K/Akt-mediated Bax phosphorylation

    PubMed Central

    Kolliputi, Narasaiah; Waxman, Aaron B.

    2009-01-01

    IL-6 overexpression protects mice from hyperoxic acute lung injury in vivo, and treatment with IL-6 protects cells from oxidant-mediated death in vitro. The mechanisms of protection, however, are not clear. We characterized the expression, localization, and regulation of Bax, a proapoptotic member of the Bcl-2 family, in wild-type (WT) and IL-6 lung-specific transgenic (Tg+) mice exposed to 100% O2 and in human umbilical vein endothelial cells (HUVEC) treated with H2O2 and IL-6. In control HUVEC treated with H2O2 or in WT mice exposed to 100% O2, a marked induction of Bax translocation and dimerization was associated with increased JNK and p38 kinase activity. In contrast, specific JNK or p38 kinase inhibitors or treatment with IL-6 inhibited Bax mitochondrial translocation and apoptosis of HUVEC. IL-6 Tg+ mice exposed to 100% O2 exhibited enhanced phosphatidylinositol 3-kinase (PI3K)/Akt kinase and increased serine phosphorylation of Bax at Ser184 compared with WT mice. The PI3K-specific inhibitor LY-2940002 blocked this IL-6-induced Bax phosphorylation and promoted cell death. Furthermore, IL-6 potently blocked hyperoxia- or oxidant-induced Bax insertion into mitochondrial membranes. Thus IL-6 functions in a cytoprotective manner, in part, by suppressing Bax translocation and dimerization through PI3K/Akt-mediated Bax phosphorylation. PMID:19376889

  10. Patterns and kinetics of T-cell chimerism after allo transplant with alemtuzumab-based conditioning: mixed chimerism protects from GVHD, but does not portend disease recurrence.

    PubMed

    van Besien, Koen; Dew, Alexander; Lin, Shang; Joseph, Loren; Godley, Lucy A; Larson, Richard A; Odenike, Toyosi; Rich, Elizabeth; Stock, Wendy; Wickrema, Amittha; Artz, Andrew S

    2009-11-01

    We analyzed the kinetics of CD3 chimerism in 120 consecutive allogeneic hematopoietic cell transplantation (HCT) recipients receiving alemtuzumab-based conditioning. Fifty-two received fludarabine/melphalan, 44 received fludarabine/busulfan, and 24 received clofarabine/melphalan in addition to alemtuzumab. Post-transplant GVHD prophylaxis consisted of tacrolimus. No prophylactic donor lymphocyte infusion or other interventions were used for mixed donor chimerism (MDC). Bone marrow (BM) and/or peripheral blood (PB) samples were obtained at 30 days, 100 days, 180 days, and 1 year following HCT. On Day 30, 15% of assessable patients had MDC in the CD3 compartment. This had increased to 50% by Day 100, and to 63% by Day 180. MDC predicted for a lower risk of acute (p = 0.08) and particularly of chronic GVHD (p = 0.01). MDC was not associated with subsequent relapse or TRM (p = 0.67 and 0.72, respectively). A decline of more than 15% in CD3 chimerism between Day 30 and Day 180 predicted for a 40% risk of subsequent disease recurrence. The observation of MDC after alemtuzumab conditioning does not by itself constitute a risk factor for relapse and should not be used to guide therapeutic intervention. By contrast, declining donor chimerism between Day 30 and Day 180 is associated with a somewhat increased risk of disease recurrence. The high incidence of MDC after alemtuzumab containing conditioning contributes to the low risk of acute and chronic GVHD. PMID:19821799

  11. Diagnosis and differential diagnosis of hepatic graft versus host disease (GVHD)

    PubMed Central

    Matsukuma, Karen E.; Wei, Dongguang; Sun, Kai; Ramsamooj, Rajendra

    2016-01-01

    Graft versus host disease (GVHD) is a common complication following allogeneic hematopoietic cell transplantation (HCT) that typically manifests as injury to the skin, gastrointestinal mucosa, and liver. In some cases, hepatic GVHD may be histologically indistinguishable from other disorders such as infection and drug-induced liver injury (DILI). Additionally, clinical signs and symptoms are frequently confounded by the superimposed effects of pretransplant chemoradiotherapy, immunotherapy (IT) (targeted to the underlying malignancy), GVHD prophylaxis, and infection. Thus, careful attention to and correlation with clinical findings, laboratory values, and histologic features is essential for diagnosis. This review, aimed at the practicing pathologist, will discuss current clinical and histologic criteria for GVHD, the approach to diagnosis of hepatic GVHD, and features helpful for distinguishing it from other entities in the differential diagnosis. PMID:27034810

  12. Pharmacologic prophylaxis regimens for acute graft-versus-host disease: past, present and future.

    PubMed

    Ram, Ron; Storb, Rainer

    2013-08-01

    Abstract Acute graft-versus-host disease (GVHD) has compromised and continues to compromise the benefits associated with allogeneic hematopoietic cell transplant to cure malignant and non-malignant diseases. Pharmacologic interventions to prevent GVHD have emerged as a major objective of research in the immunology and transplant fields. A better understanding of the pathobiology behind the GVHD process has led the way to novel approaches and medications. Here we review the present arsenal of medications used to prevent GVHD, focusing on past experience and the current evidence, and discuss future potential targets. PMID:23278640

  13. Acute graft-versus-host disease following simultaneous pancreas-kidney transplantation: report of a case.

    PubMed

    Asari, Sadaki; Matsumoto, Ippei; Toyama, Hirochika; Shinzeki, Makoto; Goto, Tadahiro; Tanaka, Masaki; Shirakawa, Sachiyo; Yamashita, Hironori; Ajiki, Tetsuo; Fukumoto, Takumi; Ku, Yonson

    2015-12-01

    Acute graft-versus-host-disease (aGVHD) is a rare complication in the setting of pancreas-kidney transplantation (PKT). We herein describe the case of a 37-year-old male with severe type 1 diabetes with chronic renal failure who received simultaneous PKT from a female donor. Diarrhea developed on postoperative day (POD) 10. Subsequently, fever and liver dysfunction occurred on POD 32. Skin rashes appeared with pain and itching on his trunk and extremities on POD 40. As pancytopenia occurred on POD 63, bone marrow biopsies demonstrated profound hypoplastic marrow. On POD 69, we eventually made a definitive diagnosis of aGVHD because skin biopsies revealed the XX chromosome signal in a fluorescence in situ hybridization analysis. Thereafter, 100 mg of prednisolone was administered for 5 days. Although every symptom was temporarily improved, on POD 156, the patient expired from the septic pneumonia without any effects of antibiotics. Clinician should be aware that PKT has the potential to induce aGVHD. PMID:25373363

  14. Effect of acute and chronic graft-versus-host disease on relapse and survival after reduced-intensity conditioning allogeneic transplantation for myeloma

    PubMed Central

    Ringdén, Olle; Shrestha, Smriti; da Silva, Gisela Tunes; Zhang, Mei-Jie; Dispenzieri, Angela; Remberger, Mats; Kamble, Rammurti; Freytes, Cesar O.; Gale, Robert Peter; Gibson, John; Gupta, Vikas; Holmberg, Leona; Lazarus, Hillard; McCarthy, Philip; Meehan, Kenneth; Schouten, Harry; Milone, Gustavo A.; Lonial, Sagar; Hari, Parameswaran N

    2011-01-01

    We evaluated the effect of acute and chronic graft-versus-host disease (GVHD) on relapse and survival after allogeneic haematopoietic stem cell transplantation (HSCT) for multiple myeloma (MM) using non-myeloablative conditioning (NMA) and reduced-intensity conditioning (RIC). The outcomes of 177 HLA-identical sibling HSCT recipients between 1997 and 2005 following NMA (n=98) or RIC (n=79) were analyzed. In 105 patients, autografting was followed by planned NMA/RIC allogeneic transplantation. The impact of GVHD was assessed as a time-dependent covariate using Cox models. The incidence of acute GVHD (grades I–IV) was 42% (95% confidence interval (CI) 35 – 49%) and of chronic GVHD at five years was 59% (95% CI 49 – 69%), with 70% developing extensive chronic GVHD. In multivariate analysis, acute GVHD (≥ grade I) was associated with an increased risk of TRM (relative risk (RR)=2.42; p=0.016), whereas limited chronic GVHD significantly decreased the risk of myeloma relapse (RR=0.35, p=0.035) and was associated with superior event-free survival (RR=0.40, p=0.027). Acute GVHD had a detrimental effect on survival, especially in those receiving autologous followed by allogeneic HSCT (RR=3.52; p=0.001). The reduction in relapse risk associated with chronic GVHD is consistent with a beneficial graft-versus-myeloma effect, but this did not translate into a survival advantage. PMID:21946381

  15. Time to unrelated donor leukocyte infusion is longer, but incidence of GVHD and overall survival are similar for recipients of unrelated DLI compared to matched sibling DLI.

    PubMed

    Kumar, Anita J; Vassilev, Pavel; Loren, Alison W; Luger, Selina M; Reshef, Ran; Gill, Saar; Smith, Jacqueline; Goldstein, Steven C; Hexner, Elizabeth; Stadtmauer, Edward A; Porter, David; Frey, Noelle V

    2016-06-01

    Donor leukocyte infusion (DLI) is used to treat relapsed leukemia after allogeneic hematopoietic stem cell transplant (HCT). Data comparing outcomes after unrelated DLI (uDLI) to matched sibling DLI (msDLI) are scant. We performed a retrospective analysis to assess differences in time to administer uDLI versus msDLI, and impact on outcomes. Fifty three patients with relapsed acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) after allogeneic HCT received uDLI (n = 18) or msDLI (n = 35) from 2000 to 2011. Median time from relapse to uDLI request was 15 days (range 0-66). Median time from relapse to uDLI was 56 days versus 40 days for msDLI patients (p = 0.034). 35% of msDLI and 44% of uDLI patients developed acute GVHD (p = 0.50). There was no significant difference in Grade C/D GVHD among uDLI and msDLI (28% and 21%, p = 0.58) or median OS after DLI between uDLI and msDLI (95 versus 75 days, p = 0.76). For patients with relapsed acute leukemia and MDS after allogeneic HCT, time from relapse to uDLI was longer than to msDLI, but incidence of GVHD and overall survival were similar. Access to uDLI does not appear to be a barrier to DLI administration. Outcomes unfortunately remain poor regardless of donor source. Am. J. Hematol. 91:426-429, 2016. © 2016 Wiley Periodicals, Inc. PMID:26820493

  16. GVHD prophylaxis with sirolimus-tacrolimus may overcome the deleterious effect on survival of HLA mismatch after reduced-intensity conditioning allo-SCT.

    PubMed

    Parody, R; Lopez-Corral, L; Godino, O L; Cadenas, I G; Martinez, A P; Vazquez, L; Martino, R; Martinez, C; Solano, C; Barba, P; Valcarcel, D; Caballero-Velazquez, T; Marquez-Malaver, F J; Sierra, J; Caballero, D; Perez-Simón, J A

    2015-01-01

    Large studies, mostly based on series of patients receiving CSA/tacrolimus (TKR) plus MTX as immunoprophylaxis, have demonstrated a deleterious effect on survival of the presence of a single mismatch out of eight loci after allogeneic hematopoietic SCT (alloHSCT). We retrospectively analyzed a series of 159 adult patients who received sirolimus(SRL)/TKR prophylaxis after alloHSCT. We compared overall outcomes according to HLA compatibility in A, B, C and DRB1 loci at the allele level: 7/8 (n=20) vs 8/8 (n=139). Donor type was unrelated in 95% vs 70% among 7/8 vs 8/8 pairs, respectively (P=0.01). No significant differences were observed in 3-year OS (68 vs 62%), 3-year EFS (53 vs 49%) and 1-year non-relapse mortality (9 vs 13%). Cumulative incidence of grades II-IV acute GVHD (aGVHD) was significantly higher in 7/8 alloHSCT (68% vs 42%, P<0.001) but no significant differences were found for III-IV aGVHD (4.5% vs 11%), overall (35% vs 53%) and extensive (20% vs 35%) chronic GHVD in 7/8 vs 8/8 subgroups, respectively. In summary, the present study indicates favorable outcomes after alloHSCT using the combination of SRL/TKR combination as GVHD prophylaxis with OS in the range of 55-70%, and non-significant differences in overall outcomes, irrespective of the presence of any mismatches at obligatory loci. PMID:25310306

  17. Epigenetic remodeling in B-cell acute lymphoblastic leukemia occurs in two tracks and employs embryonic stem cell-like signatures

    PubMed Central

    Lee, Seung-Tae; Muench, Marcus O.; Fomin, Marina E.; Xiao, Jianqiao; Zhou, Mi; de Smith, Adam; Martín-Subero, José I.; Heath, Simon; Houseman, E. Andres; Roy, Ritu; Wrensch, Margaret; Wiencke, John; Metayer, Catherine; Wiemels, Joseph L.

    2015-01-01

    We investigated DNA methylomes of pediatric B-cell acute lymphoblastic leukemias (B-ALLs) using whole-genome bisulfite sequencing and high-definition microarrays, along with RNA expression profiles. Epigenetic alteration of B-ALLs occurred in two tracks: de novo methylation of small functional compartments and demethylation of large inter-compartmental backbones. The deviations were exaggerated in lamina-associated domains, with differences corresponding to methylation clusters and/or cytogenetic groups. Our data also suggested a pivotal role of polycomb and CTBP2 in de novo methylation, which may be traced back to bivalency status of embryonic stem cells. Driven by these potent epigenetic modulations, suppression of polycomb target genes was observed along with disruption of developmental fate and cell cycle and mismatch repair pathways and altered activities of key upstream regulators. PMID:25690899

  18. Epigenetic remodeling in B-cell acute lymphoblastic leukemia occurs in two tracks and employs embryonic stem cell-like signatures.

    PubMed

    Lee, Seung-Tae; Muench, Marcus O; Fomin, Marina E; Xiao, Jianqiao; Zhou, Mi; de Smith, Adam; Martín-Subero, José I; Heath, Simon; Houseman, E Andres; Roy, Ritu; Wrensch, Margaret; Wiencke, John; Metayer, Catherine; Wiemels, Joseph L

    2015-03-11

    We investigated DNA methylomes of pediatric B-cell acute lymphoblastic leukemias (B-ALLs) using whole-genome bisulfite sequencing and high-definition microarrays, along with RNA expression profiles. Epigenetic alteration of B-ALLs occurred in two tracks: de novo methylation of small functional compartments and demethylation of large inter-compartmental backbones. The deviations were exaggerated in lamina-associated domains, with differences corresponding to methylation clusters and/or cytogenetic groups. Our data also suggested a pivotal role of polycomb and CTBP2 in de novo methylation, which may be traced back to bivalency status of embryonic stem cells. Driven by these potent epigenetic modulations, suppression of polycomb target genes was observed along with disruption of developmental fate and cell cycle and mismatch repair pathways and altered activities of key upstream regulators. PMID:25690899

  19. Extracorporeal photopheresis in steroid-refractory acute or chronic graft-versus-host disease: results of a systematic review of prospective studies.

    PubMed

    Abu-Dalle, Iman; Reljic, Tea; Nishihori, Taiga; Antar, Ahmad; Bazarbachi, Ali; Djulbegovic, Benjamin; Kumar, Ambuj; Kharfan-Dabaja, Mohamed A

    2014-11-01

    Acute and chronic graft-versus-host disease (GVHD) remain major obstacles for successful allogeneic hematopoietic cell transplantation. Extracorporeal photopheresis (ECP) modulates immune cells, such as alloreactive T cells and dendritic cells, and improves GVHD target organ function(s) in steroid-refractory GVHD patients. We performed a systematic review to evaluate the totality of evidence regarding the efficacy of ECP for treatment of acute and chronic steroid-refractory or steroid-dependent GVHD. Nine studies, including 1 randomized controlled trial, met inclusion criteria, with a total of 323 subjects. In pooled analyses, overall response rates (ORR) were .69 (95% confidence interval [CI], .34 to .95) and .64 (95% CI, .47 to .79) for acute and chronic GVHD, respectively. In acute GVHD organ-specific responses, ECP resulted in the highest ORR for cutaneous, with .84 (95% CI, .75 to .92), followed by gastrointestinal with .65 (95% CI, .52 to .78). Similar response rates were seen in chronic GVHD involving the skin and gastrointestinal tract. Conversely, ORR for chronic GVHD involving the lungs was only .15 (95% CI, 0 to .5). In chronic GVHD, grades 3 to 4 adverse events were reported at .38 (95% CI, .06 to .78). ECP-related mortality rates were extremely low. Rates of immunosuppression discontinuation were .55 (95% CI, .40 to .70) and .23 (95% CI, .07 to .44) for acute and chronic GVHD, respectively. In summary, albeit limited by numbers of available studies, pooled analyses of prospective studies demonstrate encouraging responses after ECP treatment in acute and chronic GVHD after failing corticosteroids. Further research efforts are needed to improve organ-specific responses. PMID:24867779

  20. Etanercept plus topical corticosteroids as initial therapy for grade one acute graft-versus-host disease after allogeneic hematopoietic cell transplantation.

    PubMed

    Gatza, Erin; Braun, Thomas; Levine, John E; Ferrara, James L M; Zhao, Shuang; Wang, Tianyi; Chang, Lawrence; Harris, Andrew; Pawarode, Attaphol; Kitko, Carrie; Magenau, John M; Yanik, Gregory A; Couriel, Daniel R; Goldstein, Steven; Connelly, James; Reddy, Pavan; Paczesny, Sophie; Choi, Sung Won

    2014-09-01

    Clinical diagnosis of grade 1 acute graft-versus-host disease (GVHD) marks the beginning of a potentially progressive and fatal course of GVHD after hematopoietic stem cell transplantation (HSCT). However, interventional studies to treat early GVHD are lacking. We conducted a single-arm prospective phase II trial to test the hypothesis that treatment of newly diagnosed grade 1 acute GVHD with etanercept and topical corticosteroids would reduce progression to grade 2 to 4 within 28 days. Study patients (n = 34) had a median age of 51 years (range, 10 to 67 years) and had undergone unrelated (n = 22) or related (n = 12) donor HSCT. Study patients were treated with etanercept (.4 mg/kg, maximum 25 mg/dose) twice weekly for 4 to 8 weeks. Ten of 34 patients (29%) progressed to grade 2 to 4 acute GVHD within 28 days. The cumulative incidence of grade 2 to 4 and grade 3 to 4 acute GVHD at 1 year was 41% and 3%, respectively. Nonrelapse mortality was 19% and overall survival was 63% at 2 years. Among a contemporaneous control cohort of patients who were diagnosed with grade 1 acute GVHD and treated with topical corticosteroids but not etanercept during the study period, 12 of 28 patients (43%) progressed to grade 2 to 4 GVHD within 28 days, with a 1-year incidence of grade 2 to 4 GVHD and grade 3 to 4 GVHD of 61% (41% versus 61%, P = .08) and 18% (3% versus 18%, P = .05), respectively. Patients treated with etanercept also experienced less increase in GVHD plasma biomarkers suppression of tumorigenicity 2 (P = .06) and regenerating islet-derived 3-alpha (P = .01) 28 days after grade 1 acute GVHD diagnosis compared with contemporaneous control patients. This study was terminated early because of poor accrual. Future prospective studies are needed to identify patients with grade 1 acute GVHD at risk of swift progression to more severe GVHD and to establish consensus for the treatment of grade 1 acute GVHD. This trial is registered with Clinical

  1. Thiol/Redox Metabolomic Profiling Implicates GSH Dysregulation in Early Experimental Graft versus Host Disease (GVHD)

    PubMed Central

    Suh, Jung H.; Kanathezhath, Bindu; Shenvi, Swapna; Guo, Hua; Zhou, Alicia; Tiwana, Anureet; Kuypers, Frans; Ames, Bruce N.; Walters, Mark C.

    2014-01-01

    Graft-versus-host disease (GVHD) is a common complication of allogeneic bone marrow transplantation (BMT). Upregulation of inflammatory cytokines precedes the clinical presentation of GVHD and predicts its severity. In this report, thiol/redox metabolomics was used to identify metabolic perturbations associated with early preclinical (Day+4) and clinical (Day+10) stages of GVHD by comparing effects in Syngeneic (Syn; major histocompatibility complex- identical) and allogeneic transplant recipients (Allo BMT) in experimental models. While most metabolic changes were similar in both groups, plasma glutathione (GSH) was significantly decreased, and GSH disulfide (GSSG) was increased after allogeneic compared to syngeneic recipient and non-transplant controls. The early oxidation of the plasma GSH/GSSG redox couple was also observed irrespective of radiation conditioning treatment and was accompanied by significant rise in hepatic protein oxidative damage and ROS generation. Despite a significant rise in oxidative stress, compensatory increase in hepatic GSH synthesis was absent following Allo BMT. Early shifts in hepatic oxidative stress and plasma GSH loss preceded a statistically significant rise in TNF-α. To identify metabolomic biomarkers of hepatic GVHD injury, plasma metabolite concentrations analyzed at Day+10 were correlated with hepatic organ injury. GSSG (oxidized GSH) and β-alanine, were positively correlated, and plasma GSH cysteinylglycine, and branched chain amino acids were inversely correlated with hepatic injury. Although changes in plasma concentrations of cysteine, cystathionine (GSH precursors) and cysteinylglycine (a GSH catabolite) were not significant by univariate analysis, principal component analysis (PCA) indicated that accumulation of these metabolites after Allo BMT contributed significantly to early GVHD in contrast to Syn BMT. In conclusion, thiol/redox metabolomic profiling implicates that early dysregulation of host hepatic GSH

  2. Nutritional support in patients with GVHD of the digestive tract: state of the art.

    PubMed

    van der Meij, B S; de Graaf, P; Wierdsma, N J; Langius, J A E; Janssen, J J W M; van Leeuwen, P A M; Visser, O J

    2013-04-01

    An important complication of allo-SCT is GVHD, which commonly affects the skin, liver and digestive tract. Clinical symptoms of GVHD of the digestive tract (GVHD-DT) include excessive diarrhoea, abdominal pain and cramps, nausea and vomiting, gastrointestinal bleeding, dysphagia, and weight loss. Treatment is complicated and regarding nutritional support, only a few guidelines are available. Our aim was to critically appraise the literature on nutritional assessment, nutritional status and nutritional support for patients with GVHD-DT. Evidence shows that GVHD-DT is often associated with malnutrition, protein losing enteropathy, magnesium derangements, and deficiencies of zinc, vitamin B12 and vitamin D. Limited evidence exists on derangements of magnesium, resting energy expenditure, bone mineral density and pancreatic function, and some beneficial effects of n-3 polyunsaturated fatty acids and pancreatic enzyme replacement therapy. Expert opinions recommend adequate amounts of energy, at least 1.5 g protein/kg body weight, supplied by total parenteral nutrition in cases of severe diarrhoea. When diarrhoea is <500 mL a day, a stepwise oral upgrade diet can be followed. No studies exist on probiotics, prebiotics, dietary fibre and immunonutrition in GVHD-DT patients. Future research should focus on absorption capacity, vitamin and mineral status, and nutritional support strategies. PMID:22773121

  3. Measurement of oral chronic graft-versus-host disease: results from the Chronic GVHD Consortium

    PubMed Central

    Treister, Nathaniel; Chai, Xiaoyu; Kurland, Brenda; Pavletic, Steve; Weisdorf, Daniel; Pidala, Joseph; Palmer, Jeanne; Martin, Paul; Inamoto, Yoshihiro; Arora, Mukta; Flowers, Mary; Jacobsohn, David; Jagasia, Madan; Arai, Sally; Lee, Stephanie J.; Cutler, Corey

    2014-01-01

    Oral chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation. Scales and instruments to measure oral cGVHD activity and severity have not been prospectively validated. The objective of this study was to describe the characteristics of oral cGVHD and determine the measures most sensitive to change. Patients enrolled in the cGVHD Consortium with oral involvement were included. Clinicians scored oral changes according to the NIH criteria, and patients completed symptom and quality of life measures at each visit. Both rated change on an 8-point scale. Of 458 participants, 72% (n=331) had objective oral involvement at enrollment. Lichenoid change was the most common feature (n=293; 89%). At visits where oral change could be assessed, 50% of clinicians and 56% of patients reported improvement, with worsening reported in 4–5% for both groups (weighted kappa = 0.41). Multivariable regression modeling suggested that the measurement changes most predictive of perceived change by clinicians and patients were erythema and lichenoid, NIH severity and symptom scores. Oral cGVHD is common and associated with a range of signs and symptoms. Measurement of erythema and lichenoid changes and symptoms may adequately capture the activity of oral cGVHD in clinical trials but require prospective validation. PMID:23353804

  4. Effect of the co-occurring components from olive oil and thyme extracts on the antioxidant status and its bioavailability in an acute ingestion in rats.

    PubMed

    Rubió, Laura; Serra, Aida; Chen, C-Y Oliver; Macià, Alba; Romero, Maria-Paz; Covas, Maria-Isabel; Solà, Rosa; Motilva, Maria-José

    2014-04-01

    The aim of this work was to examine whether bioactives in thyme could enhance the antioxidant capacity of phenolics in virgin olive oil and their bioavailability in Wistar rats. After acute oral administration of extracts from olive cake (OE), thyme (TE) or their combination (OTE), blood samples were collected from 0 to 360 min. Plasma antioxidant status was analyzed by DPPH and FRAP in plasma and by SOD, CAT and GPx activities in erythrocytes. Plasma pharmacokinetics of the main metabolites of bioactives in olive oil and thyme were characterized. Plasma non-enzymatic antioxidant capacity was significantly modulated by OE, TE, and OTE in a time-, assay, and extract-dependent manner. OE, TE, and OTE all significantly decreased superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity and catalase (CAT) activity was increased. Pharmacokinetic results showed that plasma concentration (Cmax) of the main olive phenolic metabolites in rats fed with OTE were similar to those of OE. These results indicate that an enhanced bioavailability of olive phenolic compounds could occur in the presence of thyme, although any synergistic effect was observed in the antioxidant status when both phenolic extracts were administered. Antioxidant protection by phenolics from olive and thyme against oxidative stress occurs primarily through a direct antioxidant effect and may be related to the phenolic plasmatic metabolites. PMID:24554091

  5. Current practice in diagnosis and treatment of acute graft-versus-host disease: results from a survey among German-Austrian-Swiss hematopoietic stem cell transplant centers.

    PubMed

    Wolff, Daniel; Ayuk, Francis; Elmaagacli, Ahmet; Bertz, Hartmut; Lawitschka, Anita; Schleuning, Michael; Meyer, Ralf-Georg; Gerbitz, Armin; Hilgendorf, Inken; Hildebrandt, Gerhard C; Edinger, Matthias; Klein, Stephan; Halter, Jörg; Mousset, Sabine; Holler, Ernst; Greinix, Hildegard T

    2013-05-01

    To assess current clinical practice in diagnosis and treatment of acute graft-versus-host disease (aGVHD), we performed a survey among German, Austrian, and Swiss allogeneic hematopoietic stem cell transplantation (allo-HSCT) centers. Thirty-four of 72 contacted centers (47%) completed both the diagnostic and therapeutic sections of the survey, representing 65% of allo-HSCT activity within the participating countries in 2011. Three pediatric centers answered as requested only the diagnostic part of the survey. In the presence of diarrhea and decreased oral intake after engraftment, only 4 centers (12%) do not perform any endoscopy before the start of immunosuppressive treatment. In case of a skin rash with the differential diagnosis of drug reaction, only 12 centers (35%) perform a skin biopsy up front, whereas 19 do so after failure of systemic steroids. In the presence of rapidly increasing cholestasis occurring without any other signs of aGVHD, 11 centers (32%) perform a liver biopsy up front and 14 only after failure of steroid treatment, whereas 9 centers do not perform a liver biopsy at all. Twenty centers (59%) use a percutaneous approach, 12 a transvenous approach, and 1 mini-laparoscopy for liver biopsies. First-line treatment of cutaneous aGVHD stage 1 consists of topical treatment alone in 17 of 31 responding centers (61%), whereas isolated cutaneous aGVHD stage III is treated with systemic steroids (prednisolone below 0.5 mg/kg/day n = 2, 0.5 to 1.0 mg/kg/day n = 10, above 1.0 to 2.5 mg/kg/day n = 19) without or with topical agents (steroids n = 10; calcineurin inhibitors n = 3). In gastrointestinal manifestations of aGVHD, 9 centers (29%) add topical to systemic steroids, and 3 consider topical steroids as the only treatment for mild gastrointestinal and cutaneous aGVHD. The choice of agent for second-line treatment as well as the sequence of administration are extremely heterogeneous, most likely due to a lack of convincing data published

  6. Benefit of STR-based chimerism analysis to identify TA-GVHD as a cause of death: Utility of various biological specimens.

    PubMed

    Raina, Anupuma; Chaudhary, Garima; Dogra, Tirath Das; Khandelwal, Deepchand; Balayan, Ajay; Jain, Vandana; Kanga, Uma; Seth, Tulika

    2016-04-01

    Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare condition. It can occur after blood transfusion in immune-compromised and occasionally even in immune-competent patients, and is associated with a mortality rate of >90%. The diagnosis of TA-GVHD is often delayed because of its non-specific clinical features. A case of an immune-competent child who developed TA-GVHD is reported here. DNA profiling (short tandem repeat analysis), a technique that has a wide application in forensic medicine, was performed to detect the presence of donor cells in this patient. The findings suggest that more studies are needed with this tool, and the diagnostic potential of using other multiple biological specimens for DNA profiling such as the hair follicle and buccal swab should be evaluated. This is the first case report where the donor's DNA fingerprinting pattern was substantiated from a patient's hair follicle sample. Chimerism was also present in the blood and buccal swab specimens. PMID:25852093

  7. Circulating miRNA panel for prediction of acute graft-versus-host disease in lymphoma patients undergoing matched unrelated hematopoietic stem cell transplantation.

    PubMed

    Gimondi, Silvia; Dugo, Matteo; Vendramin, Antonio; Bermema, Anisa; Biancon, Giulia; Cavané, Alessandra; Corradini, Paolo; Carniti, Cristiana

    2016-07-01

    Acute graft-versus-host disease (aGVHD) results in significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Noninvasive diagnostic and prognostic tests for aGVHD are currently lacking, but would be beneficial in predicting aGVHD and improving the safety of allo-HSCT. Circulating microRNAs exhibit marked stability and may serve as biomarkers in several clinical settings. Here, we evaluated the use of circulating microRNAs as predictive biomarkers of aGVHD in lymphoma patients after allo-HSCT from matched unrelated donors (MUDs). After receiving informed consent, we prospectively collected plasma samples from 24 lymphoma patients before and after unmanipulated MUD allo-HSCT; microRNAs were then isolated. Fourteen patients developed aGVHD symptoms at a median of 48 days (range: 32-90) post-transplantation. Two patients developed intestinal GVHD, eight cutaneous GVHD, and four multiorgan GVHD. The microRNA expression profile was examined using quantitative real-time polymerase chain reaction (qRT-PCR). MicroRNAs 194 and 518f were significantly upregulated in aGVHD samples compared with samples taken from non-aGVHD patients. Remarkably, these upregulated microRNAs could be detected before the onset of aGVHD. Pathway prediction analysis indicated that these microRNAs may regulate critical pathways involved in aGVHD pathogenesis. Considering the noninvasive characteristics of plasma sampling and the feasibility of detecting miRNAs after allo-HSCT using real-time polymerase chain reaction, our results indicate that circulating microRNAs have the potential to enable an earlier aGVHD diagnosis and might assist in individualizing therapeutic strategies after MUD allo-HSCT. Nevertheless, standardization of blood sampling and analysis protocols is mandatory for the introduction of miRNA profiling into routine clinical use. PMID:27013207

  8. Investigator feedback about the 2005 NIH diagnostic and scoring criteria for chronic GVHD.

    PubMed

    Inamoto, Y; Jagasia, M; Wood, W A; Pidala, J; Palmer, J; Khera, N; Weisdorf, D; Carpenter, P A; Flowers, M E D; Jacobsohn, D; Martin, P J; Lee, S J; Pavletic, S Z

    2014-04-01

    The 2005 National Institutes of Health (NIH) consensus criteria for chronic GVHD have set standards for reporting. Many questions, however, have arisen regarding their implementation and utilization. To identify perceived areas of controversy, we conducted an international survey on diagnosis and scoring of chronic GVHD. Agreement was observed for 50-83% of the 72 questions in 7 topic areas. There was agreement on the need for modifying criteria in six situations: two or more distinctive manifestations should be enough to diagnose chronic GVHD; symptoms that are not due to chronic GVHD should be scored differently; active disease and fixed deficits should be distinguished; a minimum threshold body surface area of hidebound skin involvement should be required for a skin score of 3; asymptomatic oral lichenoid changes should be considered a score 1; and lung biopsy should be unnecessary to diagnose chronic GVHD in a patient with bronchiolitis obliterans as the only manifestation. The survey also identified 26 points of controversy. Whenever possible, studies should be conducted to confirm the appropriateness of any revisions. In cases where data are not available, clarification of the NIH recommendations by consensus is necessary. This survey should inform future research in the field and revisions of the current consensus criteria. PMID:24464142

  9. Telomere shortening in enterocytes of patients with uncontrolled acute intestinal graft-versus-host disease.

    PubMed

    Hummel, Sebastian; Ventura Ferreira, Mónica S; Heudobler, Daniel; Huber, Elisabeth; Fahrenkamp, Dirk; Gremse, Felix; Schmid, Karin; Müller-Newen, Gerhard; Ziegler, Patrick; Jost, Edgar; Blasco, Maria A; Brümmendorf, Tim H; Holler, Ernst; Beier, Fabian

    2015-11-26

    Acute intestinal graft-versus-host disease (aGVHD) refractory to immunosuppressive treatment is a serious complication after allogenic hematopoietic stem cell transplantation (HSCT). The underlying mechanisms of refractory aGVHD of the gut are not fully understood. Although telomere length (TL) reflects the replicative history of a cell, critically short telomeres have been associated with replicative exhaustion and tissue failure. In this study, we demonstrate that enterocytes of patients with refractory intestinal aGVHD show significantly increased proliferation, which translates into significant and critical telomere attrition following HSCT as compared with unaffected patients undergoing HSCT. Calculated telomere loss in aGVHD patients is 190 bp/wk, thereby massively exceeding physiological steady-state TL shortening rates such as in lymphocytes (∼50 bp/y). Our data support the hypothesis that increased compensatory proliferation following continued tissue damage can result in massive telomere loss in enterocytes of aGVHD patients. The present study introduces aGVHD-triggered increased cellular turnover and telomere loss with subsequent replicative exhaustion as a mechanism for refractory gut GVHD that is compatible with the long-term clinical aspect of the disease and provides a basis for stem cell protective therapies in the treatment of aGVHD. PMID:26486788

  10. Development, preliminary usability and accuracy testing of the EBMT 'eGVHD App' to support GvHD assessment according to NIH criteria-a proof of concept.

    PubMed

    Schoemans, H; Goris, K; Durm, R V; Vanhoof, J; Wolff, D; Greinix, H; Pavletic, S; Lee, S J; Maertens, J; Geest, S D; Dobbels, F; Duarte, R F

    2016-08-01

    The EBMT Complications and Quality of Life Working Party has developed a computer-based algorithm, the 'eGVHD App', using a user-centered design process. Accuracy was tested using a quasi-experimental crossover design with four expert-reviewed case vignettes in a convenience sample of 28 clinical professionals. Perceived usefulness was evaluated by the technology acceptance model (TAM) and User satisfaction by the Post-Study System Usability Questionnaire (PSSUQ). User experience was positive, with a median of 6 TAM points (interquartile range: 1) and beneficial median total, and subscale PSSUQ scores. The initial standard practice assessment of the vignettes yielded 65% correct results for diagnosis and 45% for scoring. The 'eGVHD App' significantly increased diagnostic and scoring accuracy to 93% (+28%) and 88% (+43%), respectively (both P<0.05). The same trend was observed in the repeated analysis of case 2: accuracy improved by using the App (+31% for diagnosis and +39% for scoring), whereas performance tended to decrease once the App was taken away. The 'eGVHD App' could dramatically improve the quality of care and research as it increased the performance of the whole user group by about 30% at the first assessment and showed a trend for improvement of individual performance on repeated case evaluation. PMID:27042834

  11. Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans

    PubMed Central

    Flynn, Ryan; Du, Jing; Veenstra, Rachelle G.; Reichenbach, Dawn K.; Panoskaltsis-Mortari, Angela; Taylor, Patricia A.; Freeman, Gordon J.; Serody, Jonathan S.; Murphy, William J.; Munn, David H.; Sarantopoulos, Stefanie; Luznik, Leo; Maillard, Ivan; Koreth, John; Cutler, Corey; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome; Dubovsky, Jason A.; Byrd, John C.; MacDonald, Kelli P.; Hill, Geoff R.; Blazar, Bruce R.

    2014-01-01

    Chronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Having shown that germinal center (GC) formation and immunoglobulin deposition are required for multiorgan system cGVHD and associated bronchiolitis obliterans syndrome (BOS) in a murine model, we hypothesized that T follicular helper (Tfh) cells are necessary for cGVHD by supporting GC formation and maintenance. We show that increased frequency of Tfh cells correlated with increased GC B cells, cGVHD, and BOS. Although administering a highly depletionary anti-CD20 monoclonal antibody (mAb) to mice with established cGVHD resulted in peripheral B-cell depletion, B cells remained in the lung, and BOS was not reversed. BOS could be treated by eliminating production of interleukin-21 (IL-21) by donor T cells or IL-21 receptor (IL-21R) signaling of donor B cells. Development of BOS was dependent upon T cells expressing the chemokine receptor CXCR5 to facilitate T-cell trafficking to secondary lymphoid organ follicles. Blocking mAbs for IL-21/IL-21R, inducible T-cell costimulator (ICOS)/ICOS ligand, and CD40L/CD40 hindered GC formation and cGVHD. These data provide novel insights into cGVHD pathogenesis, indicate a role for Tfh cells in these processes, and suggest a new line of therapy using mAbs targeting Tfh cells to reverse cGVHD. PMID:24820310

  12. Clinical guidelines for gynecologic care after hematopoietic SCT. Report from the international consensus project on clinical practice in chronic GVHD.

    PubMed

    Frey Tirri, B; Häusermann, P; Bertz, H; Greinix, H; Lawitschka, A; Schwarze, C-P; Wolff, D; Halter, J P; Dörfler, D; Moffat, R

    2015-01-01

    Despite similarities relevant age- and gender-specific issues exist in the care of patients after allogeneic hematopoietic SCT (HSCT). Female genital chronic GVHD (cGVHD) has been markedly underreported in the past but has a significant impact on the patients' health and quality of life. Data on prevention and treatment of this complication are still limited. Here we present a comprehensive review summarizing the current knowledge, which was discussed during several meetings of the German, Austrian and Swiss Consensus Project on clinical practice in cGVHD. In this report, we provide recommendations for post-transplant gynecological care of cGVHD manifestations agreed upon by all participants. This includes guidelines for diagnosis, prevention, and therapeutic options and topical treatments in female patients with genital cGVHD and hormonal replacement treatment of premature ovarian failure for adult and pediatric patients and underlines the necessity for regular gynecological care and screening programs for women after HSCT. PMID:25347009

  13. Macrochimerism in intestinal transplantation: association with lower rejection rates and multivisceral transplants, without GVHD

    PubMed Central

    Zuber, Julien; Rosen, Sarah; Shonts, Brittany; Sprangers, Ben; Savage, Thomas M.; Richman, Sarah; Yang, Suxiao; Lau, Sai Ping; DeWolf, Susan; Farber, Donna; Vlad, George; Zorn, Emmanuel; Wong, Waichi; Emond, Jean; Levin, Bruce; Martinez, Mercedes; Kato, Tomoaki; Sykes, Megan

    2015-01-01

    Blood chimerism has been reported sporadically among visceral transplant recipients, mostly in association with graft-vs-host disease (GVHD). We hypothesized that a higher degree of mixed chimerism would be observed in multivisceral (MVTx) than in isolated intestinal (iITx) and isolated liver transplant (iLTx) recipients, regardless of GVHD. We performed a longitudinal prospective study investigating multilineage blood chimerism with flow cytometry in 5 iITx and 4 MVTx recipients up to one year post-transplant. Although only one iITx patient experienced GVHD, T-cell mixed chimerism was detected in 8 out of 9 iITx/MVTx recipients. Chimerism was significantly lower in the four subjects who displayed early moderate to severe rejection. Pre-formed high titer donor-specific antibodies, bound in vivo to the circulating donor cells, were associated with an accelerated decline in chimerism. Blood chimerism was also studied in 10 iLTx controls. Among non-sensitized patients, MVTx recipients exhibited greater T and B-cell chimerism than either iITx and iLTx recipients. Myeloid lineage chimerism was present exclusively among iLTx and MVTx (6/13) recipients, suggesting that its presence required the hepatic allograft. Our study demonstrates, for the first time, frequent T cell chimerism without GVHD following visceral transplantation and a possible relationship with reduced rejection rate in MVTx recipients. PMID:25988811

  14. Macrochimerism in Intestinal Transplantation: Association With Lower Rejection Rates and Multivisceral Transplants, Without GVHD.

    PubMed

    Zuber, J; Rosen, S; Shonts, B; Sprangers, B; Savage, T M; Richman, S; Yang, S; Lau, S P; DeWolf, S; Farber, D; Vlad, G; Zorn, E; Wong, W; Emond, J; Levin, B; Martinez, M; Kato, T; Sykes, M

    2015-10-01

    Blood chimerism has been reported sporadically among visceral transplant recipients, mostly in association with graft-vs-host disease (GVHD). We hypothesized that a higher degree of mixed chimerism would be observed in multivisceral (MVTx) than in isolated intestinal (iITx) and isolated liver transplant (iLTx) recipients, regardless of GVHD. We performed a longitudinal prospective study investigating multilineage blood chimerism with flow cytometry in 5 iITx and 4 MVTx recipients up to one year posttransplant. Although only one iITx patient experienced GVHD, T cell mixed chimerism was detected in 8 out of 9 iITx/MVTx recipients. Chimerism was significantly lower in the four subjects who displayed early moderate to severe rejection. Pre-formed high-titer donor-specific antibodies, bound in vivo to the circulating donor cells, were associated with an accelerated decline in chimerism. Blood chimerism was also studied in 10 iLTx controls. Among nonsensitized patients, MVTx recipients exhibited greater T and B cell chimerism than either iITx or iLTx recipients. Myeloid lineage chimerism was present exclusively among iLTx and MVTx (6/13) recipients, suggesting that its presence required the hepatic allograft. Our study demonstrates, for the first time, frequent T cell chimerism without GVHD following visceral transplantation and a possible relationship with reduced rejection rate in MVTx recipients. PMID:25988811

  15. Dichotomous regulation of GVHD through bidirectional functions of the BTLA-HVEM pathway

    PubMed Central

    Sakoda, Yukimi; Park, Jang-June; Zhao, Yuming; Kuramasu, Atsuo; Geng, Degui; Liu, Yingjia; Davila, Eduardo

    2011-01-01

    B and T lymphocyte attenuator (BTLA) is a coinhibitory receptor that interacts with herpesvirus entry mediator (HVEM), and this interaction regulates pathogenesis in various immunologic diseases. In graft-versus-host disease (GVHD), BTLA unexpectedly mediates positive effects on donor T-cell survival, whereas immunologic mechanisms of this function have yet to be explored. In this study, we elucidated a role of BTLA in GVHD by applying the newly established agonistic anti-BTLA monoclonal antibody that stimulates BTLA signal without antagonizing BTLA-HVEM interaction. Our results revealed that provision of BTLA signal inhibited donor antihost T-cell responses and ameliorated GVHD with a successful engraftment of donor hematopoietic cells. These effects were dependent on BTLA signal into donor T cells but neither donor non-T cells nor recipient cells. On the other hand, expression of BTLA mutant lacking an intracellular signaling domain restored impaired survival of BTLA-deficient T cells, suggesting that BTLA also serves as a ligand that delivers HVEM prosurvival signal in donor T cells. Collectively, current study elucidated dichotomous functions of BTLA in GVHD to serve as a costimulatory ligand of HVEM and to transmit inhibitory signal as a receptor. PMID:21220749

  16. Fecal calprotectin and α1-antitrypsin dynamics in gastrointestinal GvHD.

    PubMed

    O'Meara, A; Kapel, N; Xhaard, A; Sicre de Fontbrune, F; Manéné, D; Dhedin, N; de Latour, R P; Socié, G; Robin, M

    2015-08-01

    In a previous study, the fecal biomarkers calprotectin and α1-antitrypsin (α1-AT) at symptom onset were reported to be significantly associated with the response to steroids in gastrointestinal GvHD (GI-GvHD). The purpose of this trial was to evaluate the dynamics of the fecal biomarkers calprotectin and α1-AT throughout the course of GvHD. Patients who were refractory to steroids had initially higher biomarker levels and in the course of GvHD demonstrated a continuous increase in fecal biomarkers. In contrast, the dynamics of calprotectin and α1-AT demonstrated low and decreasing levels in cortico-sensitive GvHD. In steroid-refractory patients who received a second line of treatment, the biomarker levels at the beginning of second-line treatment did not predict the subsequent response. Nevertheless, calprotectin levels progressively decreased in subsequent responders, whereas non-responders demonstrated continuously high levels of calprotectin. α1-AT values correlated to a lesser extent with the response to second-line treatment and remained elevated in both non-responders and responders. In conclusion, calprotectin monitoring can be of use in the management of immunosuppressive treatment in GI-GvHD. PMID:25961766

  17. GVHD after haploidentical transplantation: a novel, MHC-defined rhesus macaque model identifies CD28− CD8+ T cells as a reservoir of breakthrough T-cell proliferation during costimulation blockade and sirolimus-based immunosuppression

    PubMed Central

    Miller, Weston P.; Srinivasan, Swetha; Panoskaltsis-Mortari, Angela; Singh, Karnail; Sen, Sharon; Hamby, Kelly; Deane, Taylor; Stempora, Linda; Beus, Jonathan; Turner, Alexa; Wheeler, Caleb; Anderson, Daniel C.; Sharma, Prachi; Garcia, Anapatricia; Strobert, Elizabeth; Elder, Eric; Crocker, Ian; Crenshaw, Timothy; Penedo, M. Cecilia T.; Ward, Thea; Song, Mingqing; Horan, John; Larsen, Christian P.; Blazar, Bruce R.

    2010-01-01

    We have developed a major histocompatibility complex–defined primate model of graft-versus-host disease (GVHD) and have determined the effect that CD28/CD40-directed costimulation blockade and sirolimus have on this disease. Severe GVHD developed after haploidentical transplantation without prophylaxis, characterized by rapid clinical decline and widespread T-cell infiltration and organ damage. Mechanistic analysis showed activation and possible counter-regulation, with rapid T-cell expansion and accumulation of CD8+ and CD4+ granzyme B+ effector cells and FoxP3pos/CD27high/CD25pos/CD127low CD4+ T cells. CD8+ cells down-regulated CD127 and BCl-2 and up-regulated Ki-67, consistent with a highly activated, proliferative profile. A cytokine storm also occurred, with GVHD-specific secretion of interleukin-1 receptor antagonist (IL-1Ra), IL-18, and CCL4. Costimulation Blockade and Sirolimus (CoBS) resulted in striking protection against GVHD. At the 30-day primary endpoint, CoBS-treated recipients showed 100% survival compared with no survival in untreated recipients. CoBS treatment resulted in survival, increasing from 11.6 to 62 days (P < .01) with blunting of T-cell expansion and activation. Some CoBS-treated animals did eventually develop GVHD, with both clinical and histopathologic evidence of smoldering disease. The reservoir of CoBS-resistant breakthrough immune activation included secretion of interferon-γ, IL-2, monocyte chemotactic protein-1, and IL-12/IL-23 and proliferation of cytotoxic T-lymphocyte–associated antigen 4 immunoglobulin-resistant CD28− CD8+ T cells, suggesting adjuvant treatments targeting this subpopulation will be needed for full disease control. PMID:20833977

  18. Impact of extracorporeal photopheresis on skin scores and quality of life in patients with steroid-refractory chronic GVHD.

    PubMed

    Dignan, F L; Aguilar, S; Scarisbrick, J J; Shaw, B E; Potter, M N; Cavenagh, J; Apperley, J F; Fielding, A K; Pagliuca, A; Raj, K; Marks, D I; Peniket, A; Crawley, C; Koh, M B; Child, F J

    2014-05-01

    There are few prospective studies evaluating the role of extracorporeal photopheresis (ECP) in chronic GVHD (cGVHD) and only occasional reports of the effect of ECP on patients' quality of life (QoL). We report a single-centre prospective study of patients undergoing fortnightly ECP for moderate or severe cGVHD. Response was assessed after 6 months of treatment using NIH scoring criteria and reduction in immunosuppression. QoL assessments were undertaken at baseline and at 6 months using the chronic GVHD symptom scale (cGVHD SS) and dermatology life quality index (DLQI). An intention-to-treat analysis showed that 19/38 (50%) of patients had a complete or partial response. Twenty-seven out of 38 patients completed 6 months of ECP treatment and 70% (19/27) had a complete or partial response. Eighty per cent of patients who completed 6 months of ECP treatment had a reduction in immunosuppression dose. A subset of patients completed QoL questionnaires. Seventeen out of 18 patients (94%) showed an improvement in scores. The mean cGVHD SS and mean DLQI score were both significantly lower after 6 months of ECP (22 compared with 36, P=0.012 and 3.4 compared with 6.9, P=0.009, respectively). This study confirms that ECP can lead to objective clinical responses and, in addition, may lead to an improvement in QoL in cGVHD. PMID:24566709

  19. Endothelial-cell injury in cutaneous acute graft-versus-host disease.

    PubMed Central

    Dumler, J. S.; Beschorner, W. E.; Farmer, E. R.; Di Gennaro, K. A.; Saral, R.; Santos, G. W.

    1989-01-01

    The presence of an erythematous skin rash and hemorrhagic complications in acute graft-versus-host disease (GVHD) suggest that the vasculature may be involved in the immunopathologic process. We reviewed endothelial and vascular histopathologic changes on light microscopy and on immunoperoxidase stained sections of skin biopsies obtained from 41 HLA-identical allogeneic marrow transplant recipients with at least grade 2 GVHD. Biopsies taken from 14 allogeneic HLA-identical bone marrow transplant recipients who never developed GVHD were used as controls. Sections were evaluated for evidence of immunologic vascular injury using the rank file analysis of histologic features, expression of HLA-DR antigen, and the distribution of fibrin and factor VIII-related antigen (F VIII RAg). Patients with acute GVHD had significantly greater intimal lymphocytic infiltrates, perivascular nuclear dust deposition, perivascular F VIII Rag extravasation and deposition and vascular proliferation than controls. We find significantly greater endothelial injury in GVHD patients, which may represent primary immunologic injury to the vasculature. The clinical findings in acute GVHD probably result from cumulative endothelial as well as epithelial injury. Images Figure 1 Figure 2 Figure 3 PMID:2596572

  20. Bone Marrow GvHD after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Szyska, Martin; Na, Il-Kang

    2016-01-01

    The bone marrow is the origin of all hematopoietic lineages and an important homing site for memory cells of the adaptive immune system. It has recently emerged as a graft-versus-host disease (GvHD) target organ after allogeneic stem cell transplantation (alloHSCT), marked by depletion of both hematopoietic progenitors and niche-forming cells. Serious effects on the restoration of hematopoietic function and immunological memory are common, especially in patients after myeloablative conditioning therapy. Cytopenia and durable immunodeficiency caused by the depletion of hematopoietic progenitors and destruction of bone marrow niches negatively influence the outcome of alloHSCT. The complex balance between immunosuppressive and cell-depleting treatments, GvHD and immune reconstitution, as well as the desirable graft-versus-tumor (GvT) effect remains a great challenge for clinicians. PMID:27066008

  1. Bone Marrow GvHD after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Szyska, Martin; Na, Il-Kang

    2016-01-01

    The bone marrow is the origin of all hematopoietic lineages and an important homing site for memory cells of the adaptive immune system. It has recently emerged as a graft-versus-host disease (GvHD) target organ after allogeneic stem cell transplantation (alloHSCT), marked by depletion of both hematopoietic progenitors and niche-forming cells. Serious effects on the restoration of hematopoietic function and immunological memory are common, especially in patients after myeloablative conditioning therapy. Cytopenia and durable immunodeficiency caused by the depletion of hematopoietic progenitors and destruction of bone marrow niches negatively influence the outcome of alloHSCT. The complex balance between immunosuppressive and cell-depleting treatments, GvHD and immune reconstitution, as well as the desirable graft-versus-tumor (GvT) effect remains a great challenge for clinicians. PMID:27066008

  2. Different immune reconstitution in multiple myeloma, chronic myeloid leukemia and acute myeloid leukemia patients after allogeneic transplantation of peripheral blood stem cells.

    PubMed

    Rondelli, D; Re, F; Bandini, G; Raspadori, D; Arpinati, M; Senese, B; Stanzani, M; Bonifazi, F; Falcioni, S; Chirumbolo, G; Tura, S

    2000-12-01

    In this study we compared the lymphocyte reconstitution in 13 multiple myeloma (MM), nine acute myeloid leukemia (AML) and 10 chronic myeloid leukemia (CML) patients after allogeneic G-CSF-mobilized PBSC transplantation from HLA-identical siblings. Conditioning regimens included standard total body irradiation + cyclophosphamide (CY), or busulphan + CY, whereas VP-16 was added in patients with advanced disease. Overall comparable numbers of mononuclear cells, CD34+ cells and CD3+ T cells were infused in each group. A significantly higher CD3+ T cell number was observed in MM and AML than in CML patients 1 month after transplant. However, MM patients showed a faster and better recovery of CD4+ T cells than both AML and CML patients at 3 months (P = 0.01 and P = 0.01, respectively) and 12 months (P = 0.01 vs AML, while P = NS vs CML) after transplant, and had a CD4:CD8 ratio > 1 with a median CD4+ T cell value > 400/microl 1 year after transplant. Development of acute graft-versus-host disease (GVHD) did not affect CD4:CD8 ratios but patients who experienced acute GVHD > grade I had lower CD4+ and CD8+ T cell numbers at all time points. However, after excluding patients with GVHD > grade I, MM patients still showed a significantly higher CD4+ T cell value than patients with myeloproliferative diseases 1 year after transplant. These findings suggest that although allogeneic PBSC transplantation induces rapid immune reconstitution, different kinetics may occur among patients with hematological malignancies. In particular, the rapid reconstitution of CD4+ T cells in MM patients may contribute to the low transplant-related mortality achieved in this disease. PMID:11223973

  3. Programming of donor T cells using allogeneic δ-like ligand 4-positive dendritic cells to reduce GVHD in mice.

    PubMed

    Mochizuki, Kazuhiro; Meng, Lijun; Mochizuki, Izumi; Tong, Qing; He, Shan; Liu, Yongnian; Purushe, Janaki; Fung, Henry; Zaidi, M Raza; Zhang, Yanyun; Reshef, Ran; Blazar, Bruce R; Yagita, Hideo; Mineishi, Shin; Zhang, Yi

    2016-06-23

    Alloreactive T cells play a critical role in eliminating hematopoietic malignant cells but are also the mediators of graft-versus-host disease (GVHD), a major complication that subverts the success of allogeneic hematopoietic stem cell transplantation (HSCT). However, induction of alloreactive T cells does not necessarily lead to GVHD. Here we report the development of a cellular programming approach to render alloreactive T cells incapable of causing severe GVHD in both major histocompatibility complex (MHC)-mismatched and MHC-identical but minor histocompatibility antigen-mismatched mouse models. We established a novel platform that produced δ-like ligand 4-positive dendritic cells (Dll4(hi)DCs) from murine bone marrow using Flt3 ligand and Toll-like receptor agonists. Upon allogeneic Dll4(hi)DC stimulation, CD4(+) naïve T cells underwent effector differentiation and produced high levels of interferon γ (IFN-γ) and interleukin-17 in vitro, depending on Dll4 activation of Notch signaling. Following transfer, allogeneic Dll4(hi)DC-induced T cells were unable to mediate severe GVHD but preserved antileukemic activity, significantly improving the survival of leukemic mice undergoing allogeneic HSCT. This effect of Dll4(hi)DC-induced T cells was associated with their impaired expansion in GVHD target tissues. IFN-γ was important for Dll4(hi)DC programming to reduce GVHD toxicities of alloreactive T cells. Absence of T-cell IFN-γ led to improved survival and expansion of Dll4(hi)DC-induced CD4(+) T cells in transplant recipients and caused lethal GVHD. Our findings demonstrate that Dll4(hi)DC programming can overcome GVHD toxicity of donor T cells and produce leukemia-reactive T cells for effective immunotherapy. PMID:27143255

  4. Validation of the National Institutes of Health chronic GVHD Oral Mucosal Score using component-specific measures

    PubMed Central

    Bassim, CW; Fassil, H; Mays, JW; Edwards, D; Baird, K; Steinberg, SM; Williams, KM; Cowen, EW; Mitchell, SA; Cole, K; Taylor, T; Avila, D; Zhang, D; Pulanic, D; Grkovic, L; Fowler, D; Gress, RE; Pavletic, SZ

    2016-01-01

    Oral chronic GVHD (cGVHD) is a common, late complication of alloSCT that is associated with significant patient morbidity. The NIH Oral Mucosal Score (NIH OMS) was developed to assess oral cGVHD therapeutic response, but has not been fully validated. This study’s purpose was to conduct a rigorous construct validity and internal consistency analysis of this score and its components (erythema, lichenoid, ulcers, mucoceles) using established measures of oral pain, oral function, oral-related quality-of-life, nutrition and laboratory parameters in 198 patients with cGVHD. The construct validity of the NIH OMS was supported: a moderate correlation was observed between NIH OMS and mouth pain (rho =0.43), while a weaker correlation was observed with low albumin (rho = −0.26). Total NIH OMS, erythema and lichenoid components were associated with malnutrition, oral pain and impaired oral QOL, while ulcers were only associated with oral pain. No associations were found between mucoceles and any indicator evaluated, including salivary function or xerostomia. Kappa determined between scale components was low overall (all ≤0.35), supporting a conclusion that each component measures a distinct manifestation of oral cGVHD. This study supports the use of the NIH OMS and its components (erythema, lichenoid and ulcerations) to measure clinician-reported severity of oral cGVHD. PMID:23995099

  5. NIH response criteria measures are associated with important parameters of disease severity in patients with chronic GVHD.

    PubMed

    Curtis, L M; Grkovic, L; Mitchell, S A; Steinberg, S M; Cowen, E W; Datiles, M B; Mays, J; Bassim, C; Joe, G; Comis, L E; Berger, A; Avila, D; Taylor, T; Pulanic, D; Cole, K; Baruffaldi, J; Fowler, D H; Gress, R E; Pavletic, S Z

    2014-12-01

    Lack of standardized criteria measuring therapeutic response remains an obstacle to the development of better treatments for chronic GVHD (cGVHD). This cross-sectional prospective study examined the concurrent and predictive validity of 18 clinician-reported ('Form A') and 8 patient-reported ('Form B') response measures proposed by NIH criteria. Concurrent parameters of interest were NIH global score, cGVHD activity, Lee symptom score and SF36 PCS. Patient cohort included 193 adults with moderate-to-severe cGVHD. Measures associated with the highest number of outcomes were lung function score (LFS), 2-min walk, grip strength, 4-point health-care provider (HCP) and patient global scores, 11-point clinician- and patient-reported global symptom severity scores, and Karnofsky performance score (KPS). Measures associated with survival in univariate analyses led to a Cox model containing skin erythema, LFS, KPS, eosinophil count and interval from cGVHD diagnosis to enrollment as jointly associated with survival. In conclusion, 4-point HCP and patient global scores and 11-point clinician- and patient-reported global symptom severity scores are associated with the majority of concurrent outcomes. Skin erythema is a potentially reversible sign of cGVHD that is associated with survival. These results define a subset of measures that should be prioritized for evaluation in future studies. PMID:25153693

  6. In vitro–differentiated TH17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations

    PubMed Central

    Carlson, Michael J.; West, Michelle L.; Coghill, James M.; Panoskaltsis-Mortari, Angela; Blazar, Bruce R.

    2009-01-01

    The morbidity and mortality associated with graft-host-disease (GVHD) is a significant obstacle to the greater use of allogeneic stem cell transplantation. Donor T cells that predominantly differentiate into TH1/Tc1 T cells and generate pro-inflammatory cytokines such as interferon-γ (IFN-γ) mediate GVHD. Although numerous studies have described a pathogenic role for IFN-γ, multiple reports have demonstrated that the lack of IFN-γ paradoxically exacerbated GVHD lethality. This has led to speculation that another subset of T cells may significantly contribute to GVHD mortality. Several groups have demonstrated a new lineage of CD4+ T helper cell development distinct from TH1 or TH2 differentiation. This lineage is characterized by production of interleukin (IL)–17A, IL-17F, IL-22, and IL-21 and has been termed TH17 cells. Here, we demonstrate that a highly purified population of TH17 cells is capable of inducing lethal GVHD, hallmarked by extensive pathologic cutaneous and pulmonary lesions. Upon transfer, these cells migrate to and expand in GVHD target organs and secondary lymphoid tissues. Finally, we demonstrate differential roles for tumor necrosis factor-α (TNF-α) and IL-17A in the clinical manifestations of GVHD induced by TH17 cells. Our studies demonstrate that cells other than TH1/Tc1 can mediate acute GVHD. PMID:18957685

  7. Narrow-Band Ultraviolet B Phototherapy Ameliorates Acute Graft-Versus-Host Disease of the Intestine by Expansion of Regulatory T Cells

    PubMed Central

    Iyama, Satoshi; Yoshida, Masahiro; Ibata, Soushi; Tatekoshi, Ayumi; Kamihara, Yusuke; Horiguchi, Hiroto; Murase, Kazuyuki; Kawano, Yutaka; Takada, Kohichi; Miyanishi, Koji; Kobune, Masayoshi; Ichimiya, Shingo; Kato, Junji

    2016-01-01

    Narrowband ultraviolet B (NB-UVB) has been widely used in dermatological phototherapy. As for the application of NB-UVB phototherapy to graft-versus-host disease (GVHD), we previously reported that it was highly efficacious for cutaneous lesions of acute GVHD (aGVHD) and that expansion of regulatory T (Treg) cells induced by NB-UVB might be one of the mechanisms. In order to examine whether NB-UVB irradiation through expansion of Treg cells is effective for the treatment of not only cutaneous aGVHD but also aGVHD of inner organs such as the intestine or liver, we conducted experiments in which a murine lethal aGVHD model, characterized by severe involvement of the intestine, was irradiated with NB-UVB. We found that NB-UVB irradiation improved the clinical score and survival rate. The pathological score of aGVHD was improved in all affected organs: intestine, liver, and skin. In the serum of mice irradiated with NB-UVB, the levels of Treg cells-associated cytokines such as transforming growth factor beta (TGFβ) and interleukin-10 (IL-10) were elevated. The numbers of infiltrating Treg cells in inflamed tissue of the intestine and those in spleen were increased in mice treated with NB-UVB. This is the first report demonstrating that NB-UVB phototherapy has the ability to ameliorate intestinal aGVHD through the expansion of Treg cells. PMID:27031239

  8. Conjunctival polyploid cells and donor-derived myofibroblasts in ocular GvHD.

    PubMed

    Hallberg, D; Stenberg, K; Hanson, C; Stenevi, U; Brune, M

    2016-05-01

    After allogeneic hematopoietic stem cell transplantation (allo-SCT), ocular GvHD is a common complication, typical symptoms being dry eye syndrome with features of fibrosis. In this study, we have identified and quantified two cell types-myofibroblasts (MFB) and polyploid (PP) cells-in the conjunctival surface of allo-SCT patients (pts) and have explored their kinetics and association with local and systemic GvHD. Results are compared with control groups of (a) pretransplant samples from allo-SCT patients, (b) recipients of autologous transplantation (auto-SCT) and (c) healthy controls. Imprint cytologies were obtained by pressing the conjunctival surface with a sterile, non-abrasive cellulose acetate filter (Millipore). After retraction, typically a monolayer of the outermost cells of the epithelium were retrieved. MFB were identified by immunofluorescent (IF) staining for alpha-smooth muscle protein. PP cells were detected by aberrant chromosome content analyzed via X/Y-FISH (X/Y fluorescence in situ hybridization). In female pts with a male donor (MF group), donor genotype were identified by sex chromosome detection using FISH methodology. IF and FISH methods were applied in situ on the same filter, and amounts of MFB and PP cells are expressed as the percentage of all cells on the filter. In all, 70 samples from 46 pts were obtained 1-122 months after allo-SCT. The total MFB density (MFB(TOT)) was higher in allo-SCT pts compared with healthy individuals and auto-SCT pts and increased by time after transplantation (P<0.001). In MF recipients, this increase proved to be due to a significant (P<0.001) and gradual elevation of donor-derived MFB (MFB(XY)), whereas recipient-derived MFB (MFB(XX)) did not vary over time. Clinical ocular GvHD correlated with MFB(XY)/MFB(TOT) ratio (P=0.034), whereas no association between MFB(TOT) or MFB(XY) systemic GvHD was observed. In the MF group (n=25), both MFB(XY) and MFB(XX) were detected on 28 of the 37 imprints (76

  9. Acute graft-versus-host disease: Are we close to bringing the bench to the bedside?

    PubMed Central

    Sung, Anthony D.; Chao, Nelson J.

    2013-01-01

    Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplant (AHSCT) associated with significant morbidity and mortality. This review focuses on the pathophysiology, prevention, and treatment of acute GVHD. Specifically, we explain how new discoveries in immunology have expanded our understanding of GVHD, in which tissue damage from chemotherapy or radiation results in cytokine release, activating T cells, resulting in proliferation and differentiation, trafficking to target organs, and tissue destruction and inflammation. Insights into the mechanisms of this disease relate directly to the development of preventive strategies and therapies, such as immunosuppression, calcineurin inhibitors, T-cell depletion, CCR5 antagonists, gut decontamination, extracorporeal photopheresis, and more. Understanding the immunobiology of GVHD and developing effective preventions and treatments are critical to the continuing success of AHSCT. PMID:24309532

  10. Pharmacologic Blockade of JAK1/JAK2 Reduces GvHD and Preserves the Graft-Versus-Leukemia Effect

    PubMed Central

    Choi, Jaebok; Cooper, Matthew L.; Alahmari, Bader; Ritchey, Julie; Collins, Lynne; Holt, Matthew; DiPersio, John F.

    2014-01-01

    We have recently reported that interferon gamma receptor deficient (IFNγR−/−) allogeneic donor T cells result in significantly less graft-versus-host disease (GvHD) than wild-type (WT) T cells, while maintaining an anti-leukemia or graft-versus-leukemia (GvL) effect after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We demonstrated that IFNγR signaling regulates alloreactive T cell trafficking to GvHD target organs through expression of the chemokine receptor CXCR3 in alloreactive T cells. Since IFNγR signaling is mediated via JAK1/JAK2, we tested the effect of JAK1/JAK2 inhibition on GvHD. While we demonstrated that pharmacologic blockade of JAK1/JAK2 in WT T cells using the JAK1/JAK2 inhibitor, INCB018424 (Ruxolitinib), resulted in a similar effect to IFNγR−/− T cells both in vitro (reduction of CXCR3 expression in T cells) and in vivo (mitigation of GvHD after allo-HSCT), it remains to be determined if in vivo administration of INCB018424 will result in preservation of GvL while reducing GvHD. Here, we report that INCB018424 reduces GvHD and preserves the beneficial GvL effect in two different murine MHC-mismatched allo-HSCT models and using two different murine leukemia models (lymphoid leukemia and myeloid leukemia). In addition, prolonged administration of INCB018424 further improves survival after allo-HSCT and is superior to other JAK1/JAK2 inhibitors, such as TG101348 or AZD1480. These data suggest that pharmacologic inhibition of JAK1/JAK2 might be a promising therapeutic approach to achieve the beneficial anti-leukemia effect and overcome HLA-barriers in allo-HSCT. It might also be exploited in other diseases besides GvHD, such as organ transplant rejection, chronic inflammatory diseases and autoimmune diseases. PMID:25289677

  11. Pharmacologic blockade of JAK1/JAK2 reduces GvHD and preserves the graft-versus-leukemia effect.

    PubMed

    Choi, Jaebok; Cooper, Matthew L; Alahmari, Bader; Ritchey, Julie; Collins, Lynne; Holt, Matthew; DiPersio, John F

    2014-01-01

    We have recently reported that interferon gamma receptor deficient (IFNγR-/-) allogeneic donor T cells result in significantly less graft-versus-host disease (GvHD) than wild-type (WT) T cells, while maintaining an anti-leukemia or graft-versus-leukemia (GvL) effect after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We demonstrated that IFNγR signaling regulates alloreactive T cell trafficking to GvHD target organs through expression of the chemokine receptor CXCR3 in alloreactive T cells. Since IFNγR signaling is mediated via JAK1/JAK2, we tested the effect of JAK1/JAK2 inhibition on GvHD. While we demonstrated that pharmacologic blockade of JAK1/JAK2 in WT T cells using the JAK1/JAK2 inhibitor, INCB018424 (Ruxolitinib), resulted in a similar effect to IFNγR-/- T cells both in vitro (reduction of CXCR3 expression in T cells) and in vivo (mitigation of GvHD after allo-HSCT), it remains to be determined if in vivo administration of INCB018424 will result in preservation of GvL while reducing GvHD. Here, we report that INCB018424 reduces GvHD and preserves the beneficial GvL effect in two different murine MHC-mismatched allo-HSCT models and using two different murine leukemia models (lymphoid leukemia and myeloid leukemia). In addition, prolonged administration of INCB018424 further improves survival after allo-HSCT and is superior to other JAK1/JAK2 inhibitors, such as TG101348 or AZD1480. These data suggest that pharmacologic inhibition of JAK1/JAK2 might be a promising therapeutic approach to achieve the beneficial anti-leukemia effect and overcome HLA-barriers in allo-HSCT. It might also be exploited in other diseases besides GvHD, such as organ transplant rejection, chronic inflammatory diseases and autoimmune diseases. PMID:25289677

  12. Tac, Mini-MTX, MMF Versus Tac, MTX for GVHD Prevention

    ClinicalTrials.gov

    2016-06-06

    Chronic Myelogenous Leukemia; Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Acute Biphenotypic Leukemia; Myelodysplastic Syndrome; Myeloproliferative Neoplasm; Non-Hodgkin Lymphoma; Hodgkins Disease; Chronic Lymphocytic Leukemia; Multiple Myeloma

  13. Sibling versus Unrelated Donor Allogeneic Hematopoietic Cell Transplantation for CML: Refined HLA-matching shows more GVHD but not less relapse

    PubMed Central

    Weisdorf, Daniel J.; Nelson, Gene; Lee, Stephanie J; Haagenson, Michael; Spellman, Stephen; Antin, Joseph H; Bolwell, Brian; Cahn, Jean-Yves; Cervantes, Francisco; Copelan, Edward; Gale, Robert; Gratwohl, Alois; Khoury, H. Jean; McCarthy, Philip; Marks, David I; Szer, Jeff; Woolfrey, Ann; Cortes-Franco, Jorge; Horowitz, Mary M; Arora, Mukta

    2010-01-01

    Purpose Unrelated donor (URD) hematopoietic cell transplantation (HCT) can eradicate chronic myelogenous leukemia (CML). It has been postulated that greater donor:recipient-histoincompatibility can augment the graft vs. leukemia (GvL) effect. We previously reported similar, but not equivalent outcomes of URD vs. sibling donor HCT for CML using an older, less precise classification of HLA-matching. Methods Our recently refined HLA-matching classification, suitable for interpretation when complete allele-level typing is unavailable was used to reanalyze outcomes of previous HCT for CML. Results We observed that new matching criteria identifies substantially more frequent mismatch than older, less precise “6 of 6 antigen” matched URD-HCT. Only 37% of those previously called “HLA-matched” were HLA-well-matched in new classification and 44% were partially-matched. The refined matching classification confirmed that partially matched or mismatched URD:recipient pairs have significantly greater risks of graft failure compared to either sibling or well-matched URD-HCT. Acute and chronic GVHD are significantly more frequent with all levels of recategorized URD HLA-matching. Importantly, survival and leukemia-free survival remain significantly worse following URD-HCT at any matching level. No augmented GvL effect accompanied URD HLA-mismatch. Compared to sibling donor transplants, we observed marginally increased, but not significantly different risks of relapse in either well-matched, partially-matched or mismatched URD-HCT. Conclusions These data confirm the utility of our revised HLA-matching schema as applicable for analysis of retrospective data sets when fully informative, allele level-typing is unavailable. In this analysis, greater histoincompatibility can augment GVHD but does not improve protection against relapse thus the best donor is still the most closely matched. PMID:19822308

  14. The Role of Animal Models in the Study of Hematopoietic Stem Cell Transplantation and GvHD: A Historical Overview

    PubMed Central

    Boieri, Margherita; Shah, Pranali; Dressel, Ralf; Inngjerdingen, Marit

    2016-01-01

    Bone marrow transplantation (BMT) is the only therapeutic option for many hematological malignancies, but its applicability is limited by life-threatening complications, such as graft-versus-host disease (GvHD). The last decades have seen great advances in the understanding of BMT and its related complications; in particular GvHD. Animal models are beneficial to study complex diseases, as they allow dissecting the contribution of single components in the development of the disease. Most of the current knowledge on the therapeutic mechanisms of BMT derives from studies in animal models. Parallel to BMT, the understanding of the pathophysiology of GvHD, as well as the development of new treatment regimens, has also been supported by studies in animal models. Pre-clinical experimentation is the basis for deep understanding and successful improvements of clinical applications. In this review, we retrace the history of BMT and GvHD by describing how the studies in animal models have paved the way to the many advances in the field. We also describe how animal models contributed to the understanding of GvHD pathophysiology and how they are fundamental for the discovery of new treatments. PMID:27625651

  15. The Role of Animal Models in the Study of Hematopoietic Stem Cell Transplantation and GvHD: A Historical Overview.

    PubMed

    Boieri, Margherita; Shah, Pranali; Dressel, Ralf; Inngjerdingen, Marit

    2016-01-01

    Bone marrow transplantation (BMT) is the only therapeutic option for many hematological malignancies, but its applicability is limited by life-threatening complications, such as graft-versus-host disease (GvHD). The last decades have seen great advances in the understanding of BMT and its related complications; in particular GvHD. Animal models are beneficial to study complex diseases, as they allow dissecting the contribution of single components in the development of the disease. Most of the current knowledge on the therapeutic mechanisms of BMT derives from studies in animal models. Parallel to BMT, the understanding of the pathophysiology of GvHD, as well as the development of new treatment regimens, has also been supported by studies in animal models. Pre-clinical experimentation is the basis for deep understanding and successful improvements of clinical applications. In this review, we retrace the history of BMT and GvHD by describing how the studies in animal models have paved the way to the many advances in the field. We also describe how animal models contributed to the understanding of GvHD pathophysiology and how they are fundamental for the discovery of new treatments. PMID:27625651

  16. Treatment of graft-versus-host disease with naturally occurring T regulatory cells.

    PubMed

    Trzonkowski, Piotr; Dukat-Mazurek, Anna; Bieniaszewska, Maria; Marek-Trzonkowska, Natalia; Dobyszuk, Anita; Juścińska, Jolanta; Dutka, Magdalena; Myśliwska, Jolanta; Hellmann, Andrzej

    2013-12-01

    A significant body of evidence suggests that treatment with naturally occurring CD4(+)CD25(+) T regulatory cells (Tregs) is an appropriate therapy for graft-versus-host disease (GvHD). GvHD is a major complication of bone marrow transplantation in which the transplanted immune system recognizes recipient tissues as a non-self and destroys them. In many cases, this condition significantly deteriorates the quality of life of the affected patients. It is also one of the most important causes of death after bone marrow transplantation. Tregs constitute a population responsible for dominant tolerance to self-tissues in the immune system. These cells prevent autoimmune and allergic reactions and decrease the risk of rejection of allotransplants. For these reasons, Tregs are considered as a cellular drug in GvHD. The results of the first clinical trials with these cells are already available. In this review we present important experimental facts which led to the clinical use of Tregs. We then critically evaluate specific requirements for Treg therapy in GvHD and therapies with Tregs currently under clinical investigation, including our experience and future perspectives on this kind of cellular treatment. PMID:23813436

  17. An association between human leucocyte antigen alleles and acute and chronic graft-versus-host disease after allogeneic haematopoietic stem cell transplantation.

    PubMed

    Remberger, Mats; Persson, Ulla; Hauzenberger, Dan; Ringdén, Olle

    2002-12-01

    The association between various human leucocyte antigen (HLA) alleles and the occurrence of acute and chronic graft-versus-host disease (GVHD) was evaluated in 493 haematopoietic stem-cell transplant (HSCT) patients with HLA identical sibling donors. There were 307 men and 186 women with a median age of 30 years (0.2-77). Most of the patients had a haematological malignancy and received total body irradiation or busulphan combined with cyclophosphamide as conditioning before transplantation. GVHD prophylaxis consisted of monotherapy with methotrexate (MTX) or cyclosporin (CsA) in 118 patients, MTX + CsA in 323, T-cell depletion in 28 and other combinations in 24. In total, 84 patients (17%) received a peripheral blood stem-cell graft, whereas the rest received bone marrow. The cumulative incidence of acute GVHD grades II-IV was 20%, and chronic GVHD 46%. In the multivariate analysis, HLA-A10 (OR 2.14, CI 1.04-4.41, P = 0.03) and HLA-B7 (OR 1.80, CI 1.04-3.12, P = 0.03) correlated with an increased risk of acute GVHD grades II-IV. We also found an association between HLA-B27 (RR 0.60, CI 0.37-0.95, P = 0.04) and a lower incidence of chronic GVHD. These HLA alleles were independent of other known risk factors for acute or chronic GVHD, as shown by multivariate analysis. These results show that major histocompatibility comlex (MHC) alleles may influence the incidence of GVHD in HSCT with HLA identical sibling donors. PMID:12437654

  18. Risk Factors for Acute Graft-Versus-Host Disease After Human Leukocyte Antigen–Identical Sibling Transplants for Adults With Leukemia

    PubMed Central

    Hahn, Theresa; McCarthy, Philip L.; Zhang, Mei-Jie; Wang, Dan; Arora, Mukta; Frangoul, Haydar; Gale, Robert Peter; Hale, Gregory A.; Horan, John; Isola, Luis; Maziarz, Richard T.; van Rood, Jon J.; Gupta, Vikas; Halter, Joerg; Reddy, Vijay; Tiberghien, Pierre; Litzow, Mark; Anasetti, Claudio; Pavletic, Stephen; Ringdén, Olle

    2008-01-01

    Purpose Acute graft-versus-host disease (GVHD) causes substantial morbidity and mortality after human leukocyte antigen (HLA)-identical sibling transplants. No large registry studies of acute GVHD risk factors have been reported in two decades. Risk factors may have changed in this interval as transplant-related techniques have evolved. Patients and Methods Acute GVHD risk factors were analyzed in 1,960 adults after HLA-identical sibling myeloablative transplant for acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), or chronic myeloid leukemia (CML) reported by 226 centers worldwide to the Center for International Blood and Marrow Transplant Research from 1995 to 2002. Outcome was measured as time from transplant to onset of grade 2 to 4 acute GVHD, with death without acute GVHD as a competing risk. Results Cumulative incidence of grade 2 to 4 acute GVHD was 35% (95% CI, 33% to 37%). In multivariable analyses, factors significantly associated with grade 2 to 4 acute GVHD were cyclophosphamide + total-body irradiation versus busulfan + cyclophosphamide (relative risk [RR] = 1.4; P < .0001), blood cell versus bone marrow grafts in patients age 18 to 39 years (RR = 1.43; P = .0023), recipient age 40 and older versus age 18 to 39 years receiving bone marrow grafts (RR = 1.44; P = .0005), CML versus AML/ALL (RR = 1.35; P = .0003), white/Black versus Asian/Hispanic race (RR = 1.54; P = .0003), Karnofsky performance score less than 90 versus 90 to 100 (RR = 1.27; P = .014), and recipient/donor cytomegalovirus-seronegative versus either positive (RR = 1.20; P = .04). Stratification by disease showed the same significant predictors of grade 2 to 4 acute GVHD for CML; however, KPS and cytomegalovirus serostatus were not significant predictors for AML/ALL. Conclusion This analysis confirmed several previously reported risk factors for grade 2 to 4 acute GVHD. However, several new factors were identified whereas others are no longer significant. These new data may

  19. Tocilizumab for steroid refractory acute graft-versus-host disease

    PubMed Central

    Roddy, Julianna V. F.; Haverkos, Bradley M.; McBride, Ali; Leininger, Kathryn M.; Jaglowski, Samantha; Penza, Sam; Klisovic, Rebecca; Blum, William; Vasu, Sumithira; Hofmeister, Craig C.; Benson, Don M.; Andritsos, Leslie A.; Devine, Steven M.; Efebera, Yvonne A.

    2015-01-01

    Acute graft-versus-host-disease (aGVHD) is a frequent and often lethal complication of allogeneic hematopoietic stem cell transplant despite prophylaxis. Tocilizumab is a humanized anti-IL-6 receptor monoclonal antibody that has evidence of activity in patients with steroid refractory (SR) GVHD. We retrospectively report on nine patients with grade 3 or 4 SR aGVHD who received tocilizumab. Eight mg/kg of tocilizumab was administered intravenously every 3–4 weeks. aGVHD grading and responses were based on consensus criteria. Median age at transplant was 48 years. Five patients had alternate donor sources. Median time from aGVHD onset to tocilizumab administration was 44 days. Two patients had complete responses and two had partial responses. Median survival from start of tocilizumab was 26 days (range 13–1054). Our limited experience demonstrated an overall response rate of 44% (CR + PR); however, this response was not durable. Further studies are needed to determine the optimal time for tocilizumab initiation. PMID:26140610

  20. Missing KIR ligands are associated with less relapse and increased graft-versus-host disease (GVHD) following unrelated donor allogeneic HCT

    PubMed Central

    Cooley, Sarah; Parham, Peter; Farag, Sherif S.; Verneris, Michael R.; McQueen, Karina L.; Guethlein, Lisbeth A.; Trachtenberg, Elizabeth A.; Haagenson, Michael; Horowitz, Mary M.; Klein, John P.; Weisdorf, Daniel J.

    2007-01-01

    Natural killer (NK) cells can alter the outcome of hematopoietic cell transplantation (HCT) if donor alloreactivity targets the recipient. Since most NK cells express inhibitory killer-immunoglobulin receptors (KIRs), we hypothesized that the susceptibility of recipient cells to donor NK cell–mediated lysis is genetically predetermined by the absence of known KIR ligands. We analyzed data from 2062 patients undergoing unrelated donor HCT for acute myeloid leukemia (AML; n = 556), chronic myeloid leukemia (CML; n = 1224), and myelodysplastic syndrome (MDS; n = 282). Missing 1 or more KIR ligands versus the presence of all ligands protected against relapse in patients with early myeloid leukemia (relative risk [RR] = 0.54; n = 536, 95% confidence interval [CI] 0.30-0.95, P = .03). In the subset of CML patients that received a transplant beyond 1 year from diagnosis (n = 479), missing a KIR ligand independently predicted a greater risk of developing grade 3-4 acute graft-versus-host disease (GVHD; RR = 1.58, 95% CI 1.13-2.22; P = .008). These data support a genetically determined role for NK cells following unrelated HCT in myeloid leukemia. PMID:17317850

  1. Circulating Levels of Adipokines Predict the Occurrence of Acute Graft-versus-host Disease

    PubMed Central

    Kim, Jin Sook; You, Da-Bin; Lim, Ji-Young; Lee, Sung-Eun; Kim, Yoo-Jin; Kim, Hee-Je; Min, Chang-Ki

    2015-01-01

    Currently, detecting biochemical differences before and after allogeneic stem cell transplantation (SCT) for improved prediction of acute graft-versus-host disease (aGVHD) is a major clinical challenge. In this pilot study, we analyzed the kinetics of circulating adipokine levels in patients with or without aGVHD before and after allogeneic SCT. Serum samples were obtained and stored at -80℃ within 3 hours after collection, prior to conditioning and at engraftment after transplantation. A protein array system was used to measure the levels of 7 adipokines of patients with aGVHD (n=20) and without aGVHD (n=20). The resistin level at engraftment was significantly increased (p<0.001) after transplantation, regardless of aGVHD occurrence. In the non-aGVHD group, the concentrations of the hepatocyte growth factor (HGF) (mean values±SD; 206.6±34.3 vs. 432.3±108.9 pg/ml, p=0.040) and angiopoietin-2 (ANG-2) (mean values±SD; 3,197.2±328.3 vs. 4,471.8±568.4 pg/ml, p=0.037) at engraftment were significantly higher than those of the pre-transplant period, whereas in the aGVHD group, the levels of adipokines did not change after transplantation. Our study suggests that changes in serum HGF and ANG-2 levels could be considered helpful markers for the subsequent occurrence of aGVHD. PMID:25922595

  2. Modified Extracorporeal Photopheresis with Cells from a Healthy Donor for Acute Graft-versus-Host Disease in a Mouse Model

    PubMed Central

    Budde, Holger; Kolb, Susanne; Salinas Tejedor, Laura; Wulf, Gerald; Reichardt, Holger M.; Riggert, Joachim; Legler, Tobias J.

    2014-01-01

    Background Graft-versus-host disease (GvHD) is a major challenge after hematopoietic stem cell transplantation but treatment options for patients are still limited. In many cases first-line treatment with glucocorticoids is not successful. Among second-line therapies the extracorporeal photopheresis (ECP) is frequently performed, due to induction of selective tolerance instead of general immunosuppression. However, for some patients with severe acute GvHD the leukapheresis step of the ECP procedure is physically exhausting and limits the number of ECP cycles. Methods We hypothesized that leukocytes from healthy cell donors could be used as a replacement for ECP leukocytes gained from the GvHD patient. For this purpose we used a well established mouse model of acute GvHD. The ECP therapy was based on cells with the genetic background of the initial donor of the stem cell transplantation. As a precondition we developed a protocol representing conventional ECP in mice equivalent to clinical used ECP setup. Results We could demonstrate that conventional, clinically derived ECP setup is able to alleviate acute GvHD. By using leukocytes obtained from healthy mice with the bone marrow donor’s genetic background we could not observe a statistically significant therapeutic effect. Conclusions Conventional human ECP setup is effective in the mouse model of severe acute GvHD. In addition we could not prove that ECP cells from healthy mice with bone marrow donor’s genetic background are as effective as ECP cells derived from GvHD mice. Based on our findings, new questions arise for further studies, in which the cellular characteristics for ECP mediated immune tolerance are a matter of investigation. PMID:25148404

  3. Haploidentical hematopoietic stem cell transplantation without total body irradiation for pediatric acute leukemia: a single-center experience

    PubMed Central

    Mu, Yanshun; Qin, Maoquan; Wang, Bin; Li, Sidan; Zhu, Guanghua; Zhou, Xuan; Yang, Jun; Wang, Kai; Lin, Wei; Zheng, Huyong

    2016-01-01

    Hematopoietic stem cell transplantation (HSCT) is a promising method for therapy of pediatric patients with acute leukemia. However, less availability of matched donors limited its wide application. Recently, haploidentical HSCT has become a great resource. Here, we have retrospectively reported our experience of 20 pediatric patients with acute leukemia who underwent haploidentical HSCT without total body irradiation (TBI) myeloablative regimen in our center from November 2007 to June 2014. All the patients attained successful HSCT engraftment in terms of myeloid and platelet recovery. Thirteen patients developed grade I–IV acute graft-versus-host disease (a-GVHD). The incidence of grade I–II a-GVHD, grade III–IV a-GVHD, and chronic GVHD (c-GVHD) was 45%, 20%, and 25%, respectively. The mean myeloid and platelet recovery time was 13.20±2.41 and 19.10±8.37 days. The median follow-up time was 43.95±29.26 months. During the follow-up, three patients died. The overall survival (OS) rate was 85%. The present study indicated that haploidentical HSCT without TBI myeloablative regimen significantly improved the OS rate of pediatric patients with acute leukemia. PMID:27217774

  4. Pretransplant β2-Microglobulin Is Associated with the Risk of Acute Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplant.

    PubMed

    Costa-Lima, Carolina; Miranda, Eliana Cristina Martins; Colella, Marcos Paulo; Aranha, Francisco Jose Penteado; de Souza, Carmino Antonio; Vigorito, Afonso Celso; De Paula, Erich Vinicius

    2016-07-01

    The risk of acute graft-versus-host disease (aGVHD) can be reliably estimated by the hematopoietic cell transplantation-specific comorbidity index (HCT-CI), which can be further refined by the incorporation of pre-hematopoietic cell transplantation (HCT) serum levels of inflammatory biomarkers such as ferritin and albumin. β2-Microglobulin (β2-m) is a key component of the MHC class I complex, which is independently associated with mortality and frailty in the general population. We took advantage of our institutional protocol that includes measurement of pre-HCT β2-m serum levels in the most patients to investigate whether pre-transplant β2-m levels were associated with the risk of aGVHD. One hundred three consecutive patients submitted to allogeneic HCT, of which 26 developed grades II to IV aGVHD, were included in the analysis. β2-m was significantly associated with age and HCT-CI. Higher levels of β2-m were observed in patients who developed aGVHD (P = .008). In the multivariate Cox regression model, β2-m and HCT-CI remained independently associated with the risk of developing aGVHD. In conclusion, the association between β2-m and the occurrence of aGVHD suggests that the measurement of this protein before HCT might represent an additional element for risk stratification of aGVHD. PMID:27044906

  5. Viral PCR positivity in stool before allogeneic hematopoietic cell transplantation is strongly associated with acute intestinal graft-versus-host disease.

    PubMed

    van Montfrans, Joris; Schulz, Laura; Versluys, Birgitta; de Wildt, Arianne; Wolfs, Tom; Bierings, Marc; Gerhardt, Corinne; Lindemans, Caroline; Wensing, Anne; Boelens, Jaap Jan

    2015-04-01

    Acute graft-versus-host disease (aGVHD) can be triggered by inflammatory conditions, including infections and mucositis. We investigated the association between PCR positivity for gastrointestinal (GI) viruses in stool before hematopoietic cell transplantation (HCT) and intestinal aGVHD using Cox proportional hazard models. We included 48 consecutive HCT patients (28 with malignancies and 20 with nonmalignancies) without GI symptoms before HCT. Fifteen patients were GI virus positive: 9 adenovirus, 3 norovirus, 2 parechovirus, and 1 astrovirus. Overall survival was 58% ± 8%. The cumulative incidence of aGVHD grade 2 to 4 was 43% ± 8% (n = 18) after a median of 47 days (range, 14 to 140). In univariate analysis, GI virus PCR positivity was the only predictor for aGVHD (P = .008): within the group of GI virus PCR-positive patients, the cumulative incidence of aGVHD 2 to 4 was 70% ± 12% versus 29 ± 8% in the PCR-negative group (P = .004). In conclusion, GI virus PCR positivity before HCT predicted development of intestinal aGVHD. These results may ultimately affect monitoring, aGVHD prophylaxis, and treatment, as well as rescheduling of elective HCTs. PMID:25598276

  6. Low Dose IL-2, Hematopoietic Stem Cell Transplantation, IL2 for GVHD

    ClinicalTrials.gov

    2016-01-11

    Acute Lymphoblastic Leukemia; ALL; Acute Myelogenous Leukemia; AML; Chronic Myelogenous Leukemia; Myelodysplastic Syndrome; Myeloproliferative Disorder; Hodgkin Lymphoma; Non-Hodgkin Lymphoma; Non-malignant Diseases Requiring Allogeneic HSCT

  7. Immunological reconstitution and correlation of circulating serum inflammatory mediators/cytokines with the incidence of acute graft-versus-host disease during the first 100 days following unrelated umbilical cord blood transplantation.

    PubMed

    Abu-Ghosh, A; Goldman, S; Slone, V; van de Ven, C; Suen, Y; Murphy, L; Sender, L; Cairo, M

    1999-09-01

    We investigated early immunological reconstitution and the production of circulating inflammatory mediators and their relationship to aGVHD in children during the first 100 days following unrelated UCBT. Nine patients had an underlying malignant disease (ALL, ANLL), and two, non-malignant diseases (SAA, ALD). The median age was 10 years (range: 1.25-21). Seven of 11 patients were alive by day 100, two died from regimen-related toxicity, and two died from severe aGVHD (grade >/=III). Myeloid engraftment (ANC >/=500/mm3 x 2 days) occurred at a median of 24 days (range: 14-55), while platelet engraftment (platelet count >/=20 000/mm3 untransfused x 7 days) was delayed and occurred at a median of 52 days (range: 33-95). The mean cell dose of CD34+ cells was 3.3 +/- 3.51 x 10(5)/kg, and of CD34+/CD41+ cells was 3.94 +/- 3.99 x 10(4)/kg. Acute GVHD (grade II-IV) developed in seven patients (77%), and severe aGVHD (grade III-IV) developed in five patients (55%). Serum levels of IL-2Ralpha, IL-2, IL-4, IL-7, IL-12, and IFNgamma were not significantly different between patients with grades 0-I aGVHD and patients with grades II-IV aGVHD. Evaluation of immunological reconstitution on day 90 post UCBT demonstrated an early recovery of the absolute numbers of B cells (CD19+) and NK cells (CD3-/CD56+). Immunoglobulin levels for IgG, IgM and IgA remained normal throughout the study period. PMN functional studies demonstrated normal superoxide generation, bacterial killing (BK), and chemotaxis (CTX). However, both helper (CD3+/CD4+) and suppressor (CD3+/CD8+) T cell subsets remained low during the first 100 days post UCBT with mean +/- s.e.m. values of 120 +/- 29/mm3 and 10 +/- 50/mm3, respectively (normal = 900-2860/mm3 (CD3/CD4), normal = 630-1910/mm3 (CD3/CD8)). Mitogen response studies showed low blastogenesis to PHA and PWM, with a mean c.p.m. +/- s.e.m. value of 1.7 +/- 0.67 x 10(4) for PHA (NL >/= 75 x 10(3)) and 8.42 +/- 4.1 x 10(3) for PWM (NL >/=25 x 10(3)). In

  8. Quality of Life in the Chronic GVHD Consortium Cohort: Lessons Learned and the Long Road Ahead.

    PubMed

    Krupski, Christa; Jagasia, Madan

    2015-09-01

    Patient-reported outcomes are receiving increased attention as the search for successful treatment agents of chronic graft versus host disease continues. There is currently an ongoing multicenter, prospective cohort study lead by the Chronic GVHD Consortium of patients with chronic graft versus host disease. This paper summarizes published findings to date reporting factors impacting quality of life, symptom burden, and physical functioning in this cohort. Middle age, versus younger or older age, is associated with worse quality of life, despite lower symptom burden. The presence of chronic graft versus host disease at study enrollment was associated with lower quality of life, and improvement in severity does not always change quality of life. Other factors negatively impacting quality of life include the presence of overlap syndrome, specific gastrointestinal and joint and fascia manifestations, and poorer functional status and exercise tolerance. Collecting valid and concise quality of life data is essential in developing treatment strategies for chronic graft versus host disease. PMID:26303672

  9. Post-transplant bendamustine reduces GvHD while preserving GvL in experimental haploidentical bone marrow transplantation.

    PubMed

    Stokes, Jessica; Hoffman, Emely A; Zeng, Yi; Larmonier, Nicolas; Katsanis, Emmanuel

    2016-07-01

    Advances in haploidentical bone marrow transplantation (h-BMT) have drastically broadened the treatment options for patients requiring BMT. The possibility of significantly reducing the complications resulting from graft-versus-host disease (GvHD) with the administration of post-transplant cyclophosphamide (PT-CY) has substantially improved the efficacy and applicability of T cell-replete h-BMT. However, higher frequency of disease recurrence remains a major challenge in h-BMT with PT-CY. There is a critical need to identify novel strategies to prevent GvHD while sparing the graft-versus-leukaemia (GvL) effect in h-BMT. To this end, we evaluated the impact of bendamustine (BEN), given post-transplant, on GvHD and GvL using clinically relevant murine h-BMT models. We provide results indicating that post-transplant bendamustine (PT-BEN) alleviates GvHD, significantly improving survival, while preserving engraftment and GvL effects. We further document that PT-BEN can mitigate GvHD even in the absence of Treg. Our results also indicate that PT-BEN is less myelosuppressive than PT-CY, significantly increasing the number and proportion of CD11b(+) Gr-1(hi) cells, while decreasing lymphoid cells. In vitro we observed that BEN enhances the suppressive function of myeloid-derived suppressor cells (MDSCs) while impairing the proliferation of T- and B-cells. These results advocate for the consideration of PT-BEN as a new therapeutic platform for clinical implementation in h-BMT. PMID:27030315

  10. Modulation of GvHD by suicide-gene transduced donor T lymphocytes: clinical applications in mismatched transplantation.

    PubMed

    Ciceri, F; Bonini, C; Gallo-Stampino, C; Bordignon, C

    2005-01-01

    In allogeneic hematopoietic cell transplantation (allo-HCT), donor lymphocytes play a central therapeutic role in both GvL and immune reconstitution. However, the full exploitation of these therapeutic properties is limited by the occurrence of GvHD. Different strategies have been investigated to obtain all the benefits derived from donor lymphocytes while avoiding the risk of GvHD. The genetic engineering of donor lymphocytes with the herpes simplex virus-thymidine kinase (HSV-TK) suicide gene confers the ability to modulate GvHD by invivo ganciclovir-induced elimination of the transduced cells. The suicide-gene strategy has applications in both donor lymphocyte infusion (DLI) for disease relapse and in add-back infusions after T-cell depleted allo-HCT. TK cell DLI resulted in anti-tumor activity in a relevant proportion of treated patients. Haplo-identical stem cell transplantation (haplo-HCT) is a promising therapeutic option for patients with high risk hematologic malignancies lacking an HLA-matched donor. However, the profound T-cell depletion required to overcome the risk of lethal GvHD has been associated with a marked delayed T-cell recovery with a prolonged risk of post-transplant viral, fungal and other opportunistic infections. TK cell add-backs efficiently promote early immune reconstitution after haplo-HCT and prevent disease relapse, providing a unique tool for the control of GvHD. The genetic manipulation of donor lymphocytes with a suicide gene is a promising strategy to increase feasibility and safety of allo-HCT. PMID:16040393

  11. Physical function and quality of life in patients with chronic GvHD: a summary of preclinical and clinical studies and a call for exercise intervention trials in patients.

    PubMed

    Fiuza-Luces, C; Simpson, R J; Ramírez, M; Lucia, A; Berger, N A

    2016-01-01

    Allogeneic hematopoietic stem cell transplant, to reconstitute the hematopoietic and immune status of patients undergoing myeloablative therapy for hematologic disorders, has been of great benefit in minimizing or eradicating disease and extending survival. Patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT) are subject to many comorbidities among which the most significant, affecting quality of life (QoL) and survival, are acute GvHD (aGvHD) and chronic GvHD (cGvHD), resulting from donor lymphocytes reacting to and damaging host tissues. Physical activity and exercise have clearly been shown, in both children and adults, to enhance fitness, improve symptomatology and QoL, reduce disease progression and extend survival for many diseases including malignancies. In some cases, vigorous exercise has been shown to be equal to or more effective than pharmacologic therapy. This review addresses how cGvHD affects patients' physical function and physical domain of QoL, and the potential benefits of exercise interventions along with recommendations for relevant research and evaluation targeted at incorporating this strategy as soon as possible after allo-HSCT and ideally, as soon as possible upon diagnosis of the condition leading to allo-HSCT. PMID:26367233

  12. Donor TLR9 gene tagSNPs influence susceptibility to aGVHD and CMV reactivation in the allo-HSCT setting without polymorphisms in the TLR4 and NOD2 genes.

    PubMed

    Xiao, H W; Luo, Y; Lai, X Y; Shi, J M; Tan, Y M; He, J S; Xie, W Z; Zheng, W Y; Ye, X J; Yu, X H; Cai, Z; Lin, M F; Huang, H

    2014-02-01

    Owing to ethnicity of the population, those best confirmed polymorphisms in the TLR (toll-like receptor)4 and NOD2 genes with significantly prognostic impact on allogeneic hematopoietic SCT (allo-HSCT) seem to be more applicable to Europeans and are nonpolymorphic in the Asian population. The influence of innate immunity gene polymorphisms on the outcomes of allo-HSCT in those populations has been questioned. We evaluated the influence of 10 candidate single nucleotide polymorphisms (SNPs) in the TLR1, TLR2, TLR3, TLR8 and TLR9 genes on the outcomes of allo-HSCT in a Chinese population including 138 pairs of patients and unrelated donors and a second cohort of 102 pairs of patients and HLA-identical sibling donors. We found that two tagSNPs in the TLR9 gene in the donor side, +1174 A/G (rs352139) and +1635 C/T (rs352140), influenced the risk of acute GVHD (aGVHD) and CMV reactivation. Furthermore, the presence of the susceptible haplotype (A-C) in donor may be an informative predicator of worse OS at 5 years compared with those with the G-C and G-T haplotypes (58% vs 82.9%, P=0.024). Our data suggested an unrecognized association between donor TLR9 tagSNPs and the risk of HSCT-related complications in a population without polymorphisms in the TLR4 and NOD2 genes. PMID:24121213

  13. High expression of heme oxygenase-1 in target organs may attenuate acute graft-versus-host disease through regulation of immune balance of TH17/Treg.

    PubMed

    Yu, Meisheng; Wang, Jishi; Fang, Qin; Liu, Ping; Chen, Shuya; Zhe, Nana; Lin, Xiaojing; Zhang, Yaming; Zhao, Jiangyuan; Zhou, Zhen

    2016-07-01

    The high incidence of acute graft-versus-host disease (aGVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Grades III and IV aGVHD are the leading causes of death in allo-HSCT recipients. Heme oxygenase-1(HO-1) has anti-inflammatory and immune-regulatory functions. In this study, we evaluated the none GVHD and grade I-IV patients samples which were collected at the first re-examination after successful allo-HSCT, we found that expressions of HO-1 mRNA in the bone marrow and peripheral blood mononuclear cells of allo-HSCT recipients who had subsequent non-GVHD and grade I aGVHD were significantly higher than those in patients with Grade III-IV aGVHD. We then demonstrated that enhanced expression of HO-1 in target organs by infusing HO-1-gene-modified Mesenchymal stem cells (MSCs) alleviated the clinical and histopathological severity of aGVHD in experimental mice. Flow cytometry revealed a higher expression of Treg cells and a lower expression of TH17 cells in splenic and lymph node tissues of mice with enhanced HO-1 expression, as compared to that in the aGVHD mice. This was further substantiated by lower expression levels of ROR-Υt and IL-17A mRNA, and higher levels of Foxp3 mRNA in the splenic tissue of mice with enhanced HO-1 expression. Our results indicate that high expression of HO-1 may reduce the severity of aGVHD by regulation of the TH17/Treg balance. PMID:27168057

  14. A diagnostic window for the treatment of acute graft-versus-host disease prior to visible clinical symptoms in a murine model

    PubMed Central

    2013-01-01

    Background Acute graft-versus-host disease (aGVHD) poses a major limitation for broader therapeutic application of allogeneic hematopoietic cell transplantation (allo-HCT). Early diagnosis of aGVHD remains difficult and is based on clinical symptoms and histopathological evaluation of tissue biopsies. Thus, current aGVHD diagnosis is limited to patients with established disease manifestation. Therefore, for improved disease prevention it is important to develop predictive assays to identify patients at risk of developing aGVHD. Here we address whether insights into the timing of the aGVHD initiation and effector phases could allow for the detection of migrating alloreactive T cells before clinical aGVHD onset to permit for efficient therapeutic intervention. Methods Murine major histocompatibility complex (MHC) mismatched and minor histocompatibility antigen (miHAg) mismatched allo-HCT models were employed to assess the spatiotemporal distribution of donor T cells with flow cytometry and in vivo bioluminescence imaging (BLI). Daily flow cytometry analysis of peripheral blood mononuclear cells allowed us to identify migrating alloreactive T cells based on homing receptor expression profiles. Results We identified a time period of 2 weeks of massive alloreactive donor T cell migration in the blood after miHAg mismatch allo-HCT before clinical aGVHD symptoms appeared. Alloreactive T cells upregulated α4β7 integrin and P-selectin ligand during this migration phase. Consequently, targeted preemptive treatment with rapamycin, starting at the earliest detection time of alloreactive donor T cells in the peripheral blood, prevented lethal aGVHD. Conclusions Based on this data we propose a critical time frame prior to the onset of aGVHD symptoms to identify alloreactive T cells in the peripheral blood for timely and effective therapeutic intervention. PMID:23692886

  15. Circulating Angiogenic Factors Associated with Response and Survival in Patients with Acute Graft-Versus-Host Disease: Results from BMT CTN 0302 and 0802

    PubMed Central

    Holtan, Shernan G.; Verneris, Michael R.; Schultz, Kirk R.; Newell, Laura F.; Meyers, Gabrielle; He, Fiona; DeFor, Todd E.; Vercellotti, Gregory M.; Slungaard, Arne; MacMillan, Margaret L.; Cooley, Sarah A.; Blazar, Bruce R.; Panoskaltsis-Mortari, Angela; Weisdorf, Daniel J.

    2015-01-01

    Circulating angiogenic factors (AF) reflect tissue healing capacity, although some AF can also contribute to inflammation and are indicative of endothelial dysfunction. The AF milieu in acute graft-versus-host disease (aGVHD) has not been broadly characterized. We hypothesized that patients with abundant AF involved in repair/regeneration vs. those mediating damage/inflammation would have improved outcomes. Circulating AF known predominantly for repair/regeneration (epidermal growth factor [EGF], fibroblast growth factor-1 and -2, heparin binding-EGF-like growth factor, vascular endothelial growth factor-A, -C, and -D) and for damage/inflammation (angiopoietin-2, endothelin-1, soluble endoglin [sEng], follistatin [FS], leptin, placental growth factor [PlGF]) were measured in a discovery set of HCT recipients with grade III/IV aGVHD versus controls, then validated in two aGVHD cohorts enrolled in Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trials 0302 (N=105, serum) and 0802 (N=158, plasma) versus controls without aGVHD (N=53, serum). Levels of EGF and VEGF-A were lower than controls at the onset of aGVHD in both trials and higher with complete response to first-line aGVHD therapy in CTN 0802. FS and PlGF were elevated in aGVHD measured in either serum or plasma. At day 28 after initial aGVHD therapy, elevated FS was an independent negative prognostic factor for survival in both cohorts (hazard ratio 9.3 in CTN 0302, 2.8 in CTN 0802). These data suggest that circulating AF are associated with clinical outcomes after aGVHD and thus may contribute to both pathogenesis and recovery. PMID:25759146

  16. Endothelial microparticles carrying hedgehog-interacting protein induce continuous endothelial damage in the pathogenesis of acute graft-versus-host disease.

    PubMed

    Nie, Di-Min; Wu, Qiu-Ling; Zheng, Peng; Chen, Ping; Zhang, Ran; Li, Bei-Bei; Fang, Jun; Xia, Ling-Hui; Hong, Mei

    2016-05-15

    Accumulating evidence suggests that endothelial microparticles (EMPs), a marker of endothelial damage, are elevated in acute graft-versus-host disease (aGVHD), and that endothelial damage is implicated in the pathogenesis of aGVHD, but the mechanisms remain elusive. In this study, we detected the plasma EMP levels and endothelial damage in patients and mice with aGVHD in vivo and then examined the effects of EMPs derived from injured endothelial cells (ECs) on endothelial damage and the role of hedgehog-interacting protein (HHIP) carried by EMPs in these effects in vitro. Our results showed that EMPs were persistently increased in the early posttransplantation phase in patients and mice with aGVHD. Meanwhile, endothelial damage was continuous in aGVHD mice, but was temporary in non-aGVHD mice after transplantation. In vitro, EMPs induced endothelial damage, including increased EC apoptosis, enhanced reactive oxygen species, decreased nitric oxide production and impaired angiogenic activity. Enhanced expression of HHIP, an antagonist for the Sonic hedgehog (SHH) signaling pathway, was observed in patients and mice with aGVHD and EMPs from injured ECs. The endothelial damage induced by EMPs was reversed when the HHIP incorporated into EMPs was silenced with an HHIP small interfering RNA or inhibited with the SHH pathway agonist, Smoothened agonist. This work supports a feasible vicious cycle in which EMPs generated during endothelial injury, in turn, aggravate endothelial damage by carrying HHIP into target ECs, contributing to the continuously deteriorating endothelial damage in the development of aGVHD. EMPs harboring HHIP would represent a potential therapeutic target for aGVHD. PMID:27009877

  17. Treatment of Acute Graft-versus-Host Disease in Childhood with Extracorporeal Photochemotherapy/Photopheresis: The Padova Experience.

    PubMed

    Calore, Elisabetta; Marson, Piero; Pillon, Marta; Tumino, Manuela; Tison, Tiziana; Mainardi, Chiara; De Silvestro, Giustina; Rossin, Sara; Franceschetto, Genny; Carraro, Elisa; Pescarin, Matilde; Varotto, Stefania; Destro, Roberta; Gazzola, Maria Vittoria; Basso, Giuseppe; Messina, Chiara

    2015-11-01

    Acute graft-versus-host disease (aGVHD) is the major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Systemic steroid treatment represents the first-line therapy for aGVHD and is associated with a response rate of 30% to 60%. Steroid-resistant patients have a poor prognosis with high transplantation-related mortality (TRM). Several second-line therapies have been proposed for the management of unresponsive aGVHD, without proven beneficial effects on patients' outcome or overall long-term survival. For these reasons, extracorporeal photochemotherapy/photopheresis (ECP), a cell-based approach to control GVHD that spares generalized immunosuppression, seems to be promising. In this study, we report the outcome of 72 consecutive pediatric patients treated with ECP between 1997 and 2013 for aGVHD. Among them, 21 patients had steroid-resistant aGVHD, 42 had steroid-dependent aGVHD, and 9 did not receive steroid as first-line therapy because of clinical contraindications. A complete response was obtained in 72% of patients, a partial response was observed in 11%, and there was no response in 17% of patients. At day +180, TRM was 4% in the whole cohort; TRM was 3% and 20% among responders and nonresponders to ECP, respectively (P < .0001). The 5-year overall survival was 71%, showing a difference between responders and nonresponders of 78% and 30%, respectively (P = .0004). The 5-year time to progression of primary disease was 81%, without any significant difference between the 2 groups. Moreover, the 5-year progression-free survival of primary disease was 72%, with a significant difference (P = .0007) between responders (79%) and nonresponders (30%) to ECP. In conclusion, this study demonstrates that ECP is highly effective in aGVHD without a negative impact on primary disease. PMID:26183078

  18. Serum microRNA181a: Correlates with the intracellular cytokine levels and a potential biomarker for acute graft-versus-host disease.

    PubMed

    Xie, Linna; Zhou, Fang; Liu, Ximin; Fang, Yuan; Yu, Zhe; Song, Ningxia; Kong, Fansheng

    2016-09-01

    The aim of this study was to investigate the clinical relevance of lymphocyte-related serum miRNAs to the pathogenesis of acute graft-versus-host disease (aGVHD) and evaluate the predictive and prognosis value of miRNAs. Consecutive patients who received allogeneic peripheral blood stem cell transplantation (allo-PBSCT) in General Hospital of Jinan Military District were enrolled. aGVHD patients were diagnosed and graded clinically, and divided into the training set and the testing set. Blood samples were collected, total RNA was isolated, and RT-PCR was performed for miRNA expression (miR-181a-3p, miR-214-3p and miR-326). Intracellular cytokines levels were assayed by flow cytometry, and the disease specificity assay of miRNAs for aGVHD was detected. A total of 120 patients were admitted. Serum level of miR-181a in aGVHD patients was highly increased and associated with the severity of aGVHD, but not miR-214 and miR-326. Levels of cytokines including IL-2, IL-22, and IL-17a were positively correlated with miR-181a level, while serum IL-13 level was negatively correlated with miR-181a level in aGVHD patients. Moreover, increased miR-181a level was not detected in patients with acute rejection after kidney transplantation or sepsis patients. MiR-181a level was sensitively and specifically increased, especially in severe aGVHD patients. MiR-181a may be a potential biomarker for the identification, diagnosis, and prognosis of aGVHD patients. PMID:27288630

  19. Allosuppressor- and allohelper-T cells in acute and chronic graft-vs. -host (GVH) disease. III. Different Lyt subsets of donor T cells induce different pathological syndromes

    SciTech Connect

    Rolink, A.G.; Gleichmann, E.

    1983-08-01

    Previous work from this laboratory has led to the hypothesis that the stimulatory pathological symptoms of chronic graft-vs.-host disease (GVHD) are caused by alloreactive donor T helper (TH) cells, whereas the suppressive pathological symptoms of acute GVHD are caused by alloreactive T suppressor (TS) cells of the donor. We analyzed the Lyt phenotypes of B10 donor T cells required for the induction of either acute or chronic GVHD in H-2-different (B10 X DBA/2)F1 recipients. When nonirradiated F1 mice were used as the recipients, we found unseparated B10 T cells induced only a moderate formation of systemic lupus erythematosus (SLE)-like autoantibodies, but a high percentage of lethal GVHD (LGVHD). In contrast, Lyt-1+2- donor T cells were unable to induce LGVHD in these recipients but were capable of inducing a vigorous formation of SLE-like autoantibodies and severe immune-complex glomerulonephritis. Lyt-1-2+ T cells were incapable of inducing either acute or chronic GVHD. The sensitivity and accuracy of the GVH system were increased by using irradiated F1 mice as recipients and then comparing donor-cell inocula that contained similar numbers of T lymphocytes. Donor-cell inocula were used that had been tested for their allohelper and allosuppressor effects on F1 B cells in vitro. In the irradiated F1 recipients unseparated donor T cells were superior to T cell subsets in inducing LGVHD. In contrast Lyt-1+2- T cells, but neither unseparated T cells nor Lyt-1-2+ T cells, were capable of inducing a vigorous formation of SLE-like auto-antibodies. We conclude that the stimulatory pathological symptoms of chronic GVHD are caused by Lyt-1+2- allohelper T cells. In contrast, the development of the suppressive pathological symptoms of acute GVHD appears to involve alloreactive Lyt-1+2+ T suppressor cells.

  20. Acute cerebellar ataxia

    MedlinePlus

    Cerebellar ataxia; Ataxia - acute cerebellar; Cerebellitis; Post-varicella acute cerebellar ataxia; PVACA ... Acute cerebellar ataxia in children, especially younger than age 3, may occur several weeks after an illness caused by a virus. ...

  1. Hematopoietic stem cell transplantation in children and young adults with secondary myelodysplastic syndrome and acute myelogenous leukemia after aplastic anemia.

    PubMed

    Yoshimi, Ayami; Strahm, Brigitte; Baumann, Irith; Furlan, Ingrid; Schwarz, Stephan; Teigler-Schlegel, Andrea; Walther, Joachim-Ulrich; Schlegelberger, Brigitte; Göhring, Gudrun; Nöllke, Peter; Führer, Monika; Niemeyer, Charlotte M

    2014-03-01

    Secondary myelodysplastic syndrome and acute myelogenous leukemia (sMDS/sAML) are the most serious secondary events occurring after immunosuppressive therapy in patients with aplastic anemia. Here we evaluate the outcome of hematopoietic stem cell transplantation (HSCT) in 17 children and young adults with sMDS/sAML after childhood aplastic anemia. The median interval between the diagnosis of aplastic anemia and the development of sMDS/sAML was 2.9 years (range, 1.2 to 13.0 years). At a median age of 13.1 years (range, 4.4 to 26.7 years), patients underwent HSCT with bone marrow (n = 6) or peripheral blood stem cell (n = 11) grafts from HLA-matched sibling donors (n = 2), mismatched family donors (n = 2), or unrelated donors (n = 13). Monosomy 7 was detected in 13 patients. The preparative regimen consisted of busulfan, cyclophosphamide, and melphalan in 11 patients and other agents in 6 patients. All patients achieved neutrophil engraftment. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and that of chronic GVHD was 70%. Relapse occurred in 1 patient. The major cause of death was transplant-related complication (n = 9). Overall survival and event-free survival at 5 years after HSCT were both 41%. In summary, this study indicates that HSCT is a curative therapy for some patients with sMDS/sAML after aplastic anemia. Future efforts should focus on reducing transplantation-related mortality. PMID:24316460

  2. Fludarabine and busulfan as a reduced-toxicity myeloablative conditioning regimen in allogeneic hematopoietic stem cell transplantation for acute leukemia patients

    PubMed Central

    DAI, ZHIMING; LIU, JIE; ZHANG, WANG-GANG; CAO, XINGMEI; ZHANG, YANG; DAI, ZHIJUN

    2016-01-01

    The optimal conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute leukemia remains undefined. We evaluated the outcomes in 30 patients with acute leukemia who underwent allo-HSCT from human leukocyte antigen-matched donors after conditioning with busulfan and fludarabine (BuFlu). The regimen comprised injection of busulfan 3.2 mg/kg daily on 4 consecutive days and fludarabine 30 mg/m2 daily for 4 doses. All 30 patients achieved hematopoiesis reconstitution with full donor chimerism confirmed by short tandem repeat DNA analysis. The most common regimen-related toxicity was mucositis (86.7%), followed by cytomegalovirus infection (80%). Serious regimen-related toxicities were rare. Acute graft vs. host disease (aGVHD) was detected in 46.7% of the patients; 33.4% had grade I–II aGVHD and 13.3% had grade III–IV aGVHD. Chronic GVHD (cGVHD) was noted in 20% of the patients. The overall survival and disease-free survival rates were 66.7 and 53%, respectively, with a median follow-up of 25 months for surviving patients. Therefore, BuFlu was an effective conditioning regimen with a low rate of transplant-related adverse effects and increased antileukemic effects in patients with acute leukemia undergoing allo-HSCT. PMID:27073687

  3. miR-146b antagomir-treated human Tregs acquire increased GVHD inhibitory potency.

    PubMed

    Lu, Yunjie; Hippen, Keli L; Lemire, Amanda L; Gu, Jian; Wang, Weizhi; Ni, Xuhao; Ranganathan, Parvathi; Levine, Bruce L; Riley, James L; June, Carl H; Turka, Laurence A; Munn, David H; Garzon, Ramiro; Lu, Ling; Blazar, Bruce R

    2016-09-01

    CD4(+)CD25(+)FoxP3(+) thymic-derived regulatory T cells (tTregs) are indispensable for maintaining immune system equilibrium. Adoptive transfer of tTregs is an effective means of suppressing graft-versus-host disease (GVHD) in murine models and in early human clinical trials. Tumor necrosis factor receptor-associated factor 6 (TRAF6), an ubiquitin-conjugating enzyme that mediates nuclear factor κB (NF-κB) activation, plays an essential role in modulating regulatory T cell survival and function. MicroRNAs (miRNAs) are noncoding RNAs, which mediate RNA silencing and posttranscriptional gene repression. By performing comprehensive TaqMan Low Density Array miRNA assays, we identified 10 miRNAs differentially regulated in human tTreg compared with control T cells. One candidate, miR-146b, is preferentially and highly expressed in human naive tTregs compared with naive CD4 T cells. miRNA prediction software revealed that TRAF6 was the one of the top 10 scored mRNAs involved tTreg function with the highest probability as a potential miR-146b target. Antagomir-mediated knockdown of miRNA-146b, but not another miRNA-146 family member (miRNA-146a), enhanced TRAF6 expression. TRAF6, in turn, increases NF-κB activation, which is essential for tTreg function as well as Foxp3 protein and antiapoptotic gene expression, and downregulates proapoptotic gene expression. miR-146b knockdown increased the nuclear localization and expression of genes regulated by NF-κB, which was associated with enhanced tTreg survival, proliferation, and suppressive function measured in vitro and in vivo. TRAF6 inhibition had the opposite effects. We conclude that an miR-146b-TRAF6-NF-κB-FoxP3 signaling pathway restrains regulatory T cell survival, proliferation, and suppressor function. In vitro exposure of human tTregs to miR-146b antagomirs can be exploited to improve the clinical efficacy of human adoptive tTreg transfer in a GVHD setting. PMID:27485827

  4. Prognostic factors for survival of patients with newly diagnosed chronic GVHD according to NIH criteria.

    PubMed

    Ayuk, Francis; Veit, Ronja; Zabelina, Tatjana; Bussmann, Lara; Christopeit, Maximilian; Alchalby, Haefaa; Wolschke, Christine; Lellek, Heinrich; Bacher, Ulrike; Zander, Axel R; Kröger, Nicolaus

    2015-10-01

    Chronic graft versus host disease (cGvHD) is the most common cause of late morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). We retrospectively evaluated the impact of NIH classification on outcome of patients at our center. Primary endpoint was overall survival at 5 years. Two hundred one patients with cGVHD according to NIH were included. Platelets <100,000/μl on day of diagnosis of cGvHD (HR 2.97, 95 % CI 1.7-5.3, p < 0.001), female donor (HR 1.78, 95 % CI 1.0-3.2, p = 0.05), and reduced intensity conditioning (HR 1.95, 95 % CI 1.0-3.8, p = 0.05) impacted overall survival. Non-relapse mortality (NRM) was higher for patients with low vs. high platelets: 26 % (95 % CI 14-40) vs. 6 % (95 % CI 2-10), p < 0.001, and tended to be higher for female vs. male donor: 14 % (95 % CI 7-23) vs. 7 % (95 % CI 3-13), p = 0.08. Relapse tended to be higher for recipients of reduced intensity conditioning (RIC) vs. myeloablative conditioning (MAC): 33 % (95 % CI 23-43) vs. 20 % (95 % CI 10-31), p = 0.06. After excluding patients with myeloma and lymphoma, IgG serum levels at diagnosis of cGvHD of 122 patients were correlated with survival. IgG levels above normal were associated with worse 2-year overall survival (OS), p = 0.04, compared to normal or low IgG levels. Platelet count at diagnosis remains the most valid prognostic factor for survival of patients with cGvHD even in the era of NIH grading. High IgG level at diagnosis of cGVHD represents a potential negative prognostic parameter that deserves further investigation. PMID:26204824

  5. Blocking TWEAK-Fn14 interaction inhibits hematopoietic stem cell transplantation-induced intestinal cell death and reduces GVHD.

    PubMed

    Chopra, Martin; Brandl, Andreas; Siegmund, Daniela; Mottok, Anja; Schäfer, Viktoria; Biehl, Marlene; Kraus, Sabrina; Bäuerlein, Carina A; Ritz, Miriam; Mattenheimer, Katharina; Schwinn, Stefanie; Seher, Axel; Grabinger, Thomas; Einsele, Hermann; Rosenwald, Andreas; Brunner, Thomas; Beilhack, Andreas; Wajant, Harald

    2015-07-23

    Inhibition of the tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) system reduces intestinal cell death and disease development in several models of colitis. In view of the crucial role of TNF and intestinal cell death in graft-versus-host disease (GVHD) and the ability of TWEAK to enhance TNF-induced cell death, we tested here the therapeutic potential of Fn14 blockade on allogeneic hematopoietic cell transplantation (allo-HCT)-induced intestinal GVHD. An Fn14-specific blocking human immunoglobulin G1 antibody variant with compromised antibody-dependent cellular cytotoxicity (ADCC) activity strongly inhibited the severity of murine allo-HCT-induced GVHD. Treatment of the allo-HCT recipients with this monoclonal antibody reduced cell death of gastrointestinal cells but neither affected organ infiltration by donor T cells nor cytokine production. Fn14 blockade also inhibited intestinal cell death in mice challenged with TNF. This suggests that the protective effect of Fn14 blockade in allo-HCT is based on the protection of intestinal cells from TNF-induced apoptosis and not due to immune suppression. Importantly, Fn14 blockade showed no negative effect on graft-versus-leukemia/lymphoma (GVL) activity. Thus, ADCC-defective Fn14-blocking antibodies are not only possible novel GVL effect-sparing therapeutics for the treatment of GVHD but might also be useful for the treatment of other inflammatory bowel diseases where TNF-induced cell death is of relevance. PMID:26012567

  6. Mogamulizumab Treatment Prior to Allogeneic Hematopoietic Stem Cell Transplantation Induces Severe Acute Graft-versus-Host Disease.

    PubMed

    Sugio, Takeshi; Kato, Koji; Aoki, Takatoshi; Ohta, Takanori; Saito, Noriyuki; Yoshida, Shuro; Kawano, Ichiro; Henzan, Hideho; Kadowaki, Masanori; Takase, Ken; Muta, Tsuyoshi; Miyawaki, Kohta; Yamauchi, Takuji; Shima, Takahiro; Takashima, Shuichiro; Mori, Yasuo; Yoshimoto, Goichi; Kamezaki, Kenjiro; Takenaka, Katsuto; Iwasaki, Hiromi; Ogawa, Ryosuke; Ohno, Yuju; Eto, Tetsuya; Kamimura, Tomohiko; Miyamoto, Toshihiro; Akashi, Koichi

    2016-09-01

    Mogamulizumab (MOG), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, has recently played an important role in the treatment of adult T cell leukemia/lymphoma (ATLL). Because CCR4 is expressed on normal regulatory T cells as well as on ATLL cells, MOG may accelerate graft-versus-host disease (GVHD) by eradicating regulatory T cells in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is limited information about its safety and efficacy in patients treated with MOG before allo-HSCT. In the present study, 25 patients with ATLL were treated with MOG before allo-HSCT, after which 18 patients (72%) achieved remission. The overall survival and progression-free survival at 1 year post-transplantation were 20.2% (95% CI, 6.0% to 40.3%) and 15.0% (95% CI, 4.3% to 32.0%), respectively. The cumulative incidence of acute GVHD was 64.0% (95% CI, 40.7% to 80.1%) for grade II-IV and 34.7% (95% CI, 15.8% to 54.4%) for grade III-IV. The cumulative incidence of transplantation-related mortality (TRM) was 49.0% (95% CI, 27.0% to 67.8%). Six of 7 patients with acute GVHD grade III-IV died from GVHD, which was the leading cause of death. In particular, a shorter interval from the last administration of MOG to allo-HSCT was associated with more severe GVHD. MOG use before allo-HSCT may decrease the ATLL burden; however, it is associated with an increase in TRM due to severe GVHD. Because MOG is a potent anti-ATLL agent, new treatment protocols should be developed to integrate MOG at suitable doses and timing of administration to minimize unwanted GVHD development. PMID:27220263

  7. Prevalence and determinants of fatigue in patients with moderate to severe chronic GvHD.

    PubMed

    Im, A; Mitchell, S A; Steinberg, S M; Curtis, L; Berger, A; Baird, K; Kuzmina, Z; Joe, G; Comis, L E; Juckett, M; Avila, D; Baruffaldi, J; Masuch, L; Pirsl, F; Pavletic, S Z

    2016-05-01

    Although fatigue is common after allogeneic hematopoietic cell transplantation, little is known about fatigue in patients with chronic GvHD (cGvHD). The aim of this study was to explore factors associated with fatigue in cGvHD. Data were drawn from a sequentially recruited, cross-sectional study of adults with moderate or severe cGvHD (n=263). Respondents were classified as fatigued or not fatigued based on their response to a single item regarding loss of energy from the Lee cGvHD Symptom Scale. In univariate analysis, factors significantly associated with fatigue included performance status, number of prior cGvHD therapies, cGvHD symptom bother, self-assessed physical and mental health, nutritional status, walk velocity and self-reported physical activity. There were no significant associations between fatigue and disease-related cGvHD variables. Multivariable logistic regression demonstrated that being less active and having pulmonary and/or muscle/joint symptoms were independently associated with fatigue. In conclusion, clinically significant fatigue was prevalent in more than one-third of subjects with cGvHD, and was disabling. Absence of association with measures of cGvHD severity underscores the need to elucidate the pathogenesis of fatigue and its relationship with inflammatory activity. Pulmonary and muscle/joint symptoms and physical inactivity represent potential targets for intervention in clinical studies. PMID:26828906

  8. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice

    PubMed Central

    Shono, Yusuke; Docampo, Melissa D.; Peled, Jonathan U.; Perobelli, Suelen M.; Velardi, Enrico; Tsai, Jennifer J.; Slingerland, Ann E.; Smith, Odette M.; Young, Lauren F.; Gupta, Jyotsna; Lieberman, Sophia R.; Jay, Hillary V.; Ahr, Katya F.; Rodriguez, Kori A. Porosnicu; Xu, Ke; Calarfiore, Marco; Poeck, Hendrik; Caballero, Silvia; Devlin, Sean M.; Rapaport, Franck; Dudakov, Jarrod A.; Hanash, Alan M.; Gyurkocza, Boglarka; Murphy, George F.; Gomes, Camilla; Liu, Chen; Moss, Eli L.; Falconer, Shannon B.; Bhatt, Ami S.; Taur, Ying; Pamer, Eric G.

    2016-01-01

    After allogeneic hematopoietic stem cell transplantation (allo-HSCT), intestinal bacteria modulate risks of infection and graft-versus-host disease (GVHD). Neutropenic fever is common and treated with a choice of clinically equivalent antibiotics that target obligately anaerobic bacteria (anaerobes) to varying degrees. We retrospectively examined 857 allo-HSCT recipients and found that treatment of neutropenic fever with imipenem-cilastatin and piperacillin-tazobactam was associated with increased GVHD-related mortality at 5 years (21.5% in imipenem-cilastatin-treated patients vs. 13.1% in untreated patients, p=0.025, and 19.8% in piperacillin-tazobactam-treated patients vs. 11.9% in untreated patients, p=0.007). However, two other antibiotics also used to treat neutropenic fever, aztreonam and cefepime, were not associated with GVHD-related mortality (p=0.78 and p=0.98, respectively). Analysis of stool microbiota composition showed that piperacillin-tazobactam administration was associated with increased compositional perturbation. Studies in mouse models demonstrated similar effects of these antibiotics, as well as aggravated GVHD mortality with imipenem-cilastatin or piperacillin-tazobactm compared to aztreonam (p<0.01 and p<0.05, respectively). We found pathological evidence for increased GVHD in the colon of imipenem-cilastatin-treated mice (p<0.05), but no differences in short-chain fatty acid concentrations or regulatory T cells numbers. Notably, imipenem-cilastatin treatment of mice with GVHD led to loss of the protective lining of mucus in the colon (p<0.01) and intestinal barrier function was compromised (p<0.05). Sequencing of mouse stool specimens showed expansion of Akkermansia muciniphila (p<0.001), a commensal bacterium with mucus-degrading capabilities, raising the possibility that mucus degradation can contribute to murine GVHD. We demonstrate an underappreciated risk for antibiotics with activity against anaerobes to exacerbate colonic GVHD after

  9. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice.

    PubMed

    Shono, Yusuke; Docampo, Melissa D; Peled, Jonathan U; Perobelli, Suelen M; Velardi, Enrico; Tsai, Jennifer J; Slingerland, Ann E; Smith, Odette M; Young, Lauren F; Gupta, Jyotsna; Lieberman, Sophia R; Jay, Hillary V; Ahr, Katya F; Porosnicu Rodriguez, Kori A; Xu, Ke; Calarfiore, Marco; Poeck, Hendrik; Caballero, Silvia; Devlin, Sean M; Rapaport, Franck; Dudakov, Jarrod A; Hanash, Alan M; Gyurkocza, Boglarka; Murphy, George F; Gomes, Camilla; Liu, Chen; Moss, Eli L; Falconer, Shannon B; Bhatt, Ami S; Taur, Ying; Pamer, Eric G; van den Brink, Marcel R M; Jenq, Robert R

    2016-05-18

    Intestinal bacteria may modulate the risk of infection and graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT recipients often develop neutropenic fever, which is treated with antibiotics that may target anaerobic bacteria in the gut. We retrospectively examined 857 allo-HSCT recipients and found that treatment of neutropenic fever with imipenem-cilastatin and piperacillin-tazobactam antibiotics was associated with increased GVHD-related mortality at 5 years (21.5% for imipenem-cilastatin-treated patients versus 13.1% for untreated patients, P = 0.025; 19.8% for piperacillin-tazobactam-treated patients versus 11.9% for untreated patients, P = 0.007). However, two other antibiotics also used to treat neutropenic fever, aztreonam and cefepime, were not associated with GVHD-related mortality (P = 0.78 and P = 0.98, respectively). Analysis of stool specimens from allo-HSCT recipients showed that piperacillin-tazobactam administration was associated with perturbation of gut microbial composition. Studies in mice demonstrated aggravated GVHD mortality with imipenem-cilastatin or piperacillin-tazobactam compared to aztreonam (P < 0.01 and P < 0.05, respectively). We found pathological evidence for increased GVHD in the colon of imipenem-cilastatin-treated mice (P < 0.05), but no difference in the concentration of short-chain fatty acids or numbers of regulatory T cells. Notably, imipenem-cilastatin treatment of mice with GVHD led to loss of the protective mucus lining of the colon (P < 0.01) and the compromising of intestinal barrier function (P < 0.05). Sequencing of mouse stool specimens showed an increase in Akkermansia muciniphila (P < 0.001), a commensal bacterium with mucus-degrading capabilities, raising the possibility that mucus degradation may contribute to murine GVHD. We demonstrate an underappreciated risk for the treatment of allo-HSCT recipients with antibiotics that may exacerbate GVHD in the

  10. A cross-sectional study on vision-related quality of life in patients with ocular GvHD.

    PubMed

    Pezzotta, S; Rossi, G C; Scudeller, L; Antoniazzi, E; Bianchi, P E; Perotti, C; Del Fante, C

    2015-09-01

    Ocular GvHD affects about 40-60% of patients receiving bone marrow transplantation. Ocular complaints worsen quality of life (QoL), which, besides survival time, is a primary end point in a patient's follow-up. The aim of our study was to assess the ocular surface status and vision-related QoL (VRQoL) and explore the potential determinants in VRQoL in patients with chronic GvHD with ocular involvement. In this cross-sectional study, we investigated 40 patients with ocular GvHD after allogeneic hematopoietic stem cell transplantation assessing ocular symptoms and signs, VRQoL and ophthalmologic parameters. The median age was 52.1 years; 32.5% were females. Most of them presented a multiple organ involvement. Ophthalmological parameter examinations were on average abnormal. Corneal staining was severe/very severe in 25%; conjunctival staining in 10% of subjects. The worse QoL scores were on 'general vision', 'ocular pain', 'vision-specific mental health' and 'vision-specific role difficulties'. Both symptoms and sign scores indicate poor VRQoL. A lower VRQoL was related to schooling level, job position, underlying disease and extracorporeal photopheresis. Corneal staining, Schirmer and tear film breakup time were negatively associated to visual function-related subscales. An accurate ophthalmological and VRQoL assessment should be mandatory for a long time to promptly recognize early signs of ocular suffering, and to prevent irreversible ocular complications. PMID:26052912

  11. Thrombomodulin alleviates murine GVHD in association with an increase in the proportion of regulatory T cells in the spleen.

    PubMed

    Ikezoe, T; Yang, J; Nishioka, C; Yokoyama, A

    2015-01-01

    Recombinant human soluble thrombomodulin (rTM), a potent anticoagulant, has been used for the treatment of disseminated intravascular coagulation in Japan since 2008. Interestingly, rTM possesses anti-inflammatory and cytoprotective functions. This study examined whether rTM alleviates GVHD in a murine hematopoietic SCT (HSCT) model. Use of rTM significantly improved the survival of mice on day 28 of transplantation (survival rate 70% in rTM - treated mice vs 35% in control, P<0.05) in association with a significant decrease in plasma levels of IL-6, IFN-γ and high-mobility group B1 DNA-binding protein on day 7 of HSCT. Intriguingly, the proportion of regulatory T cells in the spleen was significantly increased in rTM-treated mice on day 7 of transplantation compared with control diluent-treated mice. In addition, elevated plasma levels of TM and fibrin/fibrinogen degradation product were noted in HSCT-recipient mice, suggesting coagulopathy caused by endothelial cell damage in this GVHD model. The use of rTM potently decreased these levels. Importantly, rTM did not hamper the anti-GVL and engraftment of hematopoietic cells. Taken together, the use of rTM may prevent GVHD and serve as a potential therapeutic strategy to improve clinical outcomes in individuals who receive HSCT. PMID:25243628

  12. Impact of cytomegalovirus reactivation on relapse and survival in patients with acute leukemia who received allogeneic hematopoietic stem cell transplantation in first remission.

    PubMed

    Yoon, Jae-Ho; Lee, Seok; Kim, Hee-Je; Jeon, Young-Woo; Lee, Sung-Eun; Cho, Byung-Sik; Lee, Dong-Gun; Eom, Ki-Seong; Kim, Yoo-Jin; Min, Chang-Ki; Cho, Seok-Goo; Min, Woo-Sung; Lee, Jong Wook

    2016-03-29

    Cytomegalovirus (CMV)-reactivation is associated with graft-vs-leukemia (GVL) effect by stimulating natural-killer or T-cells, which showed leukemia relapse prevention after hematopoietic stem cell transplantation (HSCT). We enrolled patients with acute myeloid leukemia (n = 197) and acute lymphoid leukemia (n = 192) who underwent allogeneic-HSCT in first remission. We measured RQ-PCR weekly to detect CMV-reactivation and preemptively used ganciclovir (GCV) when the titer increased twice consecutively, but GCV was sometimes delayed in patients without significant graft-vs-host disease (GVHD) by reducing immunosuppressive agents. In the entire group, CMV-reactivation showed poor overall survival (OS). To evaluate subsequent effects of CMV-reactivation, we excluded early relapse and deaths within 100 days, during which most of the CMV-reactivation occurred. Untreated CMV-reactivated group (n = 173) showed superior OS (83.8% vs. 61.7% vs. 74.0%, p < 0.001) with lower relapse rate (10.1% vs 22.1% vs. 25.5%, p = 0.004) compared to GCV-treated CMV-reactivated group (n = 122) and CMV-undetected group (n = 42). After excluding chronic GVHD, untreated CMV-reactivated group still showed lower relapse rate (9.4% vs. 24.1% vs. 30.2%, p = 0.006). Multivariate analysis showed adverse-risk karyotype and patients in other than untreated CMV-reactivated group were independent factors for relapse prediction. Our data showed possible GVL effect of CMV-reactivation and minimizing antiviral therapy may benefit for relapse prevention in acute leukemia. PMID:26883100

  13. Impact of cytomegalovirus reactivation on relapse and survival in patients with acute leukemia who received allogeneic hematopoietic stem cell transplantation in first remission

    PubMed Central

    Yoon, Jae-Ho; Lee, Seok; Kim, Hee-Je; Jeon, Young-Woo; Lee, Sung-Eun; Cho, Byung-Sik; Lee, Dong-Gun; Eom, Ki-Seong; Kim, Yoo-Jin; Min, Chang-Ki; Cho, Seok-Goo; Min, Woo-Sung; Lee, Jong Wook

    2016-01-01

    Cytomegalovirus (CMV)-reactivation is associated with graft-vs-leukemia (GVL) effect by stimulating natural-killer or T-cells, which showed leukemia relapse prevention after hematopoietic stem cell transplantation (HSCT). We enrolled patients with acute myeloid leukemia (n = 197) and acute lymphoid leukemia (n = 192) who underwent allogeneic-HSCT in first remission. We measured RQ-PCR weekly to detect CMV-reactivation and preemptively used ganciclovir (GCV) when the titer increased twice consecutively, but GCV was sometimes delayed in patients without significant graft-vs-host disease (GVHD) by reducing immunosuppressive agents. In the entire group, CMV-reactivation showed poor overall survival (OS). To evaluate subsequent effects of CMV-reactivation, we excluded early relapse and deaths within 100 days, during which most of the CMV-reactivation occurred. Untreated CMV-reactivated group (n = 173) showed superior OS (83.8% vs. 61.7% vs. 74.0%, p < 0.001) with lower relapse rate (10.1% vs 22.1% vs. 25.5%, p = 0.004) compared to GCV-treated CMV-reactivated group (n = 122) and CMV-undetected group (n = 42). After excluding chronic GVHD, untreated CMV-reactivated group still showed lower relapse rate (9.4% vs. 24.1% vs. 30.2%, p = 0.006). Multivariate analysis showed adverse-risk karyotype and patients in other than untreated CMV-reactivated group were independent factors for relapse prediction. Our data showed possible GVL effect of CMV-reactivation and minimizing antiviral therapy may benefit for relapse prevention in acute leukemia. PMID:26883100

  14. Concise Review: Acute Graft-Versus-Host Disease: Immunobiology, Prevention, and Treatment

    PubMed Central

    Chao, Nelson J.

    2013-01-01

    Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplant (AHSCT) associated with significant morbidity and mortality. This review focuses on the pathophysiology, clinical features, prevention, and treatment of acute GVHD. Specifically, we explain how new discoveries in immunology have expanded our understanding of GVHD, in which tissue damage from chemotherapy or radiation results in cytokine release, which activates T cells, resulting in proliferation and differentiation, trafficking to target organs, and tissue destruction and inflammation. Insights into the mechanisms of this disease relate directly to the development of preventive strategies and therapies, such as immunosuppression, T-cell depletion, calcineurin inhibitors, CCR5 antagonists, gut decontamination, extracorporeal photopheresis, and more. We also discuss how GVHD affects the gut, liver, and skin, as well as diagnosis, grading, and scoring. We end by examining future directions of treatment, including new immunomodulators and biomarkers. Understanding the immunobiology of GVHD and developing effective preventions and treatments are critical to the continuing success of AHSCT. PMID:23283494

  15. Soluble DNAM-1, as a Predictive Biomarker for Acute Graft-Versus-Host Disease.

    PubMed

    Kanaya, Minoru; Shibuya, Kazuko; Hirochika, Rei; Kanemoto, Miyoko; Ohashi, Kazuteru; Okada, Masafumi; Wagatsuma, Yukiko; Cho, Yukiko; Kojima, Hiroshi; Teshima, Takanori; Imamura, Masahiro; Sakamaki, Hisashi; Shibuya, Akira

    2016-01-01

    Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because diagnosis of aGVHD is exclusively based on clinical symptoms and pathological findings, reliable and noninvasive laboratory tests for accurate diagnosis are required. An activating immunoreceptor, DNAM-1 (CD226), is expressed on T cells and natural killer cells and is involved in the development of aGVHD. Here, we identified a soluble form of DNAM-1 (sDNAM-1) in human sera. In retrospective univariate and multivariate analyses of allo-HSCT patients (n = 71) at a single center, cumulative incidences of all grade (grade I-IV) and sgrade II-IV aGVHD in patients with high maximal serum levels of sDNAM-1 (≥30 pM) in the 7 days before allo-HSCT were significantly higher than those in patients with low maximal serum levels of sDNAM-1 (<30 pM) in the same period. However, sDNAM-1 was not associated with other known allo-HSCT complications. Our data suggest that sDNAM-1 is potentially a unique candidate as a predictive biomarker for the development of aGVHD. PMID:27257974

  16. Acute graft-versus-host disease: a bench-to-bedside update.

    PubMed

    Holtan, Shernan G; Pasquini, Marcelo; Weisdorf, Daniel J

    2014-07-17

    Over the past 5 years, many novel approaches to early diagnosis, prevention, and treatment of acute graft-versus-host disease (aGVHD) have been translated from the bench to the bedside. In this review, we highlight recent discoveries in the context of current aGVHD care. The most significant innovations that have already reached the clinic are prophylaxis strategies based upon a refinement of our understanding of key sensors, effectors, suppressors of the immune alloreactive response, and the resultant tissue damage from the aGVHD inflammatory cascade. In the near future, aGVHD prevention and treatment will likely involve multiple modalities, including small molecules regulating immunologic checkpoints, enhancement of suppressor cytokines and cellular subsets, modulation of the microbiota, graft manipulation, and other donor-based prophylaxis strategies. Despite long-term efforts, major challenges in treatment of established aGVHD still remain. Resolution of inflammation and facilitation of rapid immune reconstitution in those with only a limited response to corticosteroids is a research arena that remains rife with opportunity and urgent clinical need. PMID:24914140

  17. Acute graft-versus-host disease: a bench-to-bedside update

    PubMed Central

    Holtan, Shernan G.; Pasquini, Marcelo

    2014-01-01

    Over the past 5 years, many novel approaches to early diagnosis, prevention, and treatment of acute graft-versus-host disease (aGVHD) have been translated from the bench to the bedside. In this review, we highlight recent discoveries in the context of current aGVHD care. The most significant innovations that have already reached the clinic are prophylaxis strategies based upon a refinement of our understanding of key sensors, effectors, suppressors of the immune alloreactive response, and the resultant tissue damage from the aGVHD inflammatory cascade. In the near future, aGVHD prevention and treatment will likely involve multiple modalities, including small molecules regulating immunologic checkpoints, enhancement of suppressor cytokines and cellular subsets, modulation of the microbiota, graft manipulation, and other donor-based prophylaxis strategies. Despite long-term efforts, major challenges in treatment of established aGVHD still remain. Resolution of inflammation and facilitation of rapid immune reconstitution in those with only a limited response to corticosteroids is a research arena that remains rife with opportunity and urgent clinical need. PMID:24914140

  18. The Nlrp3 inflammasome regulates acute graft-versus-host disease

    PubMed Central

    Jankovic, Dragana; Ganesan, Jayanthi; Bscheider, Michael; Stickel, Natalie; Weber, Felix C.; Guarda, Greta; Follo, Marie; Pfeifer, Dietmar; Tardivel, Aubry; Ludigs, Kristina; Bouazzaoui, Abdellatif; Kerl, Katrin; Fischer, Julius C.; Haas, Tobias; Schmitt-Gräff, Annette; Manoharan, Anand; Müller, Leonard; Finke, Jürgen; Martin, Stefan F.; Gorka, Oliver; Peschel, Christian; Ruland, Jürgen; Idzko, Marco; Duyster, Justus; Holler, Ernst; French, Lars E.

    2013-01-01

    The success of allogeneic hematopoietic cell transplantation is limited by acute graft-versus-host disease (GvHD), a severe complication accompanied by high mortality rates. Yet, the molecular mechanisms initiating this disease remain poorly defined. In this study, we show that, after conditioning therapy, intestinal commensal bacteria and the damage-associated molecular pattern uric acid contribute to Nlrp3 inflammasome–mediated IL-1β production and that gastrointestinal decontamination and uric acid depletion reduced GvHD severity. Early blockade of IL-1β or genetic deficiency of the IL-1 receptor in dendritic cells (DCs) and T cells improved survival. The Nlrp3 inflammasome components Nlrp3 and Asc, which are required for pro–IL-1β cleavage, were critical for the full manifestation of GvHD. In transplanted mice, IL-1β originated from multiple intestinal cell compartments and exerted its effects on DCs and T cells, the latter being preferentially skewed toward Th17. Compatible with these mouse data, increased levels of active caspase-1 and IL-1β were found in circulating leukocytes and intestinal GvHD lesions of patients. Thus, the identification of a crucial role for the Nlrp3 inflammasome sheds new light on the pathogenesis of GvHD and opens a potential new avenue for the targeted therapy of this severe complication. PMID:23980097

  19. Soluble DNAM-1, as a Predictive Biomarker for Acute Graft-Versus-Host Disease

    PubMed Central

    Kanaya, Minoru; Shibuya, Kazuko; Hirochika, Rei; Kanemoto, Miyoko; Ohashi, Kazuteru; Okada, Masafumi; Wagatsuma, Yukiko; Cho, Yukiko; Kojima, Hiroshi; Teshima, Takanori; Imamura, Masahiro; Sakamaki, Hisashi; Shibuya, Akira

    2016-01-01

    Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because diagnosis of aGVHD is exclusively based on clinical symptoms and pathological findings, reliable and noninvasive laboratory tests for accurate diagnosis are required. An activating immunoreceptor, DNAM-1 (CD226), is expressed on T cells and natural killer cells and is involved in the development of aGVHD. Here, we identified a soluble form of DNAM-1 (sDNAM-1) in human sera. In retrospective univariate and multivariate analyses of allo-HSCT patients (n = 71) at a single center, cumulative incidences of all grade (grade I–IV) and sgrade II–IV aGVHD in patients with high maximal serum levels of sDNAM-1 (≥30 pM) in the 7 days before allo-HSCT were significantly higher than those in patients with low maximal serum levels of sDNAM-1 (<30 pM) in the same period. However, sDNAM-1 was not associated with other known allo-HSCT complications. Our data suggest that sDNAM-1 is potentially a unique candidate as a predictive biomarker for the development of aGVHD. PMID:27257974

  20. High day 28 ST2 levels predict for acute graft-versus-host disease and transplant-related mortality after cord blood transplantation

    PubMed Central

    Hilden, Patrick; Mumaw, Christen; Devlin, Sean M.; Lubin, Marissa; Giralt, Sergio; Goldberg, Jenna D.; Hanash, Alan; Hsu, Katharine; Jenq, Robert; Perales, Miguel-Angel; Sauter, Craig; van den Brink, Marcel R. M.; Young, James W.; Brentjens, Renier; Kernan, Nancy A.; Prockop, Susan E.; O’Reilly, Richard J.; Scaradavou, Andromachi; Paczesny, Sophie; Barker, Juliet N.

    2015-01-01

    While cord blood transplantation (CBT) is an effective therapy for hematologic malignancies, acute graft-versus-host disease (aGVHD) is a leading cause of transplant-related mortality (TRM). We investigated if biomarkers could predict aGVHD and TRM after day 28 in CBT recipients. Day 28 samples from 113 CBT patients were analyzed. Suppressor of tumorigenicity 2 (ST2) was the only biomarker associated with grades II-IV and III-IV aGVHD and TRM. Day 180 grade III-IV aGVHD in patients with high ST2 levels was 30% (95% confidence interval [CI], 18-43) vs 13% (95% CI, 5-23) in patients with low levels (P = .024). The adverse effect of elevated ST2 was independent of HLA match. Moreover, high day 28 ST2 levels were associated with increased TRM with day 180 estimates of 23% (95% CI, 13-35) vs 5% (95% CI, 1-13) if levels were low (P = .001). GVHD was the most common cause of death in high ST2 patients. High concentrations of tumor necrosis factor receptor-1, interleukin-8, and regenerating islet-derived protein 3-α were also associated with TRM. Our results are consistent with those of adult donor allografts and warrant further prospective evaluation to facilitate future therapeutic intervention to ameliorate severe aGVHD and further improve survival after CBT. PMID:25377785

  1. TGF-β-induced CD4+Foxp3+ T cells attenuate acute graft-versus-host disease by suppressing expansion and killing of effector CD8+ cells.

    PubMed

    Gu, Jian; Lu, Ling; Chen, Maogen; Xu, Lili; Lan, Qin; Li, Qiang; Liu, Zhongmin; Chen, Guihua; Wang, Ping; Wang, Xuehao; Brand, David; Olsen, Nancy; Zheng, Song Guo

    2014-10-01

    The use of TGF-β-induced CD4(+)Foxp3(+) T cells (induced regulatory T cells [iTregs]) is an important prevention and treatment strategy in autoimmune diseases and other disorders. However, the potential use of iTregs as a treatment modality for acute graft-versus-host disease (aGVHD) has not been realized because they may be unstable and less suppressive in this disease. We restudied the ability of iTregs to prevent and treat aGVHD in two mouse models. Our results showed that, as long as an appropriate iTreg-generation protocol is used, these iTregs consistently displayed a potent ability to control aGVHD development and reduce mortality in the aGVHD animal models. iTreg infusion markedly suppressed the engraftment of donor CD8(+) cells and CD4(+) cells, the expression of granzyme A and B, the cytotoxic effect of donor CD8(+) cells, and the production of T cell cytokines in aGVHD. Therefore, we conclude that as long as the correct methods for generating iTregs are used, they can prevent and even treat aGVHD. PMID:25156367

  2. Sirolimus and Mycophenolate Mofetil in Preventing GVHD in Patients With Hematologic Malignancies Undergoing HSCT

    ClinicalTrials.gov

    2016-06-14

    Adult Hodgkin Lymphoma; Adult Myelodysplastic Syndrome; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Hodgkin Lymphoma; Childhood Myelodysplastic Syndrome; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Myelofibrosis; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Non-Hodgkin Lymphoma

  3. Impact of Ocular Chronic Graft-versus-Host Disease on Quality of Life.

    PubMed

    Sun, Yi-Chen; Chai, Xiaoyu; Inamoto, Yoshihiro; Pidala, Joseph; Martin, Paul J; Flowers, Mary E D; Shen, Tueng T; Lee, Stephanie J; Jagasia, Madan

    2015-09-01

    Ocular involvement can be quite symptomatic in patients with chronic graft-versus-host disease (GVHD). The prevalence of and risk factors for ocular GVHD and its impact on quality of life (QOL) in patients with chronic GVHD were studied in a prospective, multicenter, longitudinal, observational study. This study enrolled 342 patients with 1483 follow-up visits after allogeneic hematopoietic cell transplantation. All patients in this analysis were diagnosed with chronic GVHD requiring systemic treatment and enrolled within 3 months of chronic GVHD diagnosis. The symptom burden of ocular GVHD was based on the degree of dry eye symptoms, frequency of artificial tear usage, and impact on activities of daily living. Patients' QOL was measured by self-administered questionnaires. Variables associated with ocular GVHD at enrollment and subsequent new-onset ocular GVHD and the associations with QOL were studied. Of the 284 chronic GVHD patients, 116 (41%) had ocular GVHD within 3 months of chronic GVHD diagnosis ("early ocular GVHD"). Late ocular GVHD (new onset > 3 months after chronic GVHD diagnosis) occurred in 64 patients. Overall cumulative incidence at 2 years was 57%. Female gender (P = .005), higher acute GVHD grade (P = .04), and higher prednisone dose at study entry (P = .04) were associated with early ocular GVHD. For patients who did not have ocular GVHD within 3 months of chronic GVHD diagnosis, presence of prior grades I to IV acute GVHD (HR 1.78, P = .04) was associated with shorter time to late ocular GVHD, whereas female donor-male recipient (HR .53, P = .05) was associated with longer time to late ocular GVHD onset. Using all visit data, patients with ocular GVHD had worse QOL, as measured by Functional Assessment of Cancer Therapy Bone Marrow Transplantation (P = .002), and greater chronic GVHD symptom burden, as measured by the Lee symptom overall score excluding the eye component (P < .001), compared with patients without ocular GVHD. In conclusion

  4. Acute Bronchitis

    MedlinePlus

    ... bronchitis? Acute bronchitis is almost always caused by viruses that attack the lining of the bronchial tree ... infection. As your body fights back against these viruses, more swelling occurs and more mucus is produced. ...

  5. In Vivo T Cell Depletion with Myeloablative Regimens on Outcomes after Cord Blood Transplantation for Acute Lymphoblastic Leukemia in Children.

    PubMed

    Ponce, Doris M; Eapen, Mary; Sparapani, Rodney; O'Brien, Tracey A; Chan, Ka Wah; Chen, Junfang; Craddock, John; Schultz, Kirk R; Wagner, John E; Perales, Miguel-Angel; Barker, Juliet N

    2015-12-01

    The inclusion of antithymocyte globulin (ATG) in cord blood transplantation is controversial. We evaluated outcomes according to ATG inclusion in 297 children and adolescents with acute lymphoblastic leukemia (ALL) who received myeloablative total body irradiation-based conditioning and either single-unit (74%) or double-unit (26%) grafts. Ninety-two patients (31%) received ATG and 205 (69%) did not. ATG recipients were more likely to be cytomegalovirus seronegative. The incidences of day 100 grades II to IV acute graft-versus-host disease (GVHD; 30% versus 54%, P = .0002) and chronic GVHD (22% versus 43%, P = .0008) were lower with ATG compared with non-ATG regimens. However, day 100 grades III to IV acute GVHD was comparable (11% versus 17%, P = .15). The 3-year incidences of transplant-related mortality (16% versus 17%, P = .98), relapse (17% versus 27%, P = .12), and leukemia-free survival (66% versus 55%, P = .23) in ATG and non-ATG recipients were similar. There were no differences in viral reactivation between treatment groups (60% versus 58%, P = .83). Therefore, the data suggest that incorporation of ATG with myeloablative conditioning regimens may be useful in reducing the risk of acute and chronic GVHD without any deleterious effect on transplant-related mortality, relapse, or leukemia-free survival in children and adolescents with ALL. PMID:26327630

  6. Naturally occurring chemical carcinogens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Natural products are chemicals found in nature which have unique pharmacological effects. Humans are exposed to many of these bioactive naturally occurring chemicals via the air breathed, the water drunk and the food eaten. Exposure also occurs in clinical settings. Naturally occurring chemicals ...

  7. Peritransplant Serum Albumin Decline Predicts Subsequent Severe Acute Graft-versus-Host Disease after Mucotoxic Myeloablative Conditioning.

    PubMed

    Rashidi, Armin; DiPersio, John F; Westervelt, Peter; Abboud, Camille N; Schroeder, Mark A; Cashen, Amanda F; Pusic, Iskra; Romee, Rizwan

    2016-06-01

    Conditioning-related gut toxicity can result in a protein-losing enteropathy manifesting as a decline in serum albumin in the peritransplant period. Inspired by the pathogenesis of acute graft-versus-host disease (aGVHD), we hypothesized that the magnitude of decline in serum albumin from the day of conditioning initiation until its nadir in the first 2 weeks after hematopoietic cell transplantation HCT (DeltaAlb) predicts the risk for subsequent severe aGVHD. We reviewed the medical records of all 88 patients with acute myeloid leukemia or myelodysplastic syndrome who underwent highly mucotoxic myeloablative (busulfan/cyclophosphamide or cyclophosphamide/total body irradiation) allogeneic HCT from a matched related donor (MRD) or matched unrelated donor (MUD) at our institution between January 1, 2012 and January 1, 2015. Severe aGVHD was associated with MUD (47% versus 14% with MRD; P = .001) and DeltaAlb, which was significantly greater among patients who developed versus did not develop severe aGVHD (1.2 ± .5 versus .8 ± .4 g/dL, respectively; P < .001). In multivariate analysis DeltaAlb remained a significant predictor of severe aGVHD (odds ratio, 5.68; 95% CI, 1.65 to 19.64; P = .006; area under the ROC curve, .74; 95% CI, .63 to .86; P < .001). The best cutoff for DeltaAlb to predict severe aGVHD was .9, with a sensitivity, specificity, and overall classification accuracy of 77%, 66%, and 69%, respectively. The model was validated using the bootstrap technique, with no significant change in its performance. These results were not generalizable to a cohort of 30 patients who received less mucotoxic myeloablative or reduced-intensity conditioning. In conclusion, with mucotoxic myeloablative HCT, each .1-g/dL increase in DeltaAlb was associated with an approximately 23% increase in the odds of developing severe aGVHD. As an early biomarker of gut damage, DeltaAlb can be incorporated in composite risk models for aGVHD prediction, with hopes for

  8. Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts in Preventing GVHD in Children

    ClinicalTrials.gov

    2016-06-21

    Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Acute Biphenotypic Leukemia; Acute Leukemia of Ambiguous Lineage; Acute Myeloid Leukemia in Remission; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Acute Lymphoblastic Leukemia in Remission; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; RAEB-1; RAEB-2; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Adult Acute Lymphoblastic Leukemia; Refractory Childhood Acute Lymphoblastic Leukemia

  9. miR-146a and miR-155 Expression Levels in Acute Graft-Versus-Host Disease Incidence

    PubMed Central

    Atarod, Sadaf; Ahmed, Mohammed Mahid; Lendrem, Clare; Pearce, Kim Frances; Cope, Wei; Norden, Jean; Wang, Xiao-Nong; Collin, Matthew; Dickinson, Anne Mary

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for numerous hematological malignancies. However, acute graft-versus-host disease (aGVHD) is still the major complication causing mortality. MicroRNAs (miRNAs) play a significant role in inflammation and have potential as prognostic and diagnostic biomarkers. This study investigated the role of two immune-specific miRNAs (miR-146a and miR-155) as biomarkers for aGVHD incidence in the peripheral blood of allo-HSCT patients prior to disease onset. The study showed that miR-146a and its statistical interaction with miR-155 at day +28 were predictive of aGVHD incidence. Interestingly, the expression levels of miR-146a and miR-155 negatively correlated with the transcription factor, SPI1 (PU.1gene) mRNA expression. PMID:27014257

  10. The Role of Biomarkers in the Diagnosis and Risk Stratification of Acute Graft-versus-Host Disease: A Systematic Review.

    PubMed

    Ali, Alaa M; DiPersio, John F; Schroeder, Mark A

    2016-09-01

    Allogeneic hematopoietic cell transplantation (HCT) is an increasingly used curative modality for hematologic malignancies and other benign conditions. Attempts to reduce morbidity and mortality and improve survival in patients undergoing HCT are crucial. The ability to diagnose acute graft-versus-host disease (aGVHD) in a timely manner, or to even predict aGVHD before clinical manifestations, along with the accurate stratification of these patients, are critical steps to improve the treatment and outcomes of these patients. Many novel biomarkers that may help achieve these goals have been studied recently. This overview is intended to assist clinicians and investigators by providing a comprehensive review and analytical interpretation of the current knowledge concerning aGVHD and biomarkers likely to prove useful in diagnosis and risk stratification of this condition, along with the difficulties that hamper this approach. PMID:27158050

  11. Factors affecting long-term outcome after allogeneic haematopoietic stem cell transplantation for acute myelogenous leukaemia: a retrospective study of 172 adult patients reported to the Austrian Stem Cell Transplantation Registry.

    PubMed

    Greinix, Hildegard T; Nachbaur, David; Krieger, Otto; Eibl, Margit; Knöbl, Paul; Kalhs, Peter; Lutz, Dieter; Linkesch, Werner; Niederwieser, Dietger; Hinterberger, Wolfgang; Lechner, Klaus; Rosenmayr, Agathe; Gritsch, Beate

    2002-06-01

    Between 1982 and 2000, 172 patients with acute myelogenous leukaemia (AML) received haematopoietic stem cell transplants (SCT) from related (n = 132) or unrelated (n = 40) donors at four Austrian transplant centres and their results were reported to the Austrian Stem Cell Transplantation Registry. Conditioning for SCT consisted of cyclophosphamide and total body irradiation in 156 (91%) patients. Graft-versus-host disease (GVHD) prophylaxis was with standard cyclosporine and methotrexate in 95 (55%) patients. Median post-transplant follow-up was 5.6 years (range, 0.2--16.7). Multivariate analysis of transplant-related mortality (TRM) identified four variables associated with a lower risk: disease status of first complete remission (CR) at SCT, patient age of 45 years and younger, transplant performed during or after 1995, and lack of acute GVHD. Variables associated with significantly improved leukaemia-free survival were: bone marrow as the stem cell source, disease status of first CR at SCT, and occurrence of chronic GVHD. In multivariate analysis, transplantation performed during or after 1995, first CR at SCT, occurrence of limited chronic GVHD and lack of acute GVHD grades III to IV were associated with increased overall survival. Based on these analyses, options for the improvement of results obtained with allogeneic SCT in patients with AML could be defined. PMID:12060131

  12. Prior Rituximab Correlates with Less Acute Graft-versus-Host Disease and Better Survival in B-Cell Lymphoma Patients Who Received Allogeneic Peripheral Blood Stem Cell Transplantation (PBSCT)

    PubMed Central

    Ratanatharathorn, Voravit; Logan, Brent; Wang, Dan; Horowitz, Mary; Uberti, Joseph P.; Ringden, Olle; Gale, Robert Peter; Khoury, Hanna; Arora, Mukta; Spellman, Stephen; Cutler, Corey; Antin, Joseph; Bornhaüser, Martin; Hale, Gregory; Verdonck, Leo; Cairo, Mitchell; Gupta, Vikas; Steven, Pavletic

    2012-01-01

    Summary Prior therapy with rituximab might attenuate disparate histocompatibility antigen presentation by B cells, thus decreased the risk of acute graft-versus-host disease (GVHD) and improved survival. We tested this hypothesis by comparing the outcomes of 435 B-cell lymphoma patients who received allogeneic transplantation from 1999 to 2004 in the Center for International Blood and Marrow Transplant Research database: 179 subjects who received rituximab within 6 months prior to transplantation (RTX cohort) and 256 subjects who did not receive RTX within 6 months prior to transplantation (No-RTX cohort). The RTX cohort had a significantly lower incidence of treatment-related mortality (TRM) (relative risk [RR] = 0.68; 95% confidence interval [CI], 0.47 - 1.0; P = 0.05), lower acute grade II-IV (RR = 0.72; 95% CI, 0.53 - 0.97; P = 0.03) and III-IV GVHD (RR = 0.55; 95% CI, 0.34 - 0.91; P = 0.02). There was no difference in the risk of chronic GVHD, disease progression or relapse. Progression-free survival (PFS) (RR = 0.68; 95% CI 0.50 - 0.92; P = 0.01) and overall survival (OS) (RR = 0.63; 95% CI, 0.46 - 0.86; P = 0.004) were significantly better in the RTX cohort. Prior RTX therapy correlated with less acute GVHD, similar chronic GVHD, less TRM, better PFS and OS. PMID:19344418

  13. Co-Occurring Disorders

    MedlinePlus

    ... Care of You Top Ten Freshman Year Issues Alcohol, Substance Abuse and Depression Winter Break Survival Tips for College Students Implementing ... supporters and consumers in the mental health field. Alcohol and Drug Abuse, Addiction and Co-occurring Disorders: Co-occurring ... In Crisis? Call ...

  14. Expansion and activation kinetics of immune cells during early phase of GVHD in mouse model based on chemotherapy conditioning.

    PubMed

    Sadeghi, Behnam; Al-Hashmi, Suleiman; Hassan, Zuzana; Rozell, Bjorn; Concha, Hernan; Lundmark, Carin; Grönvik, Kjell-Olov; Abedi-Valugerdi, Manuchehr; Hassan, Moustapha

    2010-01-01

    In the present paper, we have investigated early pathophysiological events in graft-versus-host disease (GVHD), a major complication to hematopoietic stem cell transplantation (HSCT). BLLB/c female mice conditioned with busulfan/cyclophosphamide (Bu-Cy) were transplanted with allogeneic male C57BL/6. Control group consisted of syngeneic transplanted Balb/c mice. In allogeneic settings, significant expansion and maturation of donor dendritic cells (DCs) were observed at day +3, while donor T-cells CD8+ were increased at day +5 (230%) compared to syngeneic HSCT. Highest levels of inflammatory cytokines IL-2, IFN-gamma, and TNF-alfa at day +5 matched T-cell activation. Concomitantly naïve T-cells gain effecr-memory phenotype and migrated from spleen to peripheral lymphoid organs. Thus, in the very early phase of GHVD following Bu-Cy conditioning donor, DCs play an important role in the activation of donor T cells. Subsequently, donor naïve T-cells gain effector-memory phenotype and initiate GVHD. PMID:21197273

  15. Scurvy: a new problem for patients with chronic GVHD involving mucous membranes; an easy problem to resolve.

    PubMed

    Kletzel, Morris; Powers, Kim; Hayes, Meghan

    2014-08-01

    Vitamin C deficiency in developed countries is typically observed in patients with unique clinical conditions such as cystic fibrosis or anorexia nervosa, or in patients on long-term tube feeds. We report here a clinical observation in six pediatric and adolescent patients (median age 17.5 yr, range 9.8-23.5 yr) with chronic GVHD with mucous membrane involvement found to be vitamin C deficient. These patients' baseline serum vitamin C levels ranged from <0.12 to 0.94 mg/dL (normal value 0.20-1.90 mg/dL), with a mean level 0.56 ± 0.36 mg/dL and a median level 0.6 mg/dL. Among these patients, signs and symptoms of mucositis failed to respond to standard chronic GVHD therapy. After receiving treatment with 2000 mg of ascorbic acid by mouth, daily patients displayed increased serum vitamin C levels. Clinically, this correlated with a remarkable improvement in patients' mucositis and ability to eat. PMID:24816030

  16. Expansion and Activation Kinetics of Immune Cells during Early Phase of GVHD in Mouse Model Based on Chemotherapy Conditioning

    PubMed Central

    Sadeghi, Behnam; Al-Hashmi, Suleiman; Hassan, Zuzana; Rozell, Bjorn; Concha, Hernan; Lundmark, Carin; Grönvik, Kjell-Olov; Abedi-Valugerdi, Manuchehr; Hassan, Moustapha

    2010-01-01

    In the present paper, we have investigated early pathophysiological events in graft-versus-host disease (GVHD), a major complication to hematopoietic stem cell transplantation (HSCT). BLLB/c female mice conditioned with busulfan/cyclophosphamide (Bu-Cy) were transplanted with allogeneic male C57BL/6. Control group consisted of syngeneic transplanted Balb/c mice. In allogeneic settings, significant expansion and maturation of donor dendritic cells (DCs) were observed at day +3, while donor T-cells CD8+ were increased at day +5 (230%) compared to syngeneic HSCT. Highest levels of inflammatory cytokines IL-2, IFN-gamma, and TNF-alfa at day +5 matched T-cell activation. Concomitantly naïve T-cells gain effecr-memory phenotype and migrated from spleen to peripheral lymphoid organs. Thus, in the very early phase of GHVD following Bu-Cy conditioning donor, DCs play an important role in the activation of donor T cells. Subsequently, donor naïve T-cells gain effector-memory phenotype and initiate GVHD. PMID:21197273

  17. Cholecystitis occurring without stones

    SciTech Connect

    Seal, M.L.

    1986-03-01

    A case of acalculous cholecystitis in a 65-year-old man with underlying diabetes mellitus, hypertension, and peripheral arteriosclerosis is presented here. His case remained diagnostically puzzling for some time until symptoms and signs became more severe and very suggestive of acute cholecystitis. The clinical impression was then supported by an abnormal radioisotope biliary scan. The scan has fairly good sensitivity in detecting this condition but may not be totally dependable. Acalculous cholecystitis is an unusual but serious variant of a common disorder in which treatable gallbladder disease may masquerade as a less treatable liver malady. A common denominator among this disorder's many etiologies may be impairment of the gallbladder microcirculation in the presence of one or more conditions that lower the gallbladder's resistance to bacterial invasion. Prompt detection and treatment are desirable to reduce morbidity and mortality. However, early diagnosis is not always possible, because the clinical picture often is unclear, clear, gallstones are absent, and laboratory test results may be normal or equivocal. As in the case reported here, the vague clinical picture may dictate following a patient until the illness reaches an intensity acute enough to permit identification. The greatest aid to earlier diagnosis for the physician faced with circumstances similar to those described here is to think of cholecystitis and then to give strong weight to that clinical suspicion. At times, a recommendation for cholecystectomy may have to be made mainly on clinical judgment.

  18. The triterpenoid CDDO-Me delays murine acute graft-versus-host disease with the preservation of graft-versus-tumor effects after allogeneic bone marrow transplantation

    PubMed Central

    Li, Minghui; Sun, Kai; Redelman, Doug; Welniak, Lisbeth A.; Murphy, William J.

    2010-01-01

    The occurrence of acute graft-versus-host disease (GVHD) and tumor relapse represent the two major obstacles impeding the efficacy of allogeneic bone marrow transplantation (BMT) in cancer. We have previously shown that the synthetic triterpenoid CDDO can inhibit murine early acute GVHD but anti-tumor effects were not assessed. In the current study, we found that a new derivative of CDDO, CDDO-Me, had an increased ability to inhibit allogeneic T cell responses and induce cell death of alloreactive T cells in vitro. Administration of CDDO-Me to mice following allogeneic BMT resulted in significant and increased protection from acute lethal GVHD compared to CDDO. This correlated with reduced TNF-α production, reduced donor T cell proliferation and decreased adhesion molecule (α4β7 integrin) expression on the donor T cells. CDDO-Me was also superior to CDDO in inhibiting leukemia growth in vitro. When CDDO-Me was administered following an allogeneic BMT to leukemia-bearing mice, significant increases in survival were observed. These findings suggest that CDDO-Me is superior to CDDO in delaying acute GVHD while preserving or possibly even augmenting GVT effects. PMID:20338256

  19. Eculizumab Treatment in a Patient with Hematopoietic Stem Cell Transplantation-Associated Thrombotic Microangiopathy and Steroid-Refractory Acute Graft Versus Host Disease

    PubMed Central

    Fernández, Cristina; Lario, Ana; Cabrera, Rafael

    2015-01-01

    A 30-year-old man with acquired aplastic anemia underwent an HLA-identical bone marrow transplant. He developed a grade III acute graft versus host disease (GVHD) refractory to various lines of treatment. On post-transplant day 196, he was diagnosed with stem cell transplantation-associated thrombotic micro-angiopathy (HSCT-TMA) and he received treatment with eculizumab 900 mg iv weekly for 4 doses followed by a single dose of 1200 mg 2 weeks later. After the first dose of eculizumab, the patient ceased to require transfusions and a progressive improvement in analytical parameters for microangiopathy was observed until their complete normalization. Coinciding with the improved of HSCT-TMA, the patient presented a clear response to his acute GVHD with disappearance of the diarrhea and bilirubin normalization. He was discharged eight weeks after the start of treatment. Unfortunately, one month later, the patient was readmitted for a GVHD relapse and he died two weeks later by an acute respiratory distress syndrome. In our case, the rapid clinical and analytical response to early treatment with eculizumab supports the implication of the complement in HSCT-TMA and suggests that the drug has a beneficial effect when used as coadjuvant therapy in acute GVHD. PMID:26734129

  20. Acute arterial occlusion - kidney

    MedlinePlus

    ... arterial thrombosis; Renal artery embolism; Acute renal artery occlusion; Embolism - renal artery ... often result in permanent kidney failure. Acute arterial occlusion of the renal artery can occur after injury ...

  1. Tryptophan metabolite analog, N-(3,4-dimethoxycinnamonyl) anthranilic acid, ameliorates acute graft-versus-host disease through regulating T cell proliferation and polarization.

    PubMed

    Xu, Jinhuan; Wei, Jia; Huang, Min; Zhu, Xianmin; Guan, Jun; Yin, Jin; Xiao, Yi; Zhang, Yicheng

    2013-11-01

    Local catabolism of tryptophan (Trp) by indoleamine 2,3-dioxygenase (IDO) is considered an important mechanism of regulating T cell immunity. N-(3,4-dimethoxycinnamonyl) anthranilic acid (3,4-DAA) is an active synthetic anthranilic acid derivative which was proved to be effective to treat type1helper T lymphocyte (Th1) mediated autoimmune diseases such as multiple sclerosis. In this report, we investigated the effects of 3,4-DAA on the acute graft versus host disease (aGVHD) following allogeneic bone marrow transplantation (allo-BMT) and its potential mechanism of action. We established a murine aGVHD model, 3,4-DAA was injected intraperitoneally at 200mg/kg/day per mouse immediately after allo-BMT or at the onset of aGVHD for 14 consecutive days; the signs of aGVHD and the survival were recorded periodically. We revealed that administration of 3,4-DAA after allo-BMT significantly reduced the severity and the histological score of aGVHD; the survival for mice receiving 3,4-DAA prophylaxis and treatment was prolonged in comparison to the vehicle control mice. The plasma levels of IFN-γ, TNF-α, IL-12 and IL-2 in 3,4-DAA treatment group were found to be decreased, while the IDO activity, CD4(+)/CD25(+) Treg cells, and the IL-10, IL-5 and IL-4 levels elevated in these mice. In consistent with the in vivo results, 3,4-DAA also inhibited IFN-γ and IL-2 production of spleen T lymphocytes in vitro. Our findings suggest that 3,4-DAA can diminish the murine experimental aGVHD through regulating T cell proliferation and polarization; this property makes it a potential alternative agent for prevention and treatment of GVHD in the clinic. PMID:23993943

  2. Vorinostat, Tacrolimus, and Methotrexate in Preventing GVHD After Stem Cell Transplant in Patients With Hematological Malignancies

    ClinicalTrials.gov

    2015-10-13

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Grade III Lymphomatoid Granulomatosis; B-cell Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Burkitt Lymphoma; Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Contiguous Stage II Adult Lymphoblastic Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Grade 3 Follicular Lymphoma; Contiguous Stage II Mantle Cell Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Graft Versus Host Disease; Intraocular Lymphoma; Myelodysplastic Syndrome With Isolated Del(5q); Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous

  3. Age influences post-graft-versus-host disease non-relapse mortality in adults with acute graft-versus-host disease of varying severity following allogeneic hematopoietic cell transplant.

    PubMed

    Nakane, Takahiko; Fukuda, Takahiro; Kanda, Junya; Taniguchi, Shuichi; Eto, Tetsuya; Ohashi, Kazuteru; Nakamae, Hirohisa; Kurokawa, Mineo; Mori, Takehiko; Morishima, Yasuo; Nagamura-Inoue, Tokiko; Sakamaki, Hisashi; Atsuta, Yoshiko; Murata, Makoto

    2015-01-01

    We retrospectively analyzed 2682 patients who developed grade II-IV acute graft-versus-host disease (GVHD). On analysis with stratification into five age groups (20-29, 30-39, 40-49, 50-59 and ≥60), 2-year non-relapse mortality rates (NRM) after the onset of GVHD were 20.7, 26.2, 26.6, 37.0 and 40.4%, respectively (p<0.001). We found a significant interaction between the patient's age and GVHD severity with respect to NRM (p=0.004). On multivariate analyses stratified by GVHD severity, the hazard ratio (HR) for NRM in the groups aged 50 years or more (reference: age group 20-29) was about twice as great in patients with grade II acute GVHD when compared with grade III-IV disease (HR in those aged 50-59 years: 2.9 for grade II and 1.5 [p=0.03 and 0.04] for grades III-IV; HR if ≥60 years: 3.3 for grade II and 1.5 for grades III-IV [p<0.001 for both]). PMID:25629984

  4. Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD

    PubMed Central

    Alho, Ana C.; Kim, Haesook T.; Chammas, Marie J.; Reynolds, Carol G.; Matos, Tiago R.; Forcade, Edouard; Whangbo, Jennifer; Nikiforow, Sarah; Cutler, Corey S.; Koreth, John; Ho, Vincent T.; Armand, Philippe; Antin, Joseph H.; Alyea, Edwin P.; Lacerda, Joao F.; Soiffer, Robert J.

    2016-01-01

    The development and maintenance of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT) requires the balanced reconstitution of donor-derived CD4 regulatory T cells (CD4Tregs) as well as effector CD4 (conventional CD4 T cells [CD4Tcons]) and CD8 T cells. To characterize the complex mechanisms that lead to unbalanced recovery of these distinct T-cell populations, we studied 107 adult patients who received T-replete stem cell grafts after reduced-intensity conditioning. Immune reconstitution of CD4Treg, CD4Tcon, and CD8 T cells was monitored for a 2-year period. CD3 T-cell counts gradually recovered to normal levels during this period but CD8 T cells recovered more rapidly than either CD4Tregs or CD4Tcons. Reconstituting CD4Tregs and CD4Tcons were predominantly central memory (CM) and effector memory (EM) cells and CD8 T cells were predominantly terminal EM cells. Thymic generation of naive CD4Tcon and CD8 T cells was maintained but thymic production of CD4Tregs was markedly decreased with little recovery during the 2-year study. T-cell proliferation was skewed in favor of CM and EM CD4Tcon and CD8 T cells, especially 6 to 12 months after HSCT. Intracellular expression of BCL2 was increased in CD4Tcon and CD8 T cells in the first 3 to 6 months after HSCT. Early recovery of naive and CM fractions within each T-cell population 3 months after transplant was also strongly correlated with the subsequent development of chronic graft-versus-host disease (GVHD). These dynamic imbalances favor the production, expansion, and persistence of effector T cells over CD4Tregs and were associated with the development of chronic GVHD. PMID:26670634

  5. Biological quality control for extracorporeal photochemotherapy: Assessing mononuclear cell apoptosis levels in ECP bags of chronic GvHD patients.

    PubMed

    Taverna, Francesca; Coluccia, Paola; Arienti, Flavio; Birolini, Annalisa; Terranova, Laura; Mazzocchi, Arabella; Rini, Francesca; Mariani, Luigi; Melani, Cecilia; Ravagnani, Fernando

    2015-06-01

    Extracorporeal photochemotherapy (ECP) is a treatment approved by the FDA for cutaneous T-cell lymphoma, and it is currently used off-label for graft-versus-host disease (GvHD) and other conditions. In agreement with good practices for the therapeutic use of human cells, quality control has to be performed to validate the ECP procedure with the off-line technique. Since no gold-standard biological test is available, we assessed the apoptosis generated in the ECP bag using a flow cytometric analysis. Thirty-one ECP procedures performed on 13 patients with chronic GvHD were studied by monitoring the induction of mononuclear cell (MNC) apoptosis using annexin V/propidium iodide double staining; residual lymphocyte proliferation to standard mitogens was also measured in 17 of the procedures. The kinetics of apoptosis was analyzed at different times in MNCs untreated or treated with 8-methoxy-psoralen plus ultraviolet A; the variation (ΔAPOPTOSIS ) after 24 h revealed the efficacy of the treatment. In 88.6% of the 31 ECP procedures, ΔAPOPTOSIS was >15% (the "alerting" threshold for ΔAPOPTOSIS was set at 15% on the basis of our data); in the remainder (19.4%), the increment in apoptosis was lower. In four procedures, the proliferation assay was useful for assessing the effect of ECP on the apheretic bag. In conclusion, both flow cytometric assays enabled a biologically significant result to be obtained. In our opinion, the apoptosis test-being faster and easier than the proliferation test-could be a reliable way to validate ECP procedures. PMID:25220858

  6. "Naturally occurring asbestos

    NASA Astrophysics Data System (ADS)

    Cagnard, F.; Lahondère, D.; Blein, O.; Lahfid, A.; Wille, G.

    2012-04-01

    The term asbestos refers to six silicate minerals from amphibole and serpentine groups. By definition, it consists in bundles of thin and flexible long fibers, with high-tensile strength, and chemical and heat resistance. In contrast to asbestos found within commercial products and mining, the specific term ''naturally occurring asbestos'' (NOA) refers to asbestiform minerals occurring within rocks or soils that can be released by human activities or weathering processes. The fact that the exposure to asbestos is related to lung pathologies is now widely demonstrated (e.g. asbestosis, mesothelioma and lung cancer). However, if health risks associated with exposure to NOA exist, they are not yet well documented. The crystallization of natural asbestos occurs in specific Mg-rich lithologies associated with peculiar structural and metamorphic conditions. By recognizing and combining such specific geologic criteria, the presence or the absence of asbestos in bedrock terrains can be reasonably predicted and maps of NOA hazard can be drawn. We present here new results of geological mapping and petrological study concerning the evaluation of the NOA hazard in the Alps and Corsica, in France. The three folds approach consists in (1) a determination of lithologies with potential NOA from a bibliographic compilation and extraction of target zones from a geological geodatabase (2) a geological mapping of the target zones followed by a petrological characterization of sampled asbestiform minerals in the laboratory (optical microscopy, TEM, SEM, and Raman spectroscopy technics), and (3) the drawing of the final map of NOA hazard, at regional-scale. Occurrence criteria can be retained as follows: 1. NOA are abundant in the internal zones of the Alps and Corsica, especially within ophiolitic complexes. Natural asbestos are mostly concentrated within ultramafic rocks but can also occur within basic lithologies such as Mg-metagabbros, metabasalts and meta-pillow-lavas, 2. Asbestos

  7. Association of Cumulative Steroid Dose with Risk of Infection after Treatment for Severe Acute Graft-versus-Host Disease.

    PubMed

    Matsumura-Kimoto, Yayoi; Inamoto, Yoshihiro; Tajima, Kinuko; Kawajiri, Akihisa; Tanaka, Takashi; Hirakawa, Tsuneaki; Ino, Kazuko; Asao, Yu; Tamogami, Hiroyuki; Kono, Chika; Takeda, Wataru; Okinaka, Keiji; Fuji, Shigeo; Kurosawa, Saiko; Kim, Sung-Won; Tanosaki, Ryuji; Yamashita, Takuya; Fukuda, Takahiro

    2016-06-01

    This study aimed to characterize the incidence and risk factors of invasive fungal disease, cytomegalovirus infection, other viral diseases, and gram-negative rod infection after glucocorticoid treatment for severe acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation and to elucidate the associations of cumulative steroid dose with the risks of individual infections. The study cohort included 91 consecutive patients who developed maximum grades III and IV acute GVHD at our center. The mean cumulative prednisolone-equivalent dose was 41 mg/kg during the first 4 weeks. The cumulative incidence rates of fungal disease, cytomegalovirus disease, other viral diseases, and gram-negative rod infection at 6 months after glucocorticoid treatment were remarkably high, at 14%, 21%, 28%, and 20%, respectively. GVHD within 26 days after transplantation and low lymphocyte count at GVHD treatment were associated with increased risks of several infections. Cumulative prednisolone-equivalent steroid doses ≥ 55 mg/kg during the first 4 weeks were associated with an increased risk of fungal disease (hazard ratio, 3.65; P = .03) and cumulative doses ≥ 23 mg/kg were associated with an increased risk of non-cytomegalovirus viral diseases (hazard ratio, 4.14; P = .02). Strategies to reduce the risk of infectious complications are needed, particularly for patients who have risk factors and those who receive high cumulative steroid doses. PMID:26968790

  8. Risk Factors for Steroid-Refractory Acute Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation from Matched Related or Unrelated Donors.

    PubMed

    Calmettes, Claire; Vigouroux, Stéphane; Labopin, Myriam; Tabrizi, Reza; Turlure, Pascal; Lafarge, Xavier; Marit, Gérald; Pigneux, Arnaud; Leguay, Thibaut; Bouabdallah, Krimo; Dilhuydy, Marie-Sarah; Duclos, Cédric; Mohr, Catherine; Lascaux, Axelle; Dumas, Pierre-Yves; Dimicoli-Salazar, Sophie; Saint-Lézer, Arnaud; Milpied, Noël

    2015-05-01

    We performed a retrospective study to identify pretransplantation risk factors for steroid-refractory (SR) acute graft-versus host disease (aGVHD) after allogeneic stem cell transplantation from matched donors in 630 adult patients who underwent transplantation at our center between 2000 and 2012. The cumulative incidence (CI) of SR aGVHD was 11.3% ± 2.3%. The identified independent risk factors were matched unrelated donor (hazard ratio [HR], 2.52; P = .001), female donor for male recipient (HR, 1.84; P = .023) and absence of antithymocyte globulin (HR, 2.02; P = .005). Three risk groups were defined according to the presence of these risk factors. In the whole cohort, the CI of SR aGVHD was 3.5% ± 1.7% in the low-risk group (0 risk factor, n = 115), 9.3% ± 1.6% in the intermediate-risk group (1 risk factor, n = 323), and 19.3% ± 2.9% in the high-risk group (2 or 3 risk factors, n = 192). Our study suggests that pretransplantation characteristics might help identify patients at high risk for SR aGVHD. A risk adapted first-line treatment of aGVHD could be evaluated in those patients. PMID:25617807

  9. Naturally occurring cardiac glycosides.

    PubMed

    Radford, D J; Gillies, A D; Hinds, J A; Duffy, P

    1986-05-12

    Cardiac glycoside poisoning from the ingestion of plants, particularly of oleanders, occurs with reasonable frequency in tropical and subtropical areas. We have assessed a variety of plant specimens for their cardiac glycoside content by means of radioimmunoassays with antibodies that differ in their specificity for cardiac glycosides. Significant amounts of immunoreactive cardiac glycoside were found to be present in the ornamental shrubs: yellow oleander (Thevetia peruviana); oleander (Nerium oleander); wintersweet (Carissa spectabilis); bushman's poison (Carissa acokanthera); sea-mango (Cerbera manghas); and frangipani (Plumeria rubra); and in the milkweeds: redheaded cotton-bush (Asclepias curassavica); balloon cotton (Asclepias fruiticosa); king's crown (Calotropis procera); and rubber vine (Cryptostegia grandifolia). The venom gland of the cane toad (Bufo marinus) also contained large quantities of cardiac glycosides. The competitive immunoassay method permits the rapid screening of specimens that are suspected to contain cardiac glycosides. Awareness of the existence of these plant and animal toxins and their dangers allows them to be avoided and poisoning prevented. The method is also useful for the confirmation of the presence of cardiac glycosides in serum in cases of poisoning. PMID:3086679

  10. Naturally Occurring Food Toxins

    PubMed Central

    Dolan, Laurie C.; Matulka, Ray A.; Burdock, George A.

    2010-01-01

    Although many foods contain toxins as a naturally-occurring constituent or, are formed as the result of handling or processing, the incidence of adverse reactions to food is relatively low. The low incidence of adverse effects is the result of some pragmatic solutions by the US Food and Drug Administration (FDA) and other regulatory agencies through the creative use of specifications, action levels, tolerances, warning labels and prohibitions. Manufacturers have also played a role by setting limits on certain substances and developing mitigation procedures for process-induced toxins. Regardless of measures taken by regulators and food producers to protect consumers from natural food toxins, consumption of small levels of these materials is unavoidable. Although the risk for toxicity due to consumption of food toxins is fairly low, there is always the possibility of toxicity due to contamination, overconsumption, allergy or an unpredictable idiosyncratic response. The purpose of this review is to provide a toxicological and regulatory overview of some of the toxins present in some commonly consumed foods, and where possible, discuss the steps that have been taken to reduce consumer exposure, many of which are possible because of the unique process of food regulation in the United States. PMID:22069686

  11. Analyses of acute graft-versus-host-like reaction in (MRL/lpr----MRL/+) chimeric mice using MRL/lpr-Thy-1. 1 congenic mice

    SciTech Connect

    Nakagawa, T.; Nagata, N.; Hosaka, N.; Inaba, M.; Yasumizu, R.; Ogawa, R.; Ikehara, S. )

    1991-10-01

    When MRL/Mp(-)+/+(MRL/+) mice are lethally irradiated and then reconstituted with MRL/Mp-lpr/lpr (MRL/lpr) bone marrow and/or spleen cells, these MRL/+ mice develop lpr-GVHD which is similar to acute graft-versus-host disease (GVHD). Using a Thy-1 congenic strain of MRL/lpr mice (MRL/lpr-Thy-1.1), the authors analyzed T cell subpopulations in the thymus and spleen of MRL/+ mice suffering from lpr-GVHD. lpr-GVHD was induced in MRL/+ mice by transplantation of bone marrow cells (BMC) from MRL/lpr-Thy-1.1 mice; severe lymphocyte depletion associated with fibrosis was observed in the spleens after 7 weeks of bone marrow transplantation (BMT). Thymocytes of the host MRL/+ thymus were replaced with donor-derived cells from the early stage of lpr-GVHD, whereas in the spleen, a small number of host T cells (Thy-1.2+) (4-5%) were retained until the late stage of lpr-GVHD. Donor-type (Thy-1.1+) T cell subsets were not different from those of nontreated MRL/+ mice in the thymus, whereas in the spleen. CD8+ T cells (Thy-1.1+) reached a peak at 5 weeks after BMT, and CD4+ T cells (Thy-1.1+), a peak at 6 weeks. The elimination of T cells from MRL/lpr BMC had no evident effect on the prevention of lpr-GVHD. T cell subpopulations showed a similar pattern to GVHD elicited by MHC differences. Analyses of autoreactive T cells expressing V beta 5 or V beta 11 revealed that autoreactive T cells were deleted from the peripheral lymph nodes. Interestingly, the levels of IgG anti-ssDNA antibodies markedly increased, and both IgM and IgG rheumatoid factors slightly increased 5 to 7 weeks after BMT. These findings are discussed in relation to not only GVHD elicited by MHC differences but also autoimmune diseases.

  12. Effects of bone marrow mesenchymal stem cells on hematopoietic recovery and acute graft-versus-host disease in murine allogeneic umbilical cord blood transplantation model.

    PubMed

    Li, Zhen Yu; Wang, Chun Qing; Lu, Guang; Pan, Xiu Ying; Xu, Kai Lin

    2014-09-01

    To investigate the effect of bone marrow mesenchymal stem cells (MSC) on hematopoietic recovery and acute graft-versus-host disease (GVHD) in a murine allogeneic umbilical cord blood transplantation (allo-UCBT) model. MSCs were obtained from C57/BL mouse bone marrow. The MSC phenotypes were identified by flow cytometry (FCM), and their ability to differentiate into osteoblasts and adipocytes was tested. Once murine allo-UCBT and aGVHD models were established, mice were divided into five groups: (1) total body irradiation (TBI) group, each mouse receiving 0.3 ml sterile saline infusion after TBI and used as control; (2) UCB group, receiving 2 × 10(6) umbilical cord blood mononuclear cells (UCB-MNC) after TBI; (3) UCB+MSC group, receiving 2 × 10(6) UCB-MNC and 2 × 10(7) MSC after TBI; (4) UCB+SC group, receiving 2 × 10(6) UCB-MNC and 2 × 10(6) spleen cells after TBI; and (5) UCB+SC+MSC group, receiving 2 × 10(6) UCB-MNC, 2 × 10(7) MSC and 2 × 10(6) spleen cells after TBI. To evaluate the engraftment of HSC, the white blood cells, red blood cells, and platelets counts were tested at different time points after transplantation, and the ratio of chimerism was identified by FCM. The acute GVHD clinical scores, recipient mice survival, and the histopathological analyses were used to evaluate the effect of MSC on acute GVHD. MSCs were successfully obtained in vitro and FCM analysis showed that these cells are highly positive for CD90.2, CD44, and negative for CD34, CD45, and they are capable to differentiate into osteoblasts and adipocytes after being induced. Compared to UCB group, the UCB+MSC mice had shorter duration of myelosuppression and higher percentage of donor-derived cells which was up to 22.87 ± 4.3 % and the white blood cell (WBC), red blood cell (RBC), and platelet counts started to increase by day 6 after transplantation. Moreover, the average survival time for UCB+MSC mice was 25.0 ± 10.55 days, while for the UCB group it was 15.5 ± 12.50 days

  13. National Institutes of Health (NIH) Chronic GVHD Staging in Severely Affected Patients: Organ and Global Scoring Correlate with Established Indicators of Disease Severity and Prognosis

    PubMed Central

    Baird, K.; Steinberg, S.M.; Grkovic, L.; Pulanic, D.; Cowen, E.W.; Mitchell, S.A.; Williams, K.M.; Datiles, M.B.; Bishop, R.; Bassim, C.W.; Mays, J.W.; Edwards, D.; Cole, K.; Avila, D.N.; Taylor, T.; Urban, A.; Joe, G.O.; Comis, L.E.; Berger, A.; Stratton, P.; Zhang, D.; Shelhamer, J.H.; Gea-Banacloche, J.C.; Sportes, C.; Fowler, D.H.; Gress, R.E.; Pavletic, S.Z.

    2013-01-01

    Between 2004 and 2010, 189 adult patients were enrolled on the National Cancer Institute (NCI) cross-sectional chronic Graft-versus-Host disease (cGVHD) natural history study. Patients were evaluated by multiple disease scales and outcome measures including the 2005 NIH Consensus Project cGVHD severity score. The purpose of this study is to assess the validity of the NIH scoring variables as determinants of disease severity in severely affected patients in order to standardize clinician evaluation and staging of cGVHD. 125 of 189 patients met criteria for severe cGVHD on the NIH global score and 62 had moderate disease, with a median of 4 (range 1–8) involved organs. Clinician average NIH organ score and the corresponding organ scores performed by subspecialists were highly correlated (r=0.64). NIH global severity scores showed significant associations with nearly all functional and quality of life outcome measures including Lee Scale, SF-36 Physical Component Scale (PCS), 2 minutes walk, grip strength, range of motion and Human Activity Profile (HAP). Joints/fascia, skin, and lung involvement impacted function and quality of life most significantly and showed highest number of correlations with outcome measures. The final Cox model showing factors jointly predictive for survival contained the time from cGVHD diagnosis (>49 vs. ≤49 months, HR=0.23; p=0.0011), absolute eosinophil count of (0–0.5 vs. >0.5 cells/µL, HR=3.95; p=0.0006) at the time of NIH evaluation, and NIH lung score (3 vs. 0–2, HR=11.02; p <0.0001). These results demonstrate that NIH organs and global severity scores are reliable measures of cGVHD disease burden. Strong association with subspecialist evaluation suggests that NIH organs and global severity scores are appropriate for clinical and research assessments, and may serve as a surrogate for more complex sub-specialist exams. In this population of severely affected patients, NIH lung score is the strongest predictor of poor overall

  14. Treatment of acute graft-versus-host disease with prednisolone: significant survival advantage for day +5 responders and no advantage for nonresponders receiving anti-thymocyte globulin.

    PubMed

    Van Lint, Maria Teresa; Milone, Giuseppe; Leotta, Salvatore; Uderzo, Cornelio; Scimè, Rosanna; Dallorso, Sandro; Locasciulli, Anna; Guidi, Stefano; Mordini, Nicola; Sica, Simona; Cudillo, Laura; Fagioli, Franca; Selleri, Carmine; Bruno, Barbara; Arcese, William; Bacigalupo, Andrea

    2006-05-15

    Newly diagnosed patients with acute graft-versus-host disease (GvHD, grades I-IV; n = 211) were given 6-methylprednisolone (6MPred) 2 mg/kg per day for 5 consecutive days; 150 patients (71%) tapered 6MPred on day +5 and were considered responders; 61 patients (29%) could not taper their steroid dose and were considered nonresponders. The cumulative incidence of transplant-related mortality (TRM) for responders and nonresponders is, respectively, 27% and 49% (P = .009), and the 5-year survival is 53% and 35% (P = .007). Nonresponders on day +5 (n = 61) were randomized to receive 6MPred 5 mg/kg per day for 10 days alone (n = 34) or in combination with rabbit anti-thymocyte globulin (ATG, 6.25 mg/kg in 10 days; n = 27). The 2 groups were balanced for clinical and GvHD characteristics. One month after randomization, 26% had a complete response; 23%, a partial response; 33%, stable GvHD; 10%, worsened; and 8%, died. There was no significant difference in response, TRM, and survival between the non-ATG and ATG group. In conclusion, 5 days of prednisolone as first-line therapy of acute GvHD identifies patients with different risk of TRM, and second-line therapy with a combination of 6MPred + ATG does not improve patient outcome, compared with 6MPred alone. PMID:16449522

  15. Methotrexate Reduces the Incidence of Severe Acute Graft-versus-Host Disease without Increasing the Risk of Relapse after Reduced-Intensity Allogeneic Stem Cell Transplantation from Unrelated Donors.

    PubMed

    Vigouroux, Stéphane; Tabrizi, Reza; Melot, Cyril; Coiffard, Joelle; Lafarge, Xavier; Marit, Gérald; Bouabdallah, Krimo; Pigneux, Arnaud; Leguay, Thibaut; Dilhuydy, Marie-Sarah; Schmitt, Anna; Boiron, Jean-Michel; Milpied, Noël

    2011-01-01

    Optimized prophylaxis against graft-versus-host disease (GVHD) after unrelated reduced-intensity allogeneic transplantation when preceded by a conditioning regimen utilizing antithymocyte globulin (ATG) is poorly defined. To investigate the effects of methotrexate (MTX) in this treatment setting, we conducted a retrospective analysis. Sixty-three patients were selected based on the administration of a total dose of 5 mg/kg of ATG in the conditioning regimen and then separated into either group M+ (n = 39), which received MTX or group M- (n = 24), which did not. All patients received cyclosporine. In the M- and M+ groups, cumulative incidences (CI) of grade III-IV acute GVHD (aGVHD) were 43% and 10%, respectively (P = .002). Multivariate analysis indicated that grade III-IV aGVHD was favored by both the absence of MTX and the provision of a female donor for a male recipient. At 2 years, the M+ and M- groups exhibited, respectively: overall survival of 69% and 40% (P = .06), disease-free survival of 57% and 43% (P = .2), nonrelapse mortality of 20% and 44% (P = .1), and incidence of relapse of 27% and 35% (P = .6). These data suggest that MTX reduces the incidence of severe aGVHD without increasing the risk of relapse but with an accompanying trend toward improved survival after unrelated reduced-intensity transplantation with ATG in the conditioning regimen. PMID:20601038

  16. Regulatory B cells are enriched within the IgM memory and transitional subsets in healthy donors but are deficient in chronic GVHD

    PubMed Central

    Khoder, Ahmad; Sarvaria, Anushruti; Alsuliman, Abdullah; Chew, Claude; Sekine, Takuya; Cooper, Nichola; Mielke, Stephan; de Lavallade, Hugues; Muftuoglu, Muharrem; Fernandez Curbelo, Irina; Liu, Enli; Muraro, Paolo A.; Alousi, Amin; Stringaris, Kate; Parmar, Simrit; Shah, Nina; Shaim, Hila; Yvon, Eric; Molldrem, Jeffrey; Rouce, Rayne; Champlin, Richard; McNiece, Ian; Mauri, Claudia; Shpall, Elizabeth J.

    2014-01-01

    A subset of regulatory B cells (Bregs) in mice negatively regulate T-cell immune responses through the secretion of regulatory cytokines such as IL-10 and direct cell-cell contact and have been linked to experimental models of autoimmunity, inflammation, and cancer. However, the regulatory function of Bregs in human disease is much less clear. Here we demonstrate that B cells with immunoregulatory properties are enriched within both the CD19+IgM+CD27+ memory and CD19+CD24hiCD38hi transitional B-cell subsets in healthy human donors. Both subsets suppressed the proliferation and interferon-γ production of CD3/CD28-stimulated autologous CD4+ T cells in a dose-dependent manner, and both relied on IL-10 secretion as well as cell-cell contact, likely mediated through CD80 and CD86, to support their full suppressive function. Moreover, after allogeneic stem cell transplantation, Bregs from patients with chronic graft-versus-host disease (cGVHD) were less frequent and less likely to produce IL-10 than were Bregs from healthy donors and patients without cGVHD. These findings suggest that Bregs may be involved in the pathogenesis of cGVHD and support future investigation of regulatory B cell–based therapy in the treatment of this disease. PMID:25051962

  17. Specificity of T cells invading the skin during acute graft-vs.-host disease after semiallogeneic bone marrow transplantation.

    PubMed Central

    Gaschet, J; Mahé, B; Milpied, N; Devilder, M C; Dréno, B; Bignon, J D; Davodeau, F; Hallet, M M; Bonneville, M; Vié, H

    1993-01-01

    The mechanisms responsible for skin lesions during acute graft-vs.-host disease (aGVHD) after allogeneic bone marrow transplantation (BMT) are poorly understood. The exact role of various effector cell populations and "major" (particularly HLA-DP) or "minor" antigens as target molecules is not known. To investigate the nature of cells responsible for tissue injury, we cultured T cells from skin biopsy first with interleukin 2 (IL-2) alone and then in polyclonal activation conditions to avoid in vitro antigenic sensitization before specificity testing. We applied this method to two biopsies performed during aGVHD after semiallogeneic BMT and obtained cytotoxic T cells against four graft mismatches: CD8+ T cells against HLA-A2.2 and HLA-B27 and CD4+ T cells against HLA-DP101 and HLA-DP401. This demonstrates that T cells with documented specificity can be obtained from an aGVHD lesion without antigenic selection. Moreover, these data directly implicate DP as a potential target antigen for aGVHD. Images PMID:8423212

  18. Radiolabeled Anti-CD45 Antibody with Reduced-Intensity Conditioning and Allogeneic Transplantation for Younger Patients with Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome

    PubMed Central

    Mawad, Raya; Gooley, Ted A.; Rajendran, Joseph G.; Fisher, Darrell R.; Gopal, Ajay K.; Shields, Andrew T.; Sandmaier, Brenda M.; Sorror, Mohamed L.; Deeg, H. Joachim; Storb, Rainer; Green, Damian J.; Maloney, David G.; Appelbaum, Frederick R.; Press, Oliver W.; Pagel, John M.

    2014-01-01

    We treated patients under age 50 years with 131I-anti-CD45 antibody combined with fludarabine and 2 Gy total body irradiation to create an improved hematopoietic cell transplantation (HCT) strategy for advanced acute myeloid leukemia or high-risk myelodysplastic syndrome patients. Fifteen patients received 332–1,561 mCi of 131I, delivering an average of 27 Gy to bone marrow, 84 Gy to spleen, and 21 Gy to liver. Although a maximum dose of 28 Gy was delivered to the liver, no dose-limiting toxicity was observed. Marrow doses were arbitrarily capped at 43 Gy to avoid radiation-induced stromal damage; however no graft failure or evidence of stromal damage was observed. Twelve patients (80%) developed Grade II graft-versus-host disease (GVHD), one patient developed Grade III GVHD, and no patients developed Grade IV GVHD during the first 100 days after HCT. Of the 12 patients with chronic GVHD data, 10 developed chronic GVHD, generally involving the skin and mouth. Six patients (40%) are surviving after a median of 5.0 years (range, 4.2 to 8.3 years). The estimated survival at 1 year was 73% among the 15 treated patients. Eight patients relapsed, 7 of whom subsequently died. The median time to relapse among these 8 patients was 54 days (range, 26 to 1364 days). No cases of non-relapse mortality were observed in the first year after transplant. However, two patients died in remission from complications of chronic GVHD and cardiomyopathy, at 18 months and 14 months after transplant, respectively. This study suggests that patients may tolerate myeloablative doses >28 Gy delivered to the liver using 131I-anti-CD45 antibody in addition to standard reduced intensity conditioning. Moreover, the arbitrary limit of 43 Gy to the marrow may be unnecessarily conservative, and continued escalation of targeted radioimmunotherapy doses may be feasible to further reduce relapse. PMID:24858425

  19. Adiponectin and resistin in acute and chronic graft-vs-host disease patients undergoing allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Robak, Oliver; Kuzmina, Zoya; Winkler, Andreas; Kalhs, Peter; Rabitsch, Werner; Greinix, Hildegard

    2016-01-01

    Aim To investigate the association of adiponectin and resistin levels in patients undergoing hematopoietic stem cell transplantation (HSCT) with the clinical outcome, including the occurrence of acute and chronic graft-vs-host disease (GVHD), non-relapse mortality, and overall survival. Methods We prospectively collected serum samples from 40 patients undergoing either autologous (n = 12; 10 male) or allogeneic (n = 28; 11 male) HSCT for up to 12 months post HSCT and determined adiponectin and resistin serum concentrations using enzyme-linked immunosorbent assay. Results There were no significant differences in adiponectin levels (18.5 vs 9.3 µg/mL, P = 0.071) and adiponectin/BMI ratio (0.82 vs 0.39, P = 0.068) between patients with acute GVHD grades 2-4 and autologous controls. However, resistin values were significantly lower in patients with acute GVHD grades 2-4 than in autologous controls (4.6 vs 7.3 ng/mL, P = 0.030). Adiponectin levels were higher in patients with chronic GVHD (n = 17) than in autologous controls (13.5 vs 7.6 µg/mL, P = 0.051), but the difference was not significant. Adiponectin/BMI ratio was significantly higher in patients with chronic GVHD than in autologous controls (0.59 vs 0.25, P = 0.006). Patients dying from relapse also had significantly lower adiponectin levels (8.2 µg/mL) and adiponectin/BMI ratio (0.3) on admission than surviving allogeneic (15.8 µg/mL, P = 0.030 and 0.7, P = 0.004) and surviving autologous patients (19.2 µg/mL, P = 0.031 and 0.7, P = 0.021). Conclusion Adiponectin and resistin levels were altered in patients with acute and chronic GVHD compared to autologous controls and were associated with overall survival and relapse mortality in patients undergoing allogeneic HSCT. PMID:27374827

  20. Efficacy of Mesenchymal Stem Cell Therapy for Steroid-Refractory Acute Graft-Versus-Host Disease following Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

    PubMed Central

    Chen, Xiaomei; Wang, Chunyan; Yin, Jin; Xu, Jinhuan; Wei, Jia; Zhang, Yicheng

    2015-01-01

    Background Mesenchymal stem cells (MSCs) have been broadly used experimentally in various clinical contexts. The addition of MSCs to initial steroid therapy for acute graft-versus-host disease (aGVHD) may improve patient outcomes. However, investigations regarding prognostic factors affecting the efficacy of MSC therapy for steroid-refractory aGVHD remain controversial. We thus conducted a systematic review and meta-analysis of published clinical trials to determine possible prognostic factors affecting the efficacy of MSCs in treating steroid-refractory aGVHD. Methods and Findings Clinical trials using MSC therapy for steroid-refractory aGVHD were identified by searching PubMed and EMBASE databases. A total of 6,963 citations were reviewed, and 13 studies met the inclusion criteria. A total of 301 patients from thirteen studies were included. Of these, 136 patients showed a complete response (CR), and 69 patients displayed a partial (PR) or mixed response (MR). In total, 205 patients exhibited overall response (ORR). Patients with skin steroid-refractory aGVHD showed a better clinical response than gastrointestinal (CR: odds ratio [OR] = 1.93, 95% confidence interval [95%CI]: 1.05–3.57, p < 0.05) and liver (CR: OR = 2.30, 95%CI: 1.12–4.69, p < 0.05, and ORR: OR = 2.93, 95%CI: 1.06–8.08, p < 0.05) steroid-refractory aGVHD. Those with grade II steroid-refractory aGVHD exhibited a better clinical response following MSC therapy than recipients with grade III–IV (CR: OR = 3.22, 95%CI: 1.24–8.34, p < 0.05). Completion therapy may improve the CR but reduce ORR compared with induction therapy (CR: OR = 0.20, 95%CI: 0.09–0.44, p < 0.05; ORR: OR = 2.18, 95%CI: 1.17–4.05, p = 0.01). There was also a trend towards a better clinical response in children compared with adults (CR: OR = 2.41, 95%CI: 1.01–5.73, p = 0.05). Conclusions Age, skin involvement, lower aGVHD grade, and the number of infusions are the main prognostic factors affecting the efficacy of MSC

  1. Acute generalized erythematous pustulosis occurring with Hailey-Hailey disease.

    PubMed

    Deng, April; Lowitt, Mark

    2012-01-01

    A 70-year-old woman urgently presented with severe eruptive skin dermatitis associated with fever and malaise 7 days after taking clindamycin for an unknown skin eruption. She had a 40-year-long history of well-controlled Hailey-Hailey disease. Physical examination revealed erythrodermic skin changes covering more than 80% of the patient's body surface, with hundreds of nonfollicular pustules. Many of the pustules fused into large bullae, involving the intertriginous as well as the extensor areas, sparing the mucosa. Her body temperature was 103 degrees F. Laboratory workup was significant for neutrophilia with a white cell count > 10,000/mm3. PMID:23008946

  2. Selective Depletion of CD45RA+ T Cells From Allogeneic Peripheral Blood Stem Cell Grafts From HLA-Matched Related and Unrelated Donors in Preventing GVHD

    ClinicalTrials.gov

    2016-07-08

    Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Acute Biphenotypic Leukemia; Acute Leukemia of Ambiguous Lineage; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Blastic Plasmacytoid Dendritic Cell Neoplasm; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Graft Versus Host Disease; Lymphoblastic Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Anemia With Excess Blasts

  3. Acute Disseminated Encephalomyelitis.

    PubMed

    Gray, Matthew Philip; Gorelick, Marc H

    2016-06-01

    Acute disseminated encephalomyelitis is a primarily pediatric, immune-mediated disease characterized by demyelination and polyfocal neurologic symptoms that typically occur after a preceding viral infection or recent immunization. This article presents the pathophysiology, diagnostic criteria, and magnetic resonance imaging characteristics of acute disseminated encephalomyelitis. We also present evaluation and management strategies. PMID:27253358

  4. Effects of T cell depletion in radiation bone marrow chimeras. I. Evidence for a donor cell population which increases allogeneic chimerism but which lacks the potential to produce GVHD

    SciTech Connect

    Sykes, M.; Sheard, M.; Sachs, D.H.

    1988-10-01

    The opposing problems of graft-vs-host disease (GVHD) and failure of alloengraftment present major obstacles to the application of bone marrow transplantation (BMT) across complete MHC barriers. The addition of syngeneic T-cell-depleted (TCD) bone marrow (BM) to untreated fully allogeneic marrow inocula in lethally irradiated mice has been previously shown to provide protection from GVHD. We have used this model to study the effects of allogeneic T cells on levels of chimerism in recipients of mixed marrow inocula. The results indicate that T cells in allogeneic BM inocula eliminate both coadministered recipient-strain and radioresistant host hematopoietic elements to produce complete allogeneic chimerism without clinical GVHD. To determine the role of GVH reactivity in this phenomenon, we performed similar studies in an F1 into parent combination, in which the genetic potential for GVHD is lacking. The presence of T cells in F1 marrow inocula led to predominant repopulation with F1 lymphocytes in such chimeras, even when coadministered with TCD-recipient-strain BM. These results imply that the ability of allogeneic BM cells removed by T cell depletion to increase levels of allochimerism may be mediated by a population which is distinct from that which produces GVHD. These results may have implications for clinical BM transplantation.

  5. Therapeutic efficacy of cord blood-derived mesenchymal stromal cells for the prevention of acute graft-versus-host disease in a xenogenic mouse model.

    PubMed

    Gregoire-Gauthier, Joëlle; Selleri, Silvia; Fontaine, François; Dieng, Mame Massar; Patey, Natalie; Despars, Geneviève; Beauséjour, Christian M; Haddad, Elie

    2012-07-01

    Human mesenchymal stromal cells (MSCs) have been successfully utilized for the treatment of refractory graft-versus-host disease (GvHD). Despite the large number of in vitro and in vivo models developed for clarifying their immunomodulatory properties, the mechanism of action of MSCs remains elusive and their efficacy controversial. Here, we tested the ability of cord blood-derived MSCs to alleviate the symptoms of GvHD induced by the injection of human peripheral blood mononuclear cells into NOD/SCID/γc(-) mice. In this in vivo xeno-GvHD model, we demonstrate that a single MSC injection is able to inhibit GvHD in terms of clinical signs and related mortality. We also show that in this model MSCs act by both immunomodulating T-cells and fostering recovery after irradiation. The translational impact of these findings could provide a reliable preclinical model for studying the efficacy, dosage, and time of administration of human MSCs for the prevention of acute GvHD. PMID:21910645

  6. Acute Arterial Emergencies

    PubMed Central

    Dagnone, L. E.; Brown, P. M.

    1983-01-01

    The response of the primary care physician in the initial assessment and management of acute arterial injuries will often be the deciding factor in survival of life, limb or organ system. Most arterial emergencies occur as a result of trauma, disruption of vessel wall and/or occlusion of flow. The common clinical syndromes of acute arterial emergencies are injuries to and beyond the aorta, acute aortic dissection, ruptured aortic aneurysm, and thromboembolic occlusive arterial disease. The role of arteriography and the urgency of definitive surgical repair in acute arterial emergencies is summarized. PMID:21283323

  7. Consensus diagnostic histopathological criteria for acute gastrointestinal graft versus host disease improve interobserver reproducibility.

    PubMed

    Kreft, Andreas; Mottok, Anja; Mesteri, Ildiko; Cardona, Diana M; Janin, Anne; Kühl, Anja A; Andrulis, Mindaugas; Brunner, Andrea; Shulman, Howard M; Negri, Giovanni; Tzankov, Alexandar; Huber, Elisabeth

    2015-09-01

    Graft versus host disease (GvHD) is a clinically important complication after allogeneic hematopoietic stem cell transplantation (HSCT). Its diagnosis relies on clinical and histopathological findings. In order to evaluate and improve inter-institutional diagnostic agreement on histological diagnosis and grading of acute gastrointestinal GvHD, we conducted a round robin test, which included 33 biopsies from 23 patients after HSCT. Five pathologists from different institutions independently evaluated the original sections from the biopsies submitted for diagnosis. Based on their results, consensus qualitative criteria for the assessment of typical histological features of GvHD (e.g., apoptosis, crypt destruction, mucosa denudation) were proposed, including detailed descriptions as well as histological images. In a second round robin test with involvement of the same pathologists, the reproducibility of both diagnosis and grading had improved. Remaining differences were mostly related to differential diagnostic considerations, including viral infection or toxic side effects of medication, which should be resolved by integrating histopathological findings with proper clinical information. PMID:26164839

  8. Phase II Trial of Reduced-Intensity Busulfan/Clofarabine Conditioning with Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Acute Myeloid Leukemia, Myelodysplastic Syndromes, and Acute Lymphoid Leukemia.

    PubMed

    El-Jawahri, Areej; Li, Shuli; Ballen, Karen K; Cutler, Corey; Dey, Bimalangshu R; Driscoll, Jessica; Hunnewell, Chrisa; Ho, Vincent T; McAfee, Steven L; Poliquin, Cathleen; Saylor, Meredith; Soiffer, Robert J; Spitzer, Thomas R; Alyea, Edwin; Chen, Yi-Bin

    2016-01-01

    Clofarabine has potent antileukemia activity and its inclusion in reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (HSCT) for acute leukemia could potentially improve outcomes. We conducted a phase II study of busulfan (.8 mg/kg i.v. twice daily on days -5, -4, -3, and -2) with clofarabine (40 mg/m(2) i.v. daily on days -5, -4, -3, and -2) conditioning before allogeneic 8/8 HLA-matched related or unrelated HSCT. The primary endpoint was donor neutrophil engraftment by day +40. Secondary endpoints included nonrelapse mortality (NRM), acute and chronic graft-versus-host disease (GVHD), progression-free survival (PFS), and overall survival (OS). Thirty-four patients (acute myeloid leukemia [AML], n = 25; myelodysplastic syndromes, n = 5; and acute lymphoid leukemia, n = 4) were enrolled. Day 40+ engraftment with donor chimerism was achieved in 33 of 34 patients with 1 patient dying before count recovery. Day 100 and 1-year NRM were 5.9% (95% confidence interval [CI], 1.0 to 17.4) and 24% (95% CI, 11 to 39), respectively. The 2-year relapse rate was 26% (95% CI, 13 to 42). Cumulative incidences of acute and chronic GVHD were 21% and 44%, respectively. The 2-year PFS was 50% (95% CI, 32 to 65) and OS was 56% (95% CI, 38 to 71). For patients with AML in first complete remission, 2-year PFS and OS were both 82% (95% CI, 55 to 94). RIC with busulfan and clofarabine leads to successful engraftment with acceptable rates of NRM and GVHD. PMID:26260679

  9. Safety and Tolerability Trial of Abatacept-based Immunosuppression for Prevention of Acute Graft Versus Host Disease (aGVHD) During Transplant

    ClinicalTrials.gov

    2009-11-12

    AML; ALL; Undifferentiated Leukemia; Biphenotypic Leukemia; Refractory Anemia; Refractory Anemia With Ringed Sideroblasts; Refractory Cytopenia With Multilineage Dysplasia; Refractory Cytopenia With Multilineage Dysplasia and Ringed Sideroblasts; Refractory Anemia With Excess Blasts-1 (5-10% Blasts); Refractory Anemia With Excess Blasts-2 (10-20% Blasts); Myelodysplastic Syndrome, Unclassified; MDS Associated With Isolated Del (5q)

  10. Intensified Mycophenolate Mofetil Dosing and Higher Mycophenolic Acid Trough Levels Reduce Severe Acute Graft-versus-Host Disease After Double-Unit Cord Blood Transplantation

    PubMed Central

    Harnicar, S.; Ponce, D.M.; Hilden, P.; Zheng, J.; Devlin, S.M.; Lubin, M.; Pozotrigo, M.; Mathew, S.; Adel, N.; Kernan, N.A.; O'Reilly, R.; Prockop, S.; Scaradavou, A.; Hanash, A.; Jenq, R.; van den Brink, M.; Giralt, S.; Perales, M.A.; Young, J.W.; Barker, J.N.

    2015-01-01

    While mycophenolate mofetil (MMF) has replaced corticosteroids as immunosuppression in cord blood transplantation (CBT), optimal MMF dosing has yet to be established. We intensified MMF dosing from every 12 to 8 hours to augment graft-versus-host disease (GVHD) prophylaxis in double-unit CBT (dCBT) and evaluated outcomes according to the total daily MMF dose/kg in 174 double-unit CBT recipients (median age 39 years, range 1–71) transplanted for hematologic malignancies. Recipients of a MMF dose ≤ the median (36 mg/kg/day) had an increased day 100 grade III-IV acute GVHD (aGVHD) incidence compared with patients who received > 36 mg/kg/day (24% versus 8%, p = 0.008). Recipients of ≤ the median dose who had highly HLA-allele (1-3/6) mismatched dominant units had the highest day 100 grade III-IV aGVHD incidence of 37% (p = 0.009). This finding was confirmed in multivariate analysis (p = 0.053). In 83 patients evaluated for mycophenolic acid (MPA) troughs, those with a mean week 1-2 trough < 0.5 mcg/mL had an increased day 100 grade III-IV aGVHD of 26% versus 9% (p = 0.063), and those who received a low total daily MMF dose and had a low week 1-2 MPA trough had a 40% incidence (p = 0.008). Higher MMF dosing or MPA troughs had no impact on engraftment after myeloablation. This analysis supports intensified MMF dosing in mg/kg/day and MPA trough level monitoring early post-transplant in dCBT recipients. PMID:25687796

  11. Acute Bronchitis

    MedlinePlus

    ... or though physical contact (for example, on unwashed hands). Being exposed to tobacco smoke, air pollution, dusts, vapors, and fumes can also cause acute bronchitis. Less often, bacteria can also cause acute bronchitis. To diagnose acute ...

  12. Cystitis - acute

    MedlinePlus

    Uncomplicated urinary tract infection; UTI - acute; Acute bladder infection; Acute bacterial cystitis ... control. Menopause also increases the risk for a urinary tract infection. The following also increase your chances of having ...

  13. Safety and Outcomes of Extracorporeal Photopheresis With the Therakos Cellex System for Graft-Versus-Host Disease in Pediatric Patients.

    PubMed

    Uygun, Vedat; Daloglu, Hayriye; Karasu, Gulsun; Hazar, Volkan; Yeşilipek, Akif

    2015-04-01

    Extracorporeal photopheresis (ECP) is a difficult procedure to perform in the pediatric population. This is a retrospective review of 12 pediatric patients who underwent photopheresis with the Therakos Cellex system for graft-versus-host disease (GVHD). Acute GVHD (aGVHD) occurred in 6 patients, and overlap syndrome and chronic GVHD (cGVHD) occurred in 4 and 2 patients, respectively. The ECP regimen was the same for all aGVHD and cGVHD patients: initially, every week (2 sessions/wk) for 2 months; next, every 2 weeks for 2 months; and finally, every month for at least 1 year. Improvement was observed in 7 of 10 aGVHD patients (70%) and in 4 of 6 cGVHD patients (66%). Eleven patients had skin involvement before ECP; 9 of them responded to treatment (81%). Gastrointestinal involvement occurred in 8 patients; 5 of them experienced improvement during ECP treatment (62%). All 4 patients with liver involvement failed to respond. No serious adverse reactions occurred. In conclusion, our study demonstrates that ECP with the Therakos Cellex system is a safe treatment option for GVHD in children, allowing the tapering of immunosuppressants by at least half. PMID:25374287

  14. Naturally Occurring Radioactive Materials (NORM)

    SciTech Connect

    Gray, P.

    1997-02-01

    This paper discusses the broad problems presented by Naturally Occuring Radioactive Materials (NORM). Technologically Enhanced naturally occuring radioactive material includes any radionuclides whose physical, chemical, radiological properties or radionuclide concentration have been altered from their natural state. With regard to NORM in particular, radioactive contamination is radioactive material in an undesired location. This is a concern in a range of industries: petroleum; uranium mining; phosphorus and phosphates; fertilizers; fossil fuels; forestry products; water treatment; metal mining and processing; geothermal energy. The author discusses in more detail the problem in the petroleum industry, including the isotopes of concern, the hazards they present, the contamination which they cause, ways to dispose of contaminated materials, and regulatory issues. He points out there are three key programs to reduce legal exposure and problems due to these contaminants: waste minimization; NORM assesment (surveys); NORM compliance (training).

  15. Allogeneic human mesenchymal stem cell therapy (remestemcel-L, Prochymal) as a rescue agent for severe refractory acute graft-versus-host disease in pediatric patients.

    PubMed

    Kurtzberg, Joanne; Prockop, Susan; Teira, Pierre; Bittencourt, Henrique; Lewis, Victor; Chan, Ka Wah; Horn, Biljana; Yu, Lolie; Talano, Julie-An; Nemecek, Eneida; Mills, Charles R; Chaudhury, Sonali

    2014-02-01

    Severe steroid-refractory acute graft-versus-host disease (aGVHD) is related to significant mortality and morbidity after allogeneic stem cell transplantation. Early clinical trials of therapy with human mesenchymal stem cells (hMSCs) in pediatric patients with severe aGVHD resistant to multiple immunosuppressive agents showed promising results. In this study, we evaluated the risk/benefit profile of remestemcel-L (Prochymal), a third-party, off-the-shelf source of hMSCs, as a rescue agent for treatment-resistant aGVHD in pediatric patients. Children with grade B-D aGVHD failing steroids and, in most cases, other immunosuppressive agents were eligible for enrollment. Patients received 8 biweekly i.v. infusions of 2 × 10(6) hMSCs/kg for 4 weeks, with an additional 4 weekly infusions after day +28 for patients who achieved either a partial or mixed response. The enrolled patients compose a very challenging population with severe disease that was nonresponsive to the standard of care, with 88% of the patients experiencing severe aGVHD (grade C or D). Seventy-five patients (median age, 8 yr; 58.7% male; and 61.3% Caucasian) were treated in this study. Sixty-four patients (85.3%) had received an unrelated hematopoietic stem cell graft, and 28 patients (37.3%) had received a cord blood graft. At baseline, the distribution of aGVHD grades B, C, and D was 12.0%, 28.0%, and 60.0%, respectively. The median duration of aGVHD before enrollment was 30 d (range, 2 to 1639 d), and patients failed a median of 3 immunosuppressive agents. Organ involvement at baseline was 86.7% gastrointestinal, 54.7% skin, and 36.0% liver. Thirty-six patients (48.0%) had 2 organs involved, and 11 patients (14.7%) had all 3 organs involved. When stratified by aGVHD grade at baseline, the rate of overall response (complete and partial response) at day +28 was 66.7% for aGVHD grade B, 76.2% for grade C, and 53.3% for grade D. Overall response for individual organs at day +28 was 58.5% for

  16. Allogeneic peripheral blood stem cell transplantation in acute non-lymphoblastic leukemia.

    PubMed

    Arslan, O; Ustün, C; Arat, M; Celebi, H; Akan, H; Beksaç, M; Ilhan, O; Gürman, G; Ozcan, M; Konuk, N; Uysal, A; Koç, H

    1998-12-01

    Unmodified allogeneic peripheral blood stem cell transplantation (alloPBSCT) was performed in 20 consecutive acute non-lymphoblastic leukemia (ANLL) patients from their HLA-identical siblings. There were 11 males and 9 females. Median age was 34 years (range 17-43). Donors were primed with 2.5-15 micrograms/kg/day s.c. granulocyte-colony stimulating factor (G-CSF, Neupogen, Roche). Conditioning regimen was Bu (16 mg/kg) + Cy (120 mg/kg) in 19 patients and high dose Ara-C (3 gr/m2 twice daily for 3 days) for one patient who relapsed after bone marrow transplantation. Eighteen patients were in CR1. CsA + short-term MTX (n = 19) or CsA alone (n = 1) were used for graft versus host disease (GVHD) prophylaxis. The median number of apheresis procedures for each patient was 2 (2-4). A median of 6.5 (3.2-38.2) x 10(8)/kg MNC or 9.4 (2.2-12.4) x 10(6)/kg CD34+ cells were given. Median days to reach granulocyte of > 0.5 x 10(9)/l and platelet of > 50 x 10(9)/l were 12 (10-14) and 15 (11-35) respectively. Day 100 transplant-related mortality was 20 per cent (4/20). Grade 2 to 4 AGVHD was seen in 8 out of 17 (47%) evaluable patients. Severe AGVHD occurred in 3 out of 17 (18%). Clinical CGVHD of all grades developed in 12 out of 17 (70%) evaluable patients. The mean disease-free survival and overall survival were 17 (range: 8-33 months) and 18 months (range: 10-34 months), respectively. In conclusion, alloPBSCT in ANLL is associated with a faster engraftment, no greater incidence of AGVHD, but increased risk of CGVHD. PMID:10414235

  17. Cytomegalovirus induces strong antileukemic effect in acute myeloid leukemia patients following sibling HSCT without ATG-containing regimen.

    PubMed

    Bao, Xiebing; Zhu, Qian; Xue, Shengli; Hu, Xiaohui; Ma, Xiao; Chen, Feng; Chen, Suning; Sun, Aining; Wu, Depei; Yu, Jianhua; Wu, Xiaojin; Qiu, Huiying

    2016-01-01

    A considerable number of studies have demonstrated that cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) could enforce graft-versus leukemia (GVL) effect in acute myeloid leukemia (AML) patients. However, the use of antithymocyte globulin (ATG) as part of graft-versus-host disease (GVHD) prophylaxis may dampen this beneficial effect of CMV replication. In this context, we retrospectively analyzed the effect of CMV reactivation on relapse, survival and prognosis in a total of 227 AML patients who received a myeloablative (MA) conditioning regimen at a single research center between January 2010 and April 2013. Of these 227 patients, 110 cases received non-ATG-containing regimens and 117 cases received ATG-containing regimens. CMV reactivation occurred in 45 patients (41%) among non-ATG regimen group and 73 patients (62%) among ATG regimen group (P = 0.001). At a median time to follow-up of 27.5 months, a lower risk of cumulative relapse incidence associated with CMV reactivation was observed in non-ATG group in multivariate analyses (OR 0.28, 95% CI 0.10-0.79; P = 0.016). However, CMV reactivation after transplantation did not significantly decrease the cumulative incidence of relapse in our ATG group (OR 0.28, 95% CI 0.10-0.79; P = 0.016). Collectively, our results demonstrate that in AML patients following sibling HSCT, the CMV-induced beneficial effect on relapse occurs only in the MA regimens containing no ATG, although ATG promotes CMV reactivation. PMID:27158357

  18. Cytomegalovirus induces strong antileukemic effect in acute myeloid leukemia patients following sibling HSCT without ATG-containing regimen

    PubMed Central

    Bao, Xiebing; Zhu, Qian; Xue, Shengli; Hu, Xiaohui; Ma, Xiao; Chen, Feng; Chen, Suning; Sun, Aining; Wu, Depei; Yu, Jianhua; Wu, Xiaojin; Qiu, Huiying

    2016-01-01

    A considerable number of studies have demonstrated that cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) could enforce graft-versus leukemia (GVL) effect in acute myeloid leukemia (AML) patients. However, the use of antithymocyte globulin (ATG) as part of graft-versus-host disease (GVHD) prophylaxis may dampen this beneficial effect of CMV replication. In this context, we retrospectively analyzed the effect of CMV reactivation on relapse, survival and prognosis in a total of 227 AML patients who received a myeloablative (MA) conditioning regimen at a single research center between January 2010 and April 2013. Of these 227 patients, 110 cases received non-ATG-containing regimens and 117 cases received ATG-containing regimens. CMV reactivation occurred in 45 patients (41%) among non-ATG regimen group and 73 patients (62%) among ATG regimen group (P = 0.001). At a median time to follow-up of 27.5 months, a lower risk of cumulative relapse incidence associated with CMV reactivation was observed in non-ATG group in multivariate analyses (OR 0.28, 95% CI 0.10-0.79; P = 0.016). However, CMV reactivation after transplantation did not significantly decrease the cumulative incidence of relapse in our ATG group (OR 0.28, 95% CI 0.10-0.79; P = 0.016). Collectively, our results demonstrate that in AML patients following sibling HSCT, the CMV-induced beneficial effect on relapse occurs only in the MA regimens containing no ATG, although ATG promotes CMV reactivation. PMID:27158357

  19. Acute chylous peritonitis due to acute pancreatitis.

    PubMed

    Georgiou, Georgios K; Harissis, Haralampos; Mitsis, Michalis; Batsis, Haralampos; Fatouros, Michalis

    2012-04-28

    We report a case of acute chylous ascites formation presenting as peritonitis (acute chylous peritonitis) in a patient suffering from acute pancreatitis due to hypertriglyceridemia and alcohol abuse. The development of chylous ascites is usually a chronic process mostly involving malignancy, trauma or surgery, and symptoms arise as a result of progressive abdominal distention. However, when accumulation of "chyle" occurs rapidly, the patient may present with signs of peritonitis. Preoperative diagnosis is difficult since the clinical picture usually suggests hollow organ perforation, appendicitis or visceral ischemia. Less than 100 cases of acute chylous peritonitis have been reported. Pancreatitis is a rare cause of chyloperitoneum and in almost all of the cases chylous ascites is discovered some days (or even weeks) after the onset of symptoms of pancreatitis. This is the second case in the literature where the patient presented with acute chylous peritonitis due to acute pancreatitis, and the presence of chyle within the abdominal cavity was discovered simultaneously with the establishment of the diagnosis of pancreatitis. The patient underwent an exploratory laparotomy for suspected perforated duodenal ulcer, since, due to hypertriglyceridemia, serum amylase values appeared within the normal range. Moreover, abdominal computed tomography imaging was not diagnostic for pancreatitis. Following abdominal lavage and drainage, the patient was successfully treated with total parenteral nutrition and octreotide. PMID:22563182

  20. Bone marrow transplantation in the rat. III. Structure of the liver inflammatory lesion in acute graft-versus-host disease

    SciTech Connect

    Leszczynski, D.; Renkonen, R.; Haeyry, P.

    1985-08-01

    The liver is a major parenchymal target organ of acute graft-versus-host disease (aGVHD) after bone marrow transplantation in the rat. The authors have analyzed the nature of cellular infiltrates in the liver using monoclonal antibodies against white cell subsets and investigated the anatomic distribution of the inflammatory cell subsets inside the liver parenchyma. Several types of white cells are present in a normal control liver: In the portal area the T-helper (Th) cells predominate, (surface) immunoglobulin-expressing B cells are present in ample numbers, and most of the phagocytes are Ia-positive. In the central vein area the T-suppressor/killer cells (Tsk) dominate, no B cells are present, and most of the phagocytes are Ia-negative. During aGVHD the number of T cells increases rapidly in the portal area; and after an initial strong increase, the Th/Tsk ratio decreases but remains still above 1. In the central vein area there is also an increase in the number of T cells, compared with that in the syngeneic recipient, but the Th/Tsk ratio rapidly decreases and remains uniformly below 1. During aGVHD the B cells entirely disappear from the portal area, whereas a small but distinct number of mature plasma cells with intracellular immunoglobulin appear in the central vein area. Following irradiation the Ia-positive phagocytic cells entirely disappear from the portal area and decrease distinctly in number in the central vein area. During aGVHD the number of Ia-positive phagocytes increases again in both locations. In the central vein area the positive phagocytes are seen over the background level, and, concomitantly, the Ia-negative phagocytes disappear.

  1. Early detection of acute graft-versus-host disease by wireless capsule endoscopy and probe-based confocal laser endomicroscopy: results of a pilot study

    PubMed Central

    Laurent, Valerie; Malard, Florent; Le Rhun, Marc; Chevallier, Patrice; Guillaume, Thierry; Mosnier, Jean-François; Galmiche, Jean-Paul; Mohty, Mohamad

    2014-01-01

    Objective Acute gastrointestinal graft-versus-host disease (GI-GVHD) is usually diagnosed using endoscopic examinations and biopsies for conventional histology. The aim of this pilot study was to determine whether mini-invasive techniques such as probe-based confocal laser endomicroscopy (pCLE) combined with wireless capsule endoscopy (WCE) could detect early lesions of GI-GVHD prior to symptoms. Design Fifteen patients undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT) were prospectively examined with a small bowel WCE, duodenal and colorectal pCLE, and standard biopsies. Per study protocol, all these examinations were scheduled between day 21 and day 28 after allo-HSCT, independently of the presence or absence of digestive symptoms. Results During follow up, eight patients developed acute GI-GVHD. Sensitivity of WCE, pCLE, and histology were 50, 87.5, and 50%, respectively. Specificity of WCE, pCLE, and histology were 80, 71.5, and 80%, respectively. We showed a positive correlation between the Glücksberg scoring system and WCE (rho = 0.543, p = 0.036) and pCLE (rho = 0.727, p = 0.002) but not with standard histology (rho = 0.481, p = 0.069). Conclusions The results from this pilot study suggest that novel methods such as pCLE and WCE could be part of a mini-invasive algorithm for early detection of GI-GVHD. PMID:25360304

  2. Ocular graft versus host disease in allogenic haematopoetic stem cell transplantation in a tertiary care centre in India

    PubMed Central

    Khan, Rehan; Nair, Sridevi; Seth, Tullika; Mishra, Pravas; Mahapatra, Manoranjan; Agarwal, Tushar; Tandon, Radhika; Vanathi, Murugesan

    2015-01-01

    Background & objectives: This study was aimed to report the occurrence of ocular graft versus host disease (oGVHD) in allogeneic haematopoietic stem cell transplantation (allo-HSCT) patients in a tertiary care hospital setting. Methods: A cross-sectional study of ocular surface of allo-HSCT patients was done. Slit lamp biomicroscopy, symptom score, tear meniscus height, fluorescein tear break-up time, Schirmer's test I, ocular surface staining, dry eye severity, ocular surface disease index score were done. Indications for allo-HSCT, human leukocyte antigen (HLA) matching, GVHD risk factor, systemic manifestation and treatment were also noted. Results: GVHD occurred in 44.4 per cent of 54 allo-HSCT patients (mean age 26.7 ± 12 yr) included in the study. GVHD risk factors identified included female gender, relapse, older age of donor, cytomagelo virus (CMV) reactivation, and multiparous female donors. oGVHD was noted in 31.5 per cent with mean time to occurrence being 17.8 ± 21.9 months after the allo-HSCT and was observed in 89.5 per cent of chronic GVHD cases. Acute GVHD (oral and dermatological) involvement showed a significant association with GVHD in our patients (P< 0.001, 0R 23.0, CI 6.4-82.1). Chronic GVHD was observed to be associated with the occurrence of oGVHD (dry eye) (P<0.001, OR = 24.0, CI 0.02 - 0.29). Of the 34 eyes with oGHVD, dry eye of level 3 severity was seen in 16, level 2 in six, level 1 in 12 eyes. Interpretation & conclusions: GVHD occurred in 44.4 per cent of the patients studied in the present study. Acute and chronic GVHD showed a strong association with oGVHD. Dry eye disease due to chronic oGVHD was observed in 17 (31.5%) of 54 allo-HSCT patient with chronic oGVHD occurring in 17 (89.4%) of chronic GVHD cases in allo-HSCT patients. Our study on oGVHD in post allo-HSCT patients in tertiary care centre points towards the fact that ocular morbidity due to dry eye disease as a result of oGVHD is a cause for concern in these patients

  3. Efficacy of tacrolimus/mycophenolate mofetil as acute graft-versus-host disease prophylaxis and the impact of subtherapeutic tacrolimus levels in children after matched sibling donor allogeneic hematopoietic cell transplantation.

    PubMed

    Offer, Katharine; Kolb, Michelle; Jin, Zhezhen; Bhatia, Monica; Kung, Andrew L; George, Diane; Garvin, James H; Robinson, Chalitha; Sosna, Jean; Karamehmet, Esra; Satwani, Prakash

    2015-03-01

    Only a few studies in children have evaluated the efficacy of prophylactic regimens using tacrolimus on acute graft-versus-host disease (aGVHD). As a result, optimal tacrolimus levels in children after matched sibling donor allogeneic hematopoietic cell transplantation (alloHCT) are not well defined. We measured the association between subtherapeutic levels (<10 ng/mL) during weeks 1 to 4 after alloHCT and the cumulative incidence of grades II to IV aGVHD in children. Additionally, we identified optimal lower cutoff levels for tacrolimus. Sixty patients (median age, 8 years) received tacrolimus/mycophenolate mofetil between March 2003 and September 2012. Twenty-three had a malignant disease and 37 nonmalignant disorders. The stem cell source included peripheral blood stem cells (n = 12) and bone marrow or cord blood (n = 48). Conditioning regimen varied. Specifically, 38.3% received a myeloablative regimen, 36.7% receiving a reduced-toxicity regimen, and 25% receiving a reduced-intensity regimen. Tacrolimus was initiated at .03 mg/kg/day via continuous i.v. infusion or .12 mg/kg/day orally. The dose was adjusted to maintain daily steady state concentrations within a range of 10 to 20 ng/mL. The overall incidence of grades II to IV aGVHD was 33.3%. On multivariate analysis, a mean tacrolimus level < 10 ng/mL during week 3 (P = .042; 95% confidence interval, 1.051 to 14.28) was significantly associated with increased incidence of grades II to IV aGVHD. Using weekly receiver operator curves, the optimal lower cutoff for tacrolimus levels was 10 to 11.2 ng/mL. Further prospective studies are warranted to study the incidence of aGVHD comparing the conventional tacrolimus levels of 5 to 15 versus 10 to 15 ng/mL. PMID:25536217

  4. ONE ANTIGEN MISMATCHED RELATED VS. HLA-MATCHED UNRELATED DONOR HEMATOPOIETIC TRANSPLANTATION IN ADULTS WITH ACUTE LEUKEMIA: CIBMTR RESULTS IN THE ERA OF MOLECULAR HLA TYPING

    PubMed Central

    Valcárcel, David; Sierra, Jorge; Wang, Tao; Kan, Fangyu; Gupta, Vikas; Hale, Gregory A.; Marks, David I.; McCarthy, Philip L; Oudshoorn, Machteld; Petersdorf, Effie W; Ringdén, Olle; Setterholm, Michelle; Spellman, Stephen R; Waller, Edmund K.; Gajewski, James L; Marino, Susana R.; Senitzer, David; Lee, Stephanie J.

    2012-01-01

    Purpose Approximately 13% of patients lacking an HLA-identical sibling have a 1-antigen-mismatched related donor (MMRD). Historically, outcomes using a 1-antigen MMRD were considered equivalent to a matched unrelated donor (UD). Recent improvements in unrelated donor (UD) stem cell transplantation (SCT) due to better molecular HLA-matching justifies investigating if UD should be preferred to MMRD in adult patients with acute leukemia. Patients and Methods The outcomes of MMRD (n=89) and HLA-A, B, C, DRB1 allele matched UD (n=700) SCT reported to the CIBMTR between 1995 and 2005 were compared. Patients were transplanted for acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL) in first or second complete remission. Results Donor type was not associated with hematological recovery. Univariate and multivariate comparisons of MMRD vs. HLA-matched UD transplants showed no statistically significant differences in overall survival, disease free survival, transplant related mortality, relapse, and 100-day grade III–IV acute graft-versus-host disease (GVHD). MMRD SCT was associated with a lower rate of chronic GVHD at 1-year, 35% vs 47% p=0.03, which was confirmed in multivariate analysis (RR 0.58, 95% CI 0.39-0.85, p<0.01). Conclusion HLA-matched UD and MMRD SCT are associated with comparable survival. Since less chronic GVHD was observed in MMRD, this option when available remains the first choice in acute leukemia patients without an HLA-identical sibling in need of allogeneic transplantation. PMID:20674756

  5. A Multi-Center Pilot Evaluation of the National Institutes of Health Chronic Graft-versus-Host Disease (cGVHD) Therapeutic Response Measures: Feasibility, Inter-rater Reliability, and Minimum Detectable Change

    PubMed Central

    Mitchell, Sandra A.; Jacobsohn, David; Thormann Powers, Kimberly E.; Carpenter, Paul A.; Flowers, Mary E.D.; Cowen, Edward W.; Schubert, Mark; Turner, Maria; Lee, Stephanie J.; Martin, Paul; Bishop, Michael R.; Baird, Kristin; Bolaños-Meade, Javier; Boyd, Kevin; Fall-Dickson, Jane M.; Gerber, Lynn H.; Guadagnini, Jean-Pierre; Imanguli, Matin; Krumlauf, Michael C.; Lawley, Leslie; Li, Li; Reeve, Bryce B.; Clayton, Janine Austin; Vogelsang, Georgia B.; Pavletic, Steven Z.

    2011-01-01

    The lack of standardized criteria for measuring therapeutic response is a major obstacle to the development of new therapeutic agents for chronic graft-versus-host disease (cGVHD). National Institutes of Health (NIH) consensus criteria for evaluating therapeutic response were published in 2006. We report the results of four consecutive pilot trials evaluating the feasibility and estimating the inter-rater reliability and minimum detectable change of these response criteria. Hematology-oncology clinicians with limited experience in applying the NIH cGVHD response criteria (n=34), participated in a 2.5 hour training session on response evaluation in cGVHD. Feasibility and inter-rater reliability between subspecialty cGVHD experts and this panel of clinician raters were examined in a sample of 25 children and adults with cGVHD. The minimum detectable change was calculated using the standard error of measurement. Clinicians’ impressions of the brief training session, the photo atlas, and the response criteria documentation tools were generally favorable. Performing and documenting the full set of response evaluations required a median of 21 minutes (range 12 to 60 minutes) per rater. The Schirmer tear test required the greatest time of any single test (median 9 minutes). Overall, inter-rater agreement for skin and oral manifestations was modest, however, in the third and fourth trials, the agreement between clinicians and experts for all dimensions except movable sclerosis approached satisfactory values. In the final two trials, the threshold for defining change exceeding measurement error was 19–22% body surface area (BSA) for erythema, 18–26% BSA for movable sclerosis, 17–21% BSA for nonmovable sclerosis, and 2.1–2.6 points on the 15 point NIH Oral cGHVD scale. Agreement between clinician-expert pairs was moderate to substantial for the measures of functional capacity and for the gastrointestinal and global cGVHD rating scales. These results suggest that

  6. Detecting change as it occurs

    NASA Technical Reports Server (NTRS)

    Radok, Uwe; Brown, Timothy J.

    1992-01-01

    Traditionally climate changes have been detected from long series of observations and long after they have happened. Our 'inverse sequential' procedure, for detecting change as soon as it occurs, describes the existing or most recent data by their frequency distribution. Its parameter(s) are estimated both from the existing set of observations and from the same set augmented by 1,2,....j new observations. Individual-value probability products ('likelihoods') are used to form ratios which yield two probabilities for erroneously accepting the existing parameter(s) as valid for the augmented data set, and vice versa. A genuine parameter change is signaled when these probabilities (or a more stable compound probability) show a progressive decrease. New parameter values can then be estimated from the new observations alone using standard statistical techniques. The inverse sequential procedure will be illustrated for global annual mean temperatures (assumed normally distributed), and for annual numbers of North Atlantic hurricanes (assumed to represent Poisson distributions). The procedure was developed, but not yet tested, for linear or exponential trends, and for chi-squared means or degrees of freedom, a special measure of autocorrelation.

  7. Acute Bronchitis

    MedlinePlus

    Bronchitis is an inflammation of the bronchial tubes, the airways that carry air to your lungs. It ... chest tightness. There are two main types of bronchitis: acute and chronic. Most cases of acute bronchitis ...

  8. Improved accuracy of acute graft-versus-host disease staging among multiple centers.

    PubMed

    Levine, John E; Hogan, William J; Harris, Andrew C; Litzow, Mark R; Efebera, Yvonne A; Devine, Steven M; Reshef, Ran; Ferrara, James L M

    2014-01-01

    The clinical staging of acute graft-versus-host disease (GVHD) varies significantly among bone marrow transplant (BMT) centers, but adherence to long-standing practices poses formidable barriers to standardization among centers. We have analyzed the sources of variability and developed a web-based remote data entry system that can be used by multiple centers simultaneously and that standardizes data collection in key areas. This user-friendly, intuitive interface resembles an online shopping site and eliminates error-prone entry of free text with drop-down menus and pop-up detailed guidance available at the point of data entry. Standardized documentation of symptoms and therapeutic response reduces errors in grade assignment and allows creation of confidence levels regarding the diagnosis. Early review and adjudication of borderline cases improves consistency of grading and further enhances consistency among centers. If this system achieves widespread use it may enhance the quality of data in multicenter trials to prevent and treat acute GVHD. PMID:25455279

  9. Improved accuracy of acute graft-versus-host disease staging among multiple centers

    PubMed Central

    Levine, John E.; Hogan, William J.; Harris, Andrew C.; Litzow, Mark R.; Efebera, Yvonne A.; Devine, Steven M.; Reshef, Ran; Ferrara, James L.M.

    2015-01-01

    The clinical staging of acute graft-versus-host disease (GVHD) varies significantly among bone marrow transplant (BMT) centers, but adherence to long-standing practices poses formidable barriers to standardization among centers. We have analyzed the sources of variability and developed a web-based remote data entry system that can be used by multiple centers simultaneously and that standardizes data collection in key areas. This user-friendly, intuitive interface resembles an online shopping site and eliminates error-prone entry of free text with drop-down menus and pop-up detailed guidance available at the point of data entry. Standardized documentation of symptoms and therapeutic response reduces errors in grade assignment and allows creation of confidence levels regarding the diagnosis. Early review and adjudication of borderline cases improves consistency of grading and further enhances consistency among centers. If this system achieves widespread use it may enhance the quality of data in multicenter trials to prevent and treat acute GVHD. PMID:25455279

  10. REDUCED INTENSITY CONDITIONING REGIMENS FOR ALLOGENEIC TRANSPLANTATION IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA

    PubMed Central

    Verneris, Michael R.; Eapen, Mary; Duerst, Reggie; Carpenter, Paul A.; Burke, Michael J.; Afanasyev, B.V.; Cowan, Morton J.; He, Wensheng; Krance, Robert; Li, Chi-Kong; Tan, Poh-Lin; Wagner, John E.; Davies, Stella M.

    2010-01-01

    Reduced intensity conditioning (RIC) regimens have been used extensively in adults with hematological malignancies. To address whether this is a feasible approach for children with acute lymphoblastic leukemia (ALL), we evaluated transplant outcomes in 38 recipients transplanted from 1995–2005 for whom this was their first transplant. The median age at transplant was 12 years and 47% had performance scores <90%. Disease status was first complete remission (CR) in 13%, ≥CR2 in 60% of patients and 22% had active disease at transplantation. Matched related donors were available for a third of patients and about half of whom received bone marrow (BM) and the others, peripheral blood progenitor cells (PBPC). Sixty percent of unrelated donor transplant recipients received PBPC. The day-100 probability of grade 2–4 acute GVHD was 37% and the 3-year probability of chronic GVHD, 26%. At 3-years, the probability of transplant related mortality was 40%, relapse, 37% and disease-free survival (DFS), 30%. These data indicate long-term DFS can be achieved using RIC regimens in children with ALL. Given the relatively small cohort, these findings must be validated in a larger population. PMID:20302960

  11. Acute Scorpion Pancreatitis in Trinidad

    PubMed Central

    Bartholomew, Courtenay

    1970-01-01

    Over a two-month period 30 patients were admitted to hospital following stings of the scorpion of Trinidad, the Tityus trinitatis. In 24 cases acute pancreatitis developed soon after the sting, but in nine of these no abdominal pain occurred. All the patients made an uneventful recovery. Although such complications have been reported no pseudocyst formations or acute haemorrhagic pancreatitis occurred in this series. PMID:5443968

  12. Unrelated Donor Bone Marrow Transplantation for Children With Acute Myeloid Leukemia Beyond First Remission or Refractory to Chemotherapy

    PubMed Central

    Bunin, Nancy J.; Davies, Stella M.; Aplenc, Richard; Camitta, Bruce M.; DeSantes, Kenneth B.; Goyal, Rakesh K.; Kapoor, Neena; Kernan, Nancy A.; Rosenthal, Joseph; Smith, Franklin O.; Eapen, Mary

    2008-01-01

    Purpose Identify prognostic factors that influence outcome after unrelated donor bone marrow transplantation in children with acute myeloid leukemia (AML). Patients and Methods Included are 268 patients (age ≤ 18 years) with AML in second complete remission (n = 142), relapse (n = 90), or primary induction failure (n = 36) at transplantation. All patients received bone marrow grafts from an unrelated donor and a myeloablative conditioning regimen. Cox regression models were constructed to identify risk factors that influence outcome after transplantation. Results In this analysis, the only risk factor that predicted leukemia recurrence and overall and leukemia-free survival was disease status at transplantation. The 5-year probabilities of leukemia-free survival were 45%, 20%, and 12% for patients who underwent transplantation at second complete remission, relapse, and primary induction failure, respectively. As expected, risk of acute but not chronic graft-versus-host disease (GVHD) was lower with T-cell–depleted bone marrow grafts; T-cell–depleted grafts were not associated with higher risks of leukemia recurrence. We observed similar risks of leukemia relapse in patients with and without acute and chronic GVHD. Conclusion Children who underwent transplantation in remission had a superior outcome compared with children who underwent transplantation during relapse or persistent disease. Nevertheless, 20% of children who underwent transplantation in relapse are long-term survivors, suggesting that unrelated donor bone marrow transplantation is an effective therapy in a significant proportion of children with recurrent or primary refractory AML. PMID:18779619

  13. The Sequence of Cyclophosphamide and Myeloablative Total Body Irradiation in Hematopoietic Cell Transplantation for Patients with Acute Leukemia.

    PubMed

    Holter-Chakrabarty, Jennifer L; Pierson, Namali; Zhang, Mei-Jie; Zhu, Xiaochun; Akpek, Görgün; Aljurf, Mahmoud D; Artz, Andrew S; Baron, Frédéric; Bredeson, Christopher N; Dvorak, Christopher C; Epstein, Robert B; Lazarus, Hillard M; Olsson, Richard F; Selby, George B; Williams, Kirsten M; Cooke, Kenneth R; Pasquini, Marcelo C; McCarthy, Philip L

    2015-07-01

    Limited clinical data are available to assess whether the sequencing of cyclophosphamide (Cy) and total body irradiation (TBI) changes outcomes. We evaluated the sequence in 1769 (CyTBI, n = 948; TBICy, n = 821) recipients of related or unrelated hematopoietic cell transplantation who received TBI (1200 to 1500 cGY) for acute leukemia from 2003 to 2010. The 2 cohorts were comparable for median age, performance score, type of leukemia, first complete remission, Philadelphia chromosome-positive acute lymphoblastic leukemia, HLA-matched siblings, stem cell source, antithymocyte globulin use, TBI dose, and type of graft-versus-host disease (GVHD) prophylaxis. The sequence of TBI did not significantly affect transplantation-related mortality (24% versus 23% at 3 years, P = .67; relative risk, 1.01; P = .91), leukemia relapse (27% versus 29% at 3 years, P = .34; relative risk, .89, P = .18), leukemia-free survival (49% versus 48% at 3 years, P = .27; relative risk, .93; P = .29), chronic GVHD (45% versus 47% at 1 year, P = .39; relative risk, .9; P = .11), or overall survival (53% versus 52% at 3 years, P = .62; relative risk, .96; P = .57) for CyTBI and TBICy, respectively. Corresponding cumulative incidences of sinusoidal obstruction syndrome were 4% and 6% at 100 days (P = .08), respectively. This study demonstrates that the sequence of Cy and TBI does not impact transplantation outcomes and complications in patients with acute leukemia undergoing hematopoietic cell transplantation with myeloablative conditioning. PMID:25840335

  14. Acute Graft-versus-Host Disease: Novel Biological Insights.

    PubMed

    Teshima, Takanori; Reddy, Pavan; Zeiser, Robert

    2016-01-01

    Graft-versus-host disease (GVHD) continues to be a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Recent insights into intestinal homeostasis and uncovering of new pathways and targets have greatly reconciled our understanding of GVHD pathophysiology and will reshape contemporary GVHD prophylaxis and treatment. Gastrointestinal (GI) GVHD is the major cause of mortality. Emerging data indicate that intestinal stem cells (ISCs) and their niche Paneth cells are targeted, resulting in dysregulation of the intestinal homeostasis and microbial ecology. The microbiota and their metabolites shape the immune system and intestinal homeostasis, and they may alter host susceptibility to GVHD. Protection of the ISC niche system and modification of the intestinal microbiota and metabolome to restore intestinal homeostasis may, thus, represent a novel approach to modulate GVHD and infection. Damage to the intestine plays a central role in amplifying systemic GVHD by propagating a proinflammatory cytokine milieu. Molecular targeting to inhibit kinase signaling may be a promising approach to treat GVHD, ideally via targeting the redundant effect of multiple cytokines on immune cells and enterocytes. In this review, we discuss insights on the biology of GI GVHD, interaction of microflora and metabolome with the hosts, identification of potential new target organs, and identification and targeting of novel T cell-signaling pathways. Better understanding of GVHD biology will, thus, pave a way to develop novel treatment strategies with great clinical benefits. PMID:26453971

  15. Acute nephritic syndrome

    MedlinePlus

    Glomerulonephritis - acute; Acute glomerulonephritis; Nephritis syndrome - acute ... Acute nephritic syndrome is often caused by an immune response triggered by an infection or other disease. Common causes ...

  16. Acute sacroiliitis.

    PubMed

    Slobodin, Gleb; Rimar, Doron; Boulman, Nina; Kaly, Lisa; Rozenbaum, Michael; Rosner, Itzhak; Odeh, Majed

    2016-04-01

    The purpose of this study was to review the data on the etiology, risk factors, clinical presentations, and diagnosis of acute sacroiliitis. A Pubmed search utilizing the indexing term "acute sacroiliitis" was conducted and the data pertinent to the aim of the review was extracted and organized in accordance with the preplanned structure of the manuscript. The diagnosis of acute sacroiliitis is often challenging because of both the relative rarity of this presentation and diverse character of acute sacroiliac pain, frequently mimicking other, more prevalent disorders. Technetium bone scintigraphy can localize the disease process to the sacroiliac joint, while computed tomography or magnetic resonance imaging can be used for the detailed characterization and the extent of the disease as well as the diagnosis of complications. Pyogenic sacroiliitis is by far the most common cause of acute sacroiliitis. Brucellosis, acute sacroiliitis in the course of reactive arthritis, and crystalline-induced sacroiliitis frequently imitate pyogenic sacroiliitis. Acute sacroiliitis can rarely be also related to hematological malignancies or treatment with isotretinoin. Awareness to the possibility of acute sacroiliitis and a thorough physical examination are the necessary prerequisites to its timely diagnosis, while the appropriate laboratory and imaging studies should confirm the precise diagnosis and direct the appropriate treatment strategy. PMID:26847855

  17. Effect of Age on Outcome of Reduced-Intensity Hematopoietic Cell Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission or With Myelodysplastic Syndrome

    PubMed Central

    McClune, Brian L.; Weisdorf, Daniel J.; Pedersen, Tanya L.; Tunes da Silva, Gisela; Tallman, Martin S.; Sierra, Jorge; DiPersio, John; Keating, Armand; Gale, Robert P.; George, Biju; Gupta, Vikas; Hahn, Theresa; Isola, Luis; Jagasia, Madan; Lazarus, Hillard; Marks, David; Maziarz, Richard; Waller, Edmund K.; Bredeson, Chris; Giralt, Sergio

    2010-01-01

    Purpose Acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) primarily afflict older individuals. Hematopoietic cell transplantation (HCT) is generally not offered because of concerns of excess morbidity and mortality. Reduced-intensity conditioning (RIC) regimens allow increased use of allogeneic HCT for older patients. To define prognostic factors impacting long-term outcomes of RIC regimens in patients older than age 40 years with AML in first complete remission or MDS and to determine the impact of age, we analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Patients and Methods We reviewed data reported to the CIBMTR (1995 to 2005) on 1,080 patients undergoing RIC HCT. Outcomes analyzed included neutrophil recovery, incidence of acute or chronic graft-versus-host disease (GVHD), nonrelapse mortality (NRM), relapse, disease-free survival (DFS), and overall survival (OS). Results Univariate analyses demonstrated no age group differences in NRM, grade 2 to 4 acute GVHD, chronic GVHD, or relapse. Patients age 40 to 54, 55 to 59, 60 to 64, and ≥ 65 years had 2-year survival rates as follows: 44% (95% CI, 37% to 52%), 50% (95% CI, 41% to 59%), 34% (95% CI, 25% to 43%), and 36% (95% CI, 24% to 49%), respectively, for patients with AML (P = .06); and 42% (95% CI, 35% to 49%), 35% (95% CI, 27% to 43%), 45% (95% CI, 36% to 54%), and 38% (95% CI, 25% to 51%), respectively, for patients with MDS (P = .37). Multivariate analysis revealed no significant impact of age on NRM, relapse, DFS, or OS (all P > .3). Greater HLA disparity adversely affected 2-year NRM, DFS, and OS. Unfavorable cytogenetics adversely impacted relapse, DFS, and OS. Better pre-HCT performance status predicted improved 2-year OS. Conclusion With these similar outcomes observed in older patients, we conclude that older age alone should not be considered a contraindication to HCT. PMID:20212255

  18. Naturally occurring dominant drug resistance mutations occur infrequently in the setting of recently acquired hepatitis C

    PubMed Central

    Applegate, Tanya L; Gaudieri, Silvana; Plauzolles, Anne; Chopra, Abha; Grebely, Jason; Lucas, Michaela; Hellard, Margaret; Luciani, Fabio; Dore, Gregory J; Matthews, Gail V

    2014-01-01

    Background Directly Acting Antivirals (DAAs) are predicted to transform hepatitis C (HCV) therapy, yet little is known about the prevalence of naturally occurring resistance mutations in recently acquired HCV. This study aimed to determine the prevalence and frequency of drug resistance mutations in the viral quasispecies among HIV positive and negative individuals with recent HCV. Methods The NS3 protease, NS5A and NS5B polymerase genes were amplified from fifty genotype 1a participants of the Australian Trial in Acute Hepatitis C. Amino acid variations at sites known to be associated with possible drug resistance were analysed by ultra-deep pyrosequencing. Results Twelve percent of individuals harboured dominant resistance mutations, while 36% demonstrated non dominant resistant variants below that detectable by bulk sequencing (ie < 20%) but above a threshold of 1%. Resistance variants (< 1%) were observed at most sites associated with DAA resistance from all classes, with the exception of sofosbuvir. Conclusions Dominant resistant mutations were uncommonly observed in the setting of recent HCV. However, low level mutations to all DAA classes were observed by deep sequencing at the majority of sites, and in most individuals. The significance of these variants and impact on future treatment options remains to be determined. PMID:25105742

  19. Cyclosporine Plus Methotrexate or Cyclosporine Plus Mycophenolate Mofetil as Graft Versus Host Disease Prophylaxis in Acute Leukemia Transplant: Comparison of Toxicity, Engraftment Kinetics and Transplant Outcome.

    PubMed

    Gupta, Alok; Punatar, Sachin; Mathew, Libin; Kannan, Sadhana; Khattry, Navin

    2016-09-01

    We sought to compare two graft-versus-host disease (GVHD) prophylaxis regimen, cyclosporine and methotrexate (CsA+MTX) with CsA+mycophenolate mofetil (MMF) in 77 acute leukemia patients who underwent hematopoietic stem cell transplant (HSCT) between January 2008 and March 2013. Fifty-three patients received CsA+MTX while 24 received CsA+MMF. The incidence of grade 3-4 mucositis and grade 3-4 diarrhea was 74 and 6 % with CsA+MTX compared to 33 % and 21 % with CsA+MMF (P = 0.001 and 0.09 respectively). Forty-two (79 %) patients in CsA+MTX group required total parenteral nutrition compared to 14 (58 %) in CsA+MMF group (P = 0.09). The incidence of engraftment fever was 17 % with CsA+MTX and 41 % with CsA+MMF (P = 0.02). The median time to neutrophil and platelet engraftment was 14 days and 13 days with CsA+MTX compared to 12 days and 10 days with CsA+MMF (P = 0.003 and 0.08 respectively). The incidence of any grade and grade II-IV acute GVHD was 45 and 13 % with CsA+MTX compared to 42 and 29 % with CsA+MMF (P = NS). Incidence of overall and extensive chronic GVHD was 57 and 38 % with CsA+MTX compared to 42 and 17 % with CsA+MMF (P = NS). Incidence of relapse was 38 % with CsA+MTX compared to 33 % with CsA+MMF (P = NS). TRM was 6 % with CsA+MTX and 21 % with CsA+MMF (P = NS). At 2 years, overall survival (OS) was 64 % in CsA+MTX group compared to 46 % in CsA+MMF group (P = NS). We conclude that CsA+MMF is associated with lesser toxicity, faster myeloid engraftment and similar rates of acute and chronic GVHD, TRM, relapse and OS compared to CsA+MTX in acute leukemia transplant. PMID:27429515

  20. Acute malocclusion.

    PubMed

    Dupont, John S

    2006-01-01

    Acute malocclusion can result from disturbances in the maxillary/mandibular tooth relationship. These alterations in the occlusal position can result from high fillings, sinus problems, abscesses, periodontal disease, and moving or erupting teeth. Conditions seen less frequently include acute malocclusions secondary to an event (such as trauma) that make a stable dental relationship an unstable one. Patients can demonstrate any of a number of clinical conditions that interfere with their comfort and ability to function. This article provides information on some of the less familiar causes of acute malocclusion. PMID:16689064

  1. Fatal obstructive lung disease after haploidentical sibling cord blood transplantation.

    PubMed

    Ohnuma, K; Toyoda, Y; Ishida, Y; Honda, K; Nagao, T; Ijiri, R; Tanaka, Y; Goto, K; Hiroki, K; Kigasawa, H; Nishihira, H

    1998-05-01

    We report the case of a patient with fatal obstructive lung disease after an HLA-haploidentical sibling cord blood transplant (CBT), with severe acute GVHD. A 2-year-old girl developed expiratory air trapping gradually with acute and chronic GVHD after CBT for the treatment of ALL. Anti-CMV and immunosuppressive therapy were ineffective, and the patient died of progressive respiratory acidosis. Necropsy of the lung revealed severe bronchiolitis obliterans with cytomegalic inclusion cells in the granulation tissues of the bronchiolitis. Thus, immunologic and GVHD problems can occur even in CBT. PMID:9613788

  2. Acute Pericarditis

    MedlinePlus

    ... large pericardial effusions). Acute pericarditis usually responds to colchicine or NSAIDs (such as aspirin and ibuprofen ) taken ... reduce pain but relieves it by reducing inflammation. Colchicine also decreases the chance of pericarditis returning later. ...

  3. Peripheral blood stem cell versus bone marrow transplantation: A perspective from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

    PubMed

    Byrne, Michael; Savani, Bipin N; Mohty, Mohamad; Nagler, Arnon

    2016-07-01

    Over the past decade, transplantation of peripheral blood hematopoietic cells has increased and is now the predominant graft source for related or unrelated adult allogeneic hematopoietic stem cell transplantation. At the same time, increasing numbers of patients are receiving reduced-intensity conditioning (RIC) prior to hematopoietic stem cell infusion. In prior work using smaller patient numbers and limited data, RIC peripheral blood stem cell (PBSC) transplantation was shown to be noninferior to RIC bone marrow (BM) transplantation for acute leukemia. A recent, large registry analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation showed that peripheral blood grafts result in superior outcomes compared with BM after RIC regimens for acute leukemia. The T-cell-replete PBSC allografts are associated with significant graft-versus-leukemia (GVL) benefits that are important drivers of improved leukemia-free survival and overall survival. However, an increased risk of chronic graft-versus-host disease (cGVHD) after peripheral blood grafts is concerning and long-term follow-up comparing peripheral versus BM grafts after RIC regimens is needed. Further assessment of the long-standing risks should be undertaken in an effort to better understand whether the risk of cGVHD among peripheral blood graft recipients translates into continued GVL effects and long-term remissions and cures or if it results in late morbidity and mortality. PMID:27106798

  4. Takotsubo Cardiomyopathy Occurring in the Postoperative Period.

    PubMed

    Deniz, Süleyman; Bakal, Ömer; İnangil, Gökhan; Şen, Hüseyin; Özkan, Sezai

    2015-02-01

    Takotsubo cardiomyopathy simulates acute myocardial infarction, and it is characterised by reversible left ventricular failure. A case of Takotsubo cardiomyopathy diagnosed after emergency angiography performed in a patient with evidence of acute myocardial infarction in the postoperative period will be described in this report. Transurethral resection of a bladder tumour (TUR-BT) was performed in a 92-year-old male patient by the urology clinic. The patient was transferred to the post-anaesthesia care unit after the operation. An echocardiography was performed because of the sudden onset of dyspnoea, tachycardia (140-150 beats per minute, rhythm-atrial fibrillation) and ST-segment elevation on electrocardiography (ECG) at the first postoperative hour, and midapical dyskinesia was detected at the patient. An immediate angiography was performed due to suspicion of acute coronary syndrome. Patent coronary arteries and temporary aneurysmatic dilatation of the apex of the heart were revealed by angiography. As a result of these findings, the patient was diagnosed with Takotsubo cardiomyopathy by the cardiology service. The patient was discharged uneventfully following 10 days in the intensive care unit. Aneurysm of the apex of the left ventricle and normal anatomy of the coronary arteries in the angiography have diagnostic value for Takotsubo cardiomyopathy. Diuretics (furosemide) and beta-blockers (metoprolol) are commonly used for the treatment of Takotsubo cardiomyopathy. Even though Takotsubo cardiomyopathy is a rare and benign disease, it should be kept in mind in patients suspected for acute myocardial infarction in the postoperative period. PMID:27366464

  5. Long-term oral complications of allogeneic haematopoietic SCT.

    PubMed

    Hull, K M; Kerridge, I; Schifter, M

    2012-02-01

    This study assessed the incidence of long-term oral complications in 88 survivors of allogeneic haematopoietic cell transplantation (HCT). Patients examined were between 6 months and 6 years post-HCT and aged from 19 to 65 years. Subjects were investigated for both the subjective and objective features of long-term adverse oral effects of HCT. The most common oral symptoms reported were xerostomia (44%, n=39) and reduction in taste (20%, n=18). Only a minority of patients (15%) reported that oral disease had a significant adverse impact upon their quality of life. The majority of patients (53%) had clinical markers of oral chronic GVHD (cGVHD). The most frequently identified feature was salivary hypofunction, with 34% of subjects demonstrating a reduction in stimulated saliva. Oral mucosal changes consistent with cGVHD affected 21% of subjects. Oral cGVHD commonly occurs after allogeneic HCT, often coexists with cutaneous, hepatic or ocular cGVHD and may lead to debilitating symptoms. Transplant type and pre-existing acute GVHD are the major risk factors for oral cGVHD. The identification of risk factors specific for oral cGVHD may allow clinicians some foresight into identifying patients at high risk of developing oral cGVHD and encourage attention to education, regular oral surveillance and rigorous preventative oral health strategies both pre- and post-transplant. PMID:21441960

  6. [Acute respiratory failure in neuromuscular disease].

    PubMed

    Damak, H; Décosterd, D

    2015-09-30

    Neuromuscular diseases can affect all respiratory muscles, leading to acute respiratory failure, which is the most common cause of morbidity and mortality in those patients. Two situations must be distinguished. 1) Acute respiratory failure as part of a neuromuscular disorder of acute onset and possibly reversible (Guillain-Barre syndrome, myasthenic crisis...). 2) Acute respiratory failure occurring in a patient with an already advanced neuromuscular disease (amyotrophic lateral sclerosis, Duchenne muscular dystrophy...). This article describes the neuromuscular acute respiratory failure in these different aspects, discusses its initial management in the emergency department and identifies the parameters that have to be monitored. PMID:26619704

  7. Comparison of outcomes of unrelated bone marrow and umbilical cord blood transplants in children with acute leukemia.

    PubMed

    Rocha, V; Cornish, J; Sievers, E L; Filipovich, A; Locatelli, F; Peters, C; Remberger, M; Michel, G; Arcese, W; Dallorso, S; Tiedemann, K; Busca, A; Chan, K W; Kato, S; Ortega, J; Vowels, M; Zander, A; Souillet, G; Oakill, A; Woolfrey, A; Pay, A L; Green, A; Garnier, F; Ionescu, I; Wernet, P; Sirchia, G; Rubinstein, P; Chevret, S; Gluckman, E

    2001-05-15

    In order to compare the outcomes of unrelated umbilical cord blood transplants (UCBTs) or bone marrow transplants, 541 children with acute leukemia (AL) transplanted with umbilical cord blood (n = 99), T-cell-depleted unrelated bone marrow transplants (T-UBMT) (n = 180), or nonmanipulated (UBMT) (n = 262), were analyzed in a retrospective multicenter study. Comparisons were performed after adjustment for patient, disease, and transplant variables. The major difference between the 3 groups was the higher number in the UCBT group of HLA mismatches (defined by serology for class I and molecular typing for DRB1). The donor was HLA mismatched in 92% of UCBTs, in 18% of UBMTs, and in 43% of T-UBMTs (P <.001). Other significant differences were observed in pretransplant disease characteristics, preparative regimens, graft-versus-host disease (GVHD) prophylaxis, and number of cells infused. Nonadjusted estimates of 2-year survival and event-free survival rates were 49% and 43%, respectively, in the UBMT group, 41% and 37% in the T-UBMT group, and 35% and 31% in the UCBT group. After adjustment, differences in outcomes appeared in the first 100 days after the transplantation. Compared with UBMT recipients, UCBT recipients had delayed hematopoietic recovery (Hazard ratio [HR] = 0.37; 95% confidence interval [95CI]: 0.27-0.52; P <.001), increased 100 day transplant-related mortality (HR = 2.13; 95CI: 1.20-3.76; P <.01) and decreased acute graft-versus-host disease (aGVHD) (HR = 0.50; 95CI: 0.34-0.73; P <.001). T-UBMT recipients had decreased aGVHD (HR = 0.25; 95CI: 0.17-0.36; P <.0001) and increased risk of relapse (HR = 1.96; 95CI: 1.11-3.45; P =.02). After day 100 posttransplant, the 3 groups achieved similar results in terms of relapse. Chronic GVHD was decreased after T-UBMT (HR = 0.21; 95CI: 0.11-0.37; P <.0001) and UCBT (HR = 0.24; 95CI: 0.01-0.66; P =.002), and overall mortality was higher in T-UBMT recipients (HR = 1.39; 95CI: 0.97-1.99; P <.07). In conclusion, the

  8. Acute myelogenous leukemia (AML) - children

    MedlinePlus

    Acute myelogenous leukemia - children; AML; Acute myeloid leukemia - children; Acute granulocytic leukemia - children; Acute myeloblastic leukemia - children; Acute non-lymphocytic leukemia (ANLL) - children

  9. Comparison of Outcomes after Transplantation of G-CSF Stimulated Bone Marrow Grafts versus Bone Marrow or Peripheral Blood Grafts from HLA-Matched Sibling Donors for Patients with Severe Aplastic Anemia

    PubMed Central

    Chu, Roland; Brazauskas, Ruta; Kan, Fangyu; Bashey, Asad; Bredeson, Christopher; Camitta, Bruce; Chiang, Kuang-Yueh; Frangoul, Haydar; Gale, Robert Peter; Gee, Adrian; George, Biju; Goldman, Frederick D.; Gross, Thomas G.; Gupta, Vikas; Hale, Gregory A.; Isola, Luis; Ispizua, Alvaro Urbano; Lazarus, Hillard; Marsh, Judith; Russell, James; Sabloff, Mitchell; Waller, Edmund K.; Eapen, Mary

    2010-01-01

    We compared outcomes of patients with severe aplastic anemia (SAA) who received G-CSF stimulated bone marrow (G-BM) (n=78), unstimulated bone marrow (BM) (n=547), or peripheral blood progenitor cells (PBPC) (n=134) from an HLA-matched sibling. Transplantations occurred in 1997–2003. Rates of neutrophil and platelet recovery were not different among the three treatment groups. Grade 2–4 acute graft-versus-host disease (GVHD) (RR 0.82, p=0.539), grade 3–4 acute GVHD (RR 0.74, p=0.535) and chronic GVHD (RR 1.56, p=0.229) were similar after G-BM and BM transplants. Grade 2–4 acute GVHD (RR 2.37, p=0.012) but not grade 3–4 acute GVHD (RR 1.66, p=0.323) and chronic GVHD (RR 5.09, p<0.001) were higher after PBPC transplants compared to G-BM. Grade 2–4 (RR 2.90, p<0.001), grade 3–4 (RR 2.24, p=0.009) acute GVHD and chronic GVHD (RR 3.26, p<0.001) were higher after PBPC transplants compared to BM. Mortality risks were lower after transplantation of BM compared to G-BM (RR 0.63, p=0.05). These data suggest no advantage to using G-BM and the observed higher rates of acute and chronic GVHD in PBPC recipients warrants cautious use of this graft source for SAA. Taken together, BM is the preferred graft for HLA matched sibling transplants for SAA. PMID:21034842

  10. Acute Septic Arthritis

    PubMed Central

    Shirtliff, Mark E.; Mader, Jon T.

    2002-01-01

    Acute septic arthritis may develop as a result of hematogenous seeding, direct introduction, or extension from a contiguous focus of infection. The pathogenesis of acute septic arthritis is multifactorial and depends on the interaction of the host immune response and the adherence factors, toxins, and immunoavoidance strategies of the invading pathogen. Neisseria gonorrhoeae and Staphylococcus aureus are used in discussing the host-pathogen interaction in the pathogenesis of acute septic arthritis. While diagnosis rests on isolation of the bacterial species from synovial fluid samples, patient history, clinical presentation, laboratory findings, and imaging studies are also important. Acute nongonococcal septic arthritis is a medical emergency that can lead to significant morbidity and mortality. Therefore, prompt recognition, rapid and aggressive antimicrobial therapy, and surgical treatment are critical to ensuring a good prognosis. Even with prompt diagnosis and treatment, high mortality and morbidity rates still occur. In contrast, gonococcal arthritis is often successfully treated with antimicrobial therapy alone and demonstrates a very low rate of complications and an excellent prognosis for full return of normal joint function. In the case of prosthetic joint infections, the hardware must be eventually removed by a two-stage revision in order to cure the infection. PMID:12364368

  11. Acute Pneumonia.

    PubMed

    Arshad, Hammad; Fasanya, Adebayo; Cheema, Tariq; Singh, Anil C

    2016-01-01

    Acute pneumonia is an active infection of the lungs that results when an individual at risk gets exposed to a particular microbiological pathogen. Acute pneumonia is the leading cause of death in the United States that is attributable to an infection. The risk factors, pathogenesis, and microbiological organisms involved differ if the pneumonia develops in the community versus health care-associated environment. The development of concise and comprehensive guidelines has led to an improvement in the management of the problem. However, the emergence of multidrug-resistant organisms and the increase in the percentage of elderly population keep mortality risk very substantial. PMID:26919676

  12. Normal gallbladder scintigraphy in acute cholecystitis

    SciTech Connect

    Ohrt, H.J.; Posalaky, I.P.; Shafer, R.B.

    1983-03-01

    Normal gallbladder scintigraphy occurs in 2 to 5% of reported patients with acute cholecystitis. Gallbladder visualization is found in patients with acalculous cholecystitis and in those with recent relief of cystic duct obstruction but persistence of inflammation. A patient is reported who had clinical and pathologic findings of acute cholecystitis but normal gallbladder visualization. This reemphasizes that the diagnosis of acute cholecystitis cannot be excluded by normal gallbladder scintigraphy.

  13. WHERE DOES WATERBORNE GIARDIASIS OCCUR, AND WHY

    EPA Science Inventory

    Over 60 outbreaks of waterborne giardiasis occurred in the United States between 1965 and 1982, mainly in the Northeast, the Rocky Mountain states, and the Pacific states. Outbreaks most often occurred as a result of inadequate or interrupted treatment. Disinfection problems and ...

  14. Acute Pancreatitis

    PubMed Central

    Geokas, Michael C.

    1972-01-01

    For many decades two types of acute pancreatitis have been recognized: the edematous or interstitial and the hemorrhagic or necrotic. In most cases acute pancreatitis is associated with alcoholism or biliary tract disease. Elevated serum or urinary α-amylase is the most important finding in diagnosis. The presence of methemalbumin in serum and in peritoneal or pleural fluid supports the diagnosis of the hemorrhagic form of the disease in patients with a history and enzyme studies suggestive of pancreatitis. There is no characteristic clinical picture in acute pancreatitis, and its complications are legion. Pancreatic pseudocyst is probably the most common and pancreatic abscess is the most serious complication. The pathogenetic principle is autodigestion, but the precise sequence of biochemical events is unclear, especially the mode of trypsinogen activation and the role of lysosomal hydrolases. A host of metabolic derangements have been identified in acute pancreatitis, involving lipid, glucose, calcium and magnesium metabolism and changes of the blood clotting mechanism, to name but a few. Medical treatment includes intestinal decompression, analgesics, correction of hypovolemia and other supportive and protective measures. Surgical exploration is advisable in selected cases, when the diagnosis is in doubt, and is considered imperative in the presence of certain complications, especially pancreatic abscess. PMID:4559467

  15. Development of secondary skull sarcoma after treatment for childhood acute myeloid leukemia.

    PubMed

    Ohno, Makoto; Narita, Yoshitaka; Miyakita, Yasuji; Okita, Yoshiko; Kayama, Takamasa; Shibui, Soichiro

    2012-12-01

    Secondary cancer is a serious late complication in childhood leukemia survivors. Here, we report a case of secondary skull sarcoma developing after treatment for childhood acute myeloid leukemia, including bone marrow transplantation (BMT). This patient had breast cancer 1 year before treatment for the skull sarcoma. The patient underwent macroscopic total removal of the skull tumor with bone margin with postoperative radiation therapy and did not develop tumor recurrence for 25 months. Our patient's experience suggests that survivors of childhood leukemia are at risk of developing skull sarcoma and that multi-agent chemotherapy, including anthracycline, TBI used as conditioning for BMT, and development of GVHD, are possible risk factors. Considering the possibility of multiple secondary malignancies in such patients, careful long-term follow up is mandatory. PMID:22897987

  16. Ventilatory adaptation to hypoxia occurs in serotonin-depleted rats.

    PubMed

    Olson, E B

    1987-08-01

    To test the hypothesis that serotonin mediated respiratory activity is involved in ventilatory adaptation to hypoxia, rats were treated with parachlorophenylalanine (PCPA), a potent, long-acting inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in the biosynthesis of serotonin. In normoxia, a single, intraperitoneal injection of 300 mg PCPA/kg body weight decreased the Paco2 from a control level at 39.1 +/- 0.6 Torr (mean +/- 95% confidence limits) to 34.0 +/- 0.6 Torr measured during a period from 1 to 48 h following PCPA treatment. This PCPA-produced hyperventilation corresponds to an increase of 3.7 +/- 0.5 in the VA (BTPS)/Vco2 (STPD) ratio. Hyperventilation during ventilatory adaptation to hypoxia (PIO2 approximately equal to 90 Torr) was superimposed in an additive fashion on the underlying hyperventilation due to PCPA pretreatment. Specifically, PCPA pretreatment caused an average 3.5 +/- 1.2 increase in the VA/VCO2 ratio determined in acute (1 h) hypoxia, chronic (24 h) hypoxia and acute return to normoxia following chronic hypoxia. Since ventilatory adaptation to hypoxia occurred in rats treated with PCPA, the prolonged, serotonin mediated respiratory activity described by Millhorn et al. (1980b) is probably not important in ventilatory acclimatization to - or deacclimatization from - hypoxia. PMID:2957766

  17. ST elevation occurring during stress testing

    PubMed Central

    Malouf, Diana; Mugmon, Marc

    2016-01-01

    A case is presented of significant reversible ST elevation occurring during treadmill testing, and the coronary anatomy and subsequent course are described, indicating that ischemia is a potential cause of this electrocardiographic finding. PMID:27124164

  18. Human external ophthalmomyiasis occurring in Barbados.

    PubMed

    Levett, P N; Brooker, L; Reifer, C; Prussia, P R; Eberhard, M L

    2004-06-01

    Human infection with the sheep nasal botfly Oestrus ovis occurs sporadically. In most cases, there is a history of a strike in the eye by the adult fly. Human O. ovis has been reported rarely from the Americas. We report the first case of O. ovis infection in the Caribbean region, which occurred in an urban area of Barbados. The patient responded to removal of the larvae from the conjunctiva and symptomatic treatment. PMID:15352754

  19. Acute diarrhea.

    PubMed

    Barr, Wendy; Smith, Andrew

    2014-02-01

    Acute diarrhea in adults is a common problem encountered by family physicians. The most common etiology is viral gastroenteritis, a self-limited disease. Increases in travel, comorbidities, and foodborne illness lead to more bacteria-related cases of acute diarrhea. A history and physical examination evaluating for risk factors and signs of inflammatory diarrhea and/or severe dehydration can direct any needed testing and treatment. Most patients do not require laboratory workup, and routine stool cultures are not recommended. Treatment focuses on preventing and treating dehydration. Diagnostic investigation should be reserved for patients with severe dehydration or illness, persistent fever, bloody stool, or immunosuppression, and for cases of suspected nosocomial infection or outbreak. Oral rehydration therapy with early refeeding is the preferred treatment for dehydration. Antimotility agents should be avoided in patients with bloody diarrhea, but loperamide/simethicone may improve symptoms in patients with watery diarrhea. Probiotic use may shorten the duration of illness. When used appropriately, antibiotics are effective in the treatment of shigellosis, campylobacteriosis, Clostridium difficile, traveler's diarrhea, and protozoal infections. Prevention of acute diarrhea is promoted through adequate hand washing, safe food preparation, access to clean water, and vaccinations. PMID:24506120

  20. Sinusitis (acute)

    PubMed Central

    2008-01-01

    Introduction Acute sinusitis is defined pathologically, by transient inflammation of the mucosal lining of the paranasal sinuses lasting less than 4 weeks. Clinically, it is characterised by nasal congestion, rhinorrhoea, facial pain, hyposmia, sneezing, and, if more severe, additional malaise and fever. It affects 1−5% of the adult population each year in Europe. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in people with clinically diagnosed acute sinusitis, and with radiologically or bacteriologically confirmed acute sinusitis? We searched: Medline, Embase, The Cochrane Library and other important databases up to August 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 19 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics (amoxicillin, co-amoxiclav, doxycycline, cephalosporins, macrolides, different doses [amoxicillin, co-amoxiclav, doxycycline, cephalosporins, macrolides], long-course regimens), antihistamines, cephalosporins or macrolides, decongestants (xylometazoline, phenylephrine, pseudoephedrine), doxycycline, saline nasal washes, steam inhalation, and topical corticosteroids (intra-nasal). PMID:19450327

  1. Sinusitis (acute)

    PubMed Central

    2011-01-01

    Introduction Acute sinusitis is defined pathologically, by transient inflammation of the mucosal lining of the paranasal sinuses lasting less than 4 weeks. Clinically, it is characterised by nasal congestion, rhinorrhoea, facial pain, hyposmia, sneezing, and, if more severe, additional malaise and fever. It affects 1% to 5% of the adult population each year in Europe. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in people with clinically diagnosed acute sinusitis, and in people with radiologically or bacteriologically confirmed acute sinusitis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 19 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics (amoxicillin, amoxicillin–clavulanic acid [co-amoxiclav], doxycycline, cephalosporins, macrolides; different doses, long-course regimens), antihistamines, decongestants (xylometazoline, phenylephrine, pseudoephedrine), saline nasal washes, steam inhalation, and topical corticosteroids (intranasal). PMID:22189346

  2. Acute glomerulonephritis.

    PubMed

    Yoshizawa, N

    2000-09-01

    Acute glomerulonephritis (AGN) is a representative disease of acute nephritic syndrome characterized by the sudden appearance of edema, hematuria, proteinuria, and hypertension. The prototype of AGN is acute poststreptococcal glomerulonephritis (APSGN). "Nephritogenic streptococci" are defined as organisms that are cultured from a patient who develops AGN. Although only a limited number of M-types of streptococci have been recognized as "nephritogenic streptococci", all M-types of streptococci may have nephritogenic potential because the genes for major putative nephritogenic antigens such as SPEB and NAPIr are found to be present in all group A streptococci thus far examined. Pathogenic mechanisms for APSGN involving both humoral and cell-mediated immunity have been recently proposed. The role of humoral immunity is presumed to be mediated by the in situ formation of nephritogenic streptococcal antigen-antibody complexes and circulating immune complexes. While in the cellular immune component a role for delayed-type hypersensitivity has been suggested to contribute to the pathogenesis of APSGN. PMID:10969898

  3. [Acute toxic pneumopathies].

    PubMed

    Garnier, R

    1998-06-15

    The nature and extent of the acute injury due to toxic inhalants depend on the inhalant's solubility in water pH and chemical reactivity, on the aerodynamic diameter of particles (when the inhalant is an aerosol), and on the degree of exposure. Initial signs and symptoms indicate upper airways and bronchial irritation. Laryngeal oedema and (or) severe bronchospasm may be rapidly lethal. After cessation of exposure a transient improvement is generally observed; however a delayed pulmonary oedema may occur within the first 48 hours. On the following days, bacterial surinfection is a common complication. Possible long-term sequelae are reactive airways dysfunction syndrome and bronchiolitis obliterans. PMID:9781191

  4. Feedlot Acute Interstitial Pneumonia.

    PubMed

    Woolums, Amelia R

    2015-11-01

    Acute interstitial pneumonia (AIP) of feedlot cattle is a sporadically occurring respiratory condition that is often fatal. Affected cattle have a sudden onset of labored breathing. There is no confirmed effective treatment of feedlot AIP; however, administration of antibiotics effective against common bacterial respiratory pathogens and nonsteroidal anti-inflammatory drugs, especially aspirin, has been recommended. Protective strategies are not well defined, but efforts to limit dust exposure and heat stress; to ensure consistent formulation, mixing, and delivery of feed; and to identify and treat infectious respiratory disease in a timely manner may decrease rates of feedlot AIP. PMID:26253266

  5. Comparison of reduced-intensity and myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia and acute lymphoblastic leukemia: a meta-analysis.

    PubMed

    Abdul Wahid, S Fadilah; Ismail, Nor-Azimah; Mohd-Idris, Mohd-Razif; Jamaluddin, Fariza Wan; Tumian, NorRafeah; Sze-Wei, Ernie Yap; Muhammad, Norasiah; Nai, Ming Lai

    2014-11-01

    Currently, the indications to perform reduced-intensity conditioning allogeneic hematopoietic stem cell transplant (RIC-HCT) are based on data derived mainly from large registry and single-centre retrospective studies. Thus, at the present time, there is limited direct evidence supporting the current practice in selecting patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) for RIC versus myeloablative conditioning (MAC) transplants. To determine the relationship between dose intensity of conditioning regimen and survival outcomes after allografting in AML/ALL patients, we performed a meta-analysis of 23 clinical trials reported between 1990 and 2013 involving 15,258 adult patients that compare survival outcomes after RIC-HCT versus MAC-HCT. RIC-HCT resulted in comparable <2-year and 2-6 year overall survival (OS) rates post-transplantation even though the RIC-HCT recipients were older and had more active disease than MAC-HCT recipients. The 2-6 year progression-free survival (PFS), nonrelapse mortality, acute graft-versus-host disease (GvHD) and chronic GvHD rates were reduced after RIC-HCT, but relapse rate was increased. Similar outcomes were observed regardless of disease type and status at transplantation. Odds ratio for all outcomes remained comparable with or without performing separate analyses for the year of HCT and for retrospective versus prospective studies. Among RIC-HCT recipients, survival rates were superior if patients were in CR at transplantation. Significant inter-study heterogeneity for aGvHD data and publication bias for PFS data were observed. This meta-analysis showed no OS benefit of MAC-HCT over RIC-HCT across the entire cohort of patients suggesting that RIC-HCT could be an effective therapeutic option for AML/ALL patients who are ineligible for MAC-HCT and CR status is preferred before RIC-HCT. PMID:25072307

  6. Comparison of Reduced-Intensity and Myeloablative Conditioning Regimens for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia: A Meta-Analysis

    PubMed Central

    Ismail, Nor-Azimah; Mohd-Idris, Mohd-Razif; Jamaluddin, Fariza Wan; Tumian, NorRafeah; Sze-Wei, Ernie Yap; Muhammad, Norasiah; Nai, Ming Lai

    2014-01-01

    Currently, the indications to perform reduced-intensity conditioning allogeneic hematopoietic stem cell transplant (RIC-HCT) are based on data derived mainly from large registry and single-centre retrospective studies. Thus, at the present time, there is limited direct evidence supporting the current practice in selecting patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) for RIC versus myeloablative conditioning (MAC) transplants. To determine the relationship between dose intensity of conditioning regimen and survival outcomes after allografting in AML/ALL patients, we performed a meta-analysis of 23 clinical trials reported between 1990 and 2013 involving 15,258 adult patients that compare survival outcomes after RIC-HCT versus MAC-HCT. RIC-HCT resulted in comparable <2-year and 2–6 year overall survival (OS) rates post-transplantation even though the RIC-HCT recipients were older and had more active disease than MAC-HCT recipients. The 2–6 year progression-free survival (PFS), nonrelapse mortality, acute graft-versus-host disease (GvHD) and chronic GvHD rates were reduced after RIC-HCT, but relapse rate was increased. Similar outcomes were observed regardless of disease type and status at transplantation. Odds ratio for all outcomes remained comparable with or without performing separate analyses for the year of HCT and for retrospective versus prospective studies. Among RIC-HCT recipients, survival rates were superior if patients were in CR at transplantation. Significant inter-study heterogeneity for aGvHD data and publication bias for PFS data were observed. This meta-analysis showed no OS benefit of MAC-HCT over RIC-HCT across the entire cohort of patients suggesting that RIC-HCT could be an effective therapeutic option for AML/ALL patients who are ineligible for MAC-HCT and CR status is preferred before RIC-HCT. PMID:25072307

  7. Reprint of: Acute Graft-versus-Host Disease: Novel Biological Insights.

    PubMed

    Teshima, Takanori; Reddy, Pavan; Zeiser, Robert

    2016-03-01

    Graft-versus-host disease (GVHD) continues to be a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Recent insights into intestinal homeostasis and uncovering of new pathways and targets have greatly reconciled our understanding of GVHD pathophysiology and will reshape contemporary GVHD prophylaxis and treatment. Gastrointestinal (GI) GVHD is the major cause of mortality. Emerging data indicate that intestinal stem cells (ISCs) and their niche Paneth cells are targeted, resulting in dysregulation of the intestinal homeostasis and microbial ecology. The microbiota and their metabolites shape the immune system and intestinal homeostasis, and they may alter host susceptibility to GVHD. Protection of the ISC niche system and modification of the intestinal microbiota and metabolome to restore intestinal homeostasis may, thus, represent a novel approach to modulate GVHD and infection. Damage to the intestine plays a central role in amplifying systemic GVHD by propagating a proinflammatory cytokine milieu. Molecular targeting to inhibit kinase signaling may be a promising approach to treat GVHD, ideally via targeting the redundant effect of multiple cytokines on immune cells and enterocytes. In this review, we discuss insights on the biology of GI GVHD, interaction of microflora and metabolome with the hosts, identification of potential new target organs, and identification and targeting of novel T cell-signaling pathways. Better understanding of GVHD biology will, thus, pave a way to develop novel treatment strategies with great clinical benefits. PMID:26899274

  8. Acute pancreatitis: clinical vs. CT findings

    SciTech Connect

    Hill, M.C.; Barkin, J.; Isikoff, M.B.; Silver stein, W.; Kalser, M.

    1982-08-01

    In a prospective study of 91 patients with acute pancreatitis, computed tomographic (CT) findings were correlated with the clinical type of acute pancreatitis. In acute edematous pancreatitis (63 patients; 16 with repeat CT), CT was normal (28%) or showed inflammation limited to the pancreas (61%). Phlegmonous changes were present in 11%, including one patient with focal pancreatic hemorrhage, indicating that clinically unsuspected hemorrhagic pancreatitis can occur. In acute necrotizing (hemorrhagic, suppurative) pancreatitis (nine patients; eight with repeat CT), no patient had a normal CT scan and 89% had phlegmonous changes. One patient had hemorrhagic pancreatitis and three had abscesses. In acute exacerbation of chronic pancreatitis (10 patients; three with repeat CT), there were pancreatic calcifications (70%), a focal mass (40%), and pancreatic ductal dilation (30%). On follow-up CT, the findings of acute pancreatitis did not always disappear with resolution of the clinical symptons. This was especialy true of phlegmonous pancreatitis, where the CT findings could persist for months.

  9. Young Children's Reports of when Learning Occurred

    ERIC Educational Resources Information Center

    Tang, Connie M.; Bartsch, Karen; Nunez, Narina

    2007-01-01

    This study investigated young children's reports of when learning occurred. A total of 96 4-, 5-, and 6-year-olds were recruited from suburban preschools and elementary schools. The children learned an animal fact and a body movement. A week later, children learned another animal fact and another body movement and then answered questions about…

  10. Phonetic Recalibration Only Occurs in Speech Mode

    ERIC Educational Resources Information Center

    Vroomen, Jean; Baart, Martijn

    2009-01-01

    Upon hearing an ambiguous speech sound dubbed onto lipread speech, listeners adjust their phonetic categories in accordance with the lipread information (recalibration) that tells what the phoneme should be. Here we used sine wave speech (SWS) to show that this tuning effect occurs if the SWS sounds are perceived as speech, but not if the sounds…

  11. Diarrhoea in adults (acute)

    PubMed Central

    2008-01-01

    Introduction An estimated 4000 million cases of diarrhoea occurred worldwide in 1996, resulting in 2.5 million deaths. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for acute diarrhoea in adults living in resource-rich countries? What are the effects of treatments for acute mild-to-moderate diarrhoea in adults from resource-rich countries traveling to resource-poor countries? What are the effects of treatments for acute mild-to-moderate diarrhoea in adults living in resource-poor countries? What are the effects of treatments for acute severe diarrhoea in adults living in resource-poor countries? We searched: Medline, Embase, The Cochrane Library and other important databases up to January 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 71 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics, antimotility agents, antisecretory agents, bismuth subsalicylate, diet, intravenous rehydration, nasogastric tube rehydration, and oral rehydration solutions (amino acid oral rehydration solution, bicarbonate oral rehydration solution, reduced osmolarity oral rehydration solution, rice-based oral rehydration solution, standard oral rehydration solution). PMID:19450323

  12. Diarrhoea in adults (acute)

    PubMed Central

    2011-01-01

    Introduction An estimated 4.6 billion cases of diarrhoea occurred worldwide in 2004, resulting in 2.2 million deaths. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for acute diarrhoea in adults living in resource-rich countries? What are the effects of treatments for acute mild-to-moderate diarrhoea in adults from resource-rich countries travelling to resource-poor countries? What are the effects of treatments for acute mild-to-moderate diarrhoea in adults living in resource-poor countries? What are the effects of treatments for acute severe diarrhoea in adults living in resource-poor countries? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 72 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics, antimotility agents, antisecretory agents, bismuth subsalicylate, diet, intravenous rehydration, nasogastric tube rehydration, oral rehydration solutions (amino acid oral rehydration solution, bicarbonate oral rehydration solution, reduced osmolarity oral rehydration solution, rice-based oral rehydration solution, standard oral rehydration solution), vitamin A supplementation, and zinc supplementation. PMID:21718555

  13. Streptococcal acute pharyngitis.

    PubMed

    Anjos, Lais Martins Moreira; Marcondes, Mariana Barros; Lima, Mariana Ferreira; Mondelli, Alessandro Lia; Okoshi, Marina Politi

    2014-07-01

    Acute pharyngitis/tonsillitis, which is characterized by inflammation of the posterior pharynx and tonsils, is a common disease. Several viruses and bacteria can cause acute pharyngitis; however, Streptococcus pyogenes (also known as Lancefield group A β-hemolytic streptococci) is the only agent that requires an etiologic diagnosis and specific treatment. S. pyogenes is of major clinical importance because it can trigger post-infection systemic complications, acute rheumatic fever, and post-streptococcal glomerulonephritis. Symptom onset in streptococcal infection is usually abrupt and includes intense sore throat, fever, chills, malaise, headache, tender enlarged anterior cervical lymph nodes, and pharyngeal or tonsillar exudate. Cough, coryza, conjunctivitis, and diarrhea are uncommon, and their presence suggests a viral cause. A diagnosis of pharyngitis is supported by the patient's history and by the physical examination. Throat culture is the gold standard for diagnosing streptococcus pharyngitis. However, it has been underused in public health services because of its low availability and because of the 1- to 2-day delay in obtaining results. Rapid antigen detection tests have been used to detect S. pyogenes directly from throat swabs within minutes. Clinical scoring systems have been developed to predict the risk of S. pyogenes infection. The most commonly used scoring system is the modified Centor score. Acute S. pyogenes pharyngitis is often a self-limiting disease. Penicillins are the first-choice treatment. For patients with penicillin allergy, cephalosporins can be an acceptable alternative, although primary hypersensitivity to cephalosporins can occur. Another drug option is the macrolides. Future perspectives to prevent streptococcal pharyngitis and post-infection systemic complications include the development of an anti-Streptococcus pyogenes vaccine. PMID:25229278

  14. Acute Kidney Injury in Cirrhosis.

    PubMed

    Karvellas, Constantine J; Durand, Francois; Nadim, Mitra K

    2015-10-01

    Acute kidney injury (AKI) is a frequent complication of end-stage liver disease, especially in those with acute-on-chronic liver failure, occurring in up to 50% of hospitalized patients with cirrhosis. There is no specific blood or urine biomarker that can reliably identify the cause of AKI in cirrhotic patients. This review examines studies used to assess renal dysfunction in cirrhotic patients including new diagnostic criteria and potential novel biomarkers. Although biomarker development to differentiate the cause of AKI in cirrhosis has promise, the utility of biomarkers to determine irreversible renal dysfunction with liver transplant remains lacking, warranting further investigation. PMID:26410141

  15. Young children's reports of when learning occurred.

    PubMed

    Tang, Connie M; Bartsch, Karen; Nunez, Narina

    2007-06-01

    This study investigated young children's reports of when learning occurred. A total of 96 4-, 5-, and 6-year-olds were recruited from suburban preschools and elementary schools. The children learned an animal fact and a body movement. A week later, children learned another animal fact and another body movement and then answered questions about when the different learning events occurred. Responses of children who responded correctly to control questions about time supported the hypothesis that temporal distance questions would elicit more correct responses than would temporal location questions. Partial support was also found for the hypothesis that behavior learning would generate more correct reports than would fact learning. Implications for characterizations of children's developing understanding of knowledge and for applications of those characterizations in education and eyewitness testimony are discussed. PMID:17346740

  16. Changes in joint laxity occurring during pregnancy.

    PubMed Central

    Calguneri, M; Bird, H A; Wright, V

    1982-01-01

    We have studied changes in peripheral joint laxity occurring during pregnancy in 68 females using both the finger hyperextensometer to quantify laxity at the metacarpophalangeal joint of the index finger and Beighton et al.'s modification of the Carter and Wilkinson scoring system. Although the latter system recorded no change, the more sensitive hyperextensometer demonstrated a significant increase in joint laxity during the last trimester of pregnancy (0.02 greater than p greater than 0.01) over the readings from the same individuals after parturition. When primigravidae and multigravidae were compared, a highly significant increase in laxity was found in women having their second baby over those having their first (0.01 greater than p greater than 0.001), though no further increase in laxity occurred in subsequent pregnancies. PMID:7073339

  17. Synthesis of Naturally Occurring Tropones and Tropolones

    PubMed Central

    Liu, Na; Song, Wangze; Schienebeck, Casi M.; Zhang, Min; Tang, Weiping

    2014-01-01

    Tropones and tropolones are an important class of seven-membered non-benzenoid aromatic compounds. They can be prepared directly by oxidation of seven-membered rings. They can also be derived from cyclization or cycloaddition of appropriate precursors followed by elimination or rearrangement. This review discusses the types of naturally occurring tropones and tropolones and outlines important methods developed for the synthesis of tropone and tropolone natural products. PMID:25400298

  18. Naturally Occuring Fish Poisons from Plants

    NASA Astrophysics Data System (ADS)

    Cannon, Jonathan G.; Burton, Robert A.; Wood, Steven G.; Owen, Noel L.

    2004-10-01

    Since prehistoric times, cultures throughout the world have used piscicidal (fish poisoning) plants for fishing. In recent times, scientists have identified many of the plant compounds responsible for killing the fish and have found that these compounds possess other important biological properties, such as insecticidal and anti-cancer activities. This article reviews some of the chemical research that has been performed on naturally occurring fish poisons, including plant sources, methods of use, toxicity, and mechanisms of action of piscicides.

  19. Suppression of Acute Graft-Versus-Host Response by TCDD Is Independent of the CTLA-4-IFN-γ-IDO pathway

    PubMed Central

    Kerkvliet, Nancy I.

    2013-01-01

    Activation of the aryl hydrocarbon receptor (AhR) by its prototypic ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces potent suppression of an acute graft-versus-host (GVH) response and prevents GVH disease (GVHD). Suppression is associated with development of a regulatory population of donor CD4+ CD25+T-cells that express high levels of cytotoxic T-lymphocyte antigen 4 (CTLA-4). However, a direct link between these AhR-induced Tregs (AhR-Tregs) and suppression of GVHD remains to be shown. CTLA-4 is a negative regulator of T-cell responses and is associated with the induction of tolerogenic dendritic cells (DCs) that produce indoleamine 2,3-dioxygenase (IDO). We hypothesized that AhR-Tregs mediate suppression via their enhanced expression of CTLA-4, which, in turn, induces IFN-γ and IDO in host DCs. Subsequent depletion of tryptophan by IDO leads to termination of the donor T-cell response prior to development of effector CTL. Here, we show that despite increased expression of Ifng, Irf3, Irf7, Ido1, and Ido2 in the lymph nodes of TCDD-treated host mice, inhibition of IDO enzyme activity by 1-methyl-tryptophan was unable to relieve TCDD-mediated suppression of the GVH response. Furthermore, treatment with an anti-CTLA-4 antibody that blocks CTLA-4 signaling was also unable to alleviate TCDD-mediated suppression. Alternatively, we investigated the possibility that donor-derived AhR-Tregs produce IFN-γ to suppress effector CTL development. However, suppression of GVHD by TCDD was not affected by the use of Ifng-deficient donor cells. Together, these results indicate that neither overexpression of CTLA-4 nor production of IFN-γ by AhR-Tregs plays a major role in the manifestation of their immunosuppressive function in vivo. PMID:23798565

  20. Acute traumatic patellar dislocation.

    PubMed

    Duthon, V B

    2015-02-01

    Inaugural traumatic patellar dislocation is most often due to trauma sustained during physical or sports activity. Two-thirds of acute patellar dislocations occur in young active patients (less than 20 years old). Non-contact knee sprain in flexion and valgus is the leading mechanism in patellar dislocation, accounting for as many as 93% of all cases. The strong displacement of the patella tears the medial stabilizing structures, and notably the medial patellofemoral ligament (MPFL), which is almost always injured in acute patellar dislocation, most frequently at its femoral attachment. Lateral patellar glide can be assessed with the knee in extension or 20° flexion. Displacement by more than 50% of the patellar width is considered abnormal and may induce apprehension. Plain X-ray and CT are mandatory to diagnose bony risk factors for patellar dislocation, such as trochlear dysplasia or increased tibial tubercle-trochlear groove distance (TT-TG), and plan correction. MRI gives information on cartilage and capsulo-ligamentous status for treatment planning: free bodies or osteochondral fracture have to be treated surgically. If patellar dislocation occurs in an anatomically normal knee and osteochondral fracture is ruled out on MRI, non-operative treatment is usually recommended. PMID:25592052

  1. [Acute myocarditis].

    PubMed

    Combes, Alain

    2012-06-01

    Myocarditis is defined as inflammation of the myocardium accompanied by myocellular necrosis. Acute myocarditis must be considered in patients who present with recent-onset of cardiac failure or arrhythmia. Fulminant myocarditis is a distinct entity characterized by sudden onset of severe congestive heart failure or cardiogenic shock, usually following a flu-like illness, parvovirus B19, human herpesvirus 6, coxsackievirus and adenovirus being the most frequently viruses responsible for the disease. Treatment of myocarditis remains largely supportive, since immunosuppression has not been proven to be beneficial for acute lymphocytic myocarditis. Trials of antiviral therapies, or immunostimulants such as interferons, suggest a potential therapeutic role but require further investigation. Lastly, early recognition of patients rapidly progressing to refractory cardiac failure and their immediate transfer to a medical-surgical center experienced in mechanical circulatory support is warranted. In this setting, ECMO should be the first-line mechanical assistance. For highly unstable patients, a Mobile Cardiac Assistance Unit, that rapidly travels to primary care hospitals with a portable ECMO system and hooks it up before refractory multiorgan failure takes hold, is the preferred option. PMID:22515999

  2. [Acute myocarditis].

    PubMed

    Combes, Alain

    2013-05-01

    Myocarditis is defined as inflammation of the myocardium accompanied by myocellular necrosis. Acute myocarditis must be considered in patients who present with recent onset of cardiac failure or arrhythmia. Fulminant myocarditis is a distinct entity characterized by sudden onset of severe congestive heart failure or cardiogenic shock, usually following a flu-like illness, parvovirus B19, human herpesvirus 6, coxsackievirus and adenovirus being the most frequently viruses responsible for the disease. Treatment of myocarditis remains largely supportive, since immunosuppression has not been proven to be beneficial for acute lymphocytic myocarditis. Trials of antiviral therapies, or immunostimulants such as interferons, suggest a potential therapeutic role but require further investigation. Lastly, early recognition of patients rapidly progressing to refractory cardiac failure and their immediate transfer to a medical-surgical center experienced in mechanical circulatory support is warranted. In this setting, ECMO should be the first-line mechanical assistance. For highly unstable patients, a Mobile Cardiac Assistance Unit, that rapidly travels to primary care hospitals with a portable ECMO system and hooks it up before refractory multiorgan failure takes hold, is the preferred option. PMID:23789482

  3. Acute cholecystitis

    MedlinePlus

    ... that forms in the wall of the gallbladder) Pancreatitis (inflamed pancreas) Persistent bile duct blockage Inflammation of ... draining the liver (may occur after gallbladder surgery) Pancreatitis Perforation Peritonitis (inflammation of the lining of the ...

  4. Ear infection - acute

    MedlinePlus

    Otitis media - acute; Infection - inner ear; Middle ear infection - acute ... Casselbrandt ML, Mandel EM. Acute otitis media and otitis media with effusion. In: Flint PW, Haughey BH, Lund V, et al, eds. Cummings Otolaryngology: Head & Neck Surgery . 6th ed. ...

  5. Transplantation-associated thrombotic microangiopathy is associated with transplantation from unrelated donors, acute graft-versus-host disease and venoocclusive disease of the liver.

    PubMed

    Daly, Andrew S; Hasegawa, Wanda S; Lipton, Jeffrey H; Messner, Hans A; Kiss, Thomas L

    2002-08-01

    Transplantation-associated thrombotic microangiopathy (TA-TMA) has been associated with significantly reduced survival following allogeneic bone marrow transplantation. In this study we describe the course and response to plasma exchange therapy of TA-TMA as well as risk factors for its' development. Twenty-five patients who underwent plasma exchange therapy were matched to fifty control patients selected for transplant indication and stage of disease at the time of transplant. Transplant indications were acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, aplastic anemia, myelodysplastic syndrome and multiple myeloma. Groups were well balanced with respect to disease status, age at time of transplant and use of radiation-based conditioning. TA-TMA was diagnosed a median of 27 days after transplantation and neurological abnormalities were present in ten cases. Patients received a median of 10 (range 2-43) plasma exchange treatments. Hematological responses were recorded in eight cases. Risk factors for the development of TA-TMA included transplantation from unrelated donors (p = 0.002), hepatic venoocclusive disease (VOD) (p = 0.034), grade 2-4 acute graft-versus-host disease (GVHD) (p = 0.042) and bacteremia with diphtheroid organisms (p = 0.009). Only hepatic VOD (p = 0.0026) and grade 2-4 acute GVHD (p = 0.0436) remained significant risk factors for later development of TA-TMA in a multivariate logistic regression model. The median survival of patients with TA-TMA was 66 (range 32-733) days while that of unaffected patients was 742 (range 15-2392) days after transplantation. Only one patient with TA-TMA remains alive 733 days after transplantation. PMID:12201469

  6. Naturally occurring products in cancer therapy

    PubMed Central

    Rajesh, E.; Sankari, Leena S.; Malathi, L.; Krupaa, Jayasri R.

    2015-01-01

    Natural products have been used for the treatment of various diseases and are becoming an important research area for drug discovery. These products, especially phytochemicals have been extensively studies and have exhibited anti-carcinogenic activities by interfering with the initiation, development and progression of cancer through the modulation of various mechanisms including cellular proliferation, differentiation, apoptosis, angiogenesis, and metastasis. This concept is gaining attention because it is a cost-effective alternative to cancer treatment. In this article, we have discussed some of the naturally occurring products used in cancer treatment. PMID:26015704

  7. Naturally occurring anti M complicating ABO grouping.

    PubMed

    Khalid, Safoorah; Dantes, Roelyn; Varghese, Sunu; Al Hakawati, Imadeddin

    2011-01-01

    Anti M is considered a naturally occurring antibody that is usually active at temperatures below 37°C and is thus of no clinical significance. This antibody, if present in an individual, can lead to a discrepancy between forward and reverse ABO grouping and thus creates diagnostic difficulties for blood bank staff. We report a case of a 58-year-old lady who had an unexpected reaction in reverse grouping due to anti M that posed a problem for us in the interpretation of results of her blood group. We also reviewed the literature to find out the significance of such discrepancy in blood grouping. PMID:21393909

  8. Genetic change in BVDV occurs more rapidly during acute infections in pregnant rather than nonpregnant cattle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    BVDV strains show significant sequence variation, so much so that they have been divided into 2 species and the BVDV-1 species into at least 12 subgenotypes. The source of variation is the rather sloppy RNA-dependent RNA polymerase. The mechanism behind selection that results in new BVDV strains wit...

  9. Nipah virus entry can occur by macropinocytosis

    SciTech Connect

    Pernet, Olivier; Pohl, Christine; Ainouze, Michelle; Kweder, Hasan; Buckland, Robin

    2009-12-20

    Nipah virus (NiV) is a zoonotic biosafety level 4 paramyxovirus that emerged recently in Asia with high mortality in man. NiV is a member, with Hendra virus (HeV), of the Henipavirus genus in the Paramyxoviridae family. Although NiV entry, like that of other paramyxoviruses, is believed to occur via pH-independent fusion with the host cell's plasma membrane we present evidence that entry can occur by an endocytic pathway. The NiV receptor ephrinB2 has receptor kinase activity and we find that ephrinB2's cytoplasmic domain is required for entry but is dispensable for post-entry viral spread. The mutation of a single tyrosine residue (Y304F) in ephrinB2's cytoplasmic tail abrogates NiV entry. Moreover, our results show that NiV entry is inhibited by constructions and drugs specific for the endocytic pathway of macropinocytosis. Our findings could potentially permit the rapid development of novel low-cost antiviral treatments not only for NiV but also HeV.

  10. [Acute myocardial infarction during sport].

    PubMed

    Fujiwara, M; Asakuma, S; Nakamura, K; Nakamura, T; Yasutomi, N; Iwasaki, T

    1995-10-01

    Thirty patients with acute myocardial infarction which occurred during sport were investigated to identify the type of sport, prodromata, situations at the onset of disease, habit of exercise, preceding medical evaluation, coronary risk factors, and coronary angiographic findings. Infarction occurred during golf in 12 patients, bowling in 4, gateball in 4, jogging or running in 5, baseball in 2, and tennis or table tennis in 3. The majority of the patients were playing ball games. Twenty-seven patients were men (90%) and 3 were women (10%). All patients had played the same kind of sport for several years. Twenty-four patients had one or more coronary risk factors, and especially 18 patients smoked cigarettes. Nine patients had experienced anterior chest pain but only two patients had received medical evaluation. Coronary angiography was performed in 25 patients (83.3%), revealing single-vessel disease in 14, two-vessel disease in 6, three-vessel disease in 4, and disease of all left main coronary trunks in 1. The acute episode of infarction occurred mainly in spring or fall. Many patients with acute myocardial infarction occurring during sport participate in sports of low or moderate dynamic and low static exercises which are generally regarded safe. Many patients had enjoyed their sports regularly for a long time. Though many patients had coronary risk factors, only a few had received a medical check before their heart attack. PMID:7500263

  11. Acute pain.

    PubMed

    Good, M

    1999-01-01

    The review of acute pain describes the problem of unresolved pain and its effects on the neural, autonomic, and immune systems. Conceptualizations and mechanisms of pain are reviewed as well as theories of pain management. Descriptive studies of patient and nurse factors that inhibit effective pain management are discussed, followed by studies of pharmacological and nonpharmacological interventions. Critical analysis reveals that most studies were atheoretical, and therefore, this proliferation of information lacked conceptual coherence and organization. Furthermore, the nature and extent of barriers to pain management were described, but few intervention studies have been devised, as yet, to modify the knowledge, beliefs, and attitudes of nurses and patients that are barriers to pain management. Although some of the complementary therapies have sufficient research support to be used in clinical pain management, the physiological mechanisms and outcomes need to be studied. It is critical at this time to design studies of interventions to improve assessment, decision making, attentive care, and patient teaching. PMID:10418655

  12. Drug induced acute pancreatitis: does it exist?

    PubMed

    Tenner, Scott

    2014-11-28

    As the incidence of acute pancreatitis continues to rise, establishing the etiology in order to prevent recurrence is important. Although the etiology of acute pancreatitis is not difficult in the majority of patients, almost a quarter of patients are initially labeled as having idiopathic acute pancreatitis. When confronted with a patient with acute pancreatitis and no clear etiology defined as an absence alcoholism, gallstones (ultrasound and/or MRI), a normal triglyceride level, and absence of tumor, it often appears reasonable to consider a drug as the cause of acute pancreatitis. Over 100 drugs have been implicated by case reports as causing acute pancreatitis. While some of these case reports are well written, many case reports represent poorly written experiences of the clinician simply implicating a drug without a careful evaluation. Over-reliance on case reports while ignoring randomized clinical trials and large pharmacoepidemiologic surveys has led to confusion about drug induced acute pancreatitis. This review will explain that drug induced acute pancreatitis does occur, but it is rare, and over diagnosis leads to misconceptions about the disease resulting in inappropriate patient care, increased litigation and a failure to address the true entity: idiopathic acute pancreatitis. PMID:25469020

  13. Drug induced acute pancreatitis: Does it exist?

    PubMed Central

    Tenner, Scott

    2014-01-01

    As the incidence of acute pancreatitis continues to rise, establishing the etiology in order to prevent recurrence is important. Although the etiology of acute pancreatitis is not difficult in the majority of patients, almost a quarter of patients are initially labeled as having idiopathic acute pancreatitis. When confronted with a patient with acute pancreatitis and no clear etiology defined as an absence alcoholism, gallstones (ultrasound and/or MRI), a normal triglyceride level, and absence of tumor, it often appears reasonable to consider a drug as the cause of acute pancreatitis. Over 100 drugs have been implicated by case reports as causing acute pancreatitis. While some of these case reports are well written, many case reports represent poorly written experiences of the clinician simply implicating a drug without a careful evaluation. Over-reliance on case reports while ignoring randomized clinical trials and large pharmacoepidemiologic surveys has led to confusion about drug induced acute pancreatitis. This review will explain that drug induced acute pancreatitis does occur, but it is rare, and over diagnosis leads to misconceptions about the disease resulting in inappropriate patient care, increased litigation and a failure to address the true entity: idiopathic acute pancreatitis. PMID:25469020

  14. Acute and subacute idiopathic interstitial pneumonias.

    PubMed

    Taniguchi, Hiroyuki; Kondoh, Yasuhiro

    2016-07-01

    Idiopathic interstitial pneumonias (IIPs) may have an acute or subacute presentation, or acute exacerbation may occur in a previously subclinical or unrecognized chronic IIP. Acute or subacute IIPs include acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia (COP), nonspecific interstitial pneumonia (NSIP), acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) and AE-NSIP. Interstitial lung diseases (ILDs) including connective tissue disease (CTD) associated ILD, hypersensitivity pneumonitis, acute eosinophilic pneumonia, drug-induced lung disease and diffuse alveolar haemorrhage need to be differentiated from acute and subacute IIPs. Despite the severe lack of randomized controlled trials for the treatment of acute and subacute IIPs, the mainstream treatment remains corticosteroid therapy. Other potential therapies reported in the literature include corticosteroids and immunosuppression, antibiotics, anticoagulants, neutrophil elastase inhibitor, autoantibody-targeted treatment, antifibrotics and hemoperfusion therapy. With regard to mechanical ventilation, patients in recent studies with acute and subacute IIPs have shown better survival than those in previous studies. Therefore, a careful value-laden decision about the indications for endotracheal intubation should be made for each patient. Noninvasive ventilation may be beneficial to reduce ventilator associated pneumonia. PMID:27123874

  15. Acute tubular nephropathy in a patient with acute HIV infection: review of the literature.

    PubMed

    Ananworanich, Jintanat; Datta, Anandita A; Fletcher, James Lk; Townamchai, Natavudh; Chomchey, Nitiya; Kroon, Eugene; Sereti, Irini; Valcour, Victor; Kim, Jerome H

    2014-01-01

    We report a 57-year old man with diabetes mellitus and hypertension who presented with acute HIV infection. Routine blood tests showed an elevated blood urea nitrogen and creatinine. Renal biopsy showed acute tubular nephropathy, which has not been reported to occur during acute HIV infection, in the absence of rhabdomyolysis or multiple organ system failure. Antiretroviral therapy was initiated. His renal failure gradually resolved without further intervention. At one year of follow-up his HIV RNA was undetectable, and his renal function was normal. The case illustrates a rare manifestation of acute HIV infection - acute renal failure - in an older man with diabetes and hypertension. In this setting acute kidney injury might mistakenly have been attributed to his chronic comorbidities, and this case supports early HIV-1 testing in the setting of a high index of suspicion. PMID:25745498

  16. Introduction to naturally occurring radioactive material

    SciTech Connect

    Egidi, P.

    1997-08-01

    Naturally occurring radioactive material (NORM) is everywhere; we are exposed to it every day. It is found in our bodies, the food we eat, the places where we live and work, and in products we use. We are also bathed in a sea of natural radiation coming from the sun and deep space. Living systems have adapted to these levels of radiation and radioactivity. But some industrial practices involving natural resources concentrate these radionuclides to a degree that they may pose risk to humans and the environment if they are not controlled. Other activities, such as flying at high altitudes, expose us to elevated levels of NORM. This session will concentrate on diffuse sources of technologically-enhanced (TE) NORM, which are generally large-volume, low-activity waste streams produced by industries such as mineral mining, ore benefication, production of phosphate Fertilizers, water treatment and purification, and oil and gas production. The majority of radionuclides in TENORM are found in the uranium and thorium decay chains. Radium and its subsequent decay products (radon) are the principal radionuclides used in characterizing the redistribution of TENORM in the environment by human activity. We will briefly review other radionuclides occurring in nature (potassium and rubidium) that contribute primarily to background doses. TENORM is found in many waste streams; for example, scrap metal, sludges, slags, fluids, and is being discovered in industries traditionally not thought of as affected by radionuclide contamination. Not only the forms and volumes, but the levels of radioactivity in TENORM vary. Current discussions about the validity of the linear no dose threshold theory are central to the TENORM issue. TENORM is not regulated by the Atomic Energy Act or other Federal regulations. Control and regulation of TENORM is not consistent from industry to industry nor from state to state. Proposed regulations are moving from concentration-based standards to dose

  17. Umbilical Cord Blood Transplantation Outcomes in Acute Myelogenous Leukemia/Myelodysplastic Syndromes Patients ≥70 Years Old

    PubMed Central

    Sandhu, Karamjeet S; Brunstein, Claudio; DeFor, Todd; Bejanyan, Nelli; Arora, Mukta; Warlick, Erica; Weisdorf, Daniel; Ustun, Celalettin

    2016-01-01

    The maximum age of patients receiving allogeneic hematopoietic stem cell transplantation (alloHCT) has been moving up over time. However, the availability of a suitable HLA-matched sibling donor may limit access of this patient population to alloHCT. We retrospectively investigated the outcomes of umbilical cord blood transplantation (UCBT) after reduced-intensity conditioning regimens in patients aged ≥70 years with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) between 2010 and 2014. During this period 70 patients with AML/MDS were referred to our center for alloHCT consideration. Twenty-two patients (33%) received alloHCT: 10 UCBT, 9 HLA full-matched sibling donor transplantation, 2 haploidentical alloHCT, and 1 unrelated donor alloHCT. In UCBT, cumulative incidences of nonrelapse mortality and relapse were 20% and 30% at 2 years, respectively. The cumulative incidence of acute graft-versus-host disease (GVHD) at day +100 and chronic GVHD at 2 years was 10%. Seven patients had viral reactivation/infections. Rates of overall survival and disease-free survival were 60% and 50% at 2 years, respectively. Moreover, these outcomes seemed to be similar to that of patients aged 60 to 69 years receiving UCBT (n = 60) and patients aged ≥70 years receiving HLA full-matched sibling donor transplantation (n = 9). These results suggest that UCBT is feasible in selected AML/MDS patients aged ≥70 years. In fact, UCBT shortens the required time for an unrelated donor search and thus increases the chance of proceeding with alloHCT, which might contribute to higher rates of alloHCT in the referral group. Outcomes of UCBT are promising; however, larger studies with a longer follow-up are needed. PMID:26415559

  18. The Sequence of Cyclophosphamide and Myeloablative Total Body Irradiation in Hematopoietic Cell Transplant for Patients with Acute Leukemia

    PubMed Central

    Holter-Chakrabarty, Jennifer L.; Pierson, Namali; Zhang, Mei-Jie; Zhu, Xiaochun; Akpek, Görgün; Aljurf, Mahmoud D.; Artz, Andrew S.; Baron, Frédéric; Bredeson, Christopher N.; Dvorak, Christopher C.; Epstein, Robert B.; Lazarus, Hillard M.; Olsson, Richard F.; Selby, George B.; Williams, Kirsten M.; Cooke, Kenneth R.; Pasquini, Marcelo C.; McCarthy, Philip L.

    2015-01-01

    Limited clinical data are available to assess whether the sequencing of cyclophosphamide (Cy) and total body irradiation (TBI) changes outcomes. We evaluated the sequence in 1769 (CyTBI N=948, TBICy N=821) recipients of related or unrelated hematopoietic cell transplantation (HCT) who received TBI (1200-1500cGY) for acute leukemia from 2003 to 2010. The two cohorts were comparable for median age, performance score, type of leukemia, first complete remission, Ph+ ALL, HLA matched siblings, stem cell source, anti-thymocyte globulin use, TBI dose, and type of graft-versus-host disease (GVHD) prophylaxis. The sequence of TBI did not significantly affect TRM (24% vs. 23% at 3y, p=0.67; relative risk [RR] 1.01, p=0.91), leukemia relapse (27% vs. 29% at 3y, p=0.34; RR 0.89, p=0.18), leukemia-free survival (49% vs. 48% at3y, p=0.27; RR 0.93, p=0.29), chronic GVHD (45% vs. 47% at 1y, p=0.39; RR 0.9, p=0.11) or overall survival (53% vs. 52% at 3y, p=0.62; RR 0.96, p=0.57) for CyTBI and TBICy respectively. Corresponding cumulative incidences of sinusoidal obstruction syndrome were 4% and 6% at 100 days (p=0.08). This study demonstrates that the sequence of Cy and TBI does not impact transplant outcomes and complications in patients with acute leukemia undergoing HCT with myeloablative conditioning. PMID:25840335

  19. [Acute abdomen in gynecology].

    PubMed

    von Hugo, R; Meyer, B; Loos, W; Dirmeier, H

    1988-09-01

    The aim of the present study is, to describe the morbidity and mortality of 196 patients with an acute abdominal condition who underwent surgery at the Department of Gynecology and Obstetrics of the TU Munich between 1982 and 1986. This is a percentage of 2.7 of all 7,167 operations carried out during this period. 118 of these patients had an extrauterine pregnancy and were therefore excluded from the study. The second group of 79 patients, mostly with inflammatory diseases, were analyzed. In most of these cases the acute abdominal condition was caused by a tuboovarian abscess (48.1%), followed by peritonitis because of a bowel-disease (11.4%). 6 patients suffered from an abscessing endometritis due to a caesarean section with sepsis in 5 cases. A generalized peritonitis occurred in 5 cases and was treated with a planned relaparatomy with lavage. 63% of the patients had no complications within 28 days after operation, 13% developed a subileus; in 7% a relaparatomy was necessary. 6% of the patients had problems of wound-healing. One patient with stomach-cancer died 3 weeks after the operation because of a fulminant lung-embolism. Thus the mortality rate was 1.5%. A further 27% were treated at the intensive care-unit and 18% needed artificial respiration. The average postoperative period of hospitalisation was 15 days. In comparison, patients with elective operations remained 13 days. The morbidity and mortality of patients due to surgery of an acute abdominal condition was relatively small; postoperative complications could be well treated in all cases and is probably the result of a positive and early indication for surgical intervention. PMID:3181709

  20. Medicinal significance of naturally occurring cyclotetrapeptides.

    PubMed

    Abdalla, Muna Ali

    2016-10-01

    Bioactive natural products are serendipitous drug candidates, which stimulate synthetic approaches for improving and supporting drug discovery and development. Therefore, the search for bioactive metabolites from different natural sources continues to play an important role in fashioning new medicinal agents. Several cyclic peptides were produced by organisms, such as β-defensins, gramicidin S, and tyrocidine A, and exhibited a wide range of bioactivities, such as antiviral activity against HIV-1, influenza A viruses, or antibacterial activity. Cyclic tetrapeptides are a class of natural products that were found to have a broad range of biological activities, promising pharmacokinetic properties, as well as interesting conformational dynamics and ability of slow inter-conversion to several different structures. Cyclooligopeptides, particularly medium ring-sized peptides, were obtained from marine microorganisms and exhibited a wide range of pharmacological properties, including antimicrobial and anti-dinoflagellate activities, cytotoxicity, and inhibitory activity against enzyme sortase B. Most of the naturally occurring cyclotetrapeptides are obtained from fungi. Some natural cyclic tetrapeptides were found to inhibit histone deacetylase (HDAC), which regulate the expression of genes. These compounds are very useful as cancer therapeutics. Various analogues of the natural cyclotetrapeptides were successfully synthesized to find novel lead compounds for pharmacological and biotechnological applications. Therefore, in this review, previously reported novel natural cyclotetrapeptides are briefly discussed, along with their important biological activities as drug candidates, together with their promising therapeutic properties. Moreover, their future perspective in drug discovery as potential therapeutic agents will be determined. PMID:27300506

  1. Epigenetic Mechanisms in Commonly Occurring Cancers

    PubMed Central

    2012-01-01

    Cancer is a collection of very complex diseases that share many traits while differing in many ways as well. This makes a universal cure difficult to attain, and it highlights the importance of understanding each type of cancer at a molecular level. Although many strides have been made in identifying the genetic causes for some cancers, we now understand that simple changes in the primary DNA sequence cannot explain the many steps that are necessary to turn a normal cell into a rouge cancer cell. In recent years, some research has shifted to focusing on detailing epigenetic contributions to the development and progression of cancer. These changes occur apart from primary genomic sequences and include DNA methylation, histone modifications, and miRNA expression. Since these epigenetic modifications are reversible, drugs targeting epigenetic changes are becoming more common in clinical settings. Daily discoveries elucidating these complex epigenetic processes are leading to advances in the field of cancer research. These advances, however, come at a rapid and often overwhelming pace. This review specifically summarizes the main epigenetic mechanisms currently documented in solid tumors common in the United States and Europe. PMID:22519822

  2. Naturally occurring hydroxytyrosol: synthesis and anticancer potential.

    PubMed

    Bernini, R; Merendino, N; Romani, A; Velotti, F

    2013-01-01

    Several epidemiological and animal studies have suggested that polyphenols, a group of secondary plant metabolites occurring mainly in the plant kingdom, may have a protective effect against some chronic degenerative diseases such as cancer. Polyphenols are part of the human diet, being present in vegetal food and beverages. Among them, an olive biophenol named hydroxytyrosol [2-(3,4- dihydroxyphenyl)ethanol, HTyr] has recently received particular attention because of its antioxidant, antiproliferative, pro-apoptotic, and anti-inflammatory activities, which have the potential to specifically counteract all cancer hallmarks, thus representing the expectant biological activities underlying the anti-tumor properties of this polyphenol. After a description of the synthetic procedures to prepare pure HTyr, this review takes into consideration the chemopreventive and chemotherapeutic potential of HTyr as the result of its antioxidant, antiproliferative and anti-inflammatory activities. In particular, the review is focused on the current knowledge of the main cellular and molecular mechanisms used by HTyr to affect carcinogenesis, highlighting the specific oncogenic and inflammatory signaling pathways potentially targeted by HTyr. PMID:23244583

  3. Does Shear Thickening Occur in Semisolid Metals?

    NASA Astrophysics Data System (ADS)

    Atkinson, Helen V.; Favier, Veronique

    2016-04-01

    In the various forms of semisolid processing such as thixoforming and thixoforging, the entry into the die occurs in a fraction of a second so it is the transient rheological behavior which governs the initial stages of flow. In experiments in the literature, this rheological behavior is probed through applying rapid transitions in shear rate under isothermal conditions. There is contradictory evidence as to whether the behavior during these transitions is shear thinning or shear thickening, although it is clear that once in the die the material is thinning. Here the data in the literature are reanalyzed to obtain a rationalization of the contradictions which has not previously been available. It is argued that if a suspension is initially in a disagglomerated state ( i.e., one which is initially sheared), the instantaneous behavior with a jump-up in shear rate is shear thickening (even if the long-term steady-state behavior is shear thinning) provided the fraction solid is greater than about 0.36 and the final shear rate at the end of the jump is greater than about 100 s-1. If the jump-up in shear rate is made from rest then yield masks the shear thickening.

  4. Sundew adhesive: a naturally occurring hydrogel

    PubMed Central

    Huang, Yujian; Wang, Yongzhong; Sun, Leming; Agrawal, Richa; Zhang, Mingjun

    2015-01-01

    Bioadhesives have drawn increasing interest in recent years, owing to their eco-friendly, biocompatible and biodegradable nature. As a typical bioadhesive, sticky exudate observed on the stalked glands of sundew plants aids in the capture of insects and this viscoelastic adhesive has triggered extensive interests in revealing the implied adhesion mechanisms. Despite the significant progress that has been made, the structural traits of the sundew adhesive, especially the morphological characteristics in nanoscale, which may give rise to the viscous and elastic properties of this mucilage, remain unclear. Here, we show that the sundew adhesive is a naturally occurring hydrogel, consisting of nano-network architectures assembled with polysaccharides. The assembly process of the polysaccharides in this hydrogel is proposed to be driven by electrostatic interactions mediated with divalent cations. Negatively charged nanoparticles, with an average diameter of 231.9 ± 14.8 nm, are also obtained from this hydrogel and these nanoparticles are presumed to exert vital roles in the assembly of the nano-networks. Further characterization via atomic force microscopy indicates that the stretching deformation of the sundew adhesive is associated with the flexibility of its fibrous architectures. It is also observed that the adhesion strength of the sundew adhesive is susceptible to low temperatures. Both elasticity and adhesion strength of the sundew adhesive reduce in response to lowering the ambient temperature. The feasibility of applying sundew adhesive for tissue engineering is subsequently explored in this study. Results show that the fibrous scaffolds obtained from sundew adhesive are capable of increasing the adhesion of multiple types of cells, including fibroblast cells and smooth muscle cells, a property that results from the enhanced adsorption of serum proteins. In addition, in light of the weak cytotoxic activity exhibited by these scaffolds towards a variety of

  5. Sundew adhesive: a naturally occurring hydrogel.

    PubMed

    Huang, Yujian; Wang, Yongzhong; Sun, Leming; Agrawal, Richa; Zhang, Mingjun

    2015-06-01

    Bioadhesives have drawn increasing interest in recent years, owing to their eco-friendly, biocompatible and biodegradable nature. As a typical bioadhesive, sticky exudate observed on the stalked glands of sundew plants aids in the capture of insects and this viscoelastic adhesive has triggered extensive interests in revealing the implied adhesion mechanisms. Despite the significant progress that has been made, the structural traits of the sundew adhesive, especially the morphological characteristics in nanoscale, which may give rise to the viscous and elastic properties of this mucilage, remain unclear. Here, we show that the sundew adhesive is a naturally occurring hydrogel, consisting of nano-network architectures assembled with polysaccharides. The assembly process of the polysaccharides in this hydrogel is proposed to be driven by electrostatic interactions mediated with divalent cations. Negatively charged nanoparticles, with an average diameter of 231.9 ± 14.8 nm, are also obtained from this hydrogel and these nanoparticles are presumed to exert vital roles in the assembly of the nano-networks. Further characterization via atomic force microscopy indicates that the stretching deformation of the sundew adhesive is associated with the flexibility of its fibrous architectures. It is also observed that the adhesion strength of the sundew adhesive is susceptible to low temperatures. Both elasticity and adhesion strength of the sundew adhesive reduce in response to lowering the ambient temperature. The feasibility of applying sundew adhesive for tissue engineering is subsequently explored in this study. Results show that the fibrous scaffolds obtained from sundew adhesive are capable of increasing the adhesion of multiple types of cells, including fibroblast cells and smooth muscle cells, a property that results from the enhanced adsorption of serum proteins. In addition, in light of the weak cytotoxic activity exhibited by these scaffolds towards a variety of

  6. Differential dormancy of co-occurring copepods

    NASA Astrophysics Data System (ADS)

    Ohman, Mark D.; Drits, Aleksandr V.; Elizabeth Clarke, M.; Plourde, Stéphane

    1998-08-01

    Four species of planktonic calanoid copepods that co-occur in the California Current System ( Eucalanus californicus Johnson, Rhincalanus nasutus Giesbrecht, Calanus pacificus californicus Brodsky, and Metridia pacifica Brodsky) were investigated for evidence of seasonal dormancy in the San Diego Trough. Indices used to differentiate actively growing from dormant animals included developmental stage structure and vertical distribution; activity of aerobic metabolic enzymes (Citrate Synthase and the Electron Transfer System complex); investment in depot lipids (wax esters and triacylglycerols); in situ grazing activity from gut fluorescence; and egg production rates in simulated in situ conditions. None of the 4 species exhibited a canonical calanoid pattern of winter dormancy - i.e., synchronous developmental arrest as copepodid stage V, descent into deep waters, reduced metabolism, and lack of winter reproduction. Instead, Calanus pacificus californicus has a biphasic life history in this region, with an actively reproducing segment of the population in surface waters overlying a deep dormant segment in winter. Eucalanus californicus is dormant as both adult females and copepodid V's, although winter females respond relatively rapidly to elevated food and temperature conditions; they begin feeding and producing eggs within 2-3 days. Rhincalanus nasutus appears to enter dormancy as adult females, although the evidence is equivocal. Metridia pacifica shows no evidence of dormancy, with sustained active feeding, diel vertical migration behavior, and elevated activity of metabolic enzymes in December as well as in June. The four species also differ markedly in water content, classes of storage lipids, and specific activity of Citrate Synthase. These results suggest that copepod dormancy traits and structural composition reflect diverse adaptations to regional environmental conditions rather than a uniform, canonical series of traits that remain invariant among taxa

  7. Acute Inhalation Injury

    PubMed Central

    Gorguner, Metin; Akgun, Metin

    2010-01-01

    Inhaled substances may cause injury in pulmonary epithelium at various levels of respiratory tract, leading from simple symptoms to severe disease. Acute inhalation injury (AII) is not uncommon condition. There are certain high risk groups but AII may occur at various places including home or workplace. Environmental exposure is also possible. In addition to individual susceptibility, the characteristics of inhaled substances such as water solubility, size of substances and chemical properties may affect disease severity as well as its location. Although AII cases may recover in a few days but AII may cause long-term complications, even death. We aimed to discuss the effects of short-term exposures (minutes to hours) to toxic substances on the lungs. PMID:25610115

  8. Managing acute decompensated heart failure.

    PubMed

    Pauly, Daniel F

    2014-02-01

    Acute decompensated heart failure may occur de novo, but it most often occurs as an exacerbation of underlying chronic heart failure. Hospitalization for heart failure is usually a harbinger of a chronic disease that will require long-term, ongoing medical management. Leaders in the field generally agree that repeated inpatient admissions for treatment reflect a failure of the health care delivery system to manage the disease optimally. Newer management strategies focus on ameliorating symptoms by optimizing the hemodynamics, restoring neurohormonal balance, and making frequent outpatient adjustments when needed. PMID:24286585

  9. Acute pulmonary oedema in pregnant women.

    PubMed

    Dennis, A T; Solnordal, C B

    2012-06-01

    Acute pulmonary oedema in pregnant women is an uncommon but life-threatening event. The aims of this review are to address why pulmonary oedema occurs in pregnant women and to discuss immediate management. We performed a systematic literature search of electronic databases including MEDLINE, EMBASE and the Cochrane Library, using the key words obstetrics, pregnancy, acute pulmonary oedema, pregnancy complications, maternal, cardiac function and haemodynamics. We present a simple clinical classification of acute pulmonary oedema in pregnancy into pulmonary oedema occurring in normotensive or hypotensive women (i.e. without hypertension), and acute pulmonary oedema occurring in hypertensive women, which allows focused management. Pre-eclampsia remains an important cause of hypertensive acute pulmonary oedema in pregnancy and preventive strategies include close clinical monitoring and restricted fluid administration. Immediate management of acute pulmonary oedema includes oxygenation, ventilation and circulation control with venodilators. Pregnancy-specific issues include consideration of the physiological changes of pregnancy, the risk of aspiration and difficult airway, reduced respiratory and metabolic reserve, avoidance of aortocaval compression and delivery of the fetus. PMID:22420683

  10. Information Needs While A Disaster Is Occurring

    NASA Astrophysics Data System (ADS)

    Perry, S. C.

    2010-12-01

    that rainfall intensity at their homes might be less than the intensity up in the mountains where the debris flows would start. Nor did they know that debris flows travel too quickly to be outrun. These and many other examples indicate need for social and natural scientists to increase awareness of what to expect when the disaster strikes. This information must be solidly understood before the event occurs - while a disaster is unfolding there are no teachable moments. Case studies indicate that even those who come into a disaster well educated about the phenomenon can struggle to apply what they know when the real situation is at hand. In addition, psychological studies confirm diminished ability to comprehend information at times of stress.

  11. Influence of pre-existing invasive aspergillosis on allo-HSCT outcome: a retrospective EBMT analysis by the Infectious Diseases and Acute Leukemia Working Parties.

    PubMed

    Penack, O; Tridello, G; Hoek, J; Socié, G; Blaise, D; Passweg, J; Chevallier, P; Craddock, C; Milpied, N; Veelken, H; Maertens, J; Ljungman, P; Cornelissen, J; Thiebaut-Bertrand, A; Lioure, B; Michallet, M; Iacobelli, S; Nagler, A; Mohty, M; Cesaro, S

    2016-03-01

    Historically, invasive aspergillosis (IA) has been a major barrier for allogeneic hematopoietic stem cell transplantation (allo-HSCT). The influence of invasive IA on long-term survival and on transplant-related complications has not been investigated in a larger patient cohort under current conditions. Our aim was to analyze the long-term outcome of patients undergoing allo-HSCT with a history of prior IA. We used European Society for Blood and Marrow Transplantation database data of first allo-HSCTs performed between 2005 and 2010 in patients with acute leukemia. One thousand one hundred and fifty patients with data on IA before allo-HSCT were included in the analysis. The median follow-up time was 52.1 months. We found no significant impact of IA on major transplant outcome variables such as overall survival, relapse-free survival, non-relapse mortality, cumulative incidence of acute GvHD grade II-IV, chronic GvHD, pulmonary complications and leukemia relapse. However, we found a trend toward lower overall survival (P=0.078, hazard ratio (HR) (95% confidence interval (CI)): 1.16 (0.98, 1.36)) and higher non-relapse mortality (P=0.150, HR (95% CI): 1.19 (0.94, 1.50)) in allo-HSCT recipients with pre-existing IA. Our data suggest that a history of IA should not generally be a contraindication when considering the performance of allo-HSCT in patients with acute leukemia. PMID:26501769

  12. Prevention of graft-versus-host disease by adoptive T regulatory therapy is associated with active repression of peripheral blood Toll-like receptor 5 mRNA expression.

    PubMed

    Sawitzki, Birgit; Brunstein, Claudio; Meisel, Christian; Schumann, Julia; Vogt, Katrin; Appelt, Christine; Curtsinger, Julie M; Verneris, Michael R; Miller, Jeffrey S; Wagner, John E; Blazar, Bruce R

    2014-02-01

    Acute graft-versus-host disease (GVHD) occurs in 40% to 60% of recipients of partially matched umbilical cord blood transplantation (UCBT). In a phase I study, adoptive transfer of expanded CD4(+)CD25(+)Foxp3(+) natural regulatory T cells (nTregs) resulted in a reduced incidence of grade II-IV acute GVHD. To investigate potential mechanisms responsible for the reduced GVHD risk, we analyzed peripheral blood mononuclear cell mRNA expression of a tolerance gene set previously identified in operation- tolerant kidney transplant recipients, comparing healthy controls and patients who received nTregs and those who did not receive nTregs with and without experiencing GVHD. Samples from patients receiving nTregs regardless of GVHD status showed increased expression of Foxp3 expression, as well as B cell-related tolerance marker. This was correlated with early B cell recovery, predominately of naïve B cells, and nearly normal T cell reconstitution. CD8(+) T cells showed reduced signs of activation (HLA-DR(+) expression) compared with conventionally treated patients developing GVHD. In contrast, patients with GVHD had significantly increased TLR5 mRNA expression, whereas nTreg-treated patients without GVHD had reduced TLR5 mRNA expression. We identified Lin(-)HLADR(-)CD33(+)CD16(+) cells and CD14(++)CD16(-) monocytes as the main TLR5 producers, especially in samples of conventionally treated patients developing GVHD. Taken together, these data reveal interesting similarities and differences between tolerant organ and nTreg-treated hematopoietic stem cell transplantation recipients. PMID:24184334

  13. Acute Pneumothorax.

    PubMed

    Arshad, Hammad; Young, Meilin; Adurty, Rajashekar; Singh, Anil C

    2016-01-01

    Pneumothorax is defined as the abnormal presence of air within the pleural space (cavity) that results in the partial or complete collapse of a lung. It can occur spontaneously or due to a traumatic event. Symptoms can vary from a nondescriptive complaint of shortness of breath or chest pain to complete cardiopulmonary collapse. Diagnosis is based on a combination of clinical suspicion along with supporting imaging studies. Treatment often involves surgical or nonsurgical approaches with goal to alleviate symptoms and prevent recurrence. PMID:26919678

  14. Sildenafil Induced Acute Interstitial Nephritis

    PubMed Central

    Burkhart, Ryan; Shah, Nina; Lewin, Matthew

    2015-01-01

    Acute interstitial nephritis (AIN) is characterized by inflammation of the renal interstitium and usually occurs in a temporal relationship with the medication. We present a case of an Asian male who had nephrotic range proteinuria and presented with acute kidney injury. The patient reported an acute change in physical appearance and symptomatology after the ingestion of a single dose of sildenafil. Renal biopsy was notable for minimal change disease (MCD) with acute and chronic interstitial nephritis. Renal replacement and glucocorticoid therapy were initiated. Renal recovery within six weeks permitted discontinuation of dialysis. AIN superimposed on MCD is a known association of NSAID induced nephropathy. The temporal association and the absence of any new drugs suggest that the AIN was most likely due to the sildenafil. NSAIDs are less likely to have caused the AIN given their remote use. The ease of steroid responsiveness would also suggest another cause as NSAID induced AIN is often steroid resistant. The MCD was most likely idiopathic given the lack of temporal association with a secondary cause. As the number of sildenafil prescriptions increases, more cases of AIN may be identified and physician awareness for this potential drug disease association is necessary. PMID:26491581

  15. [Acute gastrointestinal bleeding].

    PubMed

    Baumbach, Robert; Faiss, Siegbert; Cordruwisch, Wolfgang; Schrader, Carsten

    2016-04-01

    Acute gastrointestinal bleeding is a common major emergency (Internal medical or gastroenterological or medical), approximately 85 % of which occur in the upper GI tract. It is estimated that about a half of upper GI bleeds are caused by peptic ulcers. Upper GI bleeds are associated with more severe bleeding and poorer outcomes when compared to middle or lower GI bleeds. Prognostic determinants include bleeding intensity, patient age, comorbid conditions and the concomitant use of anticoagulants. A focused medical history can offer insight into the bleeding intensity, location and potential cause (along with early risk stratification). Initial measures should focus on rapid assessment and resuscitation of unstable patients. The oesophagogastroduodenoscopy (OGD) is the gold standard method for localizing the source of bleeding and for interventional therapy. Bleeding as a result of peptic ulcers is treated endoscopically with mechanical and / or thermal techniques in combination with proton pump inhibitor (PPI) therapy. When variceal bleeding is suspected, pre-interventional use of vasopressin analogues and antibiotic therapies are recommended. Endoscopically, the first line treatment of esophageal varices is endoscopic ligature therapy, whereas that for gastric varices is the use of Histoacryl injection sclerotherapy. When persistent and continued massive hemorrhage occurs in a patient with known or suspected aortic disease the possibility of an aorto-enteric fistula must be considered. PMID:27078246

  16. Acute myeloid leukaemia.

    PubMed

    Khwaja, Asim; Bjorkholm, Magnus; Gale, Rosemary E; Levine, Ross L; Jordan, Craig T; Ehninger, Gerhard; Bloomfield, Clara D; Estey, Eli; Burnett, Alan; Cornelissen, Jan J; Scheinberg, David A; Bouscary, Didier; Linch, David C

    2016-01-01

    Acute myeloid leukaemia (AML) is a disorder characterized by a clonal proliferation derived from primitive haematopoietic stem cells or progenitor cells. Abnormal differentiation of myeloid cells results in a high level of immature malignant cells and fewer differentiated red blood cells, platelets and white blood cells. The disease occurs at all ages, but predominantly occurs in older people (>60 years of age). AML typically presents with a rapid onset of symptoms that are attributable to bone marrow failure and may be fatal within weeks or months when left untreated. The genomic landscape of AML has been determined and genetic instability is infrequent with a relatively small number of driver mutations. Mutations in genes involved in epigenetic regulation are common and are early events in leukaemogenesis. The subclassification of AML has been dependent on the morphology and cytogenetics of blood and bone marrow cells, but specific mutational analysis is now being incorporated. Improvements in treatment in younger patients over the past 35 years has largely been due to dose escalation and better supportive care. Allogeneic haematopoietic stem cell transplantation may be used to consolidate remission in those patients who are deemed to be at high risk of relapse. A plethora of new agents - including those targeted at specific biochemical pathways and immunotherapeutic approaches - are now in trial based on improved understanding of disease pathophysiology. These advances provide good grounds for optimism, although mortality remains high especially in older patients. PMID:27159408

  17. Hypertriglyceridemia-induced acute pancreatitis in pregnancy causing maternal death

    PubMed Central

    Jeon, Hae Rin; Cho, Yoon Jin; Chon, Seung Joo

    2016-01-01

    Acute pancreatitis in pregnancy is rare and occurs in approximately 3 in 10,000 pregnancies. It rarely complicates pregnancy, and can occur during any trimester, however over half (52%) of cases occur during the third trimester and during the post-partum period. Gallstones are the most common cause of acute pancreatitis. On the other hand, acute pancreatitis caused by hypertriglyceridemia due to increase of estrogen during the gestational period is very unusual, but complication carries a higher risk of morbidity and mortality for both the mother and the fetus. We experienced a case of pregnant woman who died of acute exacerbation of hypertriglyceridemia-induced acute pancreatitis at 23 weeks of gestation. We report on progress and management of this case along with literature reviews. PMID:27004207

  18. Allogeneic hemopoietic stem cell transplants for patients with relapsed acute leukemia: long-term outcome.

    PubMed

    Bacigalupo, A; Lamparelli, T; Gualandi, F; Occhini, D; Bregante, S; Raiola, A M; Ibatici, A; di Grazia, C; Dominietto, A; Piaggio, G; Podesta, M; Bruno, B; Lombardi, A; Frassoni, F; Viscoli, C; Sacchi, N; Van Lint, M T

    2007-03-01

    We assessed the long-term outcome of patients with relapsed acute myeloid (n=86) or acute lymphoid leukemia (n=66), undergoing an allogeneic hemopoietic stem cell transplantation in our unit. The median blast count in the marrow was 30%. Conditioning regimen included total body irradiation (TBI) (10-12 Gy) in 115 patients. The donor was a matched donor (n=132) or a family mismatched donor (n=20). Twenty-two patients (15%) survive disease free, with a median follow-up of 14 years: 18 are off medications. The cumulative incidence of transplant related mortality is 40% and the cumulative incidence of relapse related death (RRD) is 45%. In multivariate analysis of survival, favorable predictors were chronic graft-versus-host disease (GvHD) (P=0.0003), donor other than family mismatched (P=0.02), donor age less than 34 years (P=0.02) and blast count less than 30% (P=0.07). Patients with all four favorable predictors had a 54% survival. In multivariate analysis of relapse, protective variables were the use of TBI (P=0.005) and cGvHD (P=0.01). This study confirms that a fraction of relapsed leukemias is cured with an allogeneic transplant: selection of patients with a blast count <30%, identification of young, human leukocyte antigen-matched donors and the use of total body radiation may significantly improve the outcome. PMID:17277788

  19. Acute kidney failure

    MedlinePlus

    Kidney failure; Renal failure; Renal failure - acute; ARF; Kidney injury - acute ... There are many possible causes of kidney damage. They include: ... cholesterol (cholesterol emboli) Decreased blood flow due to very ...

  20. Acute arterial occlusion - kidney

    MedlinePlus

    Acute renal arterial thrombosis; Renal artery embolism; Acute renal artery occlusion; Embolism - renal artery ... kidneys need a good blood supply. The main artery to the kidney is called the renal artery. ...

  1. Acute Lymphocytic Leukemia

    MedlinePlus

    ... hard for blood to do its work. In acute lymphocytic leukemia (ALL), also called acute lymphoblastic leukemia, there are too ... of white blood cells called lymphocytes or lymphoblasts. ALL is the most common type of cancer in ...

  2. Clinical cases in acute intoxication.

    PubMed

    Smith, Sean B; Maguire, Jennifer; Mauck, Karen F

    2009-12-01

    Over 2.5 million accidental and intentional drug-related poisonings are reported annually in the United States. Early diagnosis and management of patients who present with acute intoxication can significantly reduce both morbidity and mortality. The initial evaluation of patients with suspected or proven intoxications should focus on hemodynamic stability, mental status, and respiratory function. However, early recognition of toxic ingestion is paramount to implementing life-saving treatments. Important historical clues are often found in a social history that considers intravenous drug use, alcohol use, and any access or exposure to illicit substances. A patient's medication list should also be scrutinized for psychoactive or sedative medications, such as tricyclic antidepressants or opioids. In this article we present case-based discussions of the specific diagnosis and management of 5 commonly occurring acute intoxication syndromes. PMID:20877175

  3. Recognising and managing acute hyponatraemia.

    PubMed

    Keane, Matthew

    2014-02-01

    A significant amount of clinicians' time is spent managing patients with complications arising from the use of sympatheticomimetic drugs such as cocaine and ecstasy, or MDMA. This article examines one of these complications, namely acute hyponatraemia, which can have life-threatening neurological consequences. Although there are few signs or symptoms of this condition, emergency clinicians should be able to recognise when it may have occurred, and should have a basic understanding of the role of sodium in autoregulation of cellular function, the different fluid compartments in the human body and the pathology of cerebral oedema. The article describes the importance of early recognition and swift treatment of acute hyponatraemia, as well as the methods for calculating fluid replacement to optimise chances of full recovery. PMID:24494770

  4. [Acute respiratory distress syndrome].

    PubMed

    Estenssoro, Elisa; Dubin, Arnaldo

    2016-01-01

    Acute respiratory distress syndrome (ARDS) is an acute respiratory failure produced by an inflammatory edema secondary to increased lung capillary permeability. This causes alveolar flooding and subsequently deep hypoxemia, with intrapulmonary shunt as its most important underlying mechanism. Characteristically, this alteration is unresponsive to high FIO2 and only reverses with end-expiratory positive pressure (PEEP). Pulmonary infiltrates on CXR and CT are the hallmark, together with decreased lung compliance. ARDS always occurs within a week of exposition to a precipitating factor; most frequently pneumonia, shock, aspiration of gastric contents, sepsis, and trauma. In CT scan, the disease is frequently inhomogeneous, with gravitational infiltrates coexisting with normal-density areas and also with hyperaerated parenchyma. Mortality is high (30-60%) especially in ARDS associated with septic shock and neurocritical diseases. The cornerstone of therapy lies in the treatment of the underlying cause and in the use mechanical ventilation which, if inappropriately administered, can lead to ventilator-induced lung injury. Tidal volume = 6 ml/kg of ideal body weight to maintain an end-inspiratory (plateau) pressure = 30 cm H2O ("protective ventilation") is the only variable consistently associated with decreased mortality. Moderate-to-high PEEP levels are frequently required to treat hypoxemia, yet no specific level or titration strategy has improved outcomes. Recently, the use of early prone positioning in patients with PaO2/FIO2 = 150 was associated with increased survival. In severely hypoxemic patients, it may be necessary to use adjuvants of mechanical ventilation as recruitment maneuvers, pressure-controlled modes, neuromuscular blocking agents, and extracorporeal-membrane oxygenation. Fluid restriction appears beneficial. PMID:27576283

  5. A Rare Sequela of Acute Disseminated Encephalomyelitis

    PubMed Central

    Kodadhala, Vijay; Kurukumbi, Mohankumar; Jayam-Trouth, Annapurni

    2014-01-01

    Acute disseminated encephalomyelitis is a demyelinating disease, typically occurring in children following a febrile infection or a vaccination. Primary and secondary immune responses contribute to inflammation and subsequent demyelination, but the exact pathogenesis is still unknown. Diagnosis of acute disseminated encephalomyelitis is strongly suggested by temporal relationship between an infection or an immunization and the onset of neurological symptoms. Biopsy is definitive. In general, the disease is self-limiting and the prognostic outcome is favorable with anti-inflammatory and immunosuppressive agents. Locked-in syndrome describes patients who are awake and conscious but have no means of producing limb, speech, or facial movements. Locked-in syndrome is a rare complication of acute disseminated encephalomyelitis. We present a case of incomplete locked-in syndrome occurring in a 34-year-old male secondary to acute disseminated encephalomyelitis. Our case is unique, as acute disseminated encephalomyelitis occurred in a 34-year-old which was poorly responsive to immunosuppression resulting in severe disability. PMID:24977089

  6. Outcomes after matched unrelated donor versus identical sibling hematopoietic cell transplantation in adults with acute myelogenous leukemia.

    PubMed

    Saber, Wael; Opie, Shaun; Rizzo, J Douglas; Zhang, Mei-Jie; Horowitz, Mary M; Schriber, Jeff

    2012-04-26

    Approximately one-third of patients with an indication for hematopoietic cell transplantation (HCT) have an HLA-matched related donor (MRD) available to them. For the remaining patients, a matched unrelated donor (MUD) is an alternative. Prior studies comparing MRD and MUD HCT provide conflicting results, and the relative efficacy of MRD and MUD transplantation is an area of active investigation. To address this issue, we analyzed outcomes of 2223 adult acute myelogenous leukemia patients who underwent allogeneic HCT between 2002 and 2006 (MRD, n = 624; 8/8 HLA locus matched MUD, n = 1193; 7/8 MUD, n = 406). The 100-day cumulative incidence of grades B-D acute GVHD was significantly lower in MRD HCT recipients than in 8/8 MUD and 7/8 MUD HCT recipients (33%, 51%, and 53%, respectively; P < .001). In multivariate analysis, 8/8 MUD HCT recipients had a similar survival rate compared with MRD HCT recipients (relative risk [RR], 1.03; P = .62). 7/8 MUD HCT recipients had higher early mortality than MRD HCT recipients (RR, 1.40; P < .001), but beyond 6 months after HCT, their survival rates were similar (RR, 0.88; P = .30). These results suggest that transplantation from MUD and MRD donors results in similar survival times for patients with acute myelogenous leukemia. PMID:22327226

  7. Acute visual field defect in ulcerative colitis: a case report.

    PubMed

    Besharat, S; Besharat, M; Amiriani, T; Ebadi, H; Semnani, S H

    2012-01-01

    A cerebrovascular occlusive event is a rare complication of IBD, which usually occurs during its acute phase, shortly after diagnosis. This association seems to be a complex situation, affected by a combination of factors. PMID:22647803

  8. Imaging of Acute Pancreatitis.

    PubMed

    Thoeni, Ruedi F

    2015-11-01

    Acute pancreatitis is an acute inflammation of the pancreas. Several classification systems have been used in the past but were considered unsatisfactory. A revised Atlanta classification of acute pancreatitis was published that assessed the clinical course and severity of disease; divided acute pancreatitis into interstitial edematous pancreatitis and necrotizing pancreatitis; discerned an early phase (first week) from a late phase (after the first week); and focused on systemic inflammatory response syndrome and organ failure. This article focuses on the revised classification of acute pancreatitis, with emphasis on imaging features, particularly on newly-termed fluid collections and implications for the radiologist. PMID:26526433

  9. Acute toxicity of gasoline and some additives

    SciTech Connect

    Reese, E.; Kimbrough, R.D.

    1993-12-01

    The acute toxicity of gasoline; its components benzene, toluene, and xylene; and the additives ethanol, methanol, and methyl tertiary butyl ether are reviewed. All of these chemicals are only moderately to mildly toxic at acute doses. Because of their volatility, these compounds are not extensively absorbed dermally unless the exposed skin is occluded. Absorption through the lungs and the gastrointestinal tract is quite efficient. After ingestion, the principal danger for a number of these chemicals, particularly gasoline, is aspiration pneumonia, which occurs mainly in children. It is currently not clear whether aspiration pneumonia would still be a problem if gasoline were diluted with ethanol or methanol. During the normal use of gasoline or mixtures of gasoline and the other solvents as a fuel, exposures would be much lower than the doses that have resulted in poisoning. No acute toxic health effects would occur during the normal course of using automotive fuels. 128 refs., 7 tabs.

  10. Acute toxicity of gasoline and some additives.

    PubMed Central

    Reese, E; Kimbrough, R D

    1993-01-01

    The acute toxicity of gasoline; its components benzene, toluene, and xylene; and the additives ethanol, methanol, and methyl tertiary butyl ether are reviewed. All of these chemicals are only moderately to mildly toxic at acute doses. Because of their volatility, these compounds are not extensively absorbed dermally unless the exposed skin is occluded. Absorption through the lungs and the gastrointestinal tract is quite efficient. After ingestion, the principal danger for a number of these chemicals, particularly gasoline, is aspiration pneumonia, which occurs mainly in children. It is currently not clear whether aspiration pneumonia would still be a problem if gasoline were diluted with ethanol or methanol. During the normal use of gasoline or mixtures of gasoline and the other solvents as a fuel, exposures would be much lower than the doses that have resulted in poisoning. No acute toxic health effects would occur during the normal course of using automotive fuels. PMID:8020435

  11. Epidermal elafin expression is an indicator of poor prognosis in cutaneous graft-versus-host disease.

    PubMed

    Brüggen, Marie-Charlotte; Petzelbauer, Peter; Greinix, Hildegard; Contassot, Emmanuel; Jankovic, Dragana; French, Lars; Socié, Gérard; Rabitsch, Werner; Kuzmina, Zoya; Kalhs, Peter; Knobler, Robert; Stingl, Georg; Stary, Georg

    2015-04-01

    Graft-versus-host disease (GVHD) remains a common and potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation. In the skin, GVHD can present in an acute (aGVHD), chronic lichenoid (clGVHD), or chronic sclerotic form (csGVHD). Measuring peripheral blood levels of the keratinocyte-derived protease inhibitor elafin has recently emerged as a promising tool for the diagnosis of cutaneous aGVHD. We evaluated whether the analysis of elafin expression in skin would allow distinguishing aGVHD from drug hypersensitivity rashes (DHR) and whether cutaneous elafin expression would correlate with disease severity or altered prognosis of aGVHD and clGVHD/csGVHD. Skin biopsies from aGVHD (n=22), clGVHD (n=15), csGVHD (n=7), and DHR (n=10) patients were collected and epidermal elafin expression and its association with diverse clinical/histological parameters were analyzed. Acute GVHD and DHR displayed varying degrees of elafin expression. No elafin was detectable in csGVHD, whereas the molecule was increased in clGVHD as compared with aGVHD. Elafin-high aGVHD/clGVHD lesions presented with epidermal thickening and were associated with poor prognosis-i.e., decreased overall survival in aGVHD and corticosteroid resistance in clGVHD. Although cutaneous elafin does not seem to discriminate aGVHD from DHR lesions, our study strongly suggests an association between cutaneous elafin expression and poor prognosis for patients with cutaneous GVHD. PMID:25405322

  12. Acute loss of consciousness.

    PubMed

    Tristán, Bekinschtein; Gleichgerrcht, Ezequiel; Manes, Facundo

    2015-01-01

    Acute loss of consciousness poses a fascinating scenario for theoretical and clinical research. This chapter introduces a simple yet powerful framework to investigate altered states of consciousness. We then explore the different disorders of consciousness that result from acute brain injury, and techniques used in the acute phase to predict clinical outcome in different patient populations in light of models of acute loss of consciousness. We further delve into post-traumatic amnesia as a model for predicting cognitive sequels following acute loss of consciousness. We approach the study of acute loss of consciousness from a theoretical and clinical perspective to conclude that clinicians in acute care centers must incorporate new measurements and techniques besides the classic coma scales in order to assess their patients with loss of consciousness. PMID:25702218

  13. Megakaryocyte rupture for acute platelet needs

    PubMed Central

    Stritt, Simon

    2015-01-01

    Circulating platelets were thought to arise solely from the protrusion and fragmentation of megakaryocyte cytoplasm. Now, Nishimura et al. (2015. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201410052) show that platelet release from megakaryocytes can be induced by interleukin-1α (IL-1α) via a new rupture mechanism, which yields higher platelet numbers, occurs independently of the key regulator of megakaryopoiesis thrombopoietin, and may occur during situations of acute platelet need. PMID:25963815

  14. Megakaryocyte rupture for acute platelet needs.

    PubMed

    Nieswandt, Bernhard; Stritt, Simon

    2015-05-11

    Circulating platelets were thought to arise solely from the protrusion and fragmentation of megakaryocyte cytoplasm. Now, Nishimura et al. (2015. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201410052) show that platelet release from megakaryocytes can be induced by interleukin-1α (IL-1α) via a new rupture mechanism, which yields higher platelet numbers, occurs independently of the key regulator of megakaryopoiesis thrombopoietin, and may occur during situations of acute platelet need. PMID:25963815

  15. Decitabine in Treating Children With Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2013-01-22

    Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Promyelocytic Leukemia (M3); Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

  16. [Acute pancreatitis with hypertriglyceridemia--an underestimated disease?].

    PubMed

    Wild, Wolfgang; Tajjiou, Morad; Ferschke, Melanie; Bormann, Fabian; Dörr, Pius; Schwarzbach, Matthias

    2016-01-01

    Hypertriglyceridemia is a rare, but since a long time well known etiology for acute pancreatitis. It could occure alone or coactive with other triggers like alcohlic excess. Nevertheless it found no approach to the current classifications and parameters of prognosis of the acute pancreatitis. We refer about two patients with hypertriglyceridemia and acute pancreatitis, whose initial disease was limited on the tail of the pancreas with just a circumscripted or--in the other case--no necrosis. However, in both cases and although a consequent treatment started immediately, a serious process developed including a life-threatening acute respiratory distress syndrome in one case, which necessitated an extracorporal membrane oxygenation. PMID:26710203

  17. Babesiosis-induced acute kidney injury with prominent urinary macrophages.

    PubMed

    Luciano, Randy L; Moeckel, Gilbert; Palmer, Matthew; Perazella, Mark A

    2013-10-01

    Babesia is an obligate intracellular erythrocyte parasite that can infect humans. Severe symptomatic disease from massive hemolysis and multiorgan system failure, including acute kidney injury (AKI), occurs. Acute tubular injury from a combination of volume depletion and heme pigment toxicity from profound hemolysis is the most common cause of AKI. We present a case of severe babesiosis complicated by dialysis-requiring AKI with the unique finding of large macrophages containing engulfed erythrocyte fragments in urine sediment. This urinary finding raised the possibility of another diagnosis distinct from acute tubular injury. Subsequent kidney biopsy demonstrated infection-associated acute interstitial nephritis. PMID:23643302

  18. Acute incarcerated external abdominal hernia

    PubMed Central

    Yang, Xue-Fei

    2014-01-01

    External abdominal hernia occurs when abdominal organs or tissues leave their normal anatomic site and protrude outside the skin through the congenital or acquired weakness, defects or holes on the abdominal wall, including inguinal hernia, umbilical hernia, femoral hernia and so on. Acute incarcerated hernia is a common surgical emergency. With advances in minimally invasive devices and techniques, the diagnosis and treatment have witnessed major changes, such as the use of laparoscopic surgery in some cases to achieve minimally invasive treatment. However, strict adherence to the indications and contraindications is still required. PMID:25489584

  19. Acute pain transfusion reaction.

    PubMed

    Hardwick, Jody; Osswald, Michael; Walker, Daniel

    2013-11-01

    A 34-year-old woman with a diagnosis of hemophagocytic lymphohistocytosis (HLH) received a double umbilical cord blood transplantation following a myeloablative chemotherapy preparative regimen with busulfan and cyclophosphamide. HLH is a rare, potentially fatal hematologic disorder characterized by the overactivation of histocytes and T lymphocytes, leading to organ infiltration and acute illness. On day 25 post-transplantation, the patient required a platelet transfusion for a platelet count of 6,000 per ml (normal range = 150,000-450,000 per ml). The patient's blood type prior to the cord blood transplantation was B positive and, although both umbilical cord blood donors were O positive, the patient was still B positive per blood bank testing on that day. Although the recipient of an allogenic stem cell transplantation will eventually become the blood type of the donor, the time for this process to occur varies for each person. That process must be monitored by the blood bank for the purpose of cross-matching blood products to decrease hemolysis as much as possible. The patient was premedicated with the facility's standard for platelet transfusions: acetaminophen 650 mg and diphenhydramine 25 mg about 30 minutes prior to the platelet transfusion. PMID:24161631

  20. Acute Diarrhea in Children.

    PubMed

    Radlović, Nedeljko; Leković, Zoran; Vuletić, Biljana; Radlović, Vladimir; Simić, Dušica

    2015-01-01

    Acute diarrhea (AD) is the most frequent gastroenterological disorder, and the main cause of dehydration in childhood. It is manifested by a sudden occurrence of three or more watery or loose stools per day lasting for seven to 10 days, 14 days at most. It mainly occurs in children until five years of age and particularly in neonates in the second half-year and children until the age of three years. Its primary causes are gastrointestinal infections, viral and bacterial, and more rarely alimentary intoxications and other factors. As dehydration and negative nutritive balance are the main complications of AD, it is clear that the compensation of lost body fluids and adequate diet form the basis of the child's treatment. Other therapeutic measures, except antipyretics in high febrility, antiparasitic drugs for intestinal lambliasis, anti-amebiasis and probiotics are rarely necessary. This primarily regards uncritical use of antibiotics and intestinal antiseptics in the therapy of bacterial diarrhea.The use of antiemetics, antidiarrhetics and spasmolytics is unnecessary and potentially risky, so that it is not recommended for children with AD. PMID:26946776

  1. Ecallantide: in acute hereditary angioedema.

    PubMed

    Garnock-Jones, Karly P

    2010-07-30

    Ecallantide, a recombinant protein that is a selective, highly potent and reversible inhibitor of human plasma kallikrein, is indicated for the treatment of acute attacks of hereditary angioedema (HAE) in patients aged >or=16 years. In the randomized, double-blind, placebo-controlled, multicentre, phase III trial EDEMA3, mean symptom response to treatment at 4 hours (assessed using the Treatment Outcome Score [TOS]; primary endpoint) was significantly greater with a single subcutaneous dose of ecallantide 30 mg than with placebo in patients with acute, moderate to severe attacks of HAE. In addition, the mean change from baseline in symptom severity at 4 hours (assessed using the Mean Symptom Complex Severity [MSCS] scale) was significantly greater with ecallantide than with placebo. At 4 hours in the similarly designed EDEMA4 trial, the mean change from baseline in MSCS score (primary endpoint) and mean TOS were both significantly greater in recipients of a single subcutaneous dose of ecallantide 30 mg than in placebo recipients. Subcutaneous ecallantide 30 mg was generally well tolerated in patients with acute attacks of HAE in the EDEMA3 and EDEMA4 trials. Adverse events were mostly of mild to moderate severity, and no event that was more common in ecallantide than placebo recipients occurred in >10% of patients. PMID:20614949

  2. Management of severe acute pancreatitis.

    PubMed

    Doctor, Nilesh; Agarwal, Pravin; Gandhi, Vidhyachandra

    2012-02-01

    Severe acute pancreatitis (SAP) develops in about 25% of patients with acute pancreatitis. Severity of acute pancreatitis is linked to the presence of systemic organ dysfunctions and/or necrotizing pancreatitis. Risk factors independently determining the outcome of SAP are early multiorgan failure (MOF), infection of necrosis, and extended necrosis (>50%). Morbidity of SAP is biphasic, in the first week it is strongly related to systemic inflammatory response syndrome while, sepsis due to infected pancreatic necrosis leading to MOF syndrome occurs in the later course after the first week. Contrast-enhanced computed tomography provides the highest diagnostic accuracy for necrotizing pancreatitis when performed after the first week of disease. Patients who suffer early organ dysfunctions or are at risk for developing a severe disease require early intensive care treatment. Antibiotic prophylaxis has not been shown as an effective preventive treatment. Early enteral feeding is based on a high level of evidence, resulting in a reduction of local and systemic infection. Patients suffering infected necrosis causing clinical sepsis are candidates for intervention. Hospital mortality of SAP after interventional or surgical debridement has decreased to below 20% in high-volume centers. PMID:23372306

  3. Acute abdominal complications following hip surgery.

    PubMed

    Deleanu, B; Prejbeanu, R; Vermesan, D; Haragus, H; Icma, I; Predescu, V

    2014-01-01

    Hip surgeries are some of the most common and successful orthopedic procedures. Although rarely, abdominal complications do occur and are associated with unfavorable outcomes.We aimed to identify and describe the severe abdominal complications that appear in patients under-going elective or traumatic hip surgery. A four year retrospective electronic database research identified 408 elective primary hip replacements,51 hip revisions and 1040 intra and extracapsular proximal femur fractures. Out of these, three males and 4 females between 64 - 84 years old were identified to have developed acute abdominal complications: perforated acute ulcer (3),acute cholecystitis (2), volvulus (1), toxic megacolon with peritonitis (1) and acute colonic pseudo-obstruction (1).Complications debuted 3 - 10 days after index orthopedic surgery. Acute perioperative abdominal complications are rarely encountered during orthopedic surgery. When these do occur, they do so almost exclusively in patients with hippathology, comorbidities and most often lead to life threatening situations. We thus emphasize the need for early identification and appropriate management by both orthopedic and general surgery doctors in order to improve patient safety. PMID:24742414

  4. Megadose transplantation of purified peripheral blood CD34(+) progenitor cells from HLA-mismatched parental donors in children.

    PubMed

    Handgretinger, R; Klingebiel, T; Lang, P; Schumm, M; Neu, S; Geiselhart, A; Bader, P; Schlegel, P G; Greil, J; Stachel, D; Herzog, R J; Niethammer, D

    2001-04-01

    We performed HLA-mismatched stem cell transplantation with megadoses of purified positively selected mobilized peripheral blood CD34(+) progenitor cells (PBPC) from related adult donors in 39 children lacking an otherwise suitable donor. The patients received a mean number of 20.7 +/- 9.8 x 10(6)/kg purified CD34(+) and a mean number of 15.5 +/- 20.4 x 10(3)/kg CD3(+) T lymphocytes. The first seven patients received short term (<4 weeks) GVHD prophylaxis with cyclosporin A, whereas in all the following 32 patients no GVHD prophylaxis was used. In 38 evaluable patients, five patients experienced primary acute GVHD grade I and one patient grade II. In 32 patients, no signs of primary GVHD were seen and GVHD only occurred after T cell add backs. T cell reconstitution was more rapid if the number of transplanted CD34(+) cells exceeded 20 x 10(6)/kg. Of the 39 patients, 15 are alive and well, 13 died due to relapse and 10 transplant-related deaths occurred. We conclude that the HLA barrier can be overcome by transplantation of megadoses of highly purified mismatched CD34(+) stem cells. GVHD can be prevented without pharmacological immunosuppression by the efficient T cell depletion associated with the CD34(+) positive selection procedure. This approach offers a promising therapeutic option for every child without an otherwise suitable donor. PMID:11477433

  5. Severe but reversible acute kidney injury resulting from Amanita punctata poisoning

    PubMed Central

    Kang, Eunjung; Cheong, Ka-Young; Lee, Min-Jeong; Kim, Seirhan; Shin, Gyu-Tae; Kim, Heungsoo; Park, In-Whee

    2015-01-01

    Mushroom-related poisoning can cause acute kidney injury. Here we report a case of acute kidney injury after ingestion of Amanita punctata, which is considered an edible mushroom. Gastrointestinal symptoms occurred within 24 hours from the mushroom intake and were followed by an asymptomatic period, acute kidney injury, and elevation of liver and pancreatic enzymes. Kidney function recovered with supportive care. Nephrotoxic mushroom poisoning should be considered as a cause of acute kidney injury. PMID:26779427

  6. Acute Phase Proteins and Their Role in Periodontitis: A Review.

    PubMed

    Polepalle, Tejaswin; Moogala, Srinivas; Boggarapu, Shalini; Pesala, Divya Sai; Palagi, Firoz Babu

    2015-11-01

    Acute phase proteins are a class of proteins whose plasma concentration increase (positive acute phase proteins) or decrease (negative acute phase proteins) in response to inflammation. This response is called as the acute phase reaction, also called as acute phase response, which occurs approximately 90 minutes after the onset of a systemic inflammatory reaction. In Periodontitis endotoxins released from gram negative organisms present in the sub gingival plaque samples interact with Toll- like receptors (TLR) that are expressed on the surface of Polymorphonuclear leucocytes (PMNs) and monocytes which are in abundance in periodontal inflammation. The complex formed due to interaction of Endotoxins and TLR activates the Signal transduction pathway in both innate and adaptive immunity resulting in production of Cytokines that co- ordinate the local and systemic inflammatory response. The pro inflammatory cytokines originating at the diseased site activates the liver cells to produce acute phase proteins as a part of non specific response. The production of Acute phase proteins is regulated to a great extent by Cytokines such as IL-1, IL-6, IL-8, TNF-α and to a lesser extent by Glucocorticoid hormones. These proteins bind to bacteria leading to activation of complement proteins that destroys pathogenic organisms. Studies have shown that levels of acute phase proteins are increased in otherwise healthy adults with poor periodontal status. This article highlights about the synthesis, structure, types and function of acute phase proteins and the associated relation of acute phase proteins in Periodontitis. PMID:26674303

  7. Acute Phase Proteins and Their Role in Periodontitis: A Review

    PubMed Central

    Moogala, Srinivas; Boggarapu, Shalini; Pesala, Divya Sai; Palagi, Firoz Babu

    2015-01-01

    Acute phase proteins are a class of proteins whose plasma concentration increase (positive acute phase proteins) or decrease (negative acute phase proteins) in response to inflammation. This response is called as the acute phase reaction, also called as acute phase response, which occurs approximately 90 minutes after the onset of a systemic inflammatory reaction. In Periodontitis endotoxins released from gram negative organisms present in the sub gingival plaque samples interact with Toll- like receptors (TLR) that are expressed on the surface of Polymorphonuclear leucocytes (PMNs) and monocytes which are in abundance in periodontal inflammation. The complex formed due to interaction of Endotoxins and TLR activates the Signal transduction pathway in both innate and adaptive immunity resulting in production of Cytokines that co- ordinate the local and systemic inflammatory response. The pro inflammatory cytokines originating at the diseased site activates the liver cells to produce acute phase proteins as a part of non specific response. The production of Acute phase proteins is regulated to a great extent by Cytokines such as IL-1, IL-6, IL-8, TNF-α and to a lesser extent by Glucocorticoid hormones. These proteins bind to bacteria leading to activation of complement proteins that destroys pathogenic organisms. Studies have shown that levels of acute phase proteins are increased in otherwise healthy adults with poor periodontal status. This article highlights about the synthesis, structure, types and function of acute phase proteins and the associated relation of acute phase proteins in Periodontitis. PMID:26674303

  8. Acute Cytomegalovirus Infection as a Cause of Venous Thromboembolism

    PubMed Central

    Rinaldi, Francesca; Lissandrin, Raffaella; Mojoli, Francesco; Baldanti, Fausto; Brunetti, Enrico; Pascarella, Michela; Giordani, Maria Teresa

    2014-01-01

    Acute Human Cytomegalovirus (HCMV) infection is an unusual cause of venous thromboembolism, a potentially life-threatening condition. Thrombus formation can occur at the onset of the disease or later during the recovery and may also occur in the absence of acute HCMV hepatitis. It is likely due to both vascular endothelium damage caused by HCMV and impairment of the clotting balance caused by the virus itself. Here we report on two immunocompetent women with splanchnic thrombosis that occurred during the course of acute HCMV infection. Although the prevalence of venous thrombosis in patients with acute HCMV infection is unknown, physicians should be aware of its occurrence, particularly in immunocompetent patients presenting with fever and unexplained abdominal pain. PMID:24959338

  9. [Cryo- and electrotherapy in acute thrombophlebitis].

    PubMed

    Redkiĭ, Iu K; Tret'iakova, T S

    1996-01-01

    Combinations of cryotherapy with galvanization or alternating magnetic field (AMF), of cryogalvanization with AMF were used in 43 patients with acute thrombophlebitis. Within the first 3 days of treatment the response occurred more frequently in females. Positive effects of the above combinations were registered in patients of all ages. The remission persisted for 1-3 years. The treatment proved safe and pathogenetic. Cryoelectrotherapy is thought valid for therapeutic and prophylactic application in any cases of acute thrombophlebitis and chronic venous insufficiency of the legs. PMID:8928432

  10. Acute phase reaction and acute phase proteins*

    PubMed Central

    Gruys, E.; Toussaint, M.J.M.; Niewold, T.A.; Koopmans, S.J.

    2005-01-01

    A review of the systemic acute phase reaction with major cytokines involved, and the hepatic metabolic changes, negative and positive acute phase proteins (APPs) with function and associated pathology is given. It appears that APPs represent appropriate analytes for assessment of animal health. Whereas they represent non-specific markers as biological effect reactants, they can be used for assessing nutritional deficits and reactive processes, especially when positive and negative acute phase variables are combined in an index. When such acute phase index is applied to separate healthy animals from animals with some disease, much better results are obtained than with single analytes and statistically acceptable results for culling individual animals may be reached. Unfortunately at present no cheap, comprehensive and easy to use system is available for assessing various acute phase proteins in serum or blood samples at the same time. Protein microarray or fluid phase microchip technology may satisfy this need; and permit simultaneous analysis of numerous analytes in the same small volume sample and enable integration of information derived from systemic reactivity and nutrition with disease specific variables. Applying such technology may help to solve health problems in various countries not only in animal husbandry but also in human populations. PMID:16252337

  11. Acute Shoulder Injuries in Adults.

    PubMed

    Monica, James; Vredenburgh, Zachary; Korsh, Jeremy; Gatt, Charles

    2016-07-15

    Acute shoulder injuries in adults are often initially managed by family physicians. Common acute shoulder injuries include acromioclavicular joint injuries, clavicle fractures, glenohumeral dislocations, proximal humerus fractures, and rotator cuff tears. Acromioclavicular joint injuries and clavicle fractures mostly occur in young adults as the result of a sports injury or direct trauma. Most nondisplaced or minimally displaced injuries can be treated conservatively. Treatment includes pain management, short-term use of a sling for comfort, and physical therapy as needed. Glenohumeral dislocations can result from contact sports, falls, bicycle accidents, and similar high-impact trauma. Patients will usually hold the affected arm in their contralateral hand and have pain with motion and decreased motion at the shoulder. Physical findings may include a palpable humeral head in the axilla or a dimple inferior to the acromion laterally. Reduction maneuvers usually require intra-articular lidocaine or intravenous analgesia. Proximal humerus fractures often occur in older patients after a low-energy fall. Radiography of the shoulder should include a true anteroposterior view of the glenoid, scapular Y view, and axillary view. Most of these fractures can be managed nonoperatively, using a sling, early range-of-motion exercises, and strength training. Rotator cuff tears can cause difficulty with overhead activities or pain that awakens the patient from sleep. On physical examination, patients may be unable to hold the affected arm in an elevated position. It is important to recognize the sometimes subtle signs and symptoms of acute shoulder injuries to ensure proper management and timely referral if necessary. PMID:27419328

  12. [Ultrasonography in acute pelvic pain].

    PubMed

    Kupesić, Sanja; Aksamija, Alenka; Vucić, Niksa; Tripalo, Ana; Kurjak, Asim

    2002-01-01

    Acute pelvic pain may be the manifestation of various gynecologic and non-gynecologic disorders from less alarming rupture of the follicular cyst to life threatening conditions such as rupture of ectopic pregnancy or perforation of inflamed appendix. In order to construct an algorithm for differential diagnosis we divide acute pelvic pain into gynecologic and non-gynecologic etiology, which is than subdivided into gastrointestinal and urinary causes. Appendicitis is the most common surgical emergency and should always be considered in differential diagnosis if appendix has not been removed. Apart of clinical examination and laboratory tests, an ultrasound examination is sensitive up to 90% and specific up to 95% if graded compression technique is used. Still it is user-depended and requires considerable experience in order to perform it reliably. Meckel's diverticulitis, acute terminal ileitis, mesenteric lymphadenitis and functional bowel disease are conditions that should be differentiated from other causes of low abdominal pain by clinical presentation, laboratory and imaging tests. Dilatation of renal pelvis and ureter are typical signs of obstructive uropathy and may be efficiently detected by ultrasound. Additional thinning of renal parenchyma suggests long-term obstructive uropathy. Ruptured ectopic pregnancy, salpingitis and hemorrhagic ovarian cysts are three most commonly diagnosed gynecologic conditions presenting as an acute abdomen. Degenerating leiomyomas and adnexal torsion occur less frequently. For better systematization, gynecologic causes of acute pelvic pain could be divided into conditions with negative pregnancy test and conditions with positive pregnancy test. Pelvic inflammatory disease may be ultrasonically presented with numerous signs such as thickening of the tubal wall, incomplete septa within the dilated tube, demonstration of hyperechoic mural nodules, free fluid in the "cul-de-sac" etc. Color Doppler ultrasound contributes to more

  13. Nephrology Update: Acute Kidney Injury.

    PubMed

    Sarabu, Nagaraju; Rahman, Mahboob

    2016-05-01

    Acute kidney injury (AKI) refers to any acute decrease in glomerular filtration rate, regardless of etiology. Staging of AKI has been recommended to stratify AKI patients according to severity of the condition, based on serum creatinine level and urine output. Classification of AKI into prerenal, intrinsic renal, and postrenal etiologies is helpful in differential diagnosis and management. AKI in hospitalized patients typically occurs due to decreased renal perfusion. Drug-induced, contrast-associated, postoperative, and sepsis-associated AKI also can occur. Clinical assessment of a patient with AKI involves a medical record review, thorough history and physical examination, urinary and blood tests, renal imaging, and, in some instances, renal biopsy. Contrast-induced nephropathy is a common iatrogenic etiology of AKI associated with administration of intravenous iodinated contrast media. Measures to prevent AKI should be taken before administration of intravenous iodinated contrast. AKI can result in many short- and long-term complications, including chronic kidney disease and end-stage renal disease. Appropriate treatment of AKI patients involves management of the underlying etiology, when possible, and use of nondialytic and dialytic therapies. PMID:27163760

  14. Varicella Zoster Infection: A Rare Cause of Abdominal Pain Mimicking Acute Abdomen

    PubMed Central

    Olmez, Deniz; Boz, Alper; Erkan, Nazif

    2009-01-01

    Varicella zoster is an acute viral infection that results from reactivation of a latent varicella zoster virus. It usually occurs in adult population and immune compromised patients. It rarely occurs in healthy children. Here we present a 14 years old male with varicella zoster that had abdominal pain mimicking acute abdomen to alert others who are consulted for the differentiation of acute abdomen and others who may be consulted for pain management. Keywords Varicella zoster; Abdominal pain PMID:22461879

  15. Acute fatty liver of pregnancy associated with severe acute pancreatitis: A case report

    PubMed Central

    de Oliveira, Cássio Vieira; Moreira, Alecsandro; Baima, Julio P; Franzoni, Leticia de C; Lima, Talles B; Yamashiro, Fabio da S; Coelho, Kunie Yabuki Rabelo; Sassaki, Ligia Y; Caramori, Carlos Antonio; Romeiro, Fernando G; Silva, Giovanni F

    2014-01-01

    Acute fatty liver of pregnancy is a rare disease that affects women in the third trimester of pregnancy. Although infrequent, the disease can cause maternal mortality. The diagnosis is not always clear until the pregnancy is terminated, and significant complications, such as acute pancreatitis, can occur. Pancreatic involvement typically only occurs in severe cases after the development of hepatic and renal impairment. To date, little knowledge is available regarding how the disease causes pancreatitis. Treatment involves supportive measures and pregnancy interruption. In this report, we describe a case of a previously healthy 26-year-old woman at a gestational age of 27 wk and 6 d who was admitted with severe abdominal pain and vomiting. This case illustrates the clinical and laboratory overlap between acute fatty liver of pregnancy and pancreatitis, highlighting the difficulties in differentiating each disease. Furthermore, the hypothesis for this overlapping is presented, and the therapeutic options are discussed. PMID:25068005

  16. Acute kidney injury.

    PubMed

    Lang, Joanna; Zuber, Kim; Davis, Jane

    2016-04-01

    Acute kidney injury (AKI) complicates up to 20% of all hospital admissions. Responding to the increase in admissions, complications, mortality, morbidity, and cost of AKI, Kidney Disease: Improving Global Outcomes convened an expert panel to study the issue, review the literature, and publish guidelines to evaluate and treat patients with AKI in the acute setting. This article reviews those guidelines. PMID:27023656

  17. Poznan acute Astronomical Observatory

    NASA Astrophysics Data System (ADS)

    Murdin, P.

    2000-11-01

    This Poznan acute Astronomical Observatory is a unit of the Adam Mickiewicz University, located in Poznan acute, Poland. From its foundation in 1919, it has specialized in astrometry and celestial mechanics (reference frames, dynamics of satellites and small solar system bodies). Recently, research activities have also included planetary and stellar astrophysics (asteroid photometry, catalysmic b...

  18. Causes and Outcomes of Pediatric Injuries Occurring at School.

    ERIC Educational Resources Information Center

    Di Scala, Carla; Gallagher, Susan Scavo; Schneps, Sue E.

    1997-01-01

    Used the National Pediatric Trauma Registry, which collects data on child injuries requiring hospitalization, to examine causes and outcomes of injuries occurring at school. Analysis of 1,558 cases indicated that most injuries were unintentional and occurred among students age 10-14 years. Nearly half occurred in recreational areas. Falls and…

  19. Acute aortic dissection in pregnant women.

    PubMed

    Yang, Zhaohua; Yang, Shouguo; Wang, Fangshun; Wang, Chunsheng

    2016-05-01

    Acute aortic dissection occurring during pregnancy represents a lethal risk to both the mother and fetus. Management of parturient with acute aortic dissection is complex. We report our experience of two pregnancies with type A acute aortic dissection. One patient is a 31-year-old pregnant woman (33rd gestational week) with a bicuspid aortic valve and the other is a 32-year-old pregnant woman (30th gestational week) with the Marfan syndrome. In both cases, a combined emergency operation consisting of Cesarean section, total hysterectomy prior to corrective surgery for aortic dissection was successfully performed within a relatively short period of time after the onset. Both patients' postoperative recovery was uneventful, and we achieved a favorable maternal and fetal outcome. PMID:25085319

  20. Renal graft irradiation in acute rejection

    SciTech Connect

    Pilepich, M.V.; Sicard, G.A.; Breaux, S.R.; Etheredge, E.E.; Blum, J.; Anderson, C.B.

    1983-03-01

    To evaluate the effect of graft irradiation in the treatment of acute rejection of renal transplants, a randomized study was conducted from 1978 to 1981. Patients with acute rejection were given standard medical management in the form of intravenous methylprednisolone, and were chosen randomly to receive either graft irradiation (175 rads every other day, to a total of 525 rads) or simulated (sham) irradiation. Eighty-three rejections occurring in 64 grafts were randomized to the protocol. Rejection reversal was recorded in 84.5% of control grafts and 75% of the irradiated grafts. Recurrent rejections were more frequent and graft survival was significantly lower in the irradiated group (22%) than in the control group (54%). Graft irradiation does not appear to be beneficial in the treatment of acute rejection of renal transplants when used in conjunction with high-dose steroids.

  1. Systemic thrombolysis for acute pulmonary embolism.

    PubMed

    Bartel, Billie

    2015-01-01

    Acute pulmonary embolism is a frequent cause of hospitalization and is associated with a wide range of symptom severity. Anticoagulants are the mainstay of treatment for acute pulmonary embolism; however, in patients with massive or submassive pulmonary embolism, advanced therapy with thrombolytics may be considered. The decision to use thrombolytic therapy for acute pulmonary embolism should be based on careful risk-benefit analysis for each patient, including risk of morbidity and mortality associated with the embolism and risk of bleeding associated with the thrombolytic. Alteplase is currently the thrombolytic agent most studied and with the most clinical experience for this indication, although the most appropriate dose remains controversial, especially in patients with low body weight. When considering thrombolysis, unfractionated heparin is the preferred initial anticoagulant due to its short duration of action and its reversibility should bleeding occur. PMID:25559613

  2. A SCUBA diver with acute kidney injury.

    PubMed

    Gleeson, Patrick James; Kelly, Yvelynne; Ni Sheaghdha, Eadaoin; Lappin, David

    2015-01-01

    An otherwise healthy young man was transferred to our hospital after a diving incident. He had made an uncontrolled ascent from 10 m. On arrival he appeared well. No hypotensive episodes occurred during the transfer. He denied having arthralgias, back pain, dyspnoea or neurological symptoms. Laboratory investigations revealed acutely elevated creatinine (170 µmol/L) and creatine kinase (909 U/L). Radiology was consistent with a focus of pulmonary barotrauma and intrinsic renal disease. Creatine kinase is a marker of arterial gas embolism (AGE). We determined that our patient suffered acute kidney injury as a result of gas embolisation to his renal vasculature from an area of pulmonary barotrauma. Creatinine fell the following day in response to aggressive intravenous fluids. This is the first reported case of acute kidney injury secondary to AGE. Biochemical studies should be part of the routine assessment of patients involved in diving incidents. PMID:25948841

  3. Hyperoxic Acute Lung Injury

    PubMed Central

    Kallet, Richard H; Matthay, Michael A

    2013-01-01

    Prolonged breathing of very high FIO2 (FIO2 ≥ 0.9) uniformly causes severe hyperoxic acute lung injury (HALI) and, without a reduction of FIO2, is usually fatal. The severity of HALI is directly proportional to PO2 (particularly above 450 mm Hg, or an FIO2 of 0.6) and exposure duration. Hyperoxia produces extraordinary amounts of reactive O2 species that overwhelms natural antioxidant defenses and destroys cellular structures through several pathways. Genetic predisposition has been shown to play an important role in HALI among animals, and some genetics-based epidemiologic research suggests that this may be true for humans as well. Clinically, the risk of HALI likely occurs when FIO2exceeds 0.7, and may become problematic when FIO2 exceeds 0.8 for an extended period of time. Both high-stretch mechanical ventilation and hyperoxia potentiate lung injury and may promote pulmonary infection. During the 1960s, confusion regarding the incidence and relevance of HALI largely reflected such issues as the primitive control of FIO2, the absence of PEEP, and the fact that at the time both ALI and ventilator-induced lung injury were unknown. The advent of PEEP and precise control over FIO2, as well as lung-protective ventilation, and other adjunctive therapies for severe hypoxemia, has greatly reduced the risk of HALI for the vast majority of patients requiring mechanical ventilation in the 21st century. However, a subset of patients with very severe ARDS requiring hyperoxic therapy is at substantial risk for developing HALI, therefore justifying the use of such adjunctive therapies. PMID:23271823

  4. Haploidentical Transplantation Without In Vitro T-Cell Depletion Results in Outcomes Equivalent to Those of Contemporaneous Matched Sibling and Unrelated Donor Transplantation for Acute Leukemia

    PubMed Central

    Yu, Sijian; Fan, Qian; Sun, Jing; Fan, Zhiping; Zhang, Yu; Jiang, Qianli; Huang, Fen; Xuan, Li; Dai, Min; Zhou, Hongsheng; Liu, Hui; Liu, Qi-Fa

    2016-01-01

    Abstract The aim of the study is to determine whether HLA-haploidentical-related donor (HRD) transplant can achieve equivalent outcomes and have stronger GVL compared to HLA-matched sibling donor (MSD) and HLA-matched unrelated donor (MUD) transplants. A total of 355 consecutive patients with acute leukemia undergoing allogeneic transplant at our single institute between March 2008 and March 2014 were enrolled in this retrospective investigation. Of the 355 patients, 96 cases received HRD, 153 MSD, and 106 MUD transplants. HRD transplant was associated with higher incidences of grade II to IV aGVHD (40.6%) compared with MSD (23.5%, P = 0.002) and MUD transplants (34.0%, P = 0.049), whereas incidences of grade III to IV aGVHD (11.4%, 7.8%, 10.5%, respectively; P = 0.590) and cGVHD (29.5%, 24.0%, 29.5%, respectively; P = 0.538) did not differ among 3 groups. Five-year relapse rates were 19.2%, 26.8%, and 23.0% in 3 groups, respectively (P = 0.419). However, of 206 high-risk patients, the relapse rate in HRD transplant was lower than in MSD transplant (23.8% vs 41.9%, P = 0.026). Multivariate analysis showed that HRD had beneficial impact on relapse (for MSD: P = 0.006). Five-year transplant-related mortality was lower in MSD transplant compared with those in HRD (17.3% vs 26.4%, P = 0.041) and MUD transplants (17.3% vs 24.1%, P = 0.037). Five-year overall survival were 60.4%, 64.6%, and 61.0%, respectively, in HRD, MSD, and MUD groups (P = 0.371); 5-year disease-free survival were 59.6%, 58.8%, and 54.9%, respectively (P = 0.423). Our results suggest that HRD transplant results in outcomes equivalent to MSD and MUD transplants. HRD might carry a superior GVL effect compared to MSD for high-risk patients. PMID:26986108

  5. Haploidentical Transplantation Without In Vitro T-Cell Depletion Results in Outcomes Equivalent to Those of Contemporaneous Matched Sibling and Unrelated Donor Transplantation for Acute Leukemia.

    PubMed

    Yu, Sijian; Fan, Qian; Sun, Jing; Fan, Zhiping; Zhang, Yu; Jiang, Qianli; Huang, Fen; Xuan, Li; Dai, Min; Zhou, Hongsheng; Liu, Hui; Liu, Qi-Fa

    2016-03-01

    The aim of the study is to determine whether HLA-haploidentical-related donor (HRD) transplant can achieve equivalent outcomes and have stronger GVL compared to HLA-matched sibling donor (MSD) and HLA-matched unrelated donor (MUD) transplants.A total of 355 consecutive patients with acute leukemia undergoing allogeneic transplant at our single institute between March 2008 and March 2014 were enrolled in this retrospective investigation.Of the 355 patients, 96 cases received HRD, 153 MSD, and 106 MUD transplants. HRD transplant was associated with higher incidences of grade II to IV aGVHD (40.6%) compared with MSD (23.5%, P = 0.002) and MUD transplants (34.0%, P = 0.049), whereas incidences of grade III to IV aGVHD (11.4%, 7.8%, 10.5%, respectively; P = 0.590) and cGVHD (29.5%, 24.0%, 29.5%, respectively; P = 0.538) did not differ among 3 groups. Five-year relapse rates were 19.2%, 26.8%, and 23.0% in 3 groups, respectively (P = 0.419). However, of 206 high-risk patients, the relapse rate in HRD transplant was lower than in MSD transplant (23.8% vs 41.9%, P = 0.026). Multivariate analysis showed that HRD had beneficial impact on relapse (for MSD: P = 0.006). Five-year transplant-related mortality was lower in MSD transplant compared with those in HRD (17.3% vs 26.4%, P = 0.041) and MUD transplants (17.3% vs 24.1%, P = 0.037). Five-year overall survival were 60.4%, 64.6%, and 61.0%, respectively, in HRD, MSD, and MUD groups (P = 0.371); 5-year disease-free survival were 59.6%, 58.8%, and 54.9%, respectively (P = 0.423).Our results suggest that HRD transplant results in outcomes equivalent to MSD and MUD transplants. HRD might carry a superior GVL effect compared to MSD for high-risk patients. PMID:26986108

  6. LATE ACUTE REJECTION IN LIVER TRANSPLANT: A SYSTEMATIC REVIEW

    PubMed Central

    NACIF, Lucas Souto; PINHEIRO, Rafael Soares; PÉCORA, Rafael Antônio de Arruda; DUCATTI, Liliana; ROCHA-SANTOS, Vinicius; ANDRAUS, Wellington; D'ALBUQUERQUE, Luiz Carneiro

    2015-01-01

    Introduction: Late acute rejection leads to worse patient and graft survival after liver transplantation. Aim: To analyze the reported results published in recent years by leading transplant centers in evaluating late acute rejection and update the clinical manifestations, diagnosis and treatment of liver transplantation. Method: Systematic literature review through Medline-PubMed database with headings related to late acute rejection in articles published until November 2013 was done. Were analyzed demographics, immunosuppression, rejection, infection and graft and patient survival rates. Results: Late acute rejection in liver transplantation showed poor results mainly regarding patient and graft survival. Almost all of these cohort studies were retrospective and descriptive. The incidence of late acute rejection varied from 7-40% in these studies. Late acute rejection was one cause for graft loss and resulted in different outcomes with worse patient and graft survival after liver transplant. Late acute rejection has been variably defined and may be a cause of chronic rejection with worse prognosis. Late acute rejection occurs during a period in which the goal is to maintain lower immunosuppression after liver transplantation. Conclusion: The current articles show the importance of late acute rejection. The real benefit is based on early diagnosis and adequate treatment at the onset until late follow up after liver transplantation. PMID:26537150

  7. Acute Hepatic Porphyria

    PubMed Central

    Bissell, D. Montgomery; Wang, Bruce

    2015-01-01

    The porphyrias comprise a set of diseases, each representing an individual defect in one of the eight enzymes mediating the pathway of heme synthesis. The diseases are genetically distinct but have in common the overproduction of heme precursors. In the case of the acute (neurologic) porphyrias, the cause of symptoms appears to be overproduction of a neurotoxic precursor. For the cutaneous porphyrias, it is photosensitizing porphyrins. Some types have both acute and cutaneous manifestations. The clinical presentation of acute porphyria consists of abdominal pain, nausea, and occasionally seizures. Only a small minority of those who carry a mutation for acute porphyria have pain attacks. The triggers for an acute attack encompass certain medications and severely decreased caloric intake. The propensity of females to acute attacks has been linked to internal changes in ovarian physiology. Symptoms are accompanied by large increases in delta-aminolevulinic acid and porphobilinogen in plasma and urine. Treatment of an acute attack centers initially on pain relief and elimination of inducing factors such as medications; glucose is administered to reverse the fasting state. The only specific treatment is administration of intravenous hemin. An important goal of treatment is preventing progression of the symptoms to a neurological crisis. Patients who progress despite hemin administration have undergone liver transplantation with complete resolution of symptoms. A current issue is the unavailability of a rapid test for urine porphobilinogen in the urgent-care setting. PMID:26357631

  8. Gastrointestinal Zygomycosis Masquerading as Acute Appendicitis

    PubMed Central

    Choi, Won-Tak; Chang, Tammy T.; Gill, Ryan M.

    2016-01-01

    Zygomycosis is a rare invasive opportunistic fungal infection that occurs in the setting of hematologic malignancies, chemotherapy-induced neutropenia, and immunosuppressive therapies. We report the first case of disseminated appendiceal zygomycosis due to Absidia spp. in a neutropenic patient who initially presented as acute appendicitis. A 63-year-old woman with acute myeloid leukemia presented as acute appendicitis while receiving induction chemotherapy and ultimately succumbed to overwhelming disseminated zygomycosis. Initial symptoms included loose stools and right lower abdominal pain unresponsive to broad-spectrum antibiotics. Clinical examination and cross-sectional imaging suggested acute appendicitis. The final diagnosis was established by histological evaluations of the ileocecectomy specimen, which showed angioinvasive fungal organisms within the necrotic appendiceal wall with characteristics typical of zygomycetes. Fungal cultures demonstrated Absidia spp. The patient was treated with amphotericin B but expired in the setting of fungal sepsis. A diagnosis of a fungal infection, including zygomycosis, should be considered in all chemotherapy-induced neutropenic patients who present with symptoms of acute appendicitis. A high index of clinical suspicion with prompt histologic and culture diagnosis of zygomycosis may reduce the high mortality and morbidity associated with zygomycosis of the gastrointestinal tract. PMID:27403107

  9. Acute Bacterial Prostatitis: Diagnosis and Management.

    PubMed

    Coker, Timothy J; Dierfeldt, Daniel M

    2016-01-15

    Acute bacterial prostatitis is an acute infection of the prostate gland that causes pelvic pain and urinary tract symptoms, such as dysuria, urinary frequency, and urinary retention, and may lead to systemic symptoms, such as fevers, chills, nausea, emesis, and malaise. Although the true incidence is unknown, acute bacterial prostatitis is estimated to comprise approximately 10% of all cases of prostatitis. Most acute bacterial prostatitis infections are community acquired, but some occur after transurethral manipulation procedures, such as urethral catheterization and cystoscopy, or after transrectal prostate biopsy. The physical examination should include abdominal, genital, and digital rectal examination to assess for a tender, enlarged, or boggy prostate. Diagnosis is predominantly made based on history and physical examination, but may be aided by urinalysis. Urine cultures should be obtained in all patients who are suspected of having acute bacterial prostatitis to determine the responsible bacteria and its antibiotic sensitivity pattern. Additional laboratory studies can be obtained based on risk factors and severity of illness. Radiography is typically unnecessary. Most patients can be treated as outpatients with oral antibiotics and supportive measures. Hospitalization and broad-spectrum intravenous antibiotics should be considered in patients who are systemically ill, unable to voluntarily urinate, unable to tolerate oral intake, or have risk factors for antibiotic resistance. Typical antibiotic regimens include ceftriaxone and doxycycline, ciprofloxacin, and piperacillin/tazobactam. The risk of nosocomial bacterial prostatitis can be reduced by using antibiotics, such as ciprofloxacin, before transrectal prostate biopsy. PMID:26926407

  10. Acute Lung Failure

    PubMed Central

    Mac Sweeney, Rob; McAuley, Daniel F.; Matthay, Michael A.

    2013-01-01

    Lung failure is the most common organ failure seen in the intensive care unit. The pathogenesis of acute respiratory failure (ARF) can be classified as (1) neuromuscular in origin, (2) secondary to acute and chronic obstructive airway diseases, (3) alveolar processes such as cardiogenic and noncardiogenic pulmonary edema and pneumonia, and (4) vascular diseases such as acute or chronic pulmonary embolism. This article reviews the more common causes of ARF from each group, including the pathological mechanisms and the principles of critical care management, focusing on the supportive, specific, and adjunctive therapies for each condition. PMID:21989697

  11. Acute porphyric disorders.

    PubMed

    Moore, A W; Coke, J M

    2000-09-01

    Acute porphyrias are classified into 3 distinct groups of rare genetic disorders of metabolic enzyme biosynthesis. Acute porphyrias can significantly impact multiple organ systems, which often provides a challenge to the dentist presented with such a patient. A case of hereditary coproporphyria is reported in a patient with many of the classical signs and symptoms. The patient also had complex dental needs that required special medical and pharmacotherapeutic modifications. The acute porphyrias are reviewed by the authors with presentation of this challenging case. Recommendations for other dental health care professionals encountering these patients are then presented. PMID:10982942

  12. Interferon-α: A Potentially Effective Treatment for Minimal Residual Disease in Acute Leukemia/Myelodysplastic Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Mo, Xiao-Dong; Zhang, Xiao-Hui; Xu, Lan-Ping; Wang, Yu; Yan, Chen-Hua; Chen, Huan; Chen, Yu-Hong; Han, Wei; Wang, Feng-Rong; Wang, Jing-Zhi; Liu, Kai-Yan; Huang, Xiao-Jun

    2015-11-01

    In this prospective clinical study, the safety and efficacy of preemptive interferon-α (IFN-α) treatment were investigated and compared with preemptive donor lymphocyte infusion (DLI) in patients who were minimal residual disease (MRD)-positive after allogeneic hematopoietic stem cell transplantation (HSCT). Patients undergoing allogeneic HSCT were eligible if they had acute leukemia or myelodysplastic syndrome and were MRD-positive after HSCT. Patients who were able to receive DLI were assigned to a preemptive DLI group (n = 45); patients who could not or did not agree to receive DLI after HSCT received preemptive IFN-α. A total of 22 patients received preemptive IFN-α; the median treatment duration was 35 days (range, 4 to 180 days). Seven patients relapsed, and 1 patient died from severe pneumonia. The 1-year cumulative incidence of chronic graft-versus-host disease (cGVHD) after intervention was 90.9% for the IFN-α group and 62.9% for the DLI group (P < .001). MRD status after preemptive intervention was comparable in the 2 groups, and the 1-year cumulative incidence of relapse after intervention was 27.3% for the IFN-α group and 35.6% for the DLI group (P = .514). The 1-year cumulative incidence of nonrelapse mortality after intervention was 4.5% for the IFN-α group and 4.4% for the DLI group (P = .985). The 1-year probability of disease-free survival after intervention was 68.2% for the IFN-α group and 60.0% for the DLI group (P = .517). In multivariate analysis, early-onset MRD, persistent MRD after intervention, and absence of cGVHD after intervention were significantly associated with poorer clinical outcomes. Thus, preemptive IFN-α may be a potential alternative for MRD-positive patients who cannot receive preemptive DLI after HSCT. PMID:26116088

  13. TCR-alpha/beta and CD19 depletion and treosulfan-based conditioning regimen in unrelated and haploidentical transplantation in children with acute myeloid leukemia.

    PubMed

    Maschan, M; Shelikhova, L; Ilushina, M; Kurnikova, E; Boyakova, E; Balashov, D; Persiantseva, M; Skvortsova, Y; Laberko, A; Muzalevskii, Y; Kazachenok, A; Glushkova, S; Bobrynina, V; Kalinina, V; Olshanskaya, Y; Baidildina, D; Novichkova, G; Maschan, A

    2016-05-01

    We evaluated the depletion of TCR-alpha/beta cells from the graft of children with high-risk AML, who received transplantation from unrelated (n=20) and haploidentical donors (n=13). The preparative regimen included treosulfan, melphalan, fludarabine and anti-thymocyte globulin. Grafts were PBSC engineered by TCR-alpha/beta and CD19 depletion. The graft contained a median of 9 × 10(6)/kg of CD34+ and 20 × 10(3)/kg of αβ-T cells. Post-transplant immune suppression included tacrolimus till day +30 and Mtx in 21 patients, tacrolimus in 5, Mtx in 2 and no prophylaxis in 5 patients. Sixteen patients received native or TCR-alpha/beta-depleted donor lymphocytes at a median of 47 (40-204) days. Median follow-up is 1.76 years. Primary engraftment was achieved in 33 patients (100%). Cumulative incidence of acute GvHD (aGvHD) grade 2-3 was 39 (26-60)%, half of them had skin-only aGvHD. Cumulative incidence of chronic GvHD was 30(18-50)%. Transplant-related mortality is 10(4-26)%. Event-free survival (EFS) is 60(43-76)% and overall survival (OS) is 67(50-84)% at 2 years. In a subgroup of patients, who received transplantation in CR, EFS is 66(48-84)% and OS-72(53-90)% at 2 years. Our data suggest that TCR-alpha/beta and CD19 depletion is a robust method of graft manipulation, which can be used to engineer grafts for children with AML. PMID:26808573

  14. Comparison of outcomes after umbilical cord blood and unmanipulated haploidentical hematopoietic stem cell transplantation in children with high-risk acute lymphoblastic leukemia.

    PubMed

    Mo, Xiao-Dong; Tang, Bao-Lin; Zhang, Xiao-Hui; Zheng, Chang-Cheng; Xu, Lan-Ping; Zhu, Xiao-Yu; Wang, Yu; Liu, Hui-Lan; Yan, Chen-Hua; Chu, Xian-Deng; Chen, Huan; Geng, Liang-Quan; Liu, Kai-Yan; Sun, Zi-Min; Huang, Xiao-Jun

    2016-11-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective therapy for children with high-risk acute lymphoblastic leukemia (ALL). Human leukocyte antigen (HLA)-haploidentical HSCT (haplo-HSCT) or umbilical cord blood transplantation (UCBT) are both important alternative sources of stem cells for those without an HLA-identical sibling donor or unrelated matched donor. We aimed to compare the therapeutic effects of single UCBT and unmanipulated haplo-HSCT in high-risk ALL children (n = 129). Hematopoietic recovery was significantly faster in haplo-HSCT recipients than in UCBT recipients. The 2-year cumulative incidences of relapse in the haplo-HSCT and UCBT groups were 16.1% and 24.1%, respectively (p = 0.169). The 2-year cumulative incidences of non-relapse mortality in the haplo-HSCT and UCBT groups were 12.8% and 18.8%, respectively (p = 0.277). The 2-year probabilities of overall survival in the haplo-HSCT and UCBT groups were 82.0% and 69.6%, respectively (p = 0.071), and the 2-year probability of disease-free survival in the haplo-HSCT group was higher than in the UCBT group (71.0% vs. 57.2%, p = 0.040). However, several variables (such as leukocyte count and cytogenetics at diagnosis) were different between the groups, and a possible center effect should also be considered. In addition, only mild and moderate chronic graft-versus-host disease (GVHD) was associated with significantly improved survival compared to those without chronic GVHD in multivariate analysis. Thus, our results show that both unmanipulated haplo-HSCT and UCBT are valid for high-risk ALL children lacking a HLA matched donor, and both strategies expand the donor pool for children in need. PMID:27356906

  15. Steroids Versus Steroids Plus Additional Agent in Frontline Treatment of Acute Graft-versus-Host Disease: A Systematic Review and Meta-Analysis of Randomized Trials.

    PubMed

    Rashidi, Armin; DiPersio, John F; Sandmaier, Brenda M; Colditz, Graham A; Weisdorf, Daniel J

    2016-06-01

    Despite extensive research in the last few decades, progress in treatment of acute graft-versus-host disease (aGVHD), a common complication of allogeneic hematopoietic cell transplantation (HCT), has been limited and steroids continue to be the standard frontline treatment. Randomized clinical trials (RCTs) have failed to find a beneficial effect of escalating immunosuppression using additional agents. Considering the small number of RCTs, limited sample sizes, and frequent early termination because of anticipated futility, we conducted a systematic review and an aggregate data meta-analysis to explore whether a true efficacy signal has been missed because of the limitations of individual RCTs. Seven reports met our inclusion criteria. The control arm in all studies was 2 mg/kg/day prednisone (or equivalent). The additional agent(s) used in the experimental arm(s) were higher-dose steroids, antithymocyte globulin, infliximab, anti-interleukin-2 receptor antibody (daclizumab and BT563), CD5-specific immunotoxin, and mycophenolate mofetil. Random effects meta-analysis revealed no efficacy signal in pooled response rates at various times points. Overall survival at 100 days was significantly worse in the experimental arm (relative risk [RR], .83; 95% confidence interval [CI], .74 to .94; P = .004, data from 3 studies) and showed a similar trend (albeit not statistically significantly) at 1 year as well (RR, .86; 95% CI, .68 to 1.09; P = .21, data from 5 studies). In conclusion, these results argue against the value of augmented generic immunosuppression beyond steroids for frontline treatment of aGVHD and emphasize the importance of developing alternative strategies. Novel forms of immunomodulation and targeted therapies against non-immune-related pathways may enhance the efficacy of steroids in this setting, and early predictive and prognostic biomarkers can help identify the subgroup of patients who would likely need treatments other than (or in addition to

  16. Pulmonary embolism in an immunocompetent patient with acute cytomegalovirus colitis

    PubMed Central

    Chou, Jen-Wei

    2016-01-01

    Acute cytomegalovirus (CMV) infection occurs commonly in immunocompromised and immunocompetent patients, but is usually asymptomatic in the latter. Vascular events associated with acute CMV infection have been described, but are rare. Hence, such events are rarely reported in the literature. We report a case of pulmonary embolism secondary to acute CMV colitis in an immunocompetent 78-year-old man. The patient presented with fever and diarrhea. Colonic ulcers were diagnosed based on colonoscopy findings, and CMV was the proven etiology on pathological examination. The patient subsequently experienced acute respiratory failure. Pulmonary embolism was diagnosed based on the chest radiography and computed tomography findings. A diagnosis of acute CMV colitis complicated by pulmonary embolism was made. The patient was successfully treated with intravenous administration of unfractionated heparin and intravenous ganciclovir. PMID:27175121

  17. Survival from acute renal failure after severe burns.

    PubMed

    Sawada, Y; Momma, S; Takamizawa, A; Nishida, S

    1984-12-01

    We describe a patient with 50 per cent, third degree flame burns who had a history of paint thinner inhalation for over 10 years. Moreover, chlorpromazine had been administered for the treatment of insomnia caused by chronic thinner intoxication. He developed oliguric acute renal failure soon after the burn injury, although adequate resuscitation therapy was given, and survived following frequent haemodialysis. Although survival from acute renal failure after severe burns is rare, once the diagnosis of acute renal failure has been made, haemodialysis should be instituted as early as possible. Furthermore, in a severely burnt patient with episodes of chronic and acute intoxication from organic chemicals or drugs which may have caused renal damage, acute renal failure may occur, so that careful observation is advised. PMID:6525538

  18. Acute myocardial infarction and sudden death in Sioux Indians.

    PubMed Central

    Hrabovsky, S L; Welty, T K; Coulehan, J L

    1989-01-01

    While some Indian tribes have low rates of acute myocardial infarction, Northern Plains Indians, including the Sioux, have rates of morbidity and mortality from acute myocardial infarction higher than those reported for the United States population in general. In a review of diagnosed cases of acute myocardial infarction over a 3-year period in 2 hospitals serving predominantly Sioux Indians, 8% of cases were found misclassified, and 22% failed to meet rigorous diagnostic criteria, although the patients did indeed have ischemic heart disease. Patients had high frequencies of complications and risk factors and a fatality rate of 16% within a month of admission. Sudden deaths likely due to ischemic heart disease but in persons not diagnosed as having acute myocardial infarction by chart review occurred 3 times more frequently than deaths occurring within a month of clinical diagnosis. PMID:2735047

  19. The efficacy and safety of a new reduced-toxicity conditioning with 4 days of once-daily 100 mg/m(2) intravenous busulfan associated with fludarabine and antithymocyte globulins prior to allogeneic stem cell transplantation in patients with high-risk myelodysplastic syndrome or acute leukemia.

    PubMed

    Wanquet, Anne; Crocchiolo, Roberto; Furst, Sabine; Granata, Angela; Faucher, Catherine; Devillier, Raynier; Harbi, Samia; Lemarie, Claude; Calmels, Boris; Vey, Norbert; Weiller, Pierre Jean; Chabannon, Christian; Castagna, Luca; Blaise, Didier; El-Cheikh, Jean

    2016-10-01

    The optimal intensity of myeloablation associated with a reduced-toxicity conditioning (RTC) regimen in order to decrease the relapse rate without increasing non-relapse mortality (NRM), is not well established yet. This retrospective analysis was done on 30 patients with hematological malignancies. The aim was to assess the safety of a RTC regimen based on the busulfan at a dose of 100 mg/m(2)/d intravenously for 4 d, fludarabine at a dose of 30 mg/m(2)/d for 5 d, and anti-thymoglobulins at a dose of 2.5 mg/kg/d for 2 d. The cumulative incidences of grade 2-4 acute graft-versus-host disease (GVHD) and all grades chronic GVHD were 37% and 42%, respectively. Median 1-year overall survival and disease-free survival were 66% and 50%, respectively. At 1 year, the cumulative incidence of relapse/disease progression was 33%. NRM was 3% and 17% at day 100 and 1 year, respectively. This RTC conditioning regimen can lead to a long-term disease control. Moreover, it appears to be safe with a low NRM rate among high-risk patients. PMID:26885686

  20. Incidence and outcome of invasive fungal diseases after allogeneic stem cell transplantation: a prospective study of the Gruppo Italiano Trapianto Midollo Osseo (GITMO).

    PubMed

    Girmenia, Corrado; Raiola, Anna Maria; Piciocchi, Alfonso; Algarotti, Alessandra; Stanzani, Marta; Cudillo, Laura; Pecoraro, Clara; Guidi, Stefano; Iori, Anna Paola; Montante, Barbara; Chiusolo, Patrizia; Lanino, Edoardo; Carella, Angelo Michele; Zucchetti, Elisa; Bruno, Benedetto; Irrera, Giuseppe; Patriarca, Francesca; Baronciani, Donatella; Musso, Maurizio; Prete, Arcangelo; Risitano, Antonio Maria; Russo, Domenico; Mordini, Nicola; Pastore, Domenico; Vacca, Adriana; Onida, Francesco; Falcioni, Sadia; Pisapia, Giovanni; Milone, Giuseppe; Vallisa, Daniele; Olivieri, Attilio; Bonini, Alessandro; Castagnola, Elio; Sica, Simona; Majolino, Ignazio; Bosi, Alberto; Busca, Alessandro; Arcese, William; Bandini, Giuseppe; Bacigalupo, Andrea; Rambaldi, Alessandro; Locasciulli, Anna

    2014-06-01

    Epidemiologic investigation of invasive fungal diseases (IFDs) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be useful to identify subpopulations who might benefit from targeted treatment strategies. The Gruppo Italiano Trapianto Midollo Osseo (GITMO) prospectively registered data on 1858 consecutive patients undergoing allo-HSCT between 2008 and 2010. Logistic regression analysis was performed to identify risk factors for proven/probable IFD (PP-IFD) during the early (days 0 to 40), late (days 41 to 100), and very late (days 101 to 365) phases after allo-HSCT and to evaluate the impact of PP-IFDs on 1-year overall survival. The cumulative incidence of PP-IFDs was 5.1% at 40 days, 6.7% at 100 days, and 8.8% at 12 months post-transplantation. Multivariate analysis identified the following variables as associated with PP-IFDs: transplant from an unrelated volunteer donor or cord blood, active acute leukemia at the time of transplantation, and an IFD before transplantation in the early phase; transplant from an unrelated volunteer donor or cord blood and grade II-IV acute graft-versus-host disease (GVHD) in the late phase; and grade II-IV acute GVHD and extensive chronic GVHD in the very late phase. The risk for PP-IFD was significantly higher when acute GVHD was followed by chronic GVHD and when acute GVHD occurred in patients undergoing transplantation with grafts from other than matched related donors. The presence of PP-IFD was an independent factor in long-term survival (hazard ratio, 2.90; 95% confidence interval, 2.32 to 3.62; P < .0001). Our findings indicate that tailored prevention strategies may be useful in subpopulations at differing levels of risk for PP-IFDs. PMID:24631738

  1. Weight Loss & Acute Porphyria

    MedlinePlus

    ... Sale You are here Home Diet and Nutrition Weight loss & acute Porphyria Being overweight is a particular problem ... one of these diseases before they enter a weight-loss program. Also, they should not participate in a ...

  2. Acute mountain sickness

    MedlinePlus

    High altitude cerebral edema; Altitude anoxia; Altitude sickness; Mountain sickness; High altitude pulmonary edema ... Acute mountain sickness is caused by reduced air pressure and lower oxygen levels at high altitudes. The faster you ...

  3. Acute respiratory distress syndrome

    MedlinePlus

    ... chap 33. Lee WL, Slutsky AS. Acute hypoxemic respiratory failure and ARDS. In: Broaddus VC, Mason RJ, Ernst JD, et al, eds. Murray and Nadel's Textbook of Respiratory Medicine . 6th ed. Philadelphia, PA: Elsevier Saunders; 2016: ...

  4. Acute coronary syndrome

    MedlinePlus

    Heart attack-ACS; Myocardial infarction-ACS; MI-ACS; Acute MI-ACS; ST-elevation myocardial infarction-ACS; Non-ST-elevation myocardial infarction-ACS; Unstable angina-ACS; Accelerating angina-ACS; New- ...

  5. Ear infection - acute

    MedlinePlus

    ... Risk factors for acute ear infections include: Attending day care (especially centers with more than 6 children) Changes ... hands and toys often. If possible, choose a day care that has 6 or fewer children. This can ...

  6. Acute Pancreatitis and Pregnancy

    MedlinePlus

    ... sudden inflammation of the pancreas manifested clinically by abdominal pain, nausea and dehydration that is usually self-limiting ... room for evaluation should they develop any abnormal abdominal pain symptoms. Conclusions While a rare event, acute pancreatitis ...

  7. Acute Flaccid Myelitis

    MedlinePlus

    ... on Facebook Tweet Share Compartir Acute flaccid myelitis (AFM) is a condition that affects the nervous system, ... from a variety of causes including viral infections. AFM is characterized by a sudden weakness in one ...

  8. Acute genital ulcers

    PubMed Central

    Delgado-García, Silvia; Palacios-Marqués, Ana; Martínez-Escoriza, Juan Carlos; Martín-Bayón, Tina-Aurora

    2014-01-01

    Acute genital ulcers, also known as acute vulvar ulcers, ulcus vulvae acutum or Lipschütz ulcers, refer to an ulceration of the vulva or lower vagina of non-venereal origin that usually presents in young women, predominantly virgins. Although its incidence is unknown, it seems a rare entity, with few cases reported in the literature. Their aetiology and pathogenesis are still unknown. The disease is characterised by an acute onset of flu-like symptoms with single or multiple painful ulcers on the vulva. Diagnosis is mainly clinical, after exclusion of other causes of vulvar ulcers. The treatment is mainly symptomatic, with spontaneous resolution in 2 weeks and without recurrences in most cases. We present a case report of a 13-year-old girl with two episodes of acute ulcers that fit the clinical criteria for Lipschütz ulcers. PMID:24473429

  9. Acute Radiation Syndrome

    MedlinePlus

    ... Dictionary Radiation Emergencies & Your Health Possible Health Effects Contamination and Exposure Acute Radiation Syndrome (ARS) Cutaneous Radiation ... Decision Making in Radiation Emergencies Protective Actions Internal Contamination Clinical Reference (ICCR) Application Psychological First Aid in ...

  10. Controlled trial of Penfluridol in Acute Psychosis

    PubMed Central

    van Praag, H. M.; Schut, T.; Dols, L.; van Schilfgaarden, R.

    1971-01-01

    A controlled study was made of penfluridol medication consisting of a single weekly oral dose of 30 mg in 30 patients with acute psychoses of varying type and origin. This medication was found to be effective. No significant side effects occurred. Several long-acting neuroleptics for injection are now available. The development of an oral compound of this type is an asset because of the manageability of the oral drug in the hands of family doctors and social psychiatrists. PMID:4943034

  11. Peripartum presentation of an acute aortic dissection.

    PubMed

    Lewis, S; Ryder, I; Lovell, A T

    2005-04-01

    We report the case of an acute type A aortic dissection occurring in a 35-year-old parturient. The initial diagnosis was missed; a subsequent emergency Caesarean section 3 weeks after presentation was followed by the development of left ventricular failure and pulmonary oedema in the early postoperative period. Echocardiography confirmed the diagnosis of aortic dissection and the patient underwent a successful surgical repair. PMID:15640303

  12. Acute copper toxicosis in the Canada goose.

    PubMed

    Henderson, B M; Winterfield, R W

    1975-01-01

    Acute copper toxicosis resulted in Canada geese, Branta canadensis, following ingestion of copper sulfate at about 600mg/kg from a small man-made pond on a game farm. The lesions were those associated with copper toxicosis in other avian species. The primary pathologic change was necrosis and sloughing of the proventriculus and gizzard. A greenish discoloration of the lungs also occurred. PMID:1156262

  13. Feigning Acute Intermittent Porphyria

    PubMed Central

    Elkhatib, Rania; Idowu, Modupe; Brown, Gregory S.; Jaber, Yasmeen M.; Reid, Matthew B.; Person, Cheryl

    2014-01-01

    Acute intermittent porphyria (AIP) is an autosomal dominant genetic defect in heme synthesis. Patients with this illness can have episodic life-threatening attacks characterized by abdominal pain, neurological deficits, and psychiatric symptoms. Feigning this illness has not been reported in the English language literature to date. Here, we report on a patient who presented to the hospital with an acute attack of porphyria requesting opiates. Diligent assessment of extensive prior treatment records revealed thirteen negative tests for AIP. PMID:25525547

  14. 32 CFR 716.6 - Death occurring after active service.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 5 2010-07-01 2010-07-01 false Death occurring after active service. 716.6 Section 716.6 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY PERSONNEL DEATH GRATUITY Provisions Applicable to the Navy and the Marine Corps § 716.6 Death occurring after...

  15. 32 CFR 716.6 - Death occurring after active service.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 5 2011-07-01 2011-07-01 false Death occurring after active service. 716.6 Section 716.6 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY PERSONNEL DEATH GRATUITY Provisions Applicable to the Navy and the Marine Corps § 716.6 Death occurring after...

  16. 32 CFR 716.6 - Death occurring after active service.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 5 2012-07-01 2012-07-01 false Death occurring after active service. 716.6 Section 716.6 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY PERSONNEL DEATH GRATUITY Provisions Applicable to the Navy and the Marine Corps § 716.6 Death occurring after...

  17. 32 CFR 716.6 - Death occurring after active service.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 5 2013-07-01 2013-07-01 false Death occurring after active service. 716.6 Section 716.6 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY PERSONNEL DEATH GRATUITY Provisions Applicable to the Navy and the Marine Corps § 716.6 Death occurring after...

  18. 32 CFR 716.6 - Death occurring after active service.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 5 2014-07-01 2014-07-01 false Death occurring after active service. 716.6 Section 716.6 National Defense Department of Defense (Continued) DEPARTMENT OF THE NAVY PERSONNEL DEATH GRATUITY Provisions Applicable to the Navy and the Marine Corps § 716.6 Death occurring after...

  19. [Acute cholangitis secondary to ascariasis and complicated by liver abscesses].

    PubMed

    Rakotonaivo, A; Ranoharison, H D; Razarimahefa, S H; Rakotozafindrabe, R; Rabenjanahary, T H; Ramanampamonjy, R M

    2015-01-01

    Acute cholangitis secondary to ascariasis is rare and occurs mainly in areas of high endemicity. The clinical presentation is non-specific, sometimes complicated by liver abscess. Abdominal ultrasound plays an important role in diagnosis and therapeutic surveillance. We report the case of a 35-year-old Malagasy woman with an acute cholangitis secondary to ascariasis and complicated by liver abscesses and its course to full recovery under medical treatment. PMID:26742557

  20. Acute abdominal aortic thrombosis caused by paroxysmal atrial fibrillation.

    PubMed

    Riccioni, G; Bucciarelli, V; Bisceglia, N; Totaro, G; Scotti, L; Aceto, A; Martini, F; Gallina, S; Bucciarelli, T; Macarini, L

    2013-01-01

    Acute abdominal aortic thrombosis is a rare and potential fatal event, which occurs in adult subjects. We present the case of a 72-year-old-man, who referred to the emergency Department of our hospital because of persistent severe abdominal and perineal pain. Doppler ultrasounds and computerized tomography angiography revealed the acute thrombosis of the abdominal aorta. Immediate revascularization through aortic thrombo-endoarterectomy resolved the disease. PMID:23830410

  1. Acute Demyelinating Disease after Oral Therapy with Herbal Extracts

    PubMed Central

    Kostianovsky, Alex; Maskin, Patricio; Noriega, María M.; Soler, Cristina; Bonelli, Ignacio; Riley, Claire S.; O'Connor, Kevin C.; Saubidet, Cristi´n López; Alvarez, Paulino A.

    2011-01-01

    Central nervous system demyelinating processes such as multiple sclerosis and acute disseminated encephalomyelitis constitute a group of diseases not completely understood in their physiopathology. Environmental and toxic insults are thought to play a role in priming autoimmunity. The aim of the present report is to describe a case of acute demyelinating disease with fatal outcome occurring 15 days after oral exposure to herbal extracts. PMID:21738505

  2. Plasmablastic Lymphoma Mimicking Acute Pancreatitis

    PubMed Central

    Virk, Hafeez Ul Hassan; Cheema, Ahmad R.; Saif, Muhammad Wasif

    2016-01-01

    Background. Plasmablastic lymphoma (PBL) is a rare B-cell neoplasm. It predominantly occurs in the oral cavity of human immunodeficiency virus (HIV)-positive patients and exhibits a highly aggressive clinical behavior. Case Presentation. We describe an unusual case of a 37-year-old HIV-positive male who presented with acute pancreatitis secondary to multiple peripancreatic masses compressing the pancreas. Histopathological examination of the lesions showed diffuse and cohesive pattern of large B-cells resembling immunoblasts or plasmablasts. The neoplastic cells were positive for BOB1 and MUM1, partially positive for CD79a, and negative for CD20, CD56, CD138, CD3, CD5, AE1/AE3, and HHV8. Epstein-Barr virus-encoded RNA in situ hybridization was positive. These features were consistent with PBL. The patient was initiated on cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy, demonstrating a striking response. Conclusion. To our research, this is the first report of PBL with the initial presentation of acute pancreatitis. The findings in this case suggest that PBL should be included in the differential diagnosis of pancreatic and peripancreatic tumors. PMID:27034868

  3. Epidemiology of acute lymphoblastic leukemia

    SciTech Connect

    Pendergrass, T.W.

    1985-06-01

    Although the etiology of acute leukemia is largely unknown, some facets of the puzzle are becoming clarified. Recognition of important patterns in age-specific mortality rates has suggested that events early in life, perhaps even prenatally, may have an influence on developing leukemia in childhood. The racial differences evident in mortality, incidence, and immunologic subtype of ALL suggest either differences in exposures to certain factors or differences in responses to those factors by white children. Hereditary factors appear to play a role. Familial and hereditary conditions exist that have high incidences of acute leukemia. Chromosomal anomalies are common in these conditions. Viral infections may play a role by contributing to alteration in genetic material through incorporation of the viral genome. How that virus is dealt with after primary infection seems important. The presence of immunodeficiency may allow wider dissemination or enhanced replication of such viruses, thereby increasing the likelihood of cellular transformation to an abnormal cell. Proliferation of that malignant cell to a clone may depend on other cofactors. Perhaps prolonged exposure to substances like benzene or alkylating agents may enhance these interactions between virus and genetic material. Does this change DNA repair mechanisms. Are viral infections handled differently. Is viral genomic information more easily integrated into host cells. Ionizing radiation has multiple effects. Alteration in genetic material occurs both at the molecular and chromosomal levels. DNA may be altered, lost, or added in the cell's attempt to recover from the injury.

  4. Plasmablastic Lymphoma Mimicking Acute Pancreatitis.

    PubMed

    Inayat, Faisal; Virk, Hafeez Ul Hassan; Cheema, Ahmad R; Saif, Muhammad Wasif

    2016-01-01

    Background. Plasmablastic lymphoma (PBL) is a rare B-cell neoplasm. It predominantly occurs in the oral cavity of human immunodeficiency virus (HIV)-positive patients and exhibits a highly aggressive clinical behavior. Case Presentation. We describe an unusual case of a 37-year-old HIV-positive male who presented with acute pancreatitis secondary to multiple peripancreatic masses compressing the pancreas. Histopathological examination of the lesions showed diffuse and cohesive pattern of large B-cells resembling immunoblasts or plasmablasts. The neoplastic cells were positive for BOB1 and MUM1, partially positive for CD79a, and negative for CD20, CD56, CD138, CD3, CD5, AE1/AE3, and HHV8. Epstein-Barr virus-encoded RNA in situ hybridization was positive. These features were consistent with PBL. The patient was initiated on cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy, demonstrating a striking response. Conclusion. To our research, this is the first report of PBL with the initial presentation of acute pancreatitis. The findings in this case suggest that PBL should be included in the differential diagnosis of pancreatic and peripancreatic tumors. PMID:27034868

  5. Treatment of acute silicoproteinosis by whole-lung lavage.

    PubMed

    Stafford, Marshall; Cappa, Anthony; Weyant, Michael; Lara, Abigail; Ellis, James; Weitzel, Nathaen S; Puskas, Ferenc

    2013-06-01

    Acute silicoproteinosis is a rare disease that occurs following a heavy inhalational exposure to silica dusts. Clinically, it resembles pulmonary alveolar proteinosis (PAP); silica exposure is thought to be a cause of secondary PAP. We describe a patient with biopsy-confirmed acute silicoproteinosis whose course was complicated by acute hypoxemic respiratory failure requiring mechanical ventilation. Without clinical improvement despite antibiotic and steroid treatment, the patient was scheduled for whole-lung lavage under general anesthesia. Anesthetic challenges included double-lumen tube placement and single-lung ventilation in a hypoxic patient, facilitating lung lavage, and protecting the contralateral lung from catastrophic spillage. PMID:23632425

  6. [Pre-hospital care management of acute spinal cord injury].

    PubMed

    Hess, Thorsten; Hirschfeld, Sven; Thietje, Roland; Lönnecker, Stefan; Kerner, Thoralf; Stuhr, Markus

    2016-04-01

    Acute injury to the spine and spinal cord can occur both in isolation as also in the context of multiple injuries. Whereas a few decades ago, the cause of paraplegia was almost exclusively traumatic, the ratio of traumatic to non-traumatic causes in Germany is currently almost equivalent. In acute treatment of spinal cord injury, restoration and maintenance of vital functions, selective control of circulation parameters, and avoidance of positioning or transport-related additional damage are in the foreground. This article provides information on the guideline for emergency treatment of patients with acute injury of the spine and spinal cord in the preclinical phase. PMID:27070515

  7. Cardiac Arrhythmias and Abnormal Electrocardiograms After Acute Stroke.

    PubMed

    Ruthirago, Doungporn; Julayanont, Parunyou; Tantrachoti, Pakpoom; Kim, Jongyeol; Nugent, Kenneth

    2016-01-01

    Cardiac arrhythmias and electrocardiogram (ECG) abnormalities occur frequently but are often underrecognized after strokes. Acute ischemic and hemorrhagic strokes in some particular area of brain can disrupt central autonomic control of the heart, precipitating cardiac arrhythmias, ECG abnormalities, myocardial injury and sometimes sudden death. Identification of high-risk patients after acute stroke is important to arrange appropriate cardiac monitoring and effective management of arrhythmias, and to prevent cardiac morbidity and mortality. More studies are needed to better clarify pathogenesis, localization of areas associated with arrhythmias and practical management of arrhythmias and abnormal ECGs after acute stroke. PMID:26802767

  8. Epigenetics in acute kidney injury

    PubMed Central

    Tang, Jinhua; Zhuang, Shougang

    2015-01-01

    Purpose of review Recent advances in epigenetics indicate the involvement of several epigenetic modifications in the pathogenesis of acute kidney injury (AKI). The purpose of this review is to summarize our understanding of recent advances in epigenetic regulation of AKI and provide mechanistic insight into the role of acetylation, methylation, and microRNA expression in the pathological processes of AKI. Recent findings Enhancement of protein acetylation by pharmacological inhibition of histone deacetylases (HDACs) leads to more severe tubular injury and impairment of renal structural and functional recovery. The changes in promoter DNA methylation occur in the kidney with ischemia/reperfusion. microRNA expression is associated with regulation of both renal injury and regeneration after AKI. Summary Recent studies on epigenetic regulation indicate that acetylation, methylation, and microRNA expression are critically implicated in the pathogenesis of AKI. Strategies targeting epigenetic processes may hold a therapeutic potential for patients with AKI. PMID:26050122

  9. UNDESCENDED TESTICLE COMPLICATING ACUTE APPENDICITIS*

    PubMed Central

    Herzig, Maximilian L.

    1924-01-01

    1. Symptoms referable to compression of the spermatic cord and incarceration of right testicle, obscure the underlying pathologic changes occurring in the vermiform appendix. 2. Testicular underdevelopment and resulting subnormal cerebration. 3. Operative technique: (a) Pre-operative diagnosis: Incarceration of right testicle and possible perforative appendicitis. (b) Descent of right incarcerated testicle. Bassini closure. (c) Exploratory laparotomy: Intramuscular gridiron incision. 4. Operative findings: (a) Strangulation and incarceration of undescended right testicle and spermatic cord in inguinal canal. (b) Copious pus, free in peritoneal cavity. An adherent, sloughing, perforative, retrocecal appendix identified, left undisturbed and free drainage established. 5. Progress: (a) Eventful recovery from acute suppurative appendicitis following drainage of appendical focus. (b) Marked development following the operative descent of an incarcerated testicle in a backward boy, age twelve, who had a bilateral cryptorchism. PMID:18739377

  10. Laryngeal schwannoma as an acute airway presentation.

    PubMed

    Markou, Konstantinos; Dova, Stamatia; Poulios, Christos; Karkos, Petros

    2016-01-01

    A schwannoma is a neurogenic tumour arising from nerve sheaths. Between 25% and 45% of schwannomas occur in the head and neck region. Schwannomas of the larynx are extremely rare. They usually occur in women during the fourth and fifth decades of life. We present a case of a laryngeal schwannoma in a 76-year-old patient with acute stridor, hoarseness and dysphagia. Laryngeal conservation surgery was performed without the need for a tracheostomy. One year later, the patient remains symptom-free with no evidence of recurrence. Clinical presentation, diagnosis and management are discussed and the literature is reviewed. PMID:26969364

  11. Differentiating Acute Otitis Media and Acute Mastoiditis in Hospitalized Children.

    PubMed

    Laulajainen-Hongisto, Anu; Aarnisalo, Antti A; Jero, Jussi

    2016-10-01

    Acute otitis media is a common infection in children. Most acute otitis media episodes can be treated at an outpatient setting with antimicrobials, or only expectant observation. Hospital treatment with parenteral medication, and myringotomy or tympanostomy, may be needed to treat those with severe, prolonged symptoms, or with complications. The most common intratemporal complication of acute otitis media is acute mastoiditis. If a child with acute mastoiditis does not respond to this treatment, or if complications develop, further examinations and other surgical procedures, including mastoidectomy, are considered. Since the treatment of complicated acute otitis media and complicated acute mastoiditis differs, it is important to differentiate these two conditions. This article focuses on the differential diagnostics of acute otitis media and acute mastoiditis in children. PMID:27613655

  12. [Etiological factors of acute pancreatitis].

    PubMed

    Spicák, J

    2002-09-01

    Acute pancreatitis develops immediately after the causative impulse, while chronic pancreatitis develops after the long-term action of the noxious agent. A typical representative of acute pancreatitis is biliary pancreatitis, chronic pancreatitis develops in alcoholism and has a long latency. As alcoholic pancreatitis is manifested at first as a rule by a potent attack, it is classified in this stage as acute pancreatitis. The most frequent etiological factors in our civilization are thus cholelithiasis and alcoholism (both account for 20-50% in different studies). The assumed pathogenetic principles in acute biliary pancreatitis are the common canal of both efferent ducts above the obturated papilla, duodenopancreatic reflux and intrapancreatic hypertension. A detailed interpretation is however lacking. The pathogenesis of alcoholic pancreatitis is more complicated. Among others some part is played by changes in the calcium concentration and fusion of cellular membranes. Idiopathic pancreatitis occurs in up to 10%, part of the are due to undiagnosed alcoholism and cholelithiasis. Other etiologies are exceptional. Similarly as in cholelithiasis pancreatitis develops also during other pathological processes in the area of the papilla of Vater such as dysfunction of the sphincter of Oddi, ampulloma and juxtapapillary diverticulum, it is however usually mild. The incidence of postoperative pancreatitis is declining. Its lethality is 30% and the diagnosis is difficult. In the pathogenesis changes of the ion concentration are involved, hypoxia and mechanical disorders of the integrity of the gland. Pancreatitis develops in association with other infections--frequently in mumps, rarely in hepatitis, tuberculosis, typhoid and mycoses. Viral pancreatitis is usually mild. In parasitoses pancreatitis develops due to a block of the papilla Vateri. In hyperparathyroidism chronic pancreatitis is more likely to develop, recent data are lacking. As to dyslipoproteinaemias

  13. Both rejection and tolerance of allografts can occur in the absence of secondary lymphoid tissues.

    PubMed

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

    2015-02-01

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

  14. A focused review of hematopoietic neoplasms occurring in the therapy-related setting

    PubMed Central

    Zhang, Liping; Wang, Sa A

    2014-01-01

    Hematological neoplasms developed in patients with a history of cytotoxic therapies comprise a group of diseases with a poor clinical outcome, and collectively categorized as “therapy-related myeloid neoplasms” (t-MN) in the 2008 World Health Organization (WHO) Classification. In recent years, numerous publications have emerged, and these studies have greatly expanded the scope of our understanding in this field. We here focused our review on several selected areas including secondary malignancies occurring in patients with autoimmune diseases; radiation therapy alone as a causative agent; the similarity and differences between therapy-related myelodysplastic syndromes (t-MDS) and acute myeloid leukemia (t-AML); clinical behavior and treatment outcome of t-AML patients with favorable cytogenetics; the incidence and clinical features of myelodysplastic/myeloproliferative neoplasms, as well as acute lymphoblastic leukemia and myeloproliferative neoplasms in patients with prior cytotoxic exposure. These recent studies have shown that therapy-related hematopoietic neoplasms are heterogeneous, and may manifest in various forms, more complex than we have recognized previously. Cytogenetic abnormalities and underlying mutations are likely to be the major factors dictating prognosis. PMID:25120730

  15. Comparative Toxicology of Libby Amphibole and Naturally Occurring Asbestos

    EPA Science Inventory

    Summary sentence: Comparative toxicology of Libby amphibole (LA) and site-specific naturally occurring asbestos (NOA) provides new insights on physical properties influencing health effects and mechanisms of asbestos-induced inflammation, fibrosis, and tumorigenesis.Introduction/...

  16. Unilateral eruptive vellus hair cysts occurring on the face.

    PubMed

    Lew, B-L; Lee, M-H; Haw, C-R

    2006-11-01

    Eruptive vellus hair cysts (EVHC) are small, cystic papules that usually occur on the chest and extremities. Their aetiology is unknown. Fewer than 10 cases of a variant form of EVHC that occur exclusively on the face have been reported. We describe a case of EVHC limited to the right side of the face. To the best of our knowledge, no case of unilateral EVHC has been reported. PMID:17062051

  17. Internet Censorship in China: Where Does the Filtering Occur?

    NASA Astrophysics Data System (ADS)

    Xu, Xueyang; Mao, Z. Morley; Halderman, J. Alex

    China filters Internet traffic in and out of the country. In order to circumvent the firewall, it is helpful to know where the filtering occurs. In this work, we explore the AS-level topology of China's network, and probe the firewall to find the locations of filtering devices. We find that even though most filtering occurs in border ASes, choke points also exist in many provincial networks. The result suggests that two major ISPs in China have different approaches placing filtering devices.

  18. Flavopiridol, Cytarabine, and Mitoxantrone in Treating Patients With Acute Leukemia

    ClinicalTrials.gov

    2013-10-07

    Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  19. The role of pattern-recognition receptors in graft-versus-host disease and graft-versus-leukemia after allogeneic stem cell transplantation.

    PubMed

    Heidegger, Simon; van den Brink, Marcel R M; Haas, Tobias; Poeck, Hendrik

    2014-01-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with curative potential for certain aggressive hematopoietic malignancies. Its success is limited by acute graft-versus-host disease (GVHD), a life-threatening complication that occurs when allo-reactive donor T cells attack recipient organs. There is growing evidence that microbes and innate pattern-recognition receptors (PRRs) such as toll-like receptors (TLR) and nod-like receptors (NLR) are critically involved in the pathogenesis of acute GVHD. Currently, a widely accepted model postulates that intensive chemotherapy and/or total-body irradiation during pre-transplant conditioning results in tissue damage and a loss of epithelial barrier function. Subsequent translocation of bacterial components as well as release of endogenous danger molecules stimulate PRRs of host antigen-presenting cells to trigger the production of pro-inflammatory cytokines (cytokine storm) that modulate T cell allo-reactivity against host tissues, but eventually also the beneficial graft-versus-leukemia (GVL) effect. Given the limitations of existing immunosuppressive therapies, a better understanding of the molecular mechanisms that govern GVHD versus GVL is urgently needed. This may ultimately allow to design modulators, which protect from GvHD but preserve donor T-cell attack on hematologic malignancies. Here, we will briefly summarize current knowledge about the role of innate immunity in the pathogenesis of GVHD and GVL following allo-HSCT. PMID:25101080

  20. An Unusual Case of Asystole Occurring during Deep Brain Stimulation Surgery

    PubMed Central

    Nguyen, Ha Son; Woehlck, Harvey; Pahapill, Peter

    2016-01-01

    Background. Symptomatic bradycardia and hypotension in neurosurgery can produce severe consequences if not managed appropriately. The literature is scarce regarding its occurrence during deep brain stimulation (DBS) surgery. Case Presentation. A 67-year-old female presented for left DBS lead placement for essential tremors. During lead implantation, heart rate and blood pressure dropped rapidly; the patient became unresponsive and asystolic. Chest compressions were initiated and epinephrine was given. Within 30 seconds, the patient became hemodynamically stable and conscious. A head CT demonstrated no acute findings. After deliberation, a decision was made to complete the procedure. Assuming the etiology of the episode was the Bezold-Jarisch reflex (BJR), appropriate accommodations were made. The procedure was completed uneventfully. Conclusion. The episode was consistent with a manifestation of the BJR. The patient had a history of neurocardiogenic syncope and a relatively low-volume state, factors prone to the BJR. Overall, lead implantation can still occur safely if preventive measures are employed. PMID:27217962

  1. Acute bronchial asthma.

    PubMed

    Grover, Sudhanshu; Jindal, Atul; Bansal, Arun; Singhi, Sunit C

    2011-11-01

    Acute asthma is the third commonest cause of pediatric emergency visits at PGIMER. Typically, it presents with acute onset respiratory distress and wheeze in a patient with past or family history of similar episodes. The severity of the acute episode of asthma is judged clinically and categorized as mild, moderate and severe. The initial therapy consists of oxygen, inhaled beta-2 agonists (salbutamol or terbutaline), inhaled budesonide (three doses over 1 h, at 20 min interval) in all and ipratropium bromide and systemic steroids (hydrocortisone or methylprednisolone) in acute severe asthma. Other causes of acute onset wheeze and breathing difficulty such as pneumonia, foreign body, cardiac failure etc. should be ruled out with help of chest radiography and appropriate laboratory investigations in first time wheezers and those not responding to 1 h of inhaled therapy. In case of inadequate response or worsening, intravenous infusion of magnesium sulphate, terbutaline or aminophylline may be used. Magnesium sulphate is the safest and most effective alternative among these. Severe cases may need ICU care and rarely, ventilatory support. PMID:21769523

  2. Acute Appendicitis Secondary to Acute Promyelocytic Leukemia

    PubMed Central

    Rodriguez, Eduardo A.; Lopez, Marvin A.; Valluri, Kartik; Wang, Danlu; Fischer, Andrew; Perdomo, Tatiana

    2015-01-01

    Patient: Female, 43 Final Diagnosis: Myeloid sarcoma appendicitis Symptoms: Abdominal pain • chills • fever Medication: — Clinical Procedure: Laparoscopic appendectomy, bone marrow biopsy Specialty: Gastroenterology and Hepatology Objective: Rare disease Background: The gastrointestinal tract is a rare site for extramedullary involvement in acute promyelocytic leukemia (APL). Case Report: A 43-year-old female with no past medical history presented complaining of mild abdominal pain, fever, and chills for the past day. On examination, she was tachycardic and febrile, with mild tenderness of her right lower quadrant and without signs of peritoneal irritation. Laboratory examination revealed pancytopenia and DIC, with a fibrinogen level of 290 mg/dL. CT of the abdomen showed a thickened and hyperemic appendix without perforation or abscess, compatible with acute appendicitis. The patient was given IV broad-spectrum antibiotics and was transfused with packed red blood cells and platelets. She underwent uncomplicated laparoscopic appendectomy and bone marrow biopsy, which revealed neo-plastic cells of 90% of the total bone marrow cellularity. Flow cytometry indicated presence of 92.4% of immature myeloid cells with t (15: 17) and q (22: 12) mutations, and FISH analysis for PML-RARA demonstrated a long-form fusion transcript, positive for APL. Appendix pathology described leukemic infiltration with co-expression of myeloperoxidase and CD68, consistent with myeloid sarcoma of the appendix. The patient completed a course of daunorubicin, cytarabine, and all trans-retinoic acid. Repeat bone marrow biopsy demonstrated complete remission. She will follow up with her primary care physician and hematologist/oncologist. Conclusions: Myeloid sarcoma of the appendix in the setting of APL is very rare and it might play a role in the development of acute appendicitis. Urgent management, including bone marrow biopsy for definitive diagnosis and urgent surgical intervention

  3. ELASTOGRAPHIC EVALUATION OF NATURALLY OCCURING TENDON AND LIGAMENT INJURIES OF THE EQUINE DISTAL LIMB.

    PubMed

    Lustgarten, Meghann; Redding, W Rich; Labens, Raphael; Davis, Weston; Daniel, Thomas M; Griffith, Emily; Seiler, Gabriela S

    2015-01-01

    Compression elastography is an ultrasonographic technique that estimates tissue strain and may have utility in diagnosing and monitoring soft tissue injuries in the equine athlete. Recently, elastography has been proven to be a feasible and repeatable imaging modality for evaluating normal tendons and ligaments of the equine distal forelimb. The purposes of this prospective study were to investigate the ability of elastography to detect spontaneously occurring lesions of equine tendons and ligaments diagnosed with magnetic resonance imaging (MRI) and gray-scale ultrasound (US) and to characterize the differences in the elastographic appearance of acute vs. chronic injuries. Fifty seven horses with a total of 65 lesions were evaluated. Images were assessed quantitatively and qualitatively. Acute lesions were found to be significantly softer (P < 0.0001) than chronic lesions (P < 0.0001) and the stiffness of lesions increased with progression of healing (P = 0.0138). A negative correlation between lesion hypoechogenicity and softness was appreciated with more hypoechoic lesions appearing softer (P = 0.0087) and more hyperechoic regions harder (P = 0.0002). A similar finding occurred with increased signal intensity on short tau inversion recovery (STIR) and proton density (PD) MRI sequences correlating with increased softness on elastography (P = 0.0164). Using US and MRI as references, commonly encountered soft tissue injuries of the equine distal limb could be detected with elastography. However, elastography was limited for detecting small, proximal injuries of the hindlimb proximal suspensory ligament. Elastographic evaluation of equine tendons and ligaments may allow better characterization of lesion chronicity and severity, and sequential examinations may optimize lesion management, rehabilitation, and return to training. PMID:26304065

  4. [Acute pancreatitis in children].

    PubMed

    Rottier, B L; Holl, R A; Draaisma, J M

    1998-02-21

    Acute pancreatitis is probably commoner in children than was previously thought. In children it is most commonly associated with trauma or viral infection. The presentation may be subtler than in adults, requiring a high index of suspicion in the clinician. In three children, two boys aged 4 and 10 and a girl of 15 years, acute pancreatitis was suspected because of the findings at ultrasonography and endoscopic retrograde cholangiopancreatography performed when the disease recurred (the boy aged 4), apathy and immobility without dehydration or other obvious causes (the boy aged 10), and severe abdominal pain in combination with vomiting (the girl). All three patients had severely increased (urinary) amylase levels. Most often, acute pancreatitis in children tends to be a self-limiting disease which responds well to conservative treatment. PMID:9562770

  5. Acute acalculous cholecystitis.

    PubMed

    Barie, Philip S; Eachempati, Soumitra R

    2003-08-01

    Acute cholecystitis can develop without gallstones in critically ill or injured patients. However, the development of acute acalculous cholecystitis is not limited to surgical or injured patients, or even to the intensive care unit. Diabetes, malignant disease, abdominal vasculitis, congestive heart failure, cholesterol embolization, and shock or cardiac arrest have been associated with acute acalculous cholecystitis. Children may also be affected, especially after a viral illness. The pathogenesis of acute acalculous cholecystitis is a paradigm of complexity. Ischemia and reperfusion injury, or the effects of eicosanoid proinflammatory mediators, appear to be the central mechanisms, but bile stasis, opioid therapy, positive-pressure ventilation, and total parenteral nutrition have all been implicated. Ultrasound of the gallbladder is the most accurate diagnostic modality in the critically ill patient, with gallbladder wall thickness of 3.5 mm or greater and pericholecystic fluid being the two most reliable criteria. The historical treatment of choice for acute acalculous cholecystitis has been cholecystectomy, but percutaneous cholecystostomy is now the mainstay of therapy, controlling the disease in about 85% of patients. Rapid improvement can be expected when the procedure is performed properly. The mortality rates (historically about 30%) for percutaneous and open cholecystostomy appear to be similar, reflecting the severity of illness, but improved resuscitation and critical care may portend a decreased risk of death. Interval cholecystectomy is usually not indicated after acute acalculous cholecystitis in survivors; if the absence of gallstones is confirmed and the precipitating disorder has been controlled, the cholecystostomy tube can be pulled out after the patient has recovered. PMID:12864960

  6. On co-design of filter and fault estimator against randomly occurring nonlinearities and randomly occurring deception attacks

    NASA Astrophysics Data System (ADS)

    Hu, Jun; Liu, Steven; Ji, Donghai; Li, Shanqiang

    2016-07-01

    In this paper, the co-design problem of filter and fault estimator is studied for a class of time-varying non-linear stochastic systems subject to randomly occurring nonlinearities and randomly occurring deception attacks. Two mutually independent random variables obeying the Bernoulli distribution are employed to characterize the phenomena of the randomly occurring nonlinearities and randomly occurring deception attacks, respectively. By using the augmentation approach, the co-design problem of the robust filter and fault estimator is converted into the recursive filter design problem. A new compensation scheme is proposed such that, for both randomly occurring nonlinearities and randomly occurring deception attacks, an upper bound of the filtering error covariance is obtained and such an upper bound is minimized by properly designing the filter gain at each sampling instant. Moreover, the explicit form of the filter gain is given based on the solution to two Riccati-like difference equations. It is shown that the proposed co-design algorithm is of a recursive form that is suitable for online computation. Finally, a simulation example is given to illustrate the usefulness of the developed filtering approach.

  7. Acute Prevertebral Calcific Tendinitis

    PubMed Central

    Tamm, Alexander; Jeffery, Caroline C; Ansari, Khalid; Naik, Sandeep

    2015-01-01

    We present a case of neck pain in a middle-aged woman, initially attributed to a retropharyngeal infection and treated with urgent intubation. With the help of computed tomography, the diagnosis was later revised to acute prevertebral calcific tendinitis, a self-limiting condition caused by abnormal calcium hydroxyapatite deposition in the longus colli muscles. It is critical to differentiate between these two disease entities due to dramatic differences in management. A discussion of acute prevertebral calcific tendinitis and its imaging findings is provided below. PMID:27252789

  8. The Acute Abdominal Aorta.

    PubMed

    Mellnick, Vincent M; Heiken, Jay P

    2015-11-01

    Acute disorders of the abdominal aorta are potentially lethal conditions that require prompt evaluation and treatment. Computed tomography (CT) is the primary imaging method for evaluating these conditions because of its availability and speed. Volumetric CT acquisition with multiplanar reconstruction and three-dimensional analysis is now the standard technique for evaluating the aorta. MR imaging may be useful for select applications in stable patients in whom rupture has been excluded. Imaging is indispensable for diagnosis and treatment planning, because management has shifted toward endoluminal repair. Acute abdominal aortic conditions most commonly are complications of aneurysms and atherosclerosis. PMID:26526434

  9. Acute acalculous cholecystitis

    SciTech Connect

    Fox, M.S.; Wilk, P.J.; Weissmann, H.S.; Freeman, L.M.; Gliedman, M.L.

    1984-07-01

    Sixty-eight patients with acute acalculous cholecystitis were reviewed. The results of history and physical examinations were usually nondiagnostic. IDA cholescintigraphy (93 per cent accuracy rate) was the only reliable diagnostic modality. The results of oral cholecystography, intravenous cholangiography and ultrasonography were considerably less reliable. One-half of the patients had gangrenous cholecystitis. Cholecystectomy was the preferred operation with an over-all mortality of 9 per cent. IDA cholescintigraphy is an important new modality for the diagnosis of acute acalculous cholecystitis which, in the past, has often been difficult to diagnose.

  10. Acute Gynecologic Disorders.

    PubMed

    Donaldson, Carolyn K

    2015-11-01

    Premenopausal women with acute pelvic pain comprise a significant percentage of patients who present to the emergency room. Etiologies can be gynecologic, urologic, gastrointestinal, or vascular. Signs and symptoms are often nonspecific and overlapping. The choice of imaging modality is determined by the clinically suspected differential diagnosis. Ultrasound (US) is the preferred imaging modality for suspected obstetric or gynecologic disorders. CT is more useful when gastrointestinal or urinary tract pathology is likely. MR imaging is rarely used in the emergent setting, except to exclude appendicitis in pregnant women. This article presents a comprehensive review of imaging of acute gynecologic disorders. PMID:26526439

  11. Acute oral ulcers.

    PubMed

    Lehman, Julia S; Rogers, Roy S

    2016-01-01

    Accurate diagnosis of acute oral ulcers can be challenging. Important historic details include the pattern of recurrence, anatomic areas of involvement within the mouth and elsewhere on the mucocutaneous surface, associated medical symptoms or comorbidities, and symptomology. Careful mucocutaneous examination is essential. When necessary, biopsy at an active site without ulceration is generally optimal. Depending on the clinical scenario, supplemental studies that may be useful include cultures; perilesional biopsy for direct immunofluorescence testing; and evaluation for infectious diseases, gluten sensitivity, inflammatory bowel disease, human immunodeficiency virus infection, connective tissue diseases, or hematinic deficiencies. Clinicians should maintain a broad differential diagnosis when evaluating patients with acute oral ulcers. PMID:27343961

  12. Naturally-occurring chemical analogues for repository-derived radionuclides

    SciTech Connect

    Miller, B.

    1996-12-01

    Studies of natural systems are a valuable means of gaining information on the behavior of elements and radionuclides in the geosphere or biosphere that may be used to support performance assessments for radioactive waste repositories. However, these natural system studies face the problem that some of the chemical and isotopic species that occur in radioactive wastes do not occur naturally. Therefore, when attempting to study transport processes for these species other, naturally-occurring species must be examined as {open_quote}chemical analogues{close_quote} for the waste species. Chemical analogues are chosen on the basis of some similarity with the chemical behavior of the waste species in relevant physico-chemical environments. This is a tricky procedure and each system must be considered on a case-by-case basis, although some guidelines can be established and these are given here.

  13. When Does A Gait Transition Occur During Human Locomotion?

    PubMed Central

    Hreljac, Alan; Imamura, Rodney T.; Escamilla, Rafael F.; Edwards, W. Brent

    2007-01-01

    When a treadmill accelerates continuously, the walk-run transition has generally been assumed to occur at the instant when a flight phase is first observed, while the run-walk transition has been assumed to occur at the instant of the first double support period. There is no theoretical or empirical evidence to suggest that gait transitions occur at the instant of these events, nor even whether transitions are abrupt events. The purpose of this study was to determine whether the gait transitions during human locomotion occur abruptly, and if so, to determine the instant during a stride at which a transition occurs. The time history of the vertical velocity of the hip (vhip) and the angular velocity of the ankle (ωankle) were compared between constant speed strides (walking or running) and strides at and near the walk-run and run-walk transitions to determine if and when the transition strides resemble the stride of the corresponding constant speed strides. For both the walk-run and run-walk transitions, the stride prior to the transition resembled the original gait pattern, while the stride following the transition resembled the new gait pattern. The transition stride, however, did not resemble either a walking or a running stride during either of the transition directions. It was concluded that gait transitions are initiated at about midstance of the transition stride, but the transition is not completed until after an adjustment period of between one step and one stride. Thus, gait transitions are not abrupt events during human locomotion. Key pointsGait transitions are not abrupt events.Initiation of a gait transitions occur at about midstance of the transition stride.Gait transitions are completed approximately at the next heelstrike of the ipsilateral foot.Time period between initiation and completion of transition does not resemble either a walk or a run. PMID:24149222

  14. Acute Symptomatic Seizures Caused by Electrolyte Disturbances.

    PubMed

    Nardone, Raffaele; Brigo, Francesco; Trinka, Eugen

    2016-01-01

    In this narrative review we focus on acute symptomatic seizures occurring in subjects with electrolyte disturbances. Quite surprisingly, despite its clinical relevance, this issue has received very little attention in the scientific literature. Electrolyte abnormalities are commonly encountered in clinical daily practice, and their diagnosis relies on routine laboratory findings. Acute and severe electrolyte imbalances can manifest with seizures, which may be the sole presenting symptom. Seizures are more frequently observed in patients with sodium disorders (especially hyponatremia), hypocalcemia, and hypomagnesemia. They do not entail a diagnosis of epilepsy, but are classified as acute symptomatic seizures. EEG has little specificity in differentiating between various electrolyte disturbances. The prominent EEG feature is slowing of the normal background activity, although other EEG findings, including various epileptiform abnormalities may occur. An accurate and prompt diagnosis should be established for a successful management of seizures, as rapid identification and correction of the underlying electrolyte disturbance (rather than an antiepileptic treatment) are of crucial importance in the control of seizures and prevention of permanent brain damage. PMID:26754778

  15. ACUTE APENDICITIS IN LIVER TRANSPLANT RECIPIENTS

    PubMed Central

    da FONSECA-NETO, Olival Cirilo Lucena; LIMA, Heloise Caroline de Souza; de MELO, Paulo Sérgio Vieira; LEMOS, Roberto; LEITÃO, Laércio; AMORIM, Américo Gusmão; LACERDA, Cláudio Moura

    2016-01-01

    Background : Appendicitis is a common cause of emergency surgery that in the population undergoing organ transplantation presents a rare incidence due to late diagnosis and treatment. Aim : To report the occurrence of acute appendicitis in a cohort of liver transplant recipients. Methods : Retrospective analysis in a period of 12 years among 925 liver transplants, in witch five cases of acute appendicitis were encountered. Results : Appendicitis occurred between three and 46 months after liver transplantation. The age ranged between 15 and 58 years. There were three men and two women. The clinical presentations varied, but not discordant from those found in non-transplanted patients. Pain was a symptom found in all patients, in two cases well located in the right iliac fossa (40%). Two patients had symptoms characteristic of peritoneal irritation (40%) and one patient had abdominal distention (20%). All patients were submitted to laparotomies. In 20% there were no complications. In 80% was performed appendectomy complicated by suppuration (40%) or perforation (40%). Superficial infection of the surgical site occurred in two patients, requiring clinical management. The hospital stay ranged from 48 h to 45 days. Conclusion : Acute appendicitis after liver transplantation is a rare event being associated with a high rate of drilling, due to delays in diagnosis and therapy, and an increase in hospital stay. PMID:27120736

  16. Acute Symptomatic Seizures Caused by Electrolyte Disturbances

    PubMed Central

    Nardone, Raffaele; Brigo, Francesco

    2016-01-01

    In this narrative review we focus on acute symptomatic seizures occurring in subjects with electrolyte disturbances. Quite surprisingly, despite its clinical relevance, this issue has received very little attention in the scientific literature. Electrolyte abnormalities are commonly encountered in clinical daily practice, and their diagnosis relies on routine laboratory findings. Acute and severe electrolyte imbalances can manifest with seizures, which may be the sole presenting symptom. Seizures are more frequently observed in patients with sodium disorders (especially hyponatremia), hypocalcemia, and hypomagnesemia. They do not entail a diagnosis of epilepsy, but are classified as acute symptomatic seizures. EEG has little specificity in differentiating between various electrolyte disturbances. The prominent EEG feature is slowing of the normal background activity, although other EEG findings, including various epileptiform abnormalities may occur. An accurate and prompt diagnosis should be established for a successful management of seizures, as rapid identification and correction of the underlying electrolyte disturbance (rather than an antiepileptic treatment) are of crucial importance in the control of seizures and prevention of permanent brain damage. PMID:26754778

  17. Arsenic poisoning in dairy cattle from naturally occurring arsenic pyrites.

    PubMed

    Hopkirk, R G

    1987-10-01

    An outbreak of arsenic poisoning occurred in which most of a 200 cow dairy herd were affected and six died. The source of the arsenic was naturally occurring arsenic pyrites from the Waiotapu Stream, near Rotorua. Arsenic levels in the nearby soil were as high as 6618 ppm. There was little evidence to suggest that treatment affected the course of the disease. Haematology was of little use in diagnosis, post-mortem signs were not always consistent and persistence of the element in the liver appeared short. Control of further outbreaks have been based on practical measures to minimise the intake of contaminated soil and free laying water by the stock. PMID:16031332

  18. Dialysis disequilibrium syndrome occurring during continuous renal replacement therapy

    PubMed Central

    Tuchman, Shamir; Khademian, Zarir P.; Mistry, Kirtida

    2013-01-01

    The dialysis disequilibrium syndrome (DDS) is characterized by progressive neurological symptoms and signs attributable to cerebral edema that occurs due to fluid shifts into the brain following a relatively rapid decrease in serum osmolality during hemodialysis (HD). Since continuous renal replacement therapy (CRRT) is less efficient at solute clearance than intermittent HD, it seems logical that this mode of therapy is less likely to cause DDS. This entity has not been previously reported to occur with this modality. Here, we report two cases of DDS associated with CRRT that provide insights into its pathophysiological mechanisms and suggest strategies for its prevention. PMID:26120445

  19. Addressing Naturally Occurring Asbestos in the Mining Industry

    NASA Astrophysics Data System (ADS)

    Bieber, D. W.

    2012-12-01

    Mining companies deal with naturally occurring asbestos (NOA) issues on their sites in two ways, avoidance and management. Avoidance simply means that to the extent practical, new mines are located in areas where NOA is unlikely to occur. Where mines are located in areas where NOA may be present, mines implement management procedures to identify and control potential sources of NOA. Management practices may include procedures set forth in regulations such as California's Air Toxicity Control Measure that deals with surface mining, voluntary procedures, or a combination of both. The mining industry generally recognizes that addressing NOA issues is a cost of doing business.;

  20. Adoptive transfer of T cells transduced with a chimeric antigen receptor to treat relapsed or refractory acute leukemia: efficacy and feasibility of immunotherapy approaches.

    PubMed

    Ding, Guoliang; Chen, Hu

    2016-07-01

    Treatment outcomes of acute leukemia (AL) have not improved over the past several decades and relapse rates remain high despite the availability of aggressive therapies. Conventional relapsed leukemia treatment includes second allogeneic hematopoietic stem cell transplantation (allo-HSCT) and donor lymphocyte infusion (DLI), which in most cases mediate, at best, a modest graft-versus-leukemia effect, although their clinical efficacy is still limited. Although allo-HSCT following myeloablative conditioning is a curative treatment option for younger patients with acute myeloid leukemia (AML) in a first complete remission (CR), allo-HSCT as a clinical treatment is usually limited because of treatment-related toxicity. The overall DLI remission rate is only 15%-42% and 2-year overall survival (OS) is approximately 15%-20%, with a high (40%-60%) incidence of DLI-related graft-versus-host disease (GVHD). Therefore, development of new, targeted treatment strategies for relapsed and refractory AL patients is ongoing. Adoptive transfer of T cells with genetically engineered chimeric antigen receptors (CARs) is an encouraging approach for treating hematological malignancies. These T cells are capable of selectively recognizing tumor-associated antigens and may overcome many limitations of conventional therapies, inducing remission in patients with chemotherapy-refractory or relapsed AL. In this review, we aimed to highlight the current understanding of this promising treatment modality, discussing its adverse effects and efficacy. PMID:27142351

  1. CT60 single-nucleotide polymorphism as a surrogate marker for donor lymphocyte infusion outcome after allogeneic cell transplantation for acute leukemia.

    PubMed

    Metaxas, Y; Bertz, H; Spyridonidis, A; Spyroupoulou-Vlachou, M; Porzelius, C; Finke, J

    2012-03-01

    The benefit of survival at the expense of new GVHD after DLI for acute leukemia following human allogeneic hematopoietic cell transplantation (allo-HCT) remains a matter of controversy. The detection of biological markers predicting this outcome would be an enormous breakthrough. The purpose of this study was the analysis of CT60 single-nucleotide polymorphism (SNP) of the CTLA-4 T-regulatory gene as a surrogate marker for DLI outcome in this difficult setting. Using Pyrosequencing, we genotyped the alleles of the CT60 SNP of 79 DLI donors and correlated them with the post-DLI outcome of their matching recipients. The presence of a donor 'AA' or 'AG' CT60 genotype vs a 'GG' genotype was an independent factor for remaining in complete chimerism/remission post-DLI (odds ratio (OR) 2.61 vs 0.42, respectively, P=0.05). Further, in cases with evident post-DLI allo-reactivity the importance of an 'AA' or 'AG' vs a 'GG' genotype gained significance for ongoing complete chimerism (OR 4.35 vs 0.32, P=0.03). Neither alterations in cumulative DLI dose nor any other clinical parameter significantly weakened the importance of CT60 SNP. Our results provide evidence for the necessity of genotyping CT60 SNP prior to DLI administration in patients with acute leukemia. PMID:21552305

  2. Radioimmunotherapy with [188Re]-labelled anti-CD66 antibody in the conditioning for allogeneic stem cell transplantation for high-risk acute myeloid leukemia.

    PubMed

    Koenecke, Christian; Hofmann, Michael; Bolte, Oliver; Gielow, Peter; Dammann, Elke; Stadler, Michael; Franzke, Anke; Boerner, Anne Rose; Eder, Matthias; Ganser, Arnold; Knapp, Wolfram; Hertenstein, Bernd

    2008-05-01

    Between July 2000 and June 2003 a total of 21 patients with high-risk acute myeloid leukemia (AML; n = 14), AML after myelodysplastic syndrome (MDS; n = 6) or advanced MDS (n = 1) were treated with an 188-Re labelled anti-CD66 antibody in the conditioning regimen for allogeneic stem cell transplantation. Radioimmunotherapy (RIT) was followed by standard full-dose conditioning with busulfan and high-dose cyclophosphamide in 11 patients and reduced intensity conditioning regimen in 10 patients. All patients received an unmanipulated allogeneic graft from alternative donors (n = 15) or a HLA-identical familiy donor (n = 6). With a median follow up of 42 months (23-60) disease free survival for all patients was 43%. Nine patients are still alive and in ongoing complete hematological remission. The treatment related mortality was 28.6% (n = 6) and an equal number of patients died of relapsing disease within 30-385 days after transplantation. Late organ toxicity, monitored for more than 1 year, was mild and not clinically relevant. The combination of RIT with chemotherapeutic conditioning seems to be a therapy with an acceptable risk of treatment related morbidity and mortality as well as occurrence of severe acute GvHD. PMID:18415659

  3. What Is Acute Myeloid Leukemia?

    MedlinePlus

    ... about acute myeloid leukemia? What is acute myeloid leukemia? Cancer starts when cells in a part of ... the body from doing their jobs. Types of leukemia Not all leukemias are the same. There are ...

  4. Preclinical models of acute and chronic graft-versus-host disease: how predictive are they for a successful clinical translation?

    PubMed

    Zeiser, Robert; Blazar, Bruce R

    2016-06-23

    Despite major advances in recent years, graft-versus-host disease (GVHD) remains a major life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). To improve our therapeutic armory against GVHD, preclinical evidence is most frequently generated in mouse and large animal models of GVHD. However, because every model has shortcomings, it is important to understand how predictive the different models are and why certain findings in these models could not be translated into the clinic. Weaknesses of the animal GVHD models include the irradiation only-based conditioning regimen, the homogenous donor/recipient genetics in mice, canine or non-human primates (NHP), anatomic site of T cells used for transfer in mice, the homogenous microbial environment in mice housed under specific pathogen-free conditions, and the lack of pharmacologic GVHD prevention in control groups. Despite these major differences toward clinical allo-HCT, findings generated in animal models of GVHD have led to the current gold standards for GVHD prophylaxis and therapy. The homogenous nature of the preclinical models allows for reproducibility, which is key for the characterization of the role of a new cytokine, chemokine, transcription factor, microRNA, kinase, or immune cell population in the context of GVHD. Therefore, when carefully balancing reasons to apply small and large animal models, it becomes evident that they are valuable tools to generate preclinical hypotheses, which then have to be rigorously evaluated in the clinical setting. In this study, we discuss several clinical approaches that were motivated by preclinical evidence, novel NHP models and their advantages, and highlight the recent advances in understanding the pathophysiology of GVHD. PMID:26994149

  5. Extracorporeal photopheresis for graft-versus-host disease: the role of patient, transplant, and classification criteria and hematologic values on outcome—results from a large single-center study

    PubMed Central

    Berger, Massimo; Albiani, Roberto; Sini, Bruno; Fagioli, Franca

    2015-01-01

    Background Extracorporeal photopheresis (ECP) has been shown as active therapy for graft-versus-host disease (GVHD). Study Design and Methods The aim was to ascertain the role of ECP in 71 patients with steroid-refractory or -dependent acute and chronic GVHD (aGVHD and cGVHD) with special focus on hematologic variables and GVHD staging classification. A total of 34 patients were treated for aGVHD and 37 for cGVHD. Results The overall response rate (ORR) for aGVHD was 65% and the complete aGVHD-free survival was 50% (95% confidence interval [CI], 36%-70%). The ORR for cGVHD response was 81% while the complete cGVHD-free survival was 50% (95% CI, 34%-73%). The aGVHD-free survival was associated with aGVHD grading (Grade II 81%, Grade III 33%, and Grade IV 0%, p ≤ 0.00) and the absence of visceral involvement (77% vs. 33%, p = 0.03). The cGVHD-free survival was associated with the female sex (67% vs. 25%, p = 0.01) and with the limited form according to the Seattle classification (67% vs. 20%, p = 0.003). No role for hematologic values or apheresis cell count was found, except for the cGVHD ORR (p = 0.037). Transplant-related mortality and overall survival were associated with ECP response 0% versus 54% (p = 0.0001) and 77% versus 45% (p = 0.03) for aGVHD patients and 7% versus 14% (p = 0.02) and 73% versus 20% (p = 0.0003) for cGVHD patients, respectively. Conclusions While confirming a higher probability of GVHD responses for early GVHD, our study shows no role of hematologic values or apheresis cell count on GVHD response. PMID:25355659

  6. Nutrition, Inflammation, and Acute Pancreatitis

    PubMed Central

    Petrov, Max

    2013-01-01

    Acute pancreatitis is acute inflammatory disease of the pancreas. Nutrition has a number of anti-inflammatory effects that could affect outcomes of patients with pancreatitis. Further, it is the most promising nonspecific treatment modality in acute pancreatitis to date. This paper summarizes the best available evidence regarding the use of nutrition with a view of optimising clinical management of patients with acute pancreatitis. PMID:24490104

  7. Integrative Priming Occurs Rapidly and Uncontrollably during Lexical Processing

    ERIC Educational Resources Information Center

    Estes, Zachary; Jones, Lara L.

    2009-01-01

    Lexical priming, whereby a prime word facilitates recognition of a related target word (e.g., "nurse" [right arrrow] "doctor"), is typically attributed to association strength, semantic similarity, or compound familiarity. Here, the authors demonstrate a novel type of lexical priming that occurs among unassociated, dissimilar, and unfamiliar…

  8. URBAN STORMWATER TRACING WITH THE NATURALLY OCCURRING DEUTERIUM ISOTOPE

    EPA Science Inventory

    Measurements of the naturally-occurring deuterium isotope assist the tracing of water components during wet-weather flows in an urban watershed. A transect of installations in the vadose and saturated zones was completed in the vicinity of a small stream and storm sewer. High-r...

  9. Changes occurring to minimally disturbed soil and to plant covers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    During the transition to organic production certain materials and practices, as described under US law, can not be used. During the transition period growers may, or may not, disturb the soil. There is little known about changes that occur if the soil is minimally disturbed during the transition t...

  10. Naturally occurring fatty acids: source, chemistry and uses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Natural occurring fatty acids are a large and complex class of compounds found in plants and animals. Fatty acids are abundant and of interest because of their renewability, biodegradability, biocompatibility, low cost, and fascinating chemistry. Of the many fatty acids, only 20-25 of them are widel...

  11. RUN OUTS OCCUR WHEN IRON HAS UNSEATED MOLDING SAND AND ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    RUN OUTS OCCUR WHEN IRON HAS UNSEATED MOLDING SAND AND RUN OUT OF THE MOLD UNDER POURING JACKETS AND SPILLS ONTO THE MOLDING PLATFORM. WORKERS GENERALLY WAIT SEVERAL MINUTES FOR THE IRON TO SOLIDIFY AND, WHILE IT IS STILL RED-HOT, REMOVE IT FROM THE PLATFORM AND SCRAP THE MOLD. - Southern Ductile Casting Company, Centerville Foundry, 101 Airport Road, Centreville, Bibb County, AL

  12. Social and Economic Polarization: Is It Occurring among Blacks?

    ERIC Educational Resources Information Center

    Farley, Reynolds; Bianchi, Suzanne M.

    An emerging hypothesis about black progress since the civil rights movement in the United States postulates that economic polarization is occurring in the black community. This hypothesis, which incorporates conflicting earlier theories of declining versus persistent racial differences, suggests that talented and well-educated blacks are competing…

  13. Acute coronary care 1986

    SciTech Connect

    Califf, R.M.; Wagner, G.S.

    1985-01-01

    This book contains 22 chapters. Some of the titles are: The measurement of acute myocardial infarct size by CT; Magnetic resonance imaging for evaluation of myocardial ischemia and infarction; Poistron imaging in the evaluation of ischemia and myocardial infarction; and New inotropic agents.

  14. Acute radiation risk models

    NASA Astrophysics Data System (ADS)

    Smirnova, Olga

    Biologically motivated mathematical models, which describe the dynamics of the major hematopoietic lineages (the thrombocytopoietic, lymphocytopoietic, granulocytopoietic, and erythropoietic systems) in acutely/chronically irradiated humans are developed. These models are implemented as systems of nonlinear differential equations, which variables and constant parameters have clear biological meaning. It is shown that the developed models are capable of reproducing clinical data on the dynamics of these systems in humans exposed to acute radiation in the result of incidents and accidents, as well as in humans exposed to low-level chronic radiation. Moreover, the averaged value of the "lethal" dose rates of chronic irradiation evaluated within models of these four major hematopoietic lineages coincides with the real minimal dose rate of lethal chronic irradiation. The demonstrated ability of the models of the human thrombocytopoietic, lymphocytopoietic, granulocytopoietic, and erythropoietic systems to predict the dynamical response of these systems to acute/chronic irradiation in wide ranges of doses and dose rates implies that these mathematical models form an universal tool for the investigation and prediction of the dynamics of the major human hematopoietic lineages for a vast pattern of irradiation scenarios. In particular, these models could be applied for the radiation risk assessment for health of astronauts exposed to space radiation during long-term space missions, such as voyages to Mars or Lunar colonies, as well as for health of people exposed to acute/chronic irradiation due to environmental radiological events.

  15. [Acute pancreatitis and pregnancy].

    PubMed

    Scollo, P; Licitra, G

    1993-12-01

    Aetiologic factors (gallstones, hyperlipidemia I-IV, hypertriglyceridaemia) make their occurrence, mainly, in the third trimester of gestation. Two cases of acute pancreatitis in pregnancy are described; in both cases patients referred healthy diet, no habit to smoke and no previous episode of pancreatitis. An obstructive pathology of biliary tract was the aetiologic factor. Vomiting, upper abdominal pain are aspecific symptoms that impose a differential diagnosis with acute appendicitis, cholecystitis and obstructive intestinal pathology. Laboratory data (elevated serum amylase and lipase levels) and ultrasonography carry out an accurate diagnosis. The management of acute pancreatitis is based on the use of symptomatic drugs, a low fat diet alternated to the parenteral nutrition when triglycerides levels are more than 28 mmol/L. Surgical therapy, used only in case of obstructive pathology of biliary tract, is optimally collected in the third trimester or immediately after postpartum. Our patients, treated only medically, delivered respectively at 38th and 40th week of gestation. Tempestivity of diagnosis and appropriate therapy permit to improve prognosis of a pathology that, although really associated with pregnancy, presents high maternal mortality (37%) cause of complications (shock, coagulopathy, acute respiratory insufficiency) and fetal (37.9%) by occurrence of preterm delivery. PMID:8139793

  16. [Acute blood pressure elevations].

    PubMed

    Chamontin, B; Amar, J; Chollet, F; Rouge, P; Bonetti-d'Esteve, L; Guittard, J; Salvador, M

    2000-11-01

    Blood pressure (BP) elevations may correspond to different clinical situations. Hypertensives emergencies are situations that require immediate reduction in BP because of acute or rapidly progressing target organ damage: accelerated malignant hypertension, hypertensive encephalopathy, acute myocardial infarction, acute aortic dissection, acute left ventricular failure, and eclampsia. Hypertensive urgencies are those with marked elevated BP in which it is desirable to reduce BP progressively within few hours, such as severe hypertension, progressive target organ damage, perioperative hypertension. Cerebrovascular accidents have to be individualized. In most patients in the immediate post-stroke period, BP should not be lowered. Caution is advised in lowering BP in these patients because excessive falls may precipitate cerebral ischemia. In situations without symptoms or progressive target organ it is necessary to exclude proximate causes of elevated BP such as pain and elevated BP alone rarely requires antihypertensive treatment. Among parenteral antihypertensive (AH) drugs labetalol, nicardipine, urapidil, and nitroprussiate are generally used, and the choice of AH drug depends on the clinical situation. It is not required to normalize BP immediately but to reduce mean BP no more than 25%, then toward 160/100 mmHg as recommended by JNC VI, in order to avoid an impairment of renal, cerebral or coronary ischemia. Oral long-acting dihydropyridines are often subsequently administrated, except in myocardial ischemia. Therapeutic attitudes vary considerably according to the clinical situation: abstention, immediate decrease or progressive decrease in BP have to be decided. PMID:11190294

  17. Gadolinium induced recurrent acute pancreatitis.

    PubMed

    Blasco-Perrin, H; Glaser, B; Pienkowski, M; Peron, J M; Payen, J L

    2013-01-01

    Acute pancreatitis is a sudden swelling and inflammation of the pancreas. The two most common causes are alcohol use and biliary stones. Drug-induced acute pancreatitis are rare (1.4-2%). In this present study, we present a case of recurrent acute pancreatitis induced by a specific magnetic-resonance-imaging (MRI) contrast agent called gadobenate dimeglumine. PMID:23395575

  18. Mineralogical Characteristics of Carbonate Rock-Hosted Naturally Occurring Asbestos

    NASA Astrophysics Data System (ADS)

    Shin, E.; Roh, Y.

    2012-12-01

    Naturally Occurring Asbestos (NOA) occurs in rocks and soils as a result of natural weathering and human activities. The parent rocks of asbestos have been associated with ultramafic and mafic rocks, and carbonate rock. The previous studies on naturally occurring asbestos were mainly limited to ultramafic and mafic rock-hosted asbestos and studies on carbonate rock-hosted asbestos are relatively rare in South Korea. Therefore, this study was aimed to characterize mineralogy of carbonate rock-hosted NOA at Muju and Jangsu, Jeonbuk province and Seosan and Asan, Chungnam province. The rock types at the four sites are consisting mainly of Precambrian metasedimentary rock. XRD and PLM analyses showed fibrous minerals in the sites were tremolite and actinolite of acicular and columnar forms. SEM-EDS analyses showed that asbestiform tremolite and actinolite had various ratios of length and diameters over 12:1, and needle and columnar forms. A columnar forms of tremolite and actinolite were showed small acicular at the edge of the particle. Its main chemical compositions are mainly Si, O, Mg, Ca, which were identical to tremolite. Actinolite contains Fe in addition to Si, O, Mg, Ca. EPMA analyses of asbestos occurred at Muju indicated that chemical composition are 55% SiO2, 23.2% MgO, 13.1 % CaO, and 0.61 % FeO and the chemical formula calculated as (K0.01Na0.01)Ca2.01(Mg4.94Fe0.05) (Al0.004Si7.98)O22(OH)2, which is close to ideal tremolite. In addition to tremolite, actinolite was also occurred at Seosan, Chungnam. XRD analyses showed that antigorite was existed at Muju, but PLM and SEM analyses showed the antigorite was platy structure, not asbestiform. These results indicate that asbestiform tremolite and actinolite with acicular forms contains in carbonate rocks at Muju and Jangsu, Jeonbuk and Seosan and Asan, Chungnam province South Korea.

  19. Acute hepatitis E complicated by acute pancreatitis and multiorgan dysfunction

    PubMed Central

    Karanth, Suman S; Khan, Zohaib; Rau, Nileshwar Radhakrishna; Rao, Karthik

    2014-01-01

    We report this rare case of a 27-year-old man who presented with acute hepatitis E and went on to develop acute epigastric pain. He was diagnosed to have acute severe pancreatitis with shock and acute renal failure due to hepatitis E. Such a phenomenon has rarely been reported in the literature, with patients following a benign course and complete recovery after conservative management and analgesia. Awareness of this potentially life-threatening complication, especially in young men from endemic areas with acute hepatitis E presenting with abdomen pain has been highlighted. PMID:24899005

  20. Acute Mastoiditis Caused by Streptococcus pneumoniae.

    PubMed

    Obringer, Emily; Chen, Judy L

    2016-05-01

    Acute mastoiditis (AM) is a relatively rare complication of acute otitis media (AOM). The most common pathogens include Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus. Pneumococcal vaccination and changes in antibiotic prescribing recommendations for AOM may change the incidence of AM in the future. Diagnosis of AM can be made based on clinical presentation, but computed tomography of the temporal bone with contrast should be considered if there is concern for complicated AM. Both extracranial and intracranial complications of AM may occur. Previously, routine cortical mastoidectomy was recommended for AM treatment, but new data suggest that a more conservative treatment approach can be considered, including intravenous (IV) antibiotics alone or IV antibiotics with myringotomy. [Pediatr Ann. 2016;45(5):e176-e179.]. PMID:27171806

  1. Acute pancreatitis: prognostic value of CT

    SciTech Connect

    Balthazar, E.J.; Ranson, J.H.C.; Naidich, D.P.; Megibow, A.J.; Caccavale, R.; Cooper, M.M.

    1985-09-01

    In 83 patients with acute pancreatitis, the initial computed tomographic (CT) examinations were classified by degree of disease severity (grades A-E) and were correlated with the clinical follow-up, objective prognostic signs, and complications and death. The length of hospitalization correlated well with the severity of the initial CT findings. Abscesses occurred in 21.6% of the entire group, compared with 60.0% of grade E patients. Pleural effusions were also more common in grade E patients. Abscesses were seen in 80.0% of patients with six to eight prognostic signs, compared with 12.5% of those with zero to two. The use of prognostic signs with initial CT findings results in improved prognostic accuracy. Early CT examination of patients with acute pancreatitis is a useful prognostic indicator of morbidity and mortality.

  2. [Acute transverse myelitis in a traveler].

    PubMed

    García Allende, Natalia; García Posada, Mara J; Radosta, Mariana F; Sánchez, Ana V; Mayer Wolf, Micaela; Rodríguez, Viviana

    2016-01-01

    Acute transverse myelitis is defined as an acquired neuroimmune disorder of the spinal cord, which occurs as a consequence of a primary event, or directly related to an autoimmune inflammatory disease, an infectious or post-infectious disease. Amongst infectious etiologies, Borrelia spp., a tick-bourne anthropozoonosis of the ixodidae family, prevails. Approximately 10 to 15% of patients with Lyme disease undergo neurologic manifestations, with an assorted and uncertain array of clinical syndromes. Transverse myelitis accounts for up to 5% of Lyme neuroborreliosis. We describe the case of a traveler from endemic zone for Lyme disease, with encephalomyelitis secondary to acute infection by Borrelia burgderfori, with complete resolution of symptoms after concluding adequate antibiotic treatment. PMID:27576284

  3. Acute renal failure in the Armenian earthquake.

    PubMed

    Eknoyan, G

    1992-01-01

    A destructive earthquake devastated northwestern Armenia on December 7, 1988. The size of the affected area (radius of 50 miles), the time of the day when it occurred (11:41 a.m.), deficiencies in the design and construction of buildings, and inadequate initial rescue and relief capabilities resulted in one of the most lethal and traumatic natural disasters of the century. A large but unknown number (estimated at 225 to 385) of the extricated victims who had sustained crush injury developed myoglobinuric acute renal failure requiring dialytic support. The limited number (8-10 dialysis machines) of antiquated dialysis facilities available locally were overwhelmed. International dialysis relief efforts resulted in meeting the immediate acute needs and provided the motivation and elements of the more efficient system for the future delivery of maintenance dialysis. PMID:1509155

  4. Acute Postoperative Endophthalmitis Caused by Staphylococcus lugdunensis▿

    PubMed Central

    Chiquet, C.; Pechinot, A.; Creuzot-Garcher, C.; Benito, Y.; Croize, J.; Boisset, S.; Romanet, J. P.; Lina, G.; Vandenesch, F.

    2007-01-01

    Acute postoperative endophthalmitis caused by Staphylococcus lugdunensis is infrequently reported in clinical studies. Five cases of acute postcataract surgery endophthalmitis caused by S. lugdunensis were taken from a multicenter prospective study conducted in four university-affiliated hospitals in France (2004 to 2005). These cases were characterized by severe ocular inflammation occurring with a mean delay of 7.6 days after cataract surgery, severe visual loss (hand motions or less in three cases), and dense infiltration of the vitreous. Each of these patients was initially treated by using a standard protocol with intravitreal (vancomycin and ceftazidime), systemic, and topical antibiotics. Given the severity of the endophthalmitis, even though bacteria were sensitive to intravitreal antibiotics, pars plana vitrectomy was needed in four cases. The final visual prognosis was complicated by severe retinal detachment in three cases. The microbiological diagnosis was reached by using conventional cultures with specific biochemical tests and eubacterial PCR amplification followed by direct sequencing. PMID:17392442

  5. Acute liver impairment after sodium valproate overdose

    PubMed Central

    Waring, William Stephen; Nixon, Andrew C

    2009-01-01

    Liver impairment is a recognised adverse effect of long-term sodium valproate treatment, but there are few reports concerning its occurrence after acute overdose. This report describes a 36-year-old woman who deliberately ingested 32 g of sodium valproate (Epilim). Serum valproate concentration was 4370 μmol/l (630 mg/l) at 4.3 h post-ingestion (therapeutic reference range: 300–600 μmol/l), and the elimination half-life was 14.1 h. Liver biochemistry tests were initially normal but gradually became impaired, and highest alanine aminotransferase (761 U/l) occurred 2.3 days after ingestion. Supportive measures alone were sufficient to allow recovery of liver function. This case indicates that sodium valproate overdose may cause acute hepatocellular injury, even in the absence of pre-existing liver disease. PMID:21686945

  6. Epidemiology of Acute Symptomatic Seizures among Adult Medical Admissions

    PubMed Central

    Nwani, Paul Osemeke; Nwosu, Maduaburochukwu Cosmas; Nwosu, Monica Nonyelum

    2016-01-01

    Acute symptomatic seizures are seizures occurring in close temporal relationship with an acute central nervous system (CNS) insult. The objective of the study was to determine the frequency of presentation and etiological risk factors of acute symptomatic seizures among adult medical admissions. It was a two-year retrospective study of the medical files of adults patients admitted with acute symptomatic seizures as the first presenting event. There were 94 cases of acute symptomatic seizures accounting for 5.2% (95% CI: 4.17–6.23) of the 1,802 medical admissions during the period under review. There were 49 (52.1%) males and 45 (47.9%) females aged between 18 years and 84 years. The etiological risk factors of acute symptomatic seizures were infections in 36.2% (n = 34) of cases, stroke in 29.8% (n = 28), metabolic in 12.8% (n = 12), toxic in 10.6% (n = 10), and other causes in 10.6% (n = 10). Infective causes were more among those below fifty years while stroke was more in those aged fifty years and above. CNS infections and stroke were the prominent causes of acute symptomatic seizures. This is an evidence of the “double tragedy” facing developing countries, the unresolved threat of infectious diseases on one hand and the increasing impact of noncommunicable diseases on the other one. PMID:26904280

  7. [Fibrinolysis in acute myocardial infarct].

    PubMed

    Bleifeld, W

    1987-10-24

    Fibrinolysis has opened up a new avenue in the treatment of acute myocardial infarction (AMI). In principle, the rate of reperfusion depends on the type of compound used, the mode of administration and the time between onset of symptoms and the beginning of treatment. With intracoronary streptokinase the reperfusion rate is of the order of 85%. Intravenous urokinase administered as a bolus results in a reopening rate of 50-60%; a similar rate of reperfusion is achieved with rt-PA as infusion, while i.v. streptokinase produces about 50% reopened coronary vessels. The final infarct size is decreased in 70% of patients if fibrinolysis is initiated within 2.5 hours after the onset of symptoms and followed by reopening of the occluded vessel. This results in a lowering of in-hospital mortality, which in various studies is of the order of 45-60%.- Bearing in mind the contraindications, fibrinolysis should be initiated within 3 hours. Hemodynamic improvement by a decrease of infarct size may also be achieved beyond 3 hours in large anterior myocardial infarctions and in posterior infarctions with cardiogenic shock. Early initiation of thrombolysis is of major importance in improving left ventricular function and lowering mortality following acute myocardial infarction. Therefore, prehospital thrombolytic therapy should be considered. - In the postinfarction phase coronary angiography is indicated in patients with angina at rest, stable angina of ECG signs of ischemia. In this situation transfer to a specialized cardiology division for possible percutaneous transluminal angioplasty is indicated. - Reocclusion after successful thrombolysis occurs in 20-30%, and it is therefore important to avoid reinfarction to improve the long term prognosis after AMI.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3321420

  8. [The nutrition of acute phase in patients with metabolic syndrome].

    PubMed

    Tsutsumi, Rie; Sebe, Mayu

    2016-03-01

    In this session, we describe the acute phase in patients with metabolic syndrome from two sides; acute disease that occurs higher in patients with metabolic syndrome such as colonary heart disease and stroke, and acute aggravation of diabetes such as diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome. The electrolyte imbalance is frequently detected in critical ill patients. It is reported that the extreme abnormalities of ionized calcium concentrations are independent predictors of mortality. In addition, from clinical database MIMIC-Ⅱ,calcium supplementation improves clinical outcome in intensive care unit patients. Although metabolic syndrome; lifestyle-related disease, is a chronic disease, the possibility of falling into acute disease by having it becomes very high and improvement of electrolyte imbalance, especially hypocalcaemia is expected to effective on clinical outcome. PMID:26923986

  9. Acute renal failure in patients with multiple myeloma.

    PubMed

    Cohen, D J; Sherman, W H; Osserman, E F; Appel, G B

    1984-02-01

    In the past, patients with multiple myeloma and acute renal failure have had a poor prognosis. Few patients recovered renal function and fewer still survived for prolonged time periods. This report describes the course of 10 patients with multiple myeloma and true acute renal failure treated during the decade 1970 to 1980, and reviews recent reports concerning this association. The use of radiographic contrast agents is no longer the primary predisposing factor to acute renal failure in the myeloma population. Rather, infection, hypercalcemia, and dehydration in the presence of light chain excretion are the major conditions precipitating the renal failure. Despite severe renal failure requiring dialysis, many patients may regain good renal function. Factors associated with a good or poor prognosis in this population are reviewed. The prognosis in patients with myeloma and acute renal failure has greatly improved in recent years, and prolonged survival may occur. PMID:6695948

  10. Allogeneic peripheral blood stem cell transplantation for standard risk leukemia: experience of Ibni Sina Hospital.

    PubMed

    Arslan, O; Coşkun, H; Arat, M; Celebi, H; Ozcan, M; Gürman, G; Ustün, C; Demirer, T; Akan, H; Ilhan, O; Konuk, N; Beksaç, M; Uysal, A; Koç, H

    2000-06-01

    Fifty-three patients with standard risk leukemia who underwent allogeneic peripheral blood stem cell transplantation (alloPBSCT) from their HLA-identical siblings were analyzed for engraftment, incidence and severity of GVHD, and relapse rate. Standard risk leukemia was defined as AML in first complete remission or CML in first chronic phase within the first year after diagnosis. The median age was 34.5 years (range 13-47). Stem cells were mobilized by using 10 microg/kg G-CSF subcutaneously for 5 days. A median of 5. 7 (2.1-21.4) x 106/kg CD34+ cells was collected over a median of 2 (range 1-5) apheresis procedures. Cyclosporin A (CsA) plus short-course MTX were used for GVHD prophylaxis. Recovery to granulocytes >0.5 x 109/l and platelets >20 x 109/l occurred at a median of day +13 (range 8-32) and +13 (range 8-51), respectively. Day +100 transplant-related mortality was 13.2% (7/53). Acute GVHD occurred in 20 of 49 (41%) evaluable patients and only six (12.3%) of them had severe disease (grade III-IV). Chronic GVHD occurred in 30 of 42 (71.4%) evaluable patients. Relapse rate at 2 years was 7. 5%. The median overall and leukemia-free survivals were 22 (4-44) and 20 (3-44) months, respectively. Estimated 4 year leukemia-free and overall survival rates were 60% and 62%, respectively. In conclusion, alloPBSCT in standard risk leukemia seems to be associated with a low relapse rate and no increased risk of acute GVHD, but there is a trend for higher incidence of cGVHD. Bone Marrow Transplantation (2000) 25, 1229-1232. PMID:10871726

  11. Report: structures and hepatocytotoxicity of co-occurring substances in oleanolic acid tablets.

    PubMed

    Liao, Shang-Gao; Wang, Zhen; Wu, Ya-Yun; Zhang, Li-Juan; Li, Jing; Wang, Ai-Min; Li, Yong-Jun; Lan, Yan-Yu; Wang, Yong-Lin

    2014-05-01

    Tablets of oleanolic acid (OA) have been approved by SFDA in China as an adjuvant therapy for acute and chronic hepatitis. Co-occurring substances present in the tablets of OA and their hepatocytotoxicity have not yet been reported. In the current investigation, the crude OA drug was separated by repeated column chromatography. The structures of the isolated compounds were characterized by spectral analysis and the cytotoxicity of each compound was evaluated in vitro against the human normal liver cell L02 at concentrations from 0.125 to 1000 μmol/L using the MTT method. As a result, OA and its 11 co-occurring trace compounds including one new triterpenoid, 3-O- (4-oxo-pentanoyl)-olean-12- en-28-oic acid, were isolated and structurally characterized. Cytotoxicity tests indicated that these compounds were all non-toxic at concentrations up to 50μmol/L. Clear structure-activity relationship (SAR) was also observed. The results suggested that OA tablets of similar origin might not cause obvious cytotoxicity to the normal liver cell. The work may facilitate further SAR studies of OA-type triterpenoids. PMID:24811824

  12. Bronchial hyperreactivity occurs in steroid-treated guinea pigs depleted of leukocytes by cyclophosphamide

    SciTech Connect

    Murlas, C.; Roum, J.H.

    1985-05-01

    The effects of cyclophosphamide and cortisone acetate treatment on O/sub 3/-induced changes in airway mucosal morphology and bronchial reactivity were assessed in guinea pigs. Animals in groups of four were studied at 2 or 6 h after O/sub 3/ (3.0 ppm, 2 h) and in one control group. Reactivity was determined by measuring specific airway resistance during intravenous acetylcholine infusion in intact, unanesthetized, spontaneously breathing animals. After testing, tracheal tissue was obtained from all animals for light microscopic examination. Another group of 10 drug-treated and 10 normal animals were tested at 2 h, 6 h, 1 day, and 4 days after O/sub 3/. Drug treatment resulted in substantial decreases in both circulating and airway mucosal granulocytes. Two hours after O/sub 3/, a marked decrease in airway mucosal goblet cells as well as ciliated cell damage occurred in both normal and treated animals. However, only in normal animals did neutrophilic infiltration develop thereafter. Nonetheless, hyperreactivity postozone occurred and progressed similarly in both groups. Our results indicate that acute O/sub 3/-induced bronchial hyperreactivity at 2 h is associated with signs of airway mucosal injury but appears independent of granulocyte changes. Airway neutrophilic infiltration and eosinophil depletion seem to be consequences of mucosal injury from O/sub 3/ and not causes of the bronchial hyperreactivity that results.

  13. [Legionella pneumonia which occurred in a private whirlpool bath user].

    PubMed

    Ishikawa, Akira; Okada, Jun; Kondo, Hirobumi; Takayama, Youko; Sunagawa, Keisuke; Enari, Tadako; Ishii, Yoshikazu

    2004-10-01

    A 88 year old female with active rheumatoid arthritis treated by low dose of prednisolone and methotrexate was admitted to our hospital because of severe bilateral pulmonary infiltration and acute respiratory distress syndrome. On admission, she had consciousness disturbance and was intubated because of severe respiratory failure. We heard from her family of her habit she had taking a private whirlpool bath 2 or 3 times everyday. So, we suspected a Legionella pneumophila infection. We started intravenous erythromycin (EM) (1,500mg/day) and methylprednisolone pulse therapy (1,000mg x 3days) and full controlled mechanical ventilation supported with PEEP. Her respiratory failure was gradually improved and she was discharged on the 44 the hospital day. Legionella pneumophila (serogroup 6) was isolated in her sputum by B-CYE alpha culture. Legionella pneumophila (serogroup 6) was isolated in her private whirlpool bath too. Both samples revealed the same by genetic analysis with pulse field gel electrophoresis (PFGE). This is the first adult case of Legionella pneumophila pneumonia infected from a private whirlpool bath confirmed by genetic analysis. We should always suspect Legionella pneumonia as one of the severe community-acquired pneumonia, because Legionella pneumophila were frequently detected among various water sources including the private whirlpool bath. PMID:15560380

  14. The Natural Occurring Compounds Targeting Endoplasmic Reticulum Stress

    PubMed Central

    Liu, Hai; Yang, Jianqiong; Li, Linfu; Shi, Weimei

    2016-01-01

    ER stress has been implicated in pathophysiological development of many diseases. Persistent overwhelming stimuli trigger ER stress to initiate apoptosis, autophagy, and cell death. IRE1-JNK and eIF2α-CHOP signaling pathways are the two important players of ER stress, which is also modulated by ROS production, calcium disturbance, and inflammatory factors. ER stress has been developed as a novel strategy for diseases management. Recently, a vast of research focuses on the natural occurring compounds targeting ER stress, which results in medical benefits to human diseases. These small reported molecules mainly include polyphenols, alkaloids, and saponins. Many of them have been developed for use in clinical applications. To better understand the pharmacological mechanism of these molecules in ER stress in diseases, efforts have been made to discover and deliver medical merits. In this paper, we will summarize the natural occurring compounds targeting ER stress. PMID:27563337

  15. The Natural Occurring Compounds Targeting Endoplasmic Reticulum Stress.

    PubMed

    Liu, Hai; Yang, Jianqiong; Li, Linfu; Shi, Weimei; Yuan, Xiaoliang; Wu, Longhuo

    2016-01-01

    ER stress has been implicated in pathophysiological development of many diseases. Persistent overwhelming stimuli trigger ER stress to initiate apoptosis, autophagy, and cell death. IRE1-JNK and eIF2α-CHOP signaling pathways are the two important players of ER stress, which is also modulated by ROS production, calcium disturbance, and inflammatory factors. ER stress has been developed as a novel strategy for diseases management. Recently, a vast of research focuses on the natural occurring compounds targeting ER stress, which results in medical benefits to human diseases. These small reported molecules mainly include polyphenols, alkaloids, and saponins. Many of them have been developed for use in clinical applications. To better understand the pharmacological mechanism of these molecules in ER stress in diseases, efforts have been made to discover and deliver medical merits. In this paper, we will summarize the natural occurring compounds targeting ER stress. PMID:27563337

  16. Management of iatrogenic crystalline lens injury occurred during intravitreal injection.

    PubMed

    Erdogan, Gurkan; Gunay, Betul Onal; Unlu, Cihan; Gunay, Murat; Ergin, Ahmet

    2016-08-01

    To evaluate the approach to management of iatrogenic crystalline lens injury occurred during intravitreal injection (IVI). The patients who were managed operatively or followed-up without intervention after the iatrogenic lens injury due to IVI were included in the study. Capsular breaks remained either quiescent or resulted in cataract formation in the patients with inadvertent crystalline lens capsule damage. Phacoemulsification surgery was performed in patients with cataract formation with lower fluidic settings. A total of 9 cases included in the study. Seven cases underwent phacoemulsification with intraocular lens implantation. Two cases remained as quiescent lens injury during the follow-up. In 2 cases, dislocation of lens fragments occurred during phacoemulsification where pars plana vitrectomy was performed at the same session. After iatrogenic crystalline lens injury, capsular damage could remain quiescent or progress to cataract formation. Although phacoemulsification surgery can be performed with appropriate parameters, lens fragment dislocation can be observed in cases with traumatic lens damage secondary to IVI. PMID:26631401

  17. Naturally occurring tumours in the basal metazoan Hydra.

    PubMed

    Domazet-Lošo, Tomislav; Klimovich, Alexander; Anokhin, Boris; Anton-Erxleben, Friederike; Hamm, Mailin J; Lange, Christina; Bosch, Thomas C G

    2014-01-01

    The molecular nature of tumours is well studied in vertebrates, although their evolutionary origin remains unknown. In particular, there is no evidence for naturally occurring tumours in pre-bilaterian animals, such as sponges and cnidarians. This is somewhat surprising given that recent computational studies have predicted that most metazoans might be prone to develop tumours. Here we provide first evidence for naturally occurring tumours in two species of Hydra. Histological, cellular and molecular data reveal that these tumours are transplantable and might originate by differentiation arrest of female gametes. Growth of tumour cells is independent from the cellular environment. Tumour-bearing polyps have significantly reduced fitness. In addition, Hydra tumours show a greatly altered transcriptome that mimics expression shifts in vertebrate cancers. Therefore, this study shows that spontaneous tumours have deep evolutionary roots and that early branching animals may be informative in revealing the fundamental mechanisms of tumorigenesis. PMID:24957317

  18. Hepatitis E as a Cause of Acute Jaundice Syndrome in Northern Uganda, 2010–2012

    PubMed Central

    Gerbi, Gemechu B.; Williams, Roxanne; Bakamutumaho, Barnabas; Liu, Stephen; Downing, Robert; Drobeniuc, Jan; Kamili, Saleem; Xu, Fujie; Holmberg, Scott D.; Teshale, Eyasu H.

    2015-01-01

    Hepatitis E virus (HEV) is a common cause of acute viral hepatitis in developing countries; however, its contribution to acute jaundice syndrome is not well-described. A large outbreak of hepatitis E occurred in northern Uganda from 2007 to 2009. In response to this outbreak, acute jaundice syndrome surveillance was established in 10 district healthcare facilities to determine the proportion of cases attributable to hepatitis E. Of 347 acute jaundice syndrome cases reported, the majority (42%) had hepatitis E followed by hepatitis B (14%), malaria (10%), hepatitis C (5%), and other/unknown (29%). Of hepatitis E cases, 72% occurred in Kaboong district, and 68% of these cases occurred between May and August of 2011. Residence in Kaabong district was independently associated with hepatitis E (adjusted odds ratio = 13; 95% confidence interval = 7–24). The findings from this surveillance show that an outbreak and sporadic transmission of hepatitis E occur in northern Uganda. PMID:25448237

  19. Hepatitis E as a cause of acute jaundice syndrome in northern Uganda, 2010-2012.

    PubMed

    Gerbi, Gemechu B; Williams, Roxanne; Bakamutumaho, Barnabas; Liu, Stephen; Downing, Robert; Drobeniuc, Jan; Kamili, Saleem; Xu, Fujie; Holmberg, Scott D; Teshale, Eyasu H

    2015-02-01

    Hepatitis E virus (HEV) is a common cause of acute viral hepatitis in developing countries; however, its contribution to acute jaundice syndrome is not well-described. A large outbreak of hepatitis E occurred in northern Uganda from 2007 to 2009. In response to this outbreak, acute jaundice syndrome surveillance was established in 10 district healthcare facilities to determine the proportion of cases attributable to hepatitis E. Of 347 acute jaundice syndrome cases reported, the majority (42%) had hepatitis E followed by hepatitis B (14%), malaria (10%), hepatitis C (5%), and other/unknown (29%). Of hepatitis E cases, 72% occurred in Kaboong district, and 68% of these cases occurred between May and August of 2011. Residence in Kaabong district was independently associated with hepatitis E (adjusted odds ratio = 13; 95% confidence interval = 7-24). The findings from this surveillance show that an outbreak and sporadic transmission of hepatitis E occur in northern Uganda. PMID:25448237

  20. Acute gangrenous cholecystitis: radionuclide diagnosis

    SciTech Connect

    Brachman, M.B.; Tanasescu, D.E.; Ramanna, L.; Waxman, A.D.

    1984-04-01

    Radionuclide hepatobiliary imaging with Tc-99m IDA is a useful procedure for the diagnosis of acute cholecystitis. Visualization of the gallbladder essentially rules out acute cholecystitis. Nonvisualization suggest acute cholecystitis but may also be associated with chronic gallbladder disease or other conditions. The authors recently observed five patients in whom a rim of increased parenchymal liver activity was seen adjacent to the gallbladder fossa. All five patients had acute gangrenous cholecystitis. The rim of increased activity appears to be a useful secondary sign of acute cholecystitis.