26 research outputs found
337.2: The Epidemiology of Hereditary Pancreatitis in Australia and its effect on patient of Total Pancreatectomy with Islet Auto-Transplantation (TPIAT).
No full textAbstract - 337.2Denghao Wu, James Zuiani, Christopher Drogemuller, Sunita De Sousa, David Adelson, David J Torpy, Patrick Toby H Coate
Hyperparathyroidism and Vitamin D Deficiency Predispose to Bone Loss in Renal Transplant Recipients
No full textBackground. Bone disease is common postrenal transplantation resulting in increased fracture rates and morbidity. The cause is multifactorial including hyperparathyroidism, corticosteroids, and possibly calcium and vitamin D deficiencies. The aim of this study was to identify modifiable factors contributing to bone disease in long-term renal transplant (RT) recipients. Methods. Ninety-seven RT recipients were prospectively recruited over a 6-month period from a single center. Bone-related parameters were collected including bone mineral density at lumbar spine and total hip sites, serum and urinary markers of bone-turnover and calcium metabolism, and intact parathyroid hormone levels. Results. The mean time posttransplant of RT recipients was 9.5 years and mean estimated glomerular filtration rate was 70.3 mL/min. Up to 50% of recipients had biochemical evidence of calcium and vitamin D deficiencies. In the multiple regression models, elevated intact parathyroid hormone levels and calcium deficiency, which are affected by estimated glomerular filtration rate and vitamin D levels, are significantly associated with reduction in bone mineral density measurements. Conclusions. Hyperparathyroidism and vitamin D deficiency are common and are likely to contribute to bone loss postrenal transplantation. Measures aim to correct these problems pre- and posttransplant may improve bone health in RT recipients.Lim Wai H., Coates Penelope S., Russ Graeme R. and Coates Patrick Toby H
Immune profiling and cancer post transplantation
No full textHalf of all long-term (> 10 year) australian kidney transplant recipients (KTR) will develop squamous cell carcinoma (SCC) or solid organ cancer (SOC), making cancer the leading cause of death with a functioning graft. At least 30% of KTR with a history of SCC or SOC will develop a subsequent SCC or SOC lesion. Pharmacological immunosuppression is a major contributor of the increased risk of cancer for KTR, with the cancer lesions themselves further adding to systemic immunosuppression and could explain, in part, these phenomena. Immune profiling includes; measuring immunosuppressive drug levels and pharmacokinetics, enumerating leucocytes and leucocyte subsets as well as testing leucocyte function in either an antigen specific or non-specific manner. Outputs can vary from assay to assay according to methods used. In this review we define the rationale behind post-transplant immune monitoring assays and focus on assays that associate and/or have the ability to predict cancer and rejection in the KTR. We find that immune monitoring can identify those KTR of developing multiple SCC lesions and provide evidence they may benefit from pharmacological immunosuppressive drug dose reductions. In these KTR risk of rejection needs to be assessed to determine if reduction of immunosuppression will not harm the graft.Christopher Martin Hope, Patrick Toby H Coates and Robert Peter Carrol
Studies of clinically applicable human tolerogenic dendritic cells and PD-L2 genetic modification of human islet allograft to promote graft tolerance.
No full textIslet transplantation is a developing therapy for type 1 diabetic patients (T1D), which has been limited by problems associated with hypoxia, poor revascularisation and allograft rejection. Immunosuppressive agents used to prevent rejection are associated with severe side effects including islet toxicity, increased susceptibility to the development of cancer, infections and cardio-vascular problems. In order for islet transplantation to be used widely as a potentially curative treatment for T1D there is a need to develop novel therapies to treat allograft rejection without the use of immunosuppressive agents. In chapter 3, the immunomodulatory effects of IFN-γ on human monocyte-derived DC were investigated, using a standard 7-day in vitro DC propagation protocol. IFN-γ was shown to exert its immunomodulatory function on monocytes early during DC differentiation (IFNγ-DC[subscript]D0), resulting in an immature DC (iDC) phenotype with reduced expression of maturation markers CD83 and RelB. IFNγ-DC[subscript]D0 induced a state of T-cell hyporesponsiveness in a MLR, whilst IFN-γ treatment at day 5 (IFNγ-DC[subscript]D5) did not modulate DC function. The ability of IFN-γ to promote the generation of maturation arrested DC, could potentially serve as a cellular therapy for transplant rejection. However DC propagation using the standard 7-10 day protocol is not clinically applicable in the islet transplant setting. In chapter 4, a 'FAST-DC' protocol to promote the rapid generation of tolerogenic DC was investigated and used to generate IFNγ modulated DC in 48h. These IFNγ-DC featured an iDC phenotype similar to that seen in chapter 3. Maturation arrested IFNγ-DC caused significant T-cell hyporesponsiveness and promoted a higher frequency of CD4+CD25+ Foxp3[superscript]HI T-regulatory cells. IFNγ-DC primed T-cells were shown to be functionally suppressive in an antigen specific manner. It was also confirmed that IFN-γ reduced the phosphorylation of IL-4 activated STAT-6, which in turn affected the downstream gene expression of Interferon regulatory factor 4 (IRF4). IFNγ-DC were also investigated in vivo, where a humanised model of islet allo-transplantation model was developed. Diabetic NOD-SCID mice were transplanted with human islets and challenged with donor-derived DC and allogeneic PBMNC. After 21 days post transplantation, there was no significant change to euglycaemic state, between the tested groups. Genetic modification of the allograft is an alternative therapy to protecting the graft from the recipient‟s immune system. In chapter 5, human islets were genetically modified with programmed cell death ligand 2 (PD-L2), an inhibitory molecule known inhibit T-cell immune responses. Two recombinant adenovirus constructs carrying the PD-L2 gene were generated. One construct encoded a soluble isoform, while the other expressed a full transmembrane PD-L2 molecule. Adenoviral transduction did not affect the viability or insulin producing capacity of islets. Interestingly, soluble PD-L2 was more efficient at inducing signalling by 1000 fold, compared to the transmembrane isoform. In summary, this thesis demonstrated the timing of IFN-γ exposure is crucial in determining the function of DC and their maturational state, where IFN-γ exposure only during DC differentiation resulted in the inhibition of DC maturation. Secondly, the combination of IFN-γ and a FAST-DC protocol, enabled the generation of tolerogenic DC in 48h, making DC therapy more clinically applicable. Finally, the induced expression of soluble PD-L2 by human islets potently signals through human PD-1, which may provide the basis for the protection of islets from allo- and auto T-cell responses.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 201
Pituitary involvement in Wegener's granulomatosis
No full textcopyright Springer Science+Business Media, LLC 2007Wegener’s granulomatosis (WG) is an antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis of small and medium-sized vessels. Pituitary involvement in WG is rare with only 22 previous case reports in the English medical literature between 1966 and 2006. Herein we report another patient with WG-related diabetes insipidus (DI) and partial disruption of the anterior pituitary axes. We also review the clinical features, imaging findings, treatment and outcome of WG-related pituitary involvement. Isolated pituitary involvement in the absence of lung or renal complications in WG is rare and described in only one previous patient. Pituitary involvement in WG is usually associated with other organ involvement (96% of cases)—commonly upper respiratory tract (93%), lungs (73%) and kidneys (67%). Abnormalities are often seen in the hypothalamo-pituitary region on magnetic resonance imaging (MRI) or computed tomography (CT) of the head (90% of cases). In 65% of reported cases, cyclophosphamide-based induction therapy was used with a subsequent relapse rate of 27%, occurring at a median of 10.5 months (range: 7–36 months) after initiation of treatment. In comparison, induction treatment without cyclophosphamide was associated with relapse in 50% at a median of 4.5 months (range: 4–18 months after starting treatment) suggesting more frequent and earlier relapse. Therefore, we recommend treatment with cyclophosphamide- based regimen. Despite treatment of WG, only 17% (4 patients) had full recovery in their pituitary function. The long-term prognosis of patients with WG and pituitary involvement is not known.Tuck Y. Yong, Jordan Y. Z. Li, Lisa Amato, Kumar Mahadevan, Patrick J. Phillips, Penelope S. Coates and P. Toby H. Coate
Donor human leukocyte antigen specific antibodies predict development and define prognosis in transplant glomerulopathy
No full textThe pathogenesis of transplant glomerulopathy (TG) remains unclear, with evidence of human leukocyte antigen (HLA) antibodies as important contributors to the disease. We studied the risk factors and the associations of HLA antibodies in the development of TG. Sixty-one cases with morphologic features of TG were identified and compared with contemporaneous matched patients (without TG) from a 17-year period, all undergoing renal biopsy in a single center. Univariate risk factors for TG were previous glomerulitis [odds ratio (OR) 3.3, 95% confidence interval (95% CI) [1.2-9.4], p = 0.025), delayed graft function (OR 2.3 [1.0-5.1], p = 0.042), HLA class I presensitization defined by Luminex solid-phase immunoassays (OR 5.0 [2.3-11.0]. p 50% of TG patients, suggesting HLA antibodies play a critical role in TG pathogenesis. TG patients with DSA had increased risk of graft loss (median graft survival 4.4-5.2 years), whereas patients with morphologic features of TG without DSA had similar graft survival compared with the non-TG group (median graft survival 15 years). Thus, DSA is a useful predictor for graft failure in TG patients.Hooi Sian Eng, Greg Bennett, Sean H. Chang, Hannah Dent, Stephen P. McDonald, Peter Bardy, Patrick Coghlan, Graeme R. Russ, P. Toby H. Coate
Neglected nephropathy
No full textCopyright to Australian Family Physician. Reproduced with permission. Permission to reproduce must be sought from the publisher, The Royal Australian College of General Practitioners.BACKGROUND Diabetic nephropathy is a significant contributor to the morbidity, mortality and health care cost among patients with diabetes. With increasing understanding of this problem, the natural progression of diabetic nephropathy can potentially be changed. OBJECTIVE This article examines the natural history of diabetic nephropathy and provides guidelines on detection, management and future treatment possibilities of this complication. DISCUSSION Prevention and slowing progression are the most important aspects of the management of diabetic nephropathy. This involves monitoring renal function and risk factors for renal damage and early active intervention. The angiotensin converting enzyme inhibitors and receptor antagonists are important components of therapy, both for controlling hypertension and for slowing the progression of micro and macroalbuminuria. When microalbuminuria occurs, intensive intervention on a range of risk factors can halve the number of those suffering a cardiovascular event or progressing to macroalbuminuria. When renal insufficiency occurs, particularly when creatinine clearance is <30 mL/minute, referral to an nephrologist should be considered.Tuck Y Yong, Patrick J Phillips, P Toby H Coate
Clinical significance of anti-HLA antibodies detected by Luminex (R): enhancing the interpretation of CDC-BXM and important post-transplantation monitoring tools
No full textB-cell crossmatch (BXM) was originally introduced to increase the sensitivity to detect anti-HLA antibodies of conventional CDC crossmatch in renal transplantation. Newer techniques such as Luminex((R)) have greater sensitivity in detecting anti-HLA antibodies but have not been directly evaluated versus BXM. We discuss our experience with Luminex testing and the significance of donor-specific antibodies (DSA) defined by Luminex in three populations, as compared with the CDC crossmatch. In the general transplant population, Luminex-defined DSA were found in only one third of positive CDC-BXM and were associated with graft rejection. Luminex testing enhanced the interpretation of CDC-BXM and identified patients with clinically relevant BXM. In the highly sensitized transplant population, Luminex-defined DSA were found in two thirds of positive BXM and were a better predictor of graft rejection. Therefore, Luminex assays rather than CDC-BXM should be used to facilitate kidney allocation in highly sensitized patients. In the post-transplantation population, Luminex antibody monitoring for DSA was shown to be important, as it defined low-level de novo DSA that were associated with development of transplant glomerulopathy and a significant predictor of graft loss in those patients. Thus Luminex testing facilitated the interpretation of CDC-BXM and provided a useful predictive tool for the detection of clinically significant DSA in post-transplantation antibody monitoring.Hooi Sian Eng, Greg Bennett, Peter Bardy, Patrick Coghlan, Graeme R. Russ, P. Toby H. Coate
Propagation and characterisation of dendritic cells from G-CSF mobilised peripheral blood monocytes and stem cells in common marmoset monkeys
No full textCopyright © 2009 Elsevier B.V. All rights reserved.The common marmoset is a small New World Primate that has been used as an immunological model for a number of human diseases. Dendritic cells (DC) have not been extensively characterised in this species and in particular protocols to derive DC from living donors without the need for animal sacrifice are presently lacking. This study establishes new protocols to generate substantial numbers of marmoset DC for use in cell therapy studies. Recombinant human G-CSF was used to mobilise peripheral blood monocytes and CD34(+) stem cells in sufficient numbers for large scale in-vitro DC propagation using cytokine conditioning including IL-4, GM-CSF, FLT3-L, stem cell factor and thrombopoietin. Marmoset DC exhibited morphology similar to human DC, were capable of antigen uptake and presentation and had moderate allo-stimulatory ability. Monocyte-derived DC had a maturation-resistant immature phenotype, whereas haematopoietic precursor-derived DC were semi-mature in phenotype and function. This study confirms the feasibility of the marmoset as a unique small primate model in which to pursue DC-based immunotherapy strategies.Shilpanjali Prasad, Svjetlana Kireta, Emma Leedham, Graeme R. Russ, and Patrick Toby H. Coate
Subversive blood ties: gothic decadence in three characters from murnau's and coppola's renderings of bram stoker's dracula
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Comunicação e Expressão, Programa de Pós-Graduação em Letras/Inglês e Literatura Correspondente, Florianópolis, 2013Esta dissertação consiste em investigar a construção do tema da decadência Gótica em Drácula de Bram Stoker e duas adaptações fílmicas do romance - Nosferatu, de Friedrich Wilhelm Murnau, e Drácula de Bram Stoker, de Francis Ford Coppola - tendo como centro da análise como três personagens - Drácula, Jonathan Harker e Mina Harker - se relacionam com tal tema. A decadência Gótica é um padrão literário do contexto fin-de-siècle da sociedade vitoriana inspirada pela crise social que acontecia na Inglaterra no fim do século XIX (Punter e Byron 39-40). Autores como Bram Stoker escreveram histórias que refletiam medos morais e sociais da sociedade vitoriana, retratando imagens de monstros que representavam a transgressão de fronteiras morais e sexuais estabelecidas pelas tradições vitorianas (Botting 88). Tendo tal discussão em mente, este estudo busca conectar a retratação de tal tema do romance às adaptações, também utilizando uma análise fílmica para identificar técnicas que destacam a representação do tema relacionado aos três personagens, finalmente ligando tal tema a crises e confusões sociais que aconteciam nos contextos de ambos os filmes.Abstract : The present dissertation consists of an investigation of the construction of the Gothic theme of decadence in Bram Stoker's Dracula and two film adaptations of the novel - Friedrich Wilhelm Murnau's Nosferatu and Francis Ford Coppola's Bram Stoker's Dracula - having as the centre of analysis how three characters - Dracula, Jonathan Harker and Mina Harker - relate to that theme. The Gothic decadence is a literary motif from the fin-de-siècle context of the Victorian Era inspired by the social crisis that took place in England in the late nineteenth century (Punter and Byron 39-40). Authors like Bram Stoker wrote stories that reflected moral and social fears of the Victorian society, depicting images of monsters that represented the crossing of moral and sexual boundaries established by the Victorian traditions (Botting 88). Bearing that discussion in mind, this study aims at connecting the portrayal of such a theme from novel to the two adaptations, also making use of a filmic analysis to identify techniques that highlight the depiction of the theme related to the three characters, ultimately linking such a thematic depiction to crises and social commotions that were taking place in both films' social contexts
