Background: The incidence of inadequate empiric antibiotic therapy (IET) and its clinical importance as a risk factor for hospital mortality in Canadian solid-organ transplant patients remains unknown. Methods: This retrospective cohort study evaluated all patients admitted to a transplant unit from May/2002-April/2004. Therapy was considered adequate when the organism cultured was found to be susceptible to an antibiotic administered within 24 hours of the index sample collection time. Univariate and multivariate regression analyses were conducted to determine associations between potential determinants, IET, and mortality. Results: IET was administered in 169/312 (54%) transplant patients. Regression analysis demonstrated that an increasing duration of IET (adjusted OR at 24h, 1.33; p < 0.001), ICU-associated infections (adjusted OR, 6.27; p < 0.001), prior antibiotic use (adjusted OR, 3.56; p = 0.004), and increasing APACHE-II scores (adjusted OR, 1.26; p < 0.001), were independent determinants of hospital mortality. Conclusions: IET is common and appears to be an important determinant of hospital mortality in the Canadian transplant population.

Background: The incidence of inadequate empiric antibiotic therapy (IET) and its clinical importance as a risk factor for hospital mortality in Canadian solid-organ transplant patients remains unknown. Methods: This retrospective cohort study evaluated all patients admitted to a transplant unit from May/2002-April/2004. Therapy was considered adequate when the organism cultured was found to be susceptible to an antibiotic administered within 24 hours of the index sample collection time. Univariate and multivariate regression analyses were conducted to determine associations between potential determinants, IET, and mortality. Results: IET was administered in 169/312 (54%) transplant patients. Regression analysis demonstrated that an increasing duration of IET (adjusted OR at 24h, 1.33; p < 0.001), ICU-associated infections (adjusted OR, 6.27; p < 0.001), prior antibiotic use (adjusted OR, 3.56; p = 0.004), and increasing APACHE-II scores (adjusted OR, 1.26; p < 0.001), were independent determinants of hospital mortality. Conclusions: IET is common and appears to be an important determinant of hospital mortality in the Canadian transplant population.

No description available.

Brain death has adverse effects on the organ donor, increasing organ dysfunction and affecting transplantation outcomes. It can also render organs unsuitable for transplantation. Another determinant of organ quality is ischaemia-reperfusion injury, which limits ischaemic storage time for hearts to six hours. The aim of this thesis was to investigate the effectiveness of hormone resuscitation (HR) of the donor to ameliorate the effects of brain death. Another aim was to develop a donor management and organ preservation strategy to ameliorate the effects of ischaemia-reperfusion injury on the heart, thereby extending ischaemic preservation times. A porcine model of the brain-dead multi-organ donor with orthotopic cardiac transplantation was utilised. Donor HR was shown to improve cardiac contractility and haemodynamics, thereby reducing inotrope requirements. A follow-up study investigating the effects of three different donor management protocols demonstrated that donor haemodynamics, renal arterial flow and creatinine clearance were superior in HR animals compared with animals treated with noradrenaline or intravenous fluid alone. Noradrenaline was associated with a significant deterioration in pulmonary function (PaO2 and alveolar-arterial oxygen gradient) and a decline in donor pH. HR was not associated with any detrimental effects on the lungs, liver or pancreas compared with the other two groups. Preservation strategies incorporating glyceryl trinitrate (GTN) and cariporide, a Na+-H+ exchange inhibitor, were investigated to safely extend cardiac ischaemic preservation times. Pre-treatment with intravenous cariporide prior to heart explantation (donor) and reperfusion of the transplanted heart (recipient) was shown to effectively extend ischaemic time to 14 hours, evidenced by weaning off cardiopulmonary bypass. GTN and cariporide-supplemented Celsior, used as a cardioplegic/storage solution, was also effective in extending preservation time to 14 hours, with superior cardiac contractility compared with cariporide pre-treated hearts. Both treatments also ameliorated reperfusion injury, stabilising haemodynamics for up to three hours post-bypass. This thesis has demonstrated the effectiveness of HR to ameliorate the negative effects of donor brain death. It also provides evidence that combined GTN and cariporide-supplemented Celsior improves long-term preservation of the donor heart. These strategies offer the potential to increase the proportion of transplantable organs, to improve donor organ quality, and thereby improve transplantation outcomes.

Feo-hifomicose refere-se a infecções por fungos pigmentados escuros. Revisamos a casuística brasileira entre 1953 e 2010, apresentando as características clínico-epidemiológicas e diagnósticas de 17 casos. Nas quais a coloração de hematoxilina-eosina foi usada para visualizar alterações estruturais nas lesões; a coloração da prata para identificação dos microrganismos; e coloração de Fontana-Masson confirmou a melanina na parede fúngica. Os fungos cresceram sob aspecto de micélio e produziam pigmentos de melanina, que dão às colônias cor negra característica. A observação das características microscópicas dos cultivos forneceu a identificação etiológica. A feo-hifomicose está amplamente disseminada no Brasil. Entretanto, é subestimada devido a fixação das biopsias em formol, o que impede o isolamento em cultivos. / Phaeohyphomycosis refers to infection caused by darkly pigmented fungi. We reviewed the Brazilian casuistic from 1953 to 2010 and presented the clinicalepidemiologic and diagnostic features of addictional 17 cases. In the cases hematoxilin and eosin stain was used to look for structural changes of the infected lesion; Gomori’s methenamine-silver stain identified these organisms; and Fontana-Masson staining confirm the presence of melanin fungal cell wall. The organisms formed mycelial colonies and produced melanin-like pigments that give the colonies the characteristic dark color. The microscopic study of cultures identified etiology. The phaeohyphomycosis is a widespread tropical disease in Brazil. However, it is underestimated due to formalin fixation tissue specimens that oppose the prior cultures.

Feo-hifomicose refere-se a infecções por fungos pigmentados escuros. Revisamos a casuística brasileira entre 1953 e 2010, apresentando as características clínico-epidemiológicas e diagnósticas de 17 casos. Nas quais a coloração de hematoxilina-eosina foi usada para visualizar alterações estruturais nas lesões; a coloração da prata para identificação dos microrganismos; e coloração de Fontana-Masson confirmou a melanina na parede fúngica. Os fungos cresceram sob aspecto de micélio e produziam pigmentos de melanina, que dão às colônias cor negra característica. A observação das características microscópicas dos cultivos forneceu a identificação etiológica. A feo-hifomicose está amplamente disseminada no Brasil. Entretanto, é subestimada devido a fixação das biopsias em formol, o que impede o isolamento em cultivos. / Phaeohyphomycosis refers to infection caused by darkly pigmented fungi. We reviewed the Brazilian casuistic from 1953 to 2010 and presented the clinicalepidemiologic and diagnostic features of addictional 17 cases. In the cases hematoxilin and eosin stain was used to look for structural changes of the infected lesion; Gomori’s methenamine-silver stain identified these organisms; and Fontana-Masson staining confirm the presence of melanin fungal cell wall. The organisms formed mycelial colonies and produced melanin-like pigments that give the colonies the characteristic dark color. The microscopic study of cultures identified etiology. The phaeohyphomycosis is a widespread tropical disease in Brazil. However, it is underestimated due to formalin fixation tissue specimens that oppose the prior cultures.

Feo-hifomicose refere-se a infecções por fungos pigmentados escuros. Revisamos a casuística brasileira entre 1953 e 2010, apresentando as características clínico-epidemiológicas e diagnósticas de 17 casos. Nas quais a coloração de hematoxilina-eosina foi usada para visualizar alterações estruturais nas lesões; a coloração da prata para identificação dos microrganismos; e coloração de Fontana-Masson confirmou a melanina na parede fúngica. Os fungos cresceram sob aspecto de micélio e produziam pigmentos de melanina, que dão às colônias cor negra característica. A observação das características microscópicas dos cultivos forneceu a identificação etiológica. A feo-hifomicose está amplamente disseminada no Brasil. Entretanto, é subestimada devido a fixação das biopsias em formol, o que impede o isolamento em cultivos. / Phaeohyphomycosis refers to infection caused by darkly pigmented fungi. We reviewed the Brazilian casuistic from 1953 to 2010 and presented the clinicalepidemiologic and diagnostic features of addictional 17 cases. In the cases hematoxilin and eosin stain was used to look for structural changes of the infected lesion; Gomori’s methenamine-silver stain identified these organisms; and Fontana-Masson staining confirm the presence of melanin fungal cell wall. The organisms formed mycelial colonies and produced melanin-like pigments that give the colonies the characteristic dark color. The microscopic study of cultures identified etiology. The phaeohyphomycosis is a widespread tropical disease in Brazil. However, it is underestimated due to formalin fixation tissue specimens that oppose the prior cultures.

No description available.

Zusammenfassung der Habilitationsschrift: Untersuchungen zum Einfluss von Mycophenolat Mofetil auf die Transplantat-Vaskulopathie nach allogener Aorten-Transplantation im Primaten-Modell Ein Hauptmerkmal der chronischen Rejektion nach allogener Organtransplantation ist die Transplantat-Vaskulopathie. Durch eine konzentrische Intimahyperplasie in den Arterien und Arteriolen des Transplantates, hervorgerufen durch eine Proliferation von glatten Muskelzellen und Fibroblasten, kommt es zu einer Minderperfusion des Organs und letztendlich zu einem chronisch fortschreitenden Transplantatversagen. Mycophenolat Mofetil (MMF) zeigt neben seiner Eigenschaft akute Rejektionen zu verhindern, auch eine antiproliferative Wirksamkeit auf glatte Muskelzellen, die eine Schlüsselrolle in der Entwicklung der chronischen Rejektion spielen. In mehreren Tierexperimenten konnte im Rattenmodell gezeigt werden, dass MMF die Entwicklung der Intimaproliferation hemmen kann. In der hier vorgestellten Studie wurde nun der Effekt von MMF auf eine fortgeschrittene, bereits etablierte Transplantat-Vaskulopathie im Primatenmodell geprüft. Nachdem in mehreren Vorstudien die Dosis, das Dosierungsintervall und der Applikationsweg getestet wurde, konnte MMF in einer maximal tolerierten Dosis Cynomolgus Affen verabreicht werden. Diese Tiere dienten jeweils als Spender und Empfänger eines 3 cm langen, infrarenalen Aortensegmentes. Um sicher zu stellen, dass sich eine Transplantat-Vaskulopathie etablieren konnte, erhielten die Tiere in den ersten 6 Wochen nach Transplantation keinerlei Immunsuppression. Erst ab Tag 45 wurde mit der MMF Therapie begonnen. Die Entwicklung der Intimahyperplasie wurde mit intravaskulären Ultraschalluntersuchungen dokumentiert und mit einer unbehandelten Kontrollgruppe verglichen. Während sich in der Kontrollgruppe die Intimahyperplasie ungebremst entwickelte, kam es in der Therapiegruppe zu einer Verlangsamung des Intimawachstums. Auch wenn der Unterschied zwischen den Gruppen am Versuchsende nicht signifikant war, so zeigte sich eine hohe Korrelation zwischen der verabreichten MMF Dosis und der sich entwickelten Transplantat-Vaskulopathie: Tiere, welche die MMF Therapie gut tolerierten, zeigten eine signifikant geringer Intimahyperplasie als Tiere der Kontrollgruppe. Bei den Tieren, bei denen die MMF Dosis aufgrund von Nebenwirkungen reduziert werden musste, entwickelte sich die Intimaproliferation ungehindert. Ferner konnte gezeigt werden, dass pharmakodynamische Messungen, welche die unterschiedlichen Medikamenten-Sensibilität der Tiere widerspiegelten, ebenfalls mit der Transplantat-Vaskulopathie korrelierten. / Evaluation of the influence of mycophenolate mofetil on graft vascular disease after allogenic aortic transplantation in non-human primates Graft vascular disease is pathognomonic for chronic rejection after solid organ transplantation. By inhibiting smooth muscle cell proliferation Mycophenolate Mofetil (MMF) has theoretically a beneficial effect on graft vascular disease and in rodent models MMF was able to halt graft vascular disease progress. To evaluate the efficacy of MMF on advanced graft vascular disease, a study was performed in non-human primates. Aortic allografts were exchanged between MLR mismatched, blood group compatible cynomolgus monkeys. 6 control animals received no immunosuppression, 6 animals were treated with MMF from day 45 after transplantation on in an individual maximal tolerated dose, which was determined in elaborative pre-studies in rodents and non-human primates. Until day 45 the animals did not receive any immunosuppressive treatment. The progression of graft vascular disease was quantified by intravascular ultrasound as changes in intimal area in the midsegments of all grafts every 3 weeks until day 105 when the animals were euthanized and the grafts have been harvested for histopathological analysis. Pharmacokinetik and pharmacodynamic monitoring was used to optimize the immunosuppressive efficacy. While in grafts from the control animals intimal hyperplasia developed unhindered, the increase of intimal areas over time was attenuated in the treatment group. Although this effect was not statistically significant, there was a high correlation between the daily MMF dose administered and the intimal proliferation in the treated animals. Animals which tolerated high doses of MMF showed significant lower graft vascular disease than animals of the control group. In two animals with MMF toxicity and dose reduction, high intimal hyperplasia was observed. In this demanding model evaluating advanced graft vascular disease in non-human primates MMF was able to halt GVD when given in a high maximal tolerated dose. In case of toxicity and individual necessary dose reduction, progress of GVD was not altered.

Die Schädigung des Organs durch Ischämie-Reperfusion (IR) im Rahmen der kadaverischen Organtransplantation hat bedeutenden Anteil an der Pathogenese verzögert einsetzender Organfunktion und Auswirkungen auf das Langzeitüberleben des Transplantats. In der vorliegenden Studie sollte der Einfluss unspezifischer Schädigung durch IR verglichen mit spezifischen Alloantigen-abhängigen Mechanismen während der Frühphase nach der Transplantation sowie die Auswirkungen prolongierter Aufbewahrung auf Schädigung und Immunogenität des Organs ermittelt werden. Nach vorausgegangener vierstündiger kalter Ischämiezeit wurden Organe aus syngen (Lew/Lew) und allogen (F344/Lew) transplantierten Ratten an 8 aufeinander folgenden Zeitpunkten innerhalb der ersten 10 Tage zu funktionellen, immunhistochemischen und morphologischen Veränderungen untersucht. In weiteren Gruppen wurden syngen transplantierte Organe 24 Stunden nach der Transplantation untersucht, die zuvor ansteigenden kalten Ischämiezeiten zwischen 2 und 48 Stunden ausgesetzt wurden. Im zeitlichen Verlauf zeigten sich bis 7 Tage nach der Transplantation keine wesentlichen Unterschiede zu Nierenfunktion, Morphologie, Zellinfiltration und Expression von Adhesionsmolekülen zwischen allogenen und isogenen Gruppen. Die zunächst eintretende Verschlechterung der Nierenfunktion war begleitet von einem Einstrom neutrophiler und monozytärer Zellen und morphologischen Veränderungen im Sinne von akuter Tubulusnekrose (ATN). Unter zunehmender Infiltration von Monozyten/Makrophagen kam es funktionell und morphologisch zur Regeneration. Neutrophile traten vornehmlich über Interaktion von ICAM-1/LFA-1 und Monozyten/Makrophagen über VCAM-1/VLA-4 aus dem Gefäßsystem aus. Gabe von Cyclosporin A führte zu signifikanter Reduktion ED-1-positiver Makrophagen nach 10 Tagen, ohne jedoch den Anteil des aktivierten Makrophagensubtyps ED-2 zu beeinflussen. Ansteigende kalte Aufbewahrung des Organs führte zu größerer vaskulärer Schädigung, die sich durch abnehmende Intensität und lückenhaftere Verteilung von PECAM-1 auf dem Endothel äußerte. Die Zunahme der Intensität von Tissue Factor auf Endothel und infiltrierenden Leukozyten deutete neben gesteigerter Thrombogenese auf alternative Adhäsionsmechanismen hin. Diese Ergebnisse zeigen, dass innerhalb der ersten 10 Tage nach der Transplantation wichtige Phasen der Gewebeschädigung und Regeneration ausgelöst durch die Schädigung nach IR und weitestgehend ohne Beteiligung Alloantigen-abhängiger Faktoren ablaufen. Eine bedeutende Rolle als Mediatoren während dieser Phasen kommt dabei den Monozyten/Makrophagen zu. / Organ damage due to long cold preservation is associated with delayed graft function and has important effects on graft survival. Aim of this study was to determine the impact of ischemia-reperfusion (IR) injury compared to antigen-specific mechanisms and the effect of prolonged cold ischemia on intragraft injury and antigenicity during the early phase post transplantation. Rat renal grafts were four-hours cold-preserved, transplanted to syngeneic (Lew/Lew) or allogeneic recipients (F344/Lew) and harvested at 8 different time points after transplantation for further investigation of functional, immunhistochemical and histologic changes. In five additional syngen groups organs were cold preserved from 2 hours to 48 hours and harvested after 24 hours post transplantation. No significant differences in renal function, morphologic changes, cellular infiltration and expression of adhesion molecules occurred between syngeneic and allogeneic groups within the first 7 days. Initial functional impairment was accompanied by the influx of neutrophils and monocytes/macrophages together with morphologic changes reflecting acute tubular necrosis (ATN). Increasing infiltration of monocytes/macrophages paralleled functional and morphologic regeneration. Extravasation of neutrophils was mediated mainly by interaction of ICAM-1/LFA-1 and infiltration of monocytes/macrophages by VCAM-1/VLA-4. Treatment with the standard dose of Cyclosporin A (CsA) lead to a significant decrease of ED1-positive macrophage infiltration 10 days post NTx but the portion of ED2-positive macrophage subtype was not affected. Prolonged cold organ preservation lead to more severe vascular damage indicated by decreased color intensity and continuity of PECAM-1 staining on endothelial cells. Higher staining intensity for Tissue Factor (TF) on endothelium and infiltrating leukocytes implicated enhanced intragraft procoagulant capacity and alternative adhesion mechanisms. These results show that within the first 10 days post transplantation phases of tissue injury and repair after ischemia-reperfusion are largely independent of the immunologic background and monocytes/macrophages play an important role as mediators during these processes.