Hermann M.


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Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome.

Tue, 19/07/2016 - 1:16pm

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Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome.

J Exp Med. 2016 Jun 27;213(7):1163-74

Authors: Meuwissen ME, Schot R, Buta S, Oudesluijs G, Tinschert S, Speer SD, Li Z, van Unen L, Heijsman D, Goldmann T, Lequin MH, Kros JM, Stam W, Hermann M, Willemsen R, Brouwer RW, Van IJcken WF, Martin-Fernandez M, de Coo I, Dudink J, de Vries FA, Bertoli Avella A, Prinz M, Crow YJ, Verheijen FW, Pellegrini S, Bogunovic D, Mancini GM

Abstract
Pseudo-TORCH syndrome (PTS) is characterized by microcephaly, enlarged ventricles, cerebral calcification, and, occasionally, by systemic features at birth resembling the sequelae of congenital infection but in the absence of an infectious agent. Genetic defects resulting in activation of type 1 interferon (IFN) responses have been documented to cause Aicardi-Goutières syndrome, which is a cause of PTS. Ubiquitin-specific peptidase 18 (USP18) is a key negative regulator of type I IFN signaling. In this study, we identified loss-of-function recessive mutations of USP18 in five PTS patients from two unrelated families. Ex vivo brain autopsy material demonstrated innate immune inflammation with calcification and polymicrogyria. In vitro, patient fibroblasts displayed severely enhanced IFN-induced inflammation, which was completely rescued by lentiviral transduction of USP18. These findings add USP18 deficiency to the list of genetic disorders collectively termed type I interferonopathies. Moreover, USP18 deficiency represents the first genetic disorder of PTS caused by dysregulation of the response to type I IFNs. Therapeutically, this places USP18 as a promising target not only for genetic but also acquired IFN-mediated CNS disorders.

PMID: 27325888 [PubMed - in process]

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In search for in vivo methods to visualize clot forming in cut vessels and interrupted flow.

Tue, 19/07/2016 - 1:16pm

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In search for in vivo methods to visualize clot forming in cut vessels and interrupted flow.

Br J Anaesth. 2016 Apr;116(4):554-5

Authors: Solomon C, White NJ, Hochleitner G, Hermann M, Fries D

PMID: 26994233 [PubMed - in process]

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BRAF inhibition in hairy cell leukemia with low-dose vemurafenib.

Tue, 19/07/2016 - 1:16pm

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BRAF inhibition in hairy cell leukemia with low-dose vemurafenib.

Blood. 2016 Jun 9;127(23):2847-55

Authors: Dietrich S, Pircher A, Endris V, Peyrade F, Wendtner CM, Follows GA, Hüllein J, Jethwa A, Ellert E, Walther T, Liu X, Dyer MJ, Elter T, Brummer T, Zeiser R, Hermann M, Herold M, Weichert W, Dearden C, Haferlach T, Seiffert M, Hallek M, von Kalle C, Ho AD, Gaehler A, Andrulis M, Steurer M, Zenz T

Abstract
The activating mutation of the BRAF serine/threonine protein kinase (BRAF V600E) is the key driver mutation in hairy cell leukemia (HCL), suggesting opportunities for therapeutic targeting. We analyzed the course of 21 HCL patients treated with vemurafenib outside of trials with individual dosing regimens (240-1920 mg/d; median treatment duration, 90 days). Vemurafenib treatment improved blood counts in all patients, with platelets, neutrophils, and hemoglobin recovering within 28, 43, and 55 days (median), respectively. Complete remission was achieved in 40% (6/15 of evaluable patients) and median event-free survival was 17 months. Response rate and kinetics of response were independent of vemurafenib dosing. Retreatment with vemurafenib led to similar response patterns (n = 6). Pharmacodynamic analysis of BRAF V600E downstream targets showed that vemurafenib (480 mg/d) completely abrogated extracellular signal-regulated kinase phosphorylation of hairy cells in vivo. Typical side effects also occurred at low dosing regimens. We observed the development of acute myeloid lymphoma (AML) subtype M6 in 1 patient, and the course suggested disease acceleration triggered by vemurafenib. The phosphatidylinositol 3-kinase hotspot mutation (E545K) was identified in the AML clone, providing a potential novel mechanism for paradoxical BRAF activation. These data provide proof of dependence of HCL on active BRAF signaling. We provide evidence that antitumor and side effects are observed with 480 mg vemurafenib, suggesting that dosing regimens in BRAF-driven cancers could warrant reassessment in trials with implications for cost of cancer care.

PMID: 26941398 [PubMed - in process]

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cJun N-terminal kinase (JNK) phosphorylation of serine 36 is critical for p66Shc activation.

Tue, 19/07/2016 - 1:16pm

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cJun N-terminal kinase (JNK) phosphorylation of serine 36 is critical for p66Shc activation.

Sci Rep. 2016;6:20930

Authors: Khalid S, Drasche A, Thurner M, Hermann M, Ashraf MI, Fresser F, Baier G, Kremser L, Lindner H, Troppmair J

Abstract
p66Shc-dependent ROS production contributes to many pathologies including ischemia/reperfusion injury (IRI) during solid organ transplantation. Inhibiting p66Shc activation may provide a novel therapeutic approach to prevent damage, which is poorly managed by antioxidants in vivo. Previous work suggested that pro-oxidant and a pro-apoptotic function of p66Shc required mitochondrial import, which depended on serine 36 phosphorylation. PKCß has been proposed as S36 kinase but cJun N-terminal kinases (JNKs) may also phosphorylate this residue. To simulate the early stages of ischemia/reperfusion (IR) we either used H2O2 treatment or hypoxia/reoxygenation (HR). As during reperfusion in vivo, we observed increased JNK and p38 activity in mouse embryonic fibroblasts (MEFs) and HL-1 cardiomyocytes along with significantly increased p66ShcS36 phosphorylation, ROS production and cell damage. Application of specific inhibitors caused a pronounced decrease in p66ShcS36 phosphorylation only in the case of JNK1/2. Moreover, S36 phosphorylation of recombinant p66Shc by JNK1 but not PKCß was demonstrated. We further confirmed JNK1/2-dependent regulation of p66ShcS36 phosphorylation, ROS production and cell death using JNK1/2 deficient MEFs. Finally, the low ROS phenotype of JNK1/2 knockout MEFs was reversed by the phosphomimetic p66ShcS36E mutant. Inhibiting JNK1/2-regulated p66Shc activation may thus provide a therapeutic approach for the prevention of oxidative damage.

PMID: 26868434 [PubMed - in process]

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Biopsychronology: A Method Using Live Tissue Staining to Image Cell Function in the Kidney.

Tue, 19/07/2016 - 1:16pm

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Biopsychronology: A Method Using Live Tissue Staining to Image Cell Function in the Kidney.

Methods Mol Biol. 2016;1397:81-90

Authors: Ashraf MI, Fries D, Streif W, Aigner F, Hengster P, Troppmair J, Hermann M

Abstract
Methods to monitor the status of a graft prior to transplantation are highly desirable to avoid unnecessary surgical interventions and follow-up treatments and to optimize the clinical outcome as delayed graft function may lead to costly and lengthy follow-up treatments or even organ loss. As a promising step in this direction we present a method which combines the use of fine needle biopsies, the staining of living cells with dyes suitable to monitor mitochondrial status/cellular integrity, and live confocal real-time analysis.This approach provides information about the functional and structural intactness of an organ within a few minutes. To confirm the feasibility of this approach, we recently published a pilot study using rodent kidneys. The results demonstrated that this method is suitable to monitor organ damage caused by ischemia or short periods of reperfusion. This procedure required minimal time for sample preparation and data acquisition and is suitable for recording damage resulting from unphysiological stress to the organ.

PMID: 26676129 [PubMed - in process]

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The Aplidin analogs PM01215 and PM02781 inhibit angiogenesis in vitro and in vivo.

Tue, 19/07/2016 - 1:16pm

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The Aplidin analogs PM01215 and PM02781 inhibit angiogenesis in vitro and in vivo.

BMC Cancer. 2015;15:738

Authors: Borjan B, Steiner N, Karbon S, Kern J, Francesch A, Hermann M, Willenbacher W, Gunsilius E, Untergasser G

Abstract
BACKGROUND: Novel synthesized analogs of Aplidin, PM01215 and PM02781, were tested for antiangiogenic effects on primary human endothelial cells in vitro and for inhibition of angiogenesis and tumor growth in vivo.
METHODS: Antiangiogenic activity of both derivatives was evaluated by real-time cell proliferation, capillary tube formation and vascular endothelial growth factor (VEGF)-induced spheroid sprouting assays. Distribution of endothelial cells in the different phases of the cell cycle was analyzed by flow cytometry. Aplidin analogs were tested in vivo in chicken chorioallantoic membrane (CAM) assays.
RESULTS: Both derivatives inhibited angiogenic capacities of human endothelial cells (HUVECs) in vitro at low nanomolar concentrations. Antiangiogenic effects of both analogs were observed in the CAM. In addition, growth of human multiple myeloma xenografts in vivo in CAM was significantly reduced after application of both analogs. On the molecular level, both derivatives induced cell cycle arrest in G1 phase. This growth arrest of endothelial cells correlated with induction of the cell cycle inhibitor p16(INK4A) and increased senescence-associated beta galactosidase activity. In addition, Aplidin analogs induced oxidative stress and decreased production of the vascular maturation factors Vasohibin-1 and Dickkopf-3.
CONCLUSIONS: From these findings we conclude that both analogs are promising agents for the development of antiangiogenic drugs acting independent on classical inhibition of VEGF signaling.

PMID: 26483043 [PubMed - indexed for MEDLINE]

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Langerhans cells in the sebaceous gland of the murine skin.

Tue, 19/07/2016 - 1:16pm

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Langerhans cells in the sebaceous gland of the murine skin.

Exp Dermatol. 2015 Nov;24(11):899-901

Authors: Haid B, Schlögl DE, Hermann M, Tripp CH, Stoitzner P, Romani N, Flacher V

PMID: 26174007 [PubMed - in process]

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Treatment with tetrahydrobiopterin overcomes brain death-associated injury in a murine model of pancreas transplantation.

Tue, 19/07/2016 - 1:16pm

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Treatment with tetrahydrobiopterin overcomes brain death-associated injury in a murine model of pancreas transplantation.

Am J Transplant. 2015 Nov;15(11):2865-76

Authors: Oberhuber R, Ritschl P, Fabritius C, Nguyen AV, Hermann M, Obrist P, Werner ER, Maglione M, Flörchinger B, Ebner S, Resch T, Pratschke J, Kotsch K

Abstract
Brain death (BD) has been associated with an immunological priming of donor organs and is thought to exacerbate ischemia reperfusion injury (IRI). Recently, we showed that the essential nitric oxide synthase co-factor tetrahydrobiopterin (BH4) abrogates IRI following experimental pancreas transplantation. We therefore studied the effects of BD in a murine model of syngeneic pancreas transplantation and tested the therapeutic potential of BH4 treatment. Compared with sham-operated controls, donor BD resulted in intragraft inflammation reflected by induced IL-1ß, IL-6, VCAM-1, and P-selectin mRNA expression levels and impaired microcirculation after reperfusion (p < 0.05), whereas pretreatment of the BD donor with BH4 significantly improved microcirculation after reperfusion (p < 0.05). Moreover, BD had a devastating impact on cell viability, whereas BH4-treated grafts showed a significantly higher percentage of viable cells (p < 0.001). Early parenchymal damage in pancreatic grafts was significantly more pronounced in organs from BD donors than from sham or non-BD donors (p < 0.05), but BH4 pretreatment significantly ameliorated necrotic lesions in BD organs (p < 0.05). Pretreatment of the BD donor with BH4 resulted in significant recipient survival (p < 0.05). Our data provide novel insights into the impact of BD on pancreatic isografts, further demonstrating the potential of donor pretreatment strategies including BH4 for preventing BD-associated injury after transplantation.

PMID: 26104062 [PubMed - in process]

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ROS signaling by NADPH oxidase 5 modulates the proliferation and survival of prostate carcinoma cells.

Tue, 19/07/2016 - 1:16pm

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ROS signaling by NADPH oxidase 5 modulates the proliferation and survival of prostate carcinoma cells.

Mol Carcinog. 2016 Jan;55(1):27-39

Authors: Höll M, Koziel R, Schäfer G, Pircher H, Pauck A, Hermann M, Klocker H, Jansen-Dürr P, Sampson N

Abstract
Prostate cancer (PCa) is the most commonly diagnosed cancer and second leading cause of male cancer death in Western nations. Thus, new treatment modalities are urgently needed. Elevated production of reactive oxygen species (ROS) by NADPH oxidase (Nox) enzymes is implicated in tumorigenesis of the prostate and other tissues. However, the identity of the Nox enzyme(s) involved in prostate carcinogenesis remains largely unknown. Analysis of radical prostatectomy tissue samples and benign and malignant prostate epithelial cell lines identified Nox5 as an abundantly expressed Nox isoform. Consistently, immunohistochemical staining of a human PCa tissue microarray revealed distinct Nox5 expression in epithelial cells of benign and malignant prostatic glands. shRNA-mediated knockdown of Nox5 impaired proliferation of Nox5-expressing (PC-3, LNCaP) but not Nox5-negative (DU145) PCa cell lines. Similar effects were observed upon ROS ablation via the antioxidant N-acetylcysteine confirming ROS as the mediators. In addition, Nox5 silencing increased apoptosis of PC-3 cells. Concomitantly, protein kinase C zeta (PKCζ) protein levels and c-Jun N-terminal kinase (JNK) phosphorylation were reduced. Moreover, the effect of Nox5 knockdown on PC-3 cell proliferation could be mimicked by pharmacological inhibition of JNK. Collectively, these data indicate that Nox5 is expressed at functionally relevant levels in the human prostate and clinical PCa. Moreover, findings herein suggest that Nox5-derived ROS and subsequent depletion of PKCζ and JNK inactivation play a critical role in modulating intracellular signaling cascades involved in the proliferation and survival of PCa cells. © 2014 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.

PMID: 25559363 [PubMed - indexed for MEDLINE]

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Crucial role for neuronal nitric oxide synthase in early microcirculatory derangement and recipient survival following murine pancreas transplantation.

Tue, 19/07/2016 - 1:16pm

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Crucial role for neuronal nitric oxide synthase in early microcirculatory derangement and recipient survival following murine pancreas transplantation.

PLoS One. 2014;9(11):e112570

Authors: Cardini B, Watschinger K, Hermann M, Obrist P, Oberhuber R, Brandacher G, Chuaiphichai S, Channon KM, Pratschke J, Maglione M, Werner ER

Abstract
OBJECTIVE: Aim of this study was to identify the nitric oxide synthase (NOS) isoform involved in early microcirculatory derangements following solid organ transplantation.
BACKGROUND: Tetrahydrobiopterin donor treatment has been shown to specifically attenuate these derangements following pancreas transplantation, and tetrahydrobiopterin-mediated protective effects to rely on its NOS-cofactor activity, rather than on its antioxidant capacity. However, the NOS-isoform mainly involved in this process has still to be defined.
METHODS: Using a murine pancreas transplantation model, grafts lacking one of the three NOS-isoforms were compared to grafts from wild-type controls. Donors were treated with either tetrahydrobiopterin or remained untreated. All grafts were subjected to 16 h cold ischemia time and transplanted into wild-type recipients. Following 4 h graft reperfusion, microcirculation was analysed by confocal intravital fluorescence microscopy. Recipient survival was monitored for 50 days.
RESULTS: Transplantation of the pancreas from untreated wild-type donor mice resulted in microcirculatory damage of the transplanted graft and no recipient survived more than 72 h. Transplanting grafts from untreated donor mice lacking either endothelial or inducible NOS led to similar outcomes. In contrast, donor treatment with tetrahydrobiopterin prevented microcirculatory breakdown enabling long-term survival. Sole exception was transplantation of grafts from untreated donor mice lacking neuronal NOS. It resulted in intact microvascular structure and long-term recipient survival, either if donor mice were untreated or treated with tetrahydrobiopterin.
CONCLUSION: We demonstrate for the first time the crucial involvement of neuronal NOS in early microcirculatory derangements following solid organ transplantation. In this model, protective effects of tetrahydrobiopterin are mediated by targeting this isoform.

PMID: 25389974 [PubMed - indexed for MEDLINE]

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Postprandial lipemia induces pancreatic α cell dysfunction characteristic of type 2 diabetes: studies in healthy subjects, mouse pancreatic islets, and cultured pancreatic α cells.

Tue, 19/07/2016 - 1:16pm

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Postprandial lipemia induces pancreatic α cell dysfunction characteristic of type 2 diabetes: studies in healthy subjects, mouse pancreatic islets, and cultured pancreatic α cells.

Am J Clin Nutr. 2014 Nov;100(5):1222-31

Authors: Niederwanger A, Ciardi C, Tatarczyk T, Khan MI, Hermann M, Mittermair C, Al-Zoairy R, Salzmann K, Pedrini MT

Abstract
BACKGROUND: Type 2 diabetes is associated with pancreatic α cell dysfunction, characterized by elevated fasting plasma glucagon concentrations and inadequate postprandial glucose- and insulin-induced suppression of glucagon secretion. The cause and the underlying mechanisms of α cell dysfunction are unknown.
OBJECTIVE: Because Western dietary habits cause postprandial lipemia for a major part of a day and, moreover, increase the risk of developing type 2 diabetes, we tested the hypothesis that postprandial lipemia with its characteristic elevation of triglyceride-rich lipoproteins (TGRLs) might cause pancreatic α cell dysfunction.
DESIGN: In a crossover study with 7 healthy volunteers, 2 experiments using 2 fat-enriched meals were performed on each volunteer; meal 1 was designed to increase plasma concentrations of both TGRLs and nonesterified fatty acids and meal 2 to increase TGRLs only. Intravenous glucose boli were injected at 0800 after an overnight fast and postprandially at 1300, 3 h after ingestion of a fat-enriched meal. Glucagon concentrations were measured throughout the days of the experiments. In addition to the study in humans, in vitro experiments were performed with mouse pancreatic islets and cultured pancreatic alpha TC 1 clone 9 (αTC1c9) cells, which were incubated with highly purified TGRLs.
RESULTS: In humans, postprandial lipemia increased plasma glucagon concentrations and led to an inadequate glucose- and insulin-induced suppression of glucagon. There was no difference between the 2 meal types. In mouse pancreatic islets and cultured pancreatic αTC1c9 cells, purified postprandial TGRLs induced abnormalities in glucagon kinetics comparable with those observed in humans. The TGRL-induced α cell dysfunction was due to reduced γ-aminobutyric acid A receptor activation in pancreatic α cells.
CONCLUSION: We concluded that postprandial lipemia induces pancreatic α cell dysfunction characteristic of type 2 diabetes and, therefore, propose that pancreatic α cell dysfunction could be viewed, at least partly, as a postprandial phenomenon.

PMID: 25332320 [PubMed - indexed for MEDLINE]

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C10ORF10/DEPP, a transcriptional target of FOXO3, regulates ROS-sensitivity in human neuroblastoma.

Tue, 19/07/2016 - 1:16pm

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C10ORF10/DEPP, a transcriptional target of FOXO3, regulates ROS-sensitivity in human neuroblastoma.

Mol Cancer. 2014;13:224

Authors: Salcher S, Hagenbuchner J, Geiger K, Seiter MA, Rainer J, Kofler R, Hermann M, Kiechl-Kohlendorfer U, Ausserlechner MJ, Obexer P

Abstract
BACKGROUND: FOXO transcription factors control cellular levels of reactive oxygen species (ROS) which critically contribute to cell survival and cell death in neuroblastoma. In the present study we investigated the regulation of C10orf10/DEPP by the transcription factor FOXO3. As a physiological function of C10orf10/DEPP has not been described so far we analyzed its effects on cellular ROS detoxification and death sensitization in human neuroblastoma cells.
METHODS: The effect of DEPP on cellular ROS was measured by catalase activity assay and live cell fluorescence microscopy using the ROS-sensitive dye reduced MitoTracker Red CM-H2XROS. The cellular localization of DEPP was determined by confocal microscopy of EYFP-tagged DEPP, fluorescent peroxisomal- and mitochondrial probes and co-immunoprecipitation of the PEX7 receptor.
RESULTS: We report for the first time that DEPP regulates ROS detoxification and localizes to peroxisomes and mitochondria in neuroblastoma cells. FOXO3-mediated apoptosis involves a biphasic ROS accumulation. Knockdown of DEPP prevented the primary and secondary ROS wave during FOXO3 activation and attenuated FOXO3- and H2O2-induced apoptosis. Conditional overexpression of DEPP elevates cellular ROS levels and sensitizes to H2O2 and etoposide-induced cell death. In neuronal cells, cellular ROS are mainly detoxified in peroxisomes by the enzyme CAT/catalase. As DEPP contains a peroxisomal-targeting-signal-type-2 (PTS2) sequence at its N-terminus that allows binding to the PEX7 receptor and import into peroxisomes, we analyzed the effect of DEPP on cellular detoxification by measuring enzyme activity of catalase. Catalase activity was reduced in DEPP-overexpressing cells and significantly increased in DEPP-knockdown cells. DEPP directly interacts with the PEX7 receptor and localizes to the peroxisomal compartment. In parallel, the expression of the transcription factor peroxisome proliferator-activated receptor gamma (PPARG), a critical regulator of catalase enzyme activity, was strongly upregulated in DEPP-knockdown cells.
CONCLUSION: The combined data indicate that in neuroblastoma DEPP localizes to peroxisomes and mitochondria and impairs cellular ROS detoxification, which sensitizes tumor cells to ROS-induced cell death.

PMID: 25261981 [PubMed - indexed for MEDLINE]

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Histomorphometric evaluation of ischemia-reperfusion injury and the effect of preservation solutions histidine-tryptophan-ketoglutarate and University of Wisconsin in limb transplantation.

Tue, 19/07/2016 - 1:16pm

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Histomorphometric evaluation of ischemia-reperfusion injury and the effect of preservation solutions histidine-tryptophan-ketoglutarate and University of Wisconsin in limb transplantation.

Transplantation. 2014 Oct 15;98(7):713-20

Authors: Hautz T, Hickethier T, Blumer MJ, Bitsche M, Grahammer J, Hermann M, Zelger B, Messner F, Pechriggl EJ, Krapf C, Kimelman M, Brandacher G, Lee WP, Margreiter R, Pratschke J, Schneeberger S

Abstract
BACKGROUND: The effect of cold ischemia (CI) in vascularized composite allotransplantation is unknown. We herein assess tissue-specific damage, acceptable CI time, and the effect of preservation solutions in a syngenic rat hindlimb transplant model.
METHODS: Lewis rat limbs were flushed and stored for 2, 10, or 30 hr CI in saline, histidine-tryptophan-ketoglutarate or University of Wisconsin preservation solution before transplantation. Morphologic alterations, inflammation, and damage of the individual tissues were analyzed on day 10 using histomorphology, confocal, light, and transmission-electron microscopy.
RESULTS: Two-hour CI led to mild inflammation of tissues on day 10, whereas 10-hr and 30-hr CI resulted in massive inflammation and tissue damage. Although muscle was mainly affected after prolonged CI (≥10 hr), nerve was affected in all CI groups. A perineural cell infiltrate, hypercellular appearance, pronounced vacuolization, and mucoid degeneration, appearing as Wallerian degeneration, were observed. Staining with propidium iodide and Syto 16 revealed a decrease in viable muscle cell nuclei in the anterior tibial muscle on day 10 in all groups, which was most pronounced in 10-hr and 30-hr CI animals. Transmission-electron microscopy indicated that a large number of mitochondria were degenerated in the 10-hr and 30-hr CI groups. Histidine-tryptophan-ketoglutarate preservation solution slightly decreased inflammation and tissue damage compared to University of Wisconsin-treated and saline-treated animals, especially in skin and muscle when CI times did not exceed 10 hr.
CONCLUSION: Severe inflammation and tissue damage are observed after prolonged CI in muscle and nerve. Ischemia times in vascularized composite allotransplantation should be kept as short as possible and certainly below 10 hr.

PMID: 25073033 [PubMed - indexed for MEDLINE]

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[Diagnosis of inherited diseases of platelet function. Interdisciplinary S2K guideline of the Permanent Paediatric Committee of the Society of Thrombosis and Haemostasis Research (GTH e. V.)].

Tue, 19/07/2016 - 1:16pm

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[Diagnosis of inherited diseases of platelet function. Interdisciplinary S2K guideline of the Permanent Paediatric Committee of the Society of Thrombosis and Haemostasis Research (GTH e. V.)].

Hamostaseologie. 2014;34(3):201-12

Authors: Knöfler R, Eberl W, Schulze H, Bakchoul T, Bergmann F, Gehrisch S, Geisen C, Gottstein S, Halimeh S, Harbrecht U, Kappert G, Kirchmaier C, Kehrel B, Lösche W, Krause M, Mahnel R, Meyer O, Pilgrimm AK, Pillitteri D, Rott H, Santoso S, Siegemund A, Schambeck C, Scheer M, Schmugge M, Scholl T, Strauss G, Zieger B, Zotz R, Hermann M, Streif W

Abstract
Congenital disorders of platelet function are a heterogeneous group of disorders that are often not detected until bleeding occurs. In clinical settings only a few methods have proven to be useful for identification and classification of inherited platelet disorders. For a rational diagnostic approach, a stepwise algorithm is recommended. Patient history and clinical investigation are mandatory. Von Willebrand disease and other coagulation disorders should always be ruled out prior to specific platelet testing. Platelet count, size, volume (MPV) and morphology may guide further investigations. The PFA-100® CT is suited for screening for severe platelet defects. Platelet aggregometry allows assessment of multiple aspects of platelet function. Flow cytometry enables diagnosis of thrombasthenia Glanzmann, Bernard-Soulier syndrome and storage pool defects. Molecular genetics may confirm a putative diagnosis or pave the way for identifying new defects. We present an unabridged version of the interdisciplinary guideline.

PMID: 24903476 [PubMed - indexed for MEDLINE]

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Biopsychronology: live confocal imaging of biopsies to assess organ function.

Tue, 19/07/2016 - 1:16pm

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Biopsychronology: live confocal imaging of biopsies to assess organ function.

Transpl Int. 2014 Aug;27(8):868-76

Authors: Ashraf MI, Fries D, Streif W, Aigner F, Hengster P, Troppmair J, Hermann M

Abstract
Prolonged ischemia (I) times caused by organ procurement and transport are main contributors to a decrease in organ function, which is further enhanced during reperfusion (R). This combined damage, referred to as ischemia-reperfusion injury (IRI), is a main contributor to delayed graft function, which leads to costly and lengthy follow-up treatments or even organ loss. Methods to monitor the status of a graft prior to transplantation are therefore highly desirable to optimize the clinical outcome. Here, we propose the use of fine needle biopsies, which are analyzed by real-time live confocal microscopy. Such a combination provides information about the functional and structural integrity of an organ within a few minutes. To confirm the feasibility of this approach, we obtained fine needle biopsies from rodent kidneys and exposed them to various stress conditions. Following the addition of a range of live stains, biopsies were monitored for mitochondrial function, cell viability, and tissue integrity using confocal live cell imaging. Our data demonstrate that this procedure requires minimal time for sample preparation and data acquisition and is well suitable to record organ damage resulting from unphysiological stress.

PMID: 24750326 [PubMed - indexed for MEDLINE]

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