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Functional and structural properties of dentate granule cells with hilar basal dendrites in mouse entorhino-hippocampal slice cultures
(2012)
- During postnatal development hippocampal dentate granule cells (GCs) often extend dendrites from the basal pole of their cell bodies into the hilar region. These so-called hilar basal dendrites (hBD) usually regress with maturation. However, hBDs may persist in a subset of mature GCs under certain conditions (both physiological and pathological). The functional role of these hBD-GCs remains not well understood. Here, we have studied hBD-GCs in mature (≥18 days in vitro) mouse entorhino-hippocampal slice cultures under control conditions and have compared their basic functional properties (basic intrinsic and synaptic properties) and structural properties (dendritic arborisation and spine densities) to those of neighboring GCs without hBDs in the same set of cultures. Except for the presence of hBDs, we did not detect major differences between the two GC populations. Furthermore, paired recordings of neighboring GCs with and without hBDs did not reveal evidence for a heavy aberrant GC-to-GC connectivity. Taken together, our data suggest that in control cultures the presence of hBDs on GCs is neither sufficient to predict alterations in the basic functional and structural properties of these GCs nor indicative of a heavy GC-to-GC connectivity between neighboring GCs.
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Die Xerothermrasen-Gesellschaften des unteren Unstruttales und einige ökologische Gründe für ihre Verteilung im Raum
(1999)
- Das Gebiet an der unteren Unstrut nimmt hinsichtlich seiner Vegetation und Flora eine Sonderstellung ein, da sich hier kontinental und (sub-)mediterran verbreitete Sippen mischen. In den Xerothermrasen profitieren die östlichen Sippen vom subkontinentalen Klima, während der vorherrschende Muschelkalk-Untergrund und die Sommerwärme die zahlreichen kalkliebenden südlichen Sippen begünstigen. Daneben stellt das Unstruttal ein bedeutsames Refugialgebiet reliktischer Steppen- und Mittelmeerarten dar (BECKER 2000). Alles zusammen bewirkt eine überdurchschnittlich hohe Artenvielfalt und eine hohe Zahl verschiedener Xerothermrasen-Gesellschaften. Diese Gesellschaften und die mikroklimatischen und edaphischen Gründe für ihre Verteilung im Raum zu beschreiben, ist ein Ziel der vorliegenden Arbeit (VGL. BECKER 1996; s.a. BECKER 1998a, b). Kleinere Teilgebiete des Unstruttales wurden hinsichtlich ihrer Xerothermrasen-Gesellschaften bereits untersucht, so das NSG Steinklöbe von MEUSEL (1937) sowie HÖLZEL (1997), das NSG Neue Göhle von ALTEHAGE (1951) und das NSG Tote Täler von REICHHOFF et al. (1979). Auch bei KRAUSE (1940) finden sich interessante Überlegungen zu einzelnen Arten, während HENSEN (1997), BÖTTNER et al. (1997), HENSEN & KENTRUP (1998) und HEINZ & PFEIFFER (1998) mehrere Gesellschaften im Gebiet hinsichtlich der Lebensstrategien ihrer Arten untersucht haben. Schließlich sei noch die Studie von MAHN (1965) genannt, mit der man die pflanzensoziologischen Ergebnisse in einen größeren Kontext stellen kann. Mit der Rolle von Mikroklima und Boden in herzynischen Xerothermrasen haben sich u.a. HELMECKE (1972), REICHHOFF (1979, 1980) und SCHLÜTER & BALLER (1982) befaßt. Nicht unerwähnt bleiben sollen die grundlegenden Arbeiten von VOLK (1936, 1937b), HEILIG (1931) und DÖRR (1941).
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IL-2 stimulated but not unstimulated NK cells induce selective disappearance of peripheral blood cells: concomitant results to a phase I/II study
(2011)
- In an ongoing clinical phase I/II study, 16 pediatric patients suffering from high risk leukemia/tumors received highly purified donor natural killer (NK) cell immunotherapy (NK-DLI) at day (+3) +40 and +100 post haploidentical stem cell transplantation. However, literature about the influence of NK-DLI on recipient's immune system is scarce. Here we present concomitant results of a noninvasive in vivo monitoring approach of recipient's peripheral blood (PB) cells after transfer of either unstimulated (NK-DLI(unstim)) or IL-2 (1000 U/ml, 9–14 days) activated NK cells (NK-DLI(IL-2 stim)) along with their ex vivo secreted cytokine/chemokines. We performed phenotypical and functional characterizations of the NK-DLIs, detailed flow cytometric analyses of various PB cells and comprehensive cytokine/chemokine arrays before and after NK-DLI. Patients of both groups were comparable with regard to remission status, immune reconstitution, donor chimerism, KIR mismatching, stem cell and NK-DLI dose. Only after NK-DLI(IL-2 stim) was a rapid, almost complete loss of CD56(bright)CD16(dim/−) immune regulatory and CD56(dim)CD16(+) cytotoxic NK cells, monocytes, dendritic cells and eosinophils from PB circulation seen 10 min after infusion, while neutrophils significantly increased. The reduction of NK cells was due to both, a decrease in patients' own CD69(−) NCR(low)CD62L(+) NK cells as well as to a diminishing of the transferred cells from the NK-DLI(IL-2 stim) with the CD56(bright)CD16(+/−)CD69(+)NCR(high)CD62L(−) phenotype. All cell counts recovered within the next 24 h. Transfer of NK-DLI(IL-2 stim) translated into significantly increased levels of various cytokines/chemokines (i.e. IFN-γ, IL-6, MIP-1β) in patients' PB. Those remained stable for at least 1 h, presumably leading to endothelial activation, leukocyte adhesion and/or extravasation. In contrast, NK-DLI(unstim) did not cause any of the observed effects. In conclusion, we assume that the adoptive transfer of NK-DLI(IL-2 stim) under the influence of ex vivo and in vivo secreted cytokines/chemokines may promote NK cell trafficking and therefore might enhance efficacy of immunotherapy.
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A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma
(2010)
- Background: The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC. Methods: The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 3-year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating. Discussion: If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC. (trial registered at www.clinicaltrials.gov: NCT00355862) (EudraCT Number: 2005-005362-36)
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Entorhinal denervation induces homeostatic synaptic scaling of excitatory postsynapses of dentate granule cells in mouse organotypic slice cultures
(2012)
- Denervation-induced changes in excitatory synaptic strength were studied following entorhinal deafferentation of hippocampal granule cells in mature (≥3 weeks old) mouse organotypic entorhino-hippocampal slice cultures. Whole-cell patch-clamp recordings revealed an increase in excitatory synaptic strength in response to denervation during the first week after denervation. By the end of the second week synaptic strength had returned to baseline. Because these adaptations occurred in response to the loss of excitatory afferents, they appeared to be in line with a homeostatic adjustment of excitatory synaptic strength. To test whether denervation-induced changes in synaptic strength exploit similar mechanisms as homeostatic synaptic scaling following pharmacological activity blockade, we treated denervated cultures at 2 days post lesion for 2 days with tetrodotoxin. In these cultures, the effects of denervation and activity blockade were not additive, suggesting that similar mechanisms are involved. Finally, we investigated whether entorhinal denervation, which removes afferents from the distal dendrites of granule cells while leaving the associational afferents to the proximal dendrites of granule cells intact, results in a global or a local up-scaling of granule cell synapses. By using computational modeling and local electrical stimulations in Strontium (Sr2+)-containing bath solution, we found evidence for a lamina-specific increase in excitatory synaptic strength in the denervated outer molecular layer at 3–4 days post lesion. Taken together, our data show that entorhinal denervation results in homeostatic functional changes of excitatory postsynapses of denervated dentate granule cells in vitro.
