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Assessment of neuroprotective treatment strategies to promote photoreceptor survival in a murine model of cone-rod dystrophy and a murine model of retinitis pigmentosa

2026-06-26T12:17:46Z

Title: Assessment of neuroprotective treatment strategies to promote photoreceptor survival in a murine model of cone-rod dystrophy and a murine model of retinitis pigmentosa Authors: Herrmann, Maike Abstract: Retinal dystrophies, such as cone and cone-rod-dystrophies (CODs/CORDs) or retinitis pigmentosa (RP) are characterised by the progressive loss of photoreceptors and their functionality. Patients with severely progressed retinal dystrophies display, depending on the disorder, symptoms such as photophobia, night blindness, nystagmus, central scotomas, and reduced or absent colour vision. They often exhibit abnormal electroretinograms (ERGs), indicating the loss of rod or cone functionality. These disorders often progress slowly, leading to visual deterioration and eventually blindness. Only few treatment options are currently examined for the treatment of retinal dystrophies, e.g. utilisation recombinant proteins, encapsulated cell therapy (ECT) or injections of viral particles. Fewer still are approved by drug agencies for use in patients. One of the most regarded forms of treatment is the introduction of cytokines or other small proteins into the vitreous cavity of the eye, often in form of direct intravitreal injections of recombinant proteins. However, due to the chronic and often progressive nature of retinal dystrophies, and fast turn-over of molecules in the vitreous humour, the application of such therapeutics has to be repeated regularly, which can be a burden on both patient and the attending physician. Hence, a sustained approach for the treatment of retinal dystrophies is highly desirable. The present thesis analysed the neuroprotective effect of a sustained delivery of different neurotrophic factors (NTFs), such as ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF), leukemia inhibitory factor (LIF), progranulin (PGRN) and the designer cytokine hyper-interleukin-6 (hIL6) on degenerating photoreceptors of two animal models of retinal dystrophy. A sustained delivery of the different NTFs was achieved either by application of lentivirally modified neural stem cells (NSCs) or by injection of adeno-associated viruses (AAVs) (hIL6 only). Experiments were conducted in the Atp1b2Atp1b1 knock-in (ki) mouse, a novel model of a cone-rod dystrophy, and in the rd10 mouse, a well-established model of autosomal-recessive retinitis pigmentosa. Modified NSCs were examined in vitro and in vivo to characterise their potential for adequate performance in the animals. Cells expressed the desired NTFs in sufficient amounts and could survive for a prolonged period of time, differentiating into astrocytes in vivo, still expressing the respective protein. The neuroprotective effect was examined in immunohistochemically treated retinal sections analysing different parameters, such as inflammation, retina thickness, and the number of both rod and cone photoreceptors at various time points after treatment. In Atp1b2Atp1b1 ki mice all applied neurotrophic factors, except for GDNF, were suitable to attenuate loss of photoreceptor cells for several months after application of the modified NSCs. In the rd10 mouse model, which mimics both genotype and phenotype of patients with an autosomal-recessive form of retinitis pigmentosa, sustained delivery of hIL6, either by NSCs or AAVs, can protect from rod photoreceptor degeneration for up to 2 months. The collected data suggests a not inconsiderable impact of neuroinflammation on the magnitude of neuroprotection, since better effects have been observed in retinas with a higher degree of inflammation. The present results indicate that the sustained delivery of neurotrophic factors, such as CNTF, LIF, PGRN and hIL6, by means intravitreal application of lentivirally modified NSCs or AAVs, is suitable to attenuate photoreceptor loss in the retina of Atp1b2Atp1b1 ki mice and rd10 mice. The activation of pro-survival pathways such as the JAK/STAT or the RAS/MAPK pathways as well as the degree of inflammation seem to be key factors in conveying the neuroprotective effects observed in both animal models.

Post-Anesthesia Care Unit Hypotonie bei Niedrigrisiko-Patient:innen nach nicht-kardiochirurgischen Operationen

2026-06-26T11:56:03Z

Title: Post-Anesthesia Care Unit Hypotonie bei Niedrigrisiko-Patient:innen nach nicht-kardiochirurgischen Operationen Authors: Lohr, Anneke Abstract: Die Sterblichkeit bei nicht-kardiochirurgischen Operationen beträgt innerhalb der ersten 30 postoperativen Tage 4%. Postoperative Sterblichkeit ist häufig Folge von postoperativen Komplikationen. Die postoperative Hypotonie ist mit postoperativen Komplikationen assoziiert und ist somit ein potenziell vermeidbarer Risikofaktor für postoperative Komplikationen. Gerade in der frühen postoperativen Phase, während des Aufenthaltes in der PACU, scheint ein erhöhtes Risiko für postoperative Hypotonie zu bestehen. Die Inzidenz, die Dauer und der Schweregrad der postoperativen Hypotonie in der PACU ist jedoch bisher unzureichend untersucht. Ziel dieser Studie war es, die Inzidenz, die Dauer und den Schweregrad der PACU-Hypotonie bei Niedrigrisiko-Patient:innen nach nicht-kardiochirurgischen Operationen mithilfe der nicht-invasiven kontinuierlichen Finger-Cuff-Methode zu ermitteln. PACU-Hypotonie wurde als MAD <65 mmHg für mindestens eine zusammenhängende Minute definiert. Der primäre Endpunkt dieser Studie war die Proportion von Patient:innen mit PACU-Hypotonie. Die Quantifizierung der Dauer und des Schweregrades der PACU-Hypotonie erfolgte mithilfe der sekundären Endpunkte, der kumulativen Dauer der PACU-Hypotonie, der Fläche unter einem MAD von 65 mmHg und des zeitgewichteten Durchschnitts für MAD <65 mmHg. Es wurden die Daten von 100 Patient:innen in dieser Studie analysiert. 13% der Patient:innen hatten eine ASA-I-Klassifikation, 73% eine ASA-II-Klassifikation und 14% eine ASA-III-Klassifikation. PACU-Hypotonie trat bei drei (3%) Patient:innen auf. Die Fläche unter einem MAD von 65 mmHg betrug 4, 4 und 2 mmHg x min und der zeitgewichtete Durchschnitt für MAD <65 mmHg 0,5, 0,3 und 0,2 mmHg. Die Inzidenz der PACU-Hypotonie bei Niedrigrisiko-Patient:innen nach nicht-kardiochirurgischen Operationen fiel gering aus und war von moderatem Schweregrad. Die niedrige Inzidenz der PACU-Hypotonie kann durch ein insgesamt geringeres patient:innenspezifisches und operationsspezifisches Risiko in der Studienpopulation erklärt werden. Die Studienergebnisse sind somit nicht auf Patient:innen mit höherem Ausgangsrisiko oder nach Operationen mit höherem Operationsrisiko übertragbar. Weitere Studien sind nötig, um die Inzidenz der PACU-Hypotonie bei Patient:innen mit höherem Ausgangsrisiko und nach Operationen mit höherem Operationsrisiko zu ermitteln.

Virtual Reality Paradigms for the Assessment of Human Anxiety-Related Behavior: Examining Reliability, Individual Differences, and the Introduction of a Novel Paradigm

2026-06-26T11:22:02Z

Title: Virtual Reality Paradigms for the Assessment of Human Anxiety-Related Behavior: Examining Reliability, Individual Differences, and the Introduction of a Novel Paradigm Authors: Roth, Lateefah Ayashe

Two Particle Consistent Ladder Dynamical Vertex Approximation

2026-06-26T10:09:30Z

Title: Two Particle Consistent Ladder Dynamical Vertex Approximation Authors: Stobbe, Julian