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Glaucoma affects tens of millions of people and is the leading cause of irreversible blindness worldwide. Virtually all current glaucoma therapies target elevated intraocular pressure (IOP); however, the contribution of intracranial pressure (ICP) to glaucoma has recently garnered interest. Strain at the optic nerve head is now known to depend on the translaminar pressure difference (TLPD), which is the difference between IOP and ICP, rather than IOP alone. A better understanding of how IOP and ICP relate to glaucoma development and progression is essential for developing improved therapies and diagnostic tests. Glaucoma is commonly modeled in rats, yet aqueous humor dynamics are not well-documented in healthy nor diseased rat eyes. Moreover, because rats do not develop glaucoma spontaneously, it is essential to develop low-cost, reliable, and relevant models of glaucomatous pathology in the animal. The purpose of this dissertation work is to achieve the following goals: i) quantitatively assess aqueous humor dynamics in healthy, living rat eyes, ii) develop an ideal model of experimental glaucoma in rats, iii) quantitatively characterize aqueous humor dynamics throughout experimental glaucoma in living rats, and iv) investigate the effects of ICP manipulations on aqueous humor dynamics in living rats. Chapter 2 reports physiological parameters of aqueous humor dynamics for the first time in the eyes of living, healthy Brown-Norway rats, and presents a novel perfusion technique for efficiently and accurately estimating these parameters. Chapter 3 introduces the constant-pressure perfusion model of experimental glaucoma: a powerful new model which overcomes several limitations of existing techniques. The constant-pressure perfusion model induces IOP elevations which are prescribable and easily manipulated, does not directly target the trabecular meshwork or its vasculature, and offers continuous records of IOP rather than requiring regular animal handling and tonometry. Chapter 3 characterizes IOP-induced optic neuropathies in rats and demonstrates their resemblance to human glaucoma. Chapter 4 evaluates whether the constant-pressure perfusion model affects ocular physiology, specifically showing that resting IOP and conventional outflow facility are not permanently nor significantly altered in the model. Chapter 5 examines the effect of ICP manipulations on aqueous outflow physiology in living rats, and reports for the first time a graded effect of intracranial hypertension on conventional outflow facility. Evidence for a neural feedback mechanism that may serve to regulate the TLPD is also presented. Chapter 6 summarizes the results of this dissertation, provides recommendations for future work, and gives closing remarks. These collective projects provide insight into IOP regulation in both healthy and diseased rat eyes, advancing our understanding of glaucomatous development and damage in rats. A novel model of experimental glaucoma and several perfusion systems have been developed which are distinctly tailored for use in future glaucoma studies and will allow future investigators to study the disease with enhanced efficiency and exactitude. The results of this dissertation work suggest that detecting and correcting impairments of either IOP or ICP homeostatic capabilities may be of utmost importance for improving clinical outcomes in human glaucoma.

<p>Traumatic brain injury (TBI) renders the brain more vulnerable to secondary insults. The increased vulnerability can probably be explained by a combination of disturbances in hemodynamics, metabolism and craniospinal dynamics. Reduced ability to compensate for added intracranial volume, i.e. reduced intracranial compliance (IC), is one possible mechanism. The <i>aim</i> of this thesis was to study the role of IC on the effect of secondary insults after TBI. </p><p>A rat TBI model was developed where IC could be altered without causing pathological increases in intracranial pressure (ICP). Reduction of IC was made by placing rubber film between the dura mater and bilateral bone flaps. A reduction of IC in terms of reduced Pressure Volume Index was confirmed. Microdialysis (MD) of extracellular fluid was used to monitor neurochemical changes. Reduced IC after TBI proved to increase the vulnerability of the brain to secondary intracranial volume insults according to neurochemical microdialysis markers. Reduced IC or intracranial volume insults alone did not cause any metabolic changes as compared to controls. Moderate posttraumatic hypotension (50mmHg for 30 min) induced 2 hrs after TBI, did not aggravate posttraumatic extracellular neurochemical changes significantly, irrespective of the level of IC. Although controversial, a mild to moderate hypotensive insult after initial posttraumatic stabilization may not be as detrimental as earlier believed.</p><p>The Spiegelberg Compliance Monitor and MD were simultaneously used in 10 TBI patients to get an impression of the clinical value of IC monitoring and the relationship between IC, temperature and MD Lactate/Pyruvate ratio. IC and MD could be monitored simultaneously in TBI patients. Higher L/P ratios were seen when IC was low. Patients with induced coma treatment had significantly higher average L/P ratios, possibly due to their poorer neurological condition. An indication was also found that in TBI patients with high temperatures, L/P ratio rose as IC decreased, but in patients with low temperature there was no effect of IC on L/P ratio. These data suggest the importance of avoiding hyperthermia in TBI patients, especially in patients with low or decreased IC (monitored or anticipated).</p>

Traumatic brain injury (TBI) renders the brain more vulnerable to secondary insults. The increased vulnerability can probably be explained by a combination of disturbances in hemodynamics, metabolism and craniospinal dynamics. Reduced ability to compensate for added intracranial volume, i.e. reduced intracranial compliance (IC), is one possible mechanism. The aim of this thesis was to study the role of IC on the effect of secondary insults after TBI. A rat TBI model was developed where IC could be altered without causing pathological increases in intracranial pressure (ICP). Reduction of IC was made by placing rubber film between the dura mater and bilateral bone flaps. A reduction of IC in terms of reduced Pressure Volume Index was confirmed. Microdialysis (MD) of extracellular fluid was used to monitor neurochemical changes. Reduced IC after TBI proved to increase the vulnerability of the brain to secondary intracranial volume insults according to neurochemical microdialysis markers. Reduced IC or intracranial volume insults alone did not cause any metabolic changes as compared to controls. Moderate posttraumatic hypotension (50mmHg for 30 min) induced 2 hrs after TBI, did not aggravate posttraumatic extracellular neurochemical changes significantly, irrespective of the level of IC. Although controversial, a mild to moderate hypotensive insult after initial posttraumatic stabilization may not be as detrimental as earlier believed. The Spiegelberg Compliance Monitor and MD were simultaneously used in 10 TBI patients to get an impression of the clinical value of IC monitoring and the relationship between IC, temperature and MD Lactate/Pyruvate ratio. IC and MD could be monitored simultaneously in TBI patients. Higher L/P ratios were seen when IC was low. Patients with induced coma treatment had significantly higher average L/P ratios, possibly due to their poorer neurological condition. An indication was also found that in TBI patients with high temperatures, L/P ratio rose as IC decreased, but in patients with low temperature there was no effect of IC on L/P ratio. These data suggest the importance of avoiding hyperthermia in TBI patients, especially in patients with low or decreased IC (monitored or anticipated).

Subarachnoid hemorrhage (SAH) is a disease with high risk of mortality and morbidity. Elderly patients have an even higher risk of poor outcome. The incidence of SAH increases with age and the elderly constitute a substantial and increasing proportion of the population. Thus, the management of elderly SAH patients is an imminent clinical challenge. Time trends in clinical management and outcome were investigated in 281 SAH patients aged ≥65 years admitted over an 18-year period. The volume of elderly patients, especially patients ≥70 years and patients in worse clinical condition increased over time. The proportion of patients with favorable outcome increased over time, without an increase in severely disabled patients. Technical results and clinical outcome of endovascular aneurysm treatment (EVT) was investigated in 62 elderly SAH patients. EVT can be performed in elderly SAH patients with high technical success, acceptable aneurysm occlusion degree, acceptable procedural complication rate, and fair outcome results. EVT was compared to neurosurgical clipping (NST) in 278 elderly SAH patients in the International Subarachnoid Aneurysm Trial. In good grade elderly SAH patients, EVT should probably be the favored treatment for internal carotid and posterior communicating artery aneurysms, while elderly patients with middle cerebral artery aneurysms appear to benefit from NST. Occurrence of secondary insults and their impact on clinical deterioration were studied in 99 patients with severe SAH. High intracranial pressure increased and high cerebral perfusion pressure decreased the risk of clinical deterioration. Elderly patients had less intracranial hypertension insults and more hypertensive, hypotensive and hypoxemic insults. Good outcome was achieved in 24% of elderly patients with severe SAH, and the proportion of severe disability was similar to that of younger patients. Patient age was not a significant predictor for vasospasm in 413 SAH patients when admission and treatment variables were adjusted for with multiple logistic regression.

In der vorliegenden Arbeit wurde das Outcome von 112 Patienten mit intrakranieller Blutung analysiert, um das Blutungsvolumen und die unterschiedliche Dynamik der Blutungen als Einfluss- und prädiktive Faktoren zu korrelieren. 21.4% der 112 eingeschlossenen Patienten hatten ein EDH, 38.4 % ein SDH- bzw. 40.2% ein Intrazerebralhämatom. Die Sub- und Epiduralhämatome waren mehrheitlich traumatische Läsionen, die intrazerebralen Blutungen vorwiegend spontane. Im Gesamtkollektiv hatten 28.6% ein funktionelles, respektive 71.4% ein nicht funktionelles Outcome. Das Ergebnis der 71 traumatischen Blutungen war signifikant besser (38.0% funktionell) als das der 41 spontanen (12.2% funktionell, p=0.004). Bei gleichem Hämatomvolumen haben operativ versorgte spontane Blutungen eine 88% geringere Chance für ein funktionelles Ergebnis als operierte traumatische Blutungen. Im Untersuchungskollektiv wurde der reziproke Zusammenhang von Volumen und GOS sowohl für spontane und traumatische, als auch für akute und subakute Blutungen demonstriert. Nicht signifikant verschieden waren akut und subakut verlaufende Blutungen bezüglich ihres Outcomes (32.8% vs. 23.5% funktionelles Outcome, p= 0.302), und der Volumina (47.5ml vs. 52.8ml, p=0.102)). Der vermutete Zusammenhang zwischen Hämatomgröße und zeitlichem Verlauf konnte damit nicht gezeigt werden. Wir fanden auch keinen signifikanten Unterschied des klinischen Ergebnisses in Bezug auf den chirurgischen Interventionszeitpunkt (< 6h vs. > 6h). Bei den traumatischen Hämorrhagien wurde ein Modell mit 3 unabhängigen Faktoren (Alter, initaler GCS und Volumen) zur Prädiktion des Outcomes entwickelt. Kleine Volumina, ein niedriges Alter und ein initial hoher GCS lassen ein funktionelles Outcome vorhersagen. Weitere Faktoren, die jedoch nicht unabhängig mit dem Outcome assoziiert waren, sind Mittellinienverlagerung, initiale Blutglukose, Vorliegen eines Hirnödems und arterielle Hypertonie. Die initiale Glukosekonzentration kann zur Vorhersage des Outcomes nach traumatischen Blutungen beitragen, Als einziger unabhängiger Prädiktor wurde bei den spontanen Raumforderungen die Mittellinienverlagerung ermittelt. Volumen und initiale GCS waren nicht unabhängige Prädiktoren. Das schlechte Outcome nach spontaner Blutung, unabhängig vom Versorgungszeitpunkt, unterstreicht die kontroverse Datenlage bezüglich operativer Therapie dieser Raumforderungen. Traumatische Hämorrhagien in temporaler Lokalisation zeigen ein besseres Ergebnis als vergleichbare lokalisierte spontane Blutungen.

Στην παρούσα Διπλωματική Εργασία μελετάται η ανάπτυξη ενός μοντέλου προσομοίωσης αλληλεπίδρασης ρευστού-στερεού για τον προσδιορισμό ρευστοδυναμικών παραμέτρων (Wall Shear Stress, Von Mises Stress κ.α.) μέσω των οποίων θα μπορεί μελλοντικά να προβλεφθεί η ρήξη ή όχι ενός ενδοκρανιακού ανευρύσματος. Αρχικά γίνεται μια σύντομη παρουσίαση του ιατρικού προβήματος ώστε να γίνει κατανοητή η σπουδαιότητα της ανάπτυξης του υπολογιστικού μοντέλου με σκοπό τον υπολογισμό παραμέτρων οι οποίες μπορούν να φανούν χρήσιμες. Κατά τη διάρκεια ανάπτυξης του μοντέλου αξιοποιήθηκαν πραγματικά δεδομένα απεικονιστικών διατάξεων ασθενών του Αττικού Πανεπιστημιακού Γενικού Νοσο- κομείου. Εν συνεχεία, η επεξεργασία των εικόνων αυτών διεξήχθει στο λογισμικό ανοιχτού κώδικα VMTK (Vascular Modeling Toolkit) από όπου προήλθε και η τρισδιάστα- τη ανακατασκευη τους. Στο επόμενο στάδιο, οι γεωμετρίες που προέκυψαν από την επεξεργασία εικόνας εισήχθησαν στο λογισμικό εμπορικού κώδικα ANSYS όπου και αναπτύχθηκε το υπολογιστικό μοντέλο το οποίο περιείχε και την αλληλεπίδραση ρευστού και στερεού (FSI). Αξίζει να αναφερθεί το γεγονός ότι το μοντέλο που αναπτύχθηκε περιείχε κινούμενα στοιχεία πλέγματος (Moving Mesh), τα οποία συμβάλλουν στον ακριβέστερο υπολογισμό και αποτύπωση παραμέτρων που υπολογίστηκαν στη συνέχεια. Τέλος αναφέρονται κάποιοι μελλοντικοί στόχοι και προοπτικές μέσω των αποτελεσ- μάτων που προέκυψαν από την ανάλυση του μοντέλου. / In the present M.Sc thesis we are studying the development of a numerical model that simulates fluid-solid interaction for determining fluid dynamics parameters (Wall Shear Stress, Von Mises Stress etc) through which through which could be predicted the rupture or not of an intracranial aneurysm. First, a brief presentation of the medical problem is being made, to understand the importance of developing the computational model in order to calculate parameters which can be useful. During the development of the model, real imaging data from CT scans taken from patients of Attikon General University Hospital were exploited. Thereafter, the processing of these images was performed in the open-source software VMTK (Vascular Modeling Toolkit) from where came the three-dimensional reconstruction. In the next step, the geometries obtained from the image processing have been introduced in the commercial software ANSYS where the computational model that contains the interaction of fluid and solid has been developed (FSI). It is worth mentioning that the model developed, contained moving mesh elements, which contribute to more accurate calculation and mapping of parameters which were calculated after. Finally, some future objectives and prospects are being referred, through the results obtained from the analysis of the model.

Cerebral vascular accidents (CVAs) rank as the third leading cause of death in Canada with more than 50,000 of these events occurring annually. The evidence base from which to provide end-of- life care to patients dying from a CVA is currently limited, and there is a dearth of research examining the experiences of nurses charged with the responsibility of caring for these patients. In order to begin to address this gap in the literature, a qualitative study, using van Manen’s interpretive phenomenology was conducted to examine and describe the lived experiences of nurses working on an acute neurosciences unit in a tertiary hospital. Nine nurses were interviewed initially, and two nurses participated in follow-up interviews to confirm the interpretation of the data. This manuscript will discuss the essence of nurses’ lived experience in caring for these patients, as well as implications for education, practice, and future research.

Background: Impaired homocysteine metabolism is associated with a number of vasculopathies including extracranial aneurysms. We analyzed the possible association of nine genetic variants of homocysteine metabolism with the occurrence of intracranial aneurysms. Methods: Caucasian patients (n = 255) treated at two German hospitals for intracranial aneurysms and local controls (n = 348) were genotyped for the following polymorphisms: methionine synthase (MTR) c.2756A→G, methylenetetrahydrofolate reductase (MTHFR) c.677C→T, MTHFR c.1298A→C, cystathionine β-synthase (CBS) c.844_855ins68, CBS c.833T→C, dihydrofolate reductase (DHFR) c.594 + 59del19bp, glutathione S-transferase Ω-1 (GSTO1) c.428C→A, reduced folate carrier 1 (RFC1) c.80G→A and transcobalamin 2 (Tc2) c.776C→G. Results: The G-allele of the missense polymorphism Tc2 c.777C→G was found to be underrepresented in patients, suggesting that this variant may protect from the formation of cerebral aneurysms [odds ratio per two risk alleles (OR) 0.48; 95% confidence interval (CI) 0.30–0.77; p = 0.002]. We obtained borderline results for the G-allele of RFC1 c.80G→A (OR 1.64; 95% CI 1.01–2.65; p = 0.051) and the insertion allele of DHFR c.594 + 59del19bp (OR 1.61; 95% CI 1.00–2.60; p = 0.059), which were found to be overrepresented in patients. Conclusion: Polymorphisms of homocysteine metabolism are possible risk factors for the formation of intracranial aneurysms. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Background: There is growing evidence that genetic variants have an impact on the pathogenesis of intracranial aneurysm (IA). Recently, the genetic locus around the elastin gene (7q11) has been identified as linked to IA in a Japanese population. Our aim was to confirm these results in Caucasian populations. Methods: We conducted a case-control study in 120 Caucasian patients with IA and 172 controls to investigate 8 single nucleotide polymorphisms (SNPs) and various haplotypes within the elastin gene, which were frequently found and associated with the phenotype in the Japanese populations. Real-time PCR and melting curve analysis were used for the detection of genotypes. Results: Allele frequencies and genotypes were equally distributed between Caucasian cases and controls. We failed to identify haplotypes that are associated with the phenotype in our population, which is in contrast to the Japanese study. However, allele frequencies in control populations differ between Caucasians and Japanese. Conclusions: We found no association between SNPs and haplotypes of the elastin gene and the occurrence of IA in our Caucasian populations. However, our data provide strong evidence for racial/ethnic differences in the association of SNP and specific haplotypes of the elastin gene with the phenotype. There might be other genetic variants of the elastin gene associated with IA in Caucasians. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.