Thesis (Ph. D.)--Lund University, 1995. / Summary in Swedish. Contains reprints of 5 papers authored in part by the thesis author. eContent provider-neutral record in process. Description based on print version record.

Thesis (Ph. D.)--Lund University, 1995. / Summary in Swedish. Contains reprints of 5 papers authored in part by the thesis author.

Thesis ( M.Sc.) -- University of Adelaide, Dept. of Pathology, 1983. / Typescript (photocopy).

Eclampsia is a hypertensive disorder of pregnancy and a leading cause of maternal death. The primary explanation for eclampsia is that it represents a form of hypertensive encephalopathy (HTE) with neurological symptoms including headaches, nausea, vomiting, visual disturbances, and seizures. The etiology of HTE involves an acute increase in arterial blood pressure that exceeds the autoregulatory capacity of the brain leading to forced dilatation of cerebral vessels, decreased cerebrovascular resistance, hyperperfusion, blood-brain barrier (BBB) disruption, and vasogenic cerebral edema formation. Due to the central role of the cerebral circulation in mediating these symptoms, a better understanding of how pregnancy affects the cerebral circulation is important to the treatment and prevention of eclampsia. A central goal of this dissertation was to determine pregnancy’s effect on cerebral blood flow (CBF) autoregulation, edema formation, and BBB permeability during acute hypertension. Women with eclampsia often seize at lower blood pressures than HTE patients. We hypothesized that pregnancy may predispose the brain to eclampsia by lowering the pressure of autoregulatory breakthrough and enhancing cerebral edema formation. Using an in vivo model of HTE, we found that the pressure of autoregulatory breakthrough was not different between nonpregnant (NP) and late-pregnant (LP) rats; however, cerebral edema formation was significantly increased only in LP animals. Nitric oxide synthase inhibition significantly increased the upper limit of autoregulation in both NP and LP animals and attenuated cerebral edema formation in LP animals. BBB permeability during acute hypertension was not different between these groups. Magnesium sulfate (MgSO4) is widely used to treat eclampsia despite an unclear mechanism of action. A second goal of this dissertation was to determine the cerebrovascular effects of MgSO4 during pregnancy. Specifically, we investigated the effect of MgSO4 on in vitro resistance artery vasodilation and in vivo BBB permeability during acute hypertension. We hypothesized that dilation to MgSO4 would be greater in mesenteric than cerebral vessels. MgSO4 elicited concentration-dependent vasodilation in all arteries, as determined by measuring lumen diameter of isolated and pressurized arteries, however, mesenteric arteries were considerably more sensitive than cerebral arteries. In addition, there was no effect of pregnancy on MgSO4 sensitivity in mesenteric arteries, whereas pregnancy decreased sensitivity to MgSO4 in cerebral arteries. We further hypothesized that MgSO4 would decrease BBB disruption during acute hypertension, thereby protecting the brain in eclampsia. Using an in vivo model of HTE, we showed that MgSO4 treatment decreased BBB permeability during acute hypertension in LP rats, with the greatest effect observed in the posterior cerebrum. In conclusion, this dissertation determined CBF autoregulation and cerebral edema formation during pregnancy, and also the effect of MgSO4 on cerebral resistance artery vasodilation and BBB permeability during acute hypertension in LP rats. Although pregnancy did not influence autoregulatory breakthrough, cerebral edema formation was enhanced in LP animals and this may potentiate neurological symptoms in eclampsia. In addition, MgSO4-induced cerebral vasodilation is likely not a primary mechanism of eclampsia treatment, rather MgSO4 may limit edema formation by attenuating BBB permeability during hypertension.

Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted. Includes bibliographical references.

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

Traumatic brain injury (TBI) is a major problem with an estimated cost of $76 billion per year in the US alone. The Center for Disease Control and Prevention (CDC) documented 2.53 million TBI-related emergency department visits, with approximately 288,000 TBI-related hospitalizations and 56,800 TBI-related deaths in 2014 in the US. The lack of FDA-approved treatment strategies for TBI drives the need for novel therapeutic and preventative measures. In a quest to reduce TBI-related injuries and deaths, automotive companies have focused their efforts to make safer cars for both occupants and pedestrians. Computational finite element (FE) models have been used to advance research efforts in automotive safety systems engineering in hopes of ameliorating the burden caused by TBI. The current use of FE models in the automotive industry focuses on predicting stresses and strains that occur during the accident itself to predict primary injury. However, contemporary models lack the appropriate mechanical properties required to make accurate predictions of brain tissue deformation after injury and lack the ability to model secondary injuries such as cerebral edema (brain swelling). With cerebral edema being a major cause of death and disability after TBI, and with the pattern and magnitude of cerebral edema being dependent on the initiating strain field in brain tissue during TBI, automotive safety systems could be further improved if 1) FE head models contained more accurate mechanical properties and 2) if FE models could simulate secondary injuries such as cerebral edema. Therefore, the driving purpose of this thesis is two-fold: 1) to determine the mechanical properties of different regions of the brain and 2) to present a new computational methodology that allows for modeling of cerebral edema to better predict patient outcome following TBI. The use of FE models requires appropriate constitutive formulations and associated parameters to accurately model and predict the initial mechanical response of the brain to injury loading conditions. Since patient outcome is dependent on the resulting strain field within brain tissue post-injury, accurate modeling of brain tissue deformation is important for testing the efficacy of engineered automotive safety systems using FE simulations. To address this need, the first aim of this thesis employed an inverse FE approach to characterize mechanical properties of the human hippocampus (CA1, CA3, dentate gyrus), cortex white matter, and cortex gray matter. Anatomical regions were significantly different in their mechanical properties. Although no sex dependency was observed, there were trends indicating that some male brain regions were generally stiffer than corresponding female regions. In addition, mechanical properties were not dependent on age within the examined age range (4-58 years old). Ultimately, this study provides a structure-specific description of fresh human brain tissue mechanical properties, which will be an important step toward explicitly modeling the heterogeneity of brain tissue deformation during TBI using FE modeling. Fatal brain injuries may also result from physiological changes in the brain that occur after the primary injury that immediately occurs during head injury. Secondary injuries such as cerebral edema are associated with poor outcome. Despite the severe consequences of cerebral edema, its mechanism is not fully understood. The second aim of this thesis, therefore, was to elucidate the driving mechanism of cerebral edema by demonstrating that cleavage of intracellular fixed-charge density (FCD) reduces brain swelling pressure and to measure the FCD content of rat and pig brain tissue. Thin brain samples were placed into a confined pressure chamber, and FCD content was calculated from measured swelling pressure and the Gibbs-Donnan equation. We observed that cleavage of FCD using enzymes reduced swelling pressure in rat brain tissue samples and determined that pig cortex gray matter contains more FCD than pig cortex white matter. These results demonstrate that cerebral edema may occur in accordance with principles of triphasic swelling biomechanics and demonstrates the plausibility of computationally modeling cerebral edema with triphasic material formulations. Cerebral edema leads to increased intracranial pressure (ICP) as the brain swells within the fixed volume of the skull, and there is overwhelming evidence of ICP as a powerful predictor of patient outcome following TBI. Current industry standards of patient outcome evaluation use tissue-level metrics solely from primary injury such as maximum principal strain (MPS) or cumulative strain damage measure (CSDM), but these methods can be improved especially in regards to predicting mortality. Therefore, the third aim of this thesis was to develop a new FE head model and computational methodology incorporating triphasic swelling biomechanics to simulate brain swelling following impact to improve patient outcome predictions. Patient outcome was predicted by simulating swelling and calculating the resulting ICP, which is a strong indicator of patient mortality. Calculating ICP in addition to predicting primary injury metrics such as MPS and CSDM may allow automotive safety engineers to make better predictions of patient outcome following TBI so they can develop better safety systems. Another common indicator of poor outcome following TBI is acute subdural hematoma (ASDH). ASDH is an intracranial bleed that often results from TBI because of stretching and tearing of the bridging veins which causes blood to collect in the innermost layer of the dura. Despite the poor prognosis associated with the presence of ASDH following TBI, the mechanism as to why its presence is associated with a higher likelihood of death remains uncertain. Current state of the art FE head models used in automotive safety engineering efforts do not consider ASDH, which may drastically reduce their effectiveness in predicting patient outcome following TBI. Therefore, the fourth and final aim of this thesis was to incorporate ASDH into our FE head model of swelling and elucidate the underlying secondary brain injury mechanism of ASDH that contributes to increased mortality in hopes of increasing the efficacy of current FE models to predict patient outcome and ultimately design better safety systems. Using our novel FE head model and methodology from aim 3, we showed that the higher likelihood of death associated with the presence of ASDH may be caused by exacerbated ischemic injury which increases ICP, demonstrating that modeling of ASDH is necessary for accurately modeling patient outcome following TBI. Despite decades of TBI research and FE head model improvements, more work is required to enhance the biofidelity of these models to better predict patient outcome. The work in this thesis is important, as it introduces a new tool that will allow automotive safety engineers to incorporate cerebral edema and ASDH, both of which may drastically influence patient outcome following TBI, into models of head injury to allow for better predictions of patient outcome. It is hoped that the work in this thesis lays the foundation for future work that aids in the design of improved automotive safety systems that will save countless human lives.

Un dysfonctionnement du métabolisme cérébral est observé au décours d'un traumatisme crânien (TC). L’œdème cérébral et l’hypoxie cérébrale post-traumatiques sont des acteurs principaux de l’apparition des lésions ischémiques secondaires responsables en partie de la défaillance énergétique. Cette hypoxie tissulaire résulte de troubles macrocirculatoires, de troubles de la microcirculation et/ou de troubles de la diffusion de l’oxygène des capillaires sanguins aux tissus. La baisse de la consommation en oxygène est également liée à une dysfonction mitochondriale post traumatique de la chaine respiratoire. Ces phénomènes ischémiques ou hypoxiques aboutissent ainsi à une élévation de lactate endogène en condition anaérobie. Cependant, l'élévation de lactate endogène post traumatique est liée majoritairement à une crise métabolique conduisant à une hyperglycolyse en dehors de tout phénomène hypoxique ou ischémique. L'objectif de notre étude était donc d’étudier l'œdème cérébral, l'oxygénation cérébrale, la défaillance mitochondriale post traumatique et le métabolisme cérébral dans un modèle expérimental de traumatisme crânien diffus par impact accélération chez l'animal. Nous avons étudié les effets de différents neuroprotecteurs sur le métabolisme cérébral à l'aide d'un monitorage multimodal. Les effets de la rhEpo (5000UI/Kg), du mannitol (1g/kg) et du lactate de sodium molaire (1.5 ml/Kg soit 3mOsm/kg) ont été étudiés sur l'œdème cérébral (IRM, microscopie électronique), sur l'hypoxie cérébrale tissulaire (IRM BOLD, mesure de la pression tissulaire en O2, saturation veineuse en O2 du sinus longitudinal supérieur), sur le métabolisme cérébral (spectroRMN) et sur la mitochondrie (analyse de la capacité de rétention calcique, de la chaine respiratoire, microscopie électronique et mesure du calcium intramitochondrial) chez des rats wistar mâles. Notre hypothèse était que l’injection de différents neuroprotecteurs permettrait d’améliorer le métabolisme cérébral post traumatique par des effets bénéfiques sur l’hémodynamique cérébrale et l'œdème cérébral, sur l'hypoxie tissulaire ou sur la dysfonction mitochondriale post TC. Nos résultats ont démontré que la rhEpo avait un effet bénéfique sur l'hypoxie cérébrale post traumatique par le biais d'une diminution de l'œdème cérébral péri capillaire en phase aigue associée à une diminution de la dysfonction mitochondriale proapoptotique. Le mannitol améliore l'hypoxie cérébrale post traumatique en jouant sur la microvascularisation cérébrale perturbée par l'œdème astrocytaire péri capillaire. Enfin, le lactate de sodium molaire avait des effets bénéfiques anti œdémateux et sur la dysfonction mitochondriale post TC améliorant ainsi la crise métabolique post traumatique. Ces résultats permettent d'améliorer la compréhension de la physiopathologie des lésions survenant au décours du traumatisme crânien ainsi que les mécanismes d'action de différentes molécules neuroprotectrices. / Cerebral metabolism is impaired after a Traumatic Brain Injury (TBI). Post traumatic cerebral edema and hypoxia are mainly responsible of the development of secondary ischemic lesions after TBI leading to metabolic impairment. Tissular hypoxia can result from disorders in macro and microcirculation and/or disturbance in the diffusion of oxygen from the blood capillaries to tissue. The decrease in oxygen consumption observed after brain injury is also related to a post traumatic dysfunction of the mitochondrial respiratory chain. These ischemic or hypoxic phenomena may be responsible for metabolic disorders leading to elevated level of endogenous lactate under anaerobic conditions. However, the elevation of endogenous lactate is mainly the consequence of a metabolic crisis that led to a state of hyperglycolysis without cerebral hypoxia or ischemia after TBI. The aim of our study was to investigate cerebral edema, cerebral oxygenation, mitochondrial and metabolic impairment post TBI in an experimental model of impact acceleration diffuse brain injury in rats. We also analyzed the effects of various neuroprotective agents on cerebral metabolism using a multimodal monitoring. The effects of rhEpo (5000UI/Kg), mannitol (1g/Kg) and of molar sodium lactate (1.5 ml/Kg or 3mOsm/kg) were investigated on brain edema (MRI, electronic microscopy), on brain tissue hypoxia (BOLD MRI, measurement of the tissular pressure of O2, venous O2 saturation of the upper longitudinal sinus), on brain metabolism (Magnetic Resonance Spectroscopy) and on mitochondria (study of the calcium retention capacity, of the respiratory chain, morphological analysis with electronic microscopy and measurement of intramitochondrial calcium) in male wistar rats. We hypothesized that the injection of various neuroprotective agents would improve posttraumatic cerebral metabolism by restoring a better cerebral hemodynamic status, by improving cerebral edema, tissular oxygenation and/or mitochondrial function. On the early phase of TBI, we demonstrated that rhEpo had a beneficial effect on post traumatic cerebral hypoxia by decreasing post-traumatic cerebral capillaries collapse due to astrocytic end-foot swelling. This effect was associated with an improvement in cellular apoptosis induced by mitochondrial pathways. Mannitol improved brain hypoxia by decreasing peri vascular astrocytic edema. Sodium lactate had benefic effects on cerebral hypoxia by decreasing cerebral edema and improved mitochondrial and metabolic impairments after TBI. These results help understanding physiopathological events after TBI and the various effects of neuroprotective agents that can be used in future clinical research.

L'encéphalopathie hépatique (EH) est un syndrome neuropsychiatrique dû à une dysfonction hépatique où l'ammoniaque est un facteur central. Il a déjà été rapporté que l’intoxication aiguë d'ammoniaque induise le stress oxydatif/nitrosatif. La présente étude cible à évaluer le rôle du stress oxydatif/nitrosatif dans 2 modèles de l’EH chronique : (1) l’anastomose portocave (PCA) et (2) la ligation de la voie biliaire (BDL). Ces 2 modèles sont caractérisés par une hyperammoniémie et une augmentation d’ammoniaque centrale, cependant l’œdème cérébral est trouvé seulement chez les rats BDL. Des marqueurs du stress oxydatif/nitrosatif ont été évaluées dans le plasma et cortex frontal. Un stress nitrosatif central a été observé chez les rats PCA; tandis qu’un stress oxydatif/nitrosatif systémique a été démontré seulement chez les rats BDL. Ces résultats suggèrent (1) que l’hyperammoniémie chronique n’induise pas le stress oxydatif/nitrosatif systémique et (2) qu’un synergisme existe entre l’ammoniaque et le stress oxydatif/nitrosatif, en association avec l’œdème cérébral. / Hepatic encephalopathy (HE) is a neuropsychiatric complication due to liver failure where ammonia is believed to be central in the pathogenesis. Acute ammonia intoxication has demonstrated to induce oxidative/nitrosative stress in both in vivo and in vitro models. The present study was aimed to assess the role of oxidative/nitrosative stress in 2 models of chronic liver failure/HE; 1. portacaval anastomosis (PCA) and 2. bile duct ligation (BDL). Both models are characterised with hyperammonemia and increased brain ammonia however cerebral edema is only found in BDL rats. Oxidative/nitrosative stress markers were evaluated in plasma and frontal cortex of both animal models. Central nitrosative stress was observed in PCA rats, but systemic oxidative/ntrosative stress was demonstrated only in BDL rats. The results of our study suggest i) chronic hyperammonemia does not induce oxidative stress and ii) a synergistic effect between ammonia and systemic oxidative/nitrosative stress is associated with cerebral edema.

L'encéphalopathie hépatique (EH) est un syndrome neuropsychiatrique dû à une dysfonction hépatique où l'ammoniaque est un facteur central. Il a déjà été rapporté que l’intoxication aiguë d'ammoniaque induise le stress oxydatif/nitrosatif. La présente étude cible à évaluer le rôle du stress oxydatif/nitrosatif dans 2 modèles de l’EH chronique : (1) l’anastomose portocave (PCA) et (2) la ligation de la voie biliaire (BDL). Ces 2 modèles sont caractérisés par une hyperammoniémie et une augmentation d’ammoniaque centrale, cependant l’œdème cérébral est trouvé seulement chez les rats BDL. Des marqueurs du stress oxydatif/nitrosatif ont été évaluées dans le plasma et cortex frontal. Un stress nitrosatif central a été observé chez les rats PCA; tandis qu’un stress oxydatif/nitrosatif systémique a été démontré seulement chez les rats BDL. Ces résultats suggèrent (1) que l’hyperammoniémie chronique n’induise pas le stress oxydatif/nitrosatif systémique et (2) qu’un synergisme existe entre l’ammoniaque et le stress oxydatif/nitrosatif, en association avec l’œdème cérébral. / Hepatic encephalopathy (HE) is a neuropsychiatric complication due to liver failure where ammonia is believed to be central in the pathogenesis. Acute ammonia intoxication has demonstrated to induce oxidative/nitrosative stress in both in vivo and in vitro models. The present study was aimed to assess the role of oxidative/nitrosative stress in 2 models of chronic liver failure/HE; 1. portacaval anastomosis (PCA) and 2. bile duct ligation (BDL). Both models are characterised with hyperammonemia and increased brain ammonia however cerebral edema is only found in BDL rats. Oxidative/nitrosative stress markers were evaluated in plasma and frontal cortex of both animal models. Central nitrosative stress was observed in PCA rats, but systemic oxidative/ntrosative stress was demonstrated only in BDL rats. The results of our study suggest i) chronic hyperammonemia does not induce oxidative stress and ii) a synergistic effect between ammonia and systemic oxidative/nitrosative stress is associated with cerebral edema.