<p>Each year, over 13,000 people in the United States die from a primary malignant brain tumor. Currently, primary BTs are treated most commonly by surgery, radiotherapy, and systemic chemotherapy, though each of these methods carries a risk of complications or acute side effects.</p><p>Ultrasound hyperthermia has been investigated as way to open the blood-brain barrier for improved chemotherapeutic drug delivery, but previous methods have involved either invasively removing skull bone via surgery or non-invasively dealing with the high ultrasound attenuation, reflection, and phase aberration resulting from the skull and its variable thickness. Dual-mode ultrasound transducers for image-guided therapy have also been investigated for several applications; in some instances, phased arrays are ideal, allowing control over the ultrasound energy deposition pattern and inherent spatial registration between imaging, treatment, and monitoring.</p><p>Additionally, thermosensitive liposomes can be configured to encapsulate drugs and actively target regions of tumor angiogenesis. When used in combination with localized hyperthermia, thermosensitive liposomes can provide targeted control of drug release that may enhance chemotherapeutic efficacy in many clinical settings. Meanwhile, catheter devices and endovascular techniques are used by interventional neuroradiologists to treat various intracranial diseases, including intracranial aneurysm and dural venous sinus thrombosis. These procedures can be extended to the treatment of intracranial tumors (advancement of a 5 Fr catheter as far as the frontal portion of the superior sagittal sinus has been demonstrated).</p><p>The objective of the work presented in this dissertation was the realization of a dual-mode catheter transducer for a minimally-invasive, vascular approach to deliver localized, image-guided ultrasound hyperthermia to an intracranial tumor target. Toward this end, a series of prototype ultrasound transducers were designed, simulated, built, and tested for imaging and therapeutic potential.</p><p>Two 14-Fr phased-array prototypes were built with PZT-5H ceramic and tested for real-time 3D intracranial imaging and focused-beam hyperthermia capability. These were able to visualize the lateral ventricles and Circle of Willis in a canine model, and generate a temperature rise over 4&deg;C at a 2-cm focal distance in excised tissue.</p><p>Single-channel intravascular ultrasound (IVUS) coronary imaging catheters as small as 3.5 Fr were then considered as a construction template; several possible transducer apertures were simulated before fabricating prototypes with PZT-4. The transducers exhibited a dual-frequency response, due to the presence of thickness-mode and width-mode resonances. A thermal model was developed to estimate the +4&deg;C thermal penetration depth for a given transducer aperture, predicting an effective therapeutic range of up to 12 mm with a 5 × 0.5 mm aperture.</p><p>A 3.5-Fr commercial mechanical IVUS catheter was retrofitted with a PZT-4 transducer and tested for 9-MHz imaging performance in several animal studies, successfully visualizing anatomical structures in the brain and navigating a minimally-invasive vascular pathway toward the brain. An identical PZT-4 transducer was used to build a 3.3-MHz therapy prototype, which produced a temperature rise of +13.5&deg;C at a depth of 1.5 mm in live xenograft brain tumor tissue in the mouse model.</p><p>These studies indicate that a minimally-invasive catheter transducer can be made capable of visualizing brain structures and generating localized hyperthermia to trigger drug release from thermosensitive liposomes in brain tumor tissue.</p> / Dissertation

Neurodegeneration describes the progressive loss of structure and function of neurons, leading ultimately to cell and organism death. Although the initiating factors of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and Amyotrophic Lateral Sclerosis may be different, they share common pathophysiologies. Proteinopathies, as these diseases are now termed, are characterized by atypical deposits of proteins, often due to misfolding. Associated with these deposits are dysfunctional mitochondria, oxidative stress, disrupted axonal transport, inflammation, and apoptotic cell death. If this occurs in motor neurons, as in ALS, ataxia precedes death with little or no change in cognition. On the other hand, if the deposits are found in cortical neurons, as in Alzheimer’s disease, the outcome is dementia and motor function remains largely intact. Each disease is selective for particular types of neurons and brain regions. Although research has elucidated much of the molecular biology involved in these diseases, their initiating causes remain largely unknown. Most of our current understanding originated with the identification of gene mutations that cause rare familial forms of these diseases. As a result, numerous strains of transgenic animals have been developed to study neurodegenerative disease phenomena and were central to the studies presented in this body of work. Novel routes of drug and gene delivery are described here as well as characterization of the mouse models studied. In particular, this work demonstrates that the blood brain barrier is disrupted in ALS followed by the formation of autorosettes in ALS mice. In various Alzheimer’s disease mouse models, it was demonstrated that the acute phase reactant alpha-1-antichymotrypsin (ACT) not only interacts with amyloid plaques, but also induces tau phosphorylation in vivo; tying together these disease hallmarks. It was also shown that small fragments of Aβ (1-11) could disrupt the formation of mature amyloid plaques in these mice. Lastly, it was demonstrated that mature plaques could also be decreased by intracranial delivery of granulocyte-macrophage stimulating factor (GM-CSF). My dissertation research goal was to understand and develop these treatment strategies based on protein disaggregation, neuroprotection, and inflammation, meanwhile developing novel methods for targeted delivery of molecules into the CNS of mice.

A retrospective review was made of the case records, angiograms and computed tomography (CT) relating to a total of 263 patients with subarachnoid haemorrhage (SAH) due to ruptured berry aneurysms who were admitted to the Department of Neurosurgery, Wentworth Hospital during the four years 1983-1986. The part of the thesis concerning vasospasm (VS) includes two independent studies on calcium blocker Nimodipine (NO) in the prevention and treatment of VS done by the author. The aim of the thesis is to analyse the management problems of aneurysmal SAH, and investigate factors influencing outcome in order to establish the best possible management policy. The results are discussed and related to the recent data from literature. The main factors influencing outcome were: clinical condition of the patient, the timing of admission and surgery, hypertension and hyperglycaemia on admission, presence of vasospasm and related CT appearance of a thick layer of blood or clot in subarachnoid haemorrhage (CT-Fisher 3). The systemic administration of the calcium blocker nimodipine did not reverse or prevent delayed vasospasm and caused serious adverse effects i.e. hypotension and hyperglycaemia. The results of the thesis suggest a change in management policy and timing of surgery should depend. on clinical condition of the patient on admission (Hunt & Hess grading)(HH I/II grade (HH as possible regardless of timing of admission and results of radiological investigations (CT, angiography). Early surgery (1-3 days) should be the aim of the effort including referral, transport and hospital organisation. III grade (HH surgery should be performed soon after day 10 post-SAH. Particular attention should be paid to the careful preparation and selection of patients for angiography. IV/V grade (HH in specialised units as s000n as possible, preferably neurological or neurosurgical wards, and operated on as soon as their grade improves or, in selected (by surgeon, radiologist and anaesthetist) cases by delayed surgery ( after day 10 post-SAH). / Thesis (M.Med.)-University of Natal, Durban, 1988.

Many disorders are associated with regional brain volumes. The analysis of these volumes from MR images often requires sequential processing steps such as localization and delineation. It is common to perform volumetric normalization using intracranial volume (ICV, the total volume inside the cranial cavity) when comparing regional brain volumes, since head size varies considerably between individuals. Multiple methods for estimating ICV and procedures for volume normalization exist. A method for interhemispheric surface localization and extraction, using both intensity and symmetry information and without time consuming pre-processing, was developed. Evaluations of hemisphere division accuracy as well as suitability as a pre-processing step for interhemispheric structure localization were made. The performance of the method was comparable to that of methods focusing on either of these tasks, making it suited for use in many different studies. Automated ICV estimations from Freesurfer and SPM were evaluated using 399 reference segmentations. Both methods overestimated ICV and estimations using Freesurfer contained errors associated with skull-size. Estimations from SPM contained errors associated with gender and atrophy. An experiment showed that the choice of method can affect study results. Manual ICV estimation is very time consuming, but can be performed using only a subset of voxels in an image to increase speed and decrease manual labor. Segmenting every nth slice and stereology were evaluated in terms of required manual labor and estimation error, using the previously created ICV references. An illustration showing how much manual labor is required for a given estimation error using different combinations of n and stereology grid spacing was presented. Finally, different procedures for ICV normalization of regional brain volumes when investigating gender related volume differences were theoretically explained and evaluated using both simulated and real data. Resulting volume differences were seen to depend on the procedure used. A suggested workflow for procedure selection was presented. Methodological contributions that can aid the analysis of the human brain have been presented. The performed studies also contribute to the understanding of important methodological considerations for regional brain volume analysis.

Mémoire (M.Sc.)-- Université du Québec à Chicoutimi, 1992. / Ce mémoire a été réalisé à l'UQAC dans le cadre du programme de maîtrise en médecine expérimentale (volet génétique) extensionné de l'Université Laval à l'UQAC. CaQCU Bibliogr.: f. 71-75. Document électronique également accessible en format PDF. CaQCU

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves 95-109).

Patients with a brain injury must overcome a central neurological insult and a systematic metabolic response. The systematic response includes hypermetabolism, hypercatabolism, altered vascular permeability, increased hormone and cytokine release, altered gastric emptying, altered mineral metabolism and altered immune status. This response may initiate mechanisms which lead to secondary brain injury and may adversely affect the function of other organs. Last two decades have improved our knowledge of pathophysiology in patients with primary and secondary brain injury including traumatic contusions. In a moment of injury, primary brain injury which is traumatic contusion can not be therapeutically prevented it can only have a preventive effect. Secondary brain injury can be therapeutically affected although both types of injuries have common pathophysiological signs of disturbed metabolism on cells and subcellular level. Research methods based on molecular biology opens a new zone of research reaction of central neurological system for trauma or ischemia with effort to get involved immediately at the beginning of developing adverse pathophysiological cascade leading to a death of neurotic cell. The brain contusion is a primary centre of brain injury with anatomic changes which can be graphically proved. In...

The more we know about the circulation of CSF through ventricle system, brain parenchyma, subarachnoideal space and the development of intracranial pressure (ICP), the more we understand different pathologies and pathological processes of the central cervous system. The knowledge about the basic hydrodynamic charecteristics of craniospinal system is a key factor for understanding a wide range of pathological situations affecting CNS, these are for example intracranial hypertension, normal pressure hydrocephalus and syringomyelia. In the presented paper, we are presenting a newly developed measuring system Visionbrain that enables us to gain the biological data and consequently to analyse them. At the same time, the results of such measurements were used to specify the compertmental model of CSF circulation. The model devides craniospinal system into five divisions - two intracranial and three spinal. Such model is the third generation of this model and, compared to the older version, it includes two intracranial veins. Thanks to this stucture, the model enables us simultaneous modeling of heart and respiratory pulsations of CSF. Compared to the other published models, it also includes defined structure of spinal part. The model is derived using laws of conservation and it encompasses pressure...

Submitted by JOÃO AUGUSTO LEONEL DE SOUZA null (desouza.ja@gmail.com) on 2016-09-09T16:38:02Z No. of bitstreams: 1 Dissertação final.pdf: 1556586 bytes, checksum: e53dadd03ff83fdae3ae4b4e49d912ac (MD5) / Approved for entry into archive by Juliano Benedito Ferreira (julianoferreira@reitoria.unesp.br) on 2016-09-13T13:15:00Z (GMT) No. of bitstreams: 1 souza_jal_me_jabo.pdf: 1556586 bytes, checksum: e53dadd03ff83fdae3ae4b4e49d912ac (MD5) / Made available in DSpace on 2016-09-13T13:15:00Z (GMT). No. of bitstreams: 1 souza_jal_me_jabo.pdf: 1556586 bytes, checksum: e53dadd03ff83fdae3ae4b4e49d912ac (MD5) Previous issue date: 2016-05-30 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A mielografia é muito realizada na prática veterinária, entretanto, existem importantes efeitos adversos associados a ela. O objetivo da presente pesquisa foi avaliar os possíveis efeitos sobre a pressão subaracnoide, parâmetros cardiorrespiratórios (TC, FR, FC, PAS, PAD, PAM, EtCO2, SpO2, InspISO e FeISO) e do índice de pressão-volume (PVI) em ovelhas hígidas submetidas à mielografia lombar. Foram utilizados 8 ovinos fêmeas sadios, os quais foram pré-medicados com Midazolan (0,5 mg/Kg), indução anestésica com Propofol (3-6 mg/Kg) e manutenção anestésica com Isoflurano. Primeiramente, os animais foram submetidos à punção da cisterna magna para monitoramento da pressão subaracnoide (Sap). Ato contínuo, foi realizado a mielografia lombar por meio da aplicação de Iohexol (300 mg/mL, taxa de 4,1 mL/min e dose de 0,4 mL/Kg). Os momentos estudados foram: imediatamente após a estabilização anestésica (M0), durante a punção lombar (M1), dois, quatro e seis minutos após a aplicação do contraste (M2, M3 e M4, respectivamente). A Sap foi colhida imediatamente após à punção atlanto-occipital (Sap0), o maior valor durante a aplicação do meio de contraste (Sapmax), dois, quatro e seis minutos após a aplicação do meio de contraste (Sap2, Sap3 e Sap4, respectivamente). Constataram-se diferenças significativas a 5% de confiança entre os momentos as variáveis: TC, PAS, PAD, PAM, InspISO, FeISO Sap e PPC pelo teste de Tukey. Com a correlação de Pearson TC/FR, FC/SpO2, FC/FR, FR/PAS, FR/PAD, FR/PAM, FR/PPC, Sap/PAS, PAD/Sap, PAM/Sap, EtCO2/SPO2, EtCO2/InsplSO, PAD/PAS, PAS/PAM, PAM/PAD, FelSO/InsplSO e Sap/PPC. Com base nos resultados concluímos que os valores de PVI, para a espécie ovina, com a metodologia empregada foi de 17,91 mL. Durante a realização da mielografia lombar ocorre aumento significativo da Sap (média de 101,87 mmHg), provocando grave redução da PPC. / The myelography is very accomplished in veterinary practice, however there are significant adverse effects associated with it. The aim of this research was to evaluate the possible effects of subarachnoid pressure, cardiorespiratory parameters (TC, FR, FC, PAS, PAD, PAM, EtCO2, SpO2, InspISO and FeISO) and pressure-volume index (PVI) in sheep otherwise healthy undergoing lumbar myelography. 8 healthy female sheep were used, which were pre-medicated with midazolam (0.5 mg / kg) anesthetic induction with propofol (3-6 mg / kg) and anesthesia maintained with isoflurane. First, the animals were submitted to the puncture of the cisterna magna and pressure monitoring. Subsequently, the lumbar myelography was performed by application of iohexol (300 mg / ml at rate 4.1 ml / min and a dose of 0.4 ml / kg). The time points studied were: immediately after anesthetic stabilization (M0) during a lumbar puncture (M1), two, four and six minutes after application of contrast (M2, M3 and M4, respectively). Subarachnoid pressure (Sap) was taken immediately after the atlanto-occipital punch (Sap0), the largest value during application of the contrast medium (Sapmax), two, four and six minutes after application of the contrast medium (SAP2, Sap3 and Sap4, respectively). They found significant differences at 5% confidence between times the variables TC, PAS, PAD, PAM, InspISO, FeISO Sap and PPC by Tukey test. With the Pearson correlation TC/FR, FC/SpO2, FC/FR, FR/PAS, FR/PAD, FR/PAM, FR/PPC, Sap/PAS, PAD/Sap, PAM/Sap, EtCO2/SPO2, EtCO2/InsplSO, PAD/PAS, PAS/PAM, PAM/PAD, FelSO/InsplSO and Sap/PPC Based on the results we conclude that the PVI values for the sheep, the methodology employed was 17.91 mL, close to normal values for adults of the human species. While performing the lumbar myelography is significant increase in Sap (average of 101.87 mmHg), causing severe reduction in PPC.

Introdução: A evolução clínica da trombose venosa cerebral (TVC) pode variar desde a recuperação completa ao óbito. Séries européias e um estudo multicêntrico identificaram alguns fatores indicativos de prognóstico da TVC, dado importante na decisão da melhor terapêutica para os pacientes. Este estudo busca identificar, a partir do seguimento prospectivo de cento e onze pacientes com TVC, os fatores prognósticos envolvidos na evolução clínica durante o período de 2 anos. Pacientes Métodos: Foram acompanhados prospectivamente 111 pacientes com diagnóstico de TVC desde a fase aguda do diagnóstico, confirmado por meio de RM de encéfalo e/ou angiografia cerebral (ARM, ATC ou angiografia digital). Obtidos dados do quadro clínico e seguimento por um protocolo clínico. 96% dos pacientes foram anticoagulados na fase aguda com heparina e seguida de anticoagulação com warfarina. Submetidos a investigação para os fatores predisponentes para TVC. A evolução clínica foi quantificada por meio da escala modificada de Rankin (EMR) após 3, 6, 12 e 24 meses, definindo os pacientes de bom prognóstico EMR 1, e mau prognóstico EMR 2. Comparamos dados clínicos da fase aguda e resultados encontrados nos exames de imagem e laboratoriais como possíveis fatores prognósticos, através da análise univariada pelo teste 2 e os fatores de significância estatística (p<0,1), foram analisados com regressão logística ajustada e cálculo da razão de chances (RC), (intervalo de confiança IC=95%). Resultados: A média da idade dos pacientes foi de 35 anos, 72% mulheres, 40% afro-brasileiros. As principais manifestações clínicas foram: cefaléia 97%, déficit focal 47%, crise epiléptica 40%, alteração da consciência 28%, síndrome de HIC (SHIC) isolada 40%. Quanto aos fatores predisponentes; 75% das mulheres usavam anticoncepcional, 31% dos pacientes apresentavam trombofilia hereditária, 13% SAAF, 6% eram portadores de vasculites, 25% outros estados pro trombóticos, 7 % apresentavam fatores locais (infecciosos ou MAV); e 5% das mulheres estavam no puerpério ou gestação. Os dados de neuroimagem revelaram que 42% apresentaram trombose em mais de um sistema venoso, 33% tiveram infartos hemorrágicos e 18% infartos venosos isquêmicos, e 20% dos pacientes apresentaram trombose de veias e seios profundos. Após 24 meses 18 pacientes (17%) apresentaram EMR 2 e os fatores determinantes de pior prognóstico foram: a etnia afro-brasileira p=0,001; RC= 11,37 (95% IC 2.81- 46,08), alteração do nível de consciência p=0,007; RC=4.56 (95% IC 1.61-19.45), sexo masculino p=0,049 RC=3.55 (95% IC 1.00-12.55) e idade acima de 32 anos p=0,05 RC = 3.95 (95% IC 0,97-15.20). A presença isolada de ACO como fator predisponente está associado ao melhor prognóstico p = 0,016; RC=5,17(95% IC 1.37-19.57) e após 24 meses a mortalidade foi de 4,5%. Conclusão: A análise deste trabalho evidencia que a maioria dos pacientes portadores de TVC (83%) apresenta uma evolução benigna com o tratamento, estando após 24 meses assintomáticos ou com sintomas mínimos, e a presença de ACO como fator predisponente isolado a TVC está relacionado ao melhor prognóstico. Os pacientes com pior evolução clínica têm a raça afro-brasileira, a alteração do nível de consciência, sexo masculino e idade acima de 32 anos como fatores determinantes de pior prognóstico em vinte e quatro meses. A identificação destes fatores é importante por direcionar um melhor tratamento na fase aguda da TVC para casos selecionados / Introduction: The cerebral venous thrombosis (CVT) clinical evolution is quite variable from complete recovery to death. Some European series and a multicenter study had identified prognostic factors related to CVT prognosis. The identification of these factors is important for the best therapeutic decision to patients. This study aims to identify the prognostic factors enrolled in clinical evolution of 111 patients with CVT in a prospective outcome clinical trial during two years. Subjects and Methods: One hundred and eleven patients were prospective followed with the diagnosis of CVT since acute phase diagnosis, confirmed by brain MRI and/or brain angiography (MRA , CTA or digital angiography). Information about clinical features and follow-up were filled on a clinical form. 96% of the patients were anticoagulated on heparin followed by warfarin treatment. The patients were investigated to predisposing factors to CVT. The clinical evaluation was accessed by the modified Rakin scale (mRs) after 3, 6, 12 and 24 months, considering patients with good outcome when mRs 2. The acute phase clinical features, laboratory and imaging data were compared as possible prognosis factors beyond univariate 2 test and the factors with statistical significance (p<0,1) and then analyzed by logistic regression adjusted and Odds Ratio values (confidence interval CI=95%). Results: The mean age of the patients was 35 years, 72% were women, and 40% were African Brazilian. The main clinical features observed were: headache 97%, focal sign 47%, epileptic seizure 40%, isolated ICH syndrome 40% and altered mental status 28%. All the patients were investigated to predisposing factors; 75% of the women were on oral contraceptive, 31% of the patients presented hereditary thrombophilia, 13 % antiphospholipid syndrome, 6% presented vasculitis, 25% other protrhrombotic state, 7% presented some local feature (arterialvenous malformation or infection) and 5% of women were pregnant or on puerperium. The neuroimaging data showed that 42% of the patients presented thrombosis in more than one venous system, 33% had hemorrhage infarcts, 18% ischemic venous infarcts and 20% of the patients had thrombosis of the deep venous system. After two years 17% had a mRs > 2 and the features enrolled on poor prognosis were: African Brazilian patients p=0,001; OR= 11,37 (95% IC 2.81- 46,08), altered mental status p=0,007; OR=4.56 (95% IC 1.61-19.45), male gender p=0,049 OR=3.55 (95% IC 1.00-12.55) and age over 32 years p=0,05 OR = 3.95 (95% IC 0,97- 15.20). The presence of oral contraceptives as isolated predisposing factor was related to good outcome CVT p=0,016; OR=5,17(95% IC 1.37-19.57) and after two years the mortality rate was 4,5%. Conclusion: This study data show that most patients with the diagnosis of CVT (83%) has a good outcome with the treatment, after two years follow up they have no symptoms or minimal deficits, and the presence of oral contraceptives as isolated predisposing factor was related to better outcome CVT. The patients with poor prognosis have the African Brazilian ethnic group, altered mental status, male gender and age over 32 years as the factors enrolled on bad clinical evolution in two years. The identification of these factors can have future value on treatment better choice on acute phase to selected CVT patients