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Indiana University-Purdue University Indianapolis (IUPUI) / Pediatric hydrocephalus is a complex neurological condition associated with a pathological accumulation of cerebrospinal fluid (CSF), typically within the brain ventricular system. Pediatric hydrocephalus can be primary (due to genetic abnormalities or idiopathic causes), or secondary to injuries such as hemorrhage, trauma, or infection. The current permanent treatment paradigms for pediatric hydrocephalus are exclusively surgical and include the diversion of CSF via shunt or ventriculostomy. These surgical interventions are wrought with failures, burdening both the United States healthcare system and patients with repeat neurosurgical procedures. Thus, the development of nonsurgical interventions to treat hydrocephalus represents a clinically unmet need. To study hydrocephalus, we use a genetic rat model of primary neonatal hydrocephalus, the Tmem67P394L mutant. In several proof-of-concept studies, we identify antagonism of the transient receptor potential vanilloid 4 (TRPV4) channel and associated upstream regulatory kinase, serum-andglucocorticoid-induced kinase 1 (SGK1) as therapeutics for the treatment of hydrocephalus. Using in vitro models of the choroid plexus epithelium, the tissue which produces CSF, we show compelling proof-of-mechanism for TRPV4 antagonism and SGK1 inhibition at preventing CSF production. Therefore, the studies in this dissertation provide substantive evidence on the role of TRPV4 in the choroid plexus in health and disease.

It was generally accepted that the rate of formation of cerebrospinal °uid (CSF) is independent of intraventricular pressure [26], until A. Sahar and a host of other scientists challenged this belief. A. Sahar substantiated his belief that the rate of (CSF) formation actually depends on intraventricular pressure, see A. Sahar, 1971 [26]. In this work we show that CSF formation depends on some other factors, including the intraventricular pressure. For the purpose of this study, we used the capillary blood °ow model proposed by K.Boryczko et. al., [5] in which blood °ow in the microvessels was modeled as a two-phase °ow; the solid and the liquid volume phase. CSF is formed from the blood plasma [23] which we assume to be in the liquid volume phase. CSF is a Newtonian °uid [2, 23]. The principles and methods of e®ective area" developed by N. Sauer and R. Maritz [21] for studying the penetration of °uid into permeable walls was used to investigate the ¯ltrate momentum °ux from the intracranial capillary wall through the pia mater and epithelial layer of the choroid plexus into the subarachnoid space. We coupled the dynamic boundary equation with the Navier-Stoke's constitutive equation for incompressible °uid, representing the °uid °ow in the liquid volume phase in the capillary to arrive at our model. / Mathematical sciences / M.Sc.

This critical synopsis of prior work by Clive Beggs is submitted in support of a PhD by published work. The work focuses on venous and cerebrospinal fluid (CSF) anomalies associated with multiple sclerosis (MS) and other neurological diseases. MS is characterized by focal inflammatory lesions, which are often venocentric. Recently a vascular syndrome, chronic cerebrospinal venous insufficiency (CCSVI) has been linked with MS. This syndrome, which is characterized by constricted cerebral venous outflow, has become mired in controversy, with various studies producing conflicting findings, with the result that the science associated with CCSVI has become obscured. Clive Beggs work seeks to bring clarity to the debate surrounding CCSVI by characterizing physiological changes associated with constricted cerebral venous outflow. The work submitted here involves collaborative studies with Robert Zivadinov (University of Buffalo), Paolo Zamboni (University of Ferrara), and Chih- Ping Chung (National Yang Ming University of Medicine). The key findings of these studies are: (i) MS patients, diagnosed with CCSVI, exhibit greatly increased hydraulic resistance of the cerebral venous drainage system; (ii) MS patients experience loss of the small cerebral veins; (iii) MS patients exhibit reduced CSF bulk flow, consistent with mild venous hypertension; (iv) MS patients exhibit increased CSF pulsatility in the Aqueduct of Sylvius, which appears to be linked with mild venous hypertension associated with CCSVI; and (v) jugular venous reflux is associated with white matter and parenchymal volumetric changes in Alzheimer’s patients. Collectively, these findings suggest that extracranial venous anomalies are associated with changes in the intracranial physiology.

It was generally accepted that the rate of formation of cerebrospinal °uid (CSF) is independent of intraventricular pressure [26], until A. Sahar and a host of other scientists challenged this belief. A. Sahar substantiated his belief that the rate of (CSF) formation actually depends on intraventricular pressure, see A. Sahar, 1971 [26]. In this work we show that CSF formation depends on some other factors, including the intraventricular pressure. For the purpose of this study, we used the capillary blood °ow model proposed by K.Boryczko et. al., [5] in which blood °ow in the microvessels was modeled as a two-phase °ow; the solid and the liquid volume phase. CSF is formed from the blood plasma [23] which we assume to be in the liquid volume phase. CSF is a Newtonian °uid [2, 23]. The principles and methods of e®ective area" developed by N. Sauer and R. Maritz [21] for studying the penetration of °uid into permeable walls was used to investigate the ¯ltrate momentum °ux from the intracranial capillary wall through the pia mater and epithelial layer of the choroid plexus into the subarachnoid space. We coupled the dynamic boundary equation with the Navier-Stoke's constitutive equation for incompressible °uid, representing the °uid °ow in the liquid volume phase in the capillary to arrive at our model. / Mathematical sciences / M.Sc.

This critical synopsis of prior work by Clive Beggs is submitted in support of a PhD by published work. The work focuses on venous and cerebrospinal fluid (CSF) anomalies associated with multiple sclerosis (MS) and other neurological diseases. MS is characterized by focal inflammatory lesions, which are often venocentric. Recently a vascular syndrome, chronic cerebrospinal venous insufficiency (CCSVI) has been linked with MS. This syndrome, which is characterized by constricted cerebral venous outflow, has become mired in controversy, with various studies producing conflicting findings, with the result that the science associated with CCSVI has become obscured. Clive Beggs work seeks to bring clarity to the debate surrounding CCSVI by characterizing physiological changes associated with constricted cerebral venous outflow. The work submitted here involves collaborative studies with Robert Zivadinov (University of Buffalo), Paolo Zamboni (University of Ferrara), and Chih- Ping Chung (National Yang Ming University of Medicine). The key findings of these studies are: (i) MS patients, diagnosed with CCSVI, exhibit greatly increased hydraulic resistance of the cerebral venous drainage system; (ii) MS patients experience loss of the small cerebral veins; (iii) MS patients exhibit reduced CSF bulk flow, consistent with mild venous hypertension; (iv) MS patients exhibit increased CSF pulsatility in the Aqueduct of Sylvius, which appears to be linked with mild venous hypertension associated with CCSVI; and (v) jugular venous reflux is associated with white matter and parenchymal volumetric changes in Alzheimer’s patients. Collectively, these findings suggest that extracranial venous anomalies are associated with changes in the intracranial physiology.

Application of Taenia saginata metacestodes as alternative antigen is an important alternative for neurocysticercosis (NC) serodiagnosis. The cross reaction with Echinococcus granulosus infection occurred in homologous and heterologous antigens, and could be avoid with different purified methods. This study analyzed antigen fractions obtained from crude saline extract of T. saginata metacestodes purified by affinity chromatography with the lectin jacalin (unbound and bound fraction), concanavalin A (unbound and bound fraction), concanavalin A using jacalina unbound fraction (unbound and bound fraction) and N-acetil (unbound and bound fraction). The fraction were tested for the detection of IgG antibodies by enzyme linked immunosorbent assay (ELISA) and immunoblot for the laboratory diagnosis of human NC. The application of T. saginata metacestodes as an alternative antigen for use in ELISA and WB tests compared with the metacestodes antigen of Taenia solium in CFS samples was also analyzed. Serum samples were obtained from 142 individuals: 40 were diagnosed with NC, 62 presented Taenia sp. and other parasitic diseases and 40 were apparently healthy individuals. The CSF samples were obtained from 35 patients with definitive neurocysticercosis; and 35 patients with other neurological disorder. Among the fractions, unbound concanavalin A demonstrated statically higher sensitivity and specificity by ELISA (90% and 93.1 %, respectively). By Immunoblot, the concanavalin unbound showed 100% of sensitivity and specificity, where only serum samples from patients with NC recognized the protein of 64-68 kDa, so this antigen fraction may be used as specific antigen for diagnosis of NC. The sensitivity and specificity of ELISA using antigen obtained from T. solium applied to CSF samples results of 100%. When the tests were conducted using T. saginata metacestodes, results were 100% and 94.3%, respectively. The 47-52, 64-68 and 70 kDa antigens were recognized by only CSF samples from patients with NC. The results indicated that T. saginata metacestodes can be used as alternative antigen for NC diagnosis using LCR samples. / A utilização de metacestódeos de Taenia saginata como antígeno alternativo constitui uma importante ferramenta no sorodiagnóstico da neurocisticercose humana (NC). A reatividade cruzada com indivíduos infectados por Echinococcus granulosus é comum em antígenos homólogos e heterólogos, podendo ser evitada com diferentes métodos de purificação. O presente estudo analisou as diferentes frações antigênicas obtidas, a partir do extrato salino total de metacestódeos de T. saginata, por cromatografia de afinidade em coluna de Jacalina (fração ligante e não ligante), de Concanavalina A (fração ligante e não ligante), de Concanavalina A utilizando a fração não ligante de Jacalina (fração ligante e não ligante) e Coluna de N-acetil (fração ligante e não ligante). As frações foram avaliadas quanto a detecção de anticorpos IgG anti-metacestódeos de Taenia solium nos testes ELISA e Immunoblotting. Foi avaliada a utilização do extrato salino total de metacestódeos de T. saginata como antígeno alternativo nos testes ELISA e Immunoblotting para detecção de anticorpos IgG no LCR. Foram obtidas 142 amostras de soro, sendo 40 de pacientes com diagnóstico definitivo de NC, 62 de indivíduos infectados por Taenia sp e por outros parasitos e 40 de indivíduos saudáveis. Foram coletadas 70 amostras de LCR, sendo 35 de pacientes com diagnóstico definitivo de NC e 35 de indivíduos com outras manifestações neurológicas. Entre todas as frações analisadas, a fração não ligante de Concanavalina A demonstrou maior sensibilidade e especificidade pelo teste ELISA em amostras de soro (90% e 93,1%, respectivamente). Pelo Immunoblotting esta mesma fração demonstrou 100% de sensibilidade e especificidade, sendo que apenas pacientes com NC reconheceram a banda especifica de 64-68 kDa, indicando que esta fração antigênica pode se usada como antígeno especifico no sorodiagnóstico da NC humana. A sensibilidade e especificidade do teste ELISA utilizando o antígeno homólogo no LCR humano foi de 100%. Quando este teste foi conduzido com o antígeno heterólogo obteve-se 100% de sensibilidade e 94,3% de especificidade. Na reação de Immunoblotting as bandas antigênicas de 47-52, 64-68 e 70 kDa foram reconhecidas exclusivamente no LCR de pacientes com NC. Os resultados conferem ao extrato salino de T. saginata sensibilidade e especificidade para ser utilizado como antígeno alternativo para o diagnostico da NC no LCR. / Doutor em Imunologia e Parasitologia Aplicadas

O Câncer colorretal (CCR) é um problema de saúde importante devido a sua incidência e mortalidade elevadas. O rastreamento e o diagnóstico precoce são a principal estratégia para diminuir a mortalidade pelo CCR. A colonoscopia convencional (CC), constitui o melhor método para o diagnóstico precoce do CCR e para o diagnóstico e tratamento das lesões precurssoras. Entretanto a CC apresenta taxas de falha de detecção não desprezíveis. A colonoscopia com magnificação de imagem (CM), vem sendo utilizada com o intuito de melhorar a performance da CC. A sua principal vantagem é a possibilidade de diferenciar lesões neoplásicas de não-neoplásicas, de maneira que apenas lesões neoplásicas seriam retiradas, diminuindo custos e riscos relacionados ao rastreamento por colonoscopia. O objetivo deste estudo é determinar a acurácia da CM para o diagnóstico diferencial entre lesões neoplásicas e não-neoplásicas do intestino grosso por meio da comparação entre o diagnóstico endoscópico e o fornecido pelo exame histopatológico convencional. Entre abril de 2002 e outubro de 2003, cento e vinte pacientes foram incluídos no estudo, tendo-se encontrado 200 lesões. Todas as lesões foram classificadas endoscopicamente através da CM com alta magnificação (até 200X), associada a cromoscopia com índigo carmim, de acordo com a classificação proposta por Kudo, e em seguida excisadas ou biopsiadas para estudo histopatológico. A acurácia da determinação do diagnóstico diferencial endoscópico em relação à histopatologia entre lesões neoplásicas e não-neoplásicas foi de 78,5%. A diferença da CM em relação ao exame histopatológico foi estatisticamente significativa (p<0,0001). Conclui-se que, no atual estágio de desenvolvimento, a CM, pela sua acurácia, não permite excluir o exame histopatológico para o diagnóstico diferencial entre as lesões neoplásicas e não-neoplásicas do intestino grosso. / Bacterial meningitis in the neonatal period is a severe disease, associated to elevated mortality and sequelae in around 12 to 29% of the survivors. Newborns whose birth weight is < 2,500g have a 3-fold increase in the risk of acquiring meningitis when compared to those whose weight is > or = 2,500; among those with very low birth weight (< 1,500g), the risk increases 17-fold. Objectives: General: to describe the clinical picture and the complications of bacterial meningitis in two groups of newborns, considered according to birth weight (< 2,500g or > or = 2,500g). Specific: to describe and compare the etiological agents, the frequency of neurological signs and symptoms and complications, mortality rate and duration of treatment in both groups. Methods: Observational study of 87 newborns with bacterial meningitis, admitted at the Neonatal Intensive Care Unit (NICU) of Instituto da Criança of Hospital das Clínicas of the University of São Paulo School of Medicine, during an 11-year period (January 1994 to December 2004). The data were obtained through the analysis of hospital files. Statistical analysis was carried out with Fisher\'s exact test and the non-parametric Mann Whitney test. Results: Bacteria were identified in the cerebrospinal fluid (CSF) of 39% of the patients, with 50% of them being Gram-positive and 50%, Gram-negative. Most neonates presented unspecific signs and symptoms: fever (63.2%), irritability (31%), and lethargy (26.4%). The neurological findings occurred in 35.3% of the cases. Complications occurred in 48.2% of the neonates, and were mainly seizures (23%), intracranial hemorrhage (14.9%) and hydrocephalus (13.8%) with a mortality rate of 11.5%. At the comparison between clinical evolution and birth weight, associations between weight > or = 2,500g and seizures (p=0.047), weight > or = 2,500g and concave fontanel (p=0.019), bacteria in the CSF and complications (p=0.008) and bacteria in the CSF and death (p=0.043) were observed. Conclusions: The etiological agents most often identified in the CSF were enterobacteria (41%), followed by B Streptococcus (17.5%), non-B Streptococcus (17.5%), Staphylococcus aureus (11.7%), Neisseria meningitidis (8.8%) and Enterococcus faecalis (3.0%), with no statistical difference between the type of bacteria and birth weight. The predominant signs and symptoms were unspecific, with neurological findings in 35% of the cases. The higher frequency of neurological signs and symptoms in newborns with birth weight > or = 2,500g suggest a higher degree of central nervous system maturity in these infants. Although the mortality was lower than that observed in previous studies at the same Service, the frequency of complications was high, regardless of birth weight. The presence of bacteria in the CSF was associated to a higher frequency of seizures and mortality. The need for prolonged treatment in newborns with low birth weight suggests higher disease severity in this group of neonates.

O Câncer colorretal (CCR) é um problema de saúde importante devido a sua incidência e mortalidade elevadas. O rastreamento e o diagnóstico precoce são a principal estratégia para diminuir a mortalidade pelo CCR. A colonoscopia convencional (CC), constitui o melhor método para o diagnóstico precoce do CCR e para o diagnóstico e tratamento das lesões precurssoras. Entretanto a CC apresenta taxas de falha de detecção não desprezíveis. A colonoscopia com magnificação de imagem (CM), vem sendo utilizada com o intuito de melhorar a performance da CC. A sua principal vantagem é a possibilidade de diferenciar lesões neoplásicas de não-neoplásicas, de maneira que apenas lesões neoplásicas seriam retiradas, diminuindo custos e riscos relacionados ao rastreamento por colonoscopia. O objetivo deste estudo é determinar a acurácia da CM para o diagnóstico diferencial entre lesões neoplásicas e não-neoplásicas do intestino grosso por meio da comparação entre o diagnóstico endoscópico e o fornecido pelo exame histopatológico convencional. Entre abril de 2002 e outubro de 2003, cento e vinte pacientes foram incluídos no estudo, tendo-se encontrado 200 lesões. Todas as lesões foram classificadas endoscopicamente através da CM com alta magnificação (até 200X), associada a cromoscopia com índigo carmim, de acordo com a classificação proposta por Kudo, e em seguida excisadas ou biopsiadas para estudo histopatológico. A acurácia da determinação do diagnóstico diferencial endoscópico em relação à histopatologia entre lesões neoplásicas e não-neoplásicas foi de 78,5%. A diferença da CM em relação ao exame histopatológico foi estatisticamente significativa (p<0,0001). Conclui-se que, no atual estágio de desenvolvimento, a CM, pela sua acurácia, não permite excluir o exame histopatológico para o diagnóstico diferencial entre as lesões neoplásicas e não-neoplásicas do intestino grosso. / Bacterial meningitis in the neonatal period is a severe disease, associated to elevated mortality and sequelae in around 12 to 29% of the survivors. Newborns whose birth weight is < 2,500g have a 3-fold increase in the risk of acquiring meningitis when compared to those whose weight is > or = 2,500; among those with very low birth weight (< 1,500g), the risk increases 17-fold. Objectives: General: to describe the clinical picture and the complications of bacterial meningitis in two groups of newborns, considered according to birth weight (< 2,500g or > or = 2,500g). Specific: to describe and compare the etiological agents, the frequency of neurological signs and symptoms and complications, mortality rate and duration of treatment in both groups. Methods: Observational study of 87 newborns with bacterial meningitis, admitted at the Neonatal Intensive Care Unit (NICU) of Instituto da Criança of Hospital das Clínicas of the University of São Paulo School of Medicine, during an 11-year period (January 1994 to December 2004). The data were obtained through the analysis of hospital files. Statistical analysis was carried out with Fisher\'s exact test and the non-parametric Mann Whitney test. Results: Bacteria were identified in the cerebrospinal fluid (CSF) of 39% of the patients, with 50% of them being Gram-positive and 50%, Gram-negative. Most neonates presented unspecific signs and symptoms: fever (63.2%), irritability (31%), and lethargy (26.4%). The neurological findings occurred in 35.3% of the cases. Complications occurred in 48.2% of the neonates, and were mainly seizures (23%), intracranial hemorrhage (14.9%) and hydrocephalus (13.8%) with a mortality rate of 11.5%. At the comparison between clinical evolution and birth weight, associations between weight > or = 2,500g and seizures (p=0.047), weight > or = 2,500g and concave fontanel (p=0.019), bacteria in the CSF and complications (p=0.008) and bacteria in the CSF and death (p=0.043) were observed. Conclusions: The etiological agents most often identified in the CSF were enterobacteria (41%), followed by B Streptococcus (17.5%), non-B Streptococcus (17.5%), Staphylococcus aureus (11.7%), Neisseria meningitidis (8.8%) and Enterococcus faecalis (3.0%), with no statistical difference between the type of bacteria and birth weight. The predominant signs and symptoms were unspecific, with neurological findings in 35% of the cases. The higher frequency of neurological signs and symptoms in newborns with birth weight > or = 2,500g suggest a higher degree of central nervous system maturity in these infants. Although the mortality was lower than that observed in previous studies at the same Service, the frequency of complications was high, regardless of birth weight. The presence of bacteria in the CSF was associated to a higher frequency of seizures and mortality. The need for prolonged treatment in newborns with low birth weight suggests higher disease severity in this group of neonates.