Thesis (doctoral)--Rijksuniversiteit te Utrecht.

Thesis (M.S.)--Brigham Young University. Dept. of Electrical and Computer Engineering, 2006. / Includes bibliographical references (p. 79-81).

A leading cause of male infertility is genetic variation in genes required for sperm formation and/or function. There is evidence to suggest PACRG is involved in mammalian spermatogenesis. Specifically, the loss of Pacrg function causes a spermatogenic defect and male infertility in mice. To investigate if PACRG plays a similar role in human spermatogenesis, the localisation of PACRG was determined in human testis. Using an immunohistochemical approach, this study demonstrated that PACRG is localised to the human sperm flagella. To investigate a potential role for PACRG in human male infertility, sequence analysis and an association study were performed. Sequence analysis did not identify any pathological alterations. However, 1 of 3 variants identified (rs9347683) was shown to be significantly associated with male infertility by association analysis (p=0.009, Odds Ratio=1.6, n=766). / A high degree of structural and functional conservation exists between different types of motile cilia/flagella. Evidence from studies in C.reinhardtii and T.brucei indicate Pacrg is necessary for axoneme formation and microtubule stability. To test the role of the mammalian homologue, this study characterised the Pacrg knockout mouse, quakingviable (qkv) and generated Pacrg transgenic qkv mice (qkv-Tg). Using immunohistochemistry and immunoelectron microscopy this study demonstrated that Pacrg was localised to the axonemal microtubule doublets of sperm and ependymal cilia. The absence of Pacrg was associated with compromised sperm flagella formation and male infertility. In addition, histological and MRI analysis of qkv mutant mice revealed hydrocephalus. Specifically, qkv mutant mice showed a ~2.5 fold expansion of the lateral ventricle area compared to wildtype mice. The hydrocephalus phenotype was associated with a reduction in ependymal cilial beat frequency (CBF). Transgenic expression of Pacrg was sufficient to rescue the hydrocephalus and infertility phenotypes. In conclusion, this study has demonstrated that Pacrg is a novel axonemal protein in a subset of motile cilia and loss of Pacrg function results in spermiogenic defects and hydrocephalus in mice. Further, this study has shown that variations in the human PACRG promoter are a risk factor in human male infertility. Collectively these data provide evidence for a conserved role of PACRG in the cilial axoneme. This suggests the protein may be a candidate for a variety of human diseases characterised by cilial dysfunction.

Hydrocephalus is a common pediatric neurosurgical condition affecting the body’s ability to regulate cerebral spinal fluid. Treatment commonly involves insertion of a ventriculoperitoneal (VP) shunt re-establishing cerebral spinal fluid flow. Shunts are prone to malfunction, with headache being a common symptom. Headache has predominantly been recognized as a sign of shunt malfunction and not seen as a pain event. While headache is common in pediatric hydrocephalus patients with an apparently functional shunt, it has not been rigorously investigated putting them at risk for the consequences of unresolved pain. Researchers have not addressed headache within this patient population outside of shunt functioning or the impact of headache from the child and adolescent perspective. Drawing on the Gate Control Theory, the Neuromatrix Theory of Pain and the International Headache Societies Headache Classification system, a mixed methods study design was undertaken to (a) determine the prevalence, frequency and nature of headaches, (b) describe potential child factors associated with headaches and (c) evaluate the impact of headaches on the child’s and adolescent’s’ school, social and family life. Sixty six percent of children and adolescents reported headache within a one month period. Based on the modified International Headache Society’s criteria, 13.0% of headaches were tension-like, 13.2% were unclassifiable 33.5% were migraine-like and 38.8% were mixed. Etiology was significant with children diagnosed with tumour and congenital without myelomeningocele having a decreased tendency to report headache compared to children diagnosed with congenital with myelomeningocele. Children and adolescents described hidden emotions and missing out on many of their school, social and family activities. The main themes from the qualitative analysis were invisibility, normalcy and control/out of control. Etiology and multiple psychosocial and psychological factors potentially influence the headache experience in children and adolescents with shunted hydrocephalus. Future studies are required to further explore and delineate factors impacting headache within this study population.

Hydrocephalus is a common pediatric neurosurgical condition affecting the body’s ability to regulate cerebral spinal fluid. Treatment commonly involves insertion of a ventriculoperitoneal (VP) shunt re-establishing cerebral spinal fluid flow. Shunts are prone to malfunction, with headache being a common symptom. Headache has predominantly been recognized as a sign of shunt malfunction and not seen as a pain event. While headache is common in pediatric hydrocephalus patients with an apparently functional shunt, it has not been rigorously investigated putting them at risk for the consequences of unresolved pain. Researchers have not addressed headache within this patient population outside of shunt functioning or the impact of headache from the child and adolescent perspective. Drawing on the Gate Control Theory, the Neuromatrix Theory of Pain and the International Headache Societies Headache Classification system, a mixed methods study design was undertaken to (a) determine the prevalence, frequency and nature of headaches, (b) describe potential child factors associated with headaches and (c) evaluate the impact of headaches on the child’s and adolescent’s’ school, social and family life. Sixty six percent of children and adolescents reported headache within a one month period. Based on the modified International Headache Society’s criteria, 13.0% of headaches were tension-like, 13.2% were unclassifiable 33.5% were migraine-like and 38.8% were mixed. Etiology was significant with children diagnosed with tumour and congenital without myelomeningocele having a decreased tendency to report headache compared to children diagnosed with congenital with myelomeningocele. Children and adolescents described hidden emotions and missing out on many of their school, social and family activities. The main themes from the qualitative analysis were invisibility, normalcy and control/out of control. Etiology and multiple psychosocial and psychological factors potentially influence the headache experience in children and adolescents with shunted hydrocephalus. Future studies are required to further explore and delineate factors impacting headache within this study population.

Hydrocephalus is a clinical conditon where the brain tissue is deformed by the expanding ventricules. In this thesis, the mechanical deformation of a hydrocephalic brain is studied using a biomechanical model, where the material properties of the tissue are described by a viscoelastic model. A set of governing equations is derived when the motion is quasi-static motion and deformation is small. Then, finite element method is used for spatial discretization, and finite difference and trapezoidal rule are used for time-stepping. Moreover, the computational meshes are generated from medical images of patient's brain using level set method and a program called DistMesh. Numerical stability of the time-stepping scheme is also studied. <br /><br /> Several numerical studies are conducted to investigate several aspect of the brain with hydrocephalus. The state of stress of the tissue is found to be compressive everywhere in the brain. The viscoelastic properties of the brain are investigated and found to be dominated by elastic response. Lastly, the displacement made by the ventricular wall as it expands and shrinks is found to be non-uniform.

Many patients with Spina Bifida suffer from hydrocephalus as a complication of their developmental disability and surgeons commonly treat this condition with ventriculoperitoneal shunts. Surgeons have speculated for years that these shunts may cause some type of visual disturbance because of their close proximity to the visual pathways in the brain. Little research has been done, however, to support or discourage this commonly held belief. Questions and data from the Arkansas Spina Bifida Research Project were used to examine whether ventriculoperitoneal (VP) shunts and VP shunt revisions increase reports of visual complaints for the individuals participating in this research project. This cross sectional design used responses to the vision questions from the 2005 Arkansas Spina Bifida Questionnaire. Results showed a 333% increase in reported vision complaints after receiving a VP shunt, but no significance with the increase in vision complaints for those having three or more VP shunt revisions. Females were 50% to 60% less likely to report vision complaints in both multivariate linear logistic models. While these results indicate the potential relationship between VP shunts and vision concerns, they must be viewed cautiously in light of study limitations due to the small sample size, selection bias, and study design.

Hydrocephalus is a clinical conditon where the brain tissue is deformed by the expanding ventricules. In this thesis, the mechanical deformation of a hydrocephalic brain is studied using a biomechanical model, where the material properties of the tissue are described by a viscoelastic model. A set of governing equations is derived when the motion is quasi-static motion and deformation is small. Then, finite element method is used for spatial discretization, and finite difference and trapezoidal rule are used for time-stepping. Moreover, the computational meshes are generated from medical images of patient's brain using level set method and a program called DistMesh. Numerical stability of the time-stepping scheme is also studied. <br /><br /> Several numerical studies are conducted to investigate several aspect of the brain with hydrocephalus. The state of stress of the tissue is found to be compressive everywhere in the brain. The viscoelastic properties of the brain are investigated and found to be dominated by elastic response. Lastly, the displacement made by the ventricular wall as it expands and shrinks is found to be non-uniform.

In this Thesis we develop mathematical models to analyze two proposed causative mechanisms for the ventricular expansion observed in hydrocephalus: cerebrospinal fluid pulsations and small transmantle pressure gradients. To begin, we describe a single compartment model and show that such simple one-dimensional models cannot represent the complex dynamics of the brain. Hence, all subsequent models of this Thesis are spatio-temporal. Next, we develop a poroelastic model to analyze the fluid-solid interactions caused by the pulsations. Periodic boundary conditions are applied and the system is solved analytically for the tissue displacement, pore pressure, and fluid filtration. The model demonstrates that fluid oscillates across the brain boundaries. We develop a pore flow model to determine the shear induced on a cell by this fluid flow, and a comparison with data indicates that these shear forces are negligible. Thus, only the material stresses remain as a possible mechanism for tissue damage and ventricular expansion. In order to analyze the material stresses caused by the pulsations, we develop a fractional order viscoelastic model based on the linear Zener model. Boundary conditions appropriate for infants and adults are applied and the tissue displacement and stresses are solved analytically. A comparison of the tissue stresses to tension data indicates that these stresses are insufficient to cause tissue damage and thus ventricular expansion. Using age-dependent data, we then determine the fractional Zener model parameter values for infant and adult cerebra. The predictions for displacement and stresses are recomputed and the infant displacement is found to be unphysical. We propose a new infant boundary condition which reduces the tissue displacement to a physically reasonable value. The model stresses, however, are unchanged and thus the pulsation-induced stresses remain insufficient to cause tissue damage and ventricular expansion. Lastly, we develop a fractional hyper-viscoelastic model, based on the Kelvin- Voigt model, to obtain large deformation predictions. Using boundary conditions and parameter values for infants, we determine the finite deformation caused by a small pressure gradient by summing the small strain deformation resulting from pressure gradient increments. This iterative technique predicts that pediatric hydrocephalus may be caused by the long-term existence of small transmantle pressure gradients. We conclude the Thesis with a discussion of the results and their implications for hydrocephalus research as well as a discussion of future endeavors.

In this Thesis we develop mathematical models to analyze two proposed causative mechanisms for the ventricular expansion observed in hydrocephalus: cerebrospinal fluid pulsations and small transmantle pressure gradients. To begin, we describe a single compartment model and show that such simple one-dimensional models cannot represent the complex dynamics of the brain. Hence, all subsequent models of this Thesis are spatio-temporal. Next, we develop a poroelastic model to analyze the fluid-solid interactions caused by the pulsations. Periodic boundary conditions are applied and the system is solved analytically for the tissue displacement, pore pressure, and fluid filtration. The model demonstrates that fluid oscillates across the brain boundaries. We develop a pore flow model to determine the shear induced on a cell by this fluid flow, and a comparison with data indicates that these shear forces are negligible. Thus, only the material stresses remain as a possible mechanism for tissue damage and ventricular expansion. In order to analyze the material stresses caused by the pulsations, we develop a fractional order viscoelastic model based on the linear Zener model. Boundary conditions appropriate for infants and adults are applied and the tissue displacement and stresses are solved analytically. A comparison of the tissue stresses to tension data indicates that these stresses are insufficient to cause tissue damage and thus ventricular expansion. Using age-dependent data, we then determine the fractional Zener model parameter values for infant and adult cerebra. The predictions for displacement and stresses are recomputed and the infant displacement is found to be unphysical. We propose a new infant boundary condition which reduces the tissue displacement to a physically reasonable value. The model stresses, however, are unchanged and thus the pulsation-induced stresses remain insufficient to cause tissue damage and ventricular expansion. Lastly, we develop a fractional hyper-viscoelastic model, based on the Kelvin- Voigt model, to obtain large deformation predictions. Using boundary conditions and parameter values for infants, we determine the finite deformation caused by a small pressure gradient by summing the small strain deformation resulting from pressure gradient increments. This iterative technique predicts that pediatric hydrocephalus may be caused by the long-term existence of small transmantle pressure gradients. We conclude the Thesis with a discussion of the results and their implications for hydrocephalus research as well as a discussion of future endeavors.