Apesar da introdução da HAART, formas leves de Transtornos Neurocognitivos Associados ao HIV (HAND) permanecem altamente prevalentes, afetando metade de todos os indivíduos infectados. A inflamação sistêmica e localizada induzida pelo HIV é considerada um dos mecanismos da HAND, e embora muitos biomarcadores potenciais tenham sido estudados, até o momento nenhum deles provou ser útil na prática clínica. Portanto, o objetivo desse trabalho foi investigar os níveis de biomarcadores de ativação celular, neurodegeneração e virológicos, no líquido cefalorraquidiano (CSF), e também marcadores genéticos no sangue, buscando associá-los à presença de HAND. Materiais e métodos: Utilizando um desenho transversal, níveis dos marcadores de ativação celular sCD14, Neopterina, MCP-1, IL-1b, IL-6, TNF-?, CXCL-10, IFN-? e MIP-1?; marcadores neuronais Tau, p-Tau, A?40, A?42 e Neurofilamentos; carga viral de HIV e níveis ApoE foram mensurados em 84 amostras de LCR , e a genotipagem do vírus, bem como a genotipagem da ApoE, foram feitas no sangue de 33 indivíduos infectados pelo HIV com alteração neurocognitiva assintomático (ANI), 15 com alteração neurocognitiva de leve a moderada (MND), 15 com demência associada ao HIV ( HAD), 14 controles infectados pelo HIV (C HIV +) e 7 controles não infectados pelo HIV (C HIV-). Os dados clínicos também foram avaliados. Resultados: O parâmetro de idade diferiu estatisticamente entre os grupos, por isso foi ajustado para análise posterior. Os controles HIV+ e o grupo HAND estavam todos sob HAART e aproximadamente 96% deles apresentaram carga viral plasmática e liquórica suprimidas. Os marcadores de neurodegeneração não diferiram estatisticamente entre os grupos. No entanto, os marcadores de ativação celular IFN-gama, IL-1beta e sCD14, juntamente com a ApoE, mostraram diferenças significativas. A análise discriminatória revelou que ApoE e IL-1? juntos possuem maior poder discriminatório para diferenciar o grupo HAND dos controles HIV+. A IL-1b mostrou um aumento progressivo no declínio cognitivo, enquanto os níveis de ApoE mostraram-se mais elevados nos controles HIV+, grupo que também teve a maior porcentagem de genótipo ?4. sCD14 por sua vez mostrou-se elevado no grupo HAND, enquanto IFN-? apresentou queda. Conclusão: Os resultados reforçam o conceito de que a elevação da regulação das citocinas pró-inflamatórias, como sCD14 e IL-1beta, pode desempenhar um papel na patogênese da HAND, mesmo nos pacientes com supressão viral.Em contrapartida, nenhum marcador de neurodegeneração apresentou diferença estatística entre os grupos. É possível que as diferenças encontradas em relação a ApoE nos grupos, tanto tem termos de regulação como a presença do genótipo e4, indique algum mecanismo compensatório, que poderia resultar em um fator protetor contra HAND, portanto deve ser melhor estudado. / Despite the introduction of HAART, mild forms of HIV-associated Neurocognitive Disorders (HAND) remain highly prevalent, affecting half of all infected individuals. Systemic and localized inflammation induced by HIV is considered to be one of the mechanisms of HAND, and although many potential biomarkers have been studied, none of them have proven to be useful in clinical practice. Therefore, the objective of this study was to investigate the levels of biomarkers of cellular activation, neurodegeneration and virological, in the cerebrospinal fluid (CSF), as well as genetic markers in the blood, seeking to associate them with the presence of HAND. Materials and methods: Using a cross-sectional design, levels of the cell activation markers sCD14, Neopterin, MCP-1, IL-1b, IL-6, TNF-?, CXCL-10, IFN-? and MIP-1?; neuronal markers Tau, p-Tau, A?40, A?42 and Neurofilaments; HIV viral load and ApoE levels were measured in 84 CSF samples, and virus genotyping and ApoE genotyping were done in the blood of 33 HIV-infected individuals with asymptomatic neurocognitive impairment (ANI), 15 with neurocognitive impairment (MND), 15 with HIV-associated dementia (HAD), 14 HIV-infected controls (C HIV +), and 7 non-HIV-infected controls (C HIV-). Clinical data were also evaluated. Results: The age parameter differed statistically between the groups, so it was adjusted for later analysis. HIV + controls and HAND group were all under HAART and approximately 96% of them had suppressed plasma and CSF viral load. Neurodegeneration markers did not differ statistically between the groups. However, the cell activation markers IFN-gamma, IL-1beta and sCD14, along with ApoE, showed significant differences. Discriminatory analysis revealed that ApoE and IL-1? together have greater discriminatory power to differentiate HAND group from HIV + controls. IL-1b showed a progressive increase in cognitive decline, while ApoE levels were higher in HIV + controls, which also had the highest percentage of ?4 genotype. sCD14 in turn showed to be elevated in the HAND group, while IFN-? showed decrease. Conclusion: The results reinforce the concept that increased regulation of proinflammatory cytokines, such as sCD14 and IL-1beta, may play a role in the pathogenesis of HAND, even in patients with viral suppression. On the other hand, no neurodegeneration marker presented statistical difference between groups. It is possible that the differences found regarding ApoE in the groups, both in terms of regulation and the presence of the e4 genotype, indicate some compensatory mechanism, which could result in a protective factor against HAND, so it should be better studied.

Infection with human immunodeficiency virus (HIV) and progression to acquired immune deficiency syndrome (AIDS) often result in neurologic and neuropsychiatric changes, although the prognostic information available for patients affected by HIV/AIDS-related neurologic diagnoses has been limited. The objective of the present study was to characterize the patterns and predictors of survival, including the impacts of antiretroviral therapy (ART) use and potential factors in healthcare access and disparity, among patients with one or more of the following conditions: cryptococcosis, toxoplasmosis, primary central nervous system lymphoma, progressive multifocal leukoencephalopathy, and HIV-associated dementia. To accomplish this, a cohort was drawn from the Iowa HIV/AIDS reporting system, and a non-independent, university-based cohort was then used to validate the analyses conducted for the statewide sample. Patterns of ART use were identified in each cohort using logistic regression, and survival analyses were conducted using Kaplan-Meier analysis, Cox regression, and accelerated failure time modeling. Survival was poor in both cohorts, although the university-based setting (University of Iowa Hospitals and Clinics) was associated with better overall survival. Of 230 persons in the statewide cohort, 77.0% were deceased by the end of the study period (1982-2008), and the median survival was 1.13 years (95% CI: 0.90 to 1.86 years, n=225). By contrast, 56.4% of the university-based cohort was deceased by the end of the study period (1984-2009), and the median survival in this group was 3.04 years (95% CI: 1.79 to 11.62 years, n=172). Both cohorts were predominantly male, non-Hispanic white, and residents of a small metropolitan area at the time of the AIDS diagnosis. ART use had a strong protective effect on survival in both cohorts. Use of ART among patients diagnosed during the era of highly active antiretroviral therapies (HAART) was associated with an 80% reduction in the rate of death (HR=0.20, 95% CI: 0.08 to 0.46) compared to the non-users diagnosed during the pre-HAART era (that is, prior to 1996), after adjustment for age, race, birth sex, healthcare facility type, opportunistic infection count, HIV transmission risk category, neurologic condition, years since AIDS diagnosis, and timing of neuro-AIDS in a Cox regression model. In the UIHC cohort, the adjusted expected survival time among ART/HAART users was 37.71 (95% CI: 14.44 to 99.48) times that among non-users. Women had significantly poorer outcomes than men in the statewide cohort (adjusted HR=2.31, 95% CI: 1.22 to 4.35), and a similar, non-significant trend was observed among university-based cases. Secondary analyses suggested that this difference persisted over the course of the epidemic and was not attributable to differential ART response among men and women. Evidence for a role of disease severity, psychosocial support, and/or psychiatric comorbidity in the differential survival of men and women was identified. This study provides useful prognostic data for patients and providers and may guide future research efforts aimed toward improved survival for neuro-AIDS patients. The survival disadvantage of women compared to men should be confirmed and the mechanisms underlying this disparity elucidated. Meanwhile, clinical and public health efforts might be directed towards screening, treatment, and support for women affected by neuro-AIDS, including potential assessment of comorbid psychiatric disorders.

名古屋大学博士学位論文 学位の種類 : 博士(医学)(論文) 学位授与年月日:平成11年1月22日 片桐浩久氏の博士論文として提出された

The quadrivalent (q-) human papillomavirus (HPV) vaccine is praised for its near perfect efficacy of 98% in the per-protocol population and minimal safety concerns. Adherence to the dosing schedule of 0, 2 and 6 months outside clinical trials has not yet been described. Furthermore, clinical trials were underpowered to detect rare, but serious, adverse events including convulsions, seizures and epilepsy in young girls targeted by American and Canadian national advisory committees. This retrospective cohort study followed Grade 8 girls eligible for Ontario’s HPV immunization program during the 2007/08 to 2010/11 campaign years. Using Ontario’s immunization and health databases, baseline characteristics, qHPV vaccination, dates of qHPV vaccination and diagnoses of serious neurological events were identified for each cohort member. The proportions of girls who initiated and completed the qHPV vaccine program were determined. Adherence to the recommended dosing intervals and for ‘time-to-series completion’ was calculated as the proportion of eligible girls whose number of days between doses complied with the recommended dosing interval. A self-matched, case only approach was used to estimate the age-adjusted rate ratio (RR) of neurological events in the 0-30 day period following qHPV vaccination. The primary study endpoint was a composite of the first occurrence of a convulsion, seizure or epilepsy. Secondarily, an epileptic seizure only endpoint was assessed, as were the influence of a number of predisposing risk factors. An overall uptake of 50.24% was observed, of which, 87.02% received at least three doses. Adherence to the recommended dosing interval was most difficult in scheduling of the second dose (70.80%). There was no increased risk observed for the primary endpoint in the 0-30 days following qHPV vaccination (RR 1.01, 95% CI 0.92-1.10). However, this association was modified in girls with predisposing risk factors for epilepsy. There was an increased risk observed for the epileptic seizure only endpoint (RR 1.64, 95% CI 1.28-2.10). In Ontario, the overall uptake of the qHPV vaccine is low. Once initiated, series completion is high, with the majority receiving the vaccine in a timely manner. A risk for epileptic seizures following vaccination may be limited to girls with predisposing risk factors. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2012-09-28 17:56:59.608

The overall aim of the present thesis was to study post-resuscitation care of cardiac arrest (CA) patients treated with target temperature management 33°C with a focus on evaluation of two prognostic tools: variations in cerebral venous saturation and acute magnetic resonance imaging (MRI) findings on the brain post-CA. An additional aim was to investigate patients’ neurological outcome and relatives’ experiences 6 months after the event. Paper I describes the cerebral oxygen saturation of blood obtained from a jugular bulb (SjvO2) catheter The results showed that patients with poor outcome tended to have higher SjvO2values,but this difference was only significant at 96 and108 hours post-CA. The main findings of Paper II were that patients with good outcome displayed a pathological pattern mainly in the frontal and parietal lobes on MRI of the brain. Patients with poor outcome had an extensive pathological pattern in several brain regions. Furthermore, very low apparent diffusion coefficient (ADC) values were associated with poor outcome regardless of brain region. Paper III investigated physical and cognitive function over time, between one month and 6 months post-CA, as well as d life satisfaction at 6 months. The results showed that impairment in physical and cognitive function is common in CA survivors but tends to decrease over time. Despite a severe illness, which has impaired the physical and cognitive functions, satisfaction with life as a whole was reported by 70% of CA survivors. In Paper IV, relatives described their experiences 6 months after a significant others CA. The analysis resulted in three themes reflecting relatives’ everyday life 6 months after the event: Difficulties managing a changed life situation, Feeling like I come second and Feeling new hope for the future. In conclusion, the results of the present thesis have increased our understanding of the two prognostic tools that were investigated; they have generated new and revealed aspects that should be taken into account during prognostication and assessing neurological outcome of this group of patients. The thesis has also shown that the healthcare needs to improve its routines for follow-ups and information provision to both patients and their relatives.

Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder whose characteristic features include hyperkinetic movements and abnormal red blood cell morphology. The disorder shares features with Huntington's disease and McLeod syndrome (MLS), and can sometimes be difficult to distinguish clinically from the latter. In 1997, ChAc was linked to a 6-cM region on chromosome 9q21-22. A novel gene, >em>CHAC, was identified in the critical region. CHAC (now renamed VPS13A) encodes a large protein called chorein, with a yeast homologue implicated in protein sorting. In this study, all 73 exons plus flanking intronic sequence in VPS13A were screened for mutations in 83 unrelated ChAc patients. We identified 88 different VPS13A mutations in 72 probands, comprising six deletions of entire exons, 22 nonsense, 36 frameshift, 19 splice-site and five missense mutations. This disorder therefore shows substantial allelic heterogeneity: however, evidence for common inheritance of the EX70_73del mutation in four French Canadian pedigrees indicates a possible founder effect in this population. Expression of VPS13A appears to be ubiquitous, as determined by tissue-specific analysis of mRNA and chorein distribution. However, chorein expression was markedly reduced or undetectable in lymphoblasts, fibroblasts and erythrocyte membranes from 14 ChAc patients. In contrast, MLS cells showed chorein expression similar to control levels, suggesting that loss of chorein expression is a diagnostic feature of ChAc. Yeast two-hybrid analysis of six different -600 amino-acid chorein fragments was used to screen a human brain cDNA library for proteins that may interact with chorein. One fragment interacted weakly with constructs derived from transcription factor NF-κB, putative protein phosphatase PP2Cη and TAB2, a protein implicated in the mitogen-activated kinase cascade. Although exogenously expressed chorein and TAB2 did not appear to colocalise, co-immunoprecipitation experiments supported an interaction between the two proteins, suggesting an avenue for future research into chorein function.

Perinatal asphyxia is a significant contributor to neonatal brain injury. In the clinical environment there is variability in the severity of neural injury in neonates with similar clinical histories. Whilst the duration and intensity of hypoxia is well known to influence the severity of neurological outcome, the global physiological responses to hypoxia may also affect the subsequent variability in neurological outcome. The first step in this project was to identify which physiological response/s during a constant global hypoxic-ischemic insult influence the severity of neurological outcome in the newborn piglet and to assess the relative importance of these responses. Hypoxia/hypercapnia was induced in anaesthetized piglets by reducing the fraction of inspired oxygen to 0.1 (10%) and the ventilation rate from 30-10 breaths per minute for 45 minutes. Neurological outcome was determined by using functional markers including aEEG amplitude and cerebral impedance, and the structural marker microtubule associated protein-2 immunohistochemistry at 6 hours post hypoxia. The results from the initial study indicated that there was significant variability in neurological outcome following a constant hypoxia/hypercapnia insult. Serum cortisol concentrations were highly variable at the end of hypoxia (mean ± SD; 240.7 ± 90.9 nmol/L) and associated with cardiovascular function (time heart rate below baseline; r = 0.69) and neurological outcome (r = 0.70). Cardiovascular function (time heart rate was below baseline) and neurological outcome were strongly associated (r = 0.77). In this study we observed an oscillating pattern in cardiovascular function during hypoxia in some animals. In the regression analysis variability in cortisol concentrations and cardiovascular function explained 68% of the variability in the severity of neurological outcome. Additional physiological factors did not improve the strength of the association with neurological outcome. The variability in the physiological responses, particularly cardiovascular and endocrine responses to hypoxia may be more important determinants of neurological outcome then previously recognised. Results from the initial study opened up several questions about the relationship between cortisol and cardiovascular function during hypoxia and the relationship to the subsequent neurological outcome. Since variability in cortisol concentrations was associated with both cardiovascular function and neurological outcome the second step of this thesis was to investigate what factors contributed to the variability in serum cortisol concentrations during hypoxia. It is important to understand why some individuals produce more cortisol than others, and as a result are protected against brain injury. The aim was to determine if the variability in serum cortisol concentrations was the result of variability in ACTH concentrations during acute global hypoxia. The results from this study showed that early changes in serum cortisol concentration (15 minutes) were not correlated with ACTH (R2 = 0.26, P = 0.1), however, later changes (30 – 45 minutes) were (R2 0.45 - 0.68). This suggests that the primary factor controlling serum cortisol concentrations before hypoxia and during later hypoxia is ACTH concentrations. These data suggest that other factors may control cortisol secretion during early hypoxia; a key mechanism responsible for these changes may be the activity of the sympathetic nervous system and the maturity of the adrenal medullae. Since, higher cortisol concentrations were associated with better cardiovascular function and neurological outcome. As a result of this observation the aim of this study was to determine if cortisol concentrations during hypoxia are the causative factor responsible for improved cardiovascular function and better neurological outcome. The results from this study showed that manipulating serum cortisol concentrations into high (<500nmol/l) and low (>50nmol/l) levels during hypoxia did not affect cardiovascular function (P = 0.68) or neurological outcome (P = 46). Within each group (low, high and control hypoxia group) there was significant variability in cardiovascular function during hypoxia, which was associated with neurological outcome. (r = -0.63, p = 0.01). This study showed that serum cortisol concentrations during hypoxia are not the causative factor impacting on improved cardiovascular function and neurological outcome. It is possible that factors affecting both cardiovascular function and cortisol production such as activity of the sympathetic nervous system, may be a possible mechanism behind the variability in neurological outcome and cardiovascular function. Additionally, this study showed that cortisol concentrations at 3 hours post hypoxia were associated with neurological outcome (r = -0.67, p = 0.01). The animals with poorer outcome may also be those with greater multi-organ damage and thus reduced ability to clear cortisol from the systemic circulation. In light of this finding it may be interesting to assess cortisol concentration in the human neonate at 3 hours post hypoxia and determine the relationship to neurological outcome. In the final study of this thesis the function of the cardiovascular system during hypoxia was investigated in more detail because of its strong association with neurological outcome (results observed in Chapter 2 and 4. Few researchers have reported on oscillations in cardiovascular function, particularly type-3 waves, during hypoxia in the neonate. The aim of this study was to determine the characteristics and occurrence of type-3 waves in the neonatal piglet and their relationship to neurological outcome following acute global hypoxia. The result showed that the development of type-3 waves in cardiovascular function occurred in 56% of animals. An oscillating pattern was significantly associated with better neurological outcome (p = 0.01) and a lower duration of hypotension during hypoxia (p = 0.02), and occurred more frequently in females (p = 0.024). The development of type-3 waves during acute global hypoxia is a key mechanism in promoting natural tolerance; and may be the result of greater activity, maturity or sensitivity of the sympathetic nervous system in females compared to males. This may explain the improved neurological outcome following hypoxia in the female neonate seen in the clinical setting.

Perinatal asphyxia is a significant contributor to neonatal brain injury. In the clinical environment there is variability in the severity of neural injury in neonates with similar clinical histories. Whilst the duration and intensity of hypoxia is well known to influence the severity of neurological outcome, the global physiological responses to hypoxia may also affect the subsequent variability in neurological outcome. The first step in this project was to identify which physiological response/s during a constant global hypoxic-ischemic insult influence the severity of neurological outcome in the newborn piglet and to assess the relative importance of these responses. Hypoxia/hypercapnia was induced in anaesthetized piglets by reducing the fraction of inspired oxygen to 0.1 (10%) and the ventilation rate from 30-10 breaths per minute for 45 minutes. Neurological outcome was determined by using functional markers including aEEG amplitude and cerebral impedance, and the structural marker microtubule associated protein-2 immunohistochemistry at 6 hours post hypoxia. The results from the initial study indicated that there was significant variability in neurological outcome following a constant hypoxia/hypercapnia insult. Serum cortisol concentrations were highly variable at the end of hypoxia (mean ± SD; 240.7 ± 90.9 nmol/L) and associated with cardiovascular function (time heart rate below baseline; r = 0.69) and neurological outcome (r = 0.70). Cardiovascular function (time heart rate was below baseline) and neurological outcome were strongly associated (r = 0.77). In this study we observed an oscillating pattern in cardiovascular function during hypoxia in some animals. In the regression analysis variability in cortisol concentrations and cardiovascular function explained 68% of the variability in the severity of neurological outcome. Additional physiological factors did not improve the strength of the association with neurological outcome. The variability in the physiological responses, particularly cardiovascular and endocrine responses to hypoxia may be more important determinants of neurological outcome then previously recognised. Results from the initial study opened up several questions about the relationship between cortisol and cardiovascular function during hypoxia and the relationship to the subsequent neurological outcome. Since variability in cortisol concentrations was associated with both cardiovascular function and neurological outcome the second step of this thesis was to investigate what factors contributed to the variability in serum cortisol concentrations during hypoxia. It is important to understand why some individuals produce more cortisol than others, and as a result are protected against brain injury. The aim was to determine if the variability in serum cortisol concentrations was the result of variability in ACTH concentrations during acute global hypoxia. The results from this study showed that early changes in serum cortisol concentration (15 minutes) were not correlated with ACTH (R2 = 0.26, P = 0.1), however, later changes (30 – 45 minutes) were (R2 0.45 - 0.68). This suggests that the primary factor controlling serum cortisol concentrations before hypoxia and during later hypoxia is ACTH concentrations. These data suggest that other factors may control cortisol secretion during early hypoxia; a key mechanism responsible for these changes may be the activity of the sympathetic nervous system and the maturity of the adrenal medullae. Since, higher cortisol concentrations were associated with better cardiovascular function and neurological outcome. As a result of this observation the aim of this study was to determine if cortisol concentrations during hypoxia are the causative factor responsible for improved cardiovascular function and better neurological outcome. The results from this study showed that manipulating serum cortisol concentrations into high (<500nmol/l) and low (>50nmol/l) levels during hypoxia did not affect cardiovascular function (P = 0.68) or neurological outcome (P = 46). Within each group (low, high and control hypoxia group) there was significant variability in cardiovascular function during hypoxia, which was associated with neurological outcome. (r = -0.63, p = 0.01). This study showed that serum cortisol concentrations during hypoxia are not the causative factor impacting on improved cardiovascular function and neurological outcome. It is possible that factors affecting both cardiovascular function and cortisol production such as activity of the sympathetic nervous system, may be a possible mechanism behind the variability in neurological outcome and cardiovascular function. Additionally, this study showed that cortisol concentrations at 3 hours post hypoxia were associated with neurological outcome (r = -0.67, p = 0.01). The animals with poorer outcome may also be those with greater multi-organ damage and thus reduced ability to clear cortisol from the systemic circulation. In light of this finding it may be interesting to assess cortisol concentration in the human neonate at 3 hours post hypoxia and determine the relationship to neurological outcome. In the final study of this thesis the function of the cardiovascular system during hypoxia was investigated in more detail because of its strong association with neurological outcome (results observed in Chapter 2 and 4. Few researchers have reported on oscillations in cardiovascular function, particularly type-3 waves, during hypoxia in the neonate. The aim of this study was to determine the characteristics and occurrence of type-3 waves in the neonatal piglet and their relationship to neurological outcome following acute global hypoxia. The result showed that the development of type-3 waves in cardiovascular function occurred in 56% of animals. An oscillating pattern was significantly associated with better neurological outcome (p = 0.01) and a lower duration of hypotension during hypoxia (p = 0.02), and occurred more frequently in females (p = 0.024). The development of type-3 waves during acute global hypoxia is a key mechanism in promoting natural tolerance; and may be the result of greater activity, maturity or sensitivity of the sympathetic nervous system in females compared to males. This may explain the improved neurological outcome following hypoxia in the female neonate seen in the clinical setting.

Thesis (M. App. Sc.)--Carleton University, 2004. / Includes bibliographical references (p. 119-122). Also available in electronic format on the Internet.

Thesis (Ph.D.)--University of Tennessee Health Science Center, 2008. / Title from title page screen (viewed on Sept. 17, 2008). Research advisor: Clinton Stewart, Pharm.D. Document formatted into pages (xiii, 105 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 80-102).