O Tabagismo é uma das principais causas de doenças crônicas não transmissíveis, afetando cerca de 1,6 bilhões de pessoas até 2030. Políticas de controle do tabagismo foram criadas para evitar a contaminação de indivíduos não fumantes pela poluição tabagística ambiental. Descritas principalmente no pulmão, pouco se sabe sobre a ação da fumaça do cigarro no sistema nervoso central (SNC). O presente estudo tem como objetivo avaliar os efeitos da exposição à fumaça do cigarro, por 15 dias consecutivos, em um processo de inflamação sistêmica induzida por LPS. Para tanto, camundongos C57BL/6 foram expostos a uma mistura de fumaça central e lateral do cigarro referência 3R4F (Universidade de Kentucky, EUA). No último dia, os animais foram desafiados com LPS iv. (0,1 µg/animal) ou salina, formando os grupos CO – controle, FU – fumaça do cigarro, LPS – desafio com LPS e FPS – fumaça do cigarro e desafio com LPS. As amostras foram processadas de maneira a realizar as análises de RT-PCR para os primers IL-6, IL-1β, TNF-α, TLR2, TLR4 e iNOS, além da dosagem por ELISA das citocinas IL-6, IL-10, IL-1β e TNF-α e western blot para a proteína P65. Nossos resultados demonstraram um aumento da transcrição dos genes TLR2, TLR4 e iNOS, em todas as estruturas analisadas no período de 2 horas de eutanásia após o desafio com LPS no grupo FPS em relação a todos os outros grupos estudados. Já no período de 4 horas após o desafio foi possível observar um aumento dos genes IL-1β e TNFα em ambos grupos que receberam o desafio com o LPS no hipocampo, estriado, córtex e cerebelo, sugerindo que a influência da fumaça do cigarro se de apenas 2 horas após o desafio, uma vez que no período de 4 horas observamos apenas o efeito do LPS. Os resultados da dosagem de citocinas sugerem que, no período de 4 e 6 horas após o desafio, a citocina anti-inflamatória IL-10 está diminuída no hipocampo e no córtex pré-frontal no grupo FPS em relação a todos os outros grupos estudados. Porém é possível observar um aumento estatisticamente significativo da mesma citocina no cerebelo para o grupo exposto apenas à fumaça do cigarro. Nossos dados sugerem que o processo inflamatório no SNC ocorra de maneira diferenciada dependendo da região estudada, e do período analisado. / Cigarette smoking is a major cause of chronic non-communicable diseases, affecting approximately 1.6 billion people up to 2030. Tobacco control policies were created in order to prevent contamination of non-smokers by environmental tobacco smoke. Described primarily in the lung, little is known about the action of cigarette smoke in the central nervous system (CNS). The present study aims to evaluate the effects of cigarette smoke exposure for 15 consecutive days in a process of systemic inflammation induced by LPS. To this so, C57BL/6 mice were exposed to a mixture of mainstream and sidestream cigarette smoke reference 3R4F (University of Kentucky, USA). In the last day, animals were challenged with LPS iv. (0.1 µg/animal) or saline and divided into the following groups: CO - control, FU - cigarette smoke, LPS - LPS challenge and FPS - cigarette smoke and LPS challenge. The samples were processed in order to perform the RT-PCR analysis for IL-6, IL-1β, TNF-α, TLR2, TLR4 and iNOS primers, ELISA assay of IL-6, IL-10, IL-1β and TNF-α and western blot for p65. Our results showed an increase in transcription of TLR2, TLR4 and iNOS genes in all structures analyzed within 2 hours of euthanasia after LPS challenge in the FPS group compared to all other groups. Beside this 4 hours after challenge was observed an increase of IL-1β and TNF genes in both groups that received the challenge with LPS in the hippocampus, striatum, cortex and cerebellum, suggesting that the influence of cigarette smoke can be observed only 2 hours after the challenge, justified since in a time period of 4 hours we can only observe the effect of LPS. The results suggest that cytokine assay, between 4 and 6 hours after challenge, the anti-inflammatory cytokine IL-10 is decreased in FPS group in the hippocampus and prefrontal cortex. But it is possible to observe a statistically significant increase in the same cytokine in the cerebellum exposed only to cigarette smoke group. Our data suggest that the inflammatory process in the CNS occurs differently depending on the region studied, and the period analyzed.

As enfermidades neurológicas, notadamente os tumores intracranianos, têm grande importância dentre os quadros mórbidos que acometem animais da espécie canina, principalmente em cães com mais de 5 anos de idade, com uma idade média de 9 anos. Os objetivos do presente estudo foram: avaliar os casos clínicos com suspeita de neoplasia, compilar os dados clínicos e exames complementares e relacioná-los com os achados anátomo-patológicos. Os tumores foram descritos quanto ao aspecto macro e microscópicos, elaborando-se o diagnóstico do neoplasma. Foram empregadas técnicas de imunoístoquímica para complementação das descrições de tais neoplasmas visando estabelecer comparação entre os aspectos morfológicos encontrados na espécie humana. Utilizou-se 14 cães com diagnósticos de tumores intracranianos, que foram avaliados através do exame físico geral e neurológico associado a exames de imagem (tomografia computadorizada, ressonância magnética, ecoencefalografia) e/ou eletrodiagóstico através de um eletroencéfalografo digital com mapeamento cerebral. A sintomatologia depende da localização do tumor, agressividade tumoral, tipo de formação e severidade da lesão associada. Subdividiram-se os cães em 4 grupos de acordo com a sintomatologia: grupo I (cães com alterações cerebrais); grupo II (cães com alterações cerebelares); grupo III (cães com alterações em tronco encefálico); grupo IV (cães com alteração mista). Os achados mais freqüentes nos animais acometidos foram: convulsões, alteração de comportamento, andar compulsivo, andar em círculos, progressão obstinada, déficits proprioceptivos e/ou motores e déficits vestibulares. A confirmação diagnóstica, caracterização histopatológica e classificação das neoplasias foram realizadas através de biopsia ou necropsia dos animais eutanasiados ou que vieram a óbito espontaneamente. / Neurological disorders, namely intracranial tumors, have a great importance among morbid entities in dogs, manly in animals older then five years, with a mean of age ranging nine years old. The aim of this study was to evaluate clinical cases suspected of having neoplasia and to associate ancillary clinical exams with necropsy findings. Tumors were described macro and microscopically, and a histopathological diagnosis was determinated. Immunohistochemical methods were applied to ensure the diagnosis and to compare with morphological data available in human counterparts. A number of 14 dogs with intracranial tumor were used, from this cases compilation of general physical examination, neurological evaluation, and associated image diagnosis (computerized tomography, magnetic resonance and echoencephalography) and/or eletrodiagnois by means of a digital electroencephalographic mapping of brain. The symptoms depend on tumor localization, tumor behavior - aggressivety, type of tumor and severity of associated lesions. Four groups were subdivided according to the symptoms: group I (dogs with brain alterations); group II (dogs with cerebellar alterations); group III (dogs with brain steam alterations) and group IV (dogs with mixt alterations). The most frequent findings in diseased animals were seizures, behavior alterations, compulsive walking, circling, obstinate progression, propioceptive and/or motor deficit and vestibular deficit. The diagnosis confirmation, histopathological characterization and classification of neoplasias were made by biopsy or necropsy of euthanatized or naturally dead animals.

Functional magnetic resonance imaging (fMRI) can be used to track neural activation in the brain during functional activities. The purpose of this study was to investigate brain neural responses to blood flow restricted (BFR) versus control handgrip exercise. Using a randomized crossover design, 25 subjects (12 males, 13 females) completed handgrip exercises during two conditions: BFR vs. control. To familiarize participants with the exercise conditions, one week prior to MRI scanning participants completed each exercise condition once on separate days, with 72 hours between days. The following week fMRI scans were performed at the same time of day, separated by 72 hours. The exercise protocol consisted of five 30-second sets of squeezing a nonmetallic handgrip exerciser (a reported 13.6 kg resistance), doing as many repetitions as possible, with 20-second rest intervals between sets. We saw a significant main effect of exercise condition (BFR versus control) between premotor dorsal (PMd)(F = 5.71, p = 0.022), premotor ventral (PMv)(F = 8.21, p = 0.007), and right ventral striatum (VS_R)(F = 7.36, p = 0.01). When considering anatomical regions of interest, we did not find significant differences between exercise conditions in bilateral S1 (p > 0.82), primary motor cortex (M1)(p > 0.33), supplementary motor area (SMA)(p > 0.66), cerebellum (CB)(p > 0.70), insular cortex (INS)(p > 0.45), anterior cingulate cortex (ACC)(p > 0.24), or thalamus (TH)(p > 0.66). Bilateral ACC (ACC_B), right middle frontal gyrus (MFG_R), and the right primary sensory cortex (S1_R) showed significant linear trends (p = 0.001) over the five exercise sets. Finally, the S1_R, left primary sensory cortex (S1_L), and the right anterior cingulate cortex (ACC_R) showed a main effect of set (p < 0.02). These data demonstrate that acute training with BFR during handgrip exercise results in different neural activation patterns in select areas of the brain, compared to a control. These results show that while completing less work with BFR exercise, subjects can achieve a similar amount of brain neural activation as with a higher-volume exercise. Brain neural activation is important to overall patient health and these findings may be important for prescribing training with BFR in clinical and applied research settings.

The brain renin-angiotensin system (RAS), of which angiotensin II (AngII) is the primary effector peptide, plays a critical role in the neurohumoral regulation of cardiovascular and body fluid homeostasis by modulating blood pressure, secretion of hypothalamic and pituitary hormones, and water intake. AngII produced locally in the brain or in the systemic circulation can act on brain regions called circumventricular organs (CVO), which lack the blood-brain-barrier. Dysregulation of central AngII signaling is implicated in the pathogenesis of hypertension; therefore, understanding the mechanisms of AngII in the CNS is an important area of investigation. Recently, a novel signaling mechanism for AngII in the periphery has been shown to involve NAD(P)H oxidase-derived reactive oxygen species (ROS). Although ROS are now known to be involved in numerous AngII-regulated processes in peripheral tissues, and are increasingly implicated in CNS neurodegenerative diseases, the role of ROS in central regulation of AngII-induced cardiovascular function remains unexplored. The hypothesis that ROS are critically involved in central AngII signaling and in AngII-dependent blood pressure and drinking behavior was tested by harnessing the power of an array of selective genetic tools, in combination with novel technologies for analysis of cardiovascular function in conscious mice. More specifically, central injections of adenoviruses encoding ROS-modulating molecules were used to examine the redox mechanisms in central AngII-mediated cardiovascular responses in vivo. Neuronal cell cultures were also used to investigate the involvement of NAD(P)H oxidase-derived ROS in AngII signaling, as well as to examine a link between calcium and ROS in intra-neuronal AngII signaling. Finally, in order to better understand the potential role of ROS in the brain in the pathogenesis of AngII-dependent hypertension, a mouse model that recapitulates the characteristics of human hypertension was employed in conjunction with genetic modulation of the redox state of the brain. These studies provide new evidence that ROS are involved in the intracellular signaling mechanism of AngII in the brain under normal and pathological conditions and offer new insight to how dysregulation of redox mechanisms in the brain may lead to the pathogenesis of AngII-dependent hypertension.

Corticotropin-releasing factor (CRF) is the primary hormone of the hypothalamo-pituitary adrenal axis (HPA-axis). In addition to its endocrine function, it has been proposed that CRF acts as a neurotransmitter. The widespread distribution of CRF immunoreactivity and CRF receptors in the rat central nervous system (CNS) supports this theory. Immunohistochemical studies have demonstrated high levels of CRF immunoreactivity the rat hypothalamus, a brain region involved in the regulation and integration of a variety of endocrine and autonomic homeostatic mechanisms. CRF has been shown to be involved in a number of these activities such as blood pressure control, food and water intake, behaviour and emotional integration. Many of these activities demonstrate progressive dysfunction as ageing proceeds. The aim of this thesis was to investigate the regulation of CRF in the rat CNS, particularly over the period of maturation and ageing. Tissue extraction and peptide radioimmunoassay (RIA) techniques were developed in order to measure regional CRF concentrations as a function of age in the rat CNS. Seven brain regions were examined including the hypothalamus, pituitary, medulla oblongata, pons, cerebral cortex, cerebellum and midbrain. Three age ranges were investigated: 3 – 4 weeks, 4 – 5 months and 14 – 18 months, representing young, mature and old age groups. Data for the tissues of individual rats from each age group were analysed using one-way analysis of variance (ANOVA) with post-hoc Scheffé tests (SPSS Release 6 for Windows, 1989 – 1993). CRF were detected in measurable quantities in all brain regions examined. Different age-related patterns of change were observed in each brain region. CRF concentrations (ng/g tissue) were highest in the pituitaries of young rats and were significantly reduced over the period of maturation (P< 0.05). However, the high CRF concentration of the young rat pituitary was likely to be a factor of the smaller tissue mass. Although the absolute CRF content (ng/tissue) of this tissue appeared to decline with maturation and ageing, the reduction was not significant (P>0.05). Therefore the pituitary of the young rat was relatively enriched with CRF per gram tissue. The highest CRF concentration in mature and aged rats was measured in the hypothalamus, in accordance with previous immunohistochemical studies. Hypothalamic CRF concentrations (ng/g tissue) demonstrated no significant alterations with maturation and ageing. The absolute CRF content (ng/tissue) of the hypothalamus was significantly less in the young rat compared to mature and aged animals, however this was accompanied by a smaller tissue mass (P<0.05). The CRF concentrations (ng/g tissue) of the rat cerebral cortex and medulla oblongata demonstrated significant reduction with advancing age (P<0.05), however in both cases this appeared to be due to significant increases in mean tissue mass. The absolute CRF content of these tissues (ng/tissue) were not significantly different over the period of maturation and ageing (P>0.05). CRF concentration (ng/g tissue) and absolute content (ng/tissue) of the pons demonstrated a trend to increase with advanced age in the rat, however this was not significant in both cases (P>0.05). Of interest were the significant increases observed in the CRF concentrations of the cerebellum and midbrain (ng/g tissue with advanced ageing (P<0.05). Significant increases were also observed in the mean tissue mass and absolute CRF content (ng/tissue) of these regions in aged rats (P<0.05). These findings perhaps indicate increased CRF synthesis and or decreased CRF turnover in these tissues with advancing age. The second stage of these studies examined age-related alterations in basal and potassium-stimulated hypothalamic CRF and overflow over the period of maturation and ageing in the rat, and required the preliminary development of an in vitro tissue superfusion system. The concomitant release of the co-modulatory compound, neuropeptide Y (NPY) was also measured. NPY has been shown to positively regulate CRF release and gene expression in the hypothalamus. In addition, NPY has been demonstrated to be involved in a number of hypothalamic activities, including blood pressure control and food intake regulation. Hypothalamic superfusion data were analysed using one factor repeated measures ANOVA (SPSS Release 6 for Windows, 1989-1993) followed by least significant difference tests ( Snedecor and Cochran, 1967) to enable both time and age comparisons. Basal hypothalamic CRF overflow was unaltered with maturation and ageing in the rat. Potassium stimulation (56 mM) elicted a significant 2 – 3 fold increase in hypothalamic CRF overflow across age groups (P<0.05). Stimulated hypothalamic CRF overflow was significantly greater in the young rat compared to the mature and aged animals (P<0.05). The enhanced response to depolarizing stimulus was observed at an age when the absolute CRF content of the hypothalamus was significantly less that of other age groups. It is possible that the enhanced responsiveness of the young rat may be of survival advantage in life threatening situations. Basal hypothalamic NPY overflow was much less than that of CRF, and potassium stimulation resulted in a very different age-related profile. The hypothalamic NPY response to depolarization was significantly reduced in the young rat and declined significantly with advanced ageing (P<0.05). The contrasting profiles of stimulated CRF and NPY overflow may indicate the activity of alternative regulatory factors present in the hypothalamus, whose activity may also be affected in an age-related manner. The final stage of these studies examined the nature of NPY modulation of hypothalamic CRF overflow in the mature rat. The facilitatory effect of NPY on hypothalamic CRF overflow was confirmed. The application of NPY (0.1 µM) significantly increased CRF overflow approximately 4 fold of basal (P<0.05). In addition, the role of the NPY-Y1 receptor was investigated by the prior application of Y1 receptor antagonists, GW1229 (0.05 µM). At this concentration GW1229 significantly reduced hypothalamic CRF overflow induced by perfusion with NPY (0.1 µm), P<0.05. It was concluded the Y1 receptor does have a role in the regulation of hypothalamic CRF overflow by NPY.

Thesis (Ph. D.)--University of Missouri-Columbia, 2007. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on December 18, 2007) Vita. Includes bibliographical references.

Tumours of the central nervous system (CNS) are the second most common cancers diagnosed in children, yet the cause of this disease remains largely unknown. This thesis examines whether polymorphisms in folate-metabolising and glutathione S transferase (GST) genes influence the risk and disease outcome of childhood CNS tumours. 204 children aged ≤18 years diagnosed with a CNS tumour at the Sydney Children??s Hospital between 1989 and 2004 were included in the study. DNA samples were isolated from archival frozen and formalin-fixed paraffin-embedded tumour tissue. Polymorphisms in GST and folate pathway genes were examined using real-time PCR. Genotype distributions in children with CNS tumours were compared to those observed in a control panel of cord blood samples from 363 healthy newborns. Children carrying at least one variant allele for each of MTHFR 677 C>T, MTHFR 1298 A>C, MTR 2756 A>G, MTRR 66 A>G, and RFC 80 G>A were found to have a 2.8-fold greater risk of developing a CNS tumour than non-carriers (OR=2.80; 95%CI: 1.08-7.56, P=0.022), an association which was even more apparent in those children with an embryonal tumour (OR=4.54; 95%CI: 1.13-15.85, P=0.016). Results also showed that children with the GSTP1 105 Val/Val genotype were three times more likely to develop a CNS tumour of embryonal cell origin than children with the GSTP1 105 Ile/Ile or Ile/Val genotypes (OR=3.02; 95%CI: 1.34-6.46, P=0.005). No such association was observed for CNS tumours of glial cell origin. The GSTM1, GSTT1, and GSTP1 Ala114Val polymorphisms did not appear to be associated with the development of a childhood CNS tumour. In addition, children with the MTHFR 677 TT or RFC 80 AA genotypes were found to have a higher risk of death within 5 years of diagnosis compared to children with one or more MTHFR 677 C or RFC 80 G alleles, respectively (HR=5.52, 95%CI: 1.00-30.37, P=0.049 and HR=5.69, 95%CI: 1.38-23.51, P=0.016, respectively), after adjusting for other prognostic factors such as sex, age at diagnosis, period of diagnosis, and tumour grade. Conversely, children with the MTR 2756 AG or GG genotypes, or MTRR 66 AG or GG genotypes, were more likely to survive compared to those with the MTR 2756 AA or MTRR 66 AA genotypes, respectively (HR=0.21, 95%CI: 0.05-0.93, P=0.040 and HR=0.11, 95%CI: 0.02-0.53, P=0.006). Results presented in this thesis indicate that polymorphisms in folate-metabolising and GST genes may play a role in the aetiology and survival of childhood CNS tumours, and that this may vary depending on the histological sub-type of tumour.

<p>Persons suffering from Attention deficit/hyperactivity disorder (ADHD) struggle with complications within the functions that regulate and control the brain activities, due to deficiencies in these functions within the affected nerve-paths. ADHD is a cognitive function impairment characterised by inattention, impulsiveness and over activity. According to Diagnostic and Statistic Manual of Mental Disorders, American Psychiatric Association (DSM-IV), certain diagnostic criteria of ADHD must be fulfilled in order for a person to be diagnosed with ADHD. The everyday problems caused by ADHD are individual and medication can have positive effects relieving the person’s impairing behaviour. The study is based on scientific literature, three quantitative scientific articles and preview material from the last study by Johnson, Fransson, Kadesjö & Gillberg, presently being scrutinised. Swedish as well as English literature has been used. The purpose of this study is to shed some light upon whether medication facilitates the child’s school situation. The result deals with the ADHD diagnosis and pharmacological therapy involving drugs that stimulate the central nervous system, as well as naturopathic medicine like Omega-3/6. The pedagogical aspect for children with ADHD in school has been observed and evaluated. In this matter it is important for the pedagogue to encourage the child by letting it find out that it can manage more than it thinks.</p>

Supratherapeutic doses of anabolic androgenic steroids (AASs) are administered, not only as performance-enhancing drugs in the world of sports, but also in order to modify behaviour. AAS abusers are at risk of developing serious physical and psychological side effects such as dependence and aggressive behaviour. The aim of this thesis was to investigate the impact of supratherapeutic doses of nandrolone decanoate after subchronic administration on dopamine and serotonin pathways involved in drug dependence and aggression, in the male rat brain. Adult male Sprague-Dawley rats received intramuscular injections of nandrolone decanoate (3 or 15 mg/kg) or vehicle once daily for 14 days. Nandrolone decanoate pre-exposure abolished the effect of amphetamine on the 3,4-dihydroxyphenylacetic acid (DOPAC) tissue level in the hypothalamus and on the DOPAC/dopamine ratio in the hypothalamus and the hippocampus. A significant decrease of the basal extracellular DOPAC and homovanillic acid (HVA) levels could be detected in the nucleus accumbens, which remained low during the first hour following the amphetamine challenge. Nandrolone decanoate significantly reduced the activity of both monoamine oxidase A and B (MAO-A and -B) in the caudate putamen and amygdala. The gene transcript levels of MAO-B, and the dopamine D1 and D4 receptors were altered in limbic regions. No changes in transcriptional levels could be detected among the serotonin receptor genes examined. However, the density of the serotonin transporter protein was elevated in a range of aggression-related brain regions. Taken together, subchronic administration of nandrolone decanoate causes dopaminergic and serotonergic dysregulations in distinct brain regions. These areas of the brain are involved in the development of drug dependence and expression of impulsive and aggressive behaviours. These results may contribute to explain some of the behavioural changes often reported in AAS abusers, such as polydrug use and impaired impulse control.

Persons suffering from Attention deficit/hyperactivity disorder (ADHD) struggle with complications within the functions that regulate and control the brain activities, due to deficiencies in these functions within the affected nerve-paths. ADHD is a cognitive function impairment characterised by inattention, impulsiveness and over activity. According to Diagnostic and Statistic Manual of Mental Disorders, American Psychiatric Association (DSM-IV), certain diagnostic criteria of ADHD must be fulfilled in order for a person to be diagnosed with ADHD. The everyday problems caused by ADHD are individual and medication can have positive effects relieving the person’s impairing behaviour. The study is based on scientific literature, three quantitative scientific articles and preview material from the last study by Johnson, Fransson, Kadesjö &amp; Gillberg, presently being scrutinised. Swedish as well as English literature has been used. The purpose of this study is to shed some light upon whether medication facilitates the child’s school situation. The result deals with the ADHD diagnosis and pharmacological therapy involving drugs that stimulate the central nervous system, as well as naturopathic medicine like Omega-3/6. The pedagogical aspect for children with ADHD in school has been observed and evaluated. In this matter it is important for the pedagogue to encourage the child by letting it find out that it can manage more than it thinks.