Modulation of the endocannabinoid system (ECS) is of great interest for its therapeutic relevance in several pathophysiological processes. The CB2 subtype is largely localized to immune effectors, including microglia within the central nervous system, where it promotes anti-inflammation. Recently, a rational drug design toward precise modulation of the CB2 active site revealed the novelty of Pyrrolo[2,1-c][1,4]benzodiazepines tricyclic chemotype with a high conformational similarity in comparison to the existing leads. These compounds are structurally unique, confirming their chemotype novelty. In our continuing search for new chemotypes as selective CB2 regulatory molecules, following SAR approaches, a total of 17 selected (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs were synthesized and tested for their ability to bind to the CB1 and CB2 receptor orthosteric sites. A competitive [H]CP-55,940 binding screen revealed five compounds that exhibited >60% displacement at 10 μM concentration. Further concentration-response analysis revealed two compounds, and , as potent and selective CB2 ligands with sub-micromolar activities ( = 146 nM and 137 nM, respectively). In order to support the potential efficacy and safety of the analogs, the oral and intravenous pharmacokinetic properties of compound were sought. Compound was orally bioavailable, reaching maximum brain concentrations of 602 ± 162 ng/g (p.o.) with an elimination half-life of 22.9 ± 3.73 h. Whether administered via the oral or intravenous route, the elimination half-lives ranged between 9.3 and 16.7 h in the liver and kidneys. These compounds represent novel chemotypes, which can be further optimized for improved affinity and selectivity toward the CB2 receptor.

Glioblastoma is the most aggressive type of primary tumor in the central nervous system (CNS tumors). It is hard to treat and has a poor prognosis for survival. Primary CSN tumors occur in approximately 1400 adults in Sweden every year and is the third most common cause of cancer-related deaths in individuals between 15-24 years of age.   There is no prophylaxis for primary CNS tumors. The causes of most CNS-tumors are unknown, but there are several risk factors that have been identified. Both heredity and environmental factors are likely to come into play, but clinical data does not suggest any convincing evidence of CNS tumor formation. Some cases of CNS tumors are related to known genetic conditions that cause rare syndromes and have an increased risk of getting a brain tumor.   The treatments for glioblastoma are surgery, radiotherapy, chemotherapy, TTField treatment and immunotherapy. Immunotherapy is a type of cancer treatment that uses the patient’s immune system to fight CNS tumors. New cancer immunotherapies, such as dendritic cell (DC)-based vaccines are under development to enhance anti-tumor presentation and to prime anti-tumor T-cell responses.   The objective of this study was to investigate the efficacy of DC vaccines for the treatment of glioblastoma.    Seven clinical studies from PubMed were found after searching in the Pubmed database, and filtering through the inclusion and exclusion criteria. All seven studies explored the efficacy of DC vaccines on overall survival and progression-free survival for patients with glioblastoma. In addition to investigating the safety and adverse events, the clinical trials evaluated the immune response to the DC vaccines against glioblastoma.   Combining standard of care (SOC) with DC vaccines prolonged the overall survival by several months compared to SOC alone. Severe adverse reactions (grade 3) were reported in two studies, while the rest of the studies showed that patients tolerated the DC vaccines and had only mild grade 1-2 adverse events. Half of the studies correlated prolonged median survival or progressions- free survival with immune response.   Further research is required to compare the efficacy of DC vaccines and other immunotherapies in order to conclude whether DC vaccines are a feasible effective treatment of glioblastoma in the future.

A polineuropatia inflamatória desmielinizante crônica (PIDC) é uma síndrome caracterizada fundamentalmente pela disfunção do Sistema Nervoso Periférico e que afeta muito a qualidade de vida dos pacientes. O envolvimento da PIDC com o Sistema Nervoso Central tem sido descrito, maiormente como sendo subclínico, porém não há estudos sobre a caracterização deste envolvimento de uma forma ampla e quantitativa. Avaliamos 11 pacientes com PIDC, todos tratados e sem sinais clínicos de alterações centrais, e 11 controles, pareados em gênero e faixa etária de 19 a 69 anos. Foram adquiridas neuroimagens em uma máquina de Ressonância Magnética de alto campo (3T) usando diferentes técnicas de imagens; volumétricas ponderadas em T1, volumétricas de inversão e recuperação com atenuação de fluidos e ponderadas em T2, relaxométricas de cinco ecos para mapas de T2, de transferência de magnetização e por tensor de difusão. As imagens foram processadas em diferentes ferramentas computacionais e foram obtidos resultados para estudos da difusibilidade, volumetria, morfometria, tratometria e conectividade cerebral, além de achados radiológicos para os pacientes. As análises de grupos foram executadas por; 1) testes paramétricos monocaudais de duas amostras pareadas para os resultados da volumetria, da tratometria e conectividade cerebral; 2) mapeamento estatístico paramétrico para os resultados da morfometria baseada em voxel e; 3) estatística espacial baseada em tratos para os resultados da difusibilidade. Foram detectas alterações em todas as comparações. Os principais achados indicam um envolvimento possivelmente caracterizado por uma perda volumétrica encefálica generalizada, sobretudo nas regiões periventriculares associadas a ventrículos proeminentes acrescido de, um aumento da difusibilidade transversa e oblíqua nos maiores tratos de substância branca e, também há uma perda de densidade na substância branca periventricular e um aumento na substância cinzenta em uma região que sinaliza para o espessamento trigeminal bilateral e, uma redução geral da conectividade cerebral estrutural. / Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is a severe disease fundamentally characterized by dysfunction of the Peripheral Nervous System and affects greatly the quality of life of patients. The Central Nervous System (CNS) involvement in CIDP has not been described using recent quantitative neuroimaging techniques. We evaluated 11 patients with CIDP, all treated and without clinical signs of central alterations and 11 controls matched for gender and age group of 19 to 69 years. Magnetic Resonance Imaging were performed on a 3T scanner using different imaging techniques; structural 3D T1-weighted, fluid-attenuated inversion recovery, relaxometry with 5 echoes pulse sequence for T2 maps, magnetization transfer weighted and diffusion tensor imaging. The images were processed on different tools and were obtained results for the studies of diffusivity, volumetry, morphometry, tractometry, brain connectivity, and radiological findings of patients. Different statistical group analyses were performed in the quantitative results: 1) Parametric test for volumetry, tractometry and brain connectivity; 2) Parametric mapping for voxel morphometry; 3) Tract-based spatial statistics (TBSS) for diffusion coefficients. Changes were detected in all comparisons. In the patients, our main findings are: generalized loss brain volume more pronounced in periventricular regions associated with prominent ventricles, increased simultaneously perpendiculars and parallel diffusivity in the major tracts of the TBSS analyze, white matter density loss in the periventricular area, some bilateral trigeminal thickening, and general reduction of the brain connectivity. The CIDP affects the global brain and represents a demyelination in the CNS.

This thesis deals with child problems with ADHD/ADD at Primary school and their next diagnosis.The aim of the theoretical part was to focus on the latest and available knowledge in the sphere of education and upbringing. Some thematical plans were analysed and they consider of ADHD/ADD and Specific learning disorders.The aim of the practical part was the analysis of school experience with children with ADHD/ADD. The problem was assessed from many points of view through casuists and interview with children, teachers, parents or assistents. That comes from the theoretical part.

A polineuropatia inflamatória desmielinizante crônica (PIDC) é uma síndrome caracterizada fundamentalmente pela disfunção do Sistema Nervoso Periférico e que afeta muito a qualidade de vida dos pacientes. O envolvimento da PIDC com o Sistema Nervoso Central tem sido descrito, maiormente como sendo subclínico, porém não há estudos sobre a caracterização deste envolvimento de uma forma ampla e quantitativa. Avaliamos 11 pacientes com PIDC, todos tratados e sem sinais clínicos de alterações centrais, e 11 controles, pareados em gênero e faixa etária de 19 a 69 anos. Foram adquiridas neuroimagens em uma máquina de Ressonância Magnética de alto campo (3T) usando diferentes técnicas de imagens; volumétricas ponderadas em T1, volumétricas de inversão e recuperação com atenuação de fluidos e ponderadas em T2, relaxométricas de cinco ecos para mapas de T2, de transferência de magnetização e por tensor de difusão. As imagens foram processadas em diferentes ferramentas computacionais e foram obtidos resultados para estudos da difusibilidade, volumetria, morfometria, tratometria e conectividade cerebral, além de achados radiológicos para os pacientes. As análises de grupos foram executadas por; 1) testes paramétricos monocaudais de duas amostras pareadas para os resultados da volumetria, da tratometria e conectividade cerebral; 2) mapeamento estatístico paramétrico para os resultados da morfometria baseada em voxel e; 3) estatística espacial baseada em tratos para os resultados da difusibilidade. Foram detectas alterações em todas as comparações. Os principais achados indicam um envolvimento possivelmente caracterizado por uma perda volumétrica encefálica generalizada, sobretudo nas regiões periventriculares associadas a ventrículos proeminentes acrescido de, um aumento da difusibilidade transversa e oblíqua nos maiores tratos de substância branca e, também há uma perda de densidade na substância branca periventricular e um aumento na substância cinzenta em uma região que sinaliza para o espessamento trigeminal bilateral e, uma redução geral da conectividade cerebral estrutural. / Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is a severe disease fundamentally characterized by dysfunction of the Peripheral Nervous System and affects greatly the quality of life of patients. The Central Nervous System (CNS) involvement in CIDP has not been described using recent quantitative neuroimaging techniques. We evaluated 11 patients with CIDP, all treated and without clinical signs of central alterations and 11 controls matched for gender and age group of 19 to 69 years. Magnetic Resonance Imaging were performed on a 3T scanner using different imaging techniques; structural 3D T1-weighted, fluid-attenuated inversion recovery, relaxometry with 5 echoes pulse sequence for T2 maps, magnetization transfer weighted and diffusion tensor imaging. The images were processed on different tools and were obtained results for the studies of diffusivity, volumetry, morphometry, tractometry, brain connectivity, and radiological findings of patients. Different statistical group analyses were performed in the quantitative results: 1) Parametric test for volumetry, tractometry and brain connectivity; 2) Parametric mapping for voxel morphometry; 3) Tract-based spatial statistics (TBSS) for diffusion coefficients. Changes were detected in all comparisons. In the patients, our main findings are: generalized loss brain volume more pronounced in periventricular regions associated with prominent ventricles, increased simultaneously perpendiculars and parallel diffusivity in the major tracts of the TBSS analyze, white matter density loss in the periventricular area, some bilateral trigeminal thickening, and general reduction of the brain connectivity. The CIDP affects the global brain and represents a demyelination in the CNS.

Increasing time trends in the recorded incidence of childhood cancer have been reported in many different settings. The extent to which these trends reflect real changes in incidence, rather than improvements in methods for diagnosis and registration, is controversial. Using data from the National Registry of Childhood Tumours (NRCT), this thesis investigates time trends in cancer diagnosed under age 15 in residents of Britain during 1966-2005 (54650 cases), and considers potential sources of artefact in detail. Several different methods are used to estimate completeness of NRCT registration. The history of methods for diagnosis and registration of childhood cancers in Britain is described, and predictions are made for effects on recorded incidence. For each of the 12 main diagnostic groups, Poisson regression is used to fit continuous time trends and ‘step’ models to the annual age-sex-standardised rates by year of birth and year of diagnosis. Age-specific rates by period, and quinquennial standardised rates for diagnostic subgroups, are shown graphically. For three broad groups (leukaemia, CNS tumours and other cancer), geographical variation is compared by period of diagnosis. The results of these analyses are discussed in relation to the predicted artefacts. The evidence for a positive association between affluence and recorded incidence of childhood leukaemia is briefly reviewed. A special form of diagnostic artefact, the ‘fatal infection’ hypothesis, is proposed as an explanation of both this association and the leukaemia time trend. This hypothesis is examined in a novel test based on clinical data. The recorded incidence of childhood cancer in Britain increased in each of 12 diagnostic groups during 1966-2005 (from 0.5% per year for bone cancer to 2.5% for hepatic cancer, with 0.7% for leukaemia). Evidence presented here suggests that these increases are probably artefacts of diagnosis and registration. The potential implications for epidemiological studies of childhood cancer should be considered.