Children and adolescents are thought to use oxidative metabolism to a greater extent than adults during high intensity exercise. The studies reported in this thesis examine the nature and implications of age-related differences in muscle metabolism during high intensity exercise and recovery. Chapter 4 concluded that during heavy intensity exercise, phosphocreatine (PCr) kinetics did not differ with age or sex, while Chapter 5 revealed that during very heavy intensity exercise, the fundamental τ was slower and slow component amplitude greater in men compared with adolescent boys, indicating that exercise intensity might play a role in determining age-related differences in muscle metabolism. In Chapter 6, two bouts of very heavy intensity exercise were completed, and prior exercise reduced the PCr slow component amplitude in men but not boys. Deoxyhaemoglobin (HHb) kinetics was faster in adolescents compared with adults during both heavy and very heavy intensity exercise, indicating that matching of oxygen delivery to oxygen utilisation is less precise at the onset of exercise in adolescents compared with adults. PCr recovery from high intensity exercise was faster in boys than men, but not different in girls and women, as described in Chapter 7. The speed of PCr recovery was correlated with maturity in adolescents, but was not correlated with end-exercise [PCr] or pH. Two different tests to measure mitochondrial capacity in adolescents were evaluated in Chapter 8, and a fitted curve and gated test were both used to determine PCr recovery kinetics. Finally, in Chapter 9, age-related differences in muscle metabolism and oxygenation during fatiguing exercise were examined; a strong trend for greater fatigue in adults compared with adolescents was accompanied by greater metabolic perturbation in adults. Overall, these data show that muscle metabolism and oxygenation differs between adolescents and adults during and following very high intensity exercise.

A 1H, 13C, and 6Li NMR study of 2-ethyl-1-butyllithium indicated that 2-ethyl-1-butyllithium exists only as a hexameric aggregate over the entire temperature range of 25 to - 92.1 ° C in cyclopentane. Reacting 2-ethyl-1-butyllithium with 2-ethyl-1-butanol resulted in alkyllithium/lithium alkoxide mixed aggregates, apparently of the form Ra(RO)bLia+b. A multinuclear, variable temperature NMR study of samples with O:Li ratios of 0.2 and 0.4 showed, in addition to the alkyllithium, the formation of four mixed aggregates, one of them probably an octamer. Higher O:Li ratio samples showed the formation of several other mixed aggregates. Mixing 2-ethyl-1-butyllithium with independently prepared lithium 2-ethyl-1-butoxide formed the same mixed aggregates formed by in situ synthesis of lithium alkoxide. Lithium 2-ethyl-1-butoxide also exists as aggregates in cyclopentane.

Inflammatory arthropathies and systemic rheumatic diseases (IASRDs) commonly involve the cardiovascular system, and are associated with high morbidity and mortality. Mechanisms of cardiovascular involvement in these clinical entities are not fully understood. Cardiovascular magnetic resonance (CMR) is the single imaging modality capable of assessing non-invasively cardiac function, strain, ischaemia, altered vascular function, perfusion, oedema/inflammation and fibrosis. Furthermore, magnetic resonance spectroscopy (MRS) can give further insights into the status of myocardial energetics and lipidosis. The pathophysiological mechanisms and phenotype of cardiovascular disease (CVD) in IASRDs need further clarification. CMR is an ideal tool for the early identification and monitoring of cardiac manifestations in patients with IASRDs. Hence, the aims of this D.Phil project were to (i) utilise CMR and MRS to study disease mechanisms in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), and (ii) to assess the role of anti-cytokine therapies in abrogation of cardiovascular complications and effects on cardiovascular function in patients with RA, ankylosing spondylitis (AS) and psoriatic arthritis (PsA). First, we used CMR to assess myocardial structure and function in RA, SLE and SSc patients with no known cardiovascular symptoms. Patients and controls were stratified by the presence of traditional cardiovascular risk factors (CVRFs). Our data demonstrated no differences in overall left ventricular (LV) systolic function, size and mass between patients and matched controls. There were, however, impairments in regional function and myocardial deformation, which is most severe in RA, SLE and SSc patients with CVRFs. We also found evidence of impaired vascular function in RA, SLE and SSc, using pulse wave velocity (PWV) and aortic distensibility, and again, showed that patients with CVRFs demonstrated the most severe aberrations, while patients without CVRFs and controls with CVRFs had an intermediate phenotype. Abnormalities in vascular and regional function were most severe in patients with SSc. Also, we showed that impaired vascular function correlated with abnormal systolic myocardial strain and diastolic strain rate in all groups of IASRDs studied. These data have implications for the clinical care of patients with RA, SLE and SSc and show that there is extensive cardiovascular involvement in asymptomatic patients. These results also suggest that early identification and stratification of CVD in IASRDs, with non-invasive techniques like CMR, may permit earlier intervention, thus potentially reducing the effect of CVD on morbidity and mortality in IASRDs. Lastly, these data highlight the importance of early detection and aggressive management of co-existent traditional CVRFs, as they confer incremental risk of CVD in patients with IASRDs. Second, we used CMR for comprehensive phenotyping of tissue characteristics in patients with RA, SLE and SSc. Our data confirmed that subclinical myocardial changes are common in patients with IASRDs (even with apparently normal hearts), which can be detected using multiparametric CMR. In addition to focal areas of fibrosis (detected by late gadolinium enhancement [LGE]), there were also areas of focal myocardial oedema or inflammation (detected by T2-weighted imaging). Further, using more sensitive techniques such as native T1 mapping and extracellular volume (ECV) quantification, we were able to demonstrate even more areas of myocardial involvement in IASRD patients than conventional CMR techniques can reveal, with patients showing significantly larger areas of T1 abnormality and expanded ECV, which likely represent a combination of low grade inflammation and diffuse myocardial fibrosis that are well-described disease processes in this cohort. We also found that T1 and ECV measures were associated with subtle myocardial systolic and diastolic dysfunction. The results of this study suggest that CMR, particularly T1 and ECV quantification, can be used for early detection of subclinical myocardial involvement in IASRD patients, potentially serving as an early screening tool before overt LV dysfunction or irreversible myocardial damage occurs. Third, we utilised CMR to study myocardial perfusion in patients with RA, SLE and SSc. We found that myocardial perfusion was impaired in asymptomatic IASRD with no overt heart disease. Non-segmental, subendocardial perfusion defects consistent with microvascular dysfunction were present in 47%, 31% and 41% of RA, SLE and SSc patients, respectively. Furthermore, there was a significant correlation between MPRI and systolic and diastolic regional function in all groups of patients. In RA and SSc, there was also a correlation between myocardial perfusion reserve index (MPRI) and disease activity. SSc patients had the greatest burden of ECV expansion, and in this group ECV also correlated with MPRI. These data led us to hypothesise that myocardial ischaemia likely leads to impaired myocardial relaxation and diffuse fibrosis, which predate overt dysfunction in contractility. Fourth, we investigated the effect of TNF-alpha inhibitors on myocardial and vascular function and structure in RA, AS and PsA patients. We confirmed that anti-TNF therapy was associated with improvements in serum inflammatory parameters like CRP and ESR, as well as with improved clinical measures of disease activity. Anti-TNF therapy, however, was not related to a change in left ventricular size, mass and global systolic function. We found that inhibition of TNF-alpha activity does result in better myocardial strain and strain rate, likely reflecting an improvement in myocardial inflammatory burden. Moreover, these findings were also supported by improvements in T2 weighted measures, native T1 values and ECV calculations. There was, however, no significant change in myocardial perfusion following anti-TNF therapy. These results support the hypothesis that during episodes of disease activity, myocardial oedema is present in patients with IASRDS and that by reducing the systemic inflammatory response, improvements in myocardial and vascular function can be achieved. Finally, we used CMR and MRS in asymptomatic RA and SLE patients (with normal hearts on echocardiography) to investigate cardiac metabolic status in this cohort. We found that myocardial energetics were impaired in patients, despite preserved overall ejection fraction. Interestingly, abnormal myocardial energetics were associated with presence of LGE, decreased myocardial perfusion, expanded ECV, volume fraction of T1 >990ms (which represents >2 standard deviations above the mean T1 value at 1.5T) and left atrial size. We did not find any difference in myocardial and hepatic lipid content between patients and controls. These data clearly demonstrate that abnormalities in cardiac energetics are present in IASRD patients even before the development of overt cardiac dysfunction, and may be driven by microvascular function and fibrosis.

It has been demonstrated that by using 1H NMR spectroscopy in combination with multivariate statistical modelling (PLS) it is possible, using urine samples obtained from rats, to distinguish between different types of CNS lesions. Against this background this thesis will explore whether the combination of 1H NMR and PLS modelling on biofluids can be used q-1eientify biomarkers in .. - different neurological diseases and in clinically relevant animal models of neurologic disease. The results in this thesis demonstrate that it is possible to separate sets of animals at different stages of disease in models of multiple sclerosis and to identify the presence of early brain metastasis. The same methodology was also applied to human biofluids. In MS patient cohorts (RR- MS, PP-MS and SP-MS) it was also possible to differentiate between RR-MS and SP-MS as well between MS and healthy controls. Therapy for these two stages of MS are very different and therefore a rapid test to determine a patient's stage of MS would be hugely beneficial in the clinic. Further investigation revealed that it is possible to separate MS patients from individuals with Alzheimer's disease. Metabolomics was then combined with other eo- variants in a study of cerebrospinal fluid obtained from patients with HIV associated dementia (HAD) to discover whether disease progression could be followed in this manner. The results show that it is possible to detect neurocognitive changes in patients with HAD. Indeed, the results demonstrate. that metabolomics is a far more sensitive tool for the following progression than other non-PLS biomarker techniques and should provide a useful method for early diagnosis of CNS disease and the evaluation of therapy in prospective studies.

Objetivo: Determinar a sensibilidade e a especificidade da pesquisa do nistagmo de privação vertebrobasilar (PNPVB), Angiorressonância magnética (AngioRM), investigação ultrassonográfica cervical e Doppler transcraniano (DTC) em pacientes com diagnóstico clínico de insuficiência vertebrobasilar (IVB). Método: o estudo foi aprovado pela comissão de ética local. Os participantes deram consentimento formal. Foi formado grupo de estudo (GE) e grupo controle (GC) com 12 sujeitos em cada, pareados por sexo e idade, sendo 4 masculinos e 8 femininos, com média de idade de 72,66 (±8.35 anos). Os doentes foram selecionados do Ambulatório de Otoneurologia do HC-FMUSP com idade acima de 55 anos, sem outra provável causa de tonturas. Voluntários assintomáticos do Grupo de Apoio Multidisciplinar ao Idoso Ambulatorial (GAMIA) formaram o GC. Todos os participantes realizaram avaliação cardiogeriátrica para excluir qualquer doença de base que pudesse ser a causa da tontura, que não a IVB. Assim, os dois grupos realizaram a PNPVB, a AngioRM, a avaliação ultrassonográfica cervical e DTC. Resultados: PNPVB, AngioRM e avaliação ultrassonográfica cervical não mostraram diferenças entre os grupos. No DTC, foram detectadas diferenças significantes em cinco variáveis: velocidade do pico sistólico da artéria cerebral média direita (ponto de corte em 76,00; sensibilidade de 0,83; especificidade de 0,75; p=0,012), velocidade diastólica final da artéria basilar (ponto de corte em 24,00; sensibilidade de 0,66; especificidade de 0,66; p=0,028), índice de pulsatilidade (IP) da artéria cerebral média esquerda (ponto de corte em 0,85; sensibilidade de 0,83; especificidade de 0,75; p=0,005), IP da artéria cerebral média direita (ponto de corte em 0,88; sensibilidade de 0,75; especificidade de 0,75; p=0,010), IP da artéria basilar (ponto de corte em 1,01; sensibilidade de 0,91; especificidade de 0,91; p < 0,001). Considerando-se o IP da artéria basilar, calculou-se o poder estatístico para uma amostra com 12 sujeitos em cada grupo, sendo > 95%. Conclusão: a PNPVB e a AngioRM não mostraram diferenças entre os grupos. O DTC mostrou sensibilidade de 91% e especificidade de 91% para o diagnóstico da IVB relacionada à tontura, quando o IP da artéria basilar for maior que 1,01 / Objective: To determine the sensitivity and specificity of the vertebro-basilar deprivation nystagmus (VBDN), magnetic resonance angiography (MRA), cervical ultrasonographic investigation and Transcranial Doppler Ultrasound (TDU) in patients with clinical diagnosis of vertebro-basilar insufficiency (VBI). Methods: The study was approved by the Ethics in Research Committee. The patients gave formal consent for participating in this study. We composed 2 groups: a study group (SG) and a control group (CG), comprised of 12 patients each, with sex- and age-matched patients (4 men and 8 women). Their mean age was 72.66 (±8.35) years. The study group included patients from the neurotology outpatient clinic of the HC-FMUSP who were over 55 years old, without any other possible cause for dizziness than VBI. Asymptomatic volunteers from the geriatrics outpatient clinic were included in the CG. All participants were subjected to evaluation of a cardio-geriatric professional, to exclude any subjacent disease that could cause dizziness other than VBI. Then, both groups were subjected to VBDN, MRA, cervical ultrasonographic investigation and TDU. Results: The VBDN, MRA and cervical ultrasonographic investigation did not demonstrate differences between the groups. The TDU demonstrated that the systolic pulse velocity of the right middle cerebral artery (sensitivity=0.83, specificity=0.75; p=0.028), final diastolic velocity of the basilar artery (sensitivity=0.66; specificity=0.66; p=0.028), pulsatility index (PI) of the left middle cerebral artery (sensitivity=0.83; specificity=0.75; p=0,005), PI of the right middle cerebral artery (sensitivity=0.75; specificity=0.75; p=0.010), and the PI of the basilar artery (sensitivity=0.91; specificity=0.91; p < 0.001) were significantly higher in the diseased group compared to controls. Considering the PI of the basilar artery, we observed that the statistic power of the test was higher than 95%. Conclusion: The VBDN, MRA and cervical ultrasonographic investigation did not demonstrate significant changes in patients with VBI compared to controls. The PI of the basilar artery, measured using the TDU, demonstrated high sensitivity (91%) and specificity (91%) levels in the diagnosis of VBI when the PI was higher than 1.01

A ressonância magnética (RM) é um exame de diagnóstico por imagem amplamente utilizado e permite a obtenção de imagens de diversos segmentos do corpo com alta qualidade. Embora seja um exame de excelência, os pacientes que se submetem a esta técnica, podem apresentar claustrofobia em razão do espaço limitado dentro do equipamento. A claustrofobia é considerada um estado de ansiedade e classificada como uma fobia específica pelo DSM IV. O Questionário de Claustrofobia (CLQ) é um instrumento de mensuração, que foi criado em língua inglesa e posteriormente, foi traduzido e validado para outras línguas e culturas, inclusive no Brasil em 2008. Trata-se de uma escala do tipo Likert, com escores que variam de 0 (nada ansioso) a 4 (extremamente ansioso); possui 26 itens que são distribuídos em dois domínios (sufocação 14 itens e restrição 12 itens). OBJETIVO: Avaliar as propriedades psicométricas da versão brasileira do Questionário de Claustrofobia, aplicado a pacientes submetidos à Ressonância Magnética. MATERIAL E MÈTODO: Foram realizadas a avaliação da consistência interna, análise fatorial confirmatória, validação de construto convergente (correlacionado Questionário de Claustrofobia com o Inventário de Ansiedade - Estado), validação de construto discriminante e aplicação da curva ROC para propor um ponto de corte para o instrumento. A coleta de dados foi feita em um hospital de grande porte do Município de São Paulo com 300 pacientes que realizaram ressonância magnética; pela aplicação de três instrumentos, sendo eles: o de caracterização biossociodemográfica, Questionário de Claustrofobia e Inventário de Ansiedade - Estado. RESULTADOS: A confiabilidade interna medida pelo coeficiente alfa de Cronbach obteve os seguintes valores: para o total da escala 0,94; para os domínios sufocação, 0,80 e restrição, 0,93. A análise fatorial confirmatória confirmou dois domínios e obteve valor de NNFI 0,692, considerado bom valor de ajuste para o modelo. A validação de construto convergente correlacionou o CLQ com o Inventário de Ansiedade- Estado e os valores obtidos foram muito próximos a zero, indicando que não há relação entre os instrumentos (r - 0,111). Já a validação de construto discriminante, em que foi utilizado o teste Mann-Whitney, foi capaz de discriminar os grupos claustrofóbicos com as variáveis claustrofobia referida, RM prévia e faixa etária. Foi estabelecido o ponto de corte pela curva ROC e a pontuação se for, igual ou maior que 16 pontos, sugere o potencial desenvolvimento da claustrofobia. CONCLUSÃO: Os resultados permitiram concluir que o Questionário de Claustrofobia teve desempenho satisfatório, atestando sua confiabilidade e mostrando-se válido para medir a claustrofobia no ambiente de ressonância magnética. / Magnetic resonance imaging (MRI) is a diagnostic imaging widely used and allows obtaining images of various body segments with high quality. Although an examination of excellence, patients who undergo this technique may have claustrophobia due to the limited space inside the equipment. Claustrophobia is considered a state of anxiety and classified as a specific phobia by DSM - IV. The Claustrophobia Questionnaire (CLQ) is a measurement tool, which was created in English and then translated and validated for other languages and cultures, including Brazil in 2008. It is a Likert scale, with scores ranging from 0 (not anxious) to 4 (extremely anxious); has 26 items that are divided into two domains (14 items suffocation and restriction 12 items). OBJECTIVE: To evaluate the psychometric properties of the Brazilian version of the Claustrophobia Questionnaire applied to patients undergoing MRI. MATERIAL AND METHODS: We performed an evaluation of internal consistency, confirmatory factor analysis, convergent construct validation (Claustrophobia Questionnaire correlated with Anxiety Inventory - State), discriminant construct validation and application of the ROC curve to propose a cutoff point for the instrument. Data collection was done in a large hospital in São Paulo with 300 patients who underwent MRI, the application of three instruments, namely: the characterization of bio socio demographic protocol, Claustrophobia Questionnaire and Anxiety Inventory - State. RESULTS: The internal reliability as measured by Cronbach\'s alpha obtained the following values: for the total scale 0.94; domains to suffocation, restriction and 0.80, 0.93. Factor analysis confirmed two domains and obtained value of NNFI 0.692, considered good value adjustment to the model. Validation convergent construct the CLQ correlated with State Anxiety Inventory and the values obtained were very close to zero, indicating no relationship between the instruments (r - 0.111). Already construct validation discriminant, in which we used the Mann-Whitney test was able to discriminate between claustrophobia claustrophobic with the variables mentioned, previous CABG and age. Was established cutoff by ROC score and if equal to or greater than 16 points, suggests the potential development of claustrophobia. CONCLUSION: The results showed that the Claustrophobia Questionnaire showed a satisfactory performance, proving its reliability and proving to be valid to measure the claustrophobia in MRI environment.

A carne bovina é considerada um alimento altamente nutritivo, sendo uma fonte de proteínas e vitaminas, além de minerais tal como ferro e zinco. Por outro lado, a carne vermelha atualmente tem sido associada a doenças cardiovasculares e ao câncer. No entanto, essa associação vem sendo contestada, pois a carne de ruminantes bem como o leite são fontes naturais do ácido linoléico conjugado (CLA, do inglês \"conjugated linoleic acid\"), o qual possui várias propriedades benéficas, como atividade anticarcinogênica, redução de gordura corporal, entre outras. Essas propriedades têm sido observadas em estudos com animais modelos, mas também pesquisas apontam tais benefícios para os humanos. Vários estudos têm sido realizados para aumentar a produção de CLA pelos ruminantes no Brasil. Nesse contexto, se faz necessário o desenvolvimento de métodos rápidos e eficazes para a determinação de CLA em carnes de ruminantes e no leite, pois o método atual é baseado na análise dos ésteres metílicos dos ácidos graxos por cromatografia gasosa, que envolve várias etapas, sendo um método laborioso. Assim, o principal objetivo deste trabalho foi o desenvolvimento de uma metodologia rápida, baseada na técnica de ressonância magnética nuclear de hidrogênio (RMN de 1H) para a determinação do teor do CLA na gordura de carne bovina. Para isso foi avaliada a influência dos principais parâmetros experimentais de RMN de 1H, como a largura do pulso de radiofrequência, o tempo de repetição, método de excitação seletiva, entre outros parâmetros que podem interferir na razão sinal/ruído e na reprodutibilidade das medidas. Os resultados mostraram que a utilização da RMN de 1H para a determinação do teor de CLA em carne bovina, além de ser coerente com os dados obtidos por cromatografia gasosa, representa uma abordagem mais rápida e simples para a determinação do teor de CLA em carne bovina. / Beef is considered a very nutritive food, since it is a source of proteins and vitamins, besides minerals such as iron and zinc, on the other hand it has been associated to heart diseases and cancer. However, this association has been contested because ruminant meat as well as milk, is a natural source of conjugated linoleic acid (CLA), that has several benefic properties such as anticarcinogenic activity, reduction of body fat and others. These properties have been observed in studies with animals and can be extended to humans. Several studies have been done to increase the concentration of CLA in Brazilian ruminant meat. In this context, it is necessary to develop fast and effective analytical methods to determine CLA in ruminant meat and milk, because the current method, based on the analysis of fatty acid methyl esters by gas chromatography (GC), involves several stages, being laborious. Thus, the main purpose of this work was the development of a fast methodology, based on hydrogen nuclear magnetic resonance technique (1H NMR) to determine CLA content in beef fat. In consequence, it was evaluated the influence of main experimental parameters from 1H NMR, such as radiofrequency pulse width, repetition time, method of selective excitation, between others that may interfere in signal-to-noise ratio and reproducibility. The results indicated that the use of 1H NMR spectroscopy to determine CLA content in beef have high correlation to data obtained by gas chromatography, representing a much faster and simpler methodology to determine CLA content in beef.

Foi realizada a comparação entre os achados de espectroscopia de prótons por ressonância magnética utilizando a sequência PRESS (point resolved spectroscopy), com TE curto (35ms) no cíngulo posterior e hipocampos de 29 pacientes com doença de Alzheimer (leve e moderada) e 15 controles. As relações de metabólitos com melhor sensibilidade e especificidade na diferenciação entre os grupos foram em ordem decrescente: Naa/Cr do cíngulo, mI/Naa do cíngulo, mI/Naa dos hipocampos e mI/Cr dos hipocampos. Não houve vantagens, nesta casuística, na realização da espectroscopia de prótons nos hipocampos, um local tecnicamente mais difícil e demorado em relação ao cíngulo posterior. Observou-se correlação positiva da relação Naa/Cr e negativa da relação mI/Naa do cíngulo posterior com o MMSE / The objective of this study is to compare the findings on Magnetic Resonance Spectroscopy using PRESS (point resolved spectroscopy) technique with short TE (35ms) in the posterior cingulate and hippocampi of 29 patients with Alzheimer's disease (mild and moderate) and 15 controls. The metabolic ratios with highest sensitivity and specificity were (in a decreasing order): posterior cingulate Naa/Cr, posterior cingulate mI/Naa, hippocampi mI/Naa and hippocampi mI/Cr. In the group analised it seems there is no advantage in performing MRS in the hippocampi instead of posterior cingulate, a technically challenging location, usually leading to a longer examination time. In the posterior cingulate we observed a positive correlation with Naa/Cr ratio and a negative correlation with mI/Naa ratio and the MMSE

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1980. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND SCIENCE. / Vita. / Includes bibliographical references. / by William Paul Rothwell. / Ph.D.

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1979. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND SCIENCE. / Includes bibliographical references. / Ph.D.