Background The optimal exercise load/intensity for exercise programs for individuals with metabolic syndrome (MetS) has not been investigated. One method of determining optimal exercise load is to measure the blood lactate transition threshold (BLTT), referred to as the anaerobic threshold (AT). The first part of this thesis (study 1) investigated the reproducibility of BLTT testing and the consequent determination of AT via the Mader method (Mader et al. 1986) and a modified form of the ADAPT method (Cheng et al. 1992) in patients with MetS. Furthermore, a comparison of the reproducibility of the AT determination using the Mader et al. (1986) method as opposed to the ADAPT method has not been investigated in MetS patients. The effect of specific exercise protocols on the different components of MetS has also not been investigated. Therefore, the second study in the thesis compared the effects on the components of the MetS of an exercise program that uses BLTT (specifically, the AT) to those of a comparable exercise program (not using AT) taken from the literature. The main aim of the study was to design an exercise program that optimized exercise responses and may thus improve metabolic characteristics in individuals with MetS. The third part of the thesis (study 3) focused on the relationship between cardiorespiratory fitness and the components of the metabolic syndrome. This study developed multiple regression models to find the principal variables that associated with peak vi oxygen consumption (VO2 peak) and AT in persons with MetS. Regression models were also developed to investigate whether these variables were associated with the individual metabolic and cardiovascular components of the metabolic syndrome. Methods In study 1, fifteen male patients diagnosed with MetS (age: 43.5 ± 7.52 years) and fifteen healthy, male participants (age: 44.1 ± 6.08 years) each performed a peak oxygen consumption and BLTT test simultaneously using an incremental protocol to exhaustion on a treadmill, at the same daily times, on three different days. Study 2 used three subject groups. One group consisted of ten participants (male, age: 48.3 ± 7.32 years) with MetS that exercised using the walking program of Leon et al. (1979) (MetSL). A second group consisted of ten participants (male, age: 40.8 ± 8.21 years) with MetS that exercised using velocity at AT to set training intensities (MetSV). A third group consisted of ten participants (male, age: 40.2 ± 7.90 years) without MetS that exercised using velocity at AT to set training intensities (Non-MetSV). Training durations and frequency varied from 20 – 90 minutes and 3 -5 days per week respectively. Height, body mass, waist circumference, blood pressure, fasting plasma triglyceride, total cholesterol, HDL-, LDL- cholesterol, insulin levels, VO2 peak and BLTT were measured in all groups before, during and after twenty weeks of exercise. In addition, oral glucose tolerance tests (OGTT) were administered to all participants. 0 min, 30 min and 2 hours plasma glucose and insulin levels were measured during the OGTT. HOMA-IR and insulinogenic indices were also calculated. Nutritional data were recorded at week 0, 8 and 20 of training. vii In study 3, thirty-one males diagnosed with MetS and twenty-four healthy male participants each performed a VO2 peak and a BLTT test. Height, mass, waist circumference, blood pressure, fasting plasma triglyceride, total cholesterol, HDLcholesterol and insulin levels were also measured. In addition, oral glucose tolerance tests (OGTT) were administered to all participants and HOMA indices were calculated. Results There was no significant difference in treadmill velocity at AT determined by the Mader method or the Modified ADAPT method within both groups of study 1 (p > 0.05). The mean treadmill velocity at AT was higher in the healthy compared to the MetS group using both the Mader and the ADAPT method. Regression analysis and ANCOVA in study 1 demonstrated that this difference was largely due to a higher VO2 peak in the healthy group. The study also found an association between VO2 peak and waist circumference. The coefficient of variation of repeat measurements for both the Mader method and the Adapt method was less than 4% indicating good reproducibility. This was confirmed by the typical error method of Hopkins (2000). Study 2 showed that body mass, BMI and waist circumference decreased significantly in all training groups with the training program using AT and the program not using AT showing similar outcomes in these variables among persons with MetS. Velocity at AT also improved in all training groups. While VO2 peak increased (p < 0.05) in both the MetS groups, it did not change significantly in the group without MetS. Similarly, the blood pressure response was favourable in the groups with MetS yet absent in the group viii without MetS. The training group with MetS that used AT was the only group to show significant, positive changes in any of the metabolic parameters (fasting insulin and HOMA). This group also showed the greatest change in the incidence of MetS. In study 3, presence of MetS, waist circumference and AT were found to associate with VO2 peak and VO2 peak was strongly correlated with AT. Age and body mass were found to correlate with fasting glucose, whilst only age correlated with HDL-cholesterol. Age and VO2 peak both correlated with systolic blood pressure but only VO2 peak had a significant association with diastolic blood pressure. Conclusions Study 1 demonstrated that BLTT tests are reproducible in persons with MetS. Study 2 demonstrated that an endurance exercise program using AT to set intensity is effective in eliciting favourable responses in individuals diagnosed with MetS. In addition, the training program using AT elicited the responses with a reduced exercise frequency and intensity. It also improved insulin sensitivity which was not affected by the walking program. The response to the exercise program that used AT was similar in persons with MetS and in persons without MetS, except in the central cardio-vascular adaptations of VO2 peak and in the metabolic parameters of fasting insulin and the HOMA index. Study 3 found that the lower VO2 peak of participants with MetS is associated with their higher waist circumference. The VO2 peak, in turn, was shown to correlate with anaerobic threshold. Therefore, reducing waist circumference in persons with MetS needs to be a focus of intervention programs for such a group. This study also found that both diastolic and systolic blood pressures were associated with cardio-respiratory fitness (VO2 peak). ix This further supports the benefit of increasing cardio-respiratory fitness in persons with MetS. The results of these studies showed that BLTT tests are simple, low-cost, reproducible ways of setting exercise intensity for persons with MetS that can be incorporated in the routine cardio-respiratory fitness assessment of an individual. Furthermore, the determination of AT from such tests can be used to design an individualized exercise program that can “reverse” the effects of MetS.

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No description available.

Rett syndrome (RTT) is an X-linked neurological disorder primarily caused by mutations in the MECP2 gene. The majority of RTT mutations disrupt the interaction of MeCP2 with DNA or TBL1X/TBL1XR1, which forms the scaffold of NCoR/SMRT co-repressor complex. Patients with RTT show no signs of neuronal death, although they have abnormal neuronal morphology, indicating that it is a neurodevelopmental rather than a neurodegenerative disease. It has been shown that reactivation of silenced MeCP2 in mice rescues the RTT phenotype, which implies that the disease is treatable. The RTT mutations in MeCP2 cluster to two regions - the methyl-CpG-binding domain (MBD) and NCoR/SMRT Interaction Domain (NID). While the interaction between MBD and DNA has been biochemically and structurally characterised, there are no structural data about the interaction between MeCP2 NID and TBL1XR1. The aim of this work was to understand how mutations in the NID cause RTT by characterising the interaction between MeCP2 and TBL1XR1. I have solved the structure of MeCP2 NID bound to TBL1XR1 WD40 domain. I show that a small region of the MeCP2 NID makes extensive contacts with TBL1XR1, and that these contacts are mediated primarily by MeCP2 residues known to be mutated in RTT. I also measured the affinities between TBL1XR1 and MeCP2-derived peptides using fluorescence anisotropy and surface plasmon resonance assays. I determined the affinity between MeCP2 NID peptide and TBL1XR1 to be around 10- 20 μM, and show that mutations in either MeCP2 or TBL1XR1 can abolish this interaction. Taken together, these data strongly suggest that the abolition of the interaction between MeCP2 NID and TBL1XR1 WD40 domain is sufficient to cause RTT. This knowledge can help with the rational design of small drug-like molecules that might be able to mediate the interaction between mutated MeCP2 and TBL1XR1, potentially helping to treat the disease.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Nos Ãltimos anos, a sÃndrome metabÃlica tem despertado profundo interesse e debate na comunidade cientÃfica. A ascensÃo epidemiolÃgica deste distÃrbio ocorre nas mais diversas populaÃÃes e faixas etÃrias, somada à sua capacidade de agregar vÃrios fatores de risco para doenÃas cardiovasculares, como aumento das medidas antropomÃtricas, dislipidemias aterogÃnicas, hipertensÃo arterial sistÃmica, alteraÃÃes do metabolismo dos carboidratos, estado prÃ-inflamatÃrio e prÃ-trombÃtico. Mencionada sÃndrome està associada ao maior risco de desenvolver diabetes mellitus tipo 2, doenÃa coronariana precoce e altas taxas de morbimortalidade para complicaÃÃes cardiovasculares. Teve-se como objetivo geral analisar a circunferÃncia do pescoÃo como possÃvel marcador para a sÃndrome metabÃlica em estudantes de uma universidade pÃblica de Fortaleza-CE. Trata-se de um estudo exploratÃrio, quantitativo, transversal e observacional realizado de marÃo de 2010 a junho de 2011 na Universidade Federal do CearÃ, com 702 universitÃrios das seis grandes Ãreas do conhecimento. Participaram do estudo 440 mulheres e 262 homens com idade entre 16 e 58 anos. Percebeu-se associaÃÃo entre a CP e os dados sociodemogrÃficos; 43,9 % dos homens e 7,1% das mulheres apresentaram CP elevada, sendo estatisticamente significante, p < 0,0001 em ambos os sexos. SituaÃÃo semelhante se deu com a idade (p< 0,001), com a situaÃÃo laboral (p<0,031) e com o semestre (p < 0,012). Em relaÃÃo à prÃtica de atividade fÃsica, 22,4% dos sujeitos que praticam algum tipo de atividade fÃsica regular tiveram a CP elevada (p < 0,503). O IMC tambÃm se mostrou estatisticamente significante com p<0,0001. A CP denotou correlaÃÃo positiva com todos os componentes da sÃndrome metabÃlica segundo os critÃrios do NCEP/ATP III. Conforme se concluiu, a CP à um marcador preditor para sÃndrome metabÃlica numa populaÃÃo de universitÃrios. Contudo, ressalta-se a importÃncia de outros estudos sobre essa temÃtica. / In recent years, the metabolic syndrome has aroused profound interest and debate in the scientific community. The epidemiological ascent of this disorder occurs in a wide range of populations and age groups, in addition to its capacity to aggregate various risk factors for cardiovascular illnesses, such as increased anthropometric measures, atherogenic dyslipidemias, systemic arterial hypertension, alterations in carbohydrate metabolism, pro-inflammatory and pro-thrombotic status. This syndrome is associated with a greater risk of developing type 2 diabetes mellitus, early coronary disease and high morbidity and mortality levels for cardiovascular complications. The general aim was analyze neck circumference as a possible marker for the metabolic syndrome in students at a public university in Fortaleza-CE. An exploratory, quantitative, cross-sectional and observational study was developed between March 2010 and June 2011 at University Federal of CearÃ, involving 702 college students from the six large knowledge areas. Study participants were 440 women and 262 men between 16 and 58 years of age. An association was perceived between neck circumference (NC) and sociodemographic data: 43.9% of men and 7.1% of women showed altered NC, with statistical significance at p < 0.0001. A similar situation occurred for age (p< 0.001), occupational situation (p<0.031) and the semester (p < 0.012). Concerning physical exercise, 22.4% of the subjects who exercise regularly displayed altered NC (p < 0.503). The BMI also showed statistical significance with p<0.0001. NC indicated a positive correlation with all metabolic syndrome components according to NCEP/ATP III criteria. In conclusion, NC is a predictive marker of the metabolic syndrome in a population of college students. The importance of further research on this theme is highlighted though.

Introducción: La angina variante por vasoespasmo coronario y el síndrome X han sido mencionados como responsables de angina en ausencia de lesión coronaria significativa. Sin embargo no todos los pacientes en esta situación clínica cumplen criterios para ser agrupados en estas entidades patológicas.Pacientes y Métodos: Se estudiaron 328 pacientes consecutivos divididos en 4 grupos: A: Angina vasoespástica (n:165). B: Síndrome X (SDX) [sin vasoespasmo (VSP) con prueba de esfuerzo (PE) positiva] (n:47). C: Angina de reposo o mixta, sin VSP y PE negativa (n:93) D: Angina de esfuerzo, sin VSP y PE negativa (n:23). Fueron excluidos del estudio aquellos pacientes con patología extracoronaria que justificase la angina. Se evaluaron antecedentes patológicos, factores de riesgo y características clínicas. Se realizó a todos una prueba de esfuerzo, con gammagrafía en 214 casos, y se analizó en el seguimiento a largo plazo (72±52meses) valorando la mortalidad y la aparición de eventos coronarios.Resultados: La prevalencia global de dislipemia fue elevada (67%) y no mostró diferencias significativa entre los grupos. La prevalencia del tabaquismo fue superior en los pacientes que presentaban VSP (62 vs 22%, p<0,001) y la de HTA fue superior en el SDX que en el resto de los grupos (51 vs 34%, P<0,05). Entre los pacientes vasoespásticos existía una mayor proporción con respuesta a NTG que en los no vasoespásticos (85 vs 54%,p<0,01). Un 43,2% de los pacientes de grupos C y D presentan defectos de perfusión reversibles. No existieron diferencias significativas entre los pacientes con y sin VSP en la aparición de cambios ECG (24,6 vs 29%, p:ns) ni defectos gammagráficos (53 vs 50%,p:ns) durante la PE. En el seguimiento se observó una reducida mortalidad (3%) y una baja incidencia de infarto de miocardio (5%) sin evidenciarse diferencias entre los grupos ni entre pacientes con (4,7%) o sin (7%) defectos gammagráficos de esfuerzo (p:ns).Conclusiones: Nuestros resultados indican que existe una proporción importante de pacientes anginosos sin lesiones coronarias significativas que no presentan vasoespasmo ni cambios en el ECG de esfuerzo. No obstante, casi la mitad de ellos presentan defectos de perfusión durante el esfuerzo, en su mayoría leves. Existe una baja incidencia de infarto de miocardio y de mortalidad cardiaca en el seguimiento a largo plazo. La aparición de defectos gammagráficos de esfuerzo no confiere empeoramiento en el pronóstico. / Introduction: Variant angina due to coronary spasm and syndrome X are known to be responsible for angina in the absence of significant coronary stenosis. However, not all patients in these clinical conditions meet the criteria to be labelled as these pathological entities.Patient and methods: We studied 328 consecutive patients in 4 different groups: A: vasospastic angina (n:165). B: Syndrome X (SDX) [without vasospasm (VSP) with a positive stress test (ST)] (n:47). C: Rest angina or mixed angina, without VSP and with a negative ST (n:93). D: stress angina without VSP and with negative ST (n:23). Those patients with non coronary cause of angina were excluded of this study. We evaluated pathological antecedents, risk factors and clinical characteristics. Stress tests were performed in all patients, 214 of them with scintigraphic perfusion analysis. We study incidence of mortality and coronary events in the long term follow up (72±52month).Result: The global prevalence of dislipidemia was high (67%) without significant differences between groups. The prevalence of smoking was higher in the vasospastic patients (62 vs 22%, p<0,001) and the hypertension's prevalence was higher in Group B than in the remaining groups (51 vs 34%, P<0,05). Among vasospastic patients we observed a greater proportion with response to nitroglicerine than no vasospastic patients (85 vs 54%, p<0,01). Forty tree patients from groups C and D presented reversible perfusion defects. There were not significant differences between patients with and without VSP in the ECG changes (24,6 vs. 29%, p:ns) nor in the scintigraphic defects (53 vs 50%,p:ns) during ST. In the follow-up we observed a low mortality rate (3%) and a low incidence of infarct (5%) without differences among the groups nor between patients with (4,7%) or without (7%) stress scintigraphic defects (p:ns) during ST.Conclusions: Our results indicate than there is an important proportions of patients with angina without significant coronary artery stenosis who do not nither present vasospasm nor ECG changes during ST. However, nearly a half of them present perfusion defects during ST, mild in most of them. There is a low incidence of myocardial infarct and cardiac mortality in the long-term follow-up. The presence of stress scintigraphic defects do not implicate worse prognosis.

Obesity, diabetes, hypertension, and heart disease are highly heritable conditions that in aggregate are the major causes of morbidity and mortality in the developed world and are growing problems in developing countries. To map the causal genes, we conducted a population screen for these conditions on the Pacific Island of Kosrae. Family history and genetic data were used to construct a pedigree for the island. Analysis of the pedigree showed highly significant heritability for the metabolic traits under study. DNA samples from 2,188 participants were genotyped with 405 microsatellite markers with an average intermarker distance of 11 cM. A protocol using LOKI, a Markov chain Monte Carlo sampling method, was developed to analyze the Kosraen pedigree for height, a model quantitative trait. Robust quantitative trait loci for height were found on 10q21 and 1p31. This protocol was used to map a set of metabolic traits, including plasma leptin to chromosome region 5q35; systolic blood pressure to 20p12; total cholesterol to 19p13, 12q24, and 16qter; hip circumference to 10q25 and 4q23; body mass index to 18p11 and 20q13; apolipoprotein B to 2p24-25; weight to 18q21; and fasting blood sugar to 1q31-1q43. Several of these same chromosomal regions have been identified in previous studies validating the use of LOKI. These studies add information about the genetics of the metabolic syndrome and establish an analytical approach for linkage analysis of complex pedigrees. These results also lay the foundation for whole genome scans with dense sets of SNPs aimed to identifying causal genes.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.