Abstract Previous scientific data suggest that beta-cell destruction in type 1 diabetes is mediated by an autoimmune process. This work was aimed at expanding existing knowledge of humoral autoimmunity by analysing antibodies against the intracellular part of the IA-2 protein (IA-2A) in 1200 patients with the disease, 750 siblings and more than 370 non-diabetic controls. IA-2A were present at the time of diagnosis in the overwhelming majority of patients with type 1 diabetes, and were associated with human leucocyte antigen (HLA) DR4 and DQB1*0302, but not with gender. Humoral autoimmunity was more marked in patients diagnosed when younger than 20 years of age than in older ones, but no noticeable association was observed between IA-2A and age under the age of 20 years. IA-2A in combination with antibodies to GAD65 (GADA) identified a higher proportion of patients younger than 15 years of age at the time of diagnosis than did islet cell antibodies (ICA) alone. The levels of IA-2A and the proportions of antibody-positive patients decreased with increasing duration of type 1 diabetes, although more than half of the patients still tested positive for IA-2A after 10 years of clinical disease. IA-2A, GADA, insulin autoantibodies (IAA) and ICA were detected with individual fluctuations in 8-14% of the siblings of children with type 1 diabetes monitored from the time of diagnosis of the proband, and the fluctuations were modified by HLA-defined genetic susceptibility, age of the siblings, family size and total number of detectable autoantibodies. IA-2A positivity detected at the time of diagnosis of the proband increased the risk of future disease in the siblings. The positive predictive value increased with increasing IA-2A levels, although individual risk assessment appeared to be a complex matter. In conclusion, IA-2 appears to be an important autoantigen in type 1 diabetes, since IA-2A is associated with the HLA haplotype that most strongly predisposes subjects to the disease and have the highest positive predictive value for future disease out of the four autoantibodies used for risk assessment purposes.

No description available.

Due to the increasingly documented prevalence of diarrhoeal diseases in Malaysia, a number of water-related programmes have been implemented in an attempt to improve health status through the reduction of incidence of waterborne communicable diseases associated with poor public water supplies. The implicit assumption underlying these projects is that the enhancement of the physical infrastructure, and subsequent improvements in the quality of the water supply, will substantially reduce waterrelated disease. This thesis questions the veracity of this hypothesis, and therefore the justifiability of an emphasis upon engineering and urban infrastructural interventions. Research centred upon Port Dickson, a district which typifies existing water and sanitation conditions in much of semi-rural Malaysia. The specific objectives of the thesis were: to determine the measured burden of illness of waterborne disease within the district and to estimate levels of underreporting; to determine morbidity-related factors influencing the decision to seek medical treatment; to provide a demographic profile of the population experiencing diarrhoeal episodes; and to identify risk markers or predictors of morbidity. Burden of illness was measured by health services utilization, while values for underreporting and risk markers were derived from a 268 household diarrhoeal morbidity survey. Diarrhoeal incidence was estimated to be 12-16% annually, much higher than Malaysia's official average. This incorporated a rate of non-reporting of 19~, which was influenced by chronicity, duration and severity of episodes. Individuals found to be most at risk were young children and adults in their child-bearing years, minority racial groups, and those with poor water supply and sanitation infrastructure and inappropriate hygiene habits. While water quality was found to influence diarrhoeal rates, factors in addition to infrastructure - partially hygiene - were shown to play a greater role. Thus, it is suggested that the impact of water and sanitation improvement projects would likely be minimal, unless accompanied by complementary behavioural education programmes. The spatial bias of the aforementioned risk factors suggests a need to refocus intervention initiatives upon rural areas. / Thesis / Master of Arts (MA)

Background: Parkinson’s disease (PD) is a common, progressive neurodegenerative disorder, recognized by the motor symptoms of bradykinesia, tremor, rigidity, and postural impairment. At clinical onset, extensive amounts of dopaminergic neurons have already been lost. The duration of this prodromal phase is uncertain, and it is thought to include predominantly non-motor symptoms. The progressive nature and the symptoms of PD are disabling and reduces the quality of life. Among patients affected in working age, early cessation of employment is common, and such socioeconomic consequences of PD may contribute to an impaired quality of life. The aims of this thesis were to investigate the life situation for people affected by PD in working age, with attention to factors of importance for quality of life and working situation, and to evaluate long-term associations between potential prodromal signs and the later development of PD.Methods: We used a postal survey to investigate the self-perceived life situation among working-aged individuals with PD compared to matched controls, with a specific attention to socioeconomic consequences of disease (paper I). To investigate risk markers preceding the diagnosis of PD (paper II-IV), we used data from nationwide registers. Study II was performed as a cohort study, based on the Swedish Military Service Conscription Register, and study III-IV were performed as nested case-control studies based on a cohort comprising all Swedish citizens aged ≥50 years in 2005.Results: In the survey study (paper I), 38% of the PD participants and 9% of the controls were dissatisfied with life as a whole, and the working situation was an independent risk factor for dissatisfaction with life. In total, 59% of the PD participants had reduced working hours or stopped working due to PD, and many PD participants struggled to cope with their work demands. Support from employer was associated with a higher likelihood to remain employed.We found that low muscle strength in young adulthood, (paper II) and depression (paper III) were associated with an increased risk of PD over follow-up times of more than 2 decades, and that patients with PD were at increased risk of fall-related injuries, hip fractures in particular, a decade or more before the PD diagnosis (paper IV). For depression and fall-related injuries, the association with PD was clearly time-dependent, strongest in the last years before the diagnosis of PD.Conclusions: The results suggest that the prodromal phase of PD may last for more than 2 decades and include also motor symptoms. The consequences of PD include a reduced quality of life associated with the working situation. Employer’s support appear to be particularly important for a successful vocational rehabilitation.

Whilst high levels of cardiorespiratory fitness and physical activity may protect against cardiometabolic risk factor clustering, evidence suggests these outcomes are below optimal in English youths. Adolescence is a key stage in health behaviours development, and thus represents an opportunity for interventions aiming to improve the cardiometabolic health, fitness and activity levels of this population. Recently, there has been growing interest in the efficacy of low-volume high-intensity interval training (HIT) as a time efficient way of improving health and fitness outcomes in adults. Contrastingly, the effects of low-volume HIT in adolescents remains relatively unknown. The first aim of this programme therefore was to develop a novel school-based low-volume HIT intervention. The second was to determine the effectiveness of this model for improving the cardiometabolic health, cardiorespiratory fitness and physical activity levels of adolescents. Study one examined adolescents’ views towards high-intensity exercise, and the proposed low-volume HIT intervention. This data was used to design the novel low-volume HIT model. In Study 2, participants’ heart rate and perceived exertion responses to three prototype prescriptions of low-volume HIT, based on boxing, dance and football were examined. Here, it was indicated that these activities were capable of eliciting a high-intensity training response (~90% of maximum heart rate). Study 3 incorporated the main intervention, which examined the effect of a 10-week multi-activity low-volume HIT intervention (named Project FFAB [Fun Fast Activity Blasts]) on various health and fitness outcomes in adolescents. Here, beneficial effects were detected in the intervention participants compared to the controls for triglycerides, waist circumference, lipid accumulation product and daily moderate-to-vigorous physical activity. Study 4 assessed the fidelity of the intervention, and found that this had been largely upheld. Collectively therefore, it appears that Project FFAB represents a viable strategy for improving aspects of cardiometabolic health and physical activity levels in adolescents.

The aim of the present thesis was to assess the occurrence of early lower extremity arterial disease (LEAD) in patients with diabetes and to assess novel potential risk markers for development or worsening of LEAD in the same patients. In parallel different measures of impaired peripheral circulation were evaluated. The measurement of ankle-to- brachial blood pressure index (ABI) to screen for asymptomatic LEAD in diabetic subjects is unreliable since a large proportion of patients have stiff ankle arteries (mediasclerosis) and thus may display a too high ABI. We studied type 1-, type 2 diabetic and non-diabetic subjects without a previous history of LEAD and a composite variable of ankle – plus toe blood pressures and indices was compared to ABI alone in detecting LEAD. Significantly more subjects with reduced peripheral circulation were detected using the composite variable compared to ABI alone. This was particularly true in diabetic subjects, about 30% of whom had signs of impaired peripheral circulation. Thus, it was found that toe blood pressure measurements, alone or in combination with ankle blood pressure measurements, increase the sensitivity for finding early asymptomatic LEAD in diabetic subjects. No significant difference in reproducibility between measurements of absolute ankle- and toe blood pressure and indices was found, but a correlation between systemic (brachial) and toe blood pressure variations over time may suggest that indices are more correct in assessing peripheral arterial circulation. Furthermore, toe blood pressure measurements can be performed using either the great toe or dig II and a strong concordance is found between these measurements. In addition, since the pole-test, another non-invasive method to measure peripheral blood pressure which is less sensitive to the presence of mediasclerosis compared to ABI, correlated significantly with toe blood pressure measurements this method may be used as an alternative screening method in subjects with previously known LEAD. Age, hypertension and glycemic control are well known risk factors and, in addition, high tissue plasminogen activator (tPA) activity turned out to be a novel early marker for asymptomatic LEAD in diabetic subjects, particularly in patients with type 2 diabetes. Age and hyperglycemia are the most important risk factors for development and progression of subclinical lower extremity arterial disease in type 2 diabetic subjects. No independent associations between markers of inflammation, such as CRP, interleukin-6 and TNF-α and early asymptomatic LEAD were seen among non-diabetic or diabetic subjects. In conclusion, impaired arterial circulation in the lower extremities is common in diabetic subjects even in the absence of symptoms. Including toe blood pressure measurement when screening for asymptomatic LEAD in diabetic subjects improves the ability to detect reduced peripheral circulation and this method avoids falsely elevated blood pressures readings due to mediasclerosis in the ankle arteries. Moreover, an altered fibrinolytic activity should be further evaluated as an early marker of atherosclerosis and LEAD.

Physical inactivity and obesity in adolescence are associated with an increased risk of cardiovascular disease (CVD). Although exercise is recommended for the management of obesity, we know little about which types of exercise training are the most effective in reducing excess body fat and improving CVD risk in obese adolescents. This dissertation examined the effects of aerobic training, resistance training and their combination on the cardiometabolic health (body composition, CVD risk markers, resting metabolic rate (RMR), and fitness) of obese adolescents who participated in the Healthy Eating Aerobic and Resistance Training in Youth (HEARTY) trial. After a 4-week supervised moderate-intensity exercise run-in period, 304 overweight and obese adolescents were randomized to 4 groups for 22 weeks: Aerobic training, Resistance training, Combined aerobic and resistance exercise training, or a non-exercising Control. All four groups received dietary counseling designed to promote healthy eating with a maximum daily energy deficit of 250 kcal. Participants were assessed at baseline and after 3 and 6 months. Body composition was assessed using magnetic resonance imaging. Blood tests for traditional and non-traditional CVD risk markers were measured after a 12-hour fast. RMR and cardiorespiratory fitness were assessed using indirect calorimetry at rest and during a maximal treadmill test respectively. Musculoskeletal fitness (muscular strength, endurance, flexibility) was assessed using eight repetition maximum tests (8-RM) on the leg press, chest press and upright row machines and using the Canadian Society for Exercise Physiology- Canadian Physical Activity Fitness and Lifestyle Appraisal (CSEP-CPAFLA) tests for grip strength, push-ups, sit-ups, sit and reach and vertical jump. Decreases in percent body fat and abdominal fat were greatest in the combined training group. Although body weight, RMR and traditional CVD risk markers did not improve following the exercise intervention, the combined training group showed improvements in cardiorespiratory and musculoskeletal fitness and some non-traditional CVD risk markers. Cumulatively, combined aerobic and resistance exercise training showed the greatest improvements in cardiometabolic health in overweight and obese adolescents. This thesis concludes with a knowledge translation article detailing the practical lessons learned from exercise interventions with obese youth with hopes of increasing adherence to future exercise programs and improving the overall health of children and adolescents with obesity.

Physical inactivity is one of the major public health problems in many parts of the World. In Scotland it is reported that two thirds of Scottish adults (>16yrs) and one third of Scottish children (<16yrs) do not do sufficient physical activity to gain the health benefits of physical activity. Furthermore, there is still much debate about the nature and volume of physical activity required to provide health benefits. Therefore, more investigations are required to help improve our understanding of the links between physical activity, obesity and health. In addition, the assessment of habitual physical activity needs to be accurately quantified using appropriate methods that are valid and reliable. The main aims of this thesis were thus to assess the validity and reliability of three new generations of movement sensing devices (Actigraph, ActivPAL and SenseWear PRO2) in adults and adolescents in a controlled laboratory environment and to then use the most valid and reliable device in assessing the habitual physical activity of adults (lean and overweigh/obese) and adolescents in a free-living situation. Following objectively assessing the habitual physical activity, investigation of the associations between physical activity status and cardiovascular and metabolic disease risk markers in adults and adolescents were the last main aims of this thesis. In the first study, the results indicated that the new generations of the three devices were reliable in assessing EE during walking on the flat and on a 5% incline in lean and overweight/obese adults and lean adolescents. However, none iii of these devices and the methods or programme versions that were selected and applied was able to accurately estimate EE during walking on a treadmill. However, based on the sensitivity data obtained and previous evidence, the Actigraph was considered the most appropriate device for assessing the habitual physical activity due to its ability to discriminate between physical activity intensities. The second and third studies concluded that adults (including lean and overweight/obese) met the recommended physical activity guidelines for health and wellbeing purposes. However, the data suggest that overweight/obese participants may need to be advised to spend more time in MVPA and probably more vigorous activity to not only reduce body fat but also to increase cardiorespiratory fitness and reduce their chances of future cardiovascular and metabolic disease. The fourth and fifth studies, demonstrated that the Scottish adolescents –in the cross sectional study- were below the recommended physical activity guidelines. When the method of physical activity assessment was adjusted the Scottish adolescents were similar to the adolescents in other European countries and were observed to be more active than adolescents in some of the developed countries such as American adolescents (Texas State). In the case of lean adolescents who have a low physical activity- but who are not sedentary- the cardiovascular and metabolic disease risk markers may not be obvious at this stage, but the differences in glucose and HOMA-IR suggest that there may be early signs of progression towards metabolic disease in this group. iv The importance of the associations between vigorous physical activity and body fat, as well as between body fat and the risk markers of metabolic disease, suggests that future intervention studies should focus on monitoring the outcome from vigorous physical activity interventions vs. moderate activity within current guidelines.

Diss. (sammanfattning) Umeå : Umeå universitet, 2009. / Härtill 4 uppsatser. Även tryckt utgåva.