Background: We aimed to increase the knowledge regarding the familial arrhythmogenic disorder Long QT Syndrome (LQTS) and its recessive variant Jervell and Lange-Nielsen Syndrome (JLNS) in Sweden, including prevalences and clinical phenotypes. A specific focus was directed towards two KCNQ1 mutations –p.Y111C and p.R518X- commonly identified in Swedish LQTS index cases. Methods: Cases and families with LQTS (p.Y111C or p.R518X) and JLNS were recruited via regional clinical practices, national referrals to the Clinical Genetics laboratory, Umeå University Hospital, and a national inventory. Molecular genetics methods were used for case ascertainment. Clinical data was obtained via medical records, a questionnaire, and/or an interview. Electrocardiograms were manually assessed. In p.R518X heterozygotes intra-familial phenotypic variability (QTc and cardiac events) was assessed by analysis of sequence variants (modifier genes). The origins of the mutations p.Y111C and p.R518X were investigated using genealogical and haplotype analysis (microsatellite markers). In families sharing a common haplotype mutation age and associated prevalence was analyzed using ESTIAGE and DMLE computer software. Results: We identified p.Y111C (170 mutation-carriers) and p.R518X (101 mutation-carriers) as two major causes of LQTS/JLNS in Sweden. LQTS phenotype was revealed to be relatively benign in p.Y111C and p.R518X (annual incidence of life-threatening cardiac events, before therapy 0.05% and 0.04%, respectively). Gender-specific effects of genetic modifiers on phenotypic expression were seen. A founder origin, approximately 600-700 years ago in two northern river valleys was established for p.Y111C and p.R518X, and a high prevalence of LQTS founder descendants suggested. A minimum JLNS prevalence of 1:200 000 in preadolescent Swedish children was revealed. JLNS phenotype was mainly severe, with a cumulative incidence of life-threatening cardiac events of 53% (annual incidence rate before therapy 5%) and four sudden deaths. Possible founder effects regarding four KCNQ1 mutations; p.Y111C (8%), p.R518X (50%), c.572_576del (17%) and p.Q530X (8%) together explained 83% of the JLNS mutation-spectrum in Sweden, consisting of 8 KCNQ1 mutations. Conclusion: The high prevalence of p.Y111C- and p.R518X-related LQTS as well as JLNS revealed in Sweden could be explained by the combination of mild clinical phenotypes in heterozygotes and strong founder effects present during the population development of northern Sweden. Increased knowledge regarding the occurrence of LQTS and JLNS as well as mutation- and/or genotype-specific data constitute prerequisites for possible improvement of patient management.

Abdominal aortic aneurysm (AAA) is a common problem with life-threatening consequences and was suspected to be a serious health problem in Norsjö, a municipality in northern Sweden. A screening study was undertaken to investigate the prevalence, risk factors associated with AAA and the effect of screening on quality of life (QoL). All men and women, aged 65-75 years, were invited to an ultrasonography (US) examination, 91% attended and 92 subjects were also evaluated with computed tomography (CT). Depending on diagnostic criteria, the AAA prevalence was 3.6-16.9% in men and 0.8-9.4% in women. Seventy-five percent of the differences between US- and CT anteroposterior measurements were less than 5 mm. A decrease in mental health was observed among AAA patients with low baseline SF-36 scale scores. Elevated cholesterol at age 60 years were associated with screening detected AAA after 12 years of follow-up. Smoking, atherosclerosis and having a first degree relative with AAA were associated with AAA at screening. Compared to blood samples obtained 12 years prior to screening an elevation of hsCRP over time was observed among AAA patients. Based on a systematic review of the literature, different screening strategies were analysed in a Markov cohort model. The cost per life year gained ranged from $8 309 to $14 084 and was estimated to $10 474 when 65 year old men were screened once. Conclusions: The highest prevalence of AAA ever reported, in a population-based screening program, was found in Norsjö. The risk of having an AAA at screening showed a strong but complex association with atherosclerosis and its risk factors, genetic and inflammatory mechanisms may also be important. Screening 65-year-old men for AAA may be cost-effective, but QoL aspects on the cost-effectiveness of AAA screening merits further investigation.

The general aims of this dissertation are to analyse how family situation, and especially lone parenting, influence health and life chances in Sweden and the extent to which possible relations are influenced by socioeconomic circumstances and health selection. In two population-based cohort studies we analysed overall and cause-specific mortality (1991-95), and also severe morbidity (1991-94) from different causes among lone mothers in comparison with mothers with partners. Information on the mothers was obtained from the Swedish Population and Housing censuses of 1985 and 1990. The outcomes considered were death or utilisation of (overnight) hospital care, with data taken from population-based national health registers. In the analyses we adjusted for socioeconomic and demographic circumstances, such as socioeconomic status, country of birth, receipt of social-welfare benefit, and housing situation. To take health-selection effects into account, we adjusted for previous inpatient history (1987-90). Our findings suggest that lone motherhood entails health disadvantages with regard to mortality, severe morbidity and injury. Socioeconomic circumstances were found to play a major role in accounting for increased risks, but the risks are partly independent of both socioeconomic conditions and health selection into lone motherhood. In two further studies we analysed mortality (1991-98), severe morbidity and injury (1991-99), and also educational achievement (in 1998 at ages 24-25 of offspring), of children who had lived in lone-parent families in comparison with children in two-parent families. We mainly used data from the Swedish censuses and national health-data registers. Living in a lone parent family was found to be associated with increased risks of a variety of unfavourable outcomes: psychiatric disease, suicide/suicide attempt, injury, addiction, and low educational attainment. Relatively poor educational performance and also health disadvantages are explicable to a large extent by socioeconomic conditions, especially a lack of economic resources (as measured here by receipt of social-welfare benefit and having rented accommodation). Educational achievement among children varies with cause of lone parenthood, with the best prospects found among the children of widows/widowers. In a fifth study we analysed mortality from different causes (1991-2000) among lone fathers (fathers with and without custody of their children) and childless men (with and without partners) in comparison with cohabiting fathers with children in the household. For this purpose we linked information from the Swedish censuses of 1985 and 1990 to Sweden’s Multi-Generation Register (which contains information about all known biological relations between children and parents). Lone non-custodial fathers and lone childless men suffer from the most pronounced elevated risks, especially of death from injury or addiction, but also from all-cause mortality and death from ischaemic heart disease. Being a lone custodial father also seems to entail an increased mortality risk, although generally to a much lesser degree, and not for all outcomes studied. The elevated risks for all subgroups fell when variables assumed to control health selection and socioeconomic circumstances were introduced into the initial regression model employed. However, even following adjustments, significantly increased risks, albeit greatly attenuated, remained in all the subgroups investigated. Key Words: Single parent, single mother, single father, children, risk factor, socio-economic status, mortality, morbidity, injury, psychiatric disease, education, epidemiology, longitudinal

No description available.

Diss. (sammanfattning) Umeå : Umeå universitet, 2010. / Härtill 4 uppsatser.

Pseudoexfoliation (PEX) syndrome is an age-related condition characterized by the production and accumulation of extracellular fibrillary material in the anterior segment of the eye. PEX predisposes for several pathological conditions, such as glaucoma and complications during and after cataract surgery. The pathogenesis of PEX is not yet fully understood. It is multifactorial with genetics and ageing as contributing factors. We aimed to study the proteome in aqueous humor (AH) in PEX in order to increase the knowledge about its pathophysiology. Therefore, we developed sampling techniques and evaluated separation methods necessary for analyzing small sample volumes. Other objectives were to study the lens capsule in eyes with PEX regarding small molecules, and to investigate the association between PEX and cataract surgery in a population-based 30-year follow-up study. Samples of AH from eyes with PEX and control eyes were collected during cataract surgery. In pooled, and individual samples, various liquid based separation techniques and high resolution mass spectrometry were utilized. For quantitation, various methods for labeling, and label free techniques were applied. Lens capsules were collected from some of the patients, and analysed by imaging mass spectrometry. A cohort of 1,471 elderly individuals underwent a comprehensive ophthalmological examination at baseline. Medical information was obtained by questionnaires, and from medical records. Incident cases of cataract surgery were identified by review of medical records. In the initial study, several techniques were explored for protein detection, and a number of proteins were identified as differentially expressed. In the individually labelled samples, changes in the proteome were observed. Eyes with PEX contained higher levels of proteins involved in inflammation, oxidative stress, and coagulation, suggesting that these mechanisms are involved in the pathogenesis in PEX. The levels of β/γ-crystallins were significantly increased in PEX, which is a novel finding. In the lens capsules from individuals with PEX, changes in the lipid composition was observed with time-of-flight secondary ion mass spectrometry. These changes remain to be elucidated. By multivariate analysis, lens opacities were the first, and PEX the second most important predictor for cataract surgery, the later accounting for a 2.38-fold increased risk for cataract surgery.

Background South Africa has experienced the most severe consequences of the HIV/AIDS pandemic. Every community has been affected in some way, many experiencing huge increases in mortality,particularly before antiretroviral therapies (ART) were readily available. However, the micro-level understanding of the HIV epidemic in South Africa is weak, because of a lack of detailed data for most of the population. This thesis is based on detailed individual follow-up in the Agincourt Health and Demographic Surveillance Site (HDSS) located in the Agincourt subdistrict of Mpumalanga Province and investigates micro-level determinants of HIV epidemiology and the impact of treatment provided. Methods The Agincourt HDSS has followed a geographically defined population since 1992,approximately the time when the HIV/AIDS epidemic first became apparent. This population based surveillance has included capturing details of all deaths, with cause of death determined by verbal autopsy, as well as the geographical location of individual households within the overall Agincourt area. Background information on the roll-out of ART over time was also recorded. Results A comparison immediately before and after the major roll-out of ART showed a substantial decrease in HIV-related mortality, greater in some local communities within the area than others. Individual determinants associated with a decreased risk of HIV/AIDS mortality included proximity to ART services, as well as being female, younger, and in higher socioeconomic and educational strata. There was a decrease in the use of traditional healthcare sources and an increase in the use of biomedical healthcare amongst those dying of HIV/AIDS between periods before and after the roll-out of ART. Conclusions Understanding micro-level determinants of HIV/AIDS infection and mortality was very important in terms of characterising the overall epidemic in this community. This approach will enable public health interventions to be more effectively targeted towards those who need them most in the continuing evolution of the HIV/AIDS epidemic.

No description available.

Les objectifs de l’étude de l’évolution du risque cardiométabolique (RCM) sur une période de quatre ans (2006-2010) chez des adultes béninois consistaient à: • Examiner les relations entre l’obésité abdominale selon les critères de la Fédération Internationale du Diabète (IFD) ou l’insulino-résistance mesurée par le Homeostasis Model Assessment (HOMA) et l’évolution des autres facteurs de RCM, • Examiner les liens entre les habitudes alimentaires, l’activité physique et les conditions socio-économiques et l’évolution du RCM évalué conjointement par le score de risque de maladies cardiovasculaires de Framingham (FRS) et le syndrome métabolique (SMet). Les hypothèses de recherche étaient: • L’obésité abdominale telle que définie par les critères de l’IDF est faiblement associée à une évolution défavorable des autres facteurs de RCM, alors que l’insulino-résistance mesurée par le HOMA lui est fortement associée; • Un niveau socioéconomique moyen, un cadre de vie peu urbanisé (rural ou semi-urbain), de meilleures habitudes alimentaires (score élevé de consommation d’aliments protecteurs contre le RCM) et l’activité physique contribuent à une évolution plus favorable du RCM. L’étude a inclus 541 sujets âgés de 25 à 60 ans, apparemment en bonne santé, aléatoirement sélectionnés dans la plus grande ville (n = 200), une petite ville (n = 171) et sa périphérie rurale (n = 170). Après les études de base, les sujets ont été suivis après deux et quatre ans. Les apports alimentaires et l’activité physique ont été cernés par deux ou trois rappels de 24 heures dans les études de base puis par des questionnaires de fréquence simplifiés lors des suivis. Les données sur les conditions socioéconomiques, la consommation d’alcool et le tabagisme ont été recueillies par questionnaire. Des mesures anthropométriques et la tension artérielle ont été prises. La glycémie à jeun, l’insulinémie et les lipides sanguins ont été mesurés. Un score de fréquence de consommation d’« aliments sentinelles » a été développé et utilisé. Un total de 416 sujets ont participé au dernier suivi. La prévalence initiale du SMet et du FRS≥10% était de 8,7% et 7,2%, respectivement. L’incidence du SMet et d’un FRS≥10% sur quatre ans était de 8,2% et 5%, respectivement. Le RCM s’était détérioré chez 21% des sujets. L’obésité abdominale définie par les valeurs seuils de tour de taille de l’IDF était associée à un risque plus élevé d’insulino-résistance: risque relatif (RR) = 5,7 (IC 95% : 2,8-11,5); d’un ratio cholestérol total/HDL-Cholestérol élevé: RR = 3,4 (IC 95% : 1,5-7,3); mais elle n’était pas associée à un risque significativement accru de tension artérielle élevée ou de triglycérides élevés. Les valeurs seuils de tour de taille optimales pour l’identification des sujets accusant au moins un facteur de risque du SMet étaient de 90 cm chez les femmes et de 80 cm chez les hommes. L’insulino-résistance mesurée par le HOMA était associée à un risque élevé d’hyperglycémie: RR = 5,7 (IC 95% : 2,8-11,5). En revanche, l’insulino-résistance n’était pas associée à un risque significatif de tension artérielle élevée et de triglycérides élevés. La combinaison de SMet et du FRS pour l’évaluation du RCM identifiait davantage de sujets à risque que l’utilisation de l’un ou l’autre outil isolément. Le risque de détérioration du profil de RCM était associé à un faible score de consommation des «aliments sentinelles» qui reflètent le caractère protecteur de l’alimentation (viande rouge, volaille, lait, œufs et légumes): RR = 5,6 (IC 95%: 1,9-16,1); et à l’inactivité physique: RR = 6,3 (IC 95%: 3,0-13,4). Les sujets de niveau socioéconomique faible et moyen, et ceux du milieu rural et semi-urbain avaient un moindre risque d’aggravation du RCM. L’étude a montré que les relations entre les facteurs de RCM présentaient des particularités chez les adultes béninois par rapport aux Caucasiens et a souligné le besoin de reconsidérer les composantes du SMet ainsi que leurs valeurs seuils pour les Africains sub-sahariens. La détérioration rapide du RCM nécessité des mesures préventives basées sur la promotion d’un mode de vie plus actif associé à de meilleures habitudes alimentaires. / The objectives of this study on four-year trends (2006-2010) in cardiometabolic risk (CMR) in Benin adults were: • To examine whether abdominal obesity according to International Diabetes Federation (IDF) waist circumference cut-offs, or insulin resistance measured by the homeostasis model assessment (HOMA) was associated with more unfavourable changes in other CMR factors, • To examine the effects of diet, physical activity and socioeconomic status including place of residence on the evolution of CMR assessed by both the Framingham risk score for cardiovascular diseases (FRS) and the metabolic syndrome (MetS). We hypothesized that: • Abdominal obesity as currently defined by IDF anthropometric criteria is weakly associated with unfavourable changes in other CMR factors while IR exacerbates other CMR factors in sub-Saharan Africans, • Medium income status, less urbanized place of residence (rural or semi-urban), physical activity and healthy eating patterns (higher score of consumption of foods that may protect against CMR) contribute to more favourable evolution of CMR. The study included initially 541 apparently healthy adults aged 25-60 years and randomly selected in a large city (n = 200), a small town (n = 171) and its surrounding rural area (n = 170). After baseline survey, subjects were followed-up after two and four years. Dietary intake and physical activity were assessed by two or three 24-hour recalls in baseline studies and then by short frequency questionnaires at follow-ups. Data on alcohol intake and smoking patterns were collected in personal interviews. Anthropometric data, blood pressure, insulin resistance based on homeostasis model assessment (HOMA), blood glucose and blood lipids were measured. Education, income (proxy) and place of residence were the socioeconomic variables appraised in interviews. A food score based on consumption frequency of “sentinel foods” was developed and used. Complete data at last follow-up was available in 416 subjects. Baseline prevalence of MetS and FRS ≥ 10% was 8.7% and 7.2%, respectively. The incidence of MetS, and a FRS ≥ 10% over four years was 8.2% and 5%, respectively. The CMR deteriorated in 21% of subjects. Abdominal obesity as defined by IDF thresholds of the waist circumference was associated with a higher likelihood of insulin resistance: relative risk (RR) = 5.7 (CI 95%: 2.8-11.5), high total cholesterol/HDL-Cholesterol ratio: RR = 3.4 (CI 95%: 1.5-7.3). However, abdominal obesity was not associated with a significantly increased risk of high blood pressure or high triglycerides. In the study population, the optimal cut-offs of waist circumference that predicted at least one component of MetS were 90 cm in women and 80 cm in men. Insulin resistance measured by HOMA was associated with an increased risk of hyperglycemia: RR = 5.7 (CI 95%: 2.8-11.5). However, the insulin resistance was not associated with a significant risk of high blood pressure and high triglycerides. The combination of MetS and the FRS depicted more at-risk subjects than the use of either tool alone. Diet and lifestyle mediated location and income effects on CMR evolution. Low “sentinel food” scores (foods that may reflect the protective effect of the diet against CMR): meat, poultry, milk and milk products, eggs and vegetables; and inactivity increased the likelihood of CMR deterioration: RR = 5.6 (CI 95%: 1.9-16.4) and RR = 6.3 (CI 95%: 3.0-13.4), respectively. Subjects with medium or low socioeconomic levels, and those living in the rural and semi-urban areas had a lower risk of CMR deterioration. The study showed some differences in the relationship between abdominal obesity, insulin resistance and other CMR factors in Blacks compared to Caucasians and it also highlighted the need to reconsider MetS components and their cut-offs for sub-Saharan Africans. Combining MetS and FRS might be appropriate for surveillance purposes in order to better capture CMR. The results of the present study call for urgent measures to reduce CMR deterioration focusing on more active lifestyle and dietary inadequacies.

Problématique : Plusieurs expositions résidentielles ont été associées à la prévalence de l’asthme. Toutefois, peu d’études populationnelles ont examiné la relation entre ces facteurs et un asthme mal maîtrisé chez l’enfant. Objectif : Évaluer les facteurs environnementaux résidentiels associés à un asthme mal maîtrisé chez les enfants montréalais âgés de 6 mois à 12 ans. Méthodes : Les données sont tirées d’une enquête transversale menée en 2006 sur la santé respiratoire d’enfants montréalais âgés de 6 mois à 12 ans (n=7980). La maîtrise de l’asthme a été évaluée chez les enfants avec un asthme actif au cours de l’année précédent l’enquête (n=980) selon des critères recommandés par les lignes directrices canadiennes sur l’asthme. Les rapports de prévalence (RP) et les intervalles de confiance (IC) à 95 % caractérisant l’association entre les facteurs environnementaux, incluant la présence d’allergènes, d’irritants, d’humidité et de moisissures, et le risque d’un asthme mal maîtrisé ont été estimés à l’aide de modèles de régression log-binomiale. Les sujets avec une maîtrise acceptable de l’asthme ont été comparés à ceux dont la maladie était mal maîtrisée. Résultats : Des 980 enfants avec un asthme actif au cours de l’année précédant l’enquête, 36 % ont rencontré au moins un des critères des lignes directrices canadiennes suggérant un asthme mal maîtrisé. Les caractéristiques de la population associées à un asthme mal maîtrisé sont : un plus jeune âge, des antécédents d’atopie parentale, une faible scolarisation de la mère, une mère d’origine étrangère et le statut de locataire. Après ajustement pour l’âge de l’enfant, l’atopie parentale et l’exposition à la fumée de tabac au domicile, une intensité de trafic élevée à proximité du domicile (RP, 1,35; IC 95 %, 1,00-1,81) et la localisation au sous-sol de la chambre de l’enfant ou de sa résidence (RP 1,30; IC 95 %, 1,01-1,66) étaient associées à un risque accru d’asthme mal maîtrisé. Conclusions : Une maîtrise sous-optimale de l’asthme semble être associée à l’exposition au trafic routier et à des conditions d’humidité excessive et probablement de moisissures. Cette dernière exposition étant plus fréquente, elle a probablement un plus grand impact en matière de santé publique. / Background: Home environmental exposures may impede asthma control in children. However, few population-based studies have investigated this relationship. Objective: Identify environmental home exposures associated with poor asthma control among asthmatic children less than 12 years of age in Montreal. Methods: This cross-sectional population-based study used data from a respiratory health survey of Montreal children aged 6 months to 12 years conducted in 2006 (n=7,980). Asthma control was assessed among those with active asthma in the year prior to the survey (n=980) using an adaptation of the Canadian asthma consensus report clinical parameters. Using log-binomial regression models, prevalence ratios (PR) with 95 % confidence intervals (CI) were estimated to explore the relationship between inadequate control of asthma and environmental home exposures, including allergens, irritants, mold and dampness indicators. Subjects with acceptable asthma control were compared with those with inadequate disease control. Results: Of 980 children with active asthma in the year prior to the survey, 36 % met at least one of the five criteria outlined in the Canadian asthma guidelines as to poor control of their disease. The population’s characteristics found to be related with a lack of asthma control were: younger age, a history of parental atopy, low maternal education level, foreign-born mothers and tenant occupancy. After adjustments for the child’s age, parental atopy and tobacco smoke exposure at home, children living along high-traffic density streets (PR, 1.35; 95 % CI, 1.00-1.81) and those with their bedroom or residence in the basement (PR, 1.30; 95 % CI, 1.01-1.66) were found to be at increased risk of poor asthma control. Conclusions: Suboptimal asthma control appears to be mostly associated with traffic, along with mold and moisture conditions, the latter being a more frequent exposure and therefore having a greater public health impact.