Background: Diabetes mellitus is a chronic disease that manifests as an increased level of glucose in the blood. According to the World Health Organization (WHO), 347 million people have diabetes worldwide. In year 2004, 3.4 million people died from the consequences of high blood glucose. In the Swedish population the prevalence of diabetes is estimated to 3-4 %, out of which 85-90% are Type 2. Among senior citizens a prevalence of diabetes is seen in Sweden up to 14 - 15%. Diabetes is increasing globally, particularly in developing countries, which is probably a consequence of the increased prevalence of overweight and obesity combined with low physical activity. Angiotensin converting enzyme (ACE) inhibitors are the first-line therapy in the treatment of high blood pressure among diabetics and patients suffering from congestive heart failure. The action of these inhibitors results in a decreased formation of angiotensin 2, an endogenous hormone peptide that raises the blood pressure by contracting the blood vessels. ACE inhibitors are also beneficial in the treatment of patients with renal insufficiency.Objective: The aim of this project was, with the help of published clinical trials and meta-analysis, to examine the effect of ACE inhibitors on cardiovascular diseases and mortality in type 2 diabetic and diabetic in hypertensive patients.Results: Appraisals of clinical trials within the frame of this project revealed thatACE inhibitor in patients with diabetes reduces:- Myocardial infarction (NNT = 37 during 4.5 years),- Development of stroke (NNT = 32 during 2.8 years),- Cardiovascular events (NNT = 29 during 4.5 years),- Total mortality (NNT = 20 during 2.8 years).- Left ventricular dysfunction (NNT = 6 during 3.4 years)- Complications that usually occur in association with diabetes such as nephropathy (NNT = 83 during 5 years).Conclusion: ACE inhibitors are considered well-established and safe drugs. Despite that, only 38% of the patients with diabetic in Sweden are prescribed ACE inhibitors or angiotensin II antagonists. Due to the high efficacy of ACE-inhibitors among patients with diabetes (i.e. treating 15 high-risk diabetic patients with ACE-inhibitors for a median of 4.5 years prevents one incidence of myocardial infarction, stroke, or cardiovascular mortality) measures ought to be taken in favour of a more widespread use of ACE-inhibitors among patients with diabetes. This will result not only in medical benefits, but also in reducing cost of caring for the elderly diabetics in the community. For most diabetic patients it is very cost effective to prescribe an ACE-inhibitor therapy.

Outdoor air pollution is increasingly considered as a serious risk factor for cardiovascular diseases (CVD). High levels of airborne particulate matter (PM) constitute the greatest international air pollution threat. The purpose of this thesis is to broaden our knowledge regarding the relationship between outdoor air pollution and cardiovascular diseases in the Middle Eastern countries, specifically in Lebanon. Moreover, we aimed to develop a scale as CVD screening tool among the Lebanese population. To achieve these goals, we conducted three studies. The first was a systematic review of the literature aiming to assess levels and sources of PM across the Middle East area and to search for an evidence of relationship between PM exposure and CVD (Paper I).The second manuscript was a multicenter case-control study investigating the association between outdoor pollutants and cardiovascular diseases among Lebanese adults (Paper II) while the third study was conducted to develop a score that can be used as a screening tool in clinical and epidemiological settings among the Lebanese adults (Paper III).The annual average values of PM pollutants in the Middle East region are considered to be much higher than the WHO 2006 tolerated levels (PM2.5 = 10 µg/m3, PM10 = 20 µg/m3). We uncovered evidence of an association between PM and CVD in 4 Middle East countries: Iran, Kingdom of Saudi Arabia, Qatar and the United Arab Emirates. Ambient PM pollution is considered a potential risk factor for platelet activation and atherosclerosis. Moreover, it was associated with CVD and found to be linked with an increased risk for mortality and hospital admissions (Paper I). Increased risk of CVD with an odds ratio OR of 5.04, 95% CI (4.44-12.85) for living near busy highway and 4.76, 95% CI (2.07-10.91) for living close to local diesel generator was noticed among population exposed to outdoor air pollution (Paper II). In addition, our results highlight the importance of scale generation, which includes air pollution as predictive factor, as screening tool for patients at risk of CVD. This scale can foresee the cardiovascular disease outcomes better than the established score which use the traditional CVD risk factors (Paper III).In conclusion this study brings new evidence regarding the effects of particulate matter on cardiac diseases, points out the harmful role of diesel exhaust on health and suggest a an important role of traffic exhaust particles in exacerbating heart diseases in the Middle East Region. The developed scale could detect persons at high risk for CVD in the clinical and epidemiological settings. In addition, it serves as an essential public health screening tool for the primary prevention of CVD. / Doctorat en Santé Publique / info:eu-repo/semantics/nonPublished

Outdoor air pollution is increasingly considered as a serious risk factor for cardiovascular diseases (CVD). High levels of airborne particulate matter (PM) constitute the greatest international air pollution threat. The purpose of this thesis is to broaden our knowledge regarding the relationship between outdoor air pollution and cardiovascular diseases in the Middle Eastern countries, specifically in Lebanon. Moreover, we aimed to develop a scale as CVD screening tool among the Lebanese population. To achieve these goals, we conducted three studies. The first was a systematic review of the literature aiming to assess levels and sources of PM across the Middle East area and to search for an evidence of relationship between PM exposure and CVD (Paper I).The second manuscript was a multicenter case-control study investigating the association between outdoor pollutants and cardiovascular diseases among Lebanese adults (Paper II) while the third study was conducted to develop a score that can be used as a screening tool in clinical and epidemiological settings among the Lebanese adults (Paper III).The annual average values of PM pollutants in the Middle East region are considered to be much higher than the WHO 2006 tolerated levels (PM2.5 = 10 µg/m3, PM10 = 20 µg/m3). We uncovered evidence of an association between PM and CVD in 4 Middle East countries: Iran, Kingdom of Saudi Arabia, Qatar and the United Arab Emirates. Ambient PM pollution is considered a potential risk factor for platelet activation and atherosclerosis. Moreover, it was associated with CVD and found to be linked with an increased risk for mortality and hospital admissions (Paper I). Increased risk of CVD with an odds ratio OR of 5.04, 95% CI (4.44-12.85) for living near busy highway and 4.76, 95% CI (2.07-10.91) for living close to local diesel generator was noticed among population exposed to outdoor air pollution (Paper II). In addition, our results highlight the importance of scale generation, which includes air pollution as predictive factor, as screening tool for patients at risk of CVD. This scale can foresee the cardiovascular disease outcomes better than the established score which use the traditional CVD risk factors (Paper III).In conclusion this study brings new evidence regarding the effects of particulate matter on cardiac diseases, points out the harmful role of diesel exhaust on health and suggest a an important role of traffic exhaust particles in exacerbating heart diseases in the Middle East Region. The developed scale could detect persons at high risk for CVD in the clinical and epidemiological settings. In addition, it serves as an essential public health screening tool for the primary prevention of CVD. / Doctorat en Santé Publique / info:eu-repo/semantics/nonPublished

Abstract Hypothermia deaths pose a difficult challenge from the medico-legal point of view because no specific traces are left on the cadaver to be examined post-mortem. The concentrations of urinary catecholamines, adrenaline and noradrenaline increase in various stressful situations including cold stress, and high levels have been considered to be suggestive of lethal hypothermia. There is, however, a need for a better hypothermia indicator. A potential candidate could be thrombomodulin (TM), an endothelially expressed protein whose plasma concentration has been shown to elevate in response to hypothermia. TM and catecholamine levels were studied in short-term cold exposure (human subjects, n = 7), in mild and severe hypothermia with or without rewarming (rats, n = 96) and in hypothermia deaths compared with deaths from cardiovascular diseases, traumas and other causes (autopsy cases, total n = 552). Myocardial thrombomodulin transcript expression was increased in severely hypothermic rats, but was lower in hypothermia deaths than in other causes. The circulating TM level was transiently reduced in severe hypothermia. The myocardial and urinary TM protein levels were reduced in lethal hypothermia compared with other causes of death. TM and catecholamine levels correlated significantly in blood and urine both in living subjects and post-mortem examination. In severely hypothermic rats, there was an inverse relationship between plasma adrenaline concentration and myocardial thrombomodulin transcript level. The results suggest that TM expression and secretion are altered by hypothermia, possibly linked to the actions of catecholamines. Analysing the post-mortem catecholamine and TM levels provides evidence of ante-mortem cold stress in suspected hypothermia deaths. Further studies should be conducted in order to reveal the exact mechanisms behind the regulation of TM on cell level. / Tiivistelmä Paleltumiskuolemat ovat oikeuslääketieteellisesti haastavia, koska vainajaan ei jää paleltumiseen viittaavia yksiselitteisiä löydöksiä. Virtsan katekoliamiinien, adrenaliinin ja noradrenaliinin, pitoisuudet kasvavat stressitilanteissa kuten kylmäaltistuksessa. Korkeita pitoisuuksia on pidetty paleltumiseen viittaavana tekijänä. Paremmalle paleltumista osoittavalle merkkiaineelle on kuitenkin selkeä tarve. Eräs mahdollinen merkkiaine voisi olla trombomoduliini (TM), joka on endoteelisolujen tuottama proteiini. Sen plasmapitoisuuden on aiemmin osoitettu nousevan alilämpöisyystilassa. TM- ja katekoliamiinitasoja tutkittiin lyhyessä kylmäaltistuksessa (koehenkilöt, n = 7) sekä lievässä ja vaikeassa alilämpöisyystilassa joko lämmityksen jälkeen tai ilman lämmitystä (rotat, n = 96). Lisäksi verrattiin paleltumisen, sydän- ja verisuonitautien, vammojen sekä muiden syiden aiheuttamia kuolemia (ruumiinavausaineisto, n = 552). Sydänlihaksen trombomoduliini-transkriptin taso oli kohonnut vaikeasti alilämpöisillä rotilla, mutta se oli matalampi paleltumiskuolemissa kuin muissa kuolemissa. Veren TM-taso oli hetkellisesti alentunut vaikeassa alilämpöisyystilassa. Sydänlihaksen ja virtsan TM-proteiinipitoisuudet olivat matalampia paleltumiskuolemissa kuin muissa kuolemansyissä. TM- ja katekoliamiinitasot korreloivat merkittävästi veressä ja virtsassa sekä koehenkilöillä ja -eläimillä että vainaja-aineistossa. Vaikeasti alilämpöisillä rotilla todettiin käänteinen suhde plasman adrenaliinipitoisuuden ja sydänlihaksen trombomoduliini-transkriptitason välillä. Tulosten perusteella alilämpöisyystila muuttaa TM:n ekspressiota ja erittymistä, mikä voi liittyä katekoliamiinien vaikutuksiin. Kuolemanjälkeisten TM- ja katekoliamiinitasojen määritys tuo lisänäyttöä kuolemaa edeltäneestä kylmävaikutuksesta epäiltäessä paleltumiskuolemaa. Lisätutkimuksia tarvitaan TM:n solutason säätelymekanismien selvittämiseksi.

Abstract Chlamydia pneumoniae is an obligatory intracellular pathogen that causes upper and lower respiratory tract infections. Like other Chlamydial species, also C. pneumoniae has a tendency to cause persistent infections, which have been associated with different cardiovascular, neurological, and respiratory diseases. In addition, a few studies have reported an association between C. pneumoniae seropositivity and an elevated body mass index (BMI), and it has been shown that C. pneumoniae is capable of infecting preadipocytes and adipocytes. The main aims of this study were to study if certain gene polymorphisms regulate the serum levels of innate immunity and inflammation proteins, and if the polymorphisms are associated with markers of C. pneumoniae infection; to compare different methods in detection of C pneumoniae in atherosclerotic tissue; and to study if serum levels of chlamydial LPS (cLPS) are associated with BMI. The serum levels of inflammatory and innate immunity markers, namely interleukin 6 (IL-6), C-reactive protein (CRP), LPS-binding protein (LBP), and soluble CD14, in apparently healthy individuals were found to correlate with each other and possibly be regulated by the polymorphisms of genes important in inflammation and innate immunity. Especially the serum LBP levels may be regulated by the LBP (rs2232618) and toll-like receptor 4 (rs4986790) polymorphisms. The IL-6 (rs1800795) polymorphism was found to be associated with C. pneumoniae antibody positivity. C. pneumoniae DNA and cLPS could be found from atherosclerotic tissue. A new, cLPS enzyme immunoassay method was developed in this study, and it might provide a standardized, commercial method for the detection of chlamydia in tissue samples, if the sensitivity of the method could be increased e.g. by testing multiple pieces of tissue. In situ hybridization method was found to be complicated by technical problems and the repeatability of polymerase chain reaction was poor. C. pneumoniae IgG positivity and elevated serum cLPS and CRP levels were associated with an elevated BMI. There was also a strong association between cLPS levels and inflammation as measured by CRP levels. The lack of association between serum total endotoxin activity and BMI implies that the association between infection and an elevated BMI may be specific to certain pathogens.

Abstract Oligomenorrhea (menstrual disturbances) and hirsutism (excessive growth of body hair) are typical symptoms of polycystic ovary syndrome, a common endocrine disorder with long-term health risks among fertile-age women. Associations between body size development and polycystic ovary syndrome symptoms in a cohort design (528 symptomatic and 1479 asymptomatic women) and endocrine, metabolic and clinical characteristics of women with self-reported symptoms of oligomenorrhea or hirsutism in a nested case-control design (518 cases and 1036 controls) were investigated in this general population-based study. Gynecologic ultrasonographic examinations were performed in 196 cases and 67 controls to assess the morphology of the ovaries and its relationship to biochemical and clinical parameters. The study population was derived from the Northern Finland Birth Cohort 1966, which included all births with expected birth dates in 1966 in Northern Finland and is well representative of the general female population. Polycystic ovary syndrome symptoms in adulthood were associated with obesity, particularly abdominal obesity, in adolescence and in adulthood, but not with birth weight or being small for gestational age. Hormonal changes typical of polycystic ovary syndrome, i.e. higher circulating concentrations of testosterone, luteinizing hormone (LH) and insulin and lower levels of sex hormone-binding globulin (SHBG), were detected in women with self-reported symptoms of oligomenorrhea and/or hirsutism compared with the controls. Less favorable metabolic cardiovascular disease risk factor profiles, higher body mass index (BMI), waist-hip ratio (WHR), and triglyceride and C-reactive protein (CRP) concentrations and lower high density lipoprotein cholesterol (HDL-C) levels, were detected in women with symptoms, being the most severe among women who reported both hirsutism and oligomenorrhea. Unfavorable characteristics were pronounced in the presence of overweight or obesity. Women with symptoms more often had features characteristic of polycystic ovarian morphology associated with an endocrine and clinical profile reflecting polycystic ovary syndrome. This study shows that questioning in regard to symptoms of oligomenorrhea and hirsutism is useful in detecting women at risk of polycystic ovary syndrome and associated health risks. Avoidance of being overweight is important among young women to prevent the development of insulin resistance. Systematic follow-up of women with symptoms of oligomenorrhea and hirsutism is justified for prevention and early detection of long-term health risks.

Abstract Chlamydia pneumoniae is a common respiratory pathogen worldwide. It does not only cause acute respiratory infections, but is also associated with chronic inflammatory diseases, such as asthma and coronary heart disease (CHD). Chlamydial heat shock protein 60 (Hsp60) is associated with the development of immunopathological damage following C. trachomatis infections, but the role of Hsp60 in C. pneumoniae infections is unclear. A slightly elevated level of C-reactive protein (CRP), as a marker of systemic inflammation, predicts cardiovascular events, but its role in asthma has not been studied. The aim of this study was to develop an EIA method for the measurement of Hsp60 antibodies and for studying the host immune responses to C. pneumoniae and chlamydial and human Hsp60 proteins, CRP levels and their interactions in asthma and CHD. Elevated levels of serum IgA antibodies to the Hsp60 protein of C. pneumoniae were associated with asthma and decreased pulmonary function. CRP levels were also higher in the asthma patients than in the controls. The patients with moderate asthma had higher CRP levels than those with mild asthma. The patients with a CRP level over 2 mg/l had higher levels of serum IgA antibodies to C. pneumoniae and chlamydial Hsp60 than the patients with lower CRP levels. A prospective nested case-control study was carried out, to study the role of Hsp60 antibodies as coronary risk predictors, and their association with C. pneumoniae infection and inflammation. The participants were obtained from the Helsinki Heart Study: 241 myocardial infarctions or coronary deaths occurred during the 8.5-year period among dyslipidemic middle-aged men. An elevated level of human Hsp60 IgA antibodies in baseline serum predicted the occurrence of a coronary event several years later, especially when present simultaneously with a high C. pneumoniae IgA antibody level and an elevated CRP level. Further studies showed that only persistently, not transiently, elevated levels predicted coronary events. The risk associated with elevated antibody levels increased markedly in the presence of an elevated CRP level, and vice versa. In conclusion, these results suggest that chlamydial Hsp60 is involved in the association between C. pneumoniae infection and asthma, while autoimmunity to human Hsp60 is implicated in the association between C. pneumoniae infection and CHD. Inflammation evidently plays an important role in these associations. It can also be concluded that IgA antibodies, compared to IgG antibodies, against C. pneumoniae and Hsp60 are better markers of chronicity, especially when they are persistently elevated.

This study attempts to answer the research question ‘Can a novel model of health information system strengthen process for conducting research to understand the effects of air pollution on CVD in developing countries?’ There is limited research output from Asia and in particular, from India on studies of the deleterious effects of air pollution on CVD. This research aimed to investigate the barriers in developing countries and proposed the use of a spatiotemporal methodology to assess the effects of air pollution on CVD by developing an application based on a GIS platform. Choosing Bangalore as a case study area, secondary data from various governmental departments that included demographic data, air pollution data and mortality data were obtained. An Environmental Health Information system application based on GIS platform was developed specifically for Bangalore and with the characteristics of the datasets available. Data quality assessment was carried out on these datasets that resulted in the recommendation of a generalisable data quality framework to enable better data collection that will aid in strengthening health development policies. The data was analysed using spatial and non-spatial techniques. Results showed that levels of PM10 were of concern to the city with all areas having either high or critical levels of pollution. CVD deaths also were of concern contributing to almost 40% of total mortality. The potential years of life lost (PYLL), which is an estimate of the average years a person would have lived if he or she had not died prematurely was calculated for the years from 2010 to 2013; this revealed that 2.1 million person years were lost in Bangalore due to CVD alone. These potential years lost is an important factor to consider, as preventive measures taken by the Government will result in a significant economic impact on the city. The limitations of few monitoring stations were overcome by using spatial interpolation techniques such as Inverse Distance Weighted interpolation technique. The performance of the interpolation was tested using cross-validation techniques and the results revealed that Bangalore city would benefit from increased measuring stations for PM10. The logistic regression conducted showed that pollution especially PM10 was a likely predictor of CVD in the city. Spatial analysis was conducted and included buffering, overlay maps, queries and Hotspot analysis highlighting the zone hotspots. The results from the research guided the development of the novel 5-I model that would assist other similar developing cities to assess the effects of air pollution on CVD. The impetus is that based on evidence, intervention policies and programs may be implemented to inform research and practice which will ultimately have social, economic and health impact on the population. On implementation of the model, hotspots will be identified in order to roll out interventions to priority areas and populations most at risk that will ultimately prevent millions of deaths and enhance overall quality of life.

Magister Scientiae (Physiotherapy) - MSc(Physio) / Hypertension is one of the most common non-communicable diseases, and it is the leading cause of cardiovascular diseases, death and disability worldwide, especially in developing countries. Physical activity has been regarded as a commonly accepted modality for preventing and treating hypertension. However, despite its known benefits, this modality of treatment and prevention of hypertension continues to be underused.The present study aimed to determine the demographic, social and health-related factors that are associated with levels of physical activity participation among adults with hypertension in Kigali, Rwanda. This cross-sectional study was conducted with 252 adults with hypertension and 87 healthcare professionals through the Godin Leisure-Time Exercise Questionnaire (GLTEQ) and Physical Activity Exit Interview (PAEI). Two thirds of the participants (69.44%) were classified as sedentary. The following factors were found to be significantly (P<0.05) associated with the levels of physical activity:age, marital status, and level of education, residence, tobacco; past and current users, alcohol; current user, diabetes mellitus, BMI, perceived health status, self-efficacy, and blood pressure. None of the healthcare professionals were considered good physical activity counsellor. The findings of the present study highlight the need for the implementation of health promotion strategies aimed at promoting physical activity lifestyle among individuals with hypertension in Rwanda. Efforts should be made in educating people with hypertension on the benefits of integrating regular physical activity in their daily lives. Furthermore, healthcare professionals should be educated concerning how to promote physical activity to all patients especially those with hypertension.

The miR-17- 92 cluster is necessary for cell proliferation and development of the cardiovascular system. Deletion of this cluster leads to death in neonatal mice. The role of this cluster still needs to be defined following ischemia and reperfusion. Methods and Results: Adult male mice were injected with Tamoxifen- was to induce inducible cardiac-specific miR-17- 92-deficient (miR-17- 92-def: MCM:TG:miR-17- 92 flox/flox ) and wild type (WT: MCM:NTG:miR-17-92 flox/flox ) mice were subjected to 30 minutes of myocardial ischemia via left anterior descending coronary artery ligation followed by reperfusion for 24 hours. Post I/R survival (48%) and ejection fraction were reduced, while myocardial infarct size enlarged in miR-17- 92-deficient mice as compared to WT mice (survival: 71%). Necrosis (trypan blue staining) and apoptosis (TUNEL assay) both were higher in adult cardiomyocytes isolated from miR-17- 92-deficient mice as compared to WT mice subjected to simulated ischemia/reoxygenation with a concomitant reduction of mitochondrial membrane potential (JC1 staining). The electron transport chain was compromised through dysregulation of glutamate+malate as complex I substrate and malate dehydrogenase in the hearts of miR-17- 92-deficient mice compared to WT. After 4 hours of reperfusion, PTEN expression, a downstream target of miR-20A, increased, while phosphorylation of AKT reduced in the hearts of miR-17- 92-deficient mice in comparison to WT. The induced knockdown of cardiac miR-17- 92 increases myocardial I/R injury by ceasing suppression of PTEN, leading to decreased concentrations of AKT and mitochondrial dysfunction. These results suggest that innovative therapeutic strategies can focus on genetic upregulation of miR-17- 92 in patients with coronary artery disease.