Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Thesis (Ph. D.) -- University of Texas Southwestern Medical Center at Dallas, 2004. / Vita. Bibliography: 150-177.

Título: Estresse oxidativo e hormônios esteróides na associação entre Distúrbios Respiratórios do Sono e Doença Aterosclerótica Coronariana Introdução: Estudos epidemiológicos mostram a existência de associação entre a Doença Aterosclerótica Coronariana (DAC) e os Distúrbios Respiratórios do Sono (DRS). Evidencias sugerem que o estresse oxidativo gerado pela hipóxia intermitente sofrida pelos pacientes com DRS pode estar relacionado à progressão da DAC. Os hormônios esteróides testosterona, progesterona e estradiol estão relacionados ao estresse oxidativo, e podem ter papel em ambas as doenças. A enzima glutationa S-tranferase utiliza a molécula antioxidante glutationa na detoxificação de compostos que podem ser formados neste processo. A enzima paraoxonase-1 hidrolisa peróxidos lipídicos, atuando sobre as lipoproteínas de baixa densidade oxidadas (ox-LDL). Ox-LDL são marcadores de peroxidação lipídica, e são importantes na formação da placa aterosclerótica. O vaso dilatador óxido nítrico (NO●) é considerado ateroprotetor e pode estar reduzido, agravando a DAC. Objetivos: Estudar o estresse oxidativo e as alterações fisiopatológicas decorrentes da associação entre DRS e DAC, e avaliar a participação dos hormônios esteroides neste processo. Material e Métodos: 56 pacientes com prévio diagnóstico para Doença Aterosclerótica Coronariana (DAC) e avaliação do Índice de Apneias-hipopneias (IAH) para diagnóstico de Distúrbio Respiratório do sono (DRS) foram divididos em dois grupos, 29 pacientes controles e 27 pacientes com DAC, definidos por apresentarem obstrução coronariana >30%. Foram quantificadas as concentrações séricas dos triglicerídeos, HDL, LDL, ferritina, tranferrina e ferro disponível, assim como dos níveis séricos dos hormônios testosterona, estradiol e progesterona, das enzimas paraoxonase-1 e glutationa S-transferase, e das ox-LDL. Foram quantificadas as concentrações de glutationa total, glutationa reduzida, glutationa oxidada e nitritos e nitratos (medida indireta de NO●) em eritrócitos. A concentração do marcador de dano oxidativo em DNA 8-oxo-7,8-dihidro-2’-desoxiguanosina foi obtida em leucócitos. Resultados: Pacientes com DAC possuem reduzida concentração de nitritos e nitratos. A concentração de 8-OHdG, a atividade da GsT, os níveis de glutationa total, glutationa reduzida e glutationa oxidada, assim com o estradiol e a progesterona, não apresentaram relação com DAC ou DRS. Além do IAH, a redução da testosterona e do ferro disponível estão relacionados a DAC. A redução da atividade da paraoxonase-1 e a maior concentração de ox-LDL são preditores de DAC. A testosterona está relacionada à concentração de ferritina, transferrina e ferro disponível nestes pacientes. A ferritina correlacionou-se positivamente ao dano oxidativo em proteínas e com o IAH, negativamente aos níveis de nitritos e nitratos, e é maior nos pacientes com DAC. Conclusão: Baixos níveis de testosterona e ferro disponível, assim com o aumento da ferritina podem estar relacionados à fisiopatologia da associação entre DRS e DAC. Paraoxonase-1 e ox-LDL são importantes preditores de DAC, mas parecem não estar diretamente relacionados ao IAH nestes pacientes. / Title: Oxidative stress and steroid hormones in the association between Sleep Disordered Breathing and Coronary Artery Disease Introduction: Epidemiological studies have shown a possible association between Coronary Artery Disease (CAD) and Sleep Disordered Breathing (SDB). Evidences suggest that oxidative stress generated by the intermittent hypoxia experienced by patients with sleep disorders may be related to progression of CAD. The steroid hormones testosterone, progesterone and estradiol are related to oxidative stress, and may have a role in both diseases. Glutathione S-transferase uses the antioxidant molecule glutathione in the detoxification of compounds that can be formed in this process. The enzyme paraoxonase-1 hydrolyzes lipid peroxides, acting on oxidized low-density lipoproteins (ox-LDL). Ox-LDL are lipid peroxidation markers, being important for the atherosclerotic plaque formation. The vasodilator nitric oxide (NO●) is considered atheroprotective and can be reduced, aggravating DAC. Objective: Evaluate the oxidative stress and the pathophysiological changes arising from the association between SDB and CAD, and the role of steroid hormones in this process. Material and Methods: 56 patients with prior Coronary Artery Disease (CAD) diagnosis and apnea-hypopnea index (AHI) evaluation for diagnosis of sleep-disordered breathing (SDB) were divided into two groups, 29 control patients and 27 patients with CAD, defined by present a coronary obstruction > 30%. The serum concentration of triglycerides, HDL, LDL, ferritin, transferrin and available iron was obtained, as well as the serum levels of the hormones testosterone, estradiol and progesterone, enzymes paraoxonase-1 and glutathione S-transferase, and ox-LDL. Were measured concentrations of total glutathione, reduced glutathione, glutathione disulfide and nitrites and nitrates (NO● indirect measure) in erythrocytes. The concentration of the 8-oxo-7,8-dihydro-2'-deoxyguanosine, oxidative DNA damage marker, was obtained from leukocytes. Results: CAD patients have reduced concentrations of nitrates and nitrites. The concentration of 8-OHdG, GST activity, levels of total glutathione, reduced glutathione and glutathione disulfide, and estradiol and progesterone, showed no relationship with CAD or SDB. In addition to AHI, the reduction of testosterone and iron available are related to CAD. The reduced activity of paraoxonase-1 and the highest concentration of ox-LDL are CAD predictors. Testosterone is related to the concentration of ferritin, transferrin and iron available in these patients. Ferritin was positively correlated to oxidative damage in protein and with the AHI, and negatively to the levels of nitrites and nitrates, and is higher in CAD patients. Conclusion: Low testosterone levels and iron available, as well as the increase ferritin may be related to the pathophysiology of the association between SDB and CAD. Paraoxonase-1 and ox-LDL are important CAD predictors, but do not seem to be directly related to AHI in these patients.

Título: Estresse oxidativo e hormônios esteróides na associação entre Distúrbios Respiratórios do Sono e Doença Aterosclerótica Coronariana Introdução: Estudos epidemiológicos mostram a existência de associação entre a Doença Aterosclerótica Coronariana (DAC) e os Distúrbios Respiratórios do Sono (DRS). Evidencias sugerem que o estresse oxidativo gerado pela hipóxia intermitente sofrida pelos pacientes com DRS pode estar relacionado à progressão da DAC. Os hormônios esteróides testosterona, progesterona e estradiol estão relacionados ao estresse oxidativo, e podem ter papel em ambas as doenças. A enzima glutationa S-tranferase utiliza a molécula antioxidante glutationa na detoxificação de compostos que podem ser formados neste processo. A enzima paraoxonase-1 hidrolisa peróxidos lipídicos, atuando sobre as lipoproteínas de baixa densidade oxidadas (ox-LDL). Ox-LDL são marcadores de peroxidação lipídica, e são importantes na formação da placa aterosclerótica. O vaso dilatador óxido nítrico (NO●) é considerado ateroprotetor e pode estar reduzido, agravando a DAC. Objetivos: Estudar o estresse oxidativo e as alterações fisiopatológicas decorrentes da associação entre DRS e DAC, e avaliar a participação dos hormônios esteroides neste processo. Material e Métodos: 56 pacientes com prévio diagnóstico para Doença Aterosclerótica Coronariana (DAC) e avaliação do Índice de Apneias-hipopneias (IAH) para diagnóstico de Distúrbio Respiratório do sono (DRS) foram divididos em dois grupos, 29 pacientes controles e 27 pacientes com DAC, definidos por apresentarem obstrução coronariana >30%. Foram quantificadas as concentrações séricas dos triglicerídeos, HDL, LDL, ferritina, tranferrina e ferro disponível, assim como dos níveis séricos dos hormônios testosterona, estradiol e progesterona, das enzimas paraoxonase-1 e glutationa S-transferase, e das ox-LDL. Foram quantificadas as concentrações de glutationa total, glutationa reduzida, glutationa oxidada e nitritos e nitratos (medida indireta de NO●) em eritrócitos. A concentração do marcador de dano oxidativo em DNA 8-oxo-7,8-dihidro-2’-desoxiguanosina foi obtida em leucócitos. Resultados: Pacientes com DAC possuem reduzida concentração de nitritos e nitratos. A concentração de 8-OHdG, a atividade da GsT, os níveis de glutationa total, glutationa reduzida e glutationa oxidada, assim com o estradiol e a progesterona, não apresentaram relação com DAC ou DRS. Além do IAH, a redução da testosterona e do ferro disponível estão relacionados a DAC. A redução da atividade da paraoxonase-1 e a maior concentração de ox-LDL são preditores de DAC. A testosterona está relacionada à concentração de ferritina, transferrina e ferro disponível nestes pacientes. A ferritina correlacionou-se positivamente ao dano oxidativo em proteínas e com o IAH, negativamente aos níveis de nitritos e nitratos, e é maior nos pacientes com DAC. Conclusão: Baixos níveis de testosterona e ferro disponível, assim com o aumento da ferritina podem estar relacionados à fisiopatologia da associação entre DRS e DAC. Paraoxonase-1 e ox-LDL são importantes preditores de DAC, mas parecem não estar diretamente relacionados ao IAH nestes pacientes. / Title: Oxidative stress and steroid hormones in the association between Sleep Disordered Breathing and Coronary Artery Disease Introduction: Epidemiological studies have shown a possible association between Coronary Artery Disease (CAD) and Sleep Disordered Breathing (SDB). Evidences suggest that oxidative stress generated by the intermittent hypoxia experienced by patients with sleep disorders may be related to progression of CAD. The steroid hormones testosterone, progesterone and estradiol are related to oxidative stress, and may have a role in both diseases. Glutathione S-transferase uses the antioxidant molecule glutathione in the detoxification of compounds that can be formed in this process. The enzyme paraoxonase-1 hydrolyzes lipid peroxides, acting on oxidized low-density lipoproteins (ox-LDL). Ox-LDL are lipid peroxidation markers, being important for the atherosclerotic plaque formation. The vasodilator nitric oxide (NO●) is considered atheroprotective and can be reduced, aggravating DAC. Objective: Evaluate the oxidative stress and the pathophysiological changes arising from the association between SDB and CAD, and the role of steroid hormones in this process. Material and Methods: 56 patients with prior Coronary Artery Disease (CAD) diagnosis and apnea-hypopnea index (AHI) evaluation for diagnosis of sleep-disordered breathing (SDB) were divided into two groups, 29 control patients and 27 patients with CAD, defined by present a coronary obstruction > 30%. The serum concentration of triglycerides, HDL, LDL, ferritin, transferrin and available iron was obtained, as well as the serum levels of the hormones testosterone, estradiol and progesterone, enzymes paraoxonase-1 and glutathione S-transferase, and ox-LDL. Were measured concentrations of total glutathione, reduced glutathione, glutathione disulfide and nitrites and nitrates (NO● indirect measure) in erythrocytes. The concentration of the 8-oxo-7,8-dihydro-2'-deoxyguanosine, oxidative DNA damage marker, was obtained from leukocytes. Results: CAD patients have reduced concentrations of nitrates and nitrites. The concentration of 8-OHdG, GST activity, levels of total glutathione, reduced glutathione and glutathione disulfide, and estradiol and progesterone, showed no relationship with CAD or SDB. In addition to AHI, the reduction of testosterone and iron available are related to CAD. The reduced activity of paraoxonase-1 and the highest concentration of ox-LDL are CAD predictors. Testosterone is related to the concentration of ferritin, transferrin and iron available in these patients. Ferritin was positively correlated to oxidative damage in protein and with the AHI, and negatively to the levels of nitrites and nitrates, and is higher in CAD patients. Conclusion: Low testosterone levels and iron available, as well as the increase ferritin may be related to the pathophysiology of the association between SDB and CAD. Paraoxonase-1 and ox-LDL are important CAD predictors, but do not seem to be directly related to AHI in these patients.

Background Osteoarthritis (OA) is a long-term chronic disease that affects the joints and creates stiffness, pain and impaired movement. Knee osteoarthritis is the most common form of OA and affects all tissues of the joint, including bone, muscles, synovia, and cartilage. Previously, OA was accepted as only an age- or mechanical stress-related degenerative joint disease, but more recent studies suggest that OA is a heterogenous disease including inflammatory, hormonal and metabolic factors such as abdominal obesity (visceral fat), lipids (cholesterol, HDL, LDL and triglycerides) and glucose.    Aim The aim was to investigate the association of metabolic factors including fasting blood glucose, HbA1c, triglycerides, cholesterol, LDL, HDL, visceral fat, CRP and radiographic KOA in patients with symptomatic knee osteoarthritis. Methods Data were acquired from 91patients in the ages 30 – 63 experiencing symptomatic knee osteoarthritis. All subjects where divided into two groups depending on their level of fasting glucose, high versus low. Group I (n=26) had high glucose levels ≥5,6 mg/L and group II (n=65) had low glucose levels <5,6 mg/L.  Levels of HbA1c, lipids, visceral fat, CRP and radiographic KOA were then compared between the groups. Levels of fasting glucose, HbA1c and lipids (triglycerides, cholesterol, LDL, HDL) were analyzed by an accredited laboratory at the hospital of Halmstad by the department for labmedicine. CRP levels < 1 mg/L were manually analyzed with the sandwich ELISA method (enzyme-linked immunosorbent assay), which measures high-sensitive CRP (hsCRP) in serum. Visceral fat area was measured through bioelectrical impedance analysis (BIA) with InBody 770 and radiographs of the knees to obtain information about OA. Results There was a significant difference between the two groups in HbA1c, triglycerides, cholesterol and LDL p<0,05. Group I with high fasting glucose levels showed higher significant values of HbA1c, triglycerides, cholesterol and LDL than group II with low fasting glucose levels. 23% of all subjects met the requirement for metabolic syndrome according to IDF. Conclusion The findings in this study is in line with previous research and suggest that high glucose levels are associated with elevation of other metabolic factors in patients with knee osteoarthritis. However, there are several other interacting factors beyond the scope of this study, which may explain causalities. According to the findings in this study and previous research, obesity and metabolic syndrome could explain some of the connections between metabolic factors and knee osteoarthritis. Thus, further research is necessary to understand how all these metabolic factors are associated with osteoarthritis and obtain deeper knowledge about the pathogenesis and pathophysiology of the disease. / Detection and prediction of disease course in symptomatic knee osteoarthritis

Título: Estresse oxidativo e hormônios esteróides na associação entre Distúrbios Respiratórios do Sono e Doença Aterosclerótica Coronariana Introdução: Estudos epidemiológicos mostram a existência de associação entre a Doença Aterosclerótica Coronariana (DAC) e os Distúrbios Respiratórios do Sono (DRS). Evidencias sugerem que o estresse oxidativo gerado pela hipóxia intermitente sofrida pelos pacientes com DRS pode estar relacionado à progressão da DAC. Os hormônios esteróides testosterona, progesterona e estradiol estão relacionados ao estresse oxidativo, e podem ter papel em ambas as doenças. A enzima glutationa S-tranferase utiliza a molécula antioxidante glutationa na detoxificação de compostos que podem ser formados neste processo. A enzima paraoxonase-1 hidrolisa peróxidos lipídicos, atuando sobre as lipoproteínas de baixa densidade oxidadas (ox-LDL). Ox-LDL são marcadores de peroxidação lipídica, e são importantes na formação da placa aterosclerótica. O vaso dilatador óxido nítrico (NO●) é considerado ateroprotetor e pode estar reduzido, agravando a DAC. Objetivos: Estudar o estresse oxidativo e as alterações fisiopatológicas decorrentes da associação entre DRS e DAC, e avaliar a participação dos hormônios esteroides neste processo. Material e Métodos: 56 pacientes com prévio diagnóstico para Doença Aterosclerótica Coronariana (DAC) e avaliação do Índice de Apneias-hipopneias (IAH) para diagnóstico de Distúrbio Respiratório do sono (DRS) foram divididos em dois grupos, 29 pacientes controles e 27 pacientes com DAC, definidos por apresentarem obstrução coronariana >30%. Foram quantificadas as concentrações séricas dos triglicerídeos, HDL, LDL, ferritina, tranferrina e ferro disponível, assim como dos níveis séricos dos hormônios testosterona, estradiol e progesterona, das enzimas paraoxonase-1 e glutationa S-transferase, e das ox-LDL. Foram quantificadas as concentrações de glutationa total, glutationa reduzida, glutationa oxidada e nitritos e nitratos (medida indireta de NO●) em eritrócitos. A concentração do marcador de dano oxidativo em DNA 8-oxo-7,8-dihidro-2’-desoxiguanosina foi obtida em leucócitos. Resultados: Pacientes com DAC possuem reduzida concentração de nitritos e nitratos. A concentração de 8-OHdG, a atividade da GsT, os níveis de glutationa total, glutationa reduzida e glutationa oxidada, assim com o estradiol e a progesterona, não apresentaram relação com DAC ou DRS. Além do IAH, a redução da testosterona e do ferro disponível estão relacionados a DAC. A redução da atividade da paraoxonase-1 e a maior concentração de ox-LDL são preditores de DAC. A testosterona está relacionada à concentração de ferritina, transferrina e ferro disponível nestes pacientes. A ferritina correlacionou-se positivamente ao dano oxidativo em proteínas e com o IAH, negativamente aos níveis de nitritos e nitratos, e é maior nos pacientes com DAC. Conclusão: Baixos níveis de testosterona e ferro disponível, assim com o aumento da ferritina podem estar relacionados à fisiopatologia da associação entre DRS e DAC. Paraoxonase-1 e ox-LDL são importantes preditores de DAC, mas parecem não estar diretamente relacionados ao IAH nestes pacientes. / Title: Oxidative stress and steroid hormones in the association between Sleep Disordered Breathing and Coronary Artery Disease Introduction: Epidemiological studies have shown a possible association between Coronary Artery Disease (CAD) and Sleep Disordered Breathing (SDB). Evidences suggest that oxidative stress generated by the intermittent hypoxia experienced by patients with sleep disorders may be related to progression of CAD. The steroid hormones testosterone, progesterone and estradiol are related to oxidative stress, and may have a role in both diseases. Glutathione S-transferase uses the antioxidant molecule glutathione in the detoxification of compounds that can be formed in this process. The enzyme paraoxonase-1 hydrolyzes lipid peroxides, acting on oxidized low-density lipoproteins (ox-LDL). Ox-LDL are lipid peroxidation markers, being important for the atherosclerotic plaque formation. The vasodilator nitric oxide (NO●) is considered atheroprotective and can be reduced, aggravating DAC. Objective: Evaluate the oxidative stress and the pathophysiological changes arising from the association between SDB and CAD, and the role of steroid hormones in this process. Material and Methods: 56 patients with prior Coronary Artery Disease (CAD) diagnosis and apnea-hypopnea index (AHI) evaluation for diagnosis of sleep-disordered breathing (SDB) were divided into two groups, 29 control patients and 27 patients with CAD, defined by present a coronary obstruction > 30%. The serum concentration of triglycerides, HDL, LDL, ferritin, transferrin and available iron was obtained, as well as the serum levels of the hormones testosterone, estradiol and progesterone, enzymes paraoxonase-1 and glutathione S-transferase, and ox-LDL. Were measured concentrations of total glutathione, reduced glutathione, glutathione disulfide and nitrites and nitrates (NO● indirect measure) in erythrocytes. The concentration of the 8-oxo-7,8-dihydro-2'-deoxyguanosine, oxidative DNA damage marker, was obtained from leukocytes. Results: CAD patients have reduced concentrations of nitrates and nitrites. The concentration of 8-OHdG, GST activity, levels of total glutathione, reduced glutathione and glutathione disulfide, and estradiol and progesterone, showed no relationship with CAD or SDB. In addition to AHI, the reduction of testosterone and iron available are related to CAD. The reduced activity of paraoxonase-1 and the highest concentration of ox-LDL are CAD predictors. Testosterone is related to the concentration of ferritin, transferrin and iron available in these patients. Ferritin was positively correlated to oxidative damage in protein and with the AHI, and negatively to the levels of nitrites and nitrates, and is higher in CAD patients. Conclusion: Low testosterone levels and iron available, as well as the increase ferritin may be related to the pathophysiology of the association between SDB and CAD. Paraoxonase-1 and ox-LDL are important CAD predictors, but do not seem to be directly related to AHI in these patients.

Abstract Atherosclerosis is a chronic inflammatory disease and infections potentially contribute to its pathogenesis. Oxidation of LDL (low-density lipoprotein) is a key event in atherogenesis. Lipid peroxidation produces reactive aldehydes such as malondialdehyde (MDA) and MDA-acetaldehyde that form immunogenic adducts on for example LDL particles. This thesis investigated natural IgM antibodies that recognize MDA and MDA-acetaldehyde adducts and bind, through molecular mimicry, to epitopes on oral pathogenic bacteria. In the first study, the induction of cross-reactive IgM antibodies binding to MDA adducts was investigated in mice immunized with periodontopathogen Porphyromonas gingivalis. The effect of immunization on the development of atherosclerosis was analyzed after a high fat diet. Immunization of mice with killed P. gingivalis elevated IgM levels to MDA adducts and reduced atherosclerosis. Mouse monoclonal IgM to MDA modified LDL recognized epitopes on P. gingivalis that were identified as gingipain protease enzyme of this bacterium. The presence of IgM with similar specificity was also demonstrated in human sera. In the second study the effect of immunization with MDA modified LDL in conferring protection against pathogen-accelerated atherosclerosis was investigated. Mice were immunized with MDA modified LDL before challenge with live P. gingivalis. The extent of atherosclerosis after a high fat diet was reduced in immunized mice compared to control groups. Immunized mice had elevated IgM and IgG levels to MDA modified LDL compared to controls. The third study investigated antibody recognition of MDA-acetaldehyde adducts in umbilical cord blood plasma of preterm and full-term newborns. Natural IgM to MDA-acetaldehyde adducts was enriched in umbilical cord blood plasma compared to maternal levels even in preterm neonates. This thesis highlighted the importance of immune recognition of MDA adducts by natural IgM antibodies, and demonstrated that pathogenic bacteria and MDA derived structures are recognized by natural IgM throughout the lifespan. These natural IgM are proposed to modulate the development of chronic inflammatory diseases such as atherosclerosis and periodontitis. / Tiivistelmä Valtimonkovettumatautiin, eli ateroskleroosiin, liittyy matala-asteinen tulehdustila, ja myös infektiot vaikuttavat taudin ilmentymiseen. LDL:n (low-density lipoprotein) hapettuminen on merkittävä valtimonkovettumataudin syntyä edistävä reaktio. Lipidiperoksidaatio tuottaa reaktiivisia aldehydejä, kuten malonidialdehydiä (MDA) ja MDA-asetaldehydiä, jotka muodostavat immuunijärjestelmän tunnistamia rakenteita esimerkiksi LDL-partikkeleihin. Väitöskirjassa tutkittiin luonnollisia IgM-vasta-aineita, jotka tunnistavat MDA- ja MDA-asetaldehydirakenteita, ja jotka rakenteiden samankaltaisuuden takia sitoutuvat myös parodontiittipatogeenien epitooppeihin. Ensimmäisessä työssä MDA-rakenteisiin sitoutuvien IgM-vasta-aineiden ristireaktiota tutkittiin hiirillä, jotka immunisoitiin Porphyromonas gingivalis parodontiittipatogeenillä. Hiirten immunisoiminen inaktivoidulla P. gingivalis bakteerilla lisäsi IgM-vasta-ainetasoja MDA-rakenteita vastaan ja vähensi valtimonkovettumatautia. MDA-LDL:ään sitoutuva hiiren monoklonaalinen IgM-vasta-aine sitoutui P. gingivalis bakteerin proteiineihin, joiden tunnistettiin olevan osia tämän bakteerin gingipain proteaasientsyymistä. Myös ihmisen seerumista osoitettiin IgM-vasta-aineita, joilla oli samantyyppinen sitoutumisspesifisyys. Toisessa työssä tutkittiin MDA-LDL-immunisaation suojaavaa vaikutusta infektion kiihdyttämän valtimonkovettumataudin synnyssä. Hiiret immunisoitiin MDA-LDL:llä ennen infektiota elävällä P. gingivalis bakteerilla. Valtimonkovettumatauti väheni immunisoiduilla hiirillä rasvaruokinnan jälkeen verrattuna kontrolliryhmiin. Immunisoiduilla hiirillä IgM- ja IgG-vasta-ainetasot MDA-LDL:ää vastaan olivat kohonneet verrattuna kontrolliryhmiin. Kolmannessa työssä tutkittiin, tunnistavatko ennenaikaisten ja täysiaikaisten vastasyntyneiden luonnolliset vasta-aineet MDA-asetaldehydirakenteita. IgM-vasta-aineita MDA-asetaldehydirakenteisiin esiintyi jo ennenaikaisesti syntyneiden napaverinäytteissä. MDA-asetaldehydiin sitoutuvien IgM-vasta-aineiden määrä vastasyntyneillä oli korkeampi verrattuna äiteihin. MDA-rakenteet ovat yksi tärkeä kohde immuunijärjestelmän luonnollisille IgM-vasta-aineille, jotka tunnistavat myös taudinaiheuttajabakteereja. Näillä vasta-aineilla voi olla vaikutusta kroonisten tulehdustautien, kuten valtimonkovettumataudin ja parodontiitin syntymekanismeissa.

Abstract Atherosclerosis is a multifactorial disease with numerous genes and environmental factors affecting its intiation and progression. During the past years many candidate genes for atherosclerosis have been suggested, and it has also become evident that the immune system plays a part in atherogenesis. Early atherosclerotic changes can be effectively detected by measuring carotid artery intima-media thickness (IMT). In the present study the associations between IMT and polymorphisms of three candidate genes for atherosclerosis were studied: endothelial nitric oxide synthase (eNOS), apolipoprotein E (apoE) and paraoxonase-1 (PON1). To assess the role of immunological factors determining carotid atherosclerosis, CRP and circulating autoantibodies to oxidised LDL were studied in relation to IMT. The study population consisted of 519 hypertensive and 526 control subjects from a middle-aged population in Oulu, Finland. The results showed that the investigated polymorphisms of eNOS and PON1 genes were not associated with IMT, suggesting that these polymorphisms are not major risk factors for atherosclerosis in the general Caucasian population. A significant interaction between the apoE polymorphism and smoking in relation to IMT was observed among men, indicating that carriers of the ε4 allele may be particularly prone to the atherogenic effects of smoking. This interaction was especially clear in hypertensive subjects. CRP was strongly associated with IMT before adjusting for confounding factors. After the adjustment, this association diasppeared. The finding suggests that instead of early atherosclerosis CRP may be related to the later phases of the disease. This may partly explain the strong correlation between CRP and future cardiovascular events. IgM type of autoantibodies binding to oxidised LDL were inversely associated with IMT, and this finding remained after adjusting for previously known risk factors for atherosclerosis, implying a possible protective role for these antibodies in atherogenesis.

Background: Familial hypercholesterolemia (FH) is a genetic disorder estimated to affect 0,4 % of the world's population (1 in 250). Patients with FH have abnormally high LDL-cholesterol.  Aim: The aim of this study was to estimate the prevalence of FH in Stockholm County and to evaluate the health economic impact of diagnosing people with FH early in life. Methods: Two algorithms were used to estimate the number of people with high LDLcholesterol. The first method applied data on cholesterol measurements from patients in Stockholm County between 2006-2008 and a modified version of Dutch Lipid Clinic Network. The second method was based on dispensed prescriptions of ezetimibe, lomitapide, evolucumab and alirocumab during 2019. A health economic model was created to estimate the economical outcome of diagnosing and treating patients early before undergoing a cardiovascular event. Results: The prevalence of FH in Stockholm County was estimated to 0.63 %, corresponding to a total of 12 000 individuals. The accumulated costs over 20 years for FH is estimated to be more than 1,1 billion SEK for diagnosed and treated patients, and 1,7 billion SEK for undiagnosed and untreated patients. Conclusions: The prevalence of FH in Stockholm County is probably higher than previously suggested. Early diagnosis and treatment is an investment for society and necessary for the patients to prevent cardiovascular events and improve quality of life.

This study investigated whether oxLDL and/or angiotensin (Ang) II signaling pathways mediate traffic-generated air pollution- exposure induced alterations in blood-brain barrier (BBB) integrity and permeability in a healthy wild type (C57Bl/6) mouse model; additionally, whether these outcomes are exacerbated by a high fat-diet investigated. An environmentally relevant concentration of a mixture of vehicle engine exhaust (MVE) was used. To investigate the hypotheses, 12 wk old male C57Bl/6 mice on either a high fat (HF) or low fat (LF) diet were randomly assigned to inhalational exposure of either filtered-air (FA) or 30 µg PM/m3 diesel exhaust + 70 µg PM/m3 gasoline exhaust (MVE) for 6 hr/day for 30 days. Additionally, we examined mechanisms involved in MVE-mediated alterations BBB integrity using a novel BBB co-culture in vitro model, consisting of mouse primary cerebral vascular endothelial cells on an apical transwell and astrocytes in the basal compartment, which was treated with plasma from the mice on our exposure study. Our in vivo exposure study results showed that MVE inhalation resulted in increased circulating plasma oxLDL and Ang II, compared to FA controls. Additionally, we observed increased cerebral microvascular expression of oxLDL receptors, LOX-1 and CD-36, and Ang II receptor subtype 1 (AT1) in MVE-exposed C57Bl/6 mice, which was further exacerbated with consumption of an HF diet. Increased signaling of both Ang II and oxLDL was associated with decreased BBB integrity, as evidenced by the concurrent reduction in expression of tight junction (TJ) protein claudin-5 and increased permeability of sodium fluorescein (Na-F) from the blood into the cerebral parenchyma. Our results suggest that possible mechanisms involved in oxLDL and/or Ang II-mediated alterations in BBB integrity include oxidative stress and upregulated expression and activity of matrix metalloproteinase (MMP)-9, which is associated with degradation of TJ proteins in the BBB. Our in vitro BBB co-culture results confirm our in vivo findings, as we observe increased BBB permeability (TEER) and decreased integrity (decreased expression of TJ proteins) in the endothelial (apical) layer when treated with plasma from MVE-exposed mice, which was further exacerbated when treated with plasma from MVE-exposed mice on an HF diet. Pre-treatment of the endothelial cells with the AT1 receptor antagonist, Losartan, prior to applying plasma, resulted in attenuation of the alterations observed in endothelial integrity in the BBB co-culture treated with plasma from either MVE+LF or MVE+HF animals. These results suggest Ang II – AT1 signaling mediate, at least in part, the alterations in the BBB integrity observed after exposure to MVE. Moreover, we observed that treatment of the endothelial (apical) layer with plasma from MVE-exposed animals resulted in increased production of inflammatory mediators interleukin-6 (IL-6) and transforming growth factor-β in the astrocyte media (basal compartment). Additionally, these same astrocytes also displayed increased production of angiotensin-converting enzyme (ACE) and also AT1 receptor mRNA expression, while showing decreased expression of the aryl hydrocarbon receptor (AhR) and glutathione peroxidase (GPx). Collectively, these results suggest that exposure to the ubiquitous environmental air pollutant, vehicle engine emissions, results in increased oxLDL and Ang II signaling in the cerebral microvasculature, which is associated with decreased vessel integrity and increased oxidative stress and inflammatory signaling in the CNS. The observed detrimental outcomes are even further exacerbated when coupled with the consumption of an HF diet.