Background: Dyslipidemia is strongly associated with the development of hypertension. In our previous study, it was shown that elevated TC, LDL-c, and non-HDL-c were associated with the prevalence of hypertension in Chinese men, whereas the relationship between HDL-c and hypertension shifted from no association to a positive association after adjusting for the BMI. To further accumulate epidemiological evidence in Asian women, this study aimed to investigate the relationship between lipid profile and prevalence of hypertension in Chinese adult women. Methods: This is a cross-sectional study including 54,099 Chinese women aged>20 years at 32 health screening centers in 11 cities from 2010-2016. The original data were obtained from DATADRYAD database (www.datadryad.org). Besides, the overall women were classified into non-hypertensive and hypertensive groups based on baseline blood pressure levels. Differences between the two groups were examined by Man-Whitney test or Chi-square test. Spearman’s correlation coefficient was employed to evaluate the correlation between systolic blood pressure (SBP), diastolic blood pressure (DBP) and lipid profiles. Multivariate logistic regression was performed to estimate the relationship between different lipid levels and the prevalence of hypertension. Odds ratios (ORs) and 95% confidence intervals (CIs) indicated the risk of lipid and hypertension. Bayesian model (BN) model was constructed to further assess the relationship between baseline characteristics and the prevalence of hypertension, as well as the importance of each variable for the prevalence of hypertension. Results: Compared to the non-hypertensive population, the hypertensive population was older, and had the higher body mass index (BMI), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), serum creatinine (Scr), fasting blood glucose (FPG), blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and non-high-density lipoprotein cholesterol (non-HDL-c), but HDL-c and the presence concerning the family history of diabetes were lower. Multivariate logistic regression analysis revealed that TC, LDL-c, and non-HDL-c showed a positive trend with hypertension risk (p for trend < 0.05) whereas TC and HDL-c were not significantly associated with hypertension prevalence. Moreover, each 1 mg/dl increase in TC, LDL, and non-HDL hypertension prevalence increased by 0.2% [1.002 (1.000-1.003)], 0.2% [1.002 (1.000- 1.004)], and 0.2% [1.002(1.001-1.004)], respectively. BN suggested that the importance of age, BMI, FPG, non-HDL-c on the prevalence of hypertension was 52.73%, 24.98%, 11.22%, and 2.34%, respectively. Conclusion: Overall, in Chinese adult women, TC, LDL-c and non-HDL-c levels were higher and HDL-c level was lower in the hypertensive population, whereas TG did not differ significantly from the non-hypertensive population. Meanwhile, TC, LDL-c, and non-HDL-c were positively associated with prevalence of hypertension, and HDL-c was negatively associated with prevalence of hypertension but became nonsignificant after full adjustment for variables. Moreover, BN model suggested that age, BMI, FPG, and non-HDL-c had a greater effect on the development of hypertension.

No description available.

Les accidents vasculaires cérébraux (AVC) ischémiques sont un problème majeur de santé publique. Les thérapies actuellement disponibles se fondent sur une approche vasculaire de la prise en charge. L’arrivée de la thrombectomie mécanique comme traitement de routine de l’AVC, expose le patient à des lésions de reperfusion comme les transformations hémorragiques (TH). L’hyperglycémie aiguë, augmente ce risque. Nous avons mis au point un modèle préclinique pertinent et reproductible chez la souris permettant d’étudier les mécanismes de ces TH. Les lipoprotéines de haute densité (HDL) sont des complexes moléculaires ayant des propriétés protectrices. Nous avons démontré que lors de la phase aiguë de l’AVC, ces HDL subissaient des modifications structurelles et devenaient dysfonctionnelles. Un des mécanismes de cette altération est représenté par l’oxydation des protéines de surface notamment l’apoA-1 par la myéloperoxydase (MPO) libérée par les neutrophiles recrutés dans la zone ischémiée. Le dosage du taux plasmatique de MPO en phase aiguë d’AVC pourrait permettre de mieux caractériser ce mécanisme. L’injection de HDL a déjà prouvé son efficacité dans la diminution de la taille des infarctus cérébraux ainsi que dans la survenue des complications hémorragiques sur des modèles murin d’ischémie cérébrale. L’hypothèse d’un défaut d’efficacité des HDL dans cette condition pathologique particulière nous conduit à envisager une amélioration de leurs fonctions grâce à leur propriété de vecteur de molécules protectrices. Ces HDL seraient alors utilisées comme transporteur de molécules augmentant leur potentiel neuro- et endothélio-protecteur dans le traitement de l’AVC ischémique. / Ischemic stroke is a major public health problem. Currently, available therapies are based on a vascular approach. The advent of mechanical thrombectomy as a routine treatment for stroke exposes the patient to reperfusion injury such as hemorrhagic transformation (HT). Acute hyperglycemia increases this risk. We have developed a relevant and reproducible preclinical model in mice to study the mechanisms of these HT. High density lipoproteins (HDL) are molecular complexes with protective properties. We demonstrated that during the acute phase of stroke, these HDLs become dysfunctional. One of the mechanisms of this alteration is represented by the oxidation of surface proteins including apoA-1 by myeloperoxidase (MPO) released by neutrophils recruited into the ischemic zone. The MPO plasmatic level determination in the acute phase of stroke could be relevant. The injection of HDL has already proved effective in reducing the size of infarct and in the occurrence of HT in murine models of stroke. The hypothesis of a lack of efficiency of HDL in this particular pathological condition leads us to consider an improvement of their functions thanks to their vector property of protective molecules. These HDLs would then be used as a transporter of molecules increasing their neuro- and endothelio-protective potential in the treatment of ischemic stroke.

La present tesi avalua els efectes de certs factors ambientals sobre la paraoxonasa1 (PON1), enzim antioxidant, possiblement protector enfront les malalties cardiovasculars, a través de dos estudis d'intervenció i un de transversal. En primer lloc, el tractament amb simvastatina dels pacients amb hipercolesterolèmia familiar, que presentaven una activitat paraoxonasa baixa, s'associava a un increment de l'activitat fins a valors similars als d'individus normolipèmics, independentment dels polimorfismes PON1-55 o PON1-192. En segon lloc, l'entrenament físic s'associava a un augment de l'activitat paraoxonasa en els individus QQ i una disminució de la mateixa en els portadors de l'al·lel R pel polimorfisme PON1-192. L'increment de l'activitat paraoxonasa immediatament després de l'exercici físic agut era seguit per una disminució subseqüent de l'activitat. La recuperació dels nivells basals d'activitat paraoxonasa a les 24h de l'exercici físic agut es donava en els individus QQ independentment del seu estat d'entrenament, i en els individus portadors de l'al·lel R només quan estan entrenats. En tercer lloc, el consum elevat d'àcid oleic comportava un augment de la concentració de c-HDL i de l'activitat paraoxonasa en els homes portadors dels genotips QR i RR del polimorfisme PON1-192, respectivament.Paraules claus: paraoxonasa, PON1, genotips, simvastatina, hipercolesterolèmia familiar, interacció gen-dieta, lipoproteïna d'alta densitat (HDL), exercici físic agut, entrenament físic, estrès oxidatiu, àcid oleic, oli d'oliva, peròxids lipídics, malaltia cardiovascular. / The present thesis evaluates some environmental factor effects on paraoxonase1 (PON1), an possibly protective against cardiovascular disease antioxidant enzyme, through two intervention studies and a cross-sectional one. First, treatment with simvastatin of the familial hypercholesterolemic patients, which had low paraoxonase activity, was associated with an increase in the activity to values similar to the normolipemic ones, regardless of the PON1-55 or PON1-192 polymorphisms. Second, Regular exercise was associated with an increase in PON1 activity in QQ subjects and with a decrease in R carriers. Increased PON1 activity immediately after a bout of exercise was subsequently followed by a decrease of activity. The recovery of the basal PON1 activity levels at 24 h was found in QQ subjects regardless of their training status and in trained R carriers, but not in untrained R carriers. Third, high oleic acid intake was associated with increased HDL cholesterol and PON1 activity levels only in men who were QR and RR of the PON1-192 polymorphism, respectively.

Motivation: The prevalence of non-communicable diseases such as diabetes mellitus (DM) and cardiovascular disease (CVD) is rapidly increasing in industrialized societies. Experts believe that lifestyle, and in particular its nutritional aspects, plays a decisive role in increasing the burden of these chronic conditions. Dietary habits would, therefore, be modified to exert a positive impact on the prevention and treatment of chronic diseases of lifestyle. It is believed that the state of hyperglycaemia that is observed following food intake under certain dietary regimes contributes to the development of various metabolic conditions. This is not only true for individuals with poor glycaemic control such as some diabetics, but could also be true for healthy individuals. It would, therefore, be helpful to be able to reduce the amplitude and duration of postprandial hyperglycaemia. Selecting the correct type of carbohydrate (CHO) foods may produce less postprandial hyperglycaemia, representing a possible strategy in the prevention and treatment of chronic metabolic diseases. At the same time, a key focus of sport nutrition is the optimal amount of CHO that an athlete should consume and the optimal timing of consumption. The most important nutritional goals of the athlete are to prepare body CHO stores pre-exercise, provide energy during prolonged exercise and restore glycogen stores during the recovery period. The ultimate aim of these strategies is to maintain CHO availability to the muscle and central nervous system during prolonged moderate to high intensity exercise, since these are important factors in exercise capacity and performance. However, the type of CHO has been studied less often and with less attention to practical concerns than the amount of CHO. The glycaemic index (GI) refers to the blood glucose raising potential of CHO foods and, therefore, influences secretion of insulin. In several metabolic disorders, secretion of insulin is inadequate or impossible, leading to poor glycaemic control. It has been suggested that low GI diets could potentially contribute to a significant improvement of the conditions associated with poor glycaemic control. Insulin secretion is also important to athletes since the rate of glycogen synthesis depends on insulin due to it stimulatory effect on the activity of glycogen synthase. Objectives: Three main objectives were identified for this study. The first was to conduct a meta-analysis of the effects of the GI on markers for CHO and lipid metabolism with the emphasis on randomised controlled trials (RCT's). Secondly, a systematic review was performed to determine the strength of the body of scientific evidence from epidemiological studies combined with RCT's to encourage dieticians to incorporate the GI concept in meal planning. Finally, a systematic review of the effect of the GI in sport performance was conducted on all available literature up to date to investigate whether the application of the GI in an athlete's diet can enhance physical performance. Methodology: For the meta-analysis, the search was for randomised controlled trials with a cross-over or parallel design published in English between 1981 and 2003, investigating the effect of low GI vs high GI diets on markers of carbohydrate and lipid metabolism. The main outcomes were serum fructosamine, glycosylated haemoglobin (HbA1c), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), total cholesterol (TC) and triacylglycerols (TG). For the systematic review, epidemiological studies as well as RCT's investigating the effect of LGI vs HGI diets on markers for carbohydrate and lipid metabolism were used. For the systematic review on the effect of the GI on sport performance, RCT's with either a cross-over or parallel design that were published in English between January 1981 and September 2004 were used. All relevant manuscripts for the systematic reviews as well as meta-analysis were obtained through a literature search on relevant databases such as the Cochrane Central Register of Controlled Trials, MEDLINE (1981 to present), EMBASE, LILACS, SPORTDiscus, ScienceDirect and PubMed. This thesis is presented in the article format. Results and conclusions of the individual manuscripts: For the meta-analysis, literature searches identified 16 studies that met the strict inclusion criteria. Low GI diets significantly reduced fructosamine (p<0.05), HbA1c, (p<0.03), TC(p<0.0001) and tended to reduce LDL-c (p=0.06) compared to high GI diets. No changes were observed in HDL-c and TG concentrations. Results from this meta analysis, therefore, support the use of the GI concept in choosing CHO-containing foods to reduce TC and improve blood glucose control in diabetics. The systematic review combined the results of the preceding meta-analysis and results from epidemiological studies. Prospective epidemiological studies showed improvements in HDL-c concentrations over longer time periods with low GI diets vs. high GI diets, while the RCT's failed to show an improvement in HDL-c over the short-term. This could be attributed to the short intervention period during which the RCT's were conducted. Furthermore, epidemiological studies failed to show positive relationships between LDL-c and TC and low GI diets, while RCT's reported positive results on both these lipids with low GI diets. However, the epidemiological studies, as well as the RCT's showed positive results with low GI diets on markers of CHO metabolism. Taken together, convincing evidence from RCT's as well as epidemiological studies exists to recommend the use of low GI diets to improve markers of CHO as well as of lipid metabolism. 3 From the systematic review regarding the GI and sport performance it does not seem that low GI pre-exercise meals provide any advantages over high GI pre-exercise meals. Although low GI pre-exercise meals may better maintain CHO availability during exercise, low GI pre-exercise meals offer no added advantage over high GI meals regarding performance. Furthermore, the exaggerated metabolic responses from high GI compared to low GI CHO seems not be detrimental to exercise performance. However, athletes who experience hypoglycaemia when consuming CHO-rich feedings in the hour prior to exercise are advised to rather consume low GI pre-exercise meals. No studies have been reported on the GI during exercise. Current evidence suggests a combination of CHO with differing Gl's such as glucose (high GI), sucrose (moderate GI) and fructose (low GI) will deliver the best results in terms of exogenous CHO oxidation due to different transport mechanisms. Although no studies are conducted on the effect of the GI on short-term recovery it is speculated that high GI CHO is most effective when the recovery period is between 0-8 hours, however, evidence suggests that when the recovery period is longer (20-24 hours), the total amount of CHO is more important than the type of CHO. Conclusion: There is an important body of evidence in support of a therapeutic and preventative potential of low GI diets to improve markers for CHO and lipid metabolism. By substituting high GI CHO-rich with low GI CHO-rich foods improved overall metabolic control. In addition, these diets reduced TC, tended to improve LDL-c and might have a positive effect over the long term on HDL-c. This confirms the place for low GI diets in disease prevention and management, particularly in populations characterised by already high incidences of insulin resistance, glucose intolerance and abnormal lipid levels. For athletes it seems that low GI pre-exercise meals do not provide any advantage regarding performance over high GI pre-exercise meals. However, low GI meals can be recommended to athletes who are prone to develop hypoglycaemia after a CHO-rich meal in the hour prior to exercise. No studies have been reported on the effect of the GI during exercise. However, it has been speculated that a combination of CHO with varying Gl's deliver the best results in terms of exogenous CHO oxidation. No studies exist investigating the effect of the GI on short-term recovery, however, it is speculated that high GI CHO-rich foods are suitable when the recovery period is short (0-8 h), while the total amount rather than the type of CHO is important when the recovery period is longer (20-24 h). Therefore, the GI is a scientifically based tool to enable the selection of CHO-containing foods to improve markers for CHO and lipid metabolism as well as to help athletes to prepare optimally for competitions. Recommendations: Although a step nearer has been taken to confirm a place for the GI in human health, additional randomised, controlled, medium and long-term studies as well as more epidemiological studies are needed to investigate further the effect of low GI diets on LDL-c. HDL-c and TG. These studies are essential to investigate the effect of low GI diets on endpoints such as CVD and DM. This will also show whether low GI diets can reduce the risk of diabetic complications such as neuropathy and nephropathy. Furthermore, the public at large must be educated about the usefulness and application of the GI in meal planning. For sport nutrition, randomised controlled trials should be performed to investigate the role of the GI during exercise as well as in sports of longer duration such as cricket and tennis. More studies are needed to elucidate the short-term effect of the GI post-exercise as well as to determine the mechanism of lower glycogen storage with LGI meals post-exercise. / Thesis (Ph.D. (Dietetics))--North-West University, Potchefstroom Campus, 2005.

Motivation: The prevalence of non-communicable diseases such as diabetes mellitus (DM) and cardiovascular disease (CVD) is rapidly increasing in industrialized societies. Experts believe that lifestyle, and in particular its nutritional aspects, plays a decisive role in increasing the burden of these chronic conditions. Dietary habits would, therefore, be modified to exert a positive impact on the prevention and treatment of chronic diseases of lifestyle. It is believed that the state of hyperglycaemia that is observed following food intake under certain dietary regimes contributes to the development of various metabolic conditions. This is not only true for individuals with poor glycaemic control such as some diabetics, but could also be true for healthy individuals. It would, therefore, be helpful to be able to reduce the amplitude and duration of postprandial hyperglycaemia. Selecting the correct type of carbohydrate (CHO) foods may produce less postprandial hyperglycaemia, representing a possible strategy in the prevention and treatment of chronic metabolic diseases. At the same time, a key focus of sport nutrition is the optimal amount of CHO that an athlete should consume and the optimal timing of consumption. The most important nutritional goals of the athlete are to prepare body CHO stores pre-exercise, provide energy during prolonged exercise and restore glycogen stores during the recovery period. The ultimate aim of these strategies is to maintain CHO availability to the muscle and central nervous system during prolonged moderate to high intensity exercise, since these are important factors in exercise capacity and performance. However, the type of CHO has been studied less often and with less attention to practical concerns than the amount of CHO. The glycaemic index (GI) refers to the blood glucose raising potential of CHO foods and, therefore, influences secretion of insulin. In several metabolic disorders, secretion of insulin is inadequate or impossible, leading to poor glycaemic control. It has been suggested that low GI diets could potentially contribute to a significant improvement of the conditions associated with poor glycaemic control. Insulin secretion is also important to athletes since the rate of glycogen synthesis depends on insulin due to it stimulatory effect on the activity of glycogen synthase. Objectives: Three main objectives were identified for this study. The first was to conduct a meta-analysis of the effects of the GI on markers for CHO and lipid metabolism with the emphasis on randomised controlled trials (RCT's). Secondly, a systematic review was performed to determine the strength of the body of scientific evidence from epidemiological studies combined with RCT's to encourage dieticians to incorporate the GI concept in meal planning. Finally, a systematic review of the effect of the GI in sport performance was conducted on all available literature up to date to investigate whether the application of the GI in an athlete's diet can enhance physical performance. Methodology: For the meta-analysis, the search was for randomised controlled trials with a cross-over or parallel design published in English between 1981 and 2003, investigating the effect of low GI vs high GI diets on markers of carbohydrate and lipid metabolism. The main outcomes were serum fructosamine, glycosylated haemoglobin (HbA1c), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), total cholesterol (TC) and triacylglycerols (TG). For the systematic review, epidemiological studies as well as RCT's investigating the effect of LGI vs HGI diets on markers for carbohydrate and lipid metabolism were used. For the systematic review on the effect of the GI on sport performance, RCT's with either a cross-over or parallel design that were published in English between January 1981 and September 2004 were used. All relevant manuscripts for the systematic reviews as well as meta-analysis were obtained through a literature search on relevant databases such as the Cochrane Central Register of Controlled Trials, MEDLINE (1981 to present), EMBASE, LILACS, SPORTDiscus, ScienceDirect and PubMed. This thesis is presented in the article format. Results and conclusions of the individual manuscripts: For the meta-analysis, literature searches identified 16 studies that met the strict inclusion criteria. Low GI diets significantly reduced fructosamine (p<0.05), HbA1c, (p<0.03), TC(p<0.0001) and tended to reduce LDL-c (p=0.06) compared to high GI diets. No changes were observed in HDL-c and TG concentrations. Results from this meta analysis, therefore, support the use of the GI concept in choosing CHO-containing foods to reduce TC and improve blood glucose control in diabetics. The systematic review combined the results of the preceding meta-analysis and results from epidemiological studies. Prospective epidemiological studies showed improvements in HDL-c concentrations over longer time periods with low GI diets vs. high GI diets, while the RCT's failed to show an improvement in HDL-c over the short-term. This could be attributed to the short intervention period during which the RCT's were conducted. Furthermore, epidemiological studies failed to show positive relationships between LDL-c and TC and low GI diets, while RCT's reported positive results on both these lipids with low GI diets. However, the epidemiological studies, as well as the RCT's showed positive results with low GI diets on markers of CHO metabolism. Taken together, convincing evidence from RCT's as well as epidemiological studies exists to recommend the use of low GI diets to improve markers of CHO as well as of lipid metabolism. 3 From the systematic review regarding the GI and sport performance it does not seem that low GI pre-exercise meals provide any advantages over high GI pre-exercise meals. Although low GI pre-exercise meals may better maintain CHO availability during exercise, low GI pre-exercise meals offer no added advantage over high GI meals regarding performance. Furthermore, the exaggerated metabolic responses from high GI compared to low GI CHO seems not be detrimental to exercise performance. However, athletes who experience hypoglycaemia when consuming CHO-rich feedings in the hour prior to exercise are advised to rather consume low GI pre-exercise meals. No studies have been reported on the GI during exercise. Current evidence suggests a combination of CHO with differing Gl's such as glucose (high GI), sucrose (moderate GI) and fructose (low GI) will deliver the best results in terms of exogenous CHO oxidation due to different transport mechanisms. Although no studies are conducted on the effect of the GI on short-term recovery it is speculated that high GI CHO is most effective when the recovery period is between 0-8 hours, however, evidence suggests that when the recovery period is longer (20-24 hours), the total amount of CHO is more important than the type of CHO. Conclusion: There is an important body of evidence in support of a therapeutic and preventative potential of low GI diets to improve markers for CHO and lipid metabolism. By substituting high GI CHO-rich with low GI CHO-rich foods improved overall metabolic control. In addition, these diets reduced TC, tended to improve LDL-c and might have a positive effect over the long term on HDL-c. This confirms the place for low GI diets in disease prevention and management, particularly in populations characterised by already high incidences of insulin resistance, glucose intolerance and abnormal lipid levels. For athletes it seems that low GI pre-exercise meals do not provide any advantage regarding performance over high GI pre-exercise meals. However, low GI meals can be recommended to athletes who are prone to develop hypoglycaemia after a CHO-rich meal in the hour prior to exercise. No studies have been reported on the effect of the GI during exercise. However, it has been speculated that a combination of CHO with varying Gl's deliver the best results in terms of exogenous CHO oxidation. No studies exist investigating the effect of the GI on short-term recovery, however, it is speculated that high GI CHO-rich foods are suitable when the recovery period is short (0-8 h), while the total amount rather than the type of CHO is important when the recovery period is longer (20-24 h). Therefore, the GI is a scientifically based tool to enable the selection of CHO-containing foods to improve markers for CHO and lipid metabolism as well as to help athletes to prepare optimally for competitions. Recommendations: Although a step nearer has been taken to confirm a place for the GI in human health, additional randomised, controlled, medium and long-term studies as well as more epidemiological studies are needed to investigate further the effect of low GI diets on LDL-c. HDL-c and TG. These studies are essential to investigate the effect of low GI diets on endpoints such as CVD and DM. This will also show whether low GI diets can reduce the risk of diabetic complications such as neuropathy and nephropathy. Furthermore, the public at large must be educated about the usefulness and application of the GI in meal planning. For sport nutrition, randomised controlled trials should be performed to investigate the role of the GI during exercise as well as in sports of longer duration such as cricket and tennis. More studies are needed to elucidate the short-term effect of the GI post-exercise as well as to determine the mechanism of lower glycogen storage with LGI meals post-exercise. / Thesis (Ph.D. (Dietetics))--North-West University, Potchefstroom Campus, 2005.

Dyslipidemia can be a comorbidity of both insulin-resistance and atherosclerosis. Hypertriglyceridemia is common in hyperglycemia and is associated with hypoalphalipoproteinemia (low HDL) and with altered nucleotide or purinergic signaling. We therefore hypothesized that extracellular nucleotides may affect hepatic lipoprotein metabolism. Our studies confirm this view and show that nucleotides regulate cellular proteolytic pathways in liver cells and thereby control lipoprotein secretion and their metabolism by hepatic lipase (HL). Treatment of liver cells with the nucleotide, adenosine diphosphate (ADP), stimulates VLDL-apoB100 and apoE secretion, but blocks HDL-apoA-I and HL secretion. ADP functions like a proteasomal inhibitor to block proteasomal degradation and stimulate apoB100 secretion. Blocking the proteosome is known to activate autophagic pathways. The nucleotide consequently stimulates autophagic degradation in liver cells and increases cellular levels of the autophagic proteins, LC3 and p62. Confocal studies show that ADP increases cellular LC3 levels and promotes co-localization of LC3 and apoA-I in an autophagosomal degradation compartment. ADP acts through the G-protein coupled receptor, P2Y13, to stimulate autophagy and block both HDL and HL secretion. Overexpression of P2Y13 increases cellular LC3 levels and blocks the induction of both HDL and HL secretion, while P2Y13 siRNA reduce LC3 protein levels and cause up to a ten-fold stimulation in HDL and HL secretion. P2Y13 gene expression regulates autophagy through the insulin receptor (IR-β). A reduction in P2Y13 expression increases the phosphorylation of IR-β and protein kinase B (Akt) >3-fold, while increasing P2Y13 expression inhibits the activation of IR-β and Akt. Experiments with epitope-labeled apoA-I and HL show that activation of purinergic pathways has no effect on the internalization and degradation of extracellular apoA-I and HL, which confirms the view that nucleotides primarily impact intracellular protein transport and degradation. In conclusion, elevated blood glucose levels may promote dyslipidemia by stimulating purinergic signaling through P2Y13 and IR-β and perturbing the intracellular degradation and secretion of both HDL and VLDL.

Abstract The principal aim of this study was to explore associations between systemic inflammatory status and periodontal inflammation and tissue destruction. The study population consisted of 61 patients with chronic periodontitis, 30 periodontally healthy control subjects, and 80 subjects with type 1 diabetes mellitus (T1DM). The T1DM subjects were periodontally treated and re-examined eight weeks after completion of the treatment. The periodontal measures included plaque, probing depth (PD), bleeding on probing (BOP) and attachment level (AL). The serum levels of interleukin (IL)-6, tumor necrosis factor (TNF)-&#945;, and interleukin (IL)-10, as well as the gingival crevicular fluid (GCF) level of matrix metalloproteinase (MMP)-8 were analyzed using commercially available ELISA assays, and serum high density lipoprotein (HDL) level using direct enzymatic methods. Serum IL-6 level associated significantly with the extent of inflamed periodontal pockets in T1DM subjects. Moreover, serum IL-6 modulated local periodontal inflammation in T1DM patients; periodontal healing turned out to be poorer in subjects with a high level of serum IL-6 than in those with a low level. Serum TNF-&#945;/IL-10 ratio was three times higher in chronic periodontitis patients than in periodontally healthy control subjects. In T1DM subjects a significant inverse association between serum HDL level and the extent of inflamed periodontal pockets was found; subjects with a low serum HDL level presented 50% more inflamed periodontal sites than subjects with a high serum HDL level. A significant association between GCF MMP-8 level in shallow crevices and the extent of periodontal attachment loss in chronic periodontitis patients was observed. In conclusion, we focused on analyzing associations between systemic inflammatory status and periodontal conditions. According to our results, periodontal inflammation/infection is associated with systemic inflammatory status using serum IL-6, TNF-&#945;/IL-10 ratio and HDL as indicators. Also, a high level of MMP-8 in GCF in shallow crevices could be indicative of higher susceptibility to periodontal infection and tissue destruction. / Tiivistelmä Tutkimuksen tavoitteena oli tarkastella hampaiden kiinnityskudosten tulehduksen (pardodontiitti) ja siihen liittyvän inflammaation yhteyttä systeemiseen tulehdustilaan. Tutkimusaineistoon kuului 61 yleistervettä potilasta, joilla oli kohtalaisesti tai pitkälle edennyt parodontiitti, 30 yleistervettä yksilöä, joiden hampaiden kiinnityskudokset olivat terveet/lähes terveet (kontrolliryhmä), sekä 80 tyypin 1 diabetes mellitus (T1DM) potilasta, joilla esiintyi vaihtelevasti parodontiittia. T1DM potilaiden parodontiitti hoidettiin, ja heidät tutkittiin uudelleen kahdeksan viikon kuluttua hoidon päättymisestä. Tutkittavilta tarkastettiin plakin määrä, ientaskujen syvyys, ienverenvuoto ja hampaiden kiinnityskudoksen menetys. Systeemistä tulehdustilaa mitattiin käyttäen seerumin interleukiini (IL)-6, tuumorinekroosifaktori (TNF)-&#945; ja interleukiini (IL)-10 tasoja. Lisäksi määritettiin ientaskunesteen matriksimetalloproteinaasi (MMP)-8 taso. Kaikki edellä mainitut tulehduksen välittäjäainetasot määritettiin käyttäen ELISA-menetelmää. T1DM potilaiden seerumin IL-6 pitoisuuden ja tulehtuneiden ientaskujen määrän välillä vallitsi positiivinen yhteys. Lisäksi havaittiin, että seerumin korkea IL-6 taso heikensi parodontiitin paranemista. T1DM potilailla havaittiin käänteinen yhteys seerumin HDL-pitoisuuden ja tulehtuneiden ientaskujen määrän välillä. Tutkittavilla, joilla seerumin HDL-taso oli matala (&#60;1.35 mmol/l), oli 50&#160;% enemmän tulehtuneita ientaskuja kuin niillä, joilla HDL-taso oli korkea (&#8805;1.35). Parodontiitti-ryhmässä seerumin TNF-&#945;/IL-10 suhde oli kolminkertainen verrattuna kontrolliryhmän vastaavaan ilmentäen voimakkaampaa matala-asteista tulehdusta parodontiitti-potilailla. Matalista (&#60;4&#160;mm) ientaskuista kerätyn ientasunesteen MMP-8 pitoisuuden ja parodontiitin vaikeusasteen välillä vallitsi merkittävä postiivinen yhteys parodontiitti-potilailla. Yhteenvetona, systeemisen tulehdustilan ja hampaiden kiinnityskudosten välillä vallitsee kaksisuuntainen yhteys; toisaalta parodontiitti lisää matala-asteista systeemistä tulehdustilaa ja toisaalta kohonnut systeeminen tulehdustila lisää alttiutta parodontiittiin ja siihen liittyvään inflammaatioon. Lisäksi ientaskunesteen korkea MMP-8 pitoisuus matalissa ientaskuissa voi merkitä lisääntynyttä alttiutta parodontiumin alueen tulehdukselle ja kudostuholle.

Abstract The effect of alcohol intake on the pathophysiology of atherosclerotic cardiovascular disease is controversial, especially with respect to heavy alcohol intake. The pathobiology behind atherosclerosis is a complex and multiparametric phenomenon, therefore a self-organizing map (SOM), an unsupervised learning based artificial neural network technique, was applied in the present work. This study was carried out to investigate the effect of heavy alcohol intake on the pathophysiology of atherosclerosis, including several lipoproteins and adiponectin, an adipocyte-derived cytokine that may ameliorate atherosclerosis. Firstly, the effect of heavy alcohol intake on the capacity of HDL and its subclasses (HDL2 and HDL3) to mediate cholesterol efflux from macrophages was studied. Secondly, data of ultracentrifugally isolated lipoproteins were fed into SOM analysis to investigate whether this method can find diverse lipoprotein phenotypes from the heterogeneous lipoprotein data. Thirdly, the aforementioned method was applied to multivariate data of alcohol drinkers to study whether distinct metabolic profiles are associated to heavy alcohol consumption. The results revealed that HDL2, not HDL3, of heavy alcohol drinkers had an enhanced capacity to remove cholesterol from macrophages when compared with control persons. SOM analysis enhanced the ultracentrifugally based lipoprotein data and depicted several novel lipoprotein phenotypes. In addition, lipoprotein-based SOM analysis found two distinct metabolic profiles in heavy alcohol drinkers: an anti-atherogenic and a metabolic syndrome-like profile with opposite metabolic features, such as characteristics of lipoproteins, plasma concentration of adiponectin and prevalence of metabolic syndrome. These profiles also tended to differ in their CV risk. In conclusion, the enhanced cholesterol efflux capacity of HDL2 in heavy drinkers is an anti-atherogenic change linked to alcohol drinking. However, clinically it may be important to be aware that although heavy alcohol drinkers have a low LDL-C level, they differ in their other lipoprotein measures, forming distinct phenotypes with potentially different CV risks. Finally, SOM analysis of ultracentrifugally based lipoprotein data generates in silico classification of lipoprotein particles and thereby offers a new tool for lipoprotein research. / Tiivistelmä Alkoholinkäytön vaikutus ateroskleroottisen sydän- ja verisuonitaudin patofysiologiaan on kiistanalainen, etenkin runsaan alkoholinkäytön kohdalla. Koska patobiologia ateroskleroosin taustalla on monimutkainen ilmiö, tässä työssä sovellettiin menetelmänä itseorganisoituvaa karttaa, joka on ohjaamattomaan oppimiseen perustuva neuroverkkomalli. Tutkimuksen tavoitteena oli selvittää runsaan alkoholinkäytön vaikutusta ateroskleroosin patofysiologisiin merkkiaineisiin, mukaan lukien useita lipoproteiineja sekä adiponektiini, rasvasoluperäinen sytokiini, joka voi lievittää ateroskleroosia. Ensimmäisessä osatyössä tutkittiin runsaan alkoholinkäytön vaikutusta HDL:n ja sen alafraktioiden (HDL2 ja HDL3) kykyyn poistaa kolesterolia makrofageista. Toisessa osatyössä ultrasentrifuugaukseen perustuva lipoproteiiniaineisto syötettiin itseorganisoituvaan karttaan. Työssä selvitettiin löytäisikö menetelmä erilaisia lipoproteiinifenotyyppejä heterogeenisestä aineistosta. Kolmannessa osatyössä em. menetelmää sovellettiin monimuuttuja-aineistoon, joka koostui runsaasti alkoholia käyttävistä ja verrokeista. Tutkittiin, liittyykö runsaaseen alkoholinkäyttöön erilaisia metabolisia profiileja. Tulokset osoittivat, että suurkuluttajien HDL2-hiukkasen kolesterolinpoistokyky makrofageista oli suurempi kuin verrokeilla. Itseorganisoituvaan karttaan perustuva lipoproteiinien luokittelumenetelmä löysi useita uusia lipoproteiinifenotyyppejä. Lisäksi, em. menetelmä löysi suurkuluttajilta kaksi erilaista metabolista profiilia: anti-aterogeeninen ja metabolisen syndrooman kaltainen. Näillä oli vastakkaiset metaboliset piirteet, kuten lipoproteiinien ominaisuudet, adiponektiinin pitoisuus plasmassa ja metabolisen syndrooman esiintyvyys. Profiileihin liittyi mahdollisesti myös erilainen sydän- ja verisuonitautiriski. Tutkimus osoittaa, että alkoholin suurkuluttajilla havaittu parempi HDL2:n kyky poistaa kolesterolia soluista on anti-aterogeeninen muutos, joka liittyy alkoholin käyttöön. Kliinisesti voi olla merkittävää, että vaikka alkoholin suurkuluttajilla oli pieni LDL-C pitoisuus, he jakaantuivat muiden lipoproteiiniperäisten muuttujien perusteella kahteen eri fenotyyppiryhmään, joihin liittyi erilainen sydäntautiriski. Lisäksi itseorganisoituva kartta loi ultrasentrifugoinnilla eristetyille lipoproteiineille in silico -luokittelun, joten se tarjoaa uuden työkalun lipoproteiinitutkimukseen.

La capacité des particules HDL à exercer des effets anti-athérogènes passe notamment par leur capacité à assurer le transport inverse du cholestérol (RCT). L'objectif principal de mon programme de recherche est l'étude de l'étape initiale du transport inverse du cholestérol que représente l'efflux de cholestérol du macrophage, dans le contexte des maladies métaboliques et du risque cardiovasculaire et de mortalité. J'ai étudié la relation entre l'efflux, et les conséquences sur le développement de l'athérosclérose dans un contexte métabolique particulier ; le syndrome métabolique (SM). J'ai démontré que les critères individuels du SM sont intimement liés à l'efflux et que ces deux notions sont associées de façon indépendante aux paramètres cliniques de l'athérosclérose. J'ai aussi évalué la pertinence de l'efflux de cholestérol comme biomarqueur de la mortalité. Cette étude identifie l'efflux comme prédicteur de la mortalité toutes causes confondues, indépendamment des taux de HDL-cholestérol et des facteurs de risques cardiovasculaires traditionnels, dans une population de patients traités par angioplastie coronaire primaire, suite à un infarctus du myocarde avec élévation du segment ST. Enfin, je me suis intéressée à à une situation métabolique particulière ; l'état postprandial. Mes travaux montrent que la réponse postprandiale hypertriglycéridémique physiologique observée chez des individus sans désordre métabolique ne s'accompagne pas d'altération majeure de l'efficacité du RCT ou de l'inflammation systémique. Mes travaux confirment le rôle déterminant de l'efflux dans la prévention du développement de l'athérosclérose et de la mortalité cardiovasculaire. / The contribution of high-density lipoprotein to cardiovascular benefit is closely linked to its anti-atherogenic role in the cellular cholesterol efflux. The main purpose of my project was to evaluate the efficiency of the first step of reverse cholesterol transport (RCT), which is the efflux capacity, on metabolic disorder context, on cardiovascular risk and on mortality. My research has focused on three independent and complementary parts. I have first evaluated the relationship between efflux and its consequences on atherosclerosis development in a metabolic syndrome (MetS) population. I have shown that individual criteria of MetS are closely related synergistically to cholesterol efflux capacity. In addition, established metabolic syndrome and cholesterol efflux capacity were independently associated with clinical features of atherosclerosis. In a second study I identified cholesterol efflux capacity as a predictor of all-cause mortality in consecutive ST-segment elevation myocardial infarction patients treated by primary angioplasty, independent of HDL-C, traditional cardiovascular risks or cardiac risk factors. Finally I have evaluated the consequences of postprandial hypertriglyceridemia on the functionality of key steps of RCT and associated anti-inflammatory components. My work has shown that the physiological postprandial hypertriglyceridemia response is not accompanied by a major alteration in the efficiency of RCT or systemic inflammation, on individual without metabolic syndrome. In conclusion, I have confirmed the crucial role of the first step of reverse cholesterol transport in preventing the development of atherosclerosis and cardiovascular mortality.