Circulating FABP4 Is a prognostic biomarker in patients with acute coronary syndrome but not in asymptomatic individuals.

OBJECTIVE: Blood-borne biomarkers reflecting atherosclerotic plaque burden have great potential to improve clinical management of atherosclerotic coronary artery disease and acute coronary syndrome (ACS). APPROACH AND RESULTS: Using data integration from gene expression profiling of coronary thrombi versus peripheral blood mononuclear cells and proteomic analysis of atherosclerotic plaque-derived secretomes versus healthy tissue secretomes, we identified fatty acid-binding protein 4 (FABP4) as a biomarker candidate for coronary artery disease. Its diagnostic and prognostic performance was validated in 3 different clinical settings: (1) in a cross-sectional cohort of patients with stable coronary artery disease, ACS, and healthy individuals (n=820), (2) in a nested case-control cohort of patients with ACS with 30-day follow-up (n=200), and (3) in a population-based nested case-control cohort of asymptomatic individuals with 5-year follow-up (n=414). Circulating FABP4 was marginally higher in patients with ST-segment-elevation myocardial infarction (24.9 ng/mL) compared with controls (23.4 ng/mL; P=0.01). However, elevated FABP4 was associated with adverse secondary cerebrovascular or cardiovascular events during 30-day follow-up after index ACS, independent of age, sex, renal function, and body mass index (odds ratio, 1.7; 95% confidence interval, 1.1-2.5; P=0.02). Circulating FABP4 predicted adverse events with similar prognostic performance as the GRACE in-hospital risk score or N-terminal pro-brain natriuretic peptide. Finally, no significant difference between baseline FABP4 was found in asymptomatic individuals with or without coronary events during 5-year follow-up. CONCLUSIONS: Circulating FABP4 may prove useful as a prognostic biomarker in risk stratification of patients with ACS.

Cardiovascular magnetic resonance imaging techniques for motion-suppressed multi-dimensional coronary artery imaging with high spatial and temporal resolution

L'imagerie par résonance magnétique (IRM) peut fournir aux cardiologues des informations diagnostiques importantes sur l'état de la maladie de l'artère coronarienne dans les patients. Le défi majeur pour l'IRM cardiaque est de gérer toutes les sources de mouvement qui peuvent affecter la qualité des images en réduisant l'information diagnostique. Cette thèse a donc comme but de développer des nouvelles techniques d'acquisitions des images IRM, en changeant les techniques de compensation du mouvement, pour en augmenter l'efficacité, la flexibilité, la robustesse et pour obtenir plus d'information sur le tissu et plus d'information temporelle. Les techniques proposées favorisent donc l'avancement de l'imagerie des coronaires dans une direction plus maniable et multi-usage qui peut facilement être transférée dans l'environnement clinique. La première partie de la thèse s'est concentrée sur l'étude du mouvement des artères coronariennes sur des patients en utilisant la techniques d'imagerie standard (rayons x), pour mesurer la précision avec laquelle les artères coronariennes retournent dans la même position battement après battement (repositionnement des coronaires). Nous avons découvert qu'il y a des intervalles dans le cycle cardiaque, tôt dans la systole et à moitié de la diastole, où le repositionnement des coronaires est au minimum. En réponse nous avons développé une nouvelle séquence d'acquisition (T2-post) capable d'acquérir les données aussi tôt dans la systole. Cette séquence a été testée sur des volontaires sains et on a pu constater que la qualité de visualisation des artère coronariennes est égale à celle obtenue avec les techniques standard. De plus, le rapport signal sur bruit fourni par la séquence d'acquisition proposée est supérieur à celui obtenu avec les techniques d'imagerie standard. La deuxième partie de la thèse a exploré un paradigme d'acquisition des images cardiaques complètement nouveau pour l'imagerie du coeur entier. La technique proposée dans ce travail acquiert les données sans arrêt (free-running) au lieu d'être synchronisée avec le mouvement cardiaque. De cette façon, l'efficacité de la séquence d'acquisition est augmentée de manière significative et les images produites représentent le coeur entier dans toutes les phases cardiaques (quatre dimensions, 4D). Par ailleurs, l'auto-navigation de la respiration permet d'effectuer cette acquisition en respiration libre. Cette technologie rend possible de visualiser et évaluer l'anatomie du coeur et de ses vaisseaux ainsi que la fonction cardiaque en quatre dimensions et avec une très haute résolution spatiale et temporelle, sans la nécessité d'injecter un moyen de contraste. Le pas essentiel qui a permis le développement de cette technique est l'utilisation d'une trajectoire d'acquisition radiale 3D basée sur l'angle d'or. Avec cette trajectoire, il est possible d'acquérir continûment les données d'espace k, puis de réordonner les données et choisir les paramètres temporel des images 4D a posteriori. L'acquisition 4D a été aussi couplée avec un algorithme de reconstructions itératif (compressed sensing) qui permet d'augmenter la résolution temporelle tout en augmentant la qualité des images. Grâce aux images 4D, il est possible maintenant de visualiser les artères coronariennes entières dans chaque phase du cycle cardiaque et, avec les mêmes données, de visualiser et mesurer la fonction cardiaque. La qualité des artères coronariennes dans les images 4D est la même que dans les images obtenues avec une acquisition 3D standard, acquise en diastole Par ailleurs, les valeurs de fonction cardiaque mesurées au moyen des images 4D concorde avec les valeurs obtenues avec les images 2D standard. Finalement, dans la dernière partie de la thèse une technique d'acquisition a temps d'écho ultra-court (UTE) a été développée pour la visualisation in vivo des calcifications des artères coronariennes. Des études récentes ont démontré que les acquisitions UTE permettent de visualiser les calcifications dans des plaques athérosclérotiques ex vivo. Cepandent le mouvement du coeur a entravé jusqu'à maintenant l'utilisation des techniques UTE in vivo. Pour résoudre ce problème nous avons développé une séquence d'acquisition UTE avec trajectoire radiale 3D et l'avons testée sur des volontaires. La technique proposée utilise une auto-navigation 3D pour corriger le mouvement respiratoire et est synchronisée avec l'ECG. Trois échos sont acquis pour extraire le signal de la calcification avec des composants au T2 très court tout en permettant de séparer le signal de la graisse depuis le signal de l'eau. Les résultats sont encore préliminaires mais on peut affirmer que la technique développé peut potentiellement montrer les calcifications des artères coronariennes in vivo. En conclusion, ce travail de thèse présente trois nouvelles techniques pour l'IRM du coeur entier capables d'améliorer la visualisation et la caractérisation de la maladie athérosclérotique des coronaires. Ces techniques fournissent des informations anatomiques et fonctionnelles en quatre dimensions et des informations sur la composition du tissu auparavant indisponibles. CORONARY artery magnetic resonance imaging (MRI) has the potential to provide the cardiologist with relevant diagnostic information relative to coronary artery disease of patients. The major challenge of cardiac MRI, though, is dealing with all sources of motions that can corrupt the images affecting the diagnostic information provided. The current thesis, thus, focused on the development of new MRI techniques that change the standard approach to cardiac motion compensation in order to increase the efficiency of cardioavscular MRI, to provide more flexibility and robustness, new temporal information and new tissue information. The proposed approaches help in advancing coronary magnetic resonance angiography (MRA) in the direction of an easy-to-use and multipurpose tool that can be translated to the clinical environment. The first part of the thesis focused on the study of coronary artery motion through gold standard imaging techniques (x-ray angiography) in patients, in order to measure the precision with which the coronary arteries assume the same position beat after beat (coronary artery repositioning). We learned that intervals with minimal coronary artery repositioning occur in peak systole and in mid diastole and we responded with a new pulse sequence (T2~post) that is able to provide peak-systolic imaging. Such a sequence was tested in healthy volunteers and, from the image quality comparison, we learned that the proposed approach provides coronary artery visualization and contrast-to-noise ratio (CNR) comparable with the standard acquisition approach, but with increased signal-to-noise ratio (SNR). The second part of the thesis explored a completely new paradigm for whole- heart cardiovascular MRI. The proposed techniques acquires the data continuously (free-running), instead of being triggered, thus increasing the efficiency of the acquisition and providing four dimensional images of the whole heart, while respiratory self navigation allows for the scan to be performed in free breathing. This enabling technology allows for anatomical and functional evaluation in four dimensions, with high spatial and temporal resolution and without the need for contrast agent injection. The enabling step is the use of a golden-angle based 3D radial trajectory, which allows for a continuous sampling of the k-space and a retrospective selection of the timing parameters of the reconstructed dataset. The free-running 4D acquisition was then combined with a compressed sensing reconstruction algorithm that further increases the temporal resolution of the 4D dataset, while at the same time increasing the overall image quality by removing undersampling artifacts. The obtained 4D images provide visualization of the whole coronary artery tree in each phases of the cardiac cycle and, at the same time, allow for the assessment of the cardiac function with a single free- breathing scan. The quality of the coronary arteries provided by the frames of the free-running 4D acquisition is in line with the one obtained with the standard ECG-triggered one, and the cardiac function evaluation matched the one measured with gold-standard stack of 2D cine approaches. Finally, the last part of the thesis focused on the development of ultrashort echo time (UTE) acquisition scheme for in vivo detection of calcification in the coronary arteries. Recent studies showed that UTE imaging allows for the coronary artery plaque calcification ex vivo, since it is able to detect the short T2 components of the calcification. The heart motion, though, prevented this technique from being applied in vivo. An ECG-triggered self-navigated 3D radial triple- echo UTE acquisition has then been developed and tested in healthy volunteers. The proposed sequence combines a 3D self-navigation approach with a 3D radial UTE acquisition enabling data collection during free breathing. Three echoes are simultaneously acquired to extract the short T2 components of the calcification while a water and fat separation technique allows for proper visualization of the coronary arteries. Even though the results are still preliminary, the proposed sequence showed great potential for the in vivo visualization of coronary artery calcification. In conclusion, the thesis presents three novel MRI approaches aimed at improved characterization and assessment of atherosclerotic coronary artery disease. These approaches provide new anatomical and functional information in four dimensions, and support tissue characterization for coronary artery plaques.

Pathomorphological and CT-angiographical characteristics of coronary atherosclerotic plaques in cases of sudden cardiac death.

The goal of this study was to assess the localization and types of thrombosed plaques in cases of sudden cardiac death attributed to coronary artery disease and to evaluate possible correlations with body mass index (BMI) and increased heart weight. This retrospective study was performed on forensic cases for which the cause of death was attributed to coronary artery disease. A complete autopsy and a multi-phase postmortem computed tomography (CT) angiography (MPMCTA) were performed in all cases. Eighty-five cases were selected (mean age, 55.18 ± 11.04 years; 72 men and 13 women). MPMCTA performed prior to autopsy enabled an evaluation of coronary artery perfusion before dissection of the body and helped therefore to guide sampling for histology. An acute coronary thrombosis was found in 57 cases, which included plaque erosion in 26 cases (mean age, 46.73 ± 8.33 years) and rupture or intra-plaque hemorrhage in 31 cases (mean age, 58.23 ± 10.62 years). Erosions were most frequently found in the left anterior descending artery (61.5 %), while only 35.48 % of ruptures were observed in this artery. Chronic coronary pathology was considered as the main cause of death in 28 cases (mean age, 59.64 ± 9.47 years). Sixty-two of the cases (72.94 %) had a BMI in the overweight category (BMI ≥25), with the highest mean BMI in patients with chronic coronary pathology without acute thrombosis found at autopsy. The heart weight was above the predicted reference values in 52 cases (61.18 %). Our results are in accordance with previously published studies on the spatial distribution of vulnerable plaques. We observed a higher percentage of eroded plaques than previously reported. Patients with coronary erosions were significantly younger than those with plaque rupture or those without an acute coronary thrombosis (p values <0.0001). BMI and heart weight were significantly higher for cases without thrombosis in comparison with those with plaque rupture (p values 0.028 and 0.003, respectively). Our results indicating that increased BMI and overweight hearts are associated with chronic ischemic heart disease are compatible with clinical studies. Performing more postmortem studies on forensic autopsies, including modern radiological examinations with MPMCTA, can enhance the detection of vulnerable plaques in living patients and prevent sudden cardiac death.

Thromboxane prostaglandin receptor antagonist and carotid atherosclerosis progression in patients with cerebrovascular disease of ischemic origin: a randomized controlled trial.

BACKGROUND AND PURPOSE: Thromboxane prostaglandin receptors have been implicated to be involved in the atherosclerotic process. We assessed whether Terutroban, a thromboxane prostaglandin receptor antagonist, affects the progression of atherosclerosis, as measured by common carotid intima-media thickness and carotid plaques. METHODS: A substudy was performed among 1141 participants of the aspirin-controlled Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin with Terutroban in Patients with a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM) trial. Common carotid intima-media thickness and carotid plaque occurrence was measured during a 3-year period. RESULTS: Baseline characteristics did not differ between Terutroban (n=592) and aspirin (n=549) treated patients and were similar as in the main study. Mean study and treatment duration were similar (28 and 25 months, respectively). In the Terutroban group, the annualized rate of change in common carotid intima-media thickness was 0.006 mm per year (95% confidence interval, -0.004 to 0.016) and -0.005 mm per year (95% confidence interval, -0.015 to 0.005) in the aspirin group. There was no statistically significant difference between the groups in the annualized rate of change of common carotid intima-media thickness (0.011 mm per year; 95% confidence interval, -0.003 to 0.025). At 12 months of follow-up, 66% of Terutroban patients had no emergent plaques, 31% had 1 to 2 emergent plaques, and 3% had ≥3 emergent plaques. In the aspirin group, the corresponding percentages were 64%, 32%, and 4%. Over time, there was no statistically significant difference in the number of emergent carotid plaques between treatment modalities (rate ratio, 0.91; 95% confidence interval, 0.77-1.07). CONCLUSIONS: Compared with aspirin, Terutroban did not beneficially affect progression of carotid atherosclerosis among well-treated patients with a history of ischemic stroke or transient ischemic attacks with an internal carotid stenosis <70%. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN66157730.

Voluntary Exercise Stabilizes Established Angiotensin II-Dependent Atherosclerosis in Mice through Systemic Anti-Inflammatory Effects.

We have previously demonstrated that exercise training prevents the development of Angiotensin (Ang) II-induced atherosclerosis and vulnerable plaques in Apolipoprotein E-deficient (ApoE-/-) mice. In this report, we investigated whether exercise attenuates progression and promotes stability in pre-established vulnerable lesions. To this end, ApoE-/- mice with already established Ang II-mediated advanced and vulnerable lesions (2-kidney, 1-clip [2K1C] renovascular hypertension model), were subjected to sedentary (SED) or voluntary wheel running training (EXE) regimens for 4 weeks. Mean blood pressure and plasma renin activity did not significantly differ between the two groups, while total plasma cholesterol significantly decreased in 2K1C EXE mice. Aortic plaque size was significantly reduced by 63% in 2K1C EXE compared to SED mice. Plaque stability score was significantly higher in 2K1C EXE mice than in SED ones. Aortic ICAM-1 mRNA expression was significantly down-regulated following EXE. Moreover, EXE significantly down-regulated splenic pro-inflammatory cytokines IL-18, and IL-1β mRNA expression while increasing that of anti-inflammatory cytokine IL-4. Reduction in plasma IL-18 levels was also observed in response to EXE. There was no significant difference in aortic and splenic Th1/Th2 and M1/M2 polarization markers mRNA expression between the two groups. Our results indicate that voluntary EXE is effective in slowing progression and promoting stabilization of pre-existing Ang II-dependent vulnerable lesions by ameliorating systemic inflammatory state. Our findings support a therapeutic role for voluntary EXE in patients with established atherosclerosis.

Focal pleural thickening mimicking pleural plaques on chest computed tomography: tips and tricks.

Diagnosis of pleural plaques (PPs) is commonly straightforward, especially when a typical appearance is observed in a context of previous asbestos exposure. Nevertheless, numerous causes of focal pleural thickening may be seen in routine practice. They may be related to normal structures, functional pleural thickening, previous tuberculosis, pleural metastasis, silicosis or other rarer conditions. An application of a rigorous technical approach as well as a familiarity with loco-regional anatomy and the knowledge of typical aspects of PP are required. Indeed, false-positive or false-negative results may engender psychological and medico-legal consequences or can delay diagnosis of malignant pleural involvement. Correct recognition of PPs is crucial, as they may also be an independent risk factor for mortality from lung cancer in asbestos-exposed workers particularly in either smokers or former/ex-smokers. Finally, the presence of PP(s) may help in considering asbestosis as a cause of interstitial lung disease predominating in the subpleural area of the lower lobes. The aim of this pictorial essay is to provide a brief reminder of the normal anatomy of the pleura and its surroundings as well as the various aspects of PPs. Afterwards, the common pitfalls encountered in PP diagnosis will be emphasized and practical clues to differentiate actual plaque and pseudoplaque will be concisely described.

Modeling the transport phenomena within arterial wall: porous media approach

The transport of macromolecules, such as low-density lipoprotein (LDL), and their accumulation in the layers of the arterial wall play a critical role in the creation and development of atherosclerosis. Atherosclerosis is a disease of large arteries e.g., the aorta, coronary, carotid, and other proximal arteries that involves a distinctive accumulation of LDL and other lipid-bearing materials in the arterial wall. Over time, plaque hardens and narrows the arteries. The flow of oxygen-rich blood to organs and other parts of the body is reduced. This can lead to serious problems, including heart attack, stroke, or even death. It has been proven that the accumulation of macromolecules in the arterial wall depends not only on the ease with which materials enter the wall, but also on the hindrance to the passage of materials out of the wall posed by underlying layers. Therefore, attention was drawn to the fact that the wall structure of large arteries is different than other vessels which are disease-resistant. Atherosclerosis tends to be localized in regions of curvature and branching in arteries where fluid shear stress (shear rate) and other fluid mechanical characteristics deviate from their normal spatial and temporal distribution patterns in straight vessels. On the other hand, the smooth muscle cells (SMCs) residing in the media layer of the arterial wall respond to mechanical stimuli, such as shear stress. Shear stress may affect SMC proliferation and migration from the media layer to intima. This occurs in atherosclerosis and intimal hyperplasia. The study of blood flow and other body fluids and of heat transport through the arterial wall is one of the advanced applications of porous media in recent years. The arterial wall may be modeled in both macroscopic (as a continuous porous medium) and microscopic scales (as a heterogeneous porous medium). In the present study, the governing equations of mass, heat and momentum transport have been solved for different species and interstitial fluid within the arterial wall by means of computational fluid dynamics (CFD). Simulation models are based on the finite element (FE) and finite volume (FV) methods. The wall structure has been modeled by assuming the wall layers as porous media with different properties. In order to study the heat transport through human tissues, the simulations have been carried out for a non-homogeneous model of porous media. The tissue is composed of blood vessels, cells, and an interstitium. The interstitium consists of interstitial fluid and extracellular fibers. Numerical simulations are performed in a two-dimensional (2D) model to realize the effect of the shape and configuration of the discrete phase on the convective and conductive features of heat transfer, e.g. the interstitium of biological tissues. On the other hand, the governing equations of momentum and mass transport have been solved in the heterogeneous porous media model of the media layer, which has a major role in the transport and accumulation of solutes across the arterial wall. The transport of Adenosine 5´-triphosphate (ATP) is simulated across the media layer as a benchmark to observe how SMCs affect on the species mass transport. In addition, the transport of interstitial fluid has been simulated while the deformation of the media layer (due to high blood pressure) and its constituents such as SMCs are also involved in the model. In this context, the effect of pressure variation on shear stress is investigated over SMCs induced by the interstitial flow both in 2D and three-dimensional (3D) geometries for the media layer. The influence of hypertension (high pressure) on the transport of lowdensity lipoprotein (LDL) through deformable arterial wall layers is also studied. This is due to the pressure-driven convective flow across the arterial wall. The intima and media layers are assumed as homogeneous porous media. The results of the present study reveal that ATP concentration over the surface of SMCs and within the bulk of the media layer is significantly dependent on the distribution of cells. Moreover, the shear stress magnitude and distribution over the SMC surface are affected by transmural pressure and the deformation of the media layer of the aorta wall. This work reflects the fact that the second or even subsequent layers of SMCs may bear shear stresses of the same order of magnitude as the first layer does if cells are arranged in an arbitrary manner. This study has brought new insights into the simulation of the arterial wall, as the previous simplifications have been ignored. The configurations of SMCs used here with elliptic cross sections of SMCs closely resemble the physiological conditions of cells. Moreover, the deformation of SMCs with high transmural pressure which follows the media layer compaction has been studied for the first time. On the other hand, results demonstrate that LDL concentration through the intima and media layers changes significantly as wall layers compress with transmural pressure. It was also noticed that the fraction of leaky junctions across the endothelial cells and the area fraction of fenestral pores over the internal elastic lamina affect the LDL distribution dramatically through the thoracic aorta wall. The simulation techniques introduced in this work can also trigger new ideas for simulating porous media involved in any biomedical, biomechanical, chemical, and environmental engineering applications.

Performance and Methodological Aspects in Positron Emission Tomography

Performance standards for Positron emission tomography (PET) were developed to be able to compare systems from different generations and manufacturers. This resulted in the NEMA methodology in North America and the IEC in Europe. In practices, the NEMA NU 2- 2001 is the method of choice today. These standardized methods allow assessment of the physical performance of new commercial dedicated PET/CT tomographs. The point spread in image formation is one of the factors that blur the image. The phenomenon is often called the partial volume effect. Several methods for correcting for partial volume are under research but no real agreement exists on how to solve it. The influence of the effect varies in different clinical settings and it is likely that new methods are needed to solve this problem. Most of the clinical PET work is done in the field of oncology. The whole body PET combined with a CT is the standard investigation today in oncology. Despite the progress in PET imaging technique visualization, especially quantification of small lesions is a challenge. In addition to partial volume, the movement of the object is a significant source of error. The main causes of movement are respiratory and cardiac motions. Most of the new commercial scanners are in addition to cardiac gating, also capable of respiratory gating and this technique has been used in patients with cancer of the thoracic region and patients being studied for the planning of radiation therapy. For routine cardiac applications such as assessment of viability and perfusion only cardiac gating has been used. However, the new targets such as plaque or molecular imaging of new therapies require better control of the cardiac motion also caused by respiratory motion. To overcome these problems in cardiac work, a dual gating approach has been proposed. In this study we investigated the physical performance of a new whole body PET/CT scanner with NEMA standard, compared methods for partial volume correction in PET studies of the brain and developed and tested a new robust method for dual cardiac-respiratory gated PET with phantom, animal and human data. Results from performance measurements showed the feasibility of the new scanner design in 2D and 3D whole body studies. Partial volume was corrected, but there is no best method among those tested as the correction also depends on the radiotracer and its distribution. New methods need to be developed for proper correction. The dual gating algorithm generated is shown to handle dual-gated data, preserving quantification and clearly eliminating the majority of contraction and respiration movement

Periodontal Diseases in Tanzania

Tutkimuksen tavoitteena oli kuvata hampaiden kiinnityskudossairauksien esiintyvyyttä ja suuhygieniatottumuksia Tansaniassa. Viiden eri tutkimuksen avulla kartoitettiin suuhygieniatottumuksia, kiinnityskudosten tilaa, kiinnityskudossairauksien riskitekijöitä ja hoidon tarvetta (CPITN) sekä ienvetäymiä. Tutkimukset toteutettiin eri paikkakunnilla vuosien 1987 ja 2003 välillä. Tutkittavat valittiin satunnaisesti tai harkitusti; tutkittavien määrä vaihteli 201:stä 1764:ään. Aineistot kerättiin kysymyslomakkeilla ja kliinisten tutkimusten avulla. Kliinisesti mitattiin plakin, hammaskiven ja ienten verenvuodon määrä, ientaskujen syvyys, ienvetäymien laajuus ja puuttuvien hampaiden lukumäärä. Tutkimusvälineinä käytettiin peiliä, Williamsin ja WHO:n ientaskumittareita. Muoviharjaksista hammasharjaa ilmoitti käyttävänsä 51,5-97,8% tutkituista. Ns. harjaustikun käyttö vaihteli paljon: 0,9-32,0 %. Plakkia löydettiin 65-100 %:lla tutkituista. Hammaskiveä oli suurimmalla osalla tutkituista. Myös ienverenvuotoa löytyi valtaosalta (79-100%). Ienverenvuotoa oli enemmän miehillä kuin naisilla sekä alhaisemman koulutustason omaavilla. Neljäkymmentä vuotta täyttäneiltä löydettiin 4–5 mm:n syvyisiä ientaskuja 82,1 %:lta ja ≥ 6 mm:n taskuja 43,8 %:lta. Suun terveystottumusten ohjaamiseen oli tarvetta yli 90 %:lla, hammaskiven poistoon ja juurten pinnan tasoitukseen yli 80%:lla. Yleisimmät riskitekijät kiinnityskudossairauksille olivat ikä (≥ 35 vuotta), miessukupuoli, alhainen koulutustaso, plakin, hammaskiven ja ientulehduksen määrä sekä asuminen maaseudulla. Ienvetäymiä (≥ 4 mm) löytyi noin 54%:lla tutkituista. Ienvetäymiä oli useammin miehillä kuin naisilla ja ne olivat yhteydessä ikään sekä hammaskiven ja ienverenvuodon esiintymiseen. Suuhygieniataso tutkituilla henkilöillä oli huono ja ienvetäymien esiintyvyys korkea. Syviä ientaskuja löytyi kuitenkin harvoilta tutkituilta. Riskitekijät kiinnityskudossairauksille olivat ikä, miessukupuoli, alhainen koulutustaso, plakin, hammaskiven ja ientulehduksen määrä sekä asuminen maaseudulla. Ienvetäymien riskit olivat ikä, miessukupuoli, hammaskivi ja ienverenvuoto

Fronts with continuous waiting-time distributions: Theory and application to virus infections

We generalize to arbitrary waiting-time distributions some results which were previously derived for discrete distributions. We show that for any two waiting-time distributions with the same mean delay time, that with higher dispersion will lead to a faster front. Experimental data on the speed of virus infections in a plaque are correctly explained by the theoretical predictions using a Gaussian delay-time distribution, which is more realistic for this system than the Dirac delta distribution considered previously [J. Fort and V. Méndez, Phys. Rev. Lett.89, 178101 (2002)]

Multigram synthesis and in vivo efficacy studies of a novel multitarget anti-Alzheimer's compound

We describe the multigram synthesis and in vivo efficacy studies of a donepezil‒huprine hybrid that has been found to display a promising in vitro multitarget profile of interest for the treatment of Alzheimer's disease (AD). Its synthesis features as the key step a novel multigram preparative chromatographic resolution of intermediate racemic huprine Y by chiral HPLC. Administration of this compound to transgenic CL4176 and CL2006 Caenorhabditis elegans strains expressing human Aβ42, here used as simplified animal models of AD, led to a significant protection from the toxicity induced by Aβ42. However, this protective effect was not accompanied, in CL2006 worms, by a reduction of amyloid deposits. Oral administration for 3 months to transgenic APPSL mice, a well-established animal model of AD, improved short-term memory, but did not alter brain levels of Aβ peptides nor cortical and hippocampal amyloid plaque load. Despite the clear protective and cognitive effects of AVCRI104P4, the lack of Aβ lowering effect in vivo might be related to its lower in vitro potency toward Aβ aggregation and formation as compared with its higher anticholinesterase activities. Further lead optimization in this series should thus focus on improving the anti-amyloid/anticholinesterase activity ratio.

Early Detection of Alzheimer's Disease Beta-amyloid Pathology -Applicability of Positron Emission Tomography with the Amyloid Radioligand 11C-PIB

Early Detection of Alzheimer's Disease Beta-amyloid Pathology -Applicability of Positron Emission Tomography with the Amyloid Radioligand ¹¹C-PIB Accumulation of beta amyloid (Abeta) in the brain is characteristic for Alzheimer’s disease (AD). Carbon-11 labeled 2-(4’-methylaminophenyl)-6-hydroxybenzothiazole (¹¹C-PIB) is a novel positron emission tomography (PET) amyloid imaging agent that appears to be applicable for in vivo Abeta plaque detection and quantitation. The biodistribution and radiation dosimetry of ¹¹C-PIB were investigated in 16 healthy subjects. The reproducibility of a simplified ¹¹C-PIB quantitation method was evaluated with a test-retest study on 6 AD patients and 4 healthy control subjects. Brain ¹¹C-PIB uptake and its possible association with brain atrophy rates were studied over a two-year follow-up in 14 AD patients and 13 healthy controls. Nine monozygotic and 8 dizygotic twin pairs discordant for cognitive impairment and 9 unrelated controls were examined to determine whether brain Abeta accumulation could be detected with ¹¹C-PIB PET in cognitively intact persons who are at increased genetic risk for AD. The highest absorbed radiation dose was received by the gallbladder wall (41.5 mjuGy/MBq). About 20 % of the injected radioactivity was excreted into urine, and the effective whole-body radiation dose was 4.7 mjuSv/MBq. Such a dose allows repeated scans of individual subjects. The reproducibility of the simplified ¹¹C-PIB quantitation was good or excellent both at the regional level (VAR 0.9-5.5 %) and at the voxel level (VAR 4.2-6.4 %). ¹¹C-PIB uptake did not increase during 24 months’ follow-up of subjects with mild or moderate AD, even though brain atrophy and cognitive decline progressed. Baseline neocortical ¹¹C-PIB uptake predicted subsequent volumetric brain changes in healthy control subjects (r = 0.725, p = 0.005). Cognitively intact monozygotic co-twins – but not dizygotic co-twins – of memory-impaired subjects exhibited increased ¹¹C-PIB uptake (117-121 % of control mean) in their temporal and parietal cortices and the posterior cingulate (p<0.05), when compared with unrelated controls. This increased uptake may be representative of an early AD process, and genetic factors seem to play an important role in the development of AD-like Abeta plaque pathology. ¹¹C-PIB PET may be a useful method for patient selection and follow-up for early-phase intervention trials of novel therapeutic agents. AD might be detectable in high-risk individuals in its presymptomatic stage with ¹¹C-PIB PET, which would have important consequences both for future diagnostics and for research on disease-modifying treatments.

Application of Computational Fluid Dynamics in Modeling Blood Flow in Human Thoracic Aorta

The aim of this study was to simulate blood flow in thoracic human aorta and understand the role of flow dynamics in the initialization and localization of atherosclerotic plaque in human thoracic aorta. The blood flow dynamics in idealized and realistic models of human thoracic aorta were numerically simulated in three idealized and two realistic thoracic aorta models. The idealized models of thoracic aorta were reconstructed with measurements available from literature, and the realistic models of thoracic aorta were constructed by image processing Computed Tomographic (CT) images. The CT images were made available by South Karelia Central Hospital in Lappeenranta. The reconstruction of thoracic aorta consisted of operations, such as contrast adjustment, image segmentations, and 3D surface rendering. Additional design operations were performed to make the aorta model compatible for the numerical method based computer code. The image processing and design operations were performed with specialized medical image processing software. Pulsatile pressure and velocity boundary conditions were deployed as inlet boundary conditions. The blood flow was assumed homogeneous and incompressible. The blood was assumed to be a Newtonian fluid. The simulations with idealized models of thoracic aorta were carried out with Finite Element Method based computer code, while the simulations with realistic models of thoracic aorta were carried out with Finite Volume Method based computer code. Simulations were carried out for four cardiac cycles. The distribution of flow, pressure and Wall Shear Stress (WSS) observed during the fourth cardiac cycle were extensively analyzed. The aim of carrying out the simulations with idealized model was to get an estimate of flow dynamics in a realistic aorta model. The motive behind the choice of three aorta models with distinct features was to understand the dependence of flow dynamics on aorta anatomy. Highly disturbed and nonuniform distribution of velocity and WSS was observed in aortic arch, near brachiocephalic, left common artery, and left subclavian artery. On the other hand, the WSS profiles at the roots of branches show significant differences with geometry variation of aorta and branches. The comparison of instantaneous WSS profiles revealed that the model with straight branching arteries had relatively lower WSS compared to that in the aorta model with curved branches. In addition to this, significant differences were observed in the spatial and temporal profiles of WSS, flow, and pressure. The study with idealized model was extended to study blood flow in thoracic aorta under the effects of hypertension and hypotension. One of the idealized aorta models was modified along with the boundary conditions to mimic the thoracic aorta under the effects of hypertension and hypotension. The results of simulations with realistic models extracted from CT scans demonstrated more realistic flow dynamics than that in the idealized models. During systole, the velocity in ascending aorta was skewed towards the outer wall of aortic arch. The flow develops secondary flow patterns as it moves downstream towards aortic arch. Unlike idealized models, the distribution of flow was nonplanar and heavily guided by the artery anatomy. Flow cavitation was observed in the aorta model which was imaged giving longer branches. This could not be properly observed in the model with imaging containing a shorter length for aortic branches. The flow circulation was also observed in the inner wall of the aortic arch. However, during the diastole, the flow profiles were almost flat and regular due the acceleration of flow at the inlet. The flow profiles were weakly turbulent during the flow reversal. The complex flow patterns caused a non-uniform distribution of WSS. High WSS was distributed at the junction of branches and aortic arch. Low WSS was distributed at the proximal part of the junction, while intermedium WSS was distributed in the distal part of the junction. The pulsatile nature of the inflow caused oscillating WSS at the branch entry region and inner curvature of aortic arch. Based on the WSS distribution in the realistic model, one of the aorta models was altered to induce artificial atherosclerotic plaque at the branch entry region and inner curvature of aortic arch. Atherosclerotic plaque causing 50% blockage of lumen was introduced in brachiocephalic artery, common carotid artery, left subclavian artery, and aortic arch. The aim of this part of the study was first to study the effect of stenosis on flow and WSS distribution, understand the effect of shape of atherosclerotic plaque on flow and WSS distribution, and finally to investigate the effect of lumen blockage severity on flow and WSS distributions. The results revealed that the distribution of WSS is significantly affected by plaque with mere 50% stenosis. The asymmetric shape of stenosis causes higher WSS in branching arteries than in the cases with symmetric plaque. The flow dynamics within thoracic aorta models has been extensively studied and reported here. The effects of pressure and arterial anatomy on the flow dynamic were investigated. The distribution of complex flow and WSS is correlated with the localization of atherosclerosis. With the available results we can conclude that the thoracic aorta, with complex anatomy is the most vulnerable artery for the localization and development of atherosclerosis. The flow dynamics and arterial anatomy play a role in the localization of atherosclerosis. The patient specific image based models can be used to diagnose the locations in the aorta vulnerable to the development of arterial diseases such as atherosclerosis.

Metabolic syndrome in young adults – prevalence, childhood predictors and association with subclinical atherosclerosis

Background: Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including central obesity, insulin resistance, impaired glucose tolerance, hypertension and dyslipidemia. The prevalence of MetS is increasing worldwide in all age groups. MetS is associated with increased risk of cardiovascular disease and type 2 diabetes mellitus. Aims: The aim of the present study was to investigate the prevalence, secular trends and childhood predictors of MetS in young adults. Furthermore, the relations between MetS and subclinical atherosclerosis were studied and whether apolipoproteins (apo) B and A-I, C-reactive protein (CRP) and type II secretory phospholipase A2 (sPLA2) were associated with MetS, and to what extent the atherogenicity of MetS was explained by these factors. Participants and Methods: The present thesis is part of the large scale population-based, prospective study, the Cardiovascular Risk in Young Finns Study. The first cross-sectional study was conducted in 1980 and included 3,596 participants aged 3-18 years. Carotid and brachial ultrasound studies were performed for 2,283 of these participants in 2001 and 2,200 of these participants in 2007. Results: The overall prevalence of MetS in young adults aged 24-39 years in 2001 was 10-15 % and 6 years later in 30-45 year-old adults it was 15-23 % depending on the MetS definition used. Between the years 1986 and 2001, MetS prevalence increased from 1.0 % to 7.5 % (p<0.0001) in 24-year-old participants that was mostly driven by the increased central obesity. Participants with MetS had increased carotid intima-media thickness (cIMT) and decreased carotid elasticity compared to those without the syndrome. Impaired brachial flow-mediated dilatation (FMD) was not related to MetS but it modified the relationship between MetS and cIMT (P for interaction 0.023). High levels of apoB, CRP, sPLA2 and low levels of apoA-I associated with MetS in young adults. In prospective analysis both MetS and high apoB predicted (P<0.0001) incident high cIMT, defined as cIMT>90th percentile and/or plaque. The association between MetS and incident high cIMT was attenuated by ~40 % after adjustment with apoB. Conclusions: MetS is common in young adults and increases with age. Screening for risk factors, especially obesity, at an early life stage could help identify children and adolescents at increased risk of developing MetS and cardiovascular disease later in life. MetS identifies a population of young adults with evidence of increased subclinical atherosclerosis. Impaired brachial endothelial response is not a hallmark of MetS in young adults, but the status of endothelial function modifies the association between metabolic risk factors and atherosclerosis. In addition, the atherogenicity of MetS in this population assessed by incident high cIMT appears to be substantially mediated by elevated apoB.

Pregnancy and periodontium. A clinical, microbiological, and enzymological approach via a longitudinal study

The mechanisms leading to an enhanced susceptibility to gingivitis in pregnant women have not yet been completely described. Therefore, the current study series were performed to investigate longitudinally the influence of pregnancy on periodontal tissues, and to evaluate microbial and host response factors related to pregnancy gingivitis formation. Pregnancy-related periodontal changes were analysed in 30 generally healthy women (24- 35 years old) once per trimester, till the end of lactation. Matched non-pregnant women (n=24) served as the controls, and were examined three times, once per following month. Pregnancy-related gingival inflammation was observed as enhanced tendency towards gingival bleeding and pseudopocket formation with a concomitant decrease in plaque levels. Gingivitis reached its peak during mid-pregnancy and then decreased transiently visit by visit. After lactation, no differences in periodontal status were seen between the study and control populations. In contrast to previous studies reporting increased levels of Prevotella intermedia, a specific aim was to analyse phenotypically two identical species, P. intermedia and Prevotella nigrescens, separately using a 16S ribosomal DNA-based PCR. As a result, the increased levels of P. nigrescens were related to pregnancy gingivitis. Matrix metalloproteinases (MMPs) are involved in periodontal destruction. However, their role in pregnancy gingivitis is not well studied. Therefore, neutrophilic enzymes and proteinases, such as MMP and myeloperoxidase (MPO) levels were analysed from saliva and gingival crevicular fluid (GCF) samples during the follow-up. Despite increased inflammation and microbial shift towards anaerobes, the host response did not activate the MMP, elastase and MPO secretion during pregnancy. These results demonstrate that during pregnancy gingival inflammation is enhanced especially during the second trimester, when P. nigrescens levels in subgingival plaque were increased, whereas the neutrophilic enzymes and proteinase levels in both saliva and GCF remained low. These findings could explain, at least in part, why pregnancy gingivitis itself does not predispose or proceed to periodontitis.