Osteoprotegerin and Vascular Calcification: Clinical and Prognostic Relevance

Osteoprotegerin ( OPG ) is a key regulator in bone metabolism, that also has effect in vascular system. Studies suggest that osteoprotegerin is a critical arterial calcification inhibitor, and is released by endothelial cells as a protective mechanism for their survival in certain pathological conditions, such as diabetes mellitus, chronic kidney disease, and other metabolic disorders. That has been shown in studies in vitro and in animal models. The discovery that OPG deficient mice (OPG-/- mice) develop severe osteoporosis and arterial calcification, has led to conclusion that osteoprotegerin might be mulecule linking vascular and bone system. Paradoxically however, clinical trials have shown recently that OPG serum levels is increased in coronary artery disease and correlates with its severity, ischemic cardial decompensation, and future cardiovascular events. Therefore it is possible that osteoprotegerin could have a new function as a potential biomarker in early identification and monitoring patients with cardiovascular disease. Amongst that osteoprotegerin is in association with well known atherosclerosis risc factors: undoubtedly it is proven its relationship with age, smoking and diabetes mellitus. There is evidence regarding presence of hyperlipoproteinemia and increased serum levels of osteoprotegerin. Also the researches have been directed in genetic level, linking certain single nucleotid genetic polymorphisms of osteoprotegerin and vascular calcification appearance. This review emphasises multifactorial role of OPG, presenting numerous clinical and experimental stydies regarding its role in vascular pathology, suggesting a novel biomarker in cardiovascular diseases, showing latest conclusions about this interesting topic that needs to be further explored

Neopstruktivna koronarna bolest - klinička važnost, dijagnostika, liječenje i prijedlog nove patofiziološke klasifikacije

New data gathered from large clinical trials indicate that nonobstructive coronary artery disease (non-CAD) is a clinical entity that should not be ignored. It is estimated that 50% of female population undergoing coronarography are diagnosed with non-CAD. There is also an increase in the prevalence of non-CAD in both genders, which is probably due to gradual expanding of clinical indications for angiography in patients with angina. Furthermore, considering the increased mortality risk established recently, a prognosis of non-CAD is not benign as previously thought. However, the concept and definition of non-CAD remains elusive causing difficulties in diagnosis and treatment. One of the major shortcomings is the exclusion-based diagnosis of non-CAD. Furthermore, treatment of non-CAD still presents a great challenge and optimal therapy is yet to be determined. There are two major hypotheses explaining the pathophysiological mechanisms of non-CAD, i.e. ischemic hypothesis based on abnormal microvascular dysfunction and non-ischemic one based on altered pain perception. This review encompasses a broader spectrum of pathophysiological mechanisms of non-CAD, and proposes a new way of classification based on the major disorder involved: type I (ischemic mechanisms) and type II (non-ischemic mechanisms), depending on which mechanism predominates. Hopefully, this would provide new insights in the understanding of this disorder, thus leading to accurate and early diagnosis and successful treatment, especially considering the increased mortality risk in these patients.Novi podaci prikupljeni iz velikih kliničkih ispitivanja pokazuju da je neopstruktivna koronarna bolest (ne-OKB) klinički entitet koji se ne smije zanemariti. Procjenjuje se da se u 50% ženske populacije koja se podvrgava koronarografiji dijagnosticira ne-OKB. Također postoji povećanje učestalosti ne-OKB u oba spola, što je vjerojatno posljedica postupnog širenja kliničkih indikacija za koronarografiju u bolesnika s anginom pektoris. Nadalje, s obzirom na povećani rizik od smrtnosti koji je nedavno ustanovljen, prognoza ne-OKB nije dobroćudna kao što se ranije mislilo. Međutim, koncept i definicija ne-OKB ostaju nedovoljno definirani, što uzrokuje poteškoće kako u dijagnozi tako i u liječenju. Jedan od glavnih nedostataka je dijagnostika ne-OKB koja se temelji na dijagnozi isključivanja. Nadalje, liječenje ne-OKB i dalje predstavlja velik izazov, a optimalnu terapiju tek treba odrediti. Postoje dvije glavne hipoteze koje objašnjavaju patofiziološke mehanizme ne-OKB. Ishemijska hipoteza temelji se na mikrovaskularnoj disfunkciji, a neishemijska hipoteza na promijenjenoj percepciji boli. Ovaj pregledni članak obuhvaća širok spektar patofizioloških mehanizama ne-OKB i predlaže novi način klasifikacije temeljen na glavnom poremećaju koji je uključen u patofiziologiju: tip I. (ishemijski mehanizam) i tip II. (ne-ishemijski mehanizam), ovisno o tome koji mehanizam prevladava. Nadamo se da će to omogućiti nove spoznaje u razumijevanju ovoga poremećaja, što dovodi do točne i rane dijagnoze i uspješnog liječenja, osobito s obzirom na povećani rizik smrtnosti kod ovih bolesnika

Serumska vrijednost osteoprotegerina u bolesnika s kalcificirajućom aortnom stenozom u ovisnosti o zatajenju srca

The aim of the study was to assess the role of serum osteoprotegerin (OPG) as a biomarker in patients with aortic valve stenosis (AS) in relation to heart failure and symptomatic status. This was a case control study, which included 51 patients with AS and 39 control subjects. At the time of study enrolment, detailed medical history was obtained and all subjects underwent physical examination, chest x-ray and echocardiography. OPG levels were measured in all subjects, and serum N-terminal of the pro b-type natriuretic peptide (NT pro BNP) levels were determined in patients with AS. Serum OPG levels were elevated in patients with AS compared to control subjects (p=0.001). Pa-tients with heart failure due to AS had elevated serum OPG levels in comparison to patients without heart failure (p=0.001). A significant correlation between OPG and symptomatic status was observed in all patients with AS (p<0.001), however, it was not the case in patients without heart failure (p=0.425). There was a positive correlation between OPG and NT pro BNP concentrations with objective signs of heart failure on chest x-ray (p<0.001). Negative correlation of OPG concentrations with aortic valve area was present (p<0.040), as well as with left ventricular ejection fraction (p<0.001). Serum OPG could be a valuable biomarker in the evaluation of severity of calcified AS and serve as an additional indicator besides clinical presentation and echocardiography in the assessment of surgical treatment or aortic valve replacement.Cilj ove studije bio je ocijeniti ulogu osteoprotegerina (OPG) kao biljega u bolesnika sa stenozom aortnog srčanog za-liska u odnosu na prisutne simptome kao i stupanj srčanog zatajenja. U studiju je bio uključen 51 bolesnik s aortnom steno-zom (AS) i 39 kontrolnih ispitanika. Prije uključenja u studiju uzeta je detaljna anamneza, učinjen je fizikalni pregled, ren-tgenska snimka srca i pluća te ehokardiografija. OPG je određen u svih ispitanika, a N-terminalni nastavak pro b-tipa natriu-retskog peptida (NT pro BNP) bio je određen u bolesnika s AS. OPG je bio povišen u bolesnika s AS u odnosu na kontrolne ispitanike (p=0,001). Bolesnici sa srčanim zatajenjem zbog AS imali su povišene razine OPG-a u odnosu na bolesnike bez srčanog zatajenja (p=0,001). Značajna korelacija između OPG-a i simptomatskog statusa bila je zapažena u svih bolesnika s AS (p<0,001), ali to nije bio slučaj u bolesnika bez srčanog zatajenja (p=0.425). Zabilježena je i pozitivna korelacija između koncentracije OPG-a i NT pro BNP-a s objektivnim znakovima srčanog zatajenja na rentgenskoj snimci srca i pluća (p<0,001). Također je opažena negativna korelacija OPG-a i areje aortnog zaliska (p<0,040) te istisne frakcije lijeve klijetke (p<0,001). OPG bi mogao predstavljati vrijedan biljeg u procjeni težine kalcificirane AS te bi mogao poslužiti kao dodatni indikator prilikom odlučivanja o kirurškom liječenju ili zamjeni aortnog zaliska, naravno, uz kliničku prezentaciju i ehokardiografiju

Mid-infrared Fourier-domain optical coherence tomography with a pyroelectric linear array

Optical technology in the mid-infrared wavelength range is currently a rapidly developing field initiated by the availability of novel high-power and spatially coherent sources. Non-destructive testing techniques based on these sources are very promising for industrial and medical applications. However, there are still many engineering problems due to the technical challenges and high prices of the optical elements suitable for the mid-infrared region. In this paper, we report the development and performances of the first mid-infrared Fourier-domain optical coherence tomography based on a supercontinuum source and low-cost pyroelectric detector. The system is designed to operate in the spectral region around 4?m. Experimental results are demonstrated for detections of embedded microstructures in ceramic materials and subsurface oil paint layers

Conformational Parameters and Hydrodynamic Behavior of Poly(2-Methyl-2-Oxazoline) in a Broad Molar Mass Range

In this work, we report our results on the hydrodynamic behavior of poly(2-methyl-2-oxazoline) (PMeOx). PMeOx is gaining significant attention for use as hydrophilic polymer in pharmaceutical carriers as an alternative for the commonly used poly(ethylene glycol) (PEG), for which antibodies are found in a significant fraction of the human population. The main focus of the current study is to determine the hydrodynamic characteristics of PMeOx under physiological conditions, which serves as basis for better understanding of the use of PMeOx in pharmaceutical applications. This goal was achieved by studying PMeOx solutions in phosphate-buffered saline (PBS) as a solvent at 37 °C. This study was performed based on two series of PMeOx samples; one series is synthesized by conventional living cationic ring-opening polymerization, which is limited by the maximum chain length that can be achieved, and a second series is obtained by an alternative synthesis strategy based on acetylation of well-defined linear poly(ethylene imine) (PEI) prepared by controlled side-chain hydrolysis of a defined high molar mass of poly(2-ethyl-2-oxazoline). The combination of these two series of PMeOx allowed the determination of the Kuhn–Mark–Houwink–Sakurada equations in a broad molar mass range. For intrinsic viscosity, sedimentation and diffusion coefficients, the following expressions were obtained: η=0.015M0.77, s0=0.019M0.42 and D0=2600M−0.58, respectively. As a result, it can be concluded that the phosphate-buffered saline buffer at 37 °C represents a thermodynamically good solvent for PMeOx, based on the scaling indices of the equations. The conformational parameters for PMeOx chains were also determined, revealing an equilibrium rigidity or Kuhn segment length, (A) of 1.7 nm and a polymer chain diameter (d) of 0.4 nm. The obtained value for the equilibrium rigidity is very similar to the reported values for other hydrophilic polymers, such as PEG, poly(vinylpyrrolidone) and poly(2-ethyl-2-oxazoline), making PMeOx a relevant alternative to PEG

Study of doubly strange systems using stored antiprotons

Bound nuclear systems with two units of strangeness are still poorly known despite their importance for many strong interaction phenomena. Stored antiprotons beams in the GeV range represent an unparalleled factory for various hyperon-antihyperon pairs. Their outstanding large production probability in antiproton collisions will open the floodgates for a series of new studies of systems which contain two or even more units of strangeness at the P‾ANDA experiment at FAIR. For the first time, high resolution γ-spectroscopy of doubly strange ΛΛ-hypernuclei will be performed, thus complementing measurements of ground state decays of ΛΛ-hypernuclei at J-PARC or possible decays of particle unstable hypernuclei in heavy ion reactions. High resolution spectroscopy of multistrange Ξ−-atoms will be feasible and even the production of Ω−-atoms will be within reach. The latter might open the door to the |S|=3 world in strangeness nuclear physics, by the study of the hadronic Ω−-nucleus interaction. For the first time it will be possible to study the behavior of Ξ‾+ in nuclear systems under well controlled conditions

Multimodal mid-infrared optical coherence tomography and spectroscopy

Zusammenfassung in deutscher SpracheAbweichender Titel nach Übersetzung der Verfasserin/des VerfassersDie vorliegende Dissertation behandelt die Anwendung neuartiger, leistungsfähiger Superkontinuumlichtquellen in den Bereichen der Optischen Kohärenztomographie (OCT, engl. optical coherence tomography) und der Infrarotspektroskopie. Im Rahmen dieser Arbeit wurden die einzigartigen Eigenschaften der Superkontinuumstrahlung experimentell untersucht und die zugehörigen anwendungsspezifischen Aspekte diskutiert. Basierend auf den außergewöhnlichen Spezifikationen dieser Lichtquellen wurde ein voll integriertes, multimodales Dual-Band OCT- und Infrarotspektroskopie-System entwickelt, konstruiert und getestet. Als bildgebende interferometrische Methode ermöglicht OCT die dreidimensionale zerstörungsfreie Untersuchung von Oberflächen und Sub-Strukturen bei lateraler und axialer Ortsauflösung im Mikrometerbereich. Neben klassischen Anwendungsgebieten in der biomedizinischen Bildgebung – in welchen sich OCT zur Standardanwendung entwickelte – zählt die industrielle zerstörungsfreie Werkstoffprüfung (NDT, engl. non-destructive testing) mittlerweile zu einem Kerngebiet dieser Technik. Moderne, kommerziell erhältliche OCT-Systeme werden typischerweise im Sichtbaren (VIS, engl. visible) und nahen Infrarot (near-IR, engl. near infrared) betrieben. Die in diesem Spektralbereich dominierenden Streueffekte reduzieren dabei die Untersuchungstiefe und limitieren somit das Potential von OCT im Bereich von NDT. Da das Ausmaß der auftretenden Streuung sich invers proportional zur Wellenlänge des Lichts verhält, wurde das Potential der Weiterentwicklung von OCT in Richtung längerer Wellenlängen – dem mittleren Infrarotbereich (mid-IR, engl. mid-infrared) – theoretisch untersucht und als mögliche Lösung erkannt, um die bestehenden Einschränkungen durch Streueffekte zu überwinden.Trotz der unzulänglichen Auswahl an optischen Komponenten für den mid-IR-Bereich – speziell hinsichtlich leistungsfähiger Detektoren – konnte im Rahmen dieser Arbeit die außergewöhnliche Performance von OCT bei längeren Wellenlängen nachgewiesen werden; nach bestem Wissen des Autors konnte erstmalig ein Fourier-Domain-OCT bei einer zentralen Wellenlänge von 4 um umgesetzt werden. In den zu dieser Arbeit zusammengefassten wissenschaftlichen Publikationen wird die Entwicklung eines neuartigen mid-IR-OCT-Systems unter Verwendung eines kostengünstigen pyroelektrischen Detektors im Detail diskutiert. Darüber hinaus konnte mit der Weiterentwicklung des Aufbaus vom mid-IR-OCT zum Dual-Band-OCT, welches sowohl den mittleren als auch den nahen Infrarotbereich umfasst (zentrale Wellenlänge von 2 um bzw. 4 um), hochaufgelöste Bildgebung (axial 17 um bzw. 37 um, lateral 12 um bzw. 39 um) bei erweiterter Eindringtiefe demonstriert werden. Die speziellen Eigenschaften von thermischen Detektoren im Zusammenhang mit interferometrischen Anwendungen – insbesondere deren thermische Trägheit – wurden auf besondere Weise ausgenutzt, um OCT Bilder aufzunehmen und zusammenzufügen. Das volle Potential des entwickelten Systems wurde schließlich anhand von Materialien demonstriert, die mit herkömmlichen OCT-Systemen aufgrund starker Streuung nicht untersucht werden können: Industriekeramiken, Keramiken, Kunst- und Kulturobjekte, pharmazeutische Stoffe und streuende Polymere.Da wesentliche Molekülschwingungen vor allem durch Absorption im mid-IR-Bereich angeregt werden, ist ebendieser Spektralbereich besonders interessant für die chemische Analyse mittels Infrarotspektroskopie. Das zweite erklärte Ziel dieses Projekts stellte deshalb die Untersuchung von neuartigen mid-IR Superkontinuumquellen als potentielle Lichtquelle für diese hochselektive und –sensitive analytische Methode dar.Herkömmliche Infrarotspektroskopie-Systeme basieren typischerweise auf thermischen Lichtquellen, die äußerst stabile Schwarzkörperstrahlung emittieren. Diese Emitter bringen jedoch mehrere Einschränkungen aufgrund ihrer geringen Strahlungsdichte mit sich. Neueste Superkontinuumquellen hingegen vereinen das von thermischen Strahlern bekannte ultrabreite Spektrum mit vorteilhaften laserähnlichen Eigenschaften (örtliche Kohärenz, gerichtete Strahlung, hohe Strahlungsdichte und beugungslimitierte Strahlqualität). Im Rahmen dieser Arbeit wurden mid-IR Superkontinuumquellen bezüglich ihres Rauschverhaltens charakterisiert und als Alternative zu thermischen Lichtquellen in der Fourier-Transform-Infrarotspektroskopie (FTIR) eingesetzt. Infolgedessen konnte die gepulste Strahlung einer mid-IR Superkontinuumquelle erfolgreich in ein FTIR-Spektrometer eingekoppelt werden. Die Anwendung spezieller Signalverarbeitungsmethoden führte zur Unterdrückung der auftretenden Puls-zu-Puls Fluktuationen, wodurch die Empfindlichkeit des Spektrometers deutlich erhöht werden konnte. Im Speziellen führte die Vergrößerung der Interaktionslänge zwischen Licht und Materie zu verbesserten Nachweisgrenzen. Zusätzlich konnte gezeigt werden, dass die ausgezeichnete Strahlqualität der verwendeten Superkontinuumquelle beugungslimitierte chemische Bildgebung durch mid-IR Mikrospektroskopie ermöglicht.Die interdisziplinären Arbeiten dieser Dissertation verdeutlichten das Potential eines kombinierten Aufbaus. Daher wurde ein multimodales OCT- und Spektroskopie-System basierend auf einer einzigen mid-IR Superkontinuumquelle implementiert. Die Leistungsfähigkeit dieses Instruments wurde durch die multimodale Informationsgewinnung (morphologisch und chemisch) anhand von Verbundwerkstoffen demonstriert.Als indirektes Ergebnis gibt die Arbeit schließlich einen Überblick über den aktuellen Stand der Technik in verwandten Bereichen, sowie einen Ausblick auf zukünftige Entwicklungen basierend auf den erzielten Ergebnissen.The thesis investigates the capabilities and performances of novel mid-nfrared (mid-IR) supercontinuum light sources for optical coherence tomography (OCT) and mid-IR spectroscopy. Within the scope of the work, the unique properties of the supercontinuum emission were experimentally studied; the corresponding application aspects were discussed. Due to the superior specifications of the sources, a complete and fully integrated multimodal dual-band OCT (near- and mid-IR) and mid-IR spectroscopy system has been developed, constructed and evaluated.OCT is a three-dimensional interferometric imaging technique that enables non-invasive evaluation and metrology of surface and sub-surface structures providing a lateral and axial resolution on the micrometer scale. Besides significant advances in biomedical applications in recent decades, the focus of OCT started to extend covering industrial non-destructive testing (NDT) scenarios. State-of-the-art OCT systems operate in the visible and near-infrared (near-IR) spectral regions and suffer from strong scattering, which reduces the probing depth into materials, firmly limiting the application of these inspection systems for NDT. Since the magnitude of scattering is inversely proportional to the wavelength of light, perspectives of an expansion of OCT towards longer wavelengths – into the mid-IR range – were theoretically studied and predicted as a possible solution to overcome limitations imposed by scattering.Despite detection challenges and lag of mid-IR optical components, the proposed hypothesis of superior performances of OCT at longer wavelengths was confirmed experimentally within the scope of this thesis; a Fourier-domain OCT system operating at the center wavelength of 4 μm was demonstrated - to the best of the author’s knowledge - for the first time. In the scientific publications which have been consolidated to this thesis, the solution that elegantly employs a cost-effective pyroelectric detector is presented and discussed in detail. In the course of further studies, the operating regime of the developed system was upgraded to perform dual-band detection in the near- and mid-IR spectral ranges (center wavelength of 2 μm and 4 μm respectively) enabling a high resolution (axial of 17 μm and 37 μm, transverse of 12 μm and 39 μm respectively) and enhanced penetration OCT imaging. Particular features of the thermal detectors applied in interferometry were investigated and exploited to introduce unspecific OCT image compounding based on sensitivity roll-off steering. Capabilities of the developed system were demonstrated by imaging of formerly inaccessible due to scattering materials: industrial ceramics, pottery, art and cultural objects, pharmaceutical coatings and scattering polymers.Since molecules exhibit fundamental and distinct absorption in the mid-IR range, the exploited spectral region is also of great interest for chemical analysis by mid-IR spectroscopy. Therefore, the second goal of the project was to study the potentials of novel mid-IR supercontinuum light sources for this highly selective and sensitive analytical method.Most state-of-the-art mid-IR spectroscopy systems employ thermal light sources that emit black-body radiation and provide highly stable radiation. However, these emitters impose several inherited limitations due to their low brightness. In contrast, evolving supercontinuum generators offer distinct laser-like properties (spatial coherence, directionality, high brightness and diffraction-limited beam quality), while preserving, at the same time, ultra-broadband spectral coverage. In the thesis’s framework, mid-IR supercontinuum sources were characterized in terms of their noise performance and were employed as an alternative for thermal emitters in a Fourier-transform infrared (FTIR) spectrometer. Hence, an approach to the efficient coupling of pulsed mid-IR supercontinuum sources to FTIR spectrometers was proposed and verified. It enabled to enhance sensitivity by adaptation of the signal acquisition scheme leading to suppression of the effects of pulse-to-pulse fluctuations. Thereby, the supercontinuum-based FTIR instrument allowed an increase of the light-matter interaction length, which led to improved detection limits. Furthermore, enabled by the high quality of the beam, diffraction-limited chemical imaging was achieved and demonstrated for mid-IR microspectroscopy. The interdisciplinary studies conducted within this thesis revealed potentials for a combined solution. Therefore, a multimodal mid-IR OCT and spectroscopy system based on a single supercontinuum source was implemented. The performance of the system was assessed and demonstrated by obtaining multidimensional information (morphological and chemical) from composite and turbid materials and structures.As an indirect result, the thesis finally reviews the current state of the art in related fields and provides an outlook for future developments based on a synthesis of the results obtained.21