Advancements in mesenchymal stem cell treatment for Buerger's disease

Birgerova bolest (thromboangiitis obliterans) je neaterosklerotski inflamatorni proces koji uglavnom zahvata male i srednje arterije i vene u donjim i gornjim udovima. Okarakterisan je kao vrsta vaskulitisa. Nastanak, napredovanje i težina bolesti su povezani sa pušenjem. Birgerovu bolest karakterišu bol, pojava ishemičnih ulkusa, gangrena i rizik od amputacije, što značajno utiče na kvalitet života pacijenta. Trombolitička terapija, primena nesteroidnih antiinflamatornih lekova i vaskularno-hirurški rekonstruktivni zahvati su neki od terapijskih pristupa u lečenju Birgerove bolesti. Međutim, ovi načini lečenja nisu dovoljno efikasni. Još uvek najbolji efekat na poboljšanje bolesti ima prekid pušenja. U poslednje vreme, ćelijska terapija je ponudila sasvim nove mogućnosti lečenju Birgerove bolesti. Terapija mezenhimskim matičnim ćelijama (MMĆ) je prepoznata kao novi pristup u tkivnom inženjerstvu i regenerativnoj medicini, primenljiv u lečenju različitih ishemijski poremećaja, uključujući Birgerovu bolest. Prva terapija koja koristi MMĆ u lečenju Birgerove bolesti je odobrena u Indiji 2016. godine. U martu 2017. godine Evropska komisija je terapiju autolognim MMĆ iz adipoznog tkiva uvrstila u lekove "siročiće" za Birgerovu bolest. Ovaj novi terapijski pristup je neophodno validirati u narednim studijama u više kliničkih centara.Buerger's disease or thromboangiitis obliterans, is a non-atherosclerotic inflammatory process which mostly involves medium and small sized arteries and veins in lower and upper extremities. It is categorized as vasculitis. The disease is known to be closely linked to smoking. Buerger's disease is a long-term debilitating condition because of the pain, the development of ulcers and gangrene, and the risk of amputation. Drugs effective on erythrocyte flexibility, agents acting on platelets, non-steroidal anti-inflammatory drugs and vascular reconstruction are among several therapeutic methods for Buerger's disease. However, the applied therapies are insufficiently effective. Still, the base of treatment is smoking cessation. Lately, cell therapy has offered us entirely new possibilities. Mesenchymal stem cell (MSC) treatment has been proposed as a novel approach for tissue engineering and regenerative medicine for various ischemic disorders, including Buerger's disease. In 2016, the first MSC based therapy has received regulatory approval for the treatment of Buerger's disease in India. In March 2017, orphan designation was granted by the European Commission for autologous adipose tissue-derived MSC for the treatment of Buerger's disease. Novel therapeutic approach needs to be validated in the upcoming studies conducted in different clinical centers

Copper and zinc concentrations in atherosclerotic plaque and serum in relation to lipid metabolism in patients with carotid atherosclerosis

© 2015, Institut za Vojnomedicinske Naucne Informacije/Documentaciju. All rights reserved. Background/Aim. Some oligoelements are now investigated as possibly having a role in atherosclerosis. The aim of this study was to compare the concentrations of copper and zinc in the serum and carotid plaque and parameters of lipid metabolism in patients with different morphology of carotid atherosclerotic plaque. Methods. Carotid endarterectomy due to the significant atherosclerotic stenosis was performed in 91 patients (mean age 64 ± 7). The control group consisted of 27 patients (mean age 58 ± 9), without carotid atherosclerosis. Atheroscletoric plaques were divided into four morphological groups, according to ultrasonic and intraoperative characteristics. Copper and zinc concentrations in the plaque, carotid artery and serum were measured by atomic absorption spectrophotometry. Results. Serum copper concentrations were statistically significantly higher in the patients with hemorrhagic in comparison to those with calcified plaque (1.2 ± 0.9 μmol/L vs 0.7 ± 0.2 μmol/L, respectively; p = 0.021). Zinc concentrations were statistically significantly lower in plaques of the patients with fibrolipid in comparison to those with calcified plaques (22.1 ± 16.3 μg/g vs 38.4 ± 25.8 μg/g, respectively; p = 0.024). A negative significant correlation was found for zinc and triglycerides in the serum in all the patients (r = -0.52, p = 0.025). In the control group we also demonstrated a positive significant correlation for low-density lipoprotein cholesterol and copper in the serum (r = 0.54, p = 0.04). Conclusion. The data obtained in the current study are consistent with the hypothesis that high copper and lower zinc levels may contribute to atherosclerosis and its sequelae as factors in a multifactorial disease. Further studies are necessary in order to conclude whether high concentration of copper and zinc in the serum could be risk factors for atherosclesrosis

Influence of CYP2C19*2 gene variant on therapeutic response during clopidogrel treatment in patients with carotid artery stenosis

Uvod: I pored dokazanog kliničkog efekta oralne antiagregacijske terapije, značajan broj pacijenata nema adekvatan odgovor na primenjeni klopidogrel. Cilj naše studije je bio da se utvrdi uticaj prisutne CYP2C19*2 varijante gena na terapijski odgovor u toku primene klopidogrela kod pacijenata sa stenozom karotidne arterije. Metode: U jednogodišnju prospektivnu studiju uključeno je 112 pacijenata sa stenozom karotidne arterije kod kojih je izvršena endarterektomija. Posle operativnog zahvata, pacijenti su primali 75 mg dnevno klopidogrela u trajanju od najmanje mesec dana. Svi ispitanici su praćeni od momenta prijema. Za CYP2C19 genotipizaciju korišćen je TaqMan test. Uticaj CYP2C19*2 alela na trombocitnu reaktivnost ispitivan je primenom multiple-electrode aggregometry (MEA). Rezultati: Rezultati genotipizacije su pokazali da su 82 (73,2%) ispitanika homozigoti za wild-type, 29 (25,9%) heterozigoti za CYP2C19*2 alel, dok je 1 (0,9%) bio homozigot za CYP2C19*2. Nakon 24 sata, u grupi sa wild-type genotipom 29,3% ispitanika dali su odgovor na klopidogrel, a u grupi sa CYP2C19*2 varijantom gena 10% ispitanika. U grupi sa wild-type genotipom, 74,4% ispitanika su imali terapijski odgovor nakon 7 dana, odnosno 82,9% nakon 30 dana od primene klopidogrela. U grupi sa CYP2C19*2 alelom broj ispitanika sa terapijskim odgovorom raste do 46,7% nakon 7 dana, odnosno do 53,3% nakon 30 dana od primene klopidogrela. Rizik za slab odgovor je veći kod nosilaca CYP2C19*2 alela u odnosu na nenosioce (wild-type) (OR 4,250, 95% CI 1 .695 -10.658 , P lt 0,01). Zaključak: CYP2C19*2 varijanta gena značajno utiče na terapijski odgovor u toku primene klopidogrela kod bolesnika sa stenozom karotidne arterije kod kojih je izvršena endarterektomija.Background: Despite the proven clinical effect of oral antiplatelet drugs, a considerable number of patients do not have an adequate response to clopidogrel. The aim of our study was to determine the influence of CYP2C19*2 loss-of-function variant allele on clopidogrel responsiveness in patients with carotid artery stenosis. Methods: One hundred and twelve patients with carotid artery stenosis undergoing endarterectomy were included in this one-year prospective study. All of them received clopidogrel (75 mg daily) for at least 30 days after the intervention. They were followed from the moment of hospital admission. CYP2C19*2 genotyping was performed by TaqMan Assay. The influence of c Yp 2C 19*2 variant allele on clopidogrel platelet reactivity was determined using multiple-electrode aggregometry (MEA). Results: Genotyping results showed that 82 (73.2% ) patients were homozygous for wild type, 29 (25.9%) were heterozygous for the CYP2C19*2 allele and 1 (0.9%) was CYP2C19*2 homozygous. After 24 hours, among those with the wild type 29.3% were clopidogrel responders, and in those with the CYP2C19*2 alleles 10%. In the wild type group, 74.4% were clopidogrel responders after 7 days of taking the drug; 82.9% after 30 days of clopidogrel introduction, respectively. In patients with the CYP2C19*2 alleles the number of responders increased up to 46.7% after 7 days; 53.3% after 30 days of taking the drug, respectively. The risk for being a low-responder is higher for the patients heterozygous for the c Yp 2C 19*2 allele vs. wildtype (OR 4.250, 95% CI 1.695 -10.658 , P lt 0.01). Conclusions: The CYP2C19*2 loss-of-function variant allele has significant influence on clopidogrel response in patients with carotid artery stenosis undergoing endarterectomy

Ghrelin, obesity and atherosclerosis

Cardiovascular disease (CVD) is common cause of death in humans and its major underlying pathology is atherosclerosis. Atherosclerosis is a chronic inflammatory disease that predisposes to coronary artery disease (CAD), stroke and peripheral arterial disease, responsible for most of the cardiovascular morbidity and mortality. This inflammatory process, triggered by the presence of lipids in the vascular wall, and encompasses a complex interaction among inflammatory cells, vascular elements, and lipoproteins through the expression of several adhesion molecules and cytokines. Obesity is a risk factor for CVD but this association is not fully understood. Altered levels of obesity related peptides such as ghrelin may play an important role in this pathophysiology. Recent evidence indicates that ghrelin features several cardiovascular activities, including increased myocardial contractility, vasodilatation and protection from myocardial infarction. Recent data demonstrate that ghrelin can influence important key events in atherogenesis and thus they may play a role in atherosclerosis. In this review we present the latest data from recent animal and clinical studies which focus on a novel approach to ghrelin as a potential therapeutic agent in the treatment of a complex disease like atherosclerosis. Thus, ghrelin may become a new therapeutic target for the treatment of CVD. Further studies are necessary to investigate the potential mechanisms involved in the effects of ghrelin on the cardiovascular system

Nivo protoka krvi kroz zubnu pulpu i njegova korelacija s protokom krvi kroz karotidne arterije kod dve starosne grupe opšte populacije

Introduction Vascular network of dental pulp is supplied through common and external carotid artery and terminal dental branches that supply each pulp tissue. Age related changes of pulp tissue influence pulpal vascularization as well. The aim of this study was to compare and correlate pulpal and common and external carotid artery blood flow in young and middle age individuals of general population. Material and Methods Two groups of 10 participants were included in the study, young (20-25 years) and middle age (50-55 years) group. Pulpal blood flow (PBF) measurements on intact right and left upper central incisors were performed using laser Doppler flowmetry (LDF) method. Carotid arteries blood flow was assessed using carotid ultrasonography. Results PBF levels were significantly higher in young (3.11±0.67 and 3.46±1.11, right and left upper central incisors, respectively) compared to middle age (1.93±0.47 and 2.30±0.64, right and left upper central incisors, respectively) participants (independent sample t test; p lt 0.05). There was no correlation between common and external carotid artery blood flow and upper central incisors PBF in young as well as middle age participants, for right or left side. Conclusion Absence of correlation between carotid arteries blood flow and PBF suggests that reduced PBF in middle age participants was probably not due to reduced blood supply from carotid arteries but it was result of age related changes at the level of pulpal blood vessels.Uvod Vaskularna mreža zubne pulpe dobija dotok krvi preko zajedničke i spoljašnje karotidne arterije i završnih zubnih grana koje snabdevaju svaku pojedinačnu pulpu. Mala fleksibilnost okruženja zubne pulpe pojačava promene vezane za starenje koje utiču na vaskularizaciju pulpe. Cilj ovog rada je bio da se uporedi i utvrdi međusobna povezanost pulpnog i protoka krvi u zajedničkoj i spoljašnjoj karotidnoj arteriji kod mladih i osoba srednje životne dobi opšte populacije. Materijal i metode rada Dve grupe od po 10 ispitanika su učestvovale u studiji: mladi (20-25 godina) i ispitanici srednje životne dobi (50-55 godina). Merenja protoka krvi kroz zubnu pulpu (PBF) na intaktnim desnim i levim gornjim centralnim sekutićima izvedena su metodom laser Dopler floumetrije (LDF). Protok krvi kroz karotidne arterije je procenjivan ultrazvučnim pregledom. Rezultati Nivoi PBF bili su značajno viši kod mladih ispitanika (desni gornji centralni sekutići: 3,11±0,67; levi gornji centralni sekutići: 3,46±1,11) u odnosu na ispitanike srednje dobi (desni gornji centralni sekutići: 1,93±0,47; levi gornji centralni sekutići: 2,30±0,64) (Studentov t-test za nezavisne uzorke, p lt 0,05). Nije bilo korelacije između protoka krvi kroz zajedničke i spoljašnje karotidne arterije i PBF gornjih sekutića kod mladih, niti kod ispitanika srednje dobi, za desnu i levu stranu. Zaključak Nepostojanje veze između protoka krvi kroz karotidne arterije i PBF ukazuje na to da smanjenje PBF kod ispitanika srednje životne dobi verovatno nije posledica smanjenog dotoka krvi iz karotidnih arterija, već rezultat promena u vezi sa starenjem na nivou pulpnih krvnih sudova

Correlation between pulpal and carotid arteries blood flow in two age groups

Introduction Vascular network of dental pulp is supplied through common and external carotid artery and terminal dental branches that supply each pulp tissue. Age related changes of pulp tissue influence pulpal vascularization as well. The aim of this study was to compare and correlate pulpal and common and external carotid artery blood flow in young and middle age individuals of general population. Material and Methods Two groups of 10 participants were included in the study, young (20-25 years) and middle age (50-55 years) group. Pulpal blood flow (PBF) measurements on intact right and left upper central incisors were performed using laser Doppler flowmetry (LDF) method. Carotid arteries blood flow was assessed using carotid ultrasonography. Results PBF levels were significantly higher in young (3.11±0.67 and 3.46±1.11, right and left upper central incisors, respectively) compared to middle age (1.93±0.47 and 2.30±0.64, right and left upper central incisors, respectively) participants (independent sample t test; p<0.05). There was no correlation between common and external carotid artery blood flow and upper central incisors PBF in young as well as middle age participants, for right or left side. Conclusion Absence of correlation between carotid arteries blood flow and PBF suggests that reduced PBF in middle age participants was probably not due to reduced blood supply from carotid arteries but it was result of age related changes at the level of pulpal blood vessels

Hronična niskostepena inflamacija u procesu starenja kao karika u lancu vaskularnih poremećaja koji su povezani sa gojaznošću

The pathogenesis of obesity-related vascular disorders has not been fully elucidated. The fundamental role of inflammation in aging process is now widely recognized, particularly for atherosclerotic disease which begins before birth. The number of obese individuals worldwide has reached two billion, leading to an explosion of obesity-related vascular disorders associated with increased morbidity and mortality. Obesity, as a chronic low grade inflammatory process, is important risk factor for metabolic and cardiovascular disease. Despite a well-known genetic component, this risk appears to originate from several abnormalities in adipose tissue function associated with a chronic inflammatory state. In particular, obesity as the most common nutritional disorder in industrialized countries, is closely related to impaired endothelial function, a well-known marker of preatherosclerotic disease. These conditions disrupt vascular homeostasis by causing an imbalance between the nitric oxide pathway and the endothelin-1 system, with impaired insulin- stimulated endothelium-dependent vasodilation. Having in mind the growing population of overweight and obese people worldwide, along with an increasingly aging population, understanding the pathophysiology of obesity on cardiovascular system is essential. The mechanisms linking obesity-related vascular disorders and low grade inflammation in aging process are the focus of this paper.Patogeneza vaskularnih poremećaja koji su povezani sa gojaznošću nije u potpunosti razjašnjena. Danas je poznata fundamentalna uloga inflamacije u procesu starenja, naročito kod aterosklerozne bolesti, koja počinje pre rođenja. Broj gojaznih osoba širom sveta je dostigao cifru dva biliona i doveo do “eksplozije” vaskularnih poremećaja koji su povezani sa gojaznošću i povećanim morbiditetom i mortalitetom. Gojaznost, kao hronični niskostepeni inflamacijski proces, je važan faktor rizika za nastanak metaboličkih i kardiovaskularnih bolesti. Pored dobro proučene genetske komponente, izgleda da je za ovaj rizik zaslužno i nekoliko poremećaja funkcije masnog tkiva koji se dovode u vezu sa stanjem hronične inflamacije. U tom smislu prednjači gojaznost, pošto je kao najčešći poremećaj ishrane u razvijenim zemljama blisko povezana sa endotelnom disfunkcijom, koja predstavlja uveliko poznat marker preaterosklerozne bolesti. Takvi uslovi narušavaju vaskularnu homeostazu, dovodeći do dizbalansa između metaboličkog puta azot monoksida i sistema endotelina-1, što je praćeno otežanim odvijanjem insulinom podstaknute vazodilatacije. Imajući u vidu globalni zajednički porast broja kako osoba sa viškom kilograma i gojaznih osoba, tako i starije populacije, razumevanje patogeneze gojaznosti i njenog uticaja na kardiovaskularni sistem je od esencijalnog značaja. Mehanizmi koji čine sponu između vaskularnih poremećaja povezanih sa gojaznošću i niskostepene inflamacije u procesu starenja nalaze se u fokusu ovog rada