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Background: Anterior mitral leaflet prolapse repair is a highly effective procedure, but despite excellent operative results still has an inferior long‐term durability when compared to posterior leaflet repair. Methods: We analysed mitral repair durability in 74 consecutive patients operated for anterior leaflet prolapse between 2010 and 2021. Their pre‐ and postoperative clinical, echocardiographic data and repair durability as well, were compared with 74 randomly assigned posterior leaflet prolapse patients who underwent valve repair during the same period. Results: While groups were of similar age, patients with anterior leaflet prolapse had an inferior preoperative status in terms of functional reserve, atrial fibrillation, operative risk, ejection fraction and had more dilated left heart chambers as well. 1, 5, and 10‐year freedom from repair failure was 87.1 ± 4.6%, 79.8 ± 6.5% and 50.7 ± 12.5% in the anterior, and 98.5 ± 1.5% respectively in the posterior leaflet group. Atrial fibrilation (hazard ratio [HR] 5.365; 95%; confidence interval [CI] 1.093–26.324 p = .038) and left ventricle end‐systolic diameter (HR 1.160 95%; CI 1.037–1.299 p = .010) independently predicted anterior leaflet repair failure. Receiver Operating Curve analysis established left ventricle end‐systolic diameter ≤42 mm as a cut‐off value associated with improved anterior leaflet repair durability. Accordingly, 10‐year repair durability in a subset of patients, with preserved left ventricle end‐systolic diameter (≤42 mm) was 86.4 ± 7.8%. Conclusion: Better long‐term repair durability in patients with anterior mitral leaflet prolapse and preserved sinus rhytm and left‐ventricle diameters justifies early reconstructive approach.

Hydrogen sulfide (H2 S) represents the third and the youngest member of the gaseous transmitters family. The dominant effect of H2 S on isolated vessels is vasodilation. As the mechanism of H2 S-induced relaxation in human vessels remains unclear, the present study aimed to investigate the effects of H2 S donor, sodium hydrosulfide (NaHS), on isolated human saphenous vein (HSV) and to determine the mechanism of action. Our results showed that NaHS (1 µM-3 mM) induced a concentration-dependent relaxation of endothelium-intact HSV rings pre-contracted by phenylephrine. Pre-treatment with L-NAME, ODQ and KT5823 significantly inhibited NaHS-induced relaxation, while indomethacin induced partial inhibition. Among K+ channel blockers, the combination of apamin and TRAM-34 significantly affected the relaxation produced by NaHS, while iberiotoxin and glibenclamide only reduced maximal relaxation of HSV. NaHS partially relaxed endothelium-intact rings pre-contracted by high K+ , as well as phenylephrine-contracted rings in the presence of nifedipine. Additionally, the incubation of HSV rings with NaHS increased NO production. These results demonstrate that NaHS produces the concentration- and endothelium-dependent relaxation of isolated HSV. Vasorelaxation to NaHS probably involves activation of NO/cGMP/PKG pathway and partially prostacyclin. In addition, different K+ channels subtypes, especially SKCa and IKCa , as well as BKCa and KATP channels in high concentrations of NaHS, probably participate in the NaHS-induced vasorelaxation.

Cardioprotective abilities of procyanidins, might, at least in part, attribute to their vasodilator properties. The present study was undertaken to assess the vasorelaxant effect of procyanidin B2 on isolated human saphenous vein (HSV) and its underlying mechanisms. Procyanidin B2 relaxed phenylephrine-induced contraction of HSV rings in concentration-dependent manner. The relaxation was dependent on the presence of endothelium and was strongly affected by l-NAME, hydroxocobalamin or ODQ, the inhibitors of NO/cGMP pathway. Indomethacin significantly affected only the relaxation produced by the highest concentrations of procyanidin B2. Apamin and TRAM-34 combination, in the presence of l-NAME and indomethacin, did not additionally decreased procyanidin B2-induced relaxation. In the presence of K+ channel blockers, relaxation induced by procyanidin B2 was partially attenuated by 4-aminopyridine, significantly inhibited by glibenclamide and almost abolished by iberiotoxin. Procyanidin B2 also relaxed the contractions induced by phenylephrine or caffeine in Ca2+-free solution. Finally, nifedipine slightly, while thapsigargin strongly antagonized HSV relaxation. Our results indicate that procyanidin B2 induces endothelium-dependent relaxation of HSV, which results primarily from stimulation of NO production, as well K+ channels opening, especially BKCa, and partially KATP and KV. Regulation of the intracellular Ca2+ release and inhibition of Ca2+ influx probably contribute to procyanidin B2-induced relaxation. Keywords: Endothelium, Human saphenous vein, Procyanidin B2, Vasorelaxation, K+ channels, Ca2+ channels

Dyslipidemia is the leading risk factor for the development of atherosclerosis and associated consequences, such as coronary heart disease, ischemic cerebrovascular and peripheral vascular disease. These diseases are the major cause of mortality in the world and in Europe as well, where they are responsible for around 45% of all deaths. Treatment of dyslipidemia includes the use of statins, ezetimibe, fibrates, niacin, bile acids sequestrants and omega-3 fatty acids. Although statins play the major role in dyslipidemia treatment by reducing the risk of cardiovascular (CV) events by 30%, there is a need for additional new drugs that reduce the residual risk even more. PCSK9 inhibitors, apolipoprotein B (apoB) synthesis inhibitors, MTP inhibitors and CETP inhibitors are already approved for the specific indications, or are in the advanced stages of clinical investigation. Two PCSK9 inhibitors, alirocumab and evolocumab are approved for use in combination with statins for the treatment of heterozygous familial hypercholesterolemia (FH), but also in patients with clinical atherosclerotic CV diseases who require additional low-density lipoprotein cholesterol (LDL-C) level reduction. In addition, evolocumab is approved for use in patients with homozygous FH. Mipomersen, apoB synthesis inhibitor, lomitapide, and oral MTP inhibitor are currently approved in the treatment of patients with homozygous FH as an adjunct to the maximum tolerated doses of statins and other lipid-lowering drugs. Although the new lipid-lowering agents produce significant LDL-C level reduction, more clinical studies are necessary to confirm their efficacy and safety in dyslipidemia treatment. Dislipidemije su vodeći faktor rizika za razvoj ateroskleroze i njenih posledica, kao što su koronarna bolest srca, ishemična cerebrovaskularna i periferna vaskularna bolest. Ove bolesti su glavni uzrok mortaliteta, kako u svetu tako i u Evropi, gde su odgovorne za 45% ukupne smrtnosti. Terapija dislipidemija uključuje primenu: statina, ezetimiba, fibrata, niacina, smola koje vezuju žučne kiseline i omega-3 masnih kiselina. Od pomenutih lekova, vodeću ulogu u terapiji dislipidemija imaju statini. Treba istaći da uprkos primeni statina, koji redukuju rizik od pojave kardiovaskularnih (KV) događaja za oko 30%, još uvek ostaje tzv. rezidualni rizik za nastanak KV događaja, što ukazuje da su potrebni novi lekovi koji će dalje redukovati rezidualni rizik. Novi lekovi u terapiji dislipidemija uključuju PCSK9 inhibitore, inhibitore sinteze apolipoproteina B (apoB), MTP inhibitore i CETP inhibitore, koji su ili već odobreni za primenu u određenim indikacijama, ili se nalaze u odmaklim fazama kliničkog ispitivanja. Alirokumab i evolokumab, dva PCSK9 inhibitora, odobrena su za primenu, u kombinaciji sa statinima, u terapiji heterozigotne familijarne hiperholesterolemije (FH), kao i kod bolesnika sa kliničkim aterosklerotičnim KV bolestima koji zahtevaju dodatnu redukciju nivoa lipoproteina male gustine (low-density lipoprotein cholesterol, LDL-C). Pored toga, evolokumab je odobren za primenu kod bolesnika sa homozigotnom FH. Mipomersen, inhibitor sinteze apoB, i lomitapid, oralni MTP inhibitor, su, odobreni za primenu samo kod bolesnika sa homozigotnom FH kao dodatak maksimalnoj tolerišućoj dozi statina i drugih hipolipemika. Iako novi hipolipemici značajno redukuju nivo LDL-C, neophodno je sprovesti studije, duže i sa većim brojem ispitanika, koje će potvrditi njihovu efikasnost i bezbednost i time omogućiti njihovu širu primenu u terapiji dislipidemija.

The aim of the present study was to investigate and characterize vasorelaxant effect of procyanidin B2 on human internal mammary artery (HIMA) as one of the mechanisms of its protective effect against vascular risk. Procyanidin B2 induced strong concentration-dependent relaxation of HIMA rings pre-contracted by phenylephrine. Pretreatment with L-NAME, a NO synthase inhibitor, hydroxocobalamin, a NO scavenger, and ODQ, an inhibitor of soluble guanylate cyclase, significantly inhibited procyanidin B2-induced relaxation of HIMA, while indomethacin, a cyclooxygenase inhibitor, considerably reduced effects of low concentrations. Among K+ channel blockers, iberiotoxin, a selective blocker of large conductance Ca2+-activated K+ channels (BKCa), abolished procyanidin B2-induced relaxation, glibenclamide, a selective ATP-sensitive K+(K-ATP) channels blocker, induced partial inhibition, while 4-aminopyridine, a blocker of voltage-gated K+(K-V) channels, and TRAM-34, an inhibitor of intermediate-conductance Ca2+-activated K+(IKCa) channels, slightly reduced maximal relaxation of HIMA. Further, procyanidin B2 relaxed contraction induced by phenylephrine in Ca2+-free Krebs solution, but had no effect on contraction induced by caffeine. Finally, thapsigargin, a sarcoplasmic reticulum Ca2+-ATPase inhibitor, significantly reduced relaxation of HIMA produced by procyanidin B2. These results demonstrate that procyanidin B2 produces endothelium-dependent relaxation of HIMA pre-contracted by phenylephrine. This effect is primarily the result of an increased NO synthesis and secretion by endothelial cells and partially of prostacyclin, although it involves activation of BKCa and K-ATP, as well as K-V and IKCa channels in high concentrations of procyanidin B2.

Introduction. Mitral valve calcifications are frequent finding in Barlow disease. This is making mitral repair surgery even more demanding in already complex valve pathology. Case report. A fifty-five-year-old Barlow disease patient underwent a mitral repair surgery due to posterior leaflet prolapse at P2 level and extensive posterior leaflet and annular calcifications as well. The prolapsed scallop was resected, while P1 and P3 scallops were detached from the annulus. After complete posterior annulus decalcification, so formed the large atrio-ventricular defect was reconstructed with the autologous pericardial patch and double suture line technique. The P1 and P3 segments were reattached there by the sliding technique and sutured with no strain. Annuloplasty was performed with a saddle rigid ring No 36. The patient was discharged nine days after the surgery with just a trace of mitral regurgitation. Conclusion. Annular decalcification and reconstruction in the patients with calcified Barlow mitral disease is necessary for safe and durable mitral valve surgical repair. Uvod. Kalcifikacije mitralne valvule su čest nalaz kod bolesnika sa Barlovljevom bolesti što čini rekonstruktivnu hirurgiju zalistka kod ovih bolesnika znatno složenijom. Prikaz bolesnika. Bolesniku starom 55 godina je urađena rekonstrukcija mitralnog zalistka zbog prolapsa posteriornog listića i značajnih kalcifikacija na P2 segmentu i posteriornom anulusu. Nakon resekcije P2 segmenta i odvajanja P1 i P3 segmenta od anulusa, urađena je kompletna resekcija velikog kalcifikata sa skoro polovine obima posteriornog anulusa. Nastali atrioventrikularnog defekt rekonstruisan je autolognim perikardom elipsoidnog oblika sašivenim u dva sloja. P1 i P3 segment su potom reinplantirani na rekonstruisani anulus i međusobno spojeni. Rekonstruktivna procedura je kompletirana anuloplastikom pomoću sedlastog rigidnog prstena veličine 36. Bolesnik je otpušten devetog postoperativnog dana sa neznatnom mitralnom regurgitacijom. Zaključak. Dekalcifikacija posteriornog anulusa uz preciznu rekonstrukciju nastalog atrioventikularnog defekta je neophodna procedura za bezbednu i funkcionalno trajnu rekonstrukciju mitralnog zalistka.

Introduction Findings from epidemiological studies indicate that polyphenols, widespread in human diet and with numerous biological activities, act cardioprotectively. Procyanidins are subclass of polyphenols with high content in commonly consumed foods and beverages, such as grapes, tea, chocolate, nuts and apples. Cardioprotective abilities of procyanidins, might, at least in part, attribute to their vasodilator properties. Purpose Because the exact mechanisms by which procyanidin B2 causes vasorelaxation are unclear, we aimed to investigate relaxant effect of procyanidin B2 on the isolated human internal mammary artery (HIMA) and its underlying mechanisms. Methods The HIMA segments were collected from patients suffering from coronary artery disease who were undergoing coronary artery bypass surgery and studied in organ bath. Results Procyanidin B2 induced strong concentration-dependent relaxation of HIMA rings pre-contracted by phenylephrine. Pretreatment with L-NAME, a NO synthase inhibitor, hydroxocobalamin, a NO scavenger, and ODQ, an inhibitor of soluble guanylate cyclase, significantly inhibited procyanidin B2-induced relaxation of HIMA, while indomethacin, a cyclooxygenase inhibitor, considerably reduced effects of low concentrations. Among K+ channel blockers, iberiotoxin, a selective blocker of large conductance Ca2+-activated K+ channels (BKCa), abolished procyanidin B2-induced relaxation, glibenclamide, a selective ATP-sensitive K+ (KATP) channel blocker, induced partial inhibition, while 4-aminopyridine, a blocker of voltage-gated K+ (KV) channels, and TRAM-34, an inhibitor of intermediate-conductance Ca2+-activated K+ (IKCa) channels, slightly reduced maximal relaxation of HIMA. Conclusion Our results demonstrate that, in HIMA, procyanidin B2 produces strong endothelium-dependent vasorelaxant effect. It seems that this relaxation is primarily the result of an increased NO synthesis and secretion by endothelial cells and partially of prostacyclin, although it involves activation of BKCa and KATP, as well as KV and IKCa channels in high concentrations of procyanidin B2. Acknowledgement/Funding The study was supported by a Scientific Research Grant (P175088) from Ministry of Science and Technology Serbia.

Objective To investigate the role of hydrogen sulfide (H2S) in human internal mammary arteries (IMA) and its interaction with endothelial nitric oxide synthase (eNOS) and phosphodiesterase (PDE)5A activity. Methods Human IMA segments from patients undergoing coronary artery bypass grafting (CABG) were studied by myography for acetylcholine and sodium hydrosulfide (NaHS)-induced relaxation. Locations of 3-mercaptopyruvate sulfurtransferase (3-MPST) and cysteine aminotransferase (CAT) were examined immunohistochemically. Levels of H2S, eNOS, phosphorylated-eNOSser1177, and PDE5A were measured. Results In IMA segments from 47 patients, acetylcholine-induced relaxation (resistant to NG-nitro-L-arginine and indomethacin) was significantly attenuated by aminooxyacetic acid or L-aspartate (CAT inhibitors), iberiotoxin (large-conductance calcium-activated K+ channel blocker), TRAM-34 plus apamin (intermediate- and small-conductance Ca2+-activated K+ channel blockers) or glibenclamide (ATP-sensitive K+ channel blocker). 3-MPST and mitochondrial CAT were found in endothelial and smooth muscle cells while cytosolic CAT was located only in endothelial cells. Acetylcholine significantly increased the H2S levels. The H2S donor, NaHS, increased eNOS phosphorylation and down-regulated PDE5A. Conclusions Human conduit artery endothelium releases H2S under basal and stimulated conditions, involving the 3-MPST/CAT pathway, eNOS phosphorylation, PDE5A activity, and potassium channels. These findings may provide new therapeutic targets for treating vasospasm in CABG grafts and facilitate the development of new vasodilator drugs.

Background. Graft spasm remains challenging in coronary artery bypass grafting (CABG). Calcium antagonists are commonly used in patients with coronary artery disease. This study investigated the inhibitory effect of third-generation dihydropyridine calcium channel antagonist benidipine on the vasoconstriction induced by various vasoconstrictors in the human internalmammary artery(IMA). Methods. Isolated human IMA rings (N = 65, taken from 37 patients undergoing CABG) were studied in a myograph in 2 ways: the relaxing effect of benidipine on vasoconstrictor-induced precontraction by KCl and U46619 and the depressing effect of benidipine at plasma concentrations on the contraction. Enzyme-linked immunosorbent assay (ELISA) was used to measure the change of the protein related to the L-type calcium channel. Results. Benidipine caused more relaxation in KCl-contracted (86.7% +/- 3.3%; n = 12) than in U46619-contracted (63.8% +/- 5.3%; n = 8; p lt 0.001) IMA rings. Pretreatment of IMA with plasma concentrations of benidipine (-6.92 log M) significantly depressed subsequent contraction by KCl (from 17.3 +/- 2.7 mN to 7.4 +/- 1.2 mN; n = 6; p lt 0.05) but did not significantly affect the contraction caused by U46619. Benidipine also caused a decrease of caveolin (CaV) 1.2 protein content (0.55 +/- 0.02 versus 0.63 +/- 0.02 mg/mL; p lt 0.05). Conclusions. We conclude that in human IMA, the third-generation dihydropyridine calcium channel antagonist benidipine has a potent inhibitory effect on the vasoconstriction mediated by a variety of vasoconstrictors. Use of benidipine in patients undergoing CABG may provide vasorelaxant or antispastic effects in the grafts.

Objectives We recently reported the involvement of ER stress-mediated BKCa channel inhibition in homocysteine-induced coronary dilator dysfunction. In another study, we demonstrated that tetramethylpyrazine (TMP), an active ingredient of the Chinese herb Chuanxiong, possesses potent anti-ER stress capacity. The present study investigated whether TMP protects BKCa channels from homocysteine-induced inhibition and whether suppression of ER stress is a mechanism contributing to the protection. Furthermore, we explored the signaling transduction involved in TMP-conferred protection on BKCa channels. Methods BKCa channel-mediated relaxation was studied in porcine small coronary arteries. Expressions of BKCa channel subunits, ER stress molecules, and E3 ubiquitin ligases, as well as BKCa ubiquitination were determined in porcine coronary arterial smooth muscle cells (PCASMCs). Whole-cell BKCa currents were recorded. Results Exposure of PCASMCs to homocysteine or the chemical ER stressor tunicamycin increased the expression of ER stress molecules, which was significantly inhibited by TMP. Suppression of ER stress by TMP preserved the BKCa β1 protein level and restored the BKCa current in PCASMCs, concomitant with an improved BKCa-mediated dilatation in coronary arteries. TMP attenuated homocysteine-induced BKCa β1 protein ubiquitination, in which inhibition of ER stress-mediated FoxO3a activation and FoxO3a-dependent atrogin-1 and Murf-1 was involved. Conclusions Reversal of BKCa channel inhibition via suppressing ER stress-mediated loss of β1 subunits contributes to the protective effect of TMP against homocysteine on coronary dilator function. Inhibition of FoxO3a-dependent ubiquitin ligases is involved in TMP-conferred normalization of BKCa β1 protein level. These results provide new mechanistic insights into the cardiovascular benefits of TMP.

In this study, we aimed to investigate relaxant effect of flavanol (-)-epicatechin on the isolated human saphenous vein (HSV), as a part of its cardioprotective action, and to define the mechanisms underlying this vasorelaxation. (-)-Epicatechin induced a concentration-dependent relaxation of HSV pre-contracted by phenylephrine. Among K+ channel blockers, 4-aminopyridine, margatoxin, and iberiotoxin significantly inhibited relaxation of HSV, while glibenclamide considerably reduced effects of the high concentrations of (-)-epicatechin. Additionally, (-)-epicatechin relaxed contraction induced by 80 mM K+ , whereas in the presence of nifedipine produced partial relaxation of HSV rings pre-contracted by phenylephrine. In Ca2+ -free solution, (-)-epicatechin relaxed contraction induced by phenylephrine, but had no effect on contraction induced by caffeine. A sarcoplasmic reticulum Ca2+ -ATPase inhibitor, thapsigargin, significantly reduced relaxation of HSV produced by (-)-epicatechin. These results demonstrate that (-)-epicatechin produces endothelium-independent relaxation of isolated HSV rings. Vasorelaxation to (-)-epicatechin probably involves activation of 4-aminopyridine- and margatoxin-sensitive KV channels, BKCa channels, and at least partly, KATP channels. In addition, not only the inhibition of extracellular Ca2+ influx, but regulation of the intracellular Ca2+ release, via inositol-trisphosphate receptors and reuptake into sarcoplasmic reticulum, via stimulation of Ca2+ -ATPase, as well, most likely participate in (-)-epicatechin-induced relaxation of HSV.

In this study, we aimed to investigate relaxant effect of flavanol (-)-epicatechin on the isolated human saphenous vein (HSV), as a part of its cardioprotective action, and to define the mechanisms underlying this vasorelaxation. (-)-Epicatechin induced a concentration-dependent relaxation of HSV pre-contracted by phenylephrine. Among K

Introduction Acute lower limb ischemia results from thrombosis or embolization of diseased native artery or previously implanted bypass graft. When this occurs, several options are available to restore blood flow: catheter-directed thrombolysis, mechanical thrombectomy or open surgery. Fundamental reasons to apply percutaneous interventions are avoiding open procedures in high risk patients, and avoiding difficult dissection through scar tissue. Case Outline A 67-year-old male was admitted at our Institution for critical limb ischemia. After performed angiography the diagnosis of occluded femoropopliteal graft was established. Occlusion was resolved by catheter-directed thrombolysis with plasmin. Culprit lesions were treated by angioplasty. Conclusion Our patient underwent a successful thrombolysis of occluded femoropopliteal graft with locally-delivered human plasmin. Uvod Ishemija donjih ekstremiteta je posledica tromboze ili embolizacije obolele nativne arterije ili implantiranog grafta. Postoji nekoliko načina lečenja ishemije: tromboliza kateterom, mehanička trombektomija i hirurško lečenje. Osnovni razlozi za primenu perkutanih intervencija jeste izbegavanje klasičnog hirurškog lečenja kod bolesnika s visokim rizikom, kao i izbegavanje preparisanja krvnog suda u ožiljku. Prikaz bolesnika Muškarac star 67 godina primljen je u bolnicu zbog kritične ishemije donjih ekstremiteta. Po učinjenoj angiografiji dijagnostikovana je tromboza femoropoplitealnog grafta. Okluzija je rešena primenom plazmina uz upotrebu intraarterijskog katetera. Stenoze koje su otkrivene posle trombolize lečene su angioplastikom. Zaključak Trombolizom uz primenu plazmina i intraarterijskog katetera uspešno je izlečena okluzija femoropoplitealnog grafta.

After an acute coronary syndrome, patients remain at risk of recurrent ischemic events despite the use of antiplatelet therapy. In order to reduce the risk of recurrent ischemia in the treatment of patients with acute coronary syndromes, standard oral anticoagulants, such as vitamin K antagonists, have been introduced. These drugs have an important role in preventing stroke and systemic embolism in patients with atrial fibrillation. Vitamin K antagonists (e.g., warfarin) reduce the risk of recurrent cardio­vascular events and stroke but increase the risk of bleeding. In addition, the traditional anticoagulants have other significant drawbacks. Therefore, modulation of the coagulation process represents an important target in the development of new oral anticoagulants today. The new oral anticoagulants selectively target thrombin (dabigatran etexilate) or factor Xa (rivaroxaban, apixaban, edoxaban). Unlike traditional anticoagulants, these drugs have rapid onset of action and a relatively wide therapeutic range, do not require routine prothrombin time (PT) monitoring and have low potential for food and drug interaction. Dabigatran etexilate and rivaroxaban have been already approved in many countries for the prevention of stroke and systemic embolism in patients with atrial fibrillation. The third phase of clinical studies in which rivaroxaban was investigated in patients with acute coronary syndrome has been successfully completed. . Nakon akutnog koronarnog sindroma, kod bolesnika postoji povećan rizik od rekurentnih ishemičnih događaja, uprkos primeni antiagregacione terapije. U cilju smanjenja rizika od rekurentne ishemije, u terapiju visokorizičnih bolesnika sa akutnim koronarnim sindromom uvode se standardni oralni antikoagulansi, kao što su antagonisti vitamina K. Ovi lekovi imaju važnu ulogu u prevenciji moždanog udara i sistemskog embolizma kod bolesnika sa atrijalnom fibrilacijom. Antagonisti vitamina K (varfarin) smanjuju rizik od nastanka ponovnih kardiovaskularnih događaja i moždanog udara, ali povećavaju rizik od krvarenja. Pored toga, antagonisti vitamina K poseduju i druge, značajne nedostatke, tako da modulacija procesa koagulacije danas predstavlja značajnu metu za razvoj novih oralnih antikoagulanasa. Novi oralni antikoagulansi deluju selektivno na trombin (dabigatran eteksilat) ili na faktor koagulacije Xa (rivaroksaban, apiksaban, edoksaban). Za razliku od standardnih antikoagulanasa, imaju brz početak dejstva i relativno veliku terapijsku širinu, ne zahtevaju laboratorijsku kontrolu protrombinskog vremena (PT) i retko stupaju u interakcije sa hranom i lekovima. Dabigatran eteksilat i rivaroksaban su već registrovani u mnogim zemljama za prevenciju moždanog udara i sistemskog embolizma kod bolesnika sa atrijalnom fibrilacijom. Treća faza kliničke studije u okviru koje je ispitivan rivaroksaban kod bolesnika sa akutnim koronarnim sindromom uspešno je završena. .

More than 50 years ago, vitamin K antagonists were the only available oral anticoagulants. Since their application involves a number of limitations, it was necessary to develop new oral anticoagulant drugs and introduce them into clinical practice. These drugs have many advantages over vitamin K antagonists, including rapid onset/offset, a small number of interactions with other drugs and food, simplified dosing and predictable pharmacokinetics, eliminating the need for daily laboratory monitoring. In addition, new oral anticoagulant drugs act selectively on a single coagulation factor. Currently, the following drugs are approved for use: direct thrombin inhibitor, dabigatran etexilate, direct factor Xa inhibitor, rivaroxaban, apixaban and edoxaban. Dabigatran etexilate and apixaban are approved for the primary prevention of venous thromboembolism in adult patients undergoing elective surgery of total hip or knee replacement, while in addition to these anticoagulants edoxaban is approved for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation. For the treatment and prevention of recurrent deep vein thrombosis dabigatran etexilate, rivaroxaban and edoxaban are approved. In addition, rivaroxaban is approved for the secondary prevention of atherothrombotic events in patients with acute coronary syndrome. Više od 50 godina, antagonisti vitamina K bili su jedini dostupni oralni antikoagulantni lekovi. S obzirom na to da njihova primena podrazumeva brojna ograničenja, bilo je neophodno razviti i uvesti u kliničku praksu nove oralne antikoagulantne lekove. Ovi lekovi imaju brojne prednosti u poređenju s antagonistima vitamina K, koje uključuju brz početak i prestanak dejstva, mali broj interakcija s drugim lekovima i hranom, pojednostavljen način doziranja, kao i predvidivu farmakokinetiku, čime se eliminiše potreba za svakodnevnim laboratorijskim praćenjem. Osim toga, novi oralni antikoagulantni lekovi deluju selektivno samo na jedan faktor koagulacije. Trenutno su odobreni za upotrebu direktni inhibitor trombina, dabigatran eteksilat, kao i direktni inhibitori faktora Xa, rivaroksaban, edoksaban i apiksaban. Dabigatran eteksilat i apiksaban odobreni su za primarnu prevenciju venske tromboembolije kod odraslih pacijenata koji se podvrgavaju elektivnom hirurškom zahvatu totalne zamene kuka ili kolena, dok je za prevenciju moždanog udara i sistemske embolije kod odraslih pacijenata sa nevalvularnom atrijalnom fibrilacijom, pored navedenih antikoagulantnih lekova, odobren i edoksaban. Za terapiju i prevenciju rekurentne duboke venske tromboze odobreni su dabigatran eteksilat, rivaroksaban i edoksaban. Osim toga, rivaroksaban je odobren i za sekundarnu prevenciju aterotrombotičkih događaja nakon akutnog koronarnog sindroma.

Anticoagulants are effective agents for the prevention and treatment of thrombosis and thromboembolic complications, which represent a common cause of morbidity and mortality. Despite their clinical efficiency, traditional anticoagulants are all associated with significant drawbacks. As a result, modulation of the coagulation process represents an important target in the development of new oral and parenteral anticoagulants today. The new oral anticoagulants selectively target thrombin (ximelagatran, dabigatran etexilate) or factor Xa (rivaroxaban, apixaban, edoxaban). Unlike the traditional anticoagulants, vitamin K antagonists, these drugs have rapid onset of action and a relatively wide therapeutic range, do not require routine prothrombin time (PT) monitoring and have low potential for food and drug interaction. The new parenteral anticoagulants achieve their effects through indirect (semuloparin, idrabiotaparinux) or direct inhibition of factor Xa (otamixaban), as well as through inhibition of coagulation factor IXa (RB006). The main characteristics of these agents are a rapid onset of action and a predictable anticoagulant effect, whereby the most of them can be rapidly neutralized by an adequate antidote. Antikoagulantni lekovi su delotvorni u prevenciji i lečenju tromboze i tromboembolijskih komplikacija, koje su čest uzrok morbiditeta i mortaliteta. Ipak, uprkos kliničkoj delotvornosti, standardni antikoagulansi poseduju značajne nedostatke. Zbog toga, modulacija procesa koagulacije danas predstavlja značajnu metu za razvoj novih, oralnih i parenteralnih, antikoagulanasa. Novi oralni antikoagulansi deluju selektivno na trombin (ksimelagatran, dabigatran eteksilat) ili na faktor koagulacije Xa (rivaroksaban, apiksaban, edoksaban). Za razliku od standardnih antikoagulanasa, antagonista vitamina K, imaju brz početak dejstva i relativno veliku terapijsku širinu, ne zahtevaju laboratorijsku kontrolu protrombinskog vremena (PT), i retko stupaju u interakcije sa hranom i lekovima. Novi parenteralni antikoagulansi svoje antikoagulantno dejstvo ostvaruju indirektnom (semuloparin, idrabiotaparinuks) ili direktnom inhibicijom faktora Xa (otamiksaban), kao i inhibicijom faktora koagulacije IXa (RB006). Glavne karakteristike ovih lekova su brz početak dejstva i predvidljiv antikoagulantni efekat, a kod većine je moguće postići brzu neutralizaciju adekvatnim antidotom.

The aim of this article is to present findings from observations of community meetings on acute psychiatric wards, and the implications of these findings for planning psychology and psychotherapy input to the acute care services. Community meetings were facilitated on a weekly basis on the acute wards and they were an opportunity for staff and patients to work jointly on various tasks. It was hoped that observations of these meetings would provide a greater insight into the nature of interactions between staff and patients and problems that staff might encounter in their work with acutely unwell patients, and that this would help in planning how to support staff in their work. Observations showed that in the context of community meetings, it was difficult for staff to engage with patients in a more containing and therapeutic manner, and that there were prevailing anxieties in work with patients who presented with severe emotional distress. The conclusion based on the Observation Project is that in addition to planning the provision of direct psychology input to patients, it would be equally important to plan indirect work, such as provision of staff groups facilitated by professionals who have specialist expertise in working with groups. 1

Although long a feature of inpatient mental health ward routine, community meetings have not always attracted a clear sense of purpose and value. A common complaint from patients is that community meetings are useless and have no worthwhile purpose. It was thought that staff on acute wards would benefit from having a space to think about community meetings, and a work discussion group was provided over a duration of 18 months. It was hoped that this intervention would enable facilitators to think about these meetings and about their aims and benefits. This paper presents findings from the work discussion group: staff facilitators' experience of facilitating community meetings and patients' direct feedback to facilitators about their experience of these meetings. The conclusions made are that community meetings could provide a useful forum for patients and staff if they:• are of benefit to patients• provide a forum for development of the therapeutic alliance between patients and staff• contribute towards improvement of the ward milieu• provide a forum for staff to develop therapeutic skills• provide a forum for staff to develop working relationships with colleagues and different professionals in the team.

Release of potassium (K) during biomass combustion, may cause significant operating problems in terms of ash deposition and high-temperature corrosion of superheater tubes. Other ash-forming elements, such as calcium (Ca), silicon (Si), and phosphorus (P), may to a certain degree control the K release. The aim of this work was to study the release of K from simple systems, to obtain information on the retaining effects of the elements Ca, Si, and P. Further objectives were to investigate the effects of temperature, the presence of water vapor, the speciation of K and Ca, and the sample size on the release rate of K, from the simple ternary systems K-Ca-Si and K-Ca-P. Well-defined mixtures of K, Ca, and Si (or P) species were heat-treated in a reactor, at constant temperature (900 or 1000 °C), in a gas flow of 4 nL/min N 2 containing 2% (v/v) H 2 O. Average release rates were calculated from weight measurements of the samples after every 15 min of the heat treatment (and subsequent cooling to room temperature). The presence of water in the gas flow was found to significantly enhance the K-release rate, from both the K—Ca—Si system and the K-Ca-P system. For the K-Ca-Si system, a significantly higher release rate was observed at 1000 °C compared to 900 °C. Furthermore, doubling the Ca/Si molar ratio K 2 CO 3 -CaO-SiO 2 mixture strongly enhanced the K-release rate (by about 2 times) at 1000 °C. This suggests that SiO 2 preferentially reacts with CaO, so that more K is being released to the gas phase instead of being incorporated into the silicate structure. For the K-Ca-P system, with K 2 CO 3 as the K source, the Ca/P molar ratio had a strong effect on the K-release rate: a decrease in the Ca/P molar ratio (or increase in the P content) significantly decreased the K-release rate from the K-Ca-P mixtures. As opposed to the K-Ca-Si system, it thus seems that K is preferentially incorporated in (nonvolatile) (K 2 O) k •(CaO)l • (P 2 O 5 ) m structures. The effects of temperature and Ca source on the K-release rate from this system were limited but most pronounced for the mixtures with the highest Ca/P ratio (lowest P content). Furthermore, the sample size had a strong influence on the K-release rate. In the case of K-Ca-P mixtures containing KCI as the K source, the K-release rate was significantly higher at 1000 °C compared to 900 °C in the first 15 min of the heat treatment, whereas the Ca/P ratio had no effect on the K-release rate. Selected samples of the K-Ca-Si and K-Ca-P mixtures, before and after the heat treatment, were studied by scanning electron microscopy (SEM) in combination with energy-dispersive X-ray (EDX), to investigate the morphological and compositional changes. Moreover, selected samples of the K-Ca-P mixtures were heated from room temperature to 1400 °C, in a simultaneous thermal analyzer (STA), to investigate the melting and gas-phase release behavior. Both methods confirmed the effects of the Ca/Si and Ca/P ratios and the speciation of K and Ca on the release behavior observed in the heating experiments.

This service evaluation study aimed to demonstrate the impact of implementing ward‐based multidisciplinary therapy input on an acute psychiatric ward in a London hospital for a six‐month period. The results indicated a high level of patient engagement with the project and referrals facilitated for patients following discharge. A reduction of incidents on the ward was reported over the project period compared to the previous year and there was less use of containment measures by staff by the end of the project. Recommendations are made for service improvement.

It has been noted that there are a number of biologically active phenolic compounds present in wine, particularly red wine. Such compounds include, for example, catechin, epicatechin, quercetin, rutin, trans-resveratrol and cis-resveratrol. The resveratrol isomers, in particular, have been found to promote vascular relaxation. The mechanisms by which resveratrol causes vasodilatation are uncertain. The aim of this study was to investigate the mechanism(s) of resveratrolinduced vasorelaxation in rat aorta with endothelium present. Rat aortic rings were precontracted with phenylephrine. Resveratrol induced relaxation of the rat aortic rings. L-NAME, an inhibitor of NO synthase, abolished relaxation of rat aorta, but methylene blue, an inhibitor of guanylate cyclase, did not abolish relaxation induced by resveratrol. Highly selective blocker of ATP-sensitive K+ channels, glibenclamide as well as a nonselective blocker of big Ca-sensitive K+ channels, charybdotoxin did not block resveratrol-induced relaxation of rat aorta. 4-Aminopiridine, which is a non selective blocker of voltage-gated K+ (Kv) channels, and margatoxin which inhibits Kv1 channels abolished relaxation of rat aortic rings induced by resveratrol. In conclusion, we have shown that resveratrol potently relaxed rat aortic rings with endothelium present. It seems that NO and smooth muscle KV channels are included in this relaxation. This finding is of clinical importance in both veterinary and human medicine.

It is well established that spasm of an arterial and venous graft conduit may occur during harvesting or after coronary artery bypass grafting (CABG). The antivasoconstrictor effect of levcromakalim and rilmakalim, K(+) channel openers (KCOs), was studied in isolated human internal mammary artery (HIMA) and human saphenous vein (HSV) prepared for CABG. HIMA and HSV rings were contracted by electrical field stimulation (EFS, 20 Hz ) or with exogenous noradrenaline (NA). Levcromakalim induced a concentration-dependent and equipotent inhibition of contraction of HIMA and HSV preconstricted by EFS and exogenoulsy applied NA, while rilmakalim produced a stronger inhibition of EFS- than NA-evoked contractions. Glibenclamide, a selective ATP-sensitive K(+) channel (K(ATP) channel) blocker, significantly antagonized levcromakalim-induced inhibition of EFS- and NA-evoked contractions, as well as rilmakalim-induced inhibiton of EFS-evoked contractions on HIMA and HSV. However, glibenclamide failed to antagonize rilmakalim-induced inhibition of NA-evoked contractions. The results suggest that the antivasoconstrictor effect of levcromakalim occurs postsynapticaly by the opening K(ATP) channels in the vascular smooth muscle cells. They also suggest that the effect of rilmakalim on EFS-evoked contractions involves K(ATP) channels located pre-synaptically. However, the mechanism by which rilmakalim inhibits NA-evoked contraction seems to be K(ATP) channel independent and warrants further elucidation.

The complex relationship between man and technology is the starting point of an interesting design process, aiming to highlight the lack of awareness in most of the behavioral choices of man. Man is distinguished by its nature of finding short-term solutions, with the almost complete inability to prefigure long-term effects resulting from his unconscious decisions. Technology, on the other hand, is developing fast, becoming day by day more potentially uncontrollable. Specific attention is given to the innovations that can cause unpredicted impacts on human life: knowing history by its sociological implications allows us to recognize some recursive patterns that can then be transformed into opportunities. The goal is not an attempt to predict future trends in technological innovation but to find the right formulas in order to raise the level of responsibility in individuals’ behavior. In this paper the role of the designer is analyzed within the technology of 3D printing, enhancing its potential ability of changing both technological and human environments. A first answer to the problems triggered by 3D printing can be found, for example, in the positive phenomena that are activated within collaborating groups by sharing space and knowledge, in communities with a bottom-up approach, where the designer is actively involved. Keywords: human factors, ethics, awareness, 3D printing, rapid manufacturing, behaviors, transdisciplinarity, re-thinking, re-making, metadesign.

Introduction In this report, we aim to present a rare case of isolated internal iliac artery aneurysm with associated left ureteric obstruction and consequent hydronephrosis. Case report A 66-year-old male patient was admitted for occasional pain in the lower back that appeared one month earlier. CT arteriography revealed isolated internal iliac artery (diameter 99 mm) with ureteral obstruction, hydroureter and left kidney hydronephrosis occurrence. Aneurysm was resected, after six months the patient was doing well. Bearing in mind that 77% of the patients with isolated internal iliac artery have symptoms caused by aneurysmal compression on adjacent organs, we wanted to highlight that despite the amazing expansion of endovascular procedures in the last decades, its therapeutic effect in isolated internal iliac artery’s treatment is to a great extent limited since compression symptoms cannot be solved. Conclusion Open surgery remains the gold standard for isolated internal iliac artery’s treatment considering significant limitations of endovascular procedures due to the inability to eliminate problems caused by compression.

Evidences have suggested that flavanol compound (-)-epicatechin is associated with reduced risk of cardiovascular diseases. One of the mechanisms of its cardioprotective effect is vasodilation. However, the exact mechanisms by which (-)-epicatechin causes vasodilation are not yet clearly defined. The aims of the present study were to investigate relaxant effect of flavanol (-)-epicatechin on the isolated human internal mammary artery (HIMA) and to determine the mechanisms underlying its vasorelaxation. Our results showed that (-)-epicatechin induced a concentration-dependent relaxation of HIMA rings pre-contracted by phenylephrine. Among the K(+) channel blockers, 4-aminopyridine (4-AP) and margatoxin, blockers of voltage-gated K(+) (KV) channels, and glibenclamide, a selective ATP-sensitive K(+) (KATP) channels blocker, partly inhibited the (-)-epicatechin-induced relaxation of HIMA, while iberiotoxin, a most selective blocker of large conductance Ca(2+)-activated K(+) channels (BKCa), almost completely inhibited the relaxation. In rings pre-contracted by 80mM K(+), (-)-epicatechin induced partial relaxation of HIMA, whereas in Ca(2+)-free medium, (-)-epicatechin completely relaxed HIMA rings pre-contracted by phenylephrine and caffeine. Finally, thapsigargin, a sarcoplasmic reticulum Ca(2+)-ATPase inhibitor, slightly antagonized (-)-epicatechin-induced relaxation of HIMA pre-contracted by phenylephrine. These results suggest that (-)-epicatechin induces strong endothelium-independent relaxation of HIMA pre-contracted by phenylephrine whilst 4-AP- and margatoxin-sensitive KV channels, as well as BKCa and KATP channels, located in vascular smooth muscle, mediate this relaxation. In addition, it seems that (-)-epicatechin could inhibit influx of extracellular Ca(2+), interfere with intracellular Ca(2+) release and re-uptake by the sarcoplasmic reticulum.

The author documents difficulties that arose in the work of a team working in a residential setting providing 24 hour care for patients with repeated or long-term admissions, and the different, inter-related and mutually dependent aspects of this work. Issues that emerged included the difficult nature of work with this patient group, collaborative work in the team, management issues and models of care, i.e. active rehabilitation ideology. Staff encountered problems which were not unique to this team, and which have wider implications for other staff working in similar roles and contexts with a similar patient group.