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A prothrombin activator, named ‘basparin A,’ was isolated from the venom of the crotaline snake Bothrops asper, the species responsible for the majority of snakebite cases in Central America. It is an acidic (pI 5.4), 70 kDa, single chain P-III metalloproteinase comprising, in addition to the metalloproteinase domain, disintegrin-like, and high-cysteine domains. Basparin A is a glycoprotein displaying immunological cross-reactivity with BaH1, a P-III hemorrhagic metalloproteinase isolated from the same venom. It activates prothrombin through the formation of meizothrombin, without requiring additional cofactors; it is, therefore, a class A snake venom prothrombin activator. In contrast with most venom metalloproteinases, it does not degrade components of the extracellular matrix. Apart from its clotting activity, basparin A inhibits collagen-dependent platelet aggregation in vitro, an effect that does not depend on proteolytic activity. Clotting activity on human plasma is not abrogated by the plasma proteinase inhibitors α2 macroglobulin and murinoglobulin, whereas activity is completely inhibited by Costa Rican polyvalent (Crotalinae) anti-venom. Basparin A does not induce local tissue alterations, such as hemorrhage, myonecrosis, and edema, in mice. Moreover, it does not induce systemic hemorrhage, thrombocytopenia nor prolongation of the bleeding time following intravenous administration. At low doses, the only observed effect induced by basparin A, when injected intravenously or intramuscularly into mice, is defibrin(ogen)ation. At higher doses, intravenous administration resulted in sudden death due to numerous occluding thrombi in pulmonary vessels. Basparin A is likely to play an important role in the coagulopathy associated with B. asper envenoming. Universidad de Costa Rica/[741-A2-036]/UCR/Costa Rica Universidad de Costa Rica/741-A1-504]/UCR/Costa Rica Wellcome Trust/[062043]//Inglaterra International Foundation for Science/[2707-2]/IFS/Suecia UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP)

Endokardiyal elektroda bağlı gelişen triküspit yetmezliği klinik veya ekokardiyografik olarak yeterince bilinmemektedir ve önlenebilir iatrojenik bir hastalıktır. Ciddi vakalarda sağ ventrkül yetmezliği gelişebilmekte ve triküspit kapak cerrahisi gerekmektedir. Bu komplikasyonun, yaşlı popülasyonda artış olması ve bu cihazların yeteneklerinin genişlemesi nedeniyle kalıcı kalp pil ve ICD implantasyonunda artış nedeniyle gelecekte daha da önemli olması beklenmektedir. Elektrodla ilişkili sekonder gelişen TY'de, mekanizma kapakçıkların mekanik perforasyonu veya laserasyonu, kapakçıklarda skar oluşumu ve buna bağlı kapakçık hareketlerinde kıstlılık olması ya da sağ ventrikülün asenkron olarak aktif olması olabilir. PM ilişkili TY ciddi sağ kalp yetmezliğine neden olabilir fakat mortalite ile ilgili veriler eksiktir. Bu çalışmanın amacı, PPM, ICD ve KRT elektrodlarının triküspit kapak ve sağ kalp üzerindeki etkisini iki boyutlu ekokardiyografi ile değerlendirmektir. Bu amaçla DDD-PM, ICD ve KRT ihtiyacı olan hastalar çalışmaya alınmıştır. İlk ekokardiyografik değerlendirme PM/ICD ve KRT implantasyonu öncesi yapılmış ve implantasyon sonrası takip 1., 6., 12. aylarda yapılmıştır. Toplamda 41 hasta (31 erkek, 10 kadın; ortalama yaşları:63.6±12.2) çalışmaya dahil edilmiş ve hastalar ortalama 9 ay takip edilmiştir. Bazalde hastaların 8'inde (%19.5) minimal (0), 23'ünde (%56.1) hafif derecede ve 10'unda (%24,4) orta derecede TY bulunmaktadır. Bazalde TY olmayan hastalarda implantasyon sonrası %9.8 hastada hafif, %9.8 hastada orta derecede TY gelişmiştir. Hafif TY olan hastaların %41.5'inde orta, %7.3'ünde ciddi TY ve orta derece TY olan hastaların %19.5'inde ciddi TY gelişmiştir. Hastaların %70.8'inde TY'de 1 derece, %17.1'inde 2 derece artış görülmüştür. Elektrod implantasyonu sonrası bazalde hafif veya daha az TY olan hastaların %68.3'ünde hafif ve %7.3'ünde ciddi TY gelişmiştir. TY artışı açısından kalıcı PM/ICD ve KRT grupları arasında anlamlı bir fark izlenmemiştir(p>0.05). Triküspit yetersizliğinde akut dönemde artış olmazken, birinci ay kontroldan sonra artış görülmektedir. Sağ boşluklarda fonksiyon bozukluğu meydana gelmiştir fakat elektroda bağlı sağ kalp yetmezlik tablosu izlenmemiştir. Ayrıca sol ventrikül fonksiyon bozukluğu ve mitral yetersizliğinde artış izlenmiştir. Endocardial lead–induced tricuspid regurgitation has not been well recognized, either clinically or echocardiographically, and yet it is likely a preventable iatrogenic disease. In severe cases, it can lead to right ventricular failure and require tricuspid valve surgery. This complication will become increasingly important, because the numbers of permanent pacemakers and implantable cardioverter-defibrillators are expected to increase due to the aging population and the expanding capabilities of these devices. The mechanism may be mechanical perforation or laceration of leaflets, scarring and restriction of leaflets, or asynchronized activation of the right ventricle. Pacemaker-related TR might cause severe heart failure on the right side, but data regarding associated with mortality is lacking. The aim of this study was to assess the effect of trans-tricuspid placement of permanent pacemaker (PPM), implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT) leads on tricuspid valve and right sided heart function by two-dimensional echocardiography. Patients who required dual-chamber pacemakers, ICD and CRT were enrolled in the study. Initial echocardiography was performed before PPM/ICD and CRT implantation and re-evaluation by echocardiography was performed in 1'th ,6'th and 12'th month after implant. A total of 41 patients (31 male,10 female; mean age: 63.6 ±12.2 years) were included in the study, and patients were followed up for an average of 9 months. Echocardiography results demonstrated an absent of tricuspid regurgitation (TR) in 8 (19.5%), mild in 23 (56.1%) and moderate in 10 (24.4%) patients before PPM/ICD and CRT implantation. Patients with baseline absent TR of 8 (19.5% ) developed abnormal TR (9.8% mild , 9.8% moderate) after implant. Patients with baseline mild TR of 23 (56.1%) developed abnormal TR ( 41.5% moderate, 7.3% severe) after implant. Patients with baseline moderate TR of 10 (24.4%) developed abnormal TR (19.5% severe) after implant. TR worsened by 1 grade in 70.8% and 2 grade in 17.1% after implant. After lead implantation, abnormal TR developed in 68.3% and severe TR developed in 7.3% of patients with baseline mild TR or less. In overall, there is no significant difference in the TR worsening between PPMs/ICDs and CRTs groups (P˃0.05). Our results show that implantation of permanent transvenous right ventricular electrodes is not in general associated with an acute worsening of TR. The presence of new significant TR shortly after electrode implantation have not been observed in our patients; However, worsening of TR is observed following first month. The dysfunction the right side of the heart was considered but none of the patients developed symptoms of right ventricular failure related to pacing effect on the tricuspid valves. Transvenous right ventricular electrodes are associated with left ventricular dysfunction and mitral regurgitation. 99

We determined the neutralizing activity of 12 ethanolic extracts of plants against the edema-forming, defibrinating and coagulant effects of Bothrops asper venom in Swiss Webster mice. The material used consisted of the leaves and branches of Bixa orellana (Bixaceae), Ficus nymphaeifolia (Moraceae), Struthanthus orbicularis (Loranthaceae) and Gonzalagunia panamensis (Rubiaceae); the stem barks of Brownea rosademonte (Caesalpiniaceae) and Tabebuia rosea (Bignoniaceae); the whole plant of Pleopeltis percussa (Polypodiaceae) and Trichomanes elegans (Hymenophyllaceae); rhizomes of Renealmia alpinia (Zingiberaceae), Heliconia curtispatha (Heliconiaceae) and Dracontium croatii (Araceae), and the ripe fruit of Citrus limon (Rutaceae). After preincubation of varying amounts of each extract with either 1.0 microg venom for the edema-forming effect or 2.0 microg venom for the defibrinating effect, the mixture was injected subcutaneously (sc) into the right foot pad or intravenously into the tail, respectively, to groups of four mice (18-20 g). All extracts (6.2-200 microg/mouse) partially neutralized the edema-forming activity of venom in a dose-dependent manner (58-76% inhibition), with B. orellana, S. orbicularis, G. panamensis, B. rosademonte, and D. croatii showing the highest effect. Ten extracts (3.9-2000 microg/mouse) also showed 100% neutralizing ability against the defibrinating effect of venom, and nine prolonged the coagulation time induced by the venom. When the extracts were administered either before or after venom injection, the neutralization of the edema-forming effect was lower than 40% for all extracts, and none of them neutralized the defibrinating effect of venom. When they were administered in situ (sc at the same site 5 min after venom injection), the neutralization of edema increased for six extracts, reaching levels up to 64% for C. limon.

IV ÖZET Vitronektin trombositlerin yapışmasından sorumlu olan kararlı bir glikoproteindir. Plazmadaki vitronektinin 1 mi kandaki miktarı %40'ın altına düştüğünde protrombin zamanı uzar ve bu olay defibrinasyonla sonuçlanır. Defibrinasyon (fibrin monomerlerinin oluşumu) sendromlu hastaların eritrosit ve lökosit sayıları artarken trombosit sayılarında azalış gözlenir. Bu çalışmada defibrinasyon sendromlu hastaların vitronektin düzeylerinin saptanması amacıyla kontrol gurubu olarak sağlıklı 14 birey ve 46 hastanın serum ve trombositleri ile çalışılmıştır. Kontrol gurubunda eritrosit sayısı 4,60-6,20x1 06/mm3 iken hastalarda eritrosit sayıları 6,2-7,1x1 06/mm3 olarak normal değerler üzerinde saptanmış olup vitronektin miktarları 0,1-0,037 mg/ml olarak azalmıştır. Defibrinasyon sendromlu hastalar 3 guruba ayrılarak çalışılmış ve I. gurubu trombosit sayıları normalden düşük olan (trombositopenili) 23, II. gurubu lökositoz sayısı normalden yüksek saptanan (lökositozlu) 13 ve III. gurubu ise küçük trombositli 10 hasta oluşturmuştur. Guruplar kontrollerle kıyaslandığında; lökositozlularda beklendiği gibi lökosit sayısı yüksek (11,1- 11,9x103/mm3) olarak saptanırken diğer iki grupta bu değerler kontrol değerlere yakın bulunmuştur. Trombosit sayıları ise her üç gurupta düşmüştür. Çalışmanın ikinci aşamasında bu hastalardaki vitronektin düzeyleri araştırılmıştır. I. gurupta 0,043-0,097 mg/ml. II. gurupta 0,021-0,09 mg/ml. ve III. gurupta 0,035-0,1 mg/ml. arasında bulunan vitronektin düzeyleri kontrollerdeki değerler (0,09-0,37 mg/ml) ile kıyaslandığında düşük bulunmaktadır. Daha sonra kontrol ve hasta serumlarından Heparin sefaroz 4B affinite kromatografisi iki kez uygulanarak vitronektin %100'e yakın saflaştırılmıştır. Saflaştırılan vitronektin %10'luk SDS-Poliakrilamid jel elektroforezinde (SDS-PAGE) yürütülmüş ve defibrinasyon sendromlu hastalarda parçalanma ürünü olan 45 kDa'luk ikinci bir bant gösterilmiştir, öte yandan sağlıklı kişilerin trombositlerinden elde edilen vitronektinin moleküler ağırlığı 65 kDa olarak tek bant halinde saptanmıştır. ABSTRACT Vitronectin is a stabil glycoprotein responsible for adhesion of platellets. When the vitronectin level in 1 ml blood drops below 40%, prothrombin time extends and this results in defibrination. While red blood cell and white blood cell counts of defibrination syndrome patients increase, platellet counts decrease. In this study, in order to establish the vitronectin level of defibrination (fibrin monomer accumulation) syndrome patients, 14 healthy individuals and 46 patients were studied with their serum and platellet. Red blood cell counts of patients determined above the normal level as 6,2-7, 1x106/mm3 whilst vitronectin quantities decreased to 0,1-0,037 mg/ml. Defibrination syndrome patients were studied by dividing into three groups, I. group with 23 thrombocitopenia (platellet count is low of normal), II. group with 13 leucocitosis (white blood cell is high of normal) and III. group with 10 patients with small platellet. When compared with control, white blood cell counts of leucocitosis determined high as (11,1-11,9x103/mm3) and their counts were found near to control counts for other two groups. Platellet counts were decreased in all three groups. In the second part of the study vitronectin levels of these patients were investigated. Vitronectin levels found between 0,043-0,097 mg/ml in Group I, 0,021-0,09 mg/ml in Group II and 0,035-0,1 mg/ml in Group III were found to below when compared with control group levels (0,09-0,37 mg/ml). Then, the vitronectin from control and patients were purified almost 100% with the two times application of Heparin sepharose 4B affinity chromatography. Purified vitronectin was run in 10% SDS-Polyacrylamid gel electrophoresis (SDS- PAGE) and degradation product of 45 kDa second band was detected from defibrination syndrome patients. In contrast, molecular weight of vitronectin from platellet of healty persons was found 65 kDa as a single band. 51