Spectroscopic and theoretical investigation of the [Fe2(bdt)(CO)6] hydrogenase mimic and some catalyst intermediates.

In [Fe-Fe] hydrogenase mimic systems the ene-1,2-dithiolene ligands play an important role in the stabilisation of the redox-active metal center. This is demonstrated by the benzenedithiolene (bdt) analogue, featuring six terminal carbonyl ligands connected to a di-iron metal center, i.e. [Fe2(bdt)(CO)6]. Here we present a combined experimental and theoretical study that elucidates key intermediates [Fe2(bdt)(CO)6]1- and [Fe2(bdt)(µ-CO)(CO)5]2- in the electrocatalytic production of dihydrogen. A DFT study shows that [Fe2(bdt)(CO)6]1- is the kinetic product after the first one electron reduction, while the previously proposed bridging intermediate species [Fe2(bdt)(µ-CO)(CO)5]1- is kinetically inaccessible. The doubly reduced species [Fe2(bdt)(µ-CO)(CO)5]2- was for the first time structurally characterized using EXAFS. XANES analysis confirms the existence of reduced iron zero species and confirms the distorted geometry that was suggested by the DFT calculations. Combining IR, UV-vis and XAS spectroscopic results with TD-DFT and FEFF calculations enabled us to assign the key-intermediate [Fe2(bdt)(CO)6]2-. This study emphasizes the strengths of combining computational chemistry with advanced spectroscopy techniques.

Intraoperative and postoperative risk factors for anastomotic leakage and pneumonia after esophagectomy for cancer.

Morbidity and mortality after esophagectomy are often related to anastomotic leakage or pneumonia. This study aimed to assess the relationship of intraoperative and postoperative vital parameters with anastomotic leakage and pneumonia after esophagectomy. Consecutive patients who underwent transthoracic esophagectomy with cervical anastomosis for esophageal cancer from January 2012 to December 2013 were analyzed. Univariable and multivariable logistic regression analyses were used to determine potential associations of hemodynamic and respiratory parameters with anastomotic leakage or pneumonia. From a total of 82 included patients, 19 (23%) developed anastomotic leakage and 31 (38%) experienced pneumonia. The single independent factor associated with an increased risk of anastomotic leakage in multivariable analysis included a lower minimum intraoperative pH (OR 0.85, 95% CI 0.77-0.94). An increased risk of pneumonia was associated with a lower mean arterial pressure (MAP) in the first 12 hours after surgery (OR 0.93, 95% CI 0.86-0.99) and a higher maximum intraoperative pH (OR 1.14, 95% CI 1.02-1.27). Interestingly, no differences were noted for the MAP and inotrope requirement between patients with and without anastomotic leakage. A lower minimum intraoperative pH (below 7.25) is associated with an increased risk of anastomotic leakage after esophagectomy, whereas a lower postoperative average MAP (below 83 mmHg) and a higher intraoperative pH (above 7.34) increase the risk of postoperative pneumonia. These parameters indicate the importance of setting strict perioperative goals to be protected intensively.

Estimating the risk of dengue transmission from Dutch blood donors travelling to Suriname and the Dutch Caribbean.

BACKGROUND: The risk of dengue transmitted by travellers is known. Methods to estimate the transmission by transfusion (TT) risk from blood donors travelling to risk areas are available, for instance, the European Up-Front Risk Assessment Tool (EUFRAT). This study aimed to validate the estimated risk from travelling donors obtained from EUFRAT. METHODS: Surveillance data on notified dengue cases in Suriname and the Dutch Caribbean islands (Aruba, Curaçao, St. Maarten, Bonaire, St. Eustatius and Saba) in 2001-2011 was used to calculate local incidence rates. Information on travel and donation behaviour of Dutch donors was collected. With the EUFRAT model, the TT risks from Dutch travelling donors were calculated. Model estimates were compared with the number of infections in Dutch travellers found by laboratory tests in the Netherlands. RESULTS: The expected cumulative number of donors becoming infected during travels to Suriname and the Dutch Caribbean from 2001 to 2011 was estimated at 5 (95% CI, 2-11) and 86 (45-179), respectively. The infection risk inferred from the laboratory-based study was 19 (9-61) and 28 (14-92). Given the independence of the data sources, these estimates are remarkably close. The model estimated that 0·02 (0·001-0·06) and 0·40 (0·01-1·4) recipients would have been infected by these travelling donors. CONCLUSIONS: The EUFRAT model provided an estimate close to actual observed number of dengue infections. The dengue TT risk among Dutch travelling donors can be estimated using basic transmission, travel and donation information. The TT risk from Dutch donors travelling to Suriname and the Dutch Caribbean is small.

Non-adherence to antimicrobial treatment guidelines results in more broad-spectrum but not more appropriate therapy.

Mortality in patients admitted with sepsis is high and the increasing incidence of infections with multiresistant bacteria is a worldwide problem. Many hospitals have local antimicrobial guidelines to assure effective treatment and limit the use of broad-spectrum antibiotics, thereby reducing the selection of resistant bacteria. We evaluated adherence to the antimicrobial treatment guidelines of our hospital in patients presenting to the emergency department (ED) with sepsis and assessed the in vitro susceptibility of isolated pathogens to the guideline-recommended treatment and the prescribed treatment. We included all adult patients with a known or suspected infection and two or more extended systemic inflammatory response syndrome (SIRS) criteria. Patients who did not receive antimicrobial treatment, presented with infections not included in the guidelines, or had more than one possible focus of infection were excluded. A total of 276 ED visits (262 patients) were included. Guideline-concordant treatment was prescribed in 168 visits (61%). In the case of guideline-disconcordant treatment, 87% was more broad-spectrum than guideline-recommended treatment. A microbiological diagnosis was established in 96 visits (35%). The susceptibility of the pathogens isolated from patients treated with guideline-concordant treatment (n=68) and guideline-disconcordant treatment (n=28) to guideline-recommended treatment (91% versus 89%) and to prescribed treatment (91% versus 93%) was similar (p=0.77 and p=0.79, respectively). In conclusion, non-adherence to the guidelines occurred frequently and resulted in more broad-spectrum empirical therapy. This did not result in a higher rate of susceptibility of the isolated pathogens to the prescribed empirical therapy.

Peripheral site ligand-oxime conjugates: A novel concept towards reactivation of nerve agent-inhibited human acetylcholinesterase.

A conceptually novel approach to the design of reactivators of nerve agent-inhibited acetylcholinesterase (AChE) is presented. The concept comprises the linkage of a peripheral site ligand via a spacer to a reactivating moiety with the eventual goal to develop non-ionic reactivators with sufficient affinity for AChE to induce reactivation and potentially improved blood-brain barrier penetration. Herein, the first step towards that goal-the synthesis and biological evaluation of a peripheral site ligand conjugated to a charged pyridinium oxime is discussed. It was found, that the introduction of the peripheral site ligand not only increased affinity of the construct for AChE but also enhanced reactivation of nerve agent-inhibited AChE.

Travel time from home to hospital and adverse perinatal outcomes in women at term in the Netherlands.

OBJECTIVE: To study the effect of travel time, at the start or during labour, from home to hospital on mortality and adverse outcomes in pregnant women at term in primary and secondary care. DESIGN: Population-based cohort study from 2000 up to and including 2006. SETTING: The Netherlands Perinatal Registry. POPULATION: A total of 751,926 singleton term hospital births. METHODS: We assessed the impact of travel time by car, calculated from the postal code of the woman's residence to the 99 maternity units, on neonatal outcome. Logistic regression modelling with adjustments for gestational age, maternal age, parity, ethnicity, socio-economic status, urbanisation, tertiary care centres and volume of the hospital was used. MAIN OUTCOME MEASURES: Mortality (intrapartum, and early and late neonatal mortality) and adverse neonatal outcomes (mortality, Apgar <4 and/or admission to a neonatal intensive care unit). RESULTS: The mortality was 1.5 per 1000 births, and adverse outcomes occurred in 6.0 per 1000 births. There was a positive relationship between longer travel time (≥20 minutes) and total mortality (OR 1.17, 95% CI 1.002-1.36), neonatal mortality within 24 hours (OR 1.51, 95% CI 1.13-2.02) and with adverse outcomes (OR 1.27, 95% CI 1.17-1.38). In addition to travel time, both delivery at 37 weeks of gestation (OR 2.23, 95% CI 1.81-2.73) or 41 weeks of gestation (OR 1.52, 95% CI 1.29-1.80) increased the risk of mortality. CONCLUSIONS: A travel time from home to hospital of 20 minutes or more by car is associated with an increased risk of mortality and adverse outcomes in women at term in the Netherlands. These findings should be considered in plans for the centralisation of obstetric care.

Epidemiology, surveillance and control of infectious diseases in the European overseas countries and territories, 2011.

The 25 European overseas countries and territories (OCTs) are closely associated with the European Union (EU) through the four related UE Member States: Denmark, France, the Netherlands and the United Kingdom. In 2008 and 2009, these four EU Member States, in association with the European Centre for Disease Prevention and Control (ECDC), reviewed the OCTs' needs, with the objectives of documenting their capacity to prevent and respond to infectious diseases outbreaks, and identifying deficiencies. This Euroroundup is based on the review's main findings, and presents an overview of the OCTs' geography and epidemiology, briefly introduces the legal basis on which they are linked to the EU and describes the surveillance and infectious disease response systems. As a result of their diversity the OCTs have heterogeneous epidemiological profiles. A common factor, however, is that the main burden of disease is non-communicable. Nevertheless, OCTs remain vulnerable to infectious diseases outbreaks. Their capacity for surveillance, early detection and response to such outbreaks is generally limited, with laboratory capacity issues and lack of human resources. Avenues for capacity strengthening should be explored by the OCTs and the related EU Member States, in collaboration with ECDC and regional public health networks where these exist.

[Vulnerable groups for COVID-19 control measures]. / COVID-19: over welke mensen maken we ons extra zorgen?

The COVID-19 outbreak and its control measures affect the life, livelihood and way of life of many. Vulnerable groups may require different information, practical, emotional and financial support, depending on their specific vulnerabilities. Early reports for the Dutch government on the impacts of COVID-19 control measures were used for drafting a preliminary overview of vulnerable groups and their vulnerabilities. The overview may serve as first step towards a scoping review and be of use in the professional discussion for targeting and finetuning the support to the groups most in need.

Electronic characterization of redox (non)-innocent Fe2S2 reference systems: a multi K-edge X-ray spectroscopic study.

Di-iron dithiolate hydrogenase model complexes are promising systems for electrocatalytic production of dihydrogen and have therefore been spectroscopically and theoretically investigated in this study. The direct effect of ligand substitution on the redox activity of the complex is examined. In order to understand and eventually optimize such systems, we characterised both metal and ligand in detail, using element specific X-ray absorption Fe- and S-K edge XAS. The (electronic) structure of three different [Fe2S2] hydrogenase systems in their non-reduced state was investigated. The effect of one- and two-electron reduction on the (electronic) structure was subsequently investigated. The S K-edge XAS spectra proved to be sensitive to delocalization of the electron density into the aromatic ring. The earlier postulated charge and spin localization in these complexes could now be measured directly using XANES. Moreover, the electron density (from S K-edge XANES) could be directly correlated to the Fe-CO bond length (from Fe K-edge EXAFS), which are in turn both related to the reported catalytic activity of these complexes. The delocalization of the electron density into the conjugated π-system of the aromatic moieties lowers the basicity of the diiron core and since protonation occurs at the diiron (as a rate determining step), lowering the basicity decreases the extent of protonation and consequently the catalytic activity.

Anonymous non-response analysis in the ABCD cohort study enabled by probabilistic record linkage.

Selective non-response is an important threat to study validity as it can lead to selection bias. The Amsterdam Born Children and their Development study (ABCD-study) is a large cohort study addressing the relationship between life style, psychological conditions, nutrition and sociodemographic background of pregnant women and their children's health. Possible selective non-response and selection bias in the ABCD-study were analysed using national perinatal registry data. ABCD-study data were linked with national perinatal registry data by probabilistic medical record linkage techniques. Differences in the prevalence of relevant risk factors (sociodemographic and care-related factors) and birth outcomes between respondents and non-respondents were tested using Pearson chi-squared tests. Selection bias (i.e. bias in the association between risk factors and specific outcomes) was analysed by regression analysis with and without adjustment for participation status. The ABCD non-respondents were significantly younger, more often non-western, and more often multiparae. Non-respondents entered antenatal care later, were more often under supervision of an obstetrician and had a spontaneous delivery more often. Non-response however, was not significantly associated with preterm birth (odds ratio 1.10; 95% CI 0.93, 1.29) or low birthweight (odds ratio 1.16; 95% CI 0.98, 1.37) after adjustment for sociodemographic risk factors. The associations found between risk factors and adverse pregnancy outcomes were similar for respondents and non-respondents. Anonymised record linkage of cohort study data with national registry data indicated that selective non-response was present in the ABCD-study, but selection bias was acceptably low and did not influence the main study questions.

Indicators for intervention during the expulsive second-stage arrest of labour.

OBJECTIVE: To identify antepartum and intrapartum indicators of obstetric interventions during the expulsive second-stage arrest of labour. DESIGN: Retrospective cohort study. SETTING: The Netherlands. POPULATION: A cohort of 389,086 women with singleton, cephalic, term, live-birth deliveries from 2002 to 2004 who had entered the expulsive second stage of labour. Of all these deliveries, 37,899 (9.7%) were complicated by expulsive second-stage arrest of labour. Women with a prior Caesarean section or women undergoing an elective Caesarean section were excluded. METHODS: All deliveries in the Netherlands from 2002 to 2004 were registered in the Netherlands Perinatal Registry, which contains the linked and validated data of three databases. Uni- and multivariable logistic regression analyses were performed. MAIN OUTCOME MEASURES: Ante- and intrapartum indicators for interventions during expulsive second-stage arrest of labour. RESULTS: Primiparous delivery was the most important antepartum indicator for intervention during expulsive second-stage arrest. Using multivariable analysis the following antepartum indicators were associated with intervention for expulsive second-stage arrest of primiparous labour: maternal age, gestational age, diabetes, hypertension and labour induction. Prominent intrapartum indicators for primiparous deliveries were fetal head position and oxytocin augmentation. CONCLUSION: Multiple significant antepartum and intrapartum indicators associated with intervention for expulsive second-stage arrest of labour were identified in this large retrospective study. Prominent were the associations of parity, maternal age and fetal head position with expulsive second-stage arrest. The identified factors should be further evaluated in prospective studies that aim to develop prediction models.

Local structure of reaction intermediates probed by time-resolved x-ray absorption near edge structure spectroscopy.

A method for the analysis of time-resolved x-ray absorption near edge structure (XANES) spectra is proposed. It combines principal component analysis of the series of experimental spectra, multidimensional interpolation of theoretical XANES as a function of structural parameters, and ab initio XANES calculations. It allows to determine the values of structural parameters for intermediates of chemical reactions and the concentrations of different states as a function of time. This approach is tested using numerically generated data and its possibilities and limitations are discussed. The application of this method to a reaction with methylrhenium trioxide catalyst in solution, for which experimental data were measured using stopped-flow energy-dispersive x-ray absorption spectroscopy technique, is demonstrated. Possibilities and limitations of this experimental technique are also discussed.

Medieval women's early involvement in manuscript production suggested by lapis lazuli identification in dental calculus.

During the European Middle Ages, the opening of long-distance Asian trade routes introduced exotic goods, including ultramarine, a brilliant blue pigment produced from lapis lazuli stone mined only in Afghanistan. Rare and as expensive as gold, this pigment transformed the European color palette, but little is known about its early trade or use. Here, we report the discovery of lapis lazuli pigment preserved in the dental calculus of a religious woman in Germany radiocarbon-dated to the 11th or early 12th century. The early use of this pigment by a religious woman challenges widespread assumptions about its limited availability in medieval Europe and the gendered production of illuminated texts.

An efficient validation method of probabilistic record linkage including readmissions and twins.

OBJECTIVE: To describe an efficient, generalizable approach to validate probabilistic record linkage results, in particular by a model-guided detection of linking errors, and to apply this approach to validate linkage of admissions of newborns. METHODS: Our double-blind validation procedure consisted of three steps: sample selection, data collection and data analysis. The linked Dutch national newborn admission registry contained 30,082 records for 2001 including readmissions (7.4%) and twins (9.7%). A highly informative sample was selected from the linked file by oversampling uncertain links based on model-derived linking weight. Four hundred and eight fax forms with minimal registry information (admissions of 191 children) were sent out to different pediatric units. The pediatricians were asked to create a short detailed patient history from independent sources. The linkage status and additional record data was validated against this external information. RESULTS: Response rate was 97% (395/408 faxes). Accuracy of the linkage of singleton admissions was high: except for some expected errors in the uncertain area (0.02% of record pairs), linkage was error-free. Validation of multiple birth readmissions showed 37% linkage errors due to low data quality of the multiple birth variables. The quality of the linked registry file was still high; only 1.7% of the children were from a multiple birth with multiple admissions, resulting in less than 1% linking error. CONCLUSIONS: Our external validation procedure of record linkage was feasible, efficient, and informative about identifying the source of the errors.

[Perinatal mortality in The Netherlands 2000-2006; risk factors and risk selection]. / Perinatale sterfte in Nederland gedurende 2000-2006; risicofactoren en risicoselectie.

OBJECTIVE: To gain insight in recent perinatal mortality figures in The Netherlands and their relation with important risk factors, risk groups and risk selection among pregnant women. DESIGN: Retrospective cohort study. METHOD: The National Obstetrical Registrations and the National Neonatal Registration were linked into The Netherlands Perinatal Registry to prevent double counting. From this database, data on 1.3 million births in the years 2000-2006 were analysed with perinatal mortality as outcome measure. RESULTS: In 2006, perinatal mortality was 9.8 per 1000 total births (foetal mortality 6.8 per 1000 births and early neonatal mortality 3.1 per 1000 live births). Maternal age (< 20 and > or = 40 years) and high multiparity (> or = 4) were risk factors for perinatal mortality but showed low prevalence (< 3%). Non-Western ethnicity and nulliparity were important risk factors (relative risk of both 1.4) with a prevalence of 16% and 46%, respectively. The very preterm births (22.0-25.6 weeks of gestation) provided 29% ofall perinatal mortality with a mortality risk of 935 per 1000 births. Full-term births (> or = 37.0 weeks) accounted for 26% of all perinatal mortality with a mortality risk of 2.8 per 1000 births. In the full-term born group, perinatal mortality was 0.4 per 1000 births in home births, 2.7 per 1000 births in outpatient clinics and 4.5 per 1000 births when the women were referred to the gynaecologist before start of labour. CONCLUSION: At a population level, low or high maternal age and high parity are less important risk factors than expected. More detailed research is indicated into the mortality ofvery preterm births but also offull-term born children.

Reactivation of vanadium bromoperoxidase; inhibition by metallofluoric compounds.

The effect of phosphate analogs (pyrophosphate, aluminofluoride and beryllofluoride complexes) on the reactivation of apobromoperoxidase by vanadate was studied. P2O7(4-) inhibited the reactivation in the millimolar range. Of the different aluminofluoride complexes, only AlF4- was inhibitory. In addition, BeF4(2-) also appeared to bind with high affinity to the apobromoperoxidase, thus inhibiting the reactivation very strongly. The inhibition observed supports a mechanism in which the fluorometallic complexes act as analogs of vanadate and bind accordingly to the apobromoperoxidase.

Some structural aspects of vanadium bromoperoxidase from Ascophyllum nodosum.

The stability of the vanadium containing bromoperoxidase from Ascophyllum nodosum was studied. The enzyme was very resistant against chemical denaturation. Denaturation did not occur upon incubation in 4 M guanidine hydrochloride. Circular dichroism measurements showed that the secondary structure was not affected upon incubation in 4% sodium dodecyl sulphate. The sedimentation coefficient and the molecular mass, determined by ultracentrifugation were 6.96 S and 97 kDa, respectively, indicating a very compact molecule. The protein molecule contained 16 cysteine residues, all of which participated in the formation of disulfide bridges. Circular dichroism-measurements in the far ultraviolet region revealed that the protein consisted of a large amount of alpha-helix (74%), and no beta-pleated sheet. The dissociation constant of the apoprotein vanadium-complex was 55 nM (at pH 8.5), and rapidly increased at lower pH. The data suggest that the protonation of a group with a pKa higher than 8.5 prevents the binding of vanadate. Structural analogues of vanadate (phosphate and arsenate) were competitive inhibitors with respect to the reconstitution of the bromoperoxidase. The inhibition constants were 60 and 120 microM for phosphate and arsenate, respectively. The binding of hydrogen peroxide to the enzyme was visualized by optical spectroscopy. Upon addition of H2O2 the optical absorption spectrum showed a small, but significant, decrease in absorption in the 315 nm region, which was restored upon addition of bromide, or by allowing the solution to stand for several hours. These changes are ascribed to the formation of a stable enzyme-peroxo-intermediate, in line with a previous analysis of the steady-state kinetics.

Activation of the genes for variant surface glycoproteins 117 and 118 in Trypanosoma brucei.

We have studied the activation of genes for VSGs (variant surface glycoproteins) in Trypanosoma brucei (strain 427) in six independently isolated trypanosome clones; four expressing the gene for VSG 118 and two the gene for VSG 117. In all cases, gene activation is brought about by a duplicative transposition of the gene to an expression site located close to the end of a chromosome. The DNA segments flanking the expression-linked extra gene copy are nearly devoid of restriction enzyme recognition sites and their lengths vary by more than 10,000 base-pairs among different variants. From the correspondence of five upstream restriction sites, we conclude that the same expression site is used in each case. The transposition event does not lead to detectable alterations in the sequence coding for the mature protein. All restriction enzyme recognition sites detected in the basic copy gene are present also in each of the expression-linked copies. This argues against the introduction of mutations by an error-prone polymerase during the synthesis of the expression-linked copy. In five of the six variants, the 3' end of the VSG messenger RNA differs from that of the corresponding basic copy gene by multiple point mutations, insertions and deletions, starting at positions varying from 16 nucleotides upstream to 113 downstream of the last codon of the mature protein. We attribute this end alteration to the recombination process that introduces the gene into the expression site. We confirm that the expression-linked gene copy is more sensitive to DNase I than the corresponding basic copy gene. This appears to be due to its activated state and not to its location near the end of a chromosome, because another basic copy VSG gene permanently located near a chromosome end is not hypersensitive to DNase I. The mature transcripts of the 117 and 118 genes all possess the same 35 nucleotides at their 5' ends and these are not encoded contiguously in the basic gene copies with the remainder of the mRNAs. This extends our previous conclusion, that mature VSG mRNAs are formed by a splicing process in which the 35-nucleotide sequence encoded in the expression site is fused onto the body of the mRNA contributed by the transposed gene.

Structural aspects of antioxidant activity of flavonoids.

Flavonoids, a group of naturally occurring antioxidants and iron chelators, might be used as cardioprotective agents in doxorubicin-induced cardiotoxicity, which is believed to be caused by the formation of oxygen free radicals. To investigate the underlying molecular mechanism, we tested a large group of flavonoids from all major structural subclasses on their ability to inhibit doxorubicin (enzymatically)-induced and Fe2+/ascorbate (nonenzymatically)-induced microsomal lipid peroxidation (LPO) and to chelate Fe2+. In addition, we measured half peak oxidation potentials (Ep/2). LPO inhibition data gave a good qualitative correlation with the oxidation potentials. Most flavonoids tested chelated Fe2+, but there were large differences in the chelating capacity. For good scavenging activity, a catechol moiety on ring B is required. The 3-OH moiety can function as a chelation site and can also be oxidized. The 3-OH group in combination with a C2 C3 double bond, increases the scavenging activity. Fe2+ chelation only plays a role in the LPO inhibition by less active scavengers. Chelation can then raise the activity to the level of the most active scavengers, possibly by site-specific scavenging. It can be concluded that Ep/2 values and iron chelating activity can almost completely describe the LPO inhibiting behaviour of the flavonoids.

Pre-clinical pharmacological profile of the novel glycoconjugate Org 36764 with both factor Xa and thrombin (IIa) inhibitory activities.

Org 36764, is an antithrombin III (AT) and thrombin binding carbohydrate, which accelerates the inactivation of both factor Xa and thrombin by AT. It displays in buffer an anti-Xa and anti-thrombin activity of 415 and 2 U/mg, respectively, compared to 172 and 114 U/mg, respectively, for unfractionated heparin (UFH), Org 36764 does not cross-react with HIT (heparin induced thrombocytopenia) antibodies and is not neutralised by PF4. In experimental models in rats, on a molar basis. Org 36764 was more active than the pentasaccharide SanOrg 34006 (= AT binding domain of Org 36764) in arterial thrombosis, but both were equally active in venous thrombosis. In arterial thrombosis following endothelial damage by ferric chloride, Org 36764 was more active than the LMW heparin enoxaparin and SanOrg 34006 and similar active to UFH. At AT saturating doses the bleeding enhancement was not more than 3.5 times the control value. Org 36764 was more active in suppressing in vivo thrombus formation on stents than UFH. SanOrg 34006 or a combination of ticlopidine and aspirin. The results indicate that the novel drug Org 36764 is a drug with antithrombotic potential against venous and arterial thrombosis.