bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pure subtype systems
Authors: Hutchins DeLesley S. 
Published: January 2010

This paper introduces a new approach to type theory called
pure subtype systems
. Pure subtype systems differ from traditional approaches to type theory (such as pure type systems) because the theory is based on subtyping, rather than typing. Proper types and typing are completely absent from the theory; the subtype relation is defined directly over objects. The traditional typing relation is shown to be a special case of subtyping, so the loss of types comes without any loss of generality.

Pure subtype systems provide a uniform framework which seamlessly integrates subtyping with dependent and singleton types. The framework was designed as a theoretical foundation for several problems of practical interest, including mixin modules, virtual classes, and feature-oriented programming.
The cost of using pure subtype systems is the complexity of the meta-theory. We formulate the subtype relation as an abstract reduction system, and show that the theory is sound if the underlying reductions commute. We are able to show that the reductions commute locally, but have thus far been unable to show that they commute globally. Although the proof is incomplete, it is ``close enough'' to rule out obvious counter-examples. We present it as an open problem in type theory.
Programming with angelic nondeterminism
Authors: Bodik Rastislav , Chandra Satish , Galenson Joel , Kimelman Doug , Tung Nicholas , Barman Shaon , Rodarmor Casey 
Published: January 2010

Angelic nondeterminism can play an important role in program development. It simplifies specifications, for example in deriving programs with a refinement calculus; it is the formal basis of regular expressions; and Floyd relied on it to concisely express backtracking algorithms such as N-queens.
We show that angelic nondeterminism is also useful during the development of deterministic programs. The semantics of our angelic operator are the same as Floyd's but we use it as a substitute for yet-to-be-written deterministic code; the final program is fully deterministic. The angelic operator divines a value that makes the program meet its specification, if possible. Because the operator is executable, it allows the programmer to test incomplete programs: if a program has no safe execution, it is already incorrect; if a program does have a safe execution, the execution may reveal an implementation strategy to the programmer.
We introduce refinement-based angelic programming, describe our embedding of angelic operators into Scala, report on our implementation with bounded model checking, and describe our experience with two case studies. In one of the studies, we use angelic operators to modularize the Deutsch-Schorr-Waite (DSW) algorithm. The modularization is performed with the notion of a parasitic stack, whose incomplete specification was instantiated for DSW with angelic nondeterminism.
Monads in action
Authors: Filinski Andrzej 
Published: January 2010

In functional programming, monadic characterizations of computational effects are normally understood denotationally: they describe how an effectful program can be systematically expanded or translated into a larger, pure program, which can then be evaluated according to an effect-free semantics. Any effect-specific operations expressible in the monad are also given purely functional definitions, but these definitions are only directly executable in the context of an already translated program. This approach thus takes an inherently Church-style view of effects: the nominal meaning of every effectful term in the program depends crucially on its type.
We present here a complementary, operational view of monadic effects, in which an effect definition directly induces an imperative behavior of the new operations expressible in the monad. This behavior is formalized as additional operational rules for only the new constructs; it does not require any structural changes to the evaluation judgment. Specifically, we give a small-step operational semantics of a prototypical functional language supporting programmer-definable, layered effects, and show how this semantics naturally supports reasoning by familiar syntactic techniques, such as showing soundness of a Curry-style effect-type system by the progress+preservation method.
Clot formation of neonates tested by thromboelastography correlates with gestational age
Authors: Strauss Tzipi , Levy-Shraga Yael , Ravid Bruria , Schushan-Eisen Irit , Maayan-Metzger Ayala , Kuint Jacob , Kenet Gili 
Published: January 2010

SummaryEvaluation of clot formation in neonates is troublesome. Our aim was to investigate cord blood clot formation of pre-term versus full-term infants and adults, using rotating thromboelastogram (ROTEM®, Pentafarm, Munich, Germany). ROTEM was investigated in cord blood of 184 full-term and 47 pre-term infants. Measurements of the clotting time (CT), clot formation time (CFT) and maximal clot firmness (MCF) were obtained in order to asses reference values for this age group, and compare between full-term and pre-term neonates and compared to adult controls. For each infant demographic information and data regarding pregnancy and delivery were gathered. Infants were prospectively followed until discharge. CT and CFT were significantly shorter among pre-term and term infants as compared to adults [median CT: 185, 194, 293 seconds respectively, p≤0.001, CFT: 80, 76, 103 seconds respectively, p≤0.001). MCF was lower in pre-term and term as compared to adults (p≤0.001) with significantly lower values in pre-term as compared to full-term neonates (p=0.004). Clotting time and MCF correlated with gestational age (R=0.132, p=0.045, R= 0.259, p<0.001, respectively). No association was found between any ROTEM values and the occurrence of post-natal complications in infants of our study group. This is the first study assessing clot formation by ROTEM in pre-term infants. Clot formation parameters of term and premature infants correlated with gestational age. The predictive value of clot formation tests in neonates deserves further attention.
Lower versus standard intensity oral anticoagulant therapy (OAT) in elderly warfarin-experienced patients with non-valvular atrial fibrillation
Authors: Cucchini Umberto , Denas Gentian , Davidson Bruce , Marzot Filippo , Jose Seena Padayattil , Iliceto Sabino , Pengo Vittorio 
Published: January 2010

SummaryIt has been observed that elderly patients with nonvalvular atrial fibrillation (NVAF) benefit from standard [an international normalised ratio (INR) goal of 2.0–3.0] oral anticoagulant treatment (OAT). The hypothesis that lower-intensity anticoagulation therapy can offset the higher bleeding risk in this population has never been tested in an ‘ad hoc’ clinical trial. Patients over 75 years of age with NVAF were randomised to receive warfarin to maintain the INR at 1.8 (range 1.5–2.0) or at a standard target of 2.5 (range 2.0–3.0). There were 135 patients in the low-intensity and 132 in the standard-intensity groups. During a mean follow-up lasting 5.1 years, 59 primary outcome events (thromboembolism and major haemorrhage) were recorded, 24 (3.5 per 100 patient-years) in the low-intensity group and 35 (5.0 per 100 patient-years) in the standard-intensity group (HR=0.7, 95% CI 0.4–1.1, p=0.1). The reduction in the primary endpoint was mainly due to a diminution in major bleedings (1.9 vs. 3.0 per 100 patient-years; HR=0.6, 95% CI 0.3–1.2, p=0.1). The median achieved INR value was 1.86 in the low-intensity and 2.24 in the standard-intensity group (p<0.001). The frequency of INR testing was 26.1 ± 13.5 vs. 24.3 ± 11.6 days, p<0.0001). In this exploratory study we observed a low rate of stroke and major bleeding in elderly patients (>75) being managed in an anticoagulation clinic for primary stroke prevention with low-intensity anticoagulation (INR 1.5–2.0). However, further trials are needed to confirm the hypothesis generated by the present study.
ADP-receptor blockade: A case for personalised pharmacotherapy?
Authors: Geisler Tobias , Gawaz Meinrad , Zürn Christine 
Published: January 2010

SummaryThe dual antiplatelet therapy consisting of aspirin and the ADP-receptor blocker clopidogrel is the current standard medication after acute coronary events. However, clopidogrel is characterised by a high interindividual response variability, insufficient inhibition of platelet aggregation in a significant number of patients, relatively slow onset of efficacy and potential interaction with different co-medication via diverse hepatic cytochrome enzymes. In various trials, response variability of clopidogrel was translated into a higher rate of recurrent cardiovascular events. Different clinical and non-genetic factors contribute to the phenomenon of clopidogrel response variability. An individualised antithrombotic pharmacotherapy taking these factors into account, including the definition of status of response, verification of the efficacy by standardised platelet function testing, intensified or alternative platelet inhibition would be the ultimate goal for patients treated with clopidogrel. Currently, new drugs are on the way and promise a more consistent efficacy and smaller amount of response variability. However, the bleeding risk in subgroups of patients and further side effect profile remains to be clearly defined. Therefore, risk stratification models are warranted to identify patients who benefit from personalised pharmacotherapy in terms of improved clinical net benefit. In this review, we discuss treatment failure of clopidogrel based on platelet function testing, the mechanism of established and new ADP-blockers as well as new therapeutic principles.
Macrophage-modulating cytokines predict adverse outcome in heart failure
Authors: Hohensinner Philipp , Rychli Kathrin , Zorn Gerlinde , Hülsmann Martin , Berger Rudolf , Mörtl Deddo , Richter Bernhard , Huber Kurt , Wojta Johann , Niessner Alexander , Pacher Richard 
Published: January 2010

SummaryCytokines regulating the mobilisation, recruitment and survival of mononuclear cells may play an important role in progression of heart failure. Therefore, we investigated the role of granulocyte colony stimulating factor (G-CSF), monocyte chemoattractant protein 1 (MCP-1) and macrophage colony stimulating factor (M-CSF) in patients with advanced heart failure. G-CSF, MCP-1 and M-CSF were determined in plasma of 351 patients with advanced heart failure by specific ELISAs. During a median follow up period of 16 months (95% confidence interval [CI]: 15–17 months) 175 patients (50%) experienced the composite endpoint rehospitalisation and all-cause mortality. M-CSF tertiles were associated with a gradually increasing risk with hazard ratios (HR) of 2.2 (95% CI: 1.5–3.2; for trend, p<0.001) for the composite endpoint and 2.6 (95% CI: 1.5–4.6; for trend, p=0.002) for all-cause mortality comparing third and first tertile. These associations remained significant in a multivariable Cox regression model after adjustment for BNP and other known risk factors (p=0.043 and p=0.024). High MCP-1 concentrations were associated with an increased risk of all-cause mortality with an adjusted HR of 1.9 (third vs. first tertile, 95% CI: 1.1–3.3; for trend, p=0.034). In contrast, G-CSF tertiles were not significantly associated with the composite endpoint or all-cause mortality in multivariable Cox regression. In conclusion, the independent and concentration-dependent association of macrophage-modulating cytokines and in particular of M-CSF with adverse outcome in advanced HF patients suggests that these cytokines may play an important pathophysiological role in progression of cardiomyopathy.
Polymorphisms in platelet glycoproteins Ia and IIIa are associated with arterial thrombosis and carotid atherosclerosis in type 2 diabetes
Authors: Pellitero Silvia , Tàssies Dolors , Pizarro Eduarda , Monteagudo Juan , Salinas Isabel , Aguilera Eva , Sanmartí Anna , Reverter Juan Carlos , Reverter Jordi 
Published: January 2010

SummaryTo determine the genotype distributions of the polymorphisms in platelet glycoproteins (GP) Ib-alpha, Ia/IIa and IIb/IIIa and their association with clinical arterial thrombosis and preclinical carotid atherosclerosis in type 2 diabetes we studied 229 patients with type 2 diabetes and 229 controls matched by age, gender and ethnicity. Biochemical and haemostasis analyses were performed. The GP Ib-alpha VNTR, GP Ia 807 C/T and GP IIIa Pl(A) polymorphisms were determined by PCR. Thrombotic events were registered and carotid atherosclerosis was evaluated by ultrasound examination. A total of 107 patients had clinical atherothrombosis (CA), 65 subclinical atherosclerosis (SA), and 57 had no evidence of atherosclerosis (NA). There were no differences in allele frequencies and the genotype distribution of platelet GP polymorphisms between diabetic patients and controls. The VNTR Ib-alpha polymorphism was not associated with CA. We found a significant association between CA and the 807T (odds ratio [OR]: 2.86, confidence interval [CI]: 1.65–4.93; p<0.001) and PlA2 (OR: 2.03, CI: 1.13–3.65; p=0.03) alleles (in GP Ia and GP IIIa, respectively) in comparison to SA and NA group. Diabetic patients with the coexistence of the 807T and PlA2 alleles presented the highest risk of CA (OR: 3.59, CI: 1.64–7.8; p<0.001). The coexistence of both 807T and PlA2 alleles was also associated with the presence of SA (OR: 9.00, CI: 1.10–73.42; p=0.04). In conclusion, the 807T allele of GP Ia and the PlA2 allele of GP IIIa, and specially its combination, may confer an additional risk for development of carotid atherosclerosis and arterial thrombosis in type 2 diabetes.
Integrin cleavage regulates bidirectional signalling in vascular smooth muscle cells
Authors: Kappert Kai , Furundzija Vesna , Fritzsche Jan , Margeta Christian , Krüger Janine , Meyborg Heike , Fleck Eckart , Stawowy Philipp 
Published: January 2010

SummaryIntegrins link the cytoskeleton to the extracellular matrix, providing outside-in/inside-out signalling essential for vascular smooth muscle cell (VSMC) migration in atherosclerosis. The integrin αv subunit is synthesised from its precursor via furin-dependent endoproteolytic cleavage. Furin is a proprotein convertase (PC) highly expressed in VSMCs and in human atherosclerotic lesions. Inhibition of αv processing inhibits binding to vitronectin and migration. However, the precise role of furin-dependent αv cleavage on integrin bidirectional signalling and subsequent VSMC functions is unknown. Our present study demonstrates that the furin-like PC inhibitor decanoyl-RVKR-chloromethylke-tone (dec-CMK) inhibited αv cleavage. This reduced vitronectin-induced (outside-in) focal adhesion kinase (FAK)- and paxillin-phosphorylation, and VSMC motility. Inside-out-stimulated, integrin-mediated VSMC adhesion/migration relied on integrin-adaptor protein activation following protein kinase C (PKC) and ERK1/2 phosphorylation. In contrast to outside-in signalling, PKC-dependent phosphorylation of FAK and paxillin was unaffected by the status of integrin cleavage. Still, cytoskeleton and focal adhesion site rearrangements were modulated by the inhibition of furin-dependent integrin cleavage, thereby lessening inside-out dependent migration. Hence, we find that integrin bidirectional signalling is critically controlled by furin. Furin-dependent integrin processing modulates rapid adaptive integrin/cytoskeleton changes, essential to VSMC motility, which represents a crucial component in atherosclerosis and restenosis.
Effect of intramyocardial delivery of autologous bone marrow mononuclear stem cells on the regional myocardial perfusion
Authors: Charwat Silvia , Lang Irene , Dettke Markus , Graf Senta , Nyolczas Noemi , Hemetsberger Rayyan , Zamini Sholeh , Khorsand Aliasghar , Sochor Heinz , Maurer Gerald , Glogar Dietmar , Gyöngyösi Mariann 
Published: January 2010

SummaryThe aim of the sub-study of the MYSTAR randomised trial was to analyse the changes in myocardial perfusion in NOGA-defined regions of interest (ROI) with intramyocardial injections of autologous bone marrow mononuclear cells (BM-MNC) using an elaborated transformation algorithm. Patients with recent first acute myocardial infarction (AMI) and left ventricular (LV) ejection fraction (EF) between 30–45% received BM-MNC by intramyocardial followed by intracoronary injection 68 ± 34 days post-AMI (pooled data of MYSTAR). NOGA-guided endocardial mapping and 99m-Sestamibi-SPECT (single photon emission computer tomography) were performed at baseline and at three months follow-up (FUP). ROI was delineated as a best polygon by connecting of injection points of NOGA polar maps. ROIs were projected onto baseline and FUP polar maps of SPECT calculating the perfusion severity of ROI. Infarct size was decreased (from 27.2 ± 10.7% to 24.1 ± 11.5%, p<0.001), and global EF increased (from 38 ± 6.1% to 41.5 ± 8.4%, p<0.001) three months after BM-MNC delivery. Analysis of ROI resulted in a significant increase in unipolar voltage (index of myocardial viability) (from 7.9 ± 3.0 mV to 9.9 ± 2.7 mV at FUP, p<0.001) and local linear shortening (index of local wall motion disturbances) (from 11.0 ± 3.9% to 12.7 ± 3.4%, p=0.01). NOGA-guided analysis of the intramyocardially treated area revealed a significantly increased tracer up-take both at rest (from 56.7 ± 16.1% to 62.9 ± 14.2%, p=0.003) and at stress (from 59.3 ± 14.2% to 62.3 ± 14.9%, p=0.01). Patients exhibiting ≥5% improvement in perfusion defect severity received a significantly higher number of intramyocardial BM-MNC. In conclusion, combined cardiac BM-MNC delivery induces significant improvement in myocardial viability and perfusion in the intramyocardially injected area.Clinical Trials Gov Nr: NCT00384982.
Platelet activation and reactivity in the convalescent phase of ischaemic stroke
Authors: Rozalski Marcin , Luzak Boguslawa , Michalak Slawomir , Kozubski Wojciech , Watala Cezary , Lukasik Maria 
Published: January 2010

SummaryThe study was aimed at the evaluation of blood platelet activation and reactivity in patients in the convalescent phase of stroke (n=58) and controls matched in respect to risk factors of vascular pathology (n=55). Both groups were treated daily with acetylsalicylic acid (ASA), 150 mg/day. Using flow cytometry, the expressions of P-selectin and the active GP IIb/IIIa receptor, as well as the fraction of platelet-derived microparticles (PMPs) and total platelet aggregates (Ag), were evaluated in non-stimulated platelets and in platelets stimulated in vitro by thrombin, thrombin receptor activating peptide (TRAP) or ADP. The expression of P-selectin in non-stimulated platelets was found to be significantly (p=0.04) lower in stroke patients. In parallel, these patients manifested a significantly (p=0.0008) higher proportion of PMPs and a lowered (p=0.003) proportion of Ag, as compared to the controls. In the stroke patients the increased expressions of P-selectin and active GP IIb/IIIa in TRAP- or ADP-activated cells were less pronounced (p<0.01), while the increments in PMP fraction remained higher (p<0.05). Our results may indicate that chronic platelet activation develops in patients in the convalescent phase of stroke and the process of PMP generation prevails over blood platelet degranulation and aggregation. This shift may be particularly unfavourable due to the procoagulative and proatherosclerotic properties of PMPs, accompanied by their decreased sensitivity to the action of antiplatelet drugs.Note: The results of this study were presented in part during a poster session at the XVIII European Stroke Conference in Stockholm, 26–29 May 2009.
Thrombocytopenia after abciximab use results from different mechanisms
Authors: Clofent-Sanchez Gisèle , Coste Pierre , Nurden Paquita , Lajus Sophie , Jais Catherine , Nurden Alan 
Published: January 2010

SummaryOur study concerns thrombocytopenia in patients with acute ischaemic coronary artery disease receiving antiplatelet drugs to the αIIbβ3 inte-grin (GPIIb/IIIa). We have screened for drug-dependent antibodies (DDAB) in 18 patients who suffered a fall of > 50% in platelet count (9 patients had a nadir of <50,000 platelets/μl) after receiving abciximab and related results to clinical outcome. Serum or plasma was screened for DDAB using (i) a direct ELISA against purified αIIbβ3, αIIbβ3-abciximab complexes or abciximab alone, (ii) control platelets and flow cytometry and (iii) monoclonal antibody immobilisation of platelet antigens. DDAB were found for 11 patients, with αIIbβ3 ELISA the most sensitive test. Progressive platelet consumption linked with haemoglobin loss and/or use of intra-aortic balloon pumping, another potential cause of a fall in platelet count, was also evaluated. DDAB were identified that recognised αIIbβ3 associated with abciximab and/ or abciximab alone. Screening of both progressive and delayed thrombocytopenia (appearing after 5 to 11 days) suggested that antibodies against abciximab preceded those recognising neo-epitopes on αIIbβ3, with a time-dependent broadening of antibody specificities. Higher titres were seen after second abciximab use. Five antibodies were platelet-activating. In conclusion, the mechanisms responsible for this complication of anti-αIIbβ3 therapy are multiple and often associated with a complex immune response.
A meta-analysis of potential risks of low levels of protein Z for diseases related to vascular thrombosis
Authors: Cesari Francesca , Abbate Rosanna , Gensini Franco , Broze George , Fedi Sandra , Sofi Francesco 
Published: January 2010

SummaryThe relationship between protein Z levels and thrombosis is controversial. We performed a systematic review and meta-analysis of the available studies to assess the association between protein Z and vascular thrombotic diseases. We conducted an electronic literature search through MedLine, Embase, Google Scholar, Web of Science, The Cochrane Library, bibliographies of retrieved articles and abstracts of congresses up to October, 2009. Studies were included if they analysed protein Z levels in patients with vascular thrombotic diseases. After the review process, 28 case-control studies (33 patient cohorts), including 4,218 patients with thrombotic diseases and 4,778 controls, were selected for analysis. The overall analysis using a random-effects model showed that low protein Z levels were associated with an increased risk of thrombosis (odds ratio [OR] 2.90, 95% confidence interval [CI] 2.05–4.12; p<0.00001). On subgroup analysis, a significant association was found between low protein Z levels and arterial vascular diseases (OR 2.67, 95%CI 1.60–4.48; p=0.0002), pregnancy complications (OR 4.17, 95%CI 2.31–7.52; p<0.00001), and venous thromboembolic diseases (OR 2.18, 95%CI 1.19–4.00; p=0.01). The results of this meta-analysis are consistent with a role for protein Z deficiency in thrombotic diseases, including arterial thrombosis, pregnancy complications and venous thromboembolism.