Complex trait of acute pancreatitis : Studies of candidate genes and adipokines

Acute pancreatitis (AP) is a common disease. Mild disease resolves spontaneously in a few days. Severe forms of the disease can lead to local complications, necrosis, and abscesses in and around the pancreas. Systemic inflammation in severe AP is associated with distant organ failures. The aim of this study is to identify genetically determined prognostic factors involved in the clinical features of AP. The study employs a candidate-gene approach, and the genes are involved in trysinogen activation in the initiation phase of the disease, as well as in the systemic inflammation as the disease proceeds. The last study examines adipokines, fat-derived hormones characterized with the capacity to modify inflammation. SPINK 1 is a gene coding trypsin activation inhibitor. Mutations N34S and P55N were determined by minisequencing methods in 371 AP patients and in 459 controls. The mutation N34S was more common in AP patients (7.8%) than in controls (2.6%). This suggests that SPINK 1 gene mutation N34S is a risk factor for AP. In the fourth study, in 12 matched pairs of patients with severe and mild AP, levels of adipokines, adiponectin, and leptin were evaluated. Plasma adipokine levels did not differ between patients with mild and severe AP. The results suggest that in AP, adipokine plasma levels are not factors predisposing to organ failures. This study identified the SPINK 1 mutation N34S to be a risk factor for AP in the general population. As AP is a multifactorial disease, and extensive genetic heterogeneity is likely, further identification of genetic factors in the disease requires larger future studies with more advanced genetic study models. Further identification of the patient characteristics associated with organ failures offers another direction of the study to achieve more detailed understanding of the severe form of AP.

Thrombophilia and direct thrombin inhibitor lepirudin clinical and monitoring aspects

Thrombophilia (TF) predisposes both to venous and arterial thrombosis at a young age. TF may also impact the thrombosis or stenosis of hemodialysis (HD) vascular access in patients with end-stage renal disease (ESRD). When involved in severe thrombosis TF may associate with inappropriate response to anticoagulation. Lepirudin, a potent direct thrombin inhibitor (DTI), indicated for heparin-induced thrombocytopenia-related thrombosis, could offer a treatment alternative in TF. Monitoring of narrow-ranged lepirudin demands new insights also in laboratory. The above issues constitute the targets in this thesis. We evaluated the prevalence of TF in patients with ESRD and its impact upon thrombosis- or stenosis-free survival of the vascular access. Altogether 237 ESRD patients were prospectively screened for TF and thrombogenic risk factors prior to HD access surgery in 2002-2004 (mean follow-up of 3.6 years). TF was evident in 43 (18%) of the ESRD patients, more often in males (23 vs. 9%, p=0.009). Known gene mutations of FV Leiden and FII G20210A occurred in 4%. Vascular access sufficiently matured in 226 (95%). The 1-year thrombosis- and stenosis-free access survival was 72%. Female gender (hazards ratio, HR, 2.5; 95% CI 1.6-3.9) and TF (HR 1.9, 95% CI 1.1-3.3) were independent risk factors for the shortened thrombosis- and stenosis-free survival. Additionally, TF or thrombogenic background was found in relatively young patients having severe thrombosis either in hepatic veins (Budd-Chiari syndrome, BCS, one patient) or inoperable critical limb ischemia (CLI, six patients). Lepirudin was evaluated in an off-label setting in the severe thrombosis after inefficacious traditional anticoagulation without other treatment options except severe invasive procedures, such as lower extremity amputation. Lepirudin treatments were repeatedly monitored clinically and with laboratory assessments (e.g. activated partial thromboplastin time, APTT). Our preliminary studies with lepirudin in thrombotic calamities appeared safe, and no bleeds occurred. An effective DTI lepirudin calmed thrombosis as all patients gradually recovered. Only one limb amputation was performed 3 years later during the follow-up (mean 4 years). Furthermore, we aimed to overcome the limitations of APTT and confounding effects of warfarin (INR of 1.5-3.9) and lupus anticoagulant (LA). Lepirudin responses were assessed in vitro by five specific laboratory methods. Ecarin chromogenic assay (ECA) or anti-Factor IIa (anti-FIIa) correlated precisely (r=0.99) with each other and with spiked lepirudin in all plasma pools: normal, warfarin, and LA-containing plasma. In contrast, in the presence of warfarin and LA both APTT and prothrombinase-induced clotting time (PiCT®) were limited by non-linear and imprecise dose responses. As a global coagulation test APTT is useful in parallel to the precise chromogenic methods ECA or Anti-FIIa in challenging clinical situations. Lepirudin treatment requires multidisciplinary approach to ensure appropriate patient selection, interpretation of laboratory monitoring, and treatment safety. TF seemed to be associated with complicated thrombotic events, in venous (BCS), arterial (CLI), and vascular access systems. TF screening should be aimed to patients with repeated access complications or prior unprovoked thromboembolic events. Lepirudin inhibits free and clot-bound thrombin which heparin fails to inhibit. Lepirudin seems to offer a potent and safe option for treatment of severe thrombosis. Multi-centered randomized trials are necessary to assess the possible management of complicated thrombotic events with DTIs like lepirudin and seek prevention options against access complications.

Serial Changes in Markers Measuring Coagulation, Fibrinolysis, and Vasoactivity in Patients with Ischemic Stroke

Ischemic stroke (IS) is a heterogeneous disease in which outcome is influenced by many factors. The hemostatic system is activated in association with cerebral ischemia, and thus, markers measuring coagulation, fibrinolysis, and vasoactivity could be useful tools in clinical practice. We investigated whether repeated measurements of these markers reveal patterns that might help in evaluating IS patients, including the early diagnosis of stroke subtypes, in estimating prognosis and risk of recurrence, and in selecting a treatment for secondary prevention of stroke. Vasoconstrictor peptide endothelin-1 (ET-1), homocysteine (Hcy), indicators of thrombin formation and activation (prothrombin fragment 1+2/F1+2, thrombin-antithrombin complex/TAT), indicators of plasmin formation and fibrinolysis (tissue plasminogen activator/t-PA, plasminogen activator inhibitor-1/PAI-1, and D-dimer), and natural anticoagulants (antithrombin/AT, protein C/PC, and protein S/PS) were measured in 102 consecutive mild to moderate IS patients on four occasions: on admission and at 1 week, 1 month, and 3 months after stroke, and once in controls. All patients underwent neurological examination and blood sampling in the same session. Furthermore, 42 IS patients with heterozygous factor V Leiden mutation (FVLm) were selected from 740 IS patients without an obvious etiology, and evaluated in detail for specific clinical, laboratory, and radiological features. Measurements of ET-1 and Hcy levels did not disclose information that could aid in the diagnostic evaluation of IS patients. F1+2 level at 3 months after IS had a positive correlation with recurrence of thromboembolic events, and thus, may be used as a predictive marker of subsequent cerebral events. The D-dimer and AT levels on admission and 1 week after IS were strongly associated with stroke severity, outcome, and disability. The specific analysis of IS patients with FVLm more often revealed a positive family history of thrombosis, a higher prevalence of peripheral vascular disease, and multiple infarctions in brain images, most of which were `silent infarcts´. Results of this study support the view that IS patients with sustained activation of both the fibrinolytic and the coagulation systems and increased thrombin generation may have an unfavorable prognosis. The level of activation may reflect the ongoing thrombotic process and the extent of thrombosis. Changes in these markers could be useful in predicting prognosis of IS patients. A clear need exists for a randomized prospective study to determine whether a subgroup of IS patients with markers indicating activation of fibrinolytic and coagulation systems might benefit from more aggressive secondary prevention of IS.

Thrombin regulation in newborn infants

The coagulation system of newborn infants differs markedly from that of older children and adults. The activities of most coagulation factors and anticoagulants are low, leading to altered regulation in the formation of the key enzyme, thrombin. Timely and adequate generation of thrombin is essential, as thrombin activates platelets and many coagulation factors, cleaves fibrinogen into fibrin and activates the antithrombotic and anti-inflammatory protein C pathway. On the other hand, excess thrombin may promote thrombotic complications and exacerbate harmful inflammatory reactions. Despite the characteristic features, the newborn coagulation system can be considered physiological, since healthy newborns rarely show haemorrhagic or thrombotic complications. Sick newborns, however, often encounter clinical situations that challenge their coagulation system. The aim of this study was to clarify the behaviour of the neonatal coagulation system in selected clinical situations, with a special emphasis on the generation of thrombin. Thrombin was measured by in vivo thrombin generation markers and by thrombin generation potential in vitro. The patient groups included sick newborns undergoing intensive care and receiving fresh-frozen plasma (FFP), requiring exchange transfusions (ET) or presenting with a congenital heart defect requiring open heart surgery. Additionally, healthy newborns with inherited heterozygous factor V Leiden (FVL) mutation were studied. Thrombin generation potential was also analysed in cord plasma of healthy infants and in adults. Healthy as well as sick newborn infants showed lower total thrombin generation potential in vitro but faster initiation of thrombin generation than adults. These findings were qualitatively similar when plasma was supplemented with platelets. Platelets, however, significantly altered the effect of the major anticoagulant, activated protein C (APC), on thrombin generation potential. In accordance with previous studies, thrombin generation in healthy newborn platelet-poor plasma was resistant to the anticoagulant effects of APC, but when the plasma was supplemented with platelets APC attenuated thrombin generation significantly more in newborns than in adults. In vivo generation of thrombin was elevated in nearly all of the sick newborn infants. The low-volume FFP transfusion as opposed to the change from neonatal to adult blood in ET exerted markedly different effects on neonatal thrombin generation. FFP reduced the in vivo generation of thrombin in those newborns with the highest pretransfusional thrombin generation, thus acting as an anticoagulant agent. In those infants with lower pretransfusional thrombin generation, the effect of FFP on thrombin generation was fairly neutral. On the other hand, the combination of red blood cells and FFP, used to perform ET, significantly increased the in vivo thrombin formation and shifted the balance in the newborn coagulation system to the procoagulant direction. Cardiopulmonary bypass (CPB) also significantly increased the in vivo thrombin generation, but the thrombin generation profile during CPB differed from that previously observed in adults. Escalation of thrombin at early reperfusion was not observed in newborns; in adults, its occurrence is associated with postoperative myocardial damage. Finally, in healthy newborns with FVL heterozygosity, faster initiation of thrombin generation was observed compared with controls. Interestingly, FV level was lower in FVL-heterozygous infants, possibly to counteract the procoagulant effects induced by FVL. In conclusion, unique features regarding thrombin regulation in newborn infants were observed. These features included a novel platelet effect on the regulation of the protein C pathway. The clinical challenges mainly seemed to shift the balance in the coagulation system of newborns to the procoagulant direction. Blood component transfusions markedly affected coagulation in a manner specific to the product but that could also be altered by the clinical situation. Overall, the results highlight the need for understanding developmental haemostasis for both diagnostic and therapeutic purposes.

Behaviour of Bi-adhesive Joints

The use of relatively low modulus adhesive at the ends of overlap in a bi-adhesive bondline of a bonded joint can reduce the stress concentration significantly and, therefore, potentially lead to higher strength of the joint. This study presents the two-dimensional and three-dimensional nonlinear (geometric and material) finite element analyses of adhesively bonded single lap joints having modulus-graded bondline under monotonic loading conditions. The adhesives were modelled as an elasto-plastic multi-linear material, while the substrates were regarded as both linear elastic and bi-linear elasto-plastic material. The computational simulations have been performed to investigate the bondline behaviour by studying the stress and strain distributions both at the mid-plane as well as at the interface of the bondline. It has been observed that the static strength is higher for joints with bi-adhesive bondlines compared to those with single adhesives in bondline. Higher joint strength has also been observed for optimum bi-adhesive bondline ratio through parametric studies. Effects of load level, and bondline thickness on stress distribution in the bi-adhesive bondline have also been studied. 3D analysis results reveal the existence of complex multi-axial stress/strain state at the ends of the overlap in the bondline which cannot be observed in 2D plane strain analysis. About 1/3rd of the width of the joint from the free edge in the width direction has 3D stress state, especially in the compliant adhesive of the bondline. Magnitudes of longitudinal and lateral stress/strain components are comparable to peel stress/strain components. It has also been analytically shown that the in-plane global stiffness of the joint remains unaffected by modulus gradation of the bondline adhesive. (C) Koninklijke Brill NV, Leiden, 2010.

Role Of Vertical Component Of Surface Tension Of The Droplet On The Elastic Deformation Of Pdms Membrane

Poly(dimethylsiloxane) (PDMS) has been widely used in lab-on-a-chip and micro- total analysis systems (mu-TAS), thus wetting and electrowetting behaviors of PDMS are of great importance in these devices. PDMS is a kind of soft polymer material, so the elastic deformation of PDMS membrane by a droplet cannot be neglected due to the vertical component of the interfacial tension between the liquid and vapor, and this vertical component of liquid-vapor surface tension is also balanced by the stress distribution within the PDMS membrane. Such elastic deformation and stress distribution not only affect the exact measurement of contact angle, but also have influence on the micro-fluidic behavior of the devices. Using ANSYS code, we simulated numerically the elastic deformation and stress distribution of PDMS membrane on a rigid substrate due to the liquid-vapor surface tension. It is found that the vertical elastic deformation of the PDMS membrane is on the order of several tens of nanometers due to the application of a droplet with a diameter of 2.31 mm, which is no longer negligible for lab-on-a-chip and mu-TAS. The vertical elastic deformation increases with the thickness of the PDMS membrane, and there exists a saturated membrane thickness, regarded as a semi-infinite membrane thickness, and the vertical elastic deformation reaches a limiting value when the membrane thickness is equal to or thicker than such saturated thickness. (C) Koninklijke Brill NV, Leiden, 2008.

Transitions Between Different Contact Models

The transitions between the different contact models which include the Hertz, Bradley, Johnson-Kendall-Roberts (JKR), Derjaguin-Muller-Toporov (DMT) and Maugis-Dugdale (MD) models are revealed by analyzing their contact pressure profiles and surface interactions. Inside the contact area, surface interaction/adhesion induces tensile contact pressure around the contact edge. Outside the contact area, whether or not to consider the surface interaction has a significant influence on the contact system equilibrium. The difference in contact pressure due to the surface interaction inside the contact area and the equilibrium influenced by the surface interaction outside the contact area are physically responsible for the different results of the different models. A systematic study on the transitions between different models is shown by analyzing the contact pressure profiles and the surface interactions both inside and outside the contact area. The definitions of contact radius and the flatness of contact surfaces are also discussed. (C) Koninklijke Brill NV, Leiden, 2008.

An Electrowetting Model For Rough Surfaces Under Low Voltage

Electrowetting is one of the most effective methods to enhance wettability. A significant change of contact angle for the liquid droplet can result from the surface microstructures and the external electric field, without altering the chemical composition of the system. During the electrowetting process on a rough surface, the droplet exhibits a sharp transition from the Cassie-Baxter to the Wenzel regime at a low critical voltage. In this paper, a theoretical model for electrowetting is put forth to describe the dynamic electrical control of the wetting behavior at the low voltage, considering the surface topography. The theoretical results are found to be in good agreement with the existing experimental results. (c) Koninklijke Brill NV, Leiden, 2008.

Wende und Körperdarstellung in Hensels Lärchenau

[EN] Kerstin Hensel’s literary universe is haunted by fallen heroes, outsiders and gregarious figures with no success. They experience the German Wende in a very peculiar constellation, they perceive Post-Unification Germany at times from a fantastic perspective, always from a painful experience. In this context the analysis of the representations of the body in Hensel’s narrative before and after 1989 offers a rich insight on Hensel’s critical view of Post-Unification Germany. By analysing her texts such as Hallimasch and Lärchenau this article shows that the suffering grotesque bodies in both works stand for a political metaphor of a social body with hardly a cure.

A snapshot of digitisation and OCR Developments

One of the goals of Knowledge Exchange (www.knowledge-exchange.info) is to help partners to share knowledge and expertise and facilitate the build of expert networks. In the area of digitisation, including non-textual and 3-D-digitisation, a first step is to provide a snapshot of current activities and challenges in the KE partner countries. This paper is a synthesis of the information gathered in a questionnaire that was sent to 15 infrastructure institutions, e.g. libraries and also funders, within the five partner countries of Knowledge Exchange: Denmark (DK), Finland (FIN), Germany (GER), the Netherlands (NL) and the United Kingdom (UK). The paper is based on the answers provided by 6 respondents from four countries:  DK o Danish Agency of Culture (Henrik Jarl Hansen) o State and University Library (Tonny Skovgård Jensen)  GER o German research foundation, DFG (Franziska Regner)  NL o Royal Library (Hildelies Balk) o Leiden University Library (Saskia van Bergen)  UK o Jisc (Paola Marchionni, Peter Findlay) The absence of Finnish responses may be due to Finland participating in the recent Enumerate Core Survey II that also addressed digitisation. We have included some of the outcomes of this survey to present a richer picture.

Portunus pulchricristatus (Gordon, 1931): an addition to crab fauna of Pakistan (northern Arabian Sea)

Portunus pulchricristatus (Gordon, 1931) is a rare species, to date we have obtained only three specimens, two males and a berried female which can be easily identified with the help of existing descriptions and illustrations. Brief account of the Pakistan material is given below. One male specimen (measuring 11.0 mm in carapace length) has been deposited in the National Museum of Natural History, Leiden (Reg.No.D.42393) the other two specimens housed in the Marine Reference Collection and Resource Centre (MRCC Cat. No.BRAC.491). The abbreviations used are cl. for carapace length and cb. for carapace breadth.

Some freshwater mollusca from Ceylon with notes on their distribution and biology

Very few records of freshwater molluscs of Ceylon are available in several publications and although they are of importance as food for fishes and vectors of parasites we know little of their role in these capacities in Ceylon. The present paper is to be considered more as a pointer to the group than as a study of the freshwater molluscs of Ceylon. The author collected freshwater molluscs during surveys made for the study of systematics and distribution of various freshwater invertebrates. Material of freshwater molluscs purchased by the Museum in Leiden and labelled Ceylon was also seen by the author. The nomenclature used in this paper has been simplified by the omission of sub-generic and sub-specific names. The sub-generic divisions are dealt with critically for the Gastropoda by Wenz (1938-1944) and Zilch (1959-1960).

The rediscovery of Notopoides latus Henderson in the western Indian Ocean (Crustacea-Decapoda, Raninidae)

The small brachyuran family Raninidae Dana is represented in the Indo-West Pacific region by eight genera, with only some twenty species. One of the least known genera is Notopoides, which contains only a single species. This genus was first described by Henderson (1888) on the basis of material collected by H.M.S. "Challenger" from the Kei Islands, in the Banda sea off Indonesia. There have been no subsequent reports of this species in the ninety seven years since its original discovery. During the course of the study of the benthic fauna off the coast of East Africa, the Fisheries Research Vessel "Manihine" obtained five specimens of this rare species. These new records, collected during a short period of time, indicate that the species is probably not uncommon in this region, which also represents a great increase in its known geographical range. Specimens have been deposited in the collections of the National Museum, Nairobi, the Rijksmuseum van Natuurlijke Historie, Leiden, and the National Museum, Singapore: Catalogue numbers are crust. 1092 ; Crust. D. 28567; NMS. 1972.8.4.1, male of 35x26 respectively.