3,622 research outputs found
BestMap: context-aware SKOS vocabulary mappings in OWL 2
No full textThis paper describes an approach to SKOS vocabulary mapping that takes into account the context in which vocabulary terms are used in annotations. The standard vocabulary mapping properties in SKOS only allow for binary mappings between concepts. In the BestMap ontology, annotated resources are the contexts in which annotations coincide and allow for a more fine grained control over when mappings hold.A mapping between two vocabularies is defined as a class that groups descriptions of a resource. We use the OWL 2 features for property chains, disjoint properties, union, intersection and negation together with careful use of equivalence and subsumption to specify these mappings
Publishing and Consuming Linked Data
No full textHarmelen, F.A.H. van [Promotor]Schlobach, K.S. [Copromotor]Hoekstra, R.J. [Copromotor
R.J. Sommers
No full textThe single-spaced paragraph on the “About the Author” page of R.J. Sommers’ latest novel says she lives in a one-story house on the edge of a city. It says she is renowned for writing relatable characters and compelling relationships. It says nothing about her own friends.
Gazing from a photo at the top of the page, R.J. Sommers appears to point a camera toward her readers..
Stadsentrees: Ontwerp-ingrepen als oplossing voor knelpunten in de Haagse stadsentrees
No full textDit afstudeerproject was een ontwerponderzoek dat keek naar hoe de stadsentree kan worden her gepositioneerd en geïntegreerd in het stedelijk weefsel. Dit project had als onderzoeksdoel om het onderwerp stadsentrees te verkennen. Het ontwerpdoel was om een huidige stadsentree te versterken in ruimtelijke en functionele zin. De onderzoeksvraag luidt: ‘Wat zijn de knelpunten in de belangrijkste stadsentrees van Den Haag, met welke ontwerp-ingrepen kunnen deze knelpunten worden opgelost en wat valt hieruit te leren voor stadsentrees van andere Nederlandse steden?’.UrbanismArchitecture and The Built Environmen
A Cognitive Science Perspective on Legal Ontologies
No full textWe can trace five origins of ontology engineering, and all five still play a major role in ontology engineering. Each of these roots gives a different perspective on content and use of ontologies. Philosophical ontology is concerned with "reality"; Information science with systematic terminology; Artificial Intelligence (AI) with terminological knowledge, Knowledge Engineering with the specification of knowledge bases, and Information Management with semantics. Associated with these roots, the applications differ and range from analytic clarification to automated reasoning. Also mismatches between formalism and aim occur frequently. These mismatches can often be traced to an unclear distinction between knowledge and semantics. We explain this difference in Section 4.3 using a simple cognitive architecture for natural language production. A Cognitive Science perspective is however well suited where top ontologies try to cover the core concepts of common sense, as a wealth of empirical studies have become available on the content of our "knowledge instincts". We present an example on the modeling of spatial concepts and refer to our still ongoing work on a common-sense based core ontology for legal domains: LKIF-Core (Hoekstra et al. 2007; Hoekstra 2009). <br/
Interviewen
No full textInterviewen is een veelvoorkomende wetenschappelijke methode on informatie teverzamelen. Belangrijk is dat het interview inhoudelijk goed aansluit bij jouwontwerpopgave of onderzoek. Daarnaast helpt het enorm om te werken met eensystematische aanpak bij het vastleggen, ordenen, analyseren en rapporteren vande informatie uit je interviews. En natuurlijk is een goede gespreksvoorbereidingbelangrijk. De interviewmethode omvat drie fasen:1. Voorbereiding en randvoorwaarden2. Uitvoering, gespreksvoering en vastleggen data, en3. Uitwerking, analyse en rapportage.Interviews zijn zeer geschikt voor het in kaart brengen van percepties, ervaringen,opvattingen, verwachtingen, en het ophalen van kennis uit de praktijk. Om decomplexiteit van datgene wat je onderzoekt te begrijpen, is het van belang dat je inhet interview zelf flexibel kunt opereren. Gesprekken verlopen nog al eens andersdan tijdens de voorbereiding wordt verondersteld. Dit hoofdstuk biedt concretehandvaten voor alle onderdelen van het proces.Urban StudiesSpatial Planning and Strateg
Clinical and experimental studies on the pathogenesis and the rol of bile salts
No full textChapter 1 provides a short introduction and the outline of this thesis. The aim of
the thesis was to identify clinical risk factors for non-anastomotic strictures (NAS),
by analyzing donor and patient characteristics, as well as surgical variables in relation
to postoperative outcome after orthotopic liver transplantation (OLT). Furthermore,
we have performed clinical studies and experimental studies in mice to unravel the
role of bile salt toxicity in the pathogenesis of hepatobiliary injury after OLT. The
thesis is divided in two parts.
The first part focuses on the clinical risk factors for the
development of NAS and in the second the part we investigate the role of toxic bile salts
and bile secretory function in the development of hepatobiliary injury after OLT.
Part I. Non-anastomotic biliary strictures after liver
transplantation
Chapter 2 provides an overview of the literature regarding the causes and consequences
of NAS, also called ischemic-type biliary lesions (ITBL). The aim of this chapter is to
describe the pathophysiological mechanisms, clinical presentation and the treatment
of NAS. NAS is a radiological diagnosis, characterized by intrahepatic strictures and
dilatations on cholangiography. NAS were first described after liver transplantation in
association with hepatic artery thrombosis (HAT). In case of early HAT the bile duct
becomes ischemic; resulting in a typical cholangiographic picture of biliary strictures,
dilatations and intraductal cast formation. However, these abnormalities can also be
seen in the absence of HAT, hence the term ischemic-type biliary lesions emerged. In
this thesis the term NAS was used to describe intrahepatic biliary strictures and dilations
of the bile duct in patients without HAT. The incidence of NAS varies around 15% in
different series reported in literature. Various risk factors for NAS have been identified,
strongly suggesting a multifactorial origin. The main categories include ischemia-related
injury, immune-mediated injury and toxic injury by bile salts. Nevertheless, in many
cases no specific risk factor can be identified. The clinical presentation of patients with
NAS is often not specific. Symptoms may include fever, abdominal complaints and
increased cholestatic liver function tests. The diagnosis is made by imaging studies of
the bile ducts. Treatment starts with relieving symptoms of cholestasis and dilation
of stenosed bile ducts via endoscopic retrograde cholangiopancreaticography (ERCP)
or percutaneous transhepatic cholangiodrainage (PTCD), if possible followed by
stenting. Eventually up to 50% of the patients with NAS may require retransplantation
or may die. In selected cases, retransplantation can be avoided or delayed by surgical
intervention.
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In the clinical study described in chapter 3 we aimed to determine whether Roux-Y
choledochojejunostomy is an independent risk factor for NAS after transplantation. A
total of 486 adult liver transplant recipients, transplanted between May 1992 and June
2006 with a median postoperative follow-up of 5.6 years, were included in this study.
One- and 5-year patient survival rates were 85.4 and 77.2%, respectively. Graft survival
rates at 1- and 5-years were 80.2% and 69.1%, respectively. NAS was observed in 80
of the 486 (16.5%) transplanted livers at a median time interval of 4.1 months after
OLT. A total of 18 potential risk factors for NAS were studied by comparing the group
of patients with NAS with those who did not develop NAS. Risk factors were grouped
as donor or recipient-related variables, surgical variables and postoperative outcome
variables. A univariate comparison of these demographic and clinical variables between
patients with and without NAS indicated primary sclerosing cholangitis (PSC), the
type of bile duct reconstruction and postoperative cytomegalovirus (CMV) infection as
risk factors for NAS. In patients who were transplanted for PSC, the incidence of NAS
was two-fold higher than in patients transplanted for other indications. In addition,
NAS were observed significantly more frequent when Roux-Y choledochojejunostomy
was used for biliary reconstruction, compared to patients with a duct-to-duct biliary
reconstruction. However, after multivariate regression analysis, including variables
previously reported in literature as important risk factors for the development of NAS,
Roux-Y choledochojejunostomy was not identified as independent risk factor for NAS.
Based on the results of this study, it was concluded that the association between Roux-Y
choledochojejunostomy and NAS that has been observed in previous studies can be
explained entirely by the more frequent use of Roux-Y reconstruction in patients with
PSC. Bacterial migration and (recurrent) ascending cholangitis as can be seen more
frequently in patients with a Roux-Y reconstruction, apparently do not play a role in the
pathogenesis of NAS after transplantation.
In chapter 4, outcome after transplantation is compared for livers from brain death
(DBD) or cardiac death (DCD) donors performed in The Netherlands between January
2001 and December 2006. Of a total of 526 transplant procedures performed in this
time period, in 55 cases a liver from a DCD donor was used and in 471 cases a liver
from a DBD donor was used. A national protocol was introduced for multiorgan
donation (MOD) of organs from controlled DCD donors. All three participating
Dutch liver transplant centers agreed to allocate livers from DCD donors according
159
to the national waiting list. There were no significant differences in the overall 1- and
3-year patient survival rates after DCD and DBD liver transplantation (84.6% versus
80.4%, and 86.3% versus 80.8%, respectively). Overall 1- and 3- year graft survival did
also not differ between DCD and DBD liver transplantation (74.0% versus 67.9%, and
80.5% versus 74.7%, respectively), although significant differences in the rate of graft
loss were observed between centers. NAS was observed significantly more frequently
after DCD liver transplantation (23.6% versus 7.9%, DCD versus DBD, respectively),
requiring significantly more retransplantations (10.9% versus 2.5%, DCD versus
DBD). Risk factors for graft loss and NAS were grouped as donor and recipients related
variables, surgical, and postoperative outcome variables. Multivariate regression analysis
revealed transplant center, first warm ischemic and cold ischemic time as independent
risk factors for 1-year graft survival in DCD liver transplantation. In a multivariate
regression analysis the following independent risk factors for NAS were identified:
DCD liver grafts, donor age, and PSC.
Part II . The role of bile salts in the pathogenesis of
hepatobiliary injury after liver transplantation
In chapter 5 we investigated the role of endogenous bile salts in the origin of bile duct
injury after OLT in a mouse model of arterialized liver transplantation. Previously,
Geuken et al. suggested that an increased biliary bile salt/phospholipid ratio early after
OLT, leading to toxic bile composition, may result in increased intrahepatic bile duct
injury (1). However, formal evidence for a cause-effect relationship between toxic bile
formation and bile duct injury after OLT could not be established by this observational
clinical study. In fact, it could not be ruled out that toxic bile composition and bile
duct injury both resulted from the same underlying factor. By comparing outcome after
transplantation of livers from wild-type mice or mice heterozygous for the disruption of
the Mdr2 gene (Mdr2+/-), we demonstrated that endogenous bile salts act synergistically
to ischemia/reperfusion in the origin of bile duct injury. This study provided evidence
that bile salt toxicity is an important factor that may contribute to hepatobiliary injury
after OLT.
In chapter 6 the involvement of bile secretory function in the pathogenesis of
hepatobiliary injury after the occurrence of HAT was investigated. In contrast to the
liver parenchyma, the bile ducts have a single blood supply that comes entirely from
160
the hepatic artery. HAT is a well known risk factor for the development of ischemic
bile duct strictures after OLT. Although ischemic injury of the bile ducts is a key
mechanism, it was unknown whether changes in bile composition may contribute
to the development of biliary injury in this situation as well. Previous studies have
indicated that hepatic arterial blood flow is critical for the recovery of hepatocyte
bile secretory function after OLT (2). In the absence of bile secretion, bile salts can
accumulate and act cytotoxic on hepatocytes and cholangiocytes. To study whether
changes in bile secretion could play a role in the pathogenesis of hepatobiliary injury
in the event of HAT, we developed a mouse model of impaired arterial perfusion
of the liver induced by ligation of either the hepatic artery or the peribiliary plexus,
or a combination of the two. Ligation of either the hepatic artery or the peribiliary
plexus did not result in marked histological, biochemical or molecular changes. This
means that the hepatic artery and peribiliary plexus both have the capacity to provide
sufficient blood supply to the biliary tree in this model. The combination of hepatic
artery ligation and interruption of the peribiliary plexus (complete loss of arterial
blood supply to the liver), however, resulted in severe injury of the bile ducts and liver
parenchyma, with two out of five animals dying after 14 days. As early as 24 hours
after complete dearterialization, in the absence of hepatobiliary injury, liver ATP-levels
were significantly decreased, and gene expression for the bile salt transporter Ntcp
and Bsep decreased and serum conjugated bile salt levels increased, subsequently.
Pro-inflammatory cytokine release was slowly induced and intrahepatic cholestasis
progressed in the following weeks. This study demonstrated that the expression of
hepatobiliary transporters is dysregulated early after complete loss of arterial blood
supply to the liver, leading to intrahepatic cholestasis and bile salt-mediated injury.
These data suggest that hepatobiliary injury frequently seen when HAT occurs after
OLT, may not only be due to a direct ischemic injury, but is also related to bile saltmediated
injury.
The study described in chapter 7 provides new insights in the role of cholangiocyte
bile salt transporters in biliary injury after OLT in mice. Cholangiocytes express various
bile salt transporters such as Asbt and heteromeric Ost-alpha/beta, responsible for the
uptake and secretion of bile salts, respectively. We analyzed gene and protein expression
for these transporters in our previously established mouse OLT model. To determine
the impact of biliary bile salts and the bile salt/phospholipid ratio on the expression
161
of these transporters, we compared livers transplanted from Mdr2+/- mice with livers
from wild-type donors. Since changes in cholangiocyte transporter expression are
associated with hepatic pro-inflammatory cytokine release, we also assessed the hepatic
expression for TNF-alpha and IL1-beta in the donor livers and correlated this with the
expression levels of the cholangiocyte transporters. Transplantation of Mdr2+/- livers
resulted in down-regulation of mRNA expression for Asbt, Ost-beta and Ost-alpha
after OLT. Asbt expression appeared to be regulated in direct proportion to the biliary
bile salt/phospholipid ratio, whereas Ost-alpha/beta expression correlated negatively
with the expression for TNF-alpha and IL1-beta. The unbalanced reduction of Asbt
and Ost-alpha/beta expression after OLT therefore, may result in bile salt retention in
cholangiocytes, cytotoxicity and aggravate bile duct injury.
In chapter 8 we have examined changes in the expression of cholangiocyte bile
transporters and the cholehepatic shunt in patients after OLT in humans. Expression
of ASBT, OST-alpha/beta and CFTR was determined in liver transplant biopsies and
levels of expression were correlated with biliary bile salt secretion and the development
of microscopic bile duct injury at one week after transplantation. OST-alpha transcript
levels were significantly down-regulated at the end of cold storage and immediately
after graft reperfusion, but levels had restored to normal values at one week after OLT.
OST-beta mRNA expression was more than 8-fold up-regulated at the end of cold
preservation and after graft reperfusion and increased further during the first week after
OLT. Overall the immunofluorescence staining pattern of these two transporters was
similar. The observed changes in the expression of the bile salt transporters OST-alpha
and OST-beta correlate with biliary bile salt secretion, but not with the degree of bile
duct injury. Although increased uptake of bile salts through cholangiocytes has been
linked with an increased expression for CFTR, we found no major changes in CFTR
mRNA expression. Altogether, these data suggest that the cholehepatic shunt does not
play a major role in the development of bile salt induced bile duct injury after OLT.
162
Collectively, the studies described in Part II of this thesis indicate that bile salt toxicity
and intrahepatic cholestasis are key events contributing to hepatobiliary injury after
OLT. Therapeutic strategies to prevent hepatobiliary injury after OLT therefore
should focus on options to alter bile composition and to maintain choleresis. Drugs
that could potentially reduce this type of injury should target at bile composition and
the affected bile duct epithelium itself, and ideally should also have anti-cholestatic,
anti-inflammatory and anti-fibrotic properties. Ursodeoxycholic acid (UDCA) is
known to improve cholestatic disorders and is widely used in the treatment of patients
with cholestatic liver diseases. Several mechanisms may potentially contribute to the
beneficial effect of UDCA after human OLT. Under cholestatic conditions, UDCA
stimulates hepatocyte secretion of bile salts, inhibits bile salt induced hepatocyte (and
cholangiocyte) apoptosis, protects injured cholangiocytes against the toxic effects of
endogenous bile salts, and/or stimulates Cl- and HCO3- secretion into bile via CFTR
(3). In contrast to UDCA, its side chain-shortened homologue nor-UDCA undergoes
cholehepatic shunting leading to a bicarbonate-rich hypercholeresis. Nor-UDCA has
anti-inflammatory, anti-proliferative and anti-fibrotic effects, and stimulates bile salt
detoxification. This drug may be potentially of benefit in patients undergoing OLT and
may reduce the incidence and severity of biliary injury leading to NAS. Finally, drugs
that can affect biliary phospholipid and bile salt excretion via nuclear receptors (FXR,
PPAR-alpha) could theoretically be of benefit as a prophylactic approach to prevent
bile salt-induced biliary injury after OLT. Time has come to design and initiate clinical
studies. An attractive fist option to study will be the potential benefits of UDCA or nor-
UDCA in liver transplant recipients. Since NAS is frequently observed after DCD liver
transplantation, this category of patients could be an attractive focus for future research.
The efficacy of UDCA or nor-UDCA should ideally be evaluated in a large-scale
multicenter placebo-controlled randomized trial in DCD liver transplant recipients.
Initiatives for such a multicenter study have recently been taken.
163
References
1. Geuken E, Visser D, Kuipers F, Blokzijl H, Leuvenink HG, de Jong KP, Peeters
PM, et al. Rapid increase of bile salt secretion is associated with bile duct injury
after human liver transplantation. J Hepatol 2004;41:1017-1025.
2. Wheatley AM. Hepatic artery and post-transplantation hemodynamics and
function. Am J Transplant 2004;4:290; author reply 291.
3. Beuers U. Drug insight: Mechanisms and sites of action of ursodeoxycholic acid
in cholestasis. Nat Clin Pract Gastroenterol Hepatol 2006;3:318-328.
164status: Publishe
Author Co-Citation Analysis (ACA): a powerful tool for representing implicit knowledge of scholar knowledge workers
No full textIn the last decade, knowledge has emerged as one of the most important and valuable organizational assets. Gradually this importance caused to emergence of new discipline entitled ―knowledge management‖. However one of the major challenges of knowledge management is conversion implicit or tacit knowledge to explicit knowledge. Thus Making knowledge visible so that it can be better accessed, discussed, valued or generally managed is a long-standing objective in knowledge management. Accordingly in this paper author co- citation analysis (ACA) will be proposed as an efficient technique of knowledge visualization in academia (Scholar knowledge workers)
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