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Sunday, November 11, 2012

Molecular profiling in multiple myeloma Broyl, A. Multiple Myeloma (MM) is a malignant plasma cell disorder accounting for 1% of all malignant diseases and 10% of hematological malignancies. The annual incidence world-wide of MM is approximately 0.4 to 5 per 100.000, with high incidence rates in North America, Australia/New Zealand, Northern Europe, and Western Europe compared with Asian countries. Within the United States, the incidence in African Americans is about double that in Caucasians, whereas persons of Japanese and Chinese origin have lower rates. In the Netherlands the annual incidence of MM is 5 per 100.000 and increases progressively with age, the median age of diagnosis is 70 years. MM is characterized by clonal expansion of malignant plasma cells in the bone marrow. The myeloma plasma cell is a post-germinal centre plasma cell which has undergone somatic hypermutation and immunoglobulin class switching. MM cells secrete a monoclonal protein (M-protein) which can be detected in serum and/or urine. The M-protein is IgG in 50% of patients, and IgA in 30% of patients or consists of light chain (15%). In rare cases, secretion of IgD (1%–2%), IgM (0.2%), or IgE (even less frequent), or absence of secretion (non-secretory MM) is found. Osteolytic bone lesions are the hallmark of MM. Other characteristic clinical features include renal injury, anemia, hypercalcemia and immunodeficiency with recurrent infections. These features may result directly from mass accumulation of plasma cells in tissues (plasmacytomas) or indirectly from effects of the M-protein and/or cytokines secreted by the plasma cells. Furthermore a high level of M-protein can cause hyperviscosity, renal failure and neuropathy.

Genetic determinants of Von Willebrand factor and the risk of cardiovascular disease Loon, J.E. van

Normal haemostasis requires a delicate balance between procoagulant and anticoagulant factors. Disruption of this balance may lead to bleeding disorders, such as hemophilia, or thrombotic disorders, including deep vein thrombosis of the leg. As Virchow already reported in 1877, properties of the blood vessel wall, the blood flow and blood constituents contribute to the formation of thrombi in either veins or arteries. However, through contemporary research the complexity of this process leading to thrombus formation has become more apparent. An important player in thrombus formation is von Willebrand Factor (VWF), a large multifunctional glycoprotein. VWF initiates adherence of platelets to the injured vessel wall and subsequent platelet aggregation leading inevitably to the formation of thrombi. In addition, VWF is a carrier protein of coagulation factor VIII (FVIII), thereby protecting it from clearance. In healthy subjects normal plasma VWF levels range from 0.60 – 1.40 IU/mL and are characterized by a large variation. This can be partly attributed to a number of lifestyle and environmental factors, but most importantly to genetic factors. The necessity of maintaining normal VWF levels in the circulation is illustrated by two clinical manifestations that may occur when VWF exceeds its normal range. Low levels of VWF may lead to bleeding, which is known as von Willebrand Disease (VWD), the most common inherited bleeding disorder in humans. To the contrary, high VWF antigen (VWF:Ag) levels are associated with an increased risk of venous thrombosis and arterial thrombosis, including myocardial infarction (MI) and ischemic stroke.

Short Adolescents Born Small for Gestational Age : Gonadal and thyroid function, bone mineral density, quality of life and adult height: The effects of growth hormone and additional postponement of puberty Lem, A.J.

From 1991, our research group and others have been investigating children with short stature who were born small for gestational age (SGA), both before and during treatment with biosynthetic growth hormone (GH). In 2005, GH treatment was licensed for short SGA children in the Netherlands. Many questions though remained unanswered, especially about the efficacy of GH treatment when started at an older age, just before or during puberty. This doctoral thesis describes studies evaluating short adolescents born SGA who were treated with GH, and additionally with postponement of puberty by gonadotropin-releasing hormone analogue (GnRHa).

Wednesday, September 19, 2012

Mechanistic refinement of the common marmoset model for multiple sclerosis Jagessar, S.A. 2012-05-23 Doctoral Thesis

Multiple sclerosis (MS) is a chronic neurological disease that affects the brain and spinal cord. It is thought that MS is an autoimmune disease, where a person’s immune system reacts to its own body, namely the myelin sheath that surrounds the nerve cells. Disease symptoms include vision problems, imbalance and paralysis of the limbs. The exact cause of MS is still unknown, and therapies without adverse effects are not available. Substantial evidence suggests that the disease arises as a result of a certain combination of environmental, genetic and infectious circumstances. We hypothesize that herpesviruses create a repertoire of autoreactive T-cells, which play a crucial role in the demyelination process. To unravel the contribution of these autoreactive T-cells to the pathogenesis of MS, the common marmoset is used as an animal model for MS. The common marmoset is a relevant model with a close genetic and immunological proximity to humans, and it resembles the disease in its clinical and pathological presentation. This thesis describes how the common marmoset model for MS is refined ethically, mechanistically, and conceptually to better understand the underlying pathogenic processes, as well as to develop and improve new targets for MS therapy. 

Transcriptional Regulation of the Human Hepatic Lipase Gene: Relation to Glucose and Lipid Metabolism Deursen, D. van 2012-05-23 Doctoral Thesis

Hepatic Lipase (HL; EC is an extracellular glycoprotein with phospholipase A1 and triacylglycerol hydrolase activity. The human HL protein is encoded by the LIPC gene on chromosome 15q21. Most of this protein is synthesized in the parenchymal cells of the liver and secreted into the space of Disse where it binds to heparin sulfate proteoglycans. Some synthesis of HL was also observed in macrophages. The HL protein is also present in the steroidogenic adrenal glands, ovaries and, in small amounts, in the testes. By using heparin, HL protein is displaced from its binding site. Human HL protein is a homodimer, the monomer has a molecular weight of 65 kDa. In the metabolism of plasma lipoproteins HL plays an important role; it mediates the conversion of high density lipoprotein subfraction 2 (HDL2) to high density lipoprotein subfraction 3 (HDL3), the conversion of intermediate density lipoprotein (IDL) to low density lipoproteins (LDL), and the formation of small dense LDL (sdLDL) from large buoyant LDL. HL has a role in postprandial lipid transport where it facilitates the clearance of remnant lipoproteins by the liver. In adrenals and ovaries the HL enzyme facilitates the delivery of HDL cholesterol for steroidogenesis, at least in the rat. HL expression is determined by genetic, hormonal and nutritional factors, and by body composition. HL activity is associated with a risk for Coronary Artery Diseases (CAD). Whether high HL expression is anti- or pro-atherogenic depends on other genetic or metabolic factors, e.g. concomitant hypertriglyceridemia [1,19]. Humans with visceral obesity and insulin resistance or type 2 diabetes show increased levels of HL expression. How HL gene expression is altered in insulin-resistant conditions is unknown. Relative to the common LIPC C-allele (referring to the C/T polymorphism at the -514 position), carriers of the T-allele have reduced post-heparin HL activity, and the T-allele is associated with dyslipidemia and insulin resistance in healthy controls and in Familial Combined Hyperlipidemia (FCH). In cell culture experiments using human HepG2 hepatoma cells, HL expression was found to be increased by elevated levels of fatty acids and glucose, conditions that prevail in insulin resistance. How these metabolic factors affect HL expression is largely unknown. 

Imaging Techniques for the Assessment of Atherosclerosis, Intracoronary Devices and Vessel Response after Metallic or Polymeric Scaffold Implantation Brugaletta, S. 2012-05-22 Doctoral Thesis

The recognition of the ubiquity of substantial but non-" ow limiting lesions that may be at high risk for subsequent plaque rupture and cannot be identi! ed by coronary angiography has resulted in a paradigm shift in thinking about the pathophysiology of coronary artery disease, with the focus no longer solely on the degree of arterial luminal narrowing. This growing need for more information about coronary atherosclerosis in order to identify patients and lesions at risk for complications during PCI and for future adverse cardiac events has been the primary impetus for the development of novel intra-coronary imaging methods, able to detect plaque composition. The introduction of intravascular ultrasound (IVUS) initially allowed a detailed evaluation of coronary atherosclerosis, but its limited resolution (axial 100-200 μm) precluded the visualization of certain microstructure and its capability to characterize coronary plaques, based on their greyscale-IVUS appearance, is limited. For these reasons, some other ultrasound and light based intra-coronary imaging techniques have been developed in order to provide tissue characterization of the coronary plaques. 

Prostate Cancer Screening : The effect on prostate cancer mortality and incidence Leeuwen, P.J. van 2012-05-16 Doctoral Thesis

At first glance, deciding whether to get the PSA screening test for prostate cancer seems to be pretty straightforward and attractive. It’s a simple blood test that can pick up the prostate cancer long before your symptoms appear. After all, your prostate cancer is earlier treated resulting in cure and better outcome. Therefore prostate cancer screening seems to be suitable for public commercials. However, many of the cancers that will be detected by screening are so slow-growing that might never cause problems during mens life. Moreover, their diagnosis by biopsy, and treatment, might be worse than the disease itself. Therefore, prostate cancer screening looks favourable; however, watch out for the prostate cancer bomb. 

Tuesday, September 18, 2012

Malaysian Journal of Biochemistry and Molecular Biology (ISSN 1511-2616) Volume 17 No 1 - 2009

Substitution of GPR Grade Salts in the Production of α-Amylase by Bacillus licheniformis 6346 in Solid State Fermentation
Author(s): Vasanthy Arasaratnam, Kulasingam Thayaananthan
Category(s): Research paper

Analysis of Parameters for Fatty Acid Methyl Esters Production from Refined Palm Oil for Use as Biodiesel in the Single- and Two-stage Processes
Author(s): Zul Ilham Zulkiflee Lubes, Muhamad Zakaria
Category(s): Research paper 

Sequencing and Analysis of a 40 kb Region from the Toxoplasma gondii Genome
Author(s): Siew-Fun Wai, King-Hwa Ling, Wai-Yan Yee, Rahmah Mohamed, Kiew-Lian Wan
Category(s): Research paper 

Expression of Akt and MAPK in the Normal and Regenerating Peripheral Nerves and Their Dorsal Root Ganglia
Author(s): Murali Naidu, Rosie Pamela David, Richard Asher, James Fawcett
Category(s): Short communication 

The Angiotensin-Converting Enzyme Inhibitor, Captopril, Alters Some Biochemical Laboratory Measurements In Vitro
Author(s): Ibrahim IA, Al-Joudi FS
Category(s): Short communication 

Abstracts of the 33rd Annual Conference of the Malaysian Society for Biochemistry and Molecular Biology
Author(s): Abstract
Category(s): MSBMB conference abstract 

Tuesday, June 19, 2012

Communicable disease threats report, 10-16 June 2012, week 24

Annual epidemiological report 2011 - Reporting on 2009 surveillance data and 2010 epidemic intelligence data

Annual epidemiological report 2011
This edition of the Annual Epidemiological Report presents the surveillance data reported to ECDC for 2009 and an analysis of the public health threats detected in 2010 through ECDC’s routine epidemic intelligence.
It provides an overview of communicable diseases in the European Union and describes areas where a more concerted public health response is required in order to decrease the burden of disease on society and healthcare systems.

Tuberculosis surveillance and monitoring in Europe 2012

Monitoring the Emergence of Antiretroviral Resistance

The World Health Organization (WHO) has played a leading role in developing
strategies for the surveillance and containment of antimicrobial resistance in bacterial
and parasitic diseases. The goal has been to optimize patient care and to minimize the
emergence and spread of antimicrobial drug resistance. Just as for bacterial and parasitic diseases, a global resistance monitoring programme is also needed for HIV/AIDS. In the developed world the remarkable reduction of HIVrelated morbidity and mortality produced by potent antiretroviral therapy has been
accompanied by an increase in the prevalence of drug-resistant viruses unresponsive to
available therapies. In the developing world, as access to antiretroviral agents increases,
drug resistance may be enhanced by inappropriate treatment and lack of adherence to
treatment regimens. The need to develop a global antiretroviral resistance monitoring programme was
addressed at the consultation organized by WHO in collaboration with the International
AIDS Society (IAS) and the Istituto Superiore di Sanità (ISS) and held in Rome,
October 2000. It was proposed that WHO, in collaboration with IAS, develop a detailed plan of action
involving partnerships with existing antiretroviral (ARV) resistance monitoring centres
and networks. The plan will be based on the following priorities agreed upon by the
participants at the consultation: 

• to identify sites that are currently involved in HIV-1 drug resistance monitoring
activities and to catalogue these activities
• to develop uniform criteria for the collection and reporting of HIV-1 drug resistance
• to develop and maintain a surveillance system that determines HIV-1 drug resistance
• previously untreated patients
• targeted ARV-experienced populations (e.g. those who have a history of ARV
therapy; those who are receiving active therapy; or those who have received
therapy through perinatal transmission prevention programmes)
• to monitor simultaneously the subtype of circulating HIV-1 strains by using protease
and/or reverse transcripts sequences
• to determine trends in the prevalence of drug resistance in different geographical
areas in relation to the introduction of ARV therapy
• to establish linkages between surveillance sites and quality controlled laboratories
and to promote technology transfer of drug resistance testing methodologies to sites
in the developing world
• to promote education about strategies that reduce the selection of antiretroviral

Implementing Antimicrobial Drug Resistance Surveillance and Containment for HIV, Tuberculosis and Malaria (923K) (2003)

Antimicrobial Resistance Surveillance Questionnaire for Assessment of National Networks DEPARTMENT OF

Comprehensive quality systems are essential in order to ensure the validity of results from
microbiological investigations and epidemiological analyses in antimicrobial resistance
(AMR) surveillance. To be effective such systems should:
be focused on the organisms of greatest public health importance (i.e. with high mortality
and/or morbidity, and where therapeutic options may be severely limited by antimicrobial
include organisms that are readily transmissible (i.e. may give rise to outbreaks and epidemics);
provide information for action at the local, intermediate and national levels.
The laboratories involved must be suitably staffed and equipped in order to produce
meaningful antimicrobial resistance data. The work must be organized in a way that will
detect unacceptable levels of random and systematic errors and initiate remedial actions. The
primary clinical objective of antimicrobial susceptibility testing is to guide the clinician in
the treatment of individual patients. This requires the transmission of valid information to the
decision-maker in a timely manner with appropriate interpretation for the non-expert. For
antimicrobial resistance surveillance networks it is equally important to realize that data
generated for clinical purposes will need to be adapted for epidemiological use. This includes
a precise definition of the population from which the samples are collected. It is also
desirable to include mechanisms to avoid duplicates and to be able to sort isolates according
to specific properties such as specimen type, gender, age, hospital versus community
acquisition of infection, etc. No surveillance programme can fulfil all the suggested criteria,
but a description of the programme needs to address these issues.
The present questionnaire is only one component of a strategy for quality assessment. The
aim is to provide a means for laboratory networks currently active in antimicrobial resistance
surveillance to assess the status of the individual laboratories in the network (Component I)
with respect to basic laboratory capacity and infrastructure (Part 1), the ability to isolate and
identify bacterial isolates (Part 2), and the performance of antimicrobial susceptibility testing
(Part 3). Component II is a tool for evaluation of the network coordinating centre and the
overall functioning of the surveillance network. A comprehensive description of quality
systems specifically tailored for AMR surveillance is presently being prepared by WHO.

Surveillance standards for antimicrobial resistance

The continuing emergence of pathogenic microorganisms that are resistant to first-line antimicrobials is a cause of increasing concern. This emergence is associated with higher levels of mortality
and morbidity which not only impacts on patients but also increases the burden on health care
services as a result of additional diagnostic testing, prolonged hospital stay and increased intensity and
duration of treatment. Although the mechanisms by which organisms acquire resistance are often well understood, including the selective pressures arising from exposure to antimicrobials, the precise role of drug usage in selection of drug resistance has yet to be fully elucidated. Nonetheless, there is evidence to suggest
that more prudent usage of antimicrobials particularly in the treatment of human disease, but also in
veterinary practice, animal husbandry and agriculture, could make a significant impact on the pace
and extent to which resistance emerges in microorganisms pathogenic to man.To be effective, the control and prevention of infection due to resistant microorganisms must be an integral part of the prevention and management of communicable diseases in general. Thus, describing the distribution of infection due to resistant organisms within populations, together with changes in patterns of those infections over time,
provides the basic information for action both to control disease caused by resistant microorganisms
and to contain the emergence of resistance. Used in conjunction with disease prevention and infection
control procedures and data on antibiotic usage, strategies can be developed to protect the public
health now and in the future.

WHO Global Strategy for Containment of Antimicrobial Resistance

In the late 1990s and 2000, WHO convened a series of consultative groups, expert workshops, and consensus meetings to assess the growing public health threat of antimicrobial resistance, to evaluate the impact of containment interventions, and to develop a series of recommendations for action. The culmination of this work was the publication in 2001 of the WHO Global Strategy for Containment of Antimicrobial Resistance and a series of supportive background materials and technical guidelines.

Tuesday, June 5, 2012

Self-report in Youth Health Monitoring: evidence from the Rotterdam Youth Monitor Looij-Jansen, P.M. van de 2010-04-01 Doctoral Thesis

Under Dutch law, preventive youth healthcare organisations have a duty to ensure the early identification of children with health or developmental problems. Similarly, municipalities have a duty to monitor young people’s health at least every four years. For problem identification and monitoring, both individual and collective, these organisations often use self-report questionnaires. The overall aim of this thesis is to study various methodological and validity issues related to the use of self-report questionnaires among young people in a preventive youth healthcare setting. Seven specific research questions are derived from the Rotterdam Youth Monitor (RYM), a longitudinal youth health surveillance system integrated into preventive youth healthcare in the greater Rotterdam area.

Three-Dimensional Vestibulo-Ocular Reflex in Humans: a Matter of Balance Goumans, J. 2010-04-14 Doctoral Thesis

The objective of this thesis was to quantify three-dimensional ocular stability in response to head movements in healthy human subjects and in patients with various types of peripheral vestibular disorders. Despite a large increase in our knowledge from animal and human studies about the neuronal circuitry that regulates three-dimensional (3D) vestibular organization (for a recent review see Angelaki and Cullen 2008), its application to clinical practice is still a long way ahead. In order to bridge this gap, we explored in healthy subjects the naturally occurring variability in 3D vestibulo-ocular stabilization and compared these results with changes that occur in 3D vestibulo-ocular stabilization in patients with various types of unilateral vestibular disorders. 

Wednesday, May 23, 2012

Pediatric Inflammatory Bowel Disease: from a translational perspective Damen, G.M. 2010-04-14 Doctoral Thesis

Crohn’s disease (CD) and ulcerative colitis (UC), the two main subtypes of inflammatory bowel disease (IBD), are chronic relapsing inflammatory disorders of the gastrointestinal tract that have a peak age of onset in the second decade of life in children. There is strong evidence to support that dysregulation of the normally controlled immune response to commensal bacteria in a genetically susceptible individual drives IBD. Patients typically suffer from frequent and chronically relapsing flares, resulting in abdominal pain, diarrhea, rectal bleeding and weight loss. In CD, inflammation is transmural and often discontinuous. In UC, inflammatory changes typically involve the superficial mucosal and submucosal layers of the intestinal wall. CD most commonly involves the ileum and colon, but can affect any region of the gut. UC classically involves the rectum and inflammation may extend as far as the caecum in a typical continuous pattern. Patients with IBD may have various extra-intestinal symptoms such as oral ulcers, uveitis, arthalgias or arthritis and sclerosing cholangitis. IBD is heritable, 5 to 20% of the patients have a family history of the disease. This positive family history of IBD is more frequently observed in patients with CD than in UC. In IBD, there is a significantly higher rate of disease concordance in monozygotic twins compared with dizygotic twins.

Psoriasis: Comorbidity and Treatment Wakkee, M. 2010-04-15 Doctoral Thesis Dermatology

Psoriasis is universal in occurrence, although the worldwide prevalence varies between 0.6% and 4.8%.The prevalence of psoriasis in people of Caucasian descend is approximately 2%. In the Netherlands it is therefore estimated that approximately 300,000 people are diagnosed as having psoriasis. Its prevalence is equal in men and women and can first appear at any age, from infancy to elderly, although the mean age of development has suggested to be around 30 years old. Some studies suggest the presence of two forms of psoriasis related to the age at onset. Early onset psoriasis, which comprises approximately 75% of the psoriasis population, presents itself before the age of 40 mostly with a positive family history and with more severe disease. While late onset psoriasis presents itself after the age of 40 and may have a less severe clinical course. However, other studies were not able to confirm the presence of more severe psoriasis in those subjects with an early age of onset. The extent of body surface area affected by psoriasis is variable, but in most people the severity of their psoriasis is reasonably stable over time. Based on a patient survey the prevalence of moderate to severe psoriasis (i.e. more than 3% of the body surface area affected) was recently estimated to be approximately 17%. 

Population-based screening for colorectal cancer Hol, L. 2010-04-16 Doctoral Thesis Psychiatry

The incidence of colorectal cancer (CRC) shows considerable geographical differences around the world. The highest incidence rates are mainly seen in the Western world including North America, Australia/New Zealand, Western Europe, and Japan. Development countries report the lowest incidence rates. In Europe, CRC is the second most common diagnosed cancer in women and third in men (13% of all cancer cases in both women and men). Incidence rates are somewhat higher in men (1.2:1.0). The lifetime incidence of CRC in patients at average risk is approximately five percent. Incidence rates show demographic disparities over the last decades, with a gradual increase in South/Eastern Europe, stabilising numbers in North and West Europe, and a declining trend in the United States. Age is a major risk factor for the development of CRC. CRC rarely develops before the age of 40 (IKC), except in patients with a genetic predisposition. Incidence rates rapidly increase beyond the age of 50. In Europe, CRC ranked second (12% of all cancer related mortality) in terms of cancer related mortality 1, despite the significant increase in five-year survival in the last two decades. This improvement was in particular due to resection of rectal cancer with sharp dissection of the mesorectum en bloc with the rectum (total mesorectal excision) combined with pre-operative radiotherapy, and usage of new chemotherapeutic agents in various combinations. Additionally, improvement in outcome can be attributed to detection of the disease at an earlier stage due to screening and surveillance programmes.

The development of children's problem behaviors: A twin-singlton comparison and the influence of parental divorce Robbers, S.C.C. 2012-04-19 Doctoral Thesis

Twin-family studies have largely contributed to our understanding of the etiology of behavioral and emotional problems in childhood. From these studies we learned that almost every behavioral or psychological trait is ‘heritable’ to some extent. We also learned that both nature and nurture play important roles in the etiology of behavioral and emotional problems, and that these factors may act independently of one another as well as interactively (i.e., gene-environment interplay). Moreover, twin studies have given insight into the important distinction between environmental factors shared by siblings (e.g., parental socio-economic status) and those not shared by siblings (e.g., peer groups) (Boomsma, Busjahn, & Peltonen, 2002; Hudziak & Faraone, 2010). An important assumption that is made when using twin data is that results from twin samples can be generalized to singleton populations. However, the validity of this assumption needs to be examined. 

The Manchester Triage System in paediatric emergency care Veen, M. van 2010-04-16 Doctoral Thesis

In the first part of the thesis performance of the Manchester Triage System in paediatric emergency care was evaluated. In chapter 1 we reviewed the literature to evaluate realibility and validity of triage systems in paediatric emergency care. The Manchester Triage System was used to triage patients when presenting at the emergency department of a general teaching hospital and the emergency department of a university paediatric hospital. The system’s reliability was evaluated in chapter 2. Its validity and specific patients groups for which validity was not optimal were discussed in chapter 3. Chapter 4 evaluates patient problems for which the MTS performs severe under-triage. The second part focuses on improvements of the MTS. Chapter 5 focuses on the value of temperature as discriminator in triage systems. The MTS was modified for patient groups with a low validity and the effect of the modification on the reliability and validity are studied in chapter 6. In the third part of this thesis we assess the ability of the MTS to safely identify low urgent patients. In chapter 7 determinants of hospitalisation for low urgent patients were evaluated. Chapter 8 reports about compliance and effect on costs when low urgent children, when presenting to the ED are referred to the general practitioner cooperative. Chapter 9 provides a summary of the findings and the future prospects. 

The Dutch Living Donor Kidney Exchange Program Klerk, M. de 2010-04-22 Doctoral Thesis

Kidney transplantation is the optimal option for patients with an end-stage renal disease. The first successful transplantation with a living genetically related donor has been performed since 26 October 1954, when an identical twin transplant was performed in Boston. In the years that followed, efforts to enable non-twin transplants unfortunately failed because effective immunosuppression was not yet available. It took until the early sixties after the discovery of azathiopirine that also deceased donor kidney transplantations became possible. In the eighties of the last century the wait time for a kidney transplant was approximately one year. Since that time the success rate of organ transplantation has significantly improved which attracted large numbers of transplant candidates. As the number of deceased organ donors did not increase, the wait time on the list steadily grew and at the moment patients in most Western countries face wait times up to 5 years before a deceased donor kidney is offered. Unfortunately an increasing proportion of them will never be transplanted because their clinical situation deteriorates to such an extent that they are delisted or die on the wait list. For the Netherlands we estimate that this proportion is approximately 30%. A strategy to expand the kidney donor pool includes the use of non-heart beating (NHB) donors. Educational programs in the Netherlands have resulted in an increase in the number of kidney transplants derived from NHB donors from almost 20% in the year 2000 to 43% in 2004, while in the years that followed the numbers of NHB donors stabilized. So the NHB donors have not led to expansion of the deceased kidney donor pool. Possibly substitution from heart beating to non heart beating donation procedures took place, resulting from pressure on the facilities of intensive care units. In the Netherlands, it has been suggested that the main reason for our failure to increase the number of deceased organ donors is the lack of donor detection. This is certainly not the case; both in 2005 and in 2006 almost all potential donors in the Netherlands (96%) were recognized as such and for the vast majority (86%) our national donor registry was consulted. The problem is not donor detection but the high refusal rate by the next of kin, which is inherent to our legal system. Our organ donation act dictates an opt-in system, and therefore all adult citizens are asked to register their consent for the use of their organ for transplantation purpose after death. In the Netherlands approximately 25% of the adults are now registered as potential donors, 15% have explicitly refused and thus for 60% it remains unknown. Especially in case of potential donors of the latter category high refusal rates up to 70% haven been found. Apparently next of kin argue that while the possibility was given to everybody to register as donor, their relative did not do so, therefore they are unaware of consent and thus reluctant to give permission for donation. We feel that an opt-out organ donation system would be very much helpful to expand the deceased kidney donor pool. However, we are aware that even if all potential deceased donors became actual donors, there still would be a shortage of donor kidneys. Therefore the use of kidneys from living donors is an obvious way to go. These transplants result in a superior unadjusted graft survival compared to deceased donor kidneys. It has been calculated that the difference in 10 years survival between living and deceased donor kidney transplantation is 34 %. 

Economic evaluations of health technologies: insights into the measurement and valuation of benefits Bobinac, A. 2012-05-11 Doctoral Thesis

Economic evaluations have been applied in the field of healthcare for several decades with the principle aim of improving the economic efficiency of resource allocation, i.e., help maximizing benefits from available (and constrained) resources. Broadly speaking, “economic evaluation is the comparative analysis of alternative courses of action in terms of both their costs and consequences” (Drummond et al., 1997). Economic evaluations became reasonably well-accepted in the decision-making process within the systems of different countries because they offer a promise of a systematic and transparent framework for deciding which intervention - among alternative interventions - to fund from a restricted budget. That is, once efficacy and effectiveness have been established, decision-makers can decide between competing interventions based on their relative cost-effectiveness and thus maximize the aggregate (value of) health benefits attained. 

Recovery after total hip or knee arthroplasty: physical and mental functioning Dikmans-Vissers, M.M. 2012-05-10 Doctoral Thesis

Musculoskeletal complaints are extremely common and have important consequences for the individual and society. The most prevalent chronic musculoskeletal disease is osteoarthritis (OA). OA is a disease of the articular joint and can lead to severe disability. In Western adult populations it is one of the most frequent causes of pain and stiffness, loss of function and disability. With regard to the major joints, OA is most prevalent in the knee and hip joint. In the Netherlands, in 2007 about 312,000 persons had knee OA and 238,000 persons had hip OA. Based on demographic development it is expected that the absolute number of persons with OA will increase by about 52% between 2007 and 2040. If the expected increase of patients with obesity is also taken into account, the prevalence of OA will become even greater. The initial treatment of OA consists of pain medication, physical therapy, and lifestyle recommendations. These treatments aim to suppress the symptoms and to improve or maintain functioning. When conservative treatment fails to alleviate pain and dysfunction caused by knee or hip OA, total knee arthroplasty (TKA) and total hip arthroplasty (THA) are cost-effective surgical options that can provide significant pain relief and improvement in physical functioning. The number of TKA and THA procedures performed in the Netherlands has increased substantially in the last decades. Between 1996 and 2008 the annual number of TKAs placed in the Netherlands in patients with a primary diagnosis of OA increased from 4,046 to 11,881, an increase of almost 300%. During this same period, the number of THAs placed in the Netherlands increased from 16,803 to 17,401 procedures. Because of the aging of the Western population, together with the increasing number of people with overweight and the improvements in surgical techniques, these numbers are expected to increase even further. 

Red Wine Polyphenols and Vascular Function Botden, I.P.G. 2012-05-09 Doctoral Thesis

Hippocrates, the father of modern medicine, said many centuries ago: “let food be your medicine.” Today, this quote still shows its value, amongst others by the !nding that red wine consumption attributes to a healthy life style, reducing the risk to develop cardiovascular diseases. Cardiovascular diseases are one of the leading causes of death in many economically developed countries as well as in emerging economies.1 It has become a global epidemic problem, with type 2 diabetes, hypertension and, obviously, aging as one of the major risk factors. Red wine might interfere with one or more of these factors, and thus contribute in the prevention of cardiovascular diseases. 

Physical activity and fitness in older adults with intellectual disabilities Hilgenkamp, T.I.M. 2012-05-09 Doctoral Thesis

This thesis describes the results of the 'Healthy ageing and intellectual disability"-study concerning the theme 'Physical activity and fitness'. In this study, 1050 older adults with intellectual disabilities were included, and measured with an extensive battery of tests, including pedometers, physical fitness tests, daily functioning and mobility. Reliability and feasibility of instruments new to this population were studied and proved to be acceptable. Results of the measurements showed that this group is mostly inactive and had low physical fitness levels. 

Risk assessment of cervical disease by hrHPV testing and cytology Kocken, M. 2012-05-02 Doctoral Thesis

As cervical cancer is an important health problem worldwide with over a half million patients a year and as it is the fourth most common cause of cancer-related death in women, improving the prevention of this disease is a continuing and important process. A major reduction of cancer incidence and mortality has occurred in countries with cervical cancer screening. Because cervical cancer develops through different premalignant stages it can be detected in a premalignant stage, allowing treatment before these stages would be able to develop into cervical cancer. Chapter 1 gives a general introduction about the cervix, human papillomavirus (HPV), the model(s) of cervical carcinogenesis and different measures that are taken to prevent cervical cancer. These measures include screening, triaging of abnormal test results, colposcopic examination, treatment and post-treatment surveillance. In the vast majority of cervical cancers a persistent infection with high-risk HPV types (hrHPV) has been proven to be the causative agent in their carcinogenesis. Besides almost all cervical squamous cell carcinomas, approximately 95% of all cervical adenocarcinomas (ACs) are caused by a transforming infection with a hrHPV type. The remaining ACs are rare and sometimes seem hrHPV-unrelated, which could be caused by detection error or because these tumours are indeed caused by another, not HPV-related carcinogenic mechanism. Chapter 2 describes the attribution of hrHPV in cervical clear-cell adenocarcinoma (CCAC), relatively rare tumours (<<1% of all cervical carcinoma). These tumours have a bimodal age distribution with one peak in the early twenties and another after menopause and are characterised by clear cytoplasm and Hobnail cells. In approximately 60% of the cases this tumour has been associated with intrauterine exposure to diethylstilbestrol (DES), a synthetic oestrogen in the past (falsely) used to prevent miscarriages. In this study of 28 women with CCAC, of whom 15 were DES-exposed in utero, hrHPV was found in 13 (46.4%) tumours. However, after performing immuno-histochemistry with p16INK4a and p53 to distinguish transient hrHPV infections from transforming, carcinogenic infections, only three carcinomas remained in which a causal relation of hrHPV and CCAC was plausible. This demonstrated a very limited role of hrHPV in the carcinogenesis of CCAC. None of the hrHPV-associated tumours were found in women prenatally exposed to DES. In DES-unrelated tumours only a minority (20-25%) seemed hrHPV mediated. In the Dutch population-based screening programme approximately 2.5% of screened women have borderline or mild dysplasia (BMD, PAP2/3a1). These women are retested after 6 months with either cytology of a combination of both cytology and HPV (co-testing), and after 18 months with cytology. If the tests remain abnormal, women are referred for colposcopy. However, not all women with BMD comply with this protocol. Many studies have examined the short-term value of hrHPV-testing in predicting the cumulative risk of CIN3+. In Chapter 3 we have evaluated the long-term cumulative CIN3+ risk in a group of 342 women with an abnormal cytological test result (≥ BMD). These women were followed for a time period of 17 to 19.5 years after detection. Immediate hrHPV-testing clearly stratified the CIN3+ risk; almost all CIN3+ lesions (97.1%) were found in women who tested hrHPV positive. Almost half of all hrHPV-positive women were infected with HPV16; these women had a significantly higher CIN3+ risk than women infected with other hrHPV types. This risk difference between HPV16-positive women and women positive for other hrHPV types, was only found in younger women (<30 years). In older women (≥30 years) the risks in both age groups were similar. The 5-year CIN3+ risk was lower in women who had cleared the virus within 6 months than in women with persistent hrHPV infections (2.2% versus 56.0%), with the highest risks for women with a persistent HPV16 infection (67%). We stratified the CIN3+ risks according to referral cytology and found that both women with BMD and women with >BMD referral cytology had an increased risk of developing CIN3+ within the first 5 years after detection. This risk was twice as high in women with >BMD compared to women with BMD (45% versus 22%). In the subsequent 5 years an increased risk (3.5%) remained for women with >BMD, while for women referred with BMD this risk was with 0.7% similar to that of the general population. Immediate (or delayed, i.e. after 6 months) hrHPV testing clearly stratified the risk in women with BMD; the 5-year risk in hrHPV-negative women was 0.01%, and in hrHPV-positive women 37.5%. Therefore we support the strategy to refer hrHPV-negative women with BMD to routine screening and to refer those who are hrHPV positive for additional testing or colposcopy. When these women do not develop CIN3+ within 5 years, they also may be referred to population-based screening. Additional (baseline) hrHPV-testing in women with >BMD did not result in a group with a risk low enough to refrain from colposcopy, therefore we do not advocate hrHPV testing in this group and advise to refer all these women for colposcopy. As their CIN3+ risk is elevated for at least 10 years, long-term monitoring is required. Chapter 4 focuses on women treated for high-grade cervical disease (CIN2/3). As over 10% of treated women will develop residual/recurrent (post-treatment) high-grade cervical disease, they are closely monitored by cytological testing after treatment. Most published studies concern the risk-assessment of developing post-treatment disease up to a maximum of two years. Currently, treated women in the Netherlands are referred to population-based screening when they have three consecutive negative cytological test results after treatment. This means that it would take at least another three years before women are invited for population-based screening again. In order to evaluate the safety of the current regimen, long-term follow up data is essential. Also because in several other countries yearly follow-up for up to 10 years after treatment. As successful treatment is associated with the elimination of hrHPV, hrHPV testing has been suggested as an improvement in post-treatment surveillance. In Chapter 4.1 a multi-cohort study is described that includes 435 women followed between 5 and 21.5 years after treatment. Different post-treatment test algorithms were analysed; sole cytological testing, sole hrHPV-testing and combined testing with both cytology and hrHPV (co-testing). The overall 5-year CIN2+-risk in this cohort was 16.5%. However, in women who tested consecutively negative for cytology (at 6,12 and 24 months after treatment) this risk was lowered to 2.9% and even to 1.0% in women who tested negative for co-testing at both 6 and 24 months after treatment. The risk of developing CIN3+ in treated women with three consecutive negative cytological test results is similar to the risk of developing high-grade cervical disease in women who test negative for cytology (PAP1) in population-based screening. However, by adding hrHPV-testing to post-treatment surveillance, a better risk-assessment could be reached with even fewer visits. In order to judge the results found in this multi-cohort study, studies which compared different surveillance methods (cytology, hrHPV or co-testing), tested six months after treatment, were systematically reviewed in Chapter 4.2. After a bibliographic database search, relevant studies published between January 2003 and May 2011 were identified by two reviewers with a multi-step process. Then the selected studies were methodological assessed with a modified version of the QUADAS tool (QUality Assessment of Diagnostic Accuracy Studies). Eventually, only eight out of 2410 identified studies remained, incorporating 1513 treated women. The sensitivity of hrHPV testing to predict post-treatment CIN2+ was significantly higher than of cytology (relative sensitivity 1.15; 95%CI 1.06-1.25), while the specificity of these tests was similar (relative specificity 0.95, 95%CI 0.88-1.02). The sensitivity of co-testing was the highest (95%), however this combined test had the lowest specificity (67%). In summary, this review supports the inclusion of hrHPV testing in post-treatment monitoring protocols. The general discussion in Chapter 5 summarizes the findings of this thesis and discusses possible future prospects and clinical consequences. 

Monday, April 30, 2012

The Clinical Value of Intensive Monitoring in Term Asphyxiated Newborns Swarte, R.M.C. 2010-04-22 Doctoral Thesis Pediatrics

Perinatal asphyxia is an important cause of brain injury. It may lead to hypoxic-ischaemic encephalopathy (HIE) which occurs in one to six of every 1000 full term births. The risk of death or severe handicap is 0.5-2.0 out of 1000. Following intrapartum asphyxia cerebral hypoperfusion in combination with hypoxia produces characteristic neuropathological changes and related clinical signs. After the primary insult there is a thirty minutes period of reperfusion characterized by the partial recovery of cell and metabolic processes. This is followed by a latent phase which may last up to six hours. In this phase oxidative metabolism (near) normalizes (shown by MRspectroscopy) but EEG activity is depressed and the blood flow is likely to be reduced. Secondary energy failure and secondary hyperperfusion (‘luxury perfusion’) may occur in the neonatal brain within 6-15 hours after an acute ischaemic insult, marked by the acute onset of seizures (peaking at about 12 hours post insult). Excitotoxins accumulate in the cell and cell death may take 72 hours to completion. The infant’s gestational age and thus the maturational stage of the brain, as well as type, severity and duration of the insult are determinants of the brain injury. During the insult there is redistribution of blood flow to the brain, heart and adrenals. Our current understanding of perinatal asphyxia is based on animal experiments. Different and mixed etiologies lead to a range of post asphyxial patterns, usually subdivided into different patterns; acute, chronic or a combination of these two. With chronic, possibly repetitive insults, lesions are predominantly seen in (sub)cortical structures. This has been named watershed injury for its classical distribution along the borderzones between the major pial arteries, sparing thalamus and basal ganglia. From the literature it appears that watershed injury is observed most frequently in context of term birth asphyxia. In acute and (near) total asphyxia the damage is mostly to the thalami, basal ganglia, hippocampus, cerebellum, brain stem and specific areas of the neocortex like the rolandic, calcarine and insular cortex.