Total Pageviews

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.