Erasmus University Medical Center

About: Erasmus University Medical Center is a healthcare organization based out in Rotterdam, Zuid-Holland, Netherlands. It is known for research contribution in the topics: Population & Medicine. The organization has 8162 authors who have published 11395 publications receiving 517117 citations.

CYP3A4*22: promising newly identified CYP3A4 variant allele for personalizing pharmacotherapy.

Abstract: Many studies have attempted to explain the interindividual variability observed in drug metabolism by assessing the impact of SNPs in genes implicated in drug absorption, distribution, metabolism and excretion pathways. Particular attention has been paid to the CYP450s. CYP3A4 is the main CYP isoform in human liver and intestine and is involved in the metabolism of many drugs. Its activity, however, is characterized by widespread variation in the general population, which is thought to have a genetic basis. A new CYP3A4 allele (CYP3A4*22; rs35599367 C>T in intron 6) with a frequency of 5-7% in the Caucasian population was recently discovered through its association with low hepatic CYP3A4 expression and CYP3A4 activity, and showing effects on statin, tacrolimus and cyclosporine metabolism. This review will summarize the current literature on phenotypes linked to this new promising CYP3A4 genetic marker SNP and discusses the potential clinical relevance.

Imatinib pharmacokinetics in patients with gastrointestinal stromal tumour: a retrospective population pharmacokinetic study over time. EORTC Soft Tissue and Bone Sarcoma Group

Abstract: Imatinib pharmacokinetics (PK) may be affected by a number of factors that are related to the disease being treated and to the response of that disease to imatinib. Patients in the phase I and phase II trials conducted by the EORTC in patients with gastrointestinal stromal tumours (GISTs) and other sarcomas had detailed blood sampling for imatinib PK on day 1 and on day 29. Patients with GISTs also had repeat sampling, using a limited sampling strategy, after approximately 12 months on therapy. This population PK study was carried out to examine what covariates affected imatinib PK in GIST patients and what PK changes occurred over time. In the model producing the best fit, low clearance (CL) correlated with low body weight and high granulocyte count, whereas low haemoglobin correlated with low volume of distribution. For a patient with 77% of the median body weight or with 1.87 times the median granulocyte count, the apparent CL is 6.53 l/h, about 70% of the typical apparent CL of 9.33 l/h; for a patient of 84% of the typical haemoglobin level, the volume of distribution is about 70%. Total white blood cell count correlated closely with granulocyte count and there was a moderate correlation between haemoglobin and albumin (r=0.454). There was a trend towards increased imatinib clearance after chronic exposure over 12 months. The typical apparent CL increased 33% from day 1. Nevertheless, the approximate 95% confidence interval of the increase of the typical apparent CL was 33±34.6%, which contains zero. It is not yet clear whether this is a significant factor in the amelioration of imatinib toxicity that occurs with time or is related to disease control, and further work is required to confirm this observation.

The function of the long dorsal sacroiliac ligament ; Its implication for understanding low back pain

Abstract: Study design In embalmed human bodies the tension of the long dorsal sacroiliac ligament was measured during incremental loading of anatomical structures that are biomechanically relevant. Objectives To assess the function of the long dorsal sacroiliac ligament. Summary of background data In many patients with aspecific low back pain or peripartum pelvic pain, pain is experienced in the region in which the long dorsal sacroiliac ligament is located. It is not well known that the ligament can be easily palpated in the area directly caudal to the posterior superior iliac spine. Data on the functional and clinical importance of this ligament are lacking. Methods A dissection study was performed on the sacral and lumbar regions. The tension of the long dorsal sacroiliac ligament (n = 12) was tested under loading. Tension was measured with a buckle transducer. Several structures, including the erector spinae muscle, the posterior layer of the thoracolumbar fascia, the sarcotuberous ligament, and the sacrum, were incrementally loaded (with forces of 0-50 newtons). The sacrum was loaded in two directions, causing nutation (ventral rotation of the sacrum relative to the iliac bones) and counternutation (the reverse). Results Forced nutation in the sacroiliac joints diminished the tension and forced counternutation increased the tension. Tension in the long dorsal sacroiliac ligament increased during loading of the ipsilateral sacrotuberous ligament and erector spinae muscle. The tension decreased during traction to the gluteus maximus muscle. Tension also decreased during traction to the ipsilateral and contralateral posterior layer of the thoracolumbar fascia in a direction simulating contraction of the latissimus dorsi muscle. Conclusions The long dorsal sacroiliac ligament has close anatomical relations with the erector spinae muscle, the posterior layer of the thoracolumbar fascia, and a specific part of the sacrotuberous ligament (tuberoiliac ligament). Functionally, it is an important link between legs, spine, and arms. The ligament is tensed when the sacroiliac joints are counternutated and slackened when nutated. The reverse holds for the sacrotuberous ligament. Slackening of the long dorsal sacroiliac ligament can be counterbalanced by both the sacrotuberous ligament and the erector muscle. Pain localized within the boundaries of the long ligament could indicate among other things a spinal condition with sustained counternutation of the sacroiliac joints. In diagnosing patients with aspecific low back pain or peripartum pelvic pain, the long dorsal sacroiliac ligament should not be neglected. Even in cases of arthrodesis of the sacroiliac joints, tension in the long ligament can still be altered by different structures.

Wnt signaling strength regulates normal hematopoiesis and its deregulation is involved in leukemia development

Abstract: A strict balance between self-renewal and differentiation of hematopoietic stem cells (HSCs) is required in order to maintain homeostasis, as well as to efficiently respond to injury and infections. Numbers and fate decisions made by progenitors derived from HSC must also be carefully regulated to sustain large-scale production of blood cells. The complex Wnt family of molecules generally is thought to be important to these processes, delivering critical signals to HSC and progenitors as they reside in specialized niches. Wnt proteins have also been extensively studied in connection with malignancies and are causatively involved in the development of several types of leukemias. However, studies with experimental animal models have produced contradictory findings regarding the importance of Wnt signals for normal hematopoiesis and lymphopoiesis. Here, we will argue that dose dependency of signaling via particular Wnt pathways accounts for much, if not all of this controversy. We conclude that there seems little doubt that Wnt proteins are required to sustain normal hematopoiesis, but are likely to be presented in carefully controlled gradients in a tissue-specific manner.