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Find video protocols related to scientific articles indexed in Pubmed.
Partial pyruvate kinase deficiency aggravates the phenotypic expression of band 3 deficiency in a family with hereditary spherocytosis.
Am. J. Hematol.
PUBLISHED: 08-31-2014
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In a family with mild dominant spherocytosis, affected members showed partial band 3 deficiency. The index patient showed more severe clinical symptoms than his relatives, and his red blood cells displayed concomitant low pyruvate kinase activity. We investigated the contribution of partial PK deficiency to the phenotypic expression of mutant band 3 in this family. Pyruvate kinase deficiency and band 3 deficiency were characterized by DNA analysis. Results of red cell osmotic fragility testing, the results of cell deformability obtained by the Automated Rheoscope and Cell Analyser and the results obtained by Osmotic Gradient Ektacytometry, which is a combination of these tests, were related to the red cell ATP content. Spherocytosis in this family was due to a novel heterozygous mutation in SLC4A1, the gene for band 3. Reduced PK activity of the index patient was attributed to a novel mutation in PKLR inherited from his mother, who was without clinical symptoms. Partial PK deficiency was associated with decreased red cell ATP content and markedly increased osmotic fragility. This suggests an aggravating effect of low ATP levels on the phenotypic expression of band 3 deficiency.
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Extracellular vesicles as drug delivery systems: Lessons from the liposome field.
J Control Release
PUBLISHED: 05-10-2014
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Extracellular vesicles (EVs) are membrane-derived particles surrounded by a (phospho)lipid bilayer that are released by cells in the human body. In addition to direct cell-to-cell contact and the secretion of soluble factors, EVs function as another mechanism of intercellular communication. These vesicles are able to efficiently deliver their parental cell-derived molecular cargo to recipient cells, which can result in structural changes at an RNA, protein, or even phenotypic level. For this reason, EVs have recently gained much interest for drug delivery purposes. In contrast to these 'natural delivery systems', synthetic (phospho)lipid vesicles, or liposomes, have been employed as drug carriers for decades, resulting in several approved liposomal nanomedicines used in the clinic. This review discusses the similarities and differences between EVs and liposomes with the focus on features that are relevant for drug delivery purposes such as circulation time, biodistribution, cellular interactions and cargo loading. By applying beneficial features of EVs to liposomes and vice versa, improved drug carriers can be developed which will advance the field of nanomedicines and ultimately improve patient outcomes. While the application of EVs for therapeutic drug delivery is still in its infancy, issues regarding the understanding of EV biogenesis, large-scale production and in vivo interactions need to be addressed in order to develop successful and cost-effective EV-based drug delivery systems.
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Ribosomal protein mutations induce autophagy through S6 kinase inhibition of the insulin pathway.
PLoS Genet.
PUBLISHED: 05-01-2014
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Mutations affecting the ribosome lead to several diseases known as ribosomopathies, with phenotypes that include growth defects, cytopenia, and bone marrow failure. Diamond-Blackfan anemia (DBA), for example, is a pure red cell aplasia linked to the mutation of ribosomal protein (RP) genes. Here we show the knock-down of the DBA-linked RPS19 gene induces the cellular self-digestion process of autophagy, a pathway critical for proper hematopoiesis. We also observe an increase of autophagy in cells derived from DBA patients, in CD34+ erythrocyte progenitor cells with RPS19 knock down, in the red blood cells of zebrafish embryos with RP-deficiency, and in cells from patients with Shwachman-Diamond syndrome (SDS). The loss of RPs in all these models results in a marked increase in S6 kinase phosphorylation that we find is triggered by an increase in reactive oxygen species (ROS). We show that this increase in S6 kinase phosphorylation inhibits the insulin pathway and AKT phosphorylation activity through a mechanism reminiscent of insulin resistance. While stimulating RP-deficient cells with insulin reduces autophagy, antioxidant treatment reduces S6 kinase phosphorylation, autophagy, and stabilization of the p53 tumor suppressor. Our data suggest that RP loss promotes the aberrant activation of both S6 kinase and p53 by increasing intracellular ROS levels. The deregulation of these signaling pathways is likely playing a major role in the pathophysiology of ribosomopathies.
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Microparticles as biomarkers of osteonecrosis of the hip in sickle cell disease.
Br. J. Haematol.
PUBLISHED: 04-22-2014
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Osteonecrosis of the femoral head (ONFH) is a common complication of sickle cell disease (SCD). To examine the association between microparticles and ONFH in SCD, we compared plasma microparticle levels in 20 patients with and without ONFH. Microparticles were quantified using nanoparticle tracking analysis and found to be 2·3-fold higher in patients with ONFH compared to patients without ONFH, and 2·5-fold higher than in healthy controls. These results suggest that microparticles may be a clinically useful biomarker of ONFH in SCD. Further investigations are needed to determine the functional relevance of microparticles in the pathogenesis of ONFH in SCD.
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Seasonal changes in gene expression represent cell-type composition in whole blood.
Hum. Mol. Genet.
PUBLISHED: 01-07-2014
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Seasonal patterns in behavior and biological parameters are widespread. Here, we examined seasonal changes in whole blood gene expression profiles of 233 healthy subjects. Using weighted gene co-expression network analysis, we identified three co-expression modules showing circannual patterns. Enrichment analysis suggested that this signal stems primarily from red blood cells and blood platelets. Indeed, a large clinical database with 51 142 observations of blood cell counts over 3 years confirmed a corresponding seasonal pattern of counts of red blood cells, reticulocytes and platelets. We found no direct evidence that these changes are linked to genes known to be key players in regulating immune function or circadian rhythm. It is likely, however, that these seasonal changes in cell counts and gene expression profiles in whole blood represent biological and clinical relevant phenomena. Moreover, our findings highlight possible confounding factors relevant to the study of gene expression profiles in subjects collected at geographical locations with disparaging seasonality patterns.
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Admittance-based pressure-volume loops versus gold standard cardiac magnetic resonance imaging in a porcine model of myocardial infarction.
Physiol Rep
PUBLISHED: 01-01-2014
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Abstract A novel admittance-based pressure-volume system (AS) has recently been developed and introduced. Thus far, the new technique has been validated predominantly in small animals. In large animals it has only been compared to three-dimensional echocardiography (3DE) where the AS showed to overestimate left ventricular (LV) volumes. To fully determine the accuracy of this device, we compared the AS with gold standard cardiac magnetic resonance imaging (CMRI) in a porcine model of chronic myocardial infarction (MI). Fourteen pigs were subjected to 90 min closed chest balloon occlusion of the left anterior descending artery. After 8 weeks of follow up, pigs were consecutively subjected to LV volume measurements by the AS, CMRI, and 3DE under general anesthesia. The AS overestimated end diastolic volume (EDV; +20.9 ± 30.6 mL, P = 0.024) and end systolic volume (ESV; +17.7 ± 29.4 mL, P = 0.042) but not ejection fraction (EF; +2.46 ± 6.16%, P = NS) compared to CMRI. Good correlations of EDV (R = 0.626, P = 0.017) and EF (R = 0.704, P = 0.005) between the AS and CMRI were observed. EF measured by the AS and 3DE also correlated significantly (R = 0.624, P = 0.030). After subjection of pigs to MI, the AS very moderately overestimates LV volumes and shows accurate measurements for EF compared to CMRI. This makes the AS a useful tool to determine cardiac function and dynamic changes in large animal models of cardiac disease.
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Fluorescence of neutrophil granulocytes as a biomarker for clozapine use.
Eur Neuropsychopharmacol
PUBLISHED: 06-24-2013
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Non-adherence to medication is a major issue in the treatment of schizophrenia in general and in particular for those treated with clozapine. A reliable tool to quantify patients long-term adherence to clozapine is currently unavailable. Enhanced FL3 neutrophil granulocyte fluorescence was serendipitously observed in a small population of schizophrenic patients treated with clozapine. The present study was aimed at assessing the association between clozapine use and FL3-fluorescence. A cross-sectional study was performed using data from the Utrecht Patient Oriented Database (UPOD). A total of 38,390 inpatients were included, of which 124 (0.33%) used clozapine. FL3-fluorescence was significantly higher (U=240,179, P<0.001) in clozapine users (mean (SD)=90.5 (11.8)) than in non-users (mean (SD)=69.8 (3.3)). Observed FL3-fluorescence was found to increase with increasing clozapine dose. The area under the receiver operating characteristic curve was 0.95. Our results confirm the association between use of clozapine and elevated FL3-fluorescence. Further research is needed to unravel the underlying mechanism and to investigate the true potential of FL3-fluorescence as a clozapine-adherence biomarker in clinical practice.
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Automated surveillance for healthcare-associated infections: opportunities for improvement.
Clin. Infect. Dis.
PUBLISHED: 03-26-2013
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Surveillance of healthcare-associated infections is a cornerstone of infection prevention programs, and reporting of infection rates is increasingly required. Traditionally, surveillance is based on manual medical records review; however, this is very labor intensive and vulnerable to misclassification. Existing electronic surveillance systems based on classification algorithms using microbiology results, antibiotic use data, and/or discharge codes have increased the efficiency and completeness of surveillance by preselecting high-risk patients for manual review. However, shifting to electronic surveillance using multivariable prediction models based on available clinical patient data will allow for even more efficient detection of infection. With ongoing developments in healthcare information technology, implementation of the latter surveillance systems will become increasingly feasible. As with current predominantly manual methods, several challenges remain, such as completeness of postdischarge surveillance and adequate adjustment for underlying patient characteristics, especially for comparison of healthcare-associated infection rates across institutions.
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Taxol(®)-induced phosphatidylserine exposure and microvesicle formation in red blood cells is mediated by its vehicle Cremophor(®) EL.
Nanomedicine (Lond)
PUBLISHED: 02-05-2013
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The conventional clinical formulation of paclitaxel (PTX), Taxol®, consists of Cremophor® EL (CrEL) and ethanol. CrEL-formulated PTX is associated with acute hypersensitivity reactions, anemia and cardiovascular events. In this study, the authors investigated the effects of CrEL-PTX on red blood cells (RBCs) and compared these with the effects observed after exposure to the novel nanoparticle albumin-bound PTX, marketed as Abraxane®.
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Extracellular vesicles in the circulation: are erythrocyte microvesicles a confounder in the plasma haemoglobin assay?
Biochem. Soc. Trans.
PUBLISHED: 01-30-2013
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Blood contains a mixture of extracellular vesicles from different cell types, primarily platelets, endothelial cells, leucocytes and erythrocytes. Erythrocytes are the most abundant cell type in blood and could, especially in certain pathologies, represent an important source of vesicles. Since erythrocytes contain the haemoglobin components iron and haem, which are potentially toxic, it is important to investigate the contribution of vesicle-associated haemoglobin to total cell-free haemoglobin levels. To our knowledge, this is the first time that cell-free plasma haemoglobin has been differentiated into vesicle-associated and molecular species. We investigated the contribution of vesicle-associated haemoglobin in residual patient material that was routinely analysed for total cell-free plasma haemoglobin. All patient samples included in the study were haemolytic with total cell-free haemoglobin concentration ranging from 80 to 2500 mg/l. In the majority of the samples, total cell-free haemoglobin concentration was between 100 and 200 mg/l. No haemoglobin could be detected in the vesicle fraction, indicating that the contribution of vesicle-associated haemoglobin to total cell free-haemoglobin levels in plasma is negligible. It is important to investigate whether erythrocyte vesicles are not formed in blood or that their production is not increased during pathologies associated with haemolysis or that the clearance rate of the vesicles surpasses the formation rate.
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Red blood cell vesiculation in hereditary hemolytic anemia.
Front Physiol
PUBLISHED: 01-01-2013
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Hereditary hemolytic anemia encompasses a heterogeneous group of anemias characterized by decreased red blood cell survival because of inherited membrane, enzyme, or hemoglobin disorders. Affected red blood cells are more fragile, less deformable, and more susceptible to shear stress and oxidative damage, and show increased vesiculation. Red blood cells, as essentially all cells, constitutively release phospholipid extracellular vesicles in vivo and in vitro in a process known as vesiculation. These extracellular vesicles comprise a heterogeneous group of vesicles of different sizes and intracellular origins. They are described in literature as exosomes if they originate from multi-vesicular bodies, or as microvesicles when formed by a one-step budding process directly from the plasma membrane. Extracellular vesicles contain a multitude of bioactive molecules that are implicated in intercellular communication and in different biological and pathophysiological processes. Mature red blood cells release in principle only microvesicles. In hereditary hemolytic anemias, the underlying molecular defect affects and determines red blood cell vesiculation, resulting in shedding microvesicles of different compositions and concentrations. Despite extensive research into red blood cell biochemistry and physiology, little is known about red cell deformability and vesiculation in hereditary hemolytic anemias, and the associated pathophysiological role is incompletely assessed. In this review, we discuss recent progress in understanding extracellular vesicles biology, with focus on red blood cell vesiculation. Also, we review recent scientific findings on the molecular defects of hereditary hemolytic anemias, and their correlation with red blood cell deformability and vesiculation. Integrating bio-analytical findings on abnormalities of red blood cells and their microvesicles will be critical for a better understanding of the pathophysiology of hereditary hemolytic anemias.
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A role for activated endothelial cells in red blood cell clearance: implications for vasopathology.
Haematologica
PUBLISHED: 11-18-2011
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Phosphatidylserine exposure by red blood cells is acknowledged as a signal that initiates phagocytic removal of the cells from the circulation. Several disorders and conditions are known to induce phosphatidylserine exposure. Removal of phosphatidylserine-exposing red blood cells generally occurs by macrophages in the spleen and liver. Previously, however, we have shown that endothelial cells are also capable of erythrophagocytosis. Key players in the erythrophagocytosis by endothelial cells appeared to be lactadherin and ?(v)-integrin. Phagocytosis via the phosphatidylserine-lactadherin-?(v)-integrin pathway is the acknowledged route for removal of apoptotic innate cells by phagocytes.
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Thrombocytopenia in adult cancer patients receiving cytotoxic chemotherapy: results from a retrospective hospital-based cohort study.
Drug Saf
PUBLISHED: 11-15-2011
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Data on the frequency and relative risk (RR) of chemotherapy-induced thrombocytopenia (CIT) in patients with solid tumours receiving chemotherapy in clinical practice are limited.
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Microvesicles and exosomes: opportunities for cell-derived membrane vesicles in drug delivery.
J Control Release
PUBLISHED: 08-31-2011
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Cell-derived membrane vesicles (CMVs) are endogenous carriers transporting proteins and nucleic acids between cells. They appear to play an important role in many disease processes, most notably inflammation and cancer, where their efficient functional delivery of biological cargo seems to contribute to the disease progress. CMVs encompass a variety of submicron vesicular structures that include exosomes and shedding vesicles. The lipids, proteins, mRNA and microRNA (miRNA) delivered by these vesicles change the phenotype of the receiving cells. CMVs have created excitement in the drug delivery field, because they appear to have multiple advantages over current artificial drug delivery systems. Two approaches to exploit CMVs for delivery of exogenous therapeutic cargoes in vivo are currently considered. One approach is based on engineering of natural CMVs in order to target certain cell types using CMVs loaded with therapeutic compounds. In the second approach, essential characteristics of CMVs are being used to design nano-scaled drug delivery systems. Although a number of limiting factors in the clinical translation of the exciting research findings so far exist, both approaches are promising for the development of a potentially novel generation of drug carriers based on CMVs.
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Exome sequencing and unrelated findings in the context of complex disease research: ethical and clinical implications.
Discov Med
PUBLISHED: 07-29-2011
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Exome sequencing has identified the causes of several Mendelian diseases, although it has rarely been used in a clinical setting to diagnose the genetic cause of an idiopathic disorder in a single patient. We performed exome sequencing on a pedigree with several members affected with attention deficit/hyperactivity disorder (ADHD), in an effort to identify candidate variants predisposing to this complex disease. While we did identify some rare variants that might predispose to ADHD, we have not yet proven the causality for any of them. However, over the course of the study, one subject was discovered to have idiopathic hemolytic anemia (IHA), which was suspected to be genetic in origin. Analysis of this subjects exome readily identified two rare non-synonymous mutations in PKLR gene as the most likely cause of the IHA, although these two mutations had not been documented before in a single individual. We further confirmed the deficiency by functional biochemical testing, consistent with a diagnosis of red blood cell pyruvate kinase deficiency. Our study implies that exome and genome sequencing will certainly reveal additional rare variation causative for even well-studied classical Mendelian diseases, while also revealing variants that might play a role in complex diseases. Furthermore, our study has clinical and ethical implications for exome and genome sequencing in a research setting; how to handle unrelated findings of clinical significance, in the context of originally planned complex disease research, remains a largely uncharted area for clinicians and researchers.
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Automated detection of external ventricular and lumbar drain-related meningitis using laboratory and microbiology results and medication data.
PLoS ONE
PUBLISHED: 03-14-2011
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Monitoring of healthcare-associated infection rates is important for infection control and hospital benchmarking. However, manual surveillance is time-consuming and susceptible to error. The aim was, therefore, to develop a prediction model to retrospectively detect drain-related meningitis (DRM), a frequently occurring nosocomial infection, using routinely collected data from a clinical data warehouse.
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Evaluation of hematological parameters on admission for the prediction of 7-day in-hospital mortality in a large trauma cohort.
Clin. Chem. Lab. Med.
PUBLISHED: 01-31-2011
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We evaluated the complete blood count (CBC) for the prediction of 7-day in-hospital mortality in a large adult trauma cohort.
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Frequency of laboratory measurement and hyperkalaemia in hospitalised patients using serum potassium concentration increasing drugs.
Eur. J. Clin. Pharmacol.
PUBLISHED: 01-03-2011
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Although, drug-drug interactions (DDIs) between potassium-increasing drugs (PIDs) are known risk factors for developing hyperkalaemia, not much is known about their risk and management strategies during hospitalisation. This study examines the frequency of serum potassium measurements and hyperkalaemia in hospitalised patients, based on the use of one or more PIDs, and the determinants thereof.
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Determinants of red cell distribution width (RDW) in cardiorenal patients: RDW is not related to erythropoietin resistance.
J. Card. Fail.
PUBLISHED: 01-01-2011
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Studies have shown that red cell distribution width (RDW) is related to outcome in chronic heart failure (CHF). The pathophysiological process is unknown. We studied the relationship between RDW and erythropoietin (EPO) resistance, and related factors such as erythropoietic activity, functional iron availability and hepcidin.
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Discriminative value of platelet size indices for the identification of the mechanism of chemotherapy-induced thrombocytopenia.
Biomarkers
PUBLISHED: 10-27-2010
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A biomarker for discriminating mechanisms of chemotherapy-induced thrombocytopenia (CIT) (i.e. increased platelet destruction and decreased platelet production) would be valuable in managing treatment.
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Testing bias in clinical databases: methodological considerations.
Emerg Themes Epidemiol
PUBLISHED: 05-14-2010
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Laboratory testing in clinical practice is never a random process. In this study we evaluated testing bias for neutrophil counts in clinical practice by using results from requested and non-requested hematological blood tests.
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Erythrophagocytosis by angiogenic endothelial cells is enhanced by loss of erythrocyte deformability.
Exp. Hematol.
PUBLISHED: 01-26-2010
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Angiogenic endothelial cells can function as phagocytes, and phagocytosis is initiated via the opsonin lactadherin. In this study, we examined the interaction between lactadherin-opsonized erythrocytes with reduced deformability and angiogenic endothelium, as loss of deformability is characteristic for suicidal and aged erythrocytes.
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Medication changes prior to hospitalization for obstructive lung disease: a case-crossover study.
Ann Pharmacother
PUBLISHED: 01-13-2010
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Hospitalizations have always been seen as a solid outcome parameter in pharmacoepidemiology. However, the period leading to hospitalization and prehospital management of the patient are equally important.
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Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis.
Rheumatology (Oxford)
PUBLISHED: 12-17-2009
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Macrophage activation syndrome (MAS) in systemic onset juvenile idiopathic arthritis (SoJIA) is considered to be an acquired form of familial haemophagocytic lymphohistiocytosis (fHLH). FHLH is an autosomal recessive disorder, characterized by diminished NK cell function and caused by mutations in the perforin gene (PRF1) in 20-50% of patients. Interestingly, SoJIA patients display decreased levels of perforin in NK cells and diminished NK cell function as well. Here, we analysed PRF1 and its putative promoter in SoJIA patients with or without a history of MAS.
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Laboratory tests in the clinical risk management of potential drug-drug interactions: a cross-sectional study using drug-dispensing data from 100 Dutch community pharmacies.
Drug Saf
PUBLISHED: 11-18-2009
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Patient safety and the life cycle of a drug are negatively influenced by the still increasing occurrence of potential drug-drug interactions (DDIs). Clinical risk management of potential DDIs is required in patients using drugs to influence the benefit-risk profile positively. Information about laboratory test results, in particular, may be useful in the assessment of potential DDIs for the individual patient.
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Identification of exacerbations in obstructive lung disease through biomarkers.
Biomarkers
PUBLISHED: 10-30-2009
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Inflammation has been identified as an important factor for disease exacerbation in obstructive lung disease. In this study, we used neutrophil and eosinophil counts as biomarkers for exacerbation in obstructive lung disease. We conducted a case-control study within a cohort of patients frequenting an outpatient clinic of Respiratory Medicine using data from the Utrecht Patient Oriented Database (UPOD). Cases were patients with a hospital admission for obstructive lung disease in 2005. For each case, one control patient was sampled from the same study base. We identified 143 cases (118 patients with chronic obstructive pulmonary disease and 25 asthma patients) and 143 controls. Admission was associated with both neutrophilia (adjusted odds ratio (OR) 4.3; 95% confidence interval (CI) 2.2-8.5), and eosinophilia (adjusted OR 2.6; 95% CI 1.1-6.2). The association with eosinophilia was only seen in asthma patients. In conclusion, neutrophil and eosinophil counts seem to be useful biomarkers for identifying exacerbations in pharmacoepidemiological studies on obstructive lung disease.
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Frequency and nature of drug-drug interactions in a Dutch university hospital.
Br J Clin Pharmacol
PUBLISHED: 08-22-2009
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Drug-drug interactions (DDIs) may lead to often preventable adverse drug events and health damage. Especially within hospitals, this might be an important factor, as patients are severely ill and multiple medications may be prescribed simultaneously. The objective of this study was to measure the frequency and nature of DDI alerts in a Dutch university hospital.
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Compliance with platelet count monitoring recommendations and management of possible heparin-induced thrombocytopenia in hospitalized patients receiving low-molecular-weight heparin.
Ann Pharmacother
PUBLISHED: 08-18-2009
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Summaries of product characteristics (SPCs) and clinical guideline recommendations are available for monitoring the platelet count for heparin-induced thrombocytopenia (HIT) in patients receiving low-molecular-weight heparin (LMWH). Testing for the presence of heparin-platelet factor 4 antibodies (HPF4-Ab) and starting alternative anticoagulation is recommended when HIT is suspected.
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First mutation in the red blood cell-specific promoter of hexokinase combined with a novel missense mutation causes hexokinase deficiency and mild chronic hemolysis.
Haematologica
PUBLISHED: 07-16-2009
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Hexokinase is one of the key enzymes of glycolysis and catalyzes the phosphorylation of glucose to glucose-6-phosphate. Red blood cell-specific hexokinase is transcribed from HK1 by use of an erythroid-specific promoter. The aim of this study was to investigate the molecular basis for hexokinase deficiency in a patient with chronic hemolysis.
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Effects of corticosteroid use on readmission in obstructive lung disease.
Respir Med
PUBLISHED: 06-02-2009
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Obstructive lung disease is a leading cause of morbidity and mortality worldwide. Some patients are readmitted, but currently predicting parameters for identifying these patients are lacking. The aim of this study was to quantify the incidence of readmission in chronic obstructive lung disease and to identify determinants for hospital readmission.
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Fifteen novel mutations in PKLR associated with pyruvate kinase (PK) deficiency: structural implications of amino acid substitutions in PK.
Hum. Mutat.
PUBLISHED: 05-29-2009
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Pyruvate kinase (PK) deficiency is a rare disease but an important cause of hereditary nonspherocytic hemolytic anemia. The disease is caused by mutations in the PKLR gene and shows a marked variability in clinical expression. We report on the molecular characterization of 38 PK-deficient patients from 35 unrelated families. Twenty-nine different PKLR mutations were detected, of which 15 are reported here for the first time. Two novel deletions are reported: c.142_159del18 is the largest in-frame deletion described thus far and predicts the loss of six consecutive amino acids (p.Thr48_Thr53del) in the N-terminal domain of red blood cell PK. The other deletion removes nearly 1.5 kb of genomic DNA sequence (c.1618+37_2064del1477) and is one of a few large deletional mutants in PKLR. In addition, 13 novel point mutations were identified: one nonsense mutant, p.Arg488X, and 12 missense mutations, predicting the substitution of a single amino acid: p.Arg40Trp, p.Leu73Pro, p.Ile90Asn, p.Gly111Arg, p.Ala154Thr, p.Arg163Leu, p.Gly165Val, p.Leu272Val, p.Ile310Asn, p.Val320Leu, p.Gly358Glu, and p.Leu374Pro. We used the three-dimensional (3D) structure of recombinant human tetrameric PK to evaluate the protein structural context of the affected residues. In addition, in selected patients red blood cell PK antigen levels were measured by enzyme-linked immunosorbent assay (ELISA). Collectively, the results provided us with a rationale for the observed enzyme deficiency and contribute to both a better understanding of the genotype-to-phenotype correlation in PK deficiency as well as the enzymes structure and function.
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Hematocytometry analysis as discriminative marker for asthma phenotypes.
Clin. Chem. Lab. Med.
PUBLISHED: 04-29-2009
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There is an increasing demand for easy to measure biomarkers in clinical practice. We created the relational database Utrecht Patient Oriented Database (UPOD) to develop tools for identifying new biomarkers for disease. In this study, we used UPOD to identify better biomarkers for discriminating different asthma phenotypes.
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Effects of glucocorticoids on the neutrophil count: a cohort study among hospitalized patients.
Pulm Pharmacol Ther
PUBLISHED: 03-30-2009
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Systemic glucocorticoids are often used in clinical practice for a large variety of indications. Clinical observations have shown that patients using glucocorticoids often have higher neutrophil counts. Debate remains whether this observed neutrophilia is associated with glucocorticoid use or that other factors, like disease and severity of disease, should be considered. The objective of this study was to investigate the effect of systemic glucocorticoids on the absolute neutrophil count in hospitalized patients.
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Quantitative erythrocyte membrane proteome analysis with Blue-native/SDS PAGE.
J Proteomics
PUBLISHED: 03-12-2009
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The erythrocyte membrane plays a pivotal role in erythrocyte functioning. Many membrane protein aberrations are known that result in hemolytic anemia, however, the origin of numerous disorders is not known to date. To extend the current set of diagnostic tools, we used a novel proteome-wide approach to quantitatively analyze membrane proteins of healthy donor and patient erythrocytes. Blue-native PAGE has proven to be a powerful tool for separation of membrane proteins and their complexes, but has hitherto not been applied to erythrocyte membranes to find biomarkers. Using this technique, we detected almost 150 protein spots, from which more than 500 proteins could be identified by LC-MS/MS. Further, we successfully assessed the potential of using CyDye labeling to quantify the membrane proteins. Our final goal was to determine if this approach is suited to detect protein level changes in disordered erythrocyte membranes, and we could successfully confirm that erythrocyte spectrin levels were dramatically decreased for a hemolytic anemia patient. This approach provides a new tool to detect potential biomarkers and can contribute to an improved understanding of the causes of erythrocyte membrane defects in patients suffering from hemolytic anemia.
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Management of gene promoter mutations in molecular diagnostics.
Clin. Chem.
PUBLISHED: 02-26-2009
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Although promoter mutations are known to cause functionally important consequences for gene expression, promoter analysis is not a regular part of DNA diagnostics.
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Platelet measurements versus discharge diagnoses for identification of patients with potential drug-induced thrombocytopenia: a cross-sectional study in the Netherlands.
Drug Saf
PUBLISHED: 01-10-2009
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In pharmacoepidemiological studies on the risk of drug-induced blood dyscrasias, including drug-induced thrombocytopenia (DIT), hospital discharge diagnoses have been used to identify potential cases. One of the possible limitations of discharge diagnoses is that due to incomplete registration not all potential cases are identified, which may limit statistical power. Clinical laboratory data have been suggested as a data type that is potentially more sensitive for identifying potential cases of adverse drug reactions than discharge diagnoses.
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The effect of a preoperative erythropoietin protocol as part of a multifaceted blood management program in daily clinical practice (CME).
Transfusion
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The effectiveness of a preoperative erythropoietin (EPO) protocol to reduce allogeneic blood transfusions (ABTs) in daily clinical practice has been insufficiently studied. This study evaluated the effect of such a protocol, as part of a multifaceted blood management program, in patients undergoing total hip arthroplasty (THA).
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Automated detection of healthcare associated infections: external validation and updating of a model for surveillance of drain-related meningitis.
PLoS ONE
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Automated surveillance of healthcare-associated infections can improve efficiency and reliability of surveillance. The aim was to validate and update a previously developed multivariable prediction model for the detection of drain-related meningitis (DRM).
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Valproic acid treatment is associated with altered leukocyte subset development.
J Clin Psychopharmacol
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Valproic acid (VPA) has been used for decades in the treatment of epilepsy and psychiatric disorders, and the long-term use of VPA is regularly accompanied by hematological toxicity, including neutropenia. More recently, it has been demonstrated that VPA can be used as a histone deacetylase inhibitor (HDACi) for the treatment of hematological malignancies. In order to determine the specific effects of VPA in both hematological malignancies and normal hematopoiesis, recent studies have demonstrated that VPA treatment affects the differentiation of normal myeloid progenitors in vitro. In this study, we demonstrate that in a large patient population treated for neurological or psychiatric disorders, VPA treatment affects neutrophil as well as lymphocyte subset counts.
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Persistent A-antigen after stem cell transplantation of blood group A patient with non-A donor.
Am. J. Hematol.
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Patients receiving an ABO-incompatible hematopoietic stem cell transplantation (SCT) are at an increased risk for immune-mediated hematological complications including immediate and delayed hemolysis, late red blood cell engraftment, and pure red cell aplasia. Much research effort has been invested in the unraveling of the immunological mechanisms underyling these complications and approaches to prevent them. Only minimal attention has been paid to the fact that in some SCT patients, even after years, a persistent patient A- and/or B-antigen is detected in the clinical laboratory, despite 100% white cell donor chimerism. The impact for the patient can be substantial: fear that the transplantation was not successful, concern of relapse, and other anxieties influence the quality of life. Little is known about the possible causes of this phenomenon, making appropriate counseling and reassurance of patients by the clinician difficult. In this letter, we describe two cases and a short review on the putative causes of persistent blood group antigens after SCT.
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Information comparison of the effects of drugs on laboratory tests in drug labels and Youngs book.
Clin. Chem. Lab. Med.
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The effects of drugs on laboratory tests may lead to misinterpretation of laboratory data, unnecessary tests, higher costs and missed diagnoses. This study compared the information on drug-laboratory effects (DLE) described in 200 drug labels with that in Youngs book.
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Potassium but not lactate dehydrogenase elevation due to in vitro hemolysis is higher in capillary than in venous blood samples.
Arch. Pathol. Lab. Med.
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Elevated potassium concentrations due to in vitro hemolysis can lead to errors in diagnoses and treatment. Recently, we observed that potassium elevation in capillary samples appeared higher than expected, based on hemolytic index (H-index).
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Comparison between the prognostic value of the white blood cell differential count and morphological parameters of neutrophils and lymphocytes in severely injured patients for 7-day in-hospital mortality.
Biomarkers
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Current laboratory parameters provide limited information about the prognosis of severely injured patients; therefore, novel laboratory parameters are needed.
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Instructions on laboratory monitoring in 200 drug labels.
Clin. Chem. Lab. Med.
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Monitoring drug treatment is important to assess the therapeutic effects and to prevent adverse drug reactions. Unfortunately, the clinical evidence for monitoring is often missing. To attain evidence-based laboratory monitoring and to improve patient safety it is mandatory for the clinical chemist to develop effective and rational methods for monitoring. The legal source for this evidence-based information is the drug label. We analysed frequency, nature, and applicability of instructions on laboratory monitoring described in 200 drug labels.
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Rituximab-induced thrombocytopenia: a cohort study.
Eur. J. Haematol.
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The combined information of drug exposure and laboratory test results on an individual patient level obtained in daily clinical practice can add important information about the safety of a drug. Thrombocytopenia is a known adverse drug reaction of rituximab, which has already been identified during the preregistration trials, but knowledge on incidence and risk factors in clinical practice is limited. We, therefore, aimed to estimate the incidence and explore the risk factors for the development of rituximab-induced thrombocytopenia (a platelet count, <100 × 10(9) platelets/L) in clinical practice. Ninety patients were eligible for inclusion of which 27 developed thrombocytopenia (cumulative incidence, 30%) within 30 days after administration of rituximab and 18 patients developed grade 3/4 thrombocytopenia (cumulative incidence, 20%). Patients with and without thrombocytopenia were compared to explore risk factors. Patients with a relatively low platelet count (217 vs. 324 × 10(9) /L, P = 0.011) before administration of rituximab had a higher risk for the development of thrombocytopenia, and although not statistically significant, patients treated with rituximab within the oncology setting (OR, 4.7; 95% CI, 1.0-23.3), independent of concomitant use of cytostatics, as compared to the autoimmune diseases and patients with a high platelet distribution width (PDW) (16.1 vs. 15.8, P = 0.051). In conclusion, the incidence of rituximab-induced thrombocytopenia was higher than that identified during the clinical trials. Healthcare professionals should consider thrombocytopenia as a relevant reaction during treatment with rituximab. More frequent monitoring of the platelet count is especially advised in patients treated in the oncology indication and/or with a low platelet count and high PDW.
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Exosome mimetics: a novel class of drug delivery systems.
Int J Nanomedicine
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The identification of extracellular phospholipid vesicles as conveyors of cellular information has created excitement in the field of drug delivery. Biological therapeutics, including short interfering RNA and recombinant proteins, are prone to degradation, have limited ability to cross biological membranes, and may elicit immune responses. Therefore, delivery systems for such drugs are under intensive investigation. Exploiting extracellular vesicles as carriers for biological therapeutics is a promising strategy to overcome these issues and to achieve efficient delivery to the cytosol of target cells. Exosomes are a well studied class of extracellular vesicles known to carry proteins and nucleic acids, making them especially suitable for such strategies. However, the considerable complexity and the related high chance of off-target effects of these carriers are major barriers for translation to the clinic. Given that it is well possible that not all components of exosomes are required for their proper functioning, an alternative strategy would be to mimic these vesicles synthetically. By assembly of liposomes harboring only crucial components of natural exosomes, functional exosome mimetics may be created. The low complexity and use of well characterized components strongly increase the pharmaceutical acceptability of such systems. However, exosomal components that would be required for the assembly of functional exosome mimetics remain to be identified. This review provides insights into the composition and functional properties of exosomes, and focuses on components which could be used to enhance the drug delivery properties of exosome mimetics.
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Prevalence of hyponatremia on geriatric wards compared to other settings over four decades: a systematic review.
Ageing Res. Rev.
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Aim of the study was to analyze temporal trends in prevalence of hyponatremia over four decades in different settings. A systematic review of the literature from 1966 to 2009 yielded prevalences of hyponatremia, with standard errors (SE) and pooled estimated means (PEM), calculated by year and setting (geriatric, ICU, other hospital wards, psychiatric hospitals, nursing homes, outpatients). 53 studies were included. Prevalence of hyponatremia was stable from 1976 to 2006, and higher on geriatric wards accept for ICU: e.g. PEM prevalence of mild hyponatremia (serum sodium <135 mM) was 22.2% (95%CI 20.2-24.3) on geriatric wards, 6.0% (95%CI 5.9-6.1) on other hospital wards and 17.2% (SE 7.0) in one ICU-study; for severe hyponatremia (serum sodium<125 mM) these figures were 4.5% (95%CI 3.0-6.1), 0.8% (95%CI 0.7-0.8) and 10.3% (SE 5.6). In nursing homes PEM prevalence of mild hyponatremia was 18.8% (95%CI 15.6-22.2). The higher prevalence on geriatric wards could partly be explained by age-related changes in the regulation of serum sodium. Other underlying factors can be the presence of multiple diagnoses and the use of polypharmacy.
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Serum potassium influencing interacting drugs: risk-modifying strategies also needed at discontinuation.
Ann Pharmacother
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Although the discontinuation of a medication may have important clinical consequences, there is generally much less attention given to medication surveillance when a drug is stopped than when it is started.
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Novel type of red blood cell pyruvate kinase hyperactivity predicts a remote regulatory locus involved in PKLR gene expression.
Am. J. Hematol.
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Red blood cell pyruvate kinase (PK-R) is a key regulatory enzyme of red cell metabolism. Hereditary deficiency of PK-R is caused by mutations in the PKLR gene, leading to chronic nonspherocytic hemolytic anemia. In contrast to PK deficiency, inherited PK hyperactivity has also been described. This very rare abnormality of RBC metabolism has been documented in only two families and appears to be without clinical consequences. Thus far, it has been attributed to either a gain of function mutation in PKLR or to persistent expression of the fetal PK isozyme PK-M2 in mature red blood cells. We here report on a novel type of inherited PK hyperactivity that is characterized by solely increased expression of a kinetically normal PK-R. In line with the latter, no mutations were detected in PKLR. Mutations in regulatory regions as well as variations in PKLR copy number were also absent. In addition, linkage analysis suggested that PK hyperactivity segregated independently from the PKLR locus. We therefore postulate that the causative mutation resides in a novel yet-unidentified locus, and upregulates PKLR gene expression. Other mutations of the same locus may be involved in those cases of PK deficiency that fail to reveal mutations in PKLR.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.