Anders Gabrielsen

Cardiology, Bioinformatics, Physiology

MD, PhD, Associate Professor
37.91

Publications

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    ABSTRACT: In heart failure (HF), activation of brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP) and adrenomedullin (ADM) is adaptive. The activation of these peptides in relation to different HF phenotypes such as HF with preserved ejection fraction (HFpEF), reduced ejection fraction (HFrEF) and after left ventricular assist device (LVAD) and heart transplantation (HTx) remains poorly characterized. We measured and compared N-terminal (NT)-proBNP, mid-regional (MR)-proANP and mid-regional (MR)-proADM in 86 patients with HFpEF, 49 patients with HFrEF, 13 patients one year post-LVAD and 22 patients one year post-HTx. We assessed their prognostic impact using Kaplan-Meier analysis and multivariable Cox regression. In HFpEF, HFrEF, LVAD and HTx, NT-proBNP, median (inter-quartile range), was 1000 (465-2335), 3145 (1475-5190), 1430 (986-2570), and 208 (127-353) pmol/L, p<0.001. MR-proANP was 313 (192-381), 449 (325-596), 276 (216-305), and 118 (96-163) pmol/L, p<0.001. MR-proADM was 1.2 (0.9-1.6), 1.3 (0.9-2.0), 0.9 (0.7-1.4), and 0.7 (0.6-0.9) nmol/L, p<0.001 overall and p=0.212 HFpEF versus HFrEF. In both HFpEF and HFrEF, NT-proBNP and MR-proANP predicted survival free from HTx or LVAD, independent of age, gender, NYHA class and eGFR, whereas MR-proADM did not. Patterns of the cardiomyocyte stress hormones NT-proBNP and MR-proANP suggest that compared to HFrEF, HFpEF may represent milder disease and LVAD and HTx may represent progressive resolution of HF severity. NT-proBNP and MR-proANP independently predicted prognosis in both HFpEF and HFrEF. In contrast, MR-proADM did not distinguish between HFpEF and HFrEF, did not predict prognosis in either, and may be more non-specific in HF. Copyright © 2015. Published by Elsevier Ireland Ltd.
    International journal of cardiology 03/2015; 189:6-11. DOI:10.1016/j.ijcard.2015.03.381 · 6.18 Impact Factor
  • Lars H. Lund, Anders Gabrielsen
    The Journal of Heart and Lung Transplantation 09/2014; DOI:10.1016/j.healun.2014.08.021 · 5.61 Impact Factor
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    ABSTRACT: Background The hemodynamic and cardiac responses to exercise have been widely investigated in adults. However, little is known regarding myocardial performance in response to a short bout of maximal exercise in adolescents. We therefore sought to study alterations in myocardial function and investigate sex-influences in young athletes after maximal cardiopulmonary testing. Methods 51 adolescent (13-19 years old) floor-ball players (24 females) were recruited. All subjects underwent a maximal exercise test to determine maximal oxygen uptake (VO2max) and cardiac output. Cardiac performance was investigated using conventional and tissue velocity imaging, as well as 2D strain echocardiography before and 30 minutes following exercise. Arterio-ventricular coupling was evaluated by means of single beat ventricular elastance and arterial elastance. Results Compared to baseline the early diastolic myocardial velocity (E′LV) at the basal left ventricular (LV) segments declined significantly (females: E′LV: 14.7 +/- 2.6 to 13.6 +/- 2.9 cm/s; males: 15.2 +/- 2.2 to 13.9 +/- 2.3 cm/s, p < 0.001 for both). Similarly, 2D strain decreased significantly following exercise (2D strain LV: from 21.5 +/- 2.4 to 20.2 +/- 2.7% in females, and from 20 +/- 1 to 17.9 +/- 1.5% in males, p < 0.05 for both). However, there were no significant changes in LV contractility estimated by elastance in either sex following exercise (p > 0.05). Arterial elastance) Ea) at baseline was identified as the only predictor of VO2max in males (r = 0.76, p < 0.001) but not in females (p > 0.05). Conclusions The present study demonstrates that vigorous exercise of short duration results in a significant decrease of longitudinal myocardial motion in both sexes. However, in view of unaltered end systolic LV elastance (Ees), these reductions most probably reflect changes in the loading conditions and not an attenuation of myocardial function per se. Importantly, we show that arterial load at rest acts as a strong predictor of VO2max in males but not in female subjects.
    06/2014; 6:24. DOI:10.1186/2052-1847-6-24
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    ABSTRACT: Genetic factors influence the risk for disease as well as the clinical picture seen in sarcoidosis and especially the genes localized to the human leukocyte antigen (HLA) region on chromosome 6 are of importance. The aim of this study was to further investigate associations between HLA-DRB1 alleles and the risk for extra-pulmonary manifestations (EPMs), i.e. engagement of the skin, superficial lymph nodes, eyes, nervous system, kidneys, hypercalcemia, parotid and salivary glands, heart, liver, spleen and bone marrow in Scandinavian sarcoidosis patients. One thousand patients with together with a group of 2000 healthy individuals, matched for sex and age. HLA-DRB1 alleles were determined for all patients and controls. Excluding erythema nodosum and ankle arthritis, we found 288 of 1000 patients to have EPMs. There were 383 patients with Löfgren's syndrome (LS), and among them EPM were relatively uncommon and diagnosed in only 31 (8.1%) of the patients. In contrast, among the 617 non-LS patients, 257 (41.6%) had EPM (P < 0.0001). In LS patients, the absence of HLA-DRB1*03 substantially increased the risk factor for EPM (erythema nodosum and ankle arthritis excluded) (P < 0.0001). A distinct HLA allele combination, HLA-DRB1*04/*15, was identified as a risk factor for EPM in all patients (25 of 50 with DRB1*04/15 had EPM). In conclusion, EPM are common in non-LS sarcoidosis. Furthermore, HLA-typing of sarcoidosis patients can be used in the clinic to identify patients with an increased risk for EPM.
    Tissue Antigens 04/2014; 83(4). DOI:10.1111/tan.12326 · 2.35 Impact Factor
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    ABSTRACT: Cardiac sarcoidosis (CS) is a potentially life-threatening condition. At present, there is no consensus with regard to the optimal non-invasive clinical evaluation and diagnostic procedures of cardiac involvement in patients with sarcoidosis. The aim of this study in a large homogenous Scandinavian sarcoidosis cohort was therefore to identify risk factors of cardiac involvement in patients with sarcoidosis, and the value of initial routine investigation with ECG and cardiac related symptoms in screening for CS. In this retrospective study a cohort of 1017 Caucasian patients with sarcoidosis were included. They were all screened with ECG at disease onset and investigated for CS according to clinical routine. An abnormal ECG was recorded in 166 (16.3%) of the 1017 patients and CS was later diagnosed in 22 (13.2%) of them, compared to in one (0.1%) of the 851 sarcoidosis patients with a normal ECG (p < 0.0001). The risk for CS was higher in patients with a pathologic ECG combined with cardiac related symptoms (11/40) (27.5%) compared to those with pathologic ECG changes without symptoms (11/126) (8.7%) (p < 0.01). Furthermore, patients with Lofgren's syndrome had a reduced risk for CS compared to those without (p < 0.05) the syndrome. This study on an unusually large and homogenous sarcoidosis population demonstrate the importance of an abnormal ECG and cardiac related symptoms at disease onset as powerful predictors of a later diagnosis of cardiac sarcoidosis. In contrast, CS is very rare in subjects without symptoms and with a normal ECG. This knowledge is of importance, and may be used in a clinical algorithm, in identifying patients that should be followed and investigated extensively for the presence of CS.
    Respiratory research 02/2014; 15(1):15. DOI:10.1186/1465-9921-15-15 · 3.38 Impact Factor
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    Circulation Heart Failure 01/2014; 7(1):229-30. DOI:10.1161/CIRCHEARTFAILURE.113.001012 · 5.95 Impact Factor
  • The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 06/2013; 32(6):651-654. DOI:10.1016/j.healun.2013.02.008 · 5.61 Impact Factor
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    ABSTRACT: Patients with severe heart failure despite cardiac resynchronization therapy (CRT) / implantable cardioverter-defibrillator (ICD) may benefit from heart transplantation (HTx) and/or left ventricular assist device (LVAD). We hypothesized that CRT/ICD patients are underserved by HTx/LVAD and that screening can identify appropriate candidates.Methods and MaterialsWe performed a single-center pilot study screening CRT/ICD patients. Extensive patient data were collected and standard indications and contraindications for HTx and LVAD were assessed. We also characterized patients listed for HTx/implanted with LVAD through normal channels during the same period.ResultsThe flow chart describes results: 194 screened, 55 included, and for HTx and LVAD: 2 and 12 had indication without contraindication (which was overwhelmingly age: >65 for HTx and >75 for destination therapy LVAD). This yields a HTx candidate rate of 1% and LVAD candidate rate of 6% of all screened CRT/ICD patients Figure 1. Among 4,645 patients living with CRT/ICD in the Mid-Sweden Transplant Region, 2 were listed for HTx and 6 were implanted with LVAD through normal channels. By study end 1 HTx and 5 LVAD had taken place in screened patients. This yields an actuarial increase in screened vs. un-screened HTx by 13-fold and of LVAD by 20-fold.Conclusions This pilot study suggests that patients with heart failure and CRT/ICD may be underserved by HTx and LVAD. Screening patients with CRT/ICD may identify patients who otherwise would not be referred. The feasibility of screening and the magnitude of the effect should be assessed in larger multicenter studies.
    The Journal of Heart and Lung Transplantation 04/2013; 32(4):S161. DOI:10.1016/j.healun.2013.01.376 · 5.61 Impact Factor
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    ABSTRACT: Discovery of novel biomarkers for atherosclerosis is important to aid in early diagnosis of pre-symptomatic patients at high risk of cardiovascular events. The aim of the present study was therefore to identify potential biomarkers in circulating cells reflecting atherosclerotic lesion progression in the vessel wall. We performed gene arrays on circulating leucocytes from atherosclerosis prone Apoe(-/-) mice with increasing ages, using C57BL/6 mice as healthy controls. We identified fatty acid binding protein 4 (FABP4) mRNA to be augmented in mice with established disease compared with young Apoe(-/-) or controls. Interestingly, the transcript FABP4 correlated significantly with lesion size, further supporting a disease associated increase. In addition, validation of our finding on protein level showed augmented FABP4 in circulating leucocytes whereas, importantly, no change could be observed in plasma. Immunofluorescence analysis demonstrated FABP4 to be present mainly in circulating neutrophils and to some extent in monocytes. Moreover, FABP4-positive neutrophils and macrophages could be identified in the subintimal space in the plaque. Using human circulating leucocytes, we confirmed the presence of FABP4 protein in neutrophils and monocytes. In conclusion, we have showed that cellular levels of FABP4 in circulating leucocytes associate with lesion development in the experimental Apoe(-/-) model. The increased expression is primarily localized to neutrophils, but also in monocytes. We have identified FABP4 in leucocytes as a potential and easy accessible biomarker of atherosclerosis which could be of future clinical relevance.
    Journal of Cellular and Molecular Medicine 02/2013; 17(2). DOI:10.1111/jcmm.12011 · 3.70 Impact Factor
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    Journal of Cardiovascular Magnetic Resonance 01/2013; 15(1). DOI:10.1186/1532-429X-15-S1-O31 · 5.11 Impact Factor
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    ABSTRACT: BACKGROUND: -Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse. METHODS AND RESULTS: -In order to identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3,430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE study. Segment-specific IMT measurements of common carotid (CC), bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMT(mean), IMT(max), and IMT(mean-max)), were analysed. A replication stage investigating 42 single nucleotide polymorphisms (SNPs) for association with CC-IMT was undertaken in five independent European cohorts (total n=11,590). A locus on chromosome 16 (lead SNP rs4888378, intronic in CFDP1) was associated with cIMT at significance levels passing multiple-testing correction at both stages (array-wide significant discovery P=6.75x10(-7) for IMT(max); replication P=7.24x10(-6) for CC-IMT; adjustments for sex, age and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort (P=0.04, n=2120), and lower coronary artery disease (CAD) risk in two case-control studies of subjects with European ancestry (odds ratio [95%CI] 0.83 [0.77-0.90], P=6.53x10(-6); n=13,591, and 0.95 [0.92-0.98], P=1.83x10(-4), n=82,297, respectively). Queries of human biobank datasets (n=126-138) revealed associations of rs4888378 with nearby gene expression in vascular tissues. CONCLUSIONS: -This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and CAD risk in individuals of European descent.
    Circulation Cardiovascular Genetics 11/2012; DOI:10.1161/CIRCGENETICS.112.963660 · 5.34 Impact Factor
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    ABSTRACT: BACKGROUND: The role of adiponectin as a risk factor for mortality and recurrent ischemic cardiovascular events in patients with carotid artery disease is unknown. METHODS: Consecutive patients (n = 292) undergoing carotid endarterectomy for symptomatic and asymptomatic carotid stenosis were included in the study. Mortality and cardiovascular ischemic events were recorded during a median follow-up of 5.2 years. Baseline plasma concentrations of adiponectin were measured. Cox regression models stratified for gender were used for estimation of risk of events. RESULTS: Fifty-two patients died and 73 had an ischemic event (ischemic stroke, n = 52 and/or MI, n = 28) during follow-up. In univariate analyses, adiponectin was associated with mortality, hazard ratio (HR) per standard deviation (SD) increase of adiponectin, 1.46 (95% confidence interval [CI], 1.14-1.86). In multivariate analysis age, type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), plasma interleukin-6 (IL-6) and plasma adiponectin (HR per SD increase of adiponectin, 1.73 [95% CI, 1.29-2.32]) were independently associated with mortality. T2DM, CHD, fibrinogen, contralateral carotid artery stenosis, systolic blood pressure, symptomatic carotid artery stenosis were independently associated with ischemic events, whereas plasma adiponectin was not (HR per SD increase of adiponectin, 0.96 [95% CI, 0.75-1.23]). CONCLUSIONS: High plasma adiponectin concentration is associated with mortality in patients with established atherosclerosis undergoing surgery for carotid artery stenosis. Further studies to determine the role for adiponectin as a biomarker are warranted.
    Atherosclerosis 10/2012; 225(2). DOI:10.1016/j.atherosclerosis.2012.09.036 · 3.97 Impact Factor
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    ABSTRACT: Sex comparisons between girls and boys in response to exercise in trained adolescents are missing and we investigated similarities and differences as a basis for clinical interpretation and guidance. A total of 24 adolescent females and 27 adolescent males aged 13-19 years underwent a maximal bicycle exercise stress test with measurement of cardiovascular variables, cardiac output, lung volumes, metabolic factors/lactate concentrations and breath-by-breath monitoring of ventilation, and determination of peak VO2. Maximum heart rate was similar in females (191 ± 9 bpm) and males (194 ± 7 bpm), cardiac index at maximum exercise was lower in females (7.0 ± 1.0 l/min/m2) than in males (8.3 ± 1.4 l/min/m2, P < 0.05). Metabolic responses and RQ at maximum exercise were similar (females: 1.04 ± 0.06 vs. males: 1.05 ± 0.05). Peak VO2 was lower in females (2.37 ± 0.34 l/min) than in males (3.38 ± 0.49 l/min, P < 0.05). When peak VO2 was normalized to leg muscle mass sex differences disappeared (females: 161 ± 21 ml/min/kg vs. males: 170 ± 23 ml/min/kg). The increase in cardiac index during exercise is the key factor responsible for the greater peak VO2 in adolescent boys compared to girls. Differences in peak VO2 in adolescent boys and girls disappear when peak VO2 is normalized to estimated leg muscle mass and therefore provide a tool to conduct individual and intersex comparisons of fitness when evaluating adolescent athletes in aerobic sports.
    BMC Pediatrics 08/2012; 12:127. DOI:10.1186/1471-2431-12-127 · 1.92 Impact Factor
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    ABSTRACT: Cysteinyl-leukotrienes (cys-LT) are powerful spasmogenic and immune modulating lipid mediators involved in inflammatory diseases, in particular asthma. Here, we investigated whether cys-LT signaling, in the context of atherosclerotic heart disease, compromises the myocardial microcirculation and its response to hypoxic stress. To this end, we examined Apoe(-/-) mice fed a hypercholesterolemic diet and analysed the expression of key enzymes of the cys-LT pathway and their receptors (CysLT1/CysLT2) in normal and hypoxic myocardium as well as the potential contribution of cys-LT signaling to the acute myocardial response to hypoxia. Myocardial biopsies from Apoe(-/-) mice demonstrated signs of chronic inflammation with fibrosis, increased apoptosis and expression of IL-6, as compared to biopsies from C57BL/6J control mice. In addition, we found increased leukotriene C(4) synthase (LTC(4)S) and CysLT1 expression in the myocardium of Apoe(-/-) mice. Acute bouts of hypoxia further induced LTC(4)S expression, increased LTC(4)S enzyme activity and CysLT1 expression, and were associated with increased extension of hypoxic areas within the myocardium. Inhibition of cys-LT signaling by treatment with montelukast, a selective CysLT1 receptor antagonist, during acute bouts of hypoxic stress reduced myocardial hypoxic areas in Apoe(-/-) mice to levels equal to those observed under normoxic conditions. In human heart biopsies from 14 patients with chronic coronary artery disease mRNA expression levels of LTC(4)S and CysLT1 were increased in chronic ischemic compared to non-ischemic myocardium, constituting a molecular basis for increased cys-LT signaling. Our results suggest that CysLT1 antagonists may have protective effects on the hypoxic heart, and improve the oxygen supply to areas of myocardial ischemia, for instance during episodes of sleep apnea.
    PLoS ONE 07/2012; 7(7):e41786. DOI:10.1371/journal.pone.0041786 · 3.53 Impact Factor
  • Circulation Heart Failure 07/2012; 5(4):e65-7. DOI:10.1161/CIRCHEARTFAILURE.111.965764 · 5.95 Impact Factor
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    ABSTRACT: Genome-wide association studies have identified a coronary artery disease (CAD) risk locus in a non-coding region at 9p21.3, the nearest genes being CDKN2A and CDKN2B. To understand the pathways by which this locus might influence CAD susceptibility, we investigated associations between the 9p21.3 risk genotype and global gene expression in heart tissue from donors with no diagnosed heart disease (n = 108, predominant cause of death, cerebral vascular accident) and in carotid plaque (n = 106), aorta (n = 104) and mammary artery (n = 88) tissues from heart valve and carotid endarterectomy patients. Genotyping was performed with Taqman assays and Illumina arrays, and gene expression profiles generated with Affymetrix microarrays. Associations were analyzed with an additive genetic model. In heart tissue, 46 genes were putatively altered in association with the 9p21.3 risk allele (70% down-regulated, fold-change >1.1 per allele, p<0.05 adjusted for age, gender, ethnicity, cause of death). These genes were enriched for biomarkers of myocardial infarction (p = 1.53×10(-9)), response to wounding (p = 2.65×10(-10)) and inflammatory processes (p<1.97×10(-7)). Among the top 10 most down-regulated genes, 7 genes shared a set of transcription factor binding sites within conserved promoter regions (p<1.14×10(-5)), suggesting they may be co-regulated. Canonical pathway modelling of the most differentially expressed transcripts across all tissues (154 genes, 60% down-regulated, fold-change >1.1 per allele, p<0.01) showed that 75% of the genes could be transcriptionally regulated through the cell cycle G1 phase progression pathway (p<1.08×10(-258)), in which CDKN2A and CDKN2B play a regulatory role. These data suggest that the cell cycle G1 phase progression pathway is activated in individuals with the 9p21.3 risk allele. This may contribute to a proliferative phenotype that promotes adverse cardiac hypertrophy and vascular remodeling, leading to an increased CAD risk.
    PLoS ONE 06/2012; 7(6):e39574. DOI:10.1371/journal.pone.0039574 · 3.53 Impact Factor
  • Vascular Pharmacology 05/2012; 56(5-6):377. DOI:10.1016/j.vph.2011.08.194 · 4.62 Impact Factor
  • The Journal of Heart and Lung Transplantation 04/2012; 31(4):S157. DOI:10.1016/j.healun.2012.01.457 · 5.61 Impact Factor
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    ABSTRACT: Continuous-flow left ventricular assist devices/systems (LVADs/LVASs) reduce symptoms and mortality in severe heart failure. The impeller or centrifugal designs provide challenges in assessing and titrating pump speed (revolutions per minute [RPM]), flow, and native heart pulsatility, and contribution to cardiac output. The Thoratec HeartMate II (HM II) LVAS is the most commonly used LVAD worldwide. The user sets the RPM and the monitor provides online data on RPM, power consumption, flow, and pulsatility. These parameters are routinely used by clinicians to assess native heart function and to optimize pump settings. However, little is known about their reliability, reproducibility, and variability. Therefore, we assessed HM II controller parameters and concurrent echocardiography during titrations of RPM to low and high values. We found that data displayed on the monitor and logged in the controller are consistent for power consumption and for flow at settings above 8,000 RPM but inconsistent and unreliable for flow at or below 8,000 RPM and for pulsatility throughout a range of common settings and specifically at 9,000 RPM. These findings have implications for clinicians attempting to optimize settings and assess pump and native heart function.
    ASAIO journal (American Society for Artificial Internal Organs: 1992) 03/2012; 58(3):183-90. DOI:10.1097/MAT.0b013e3182496d9a · 1.39 Impact Factor
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    ABSTRACT: Classic risk factors, including age, smoking, serum cholesterol, diabetes and blood pressure, constitute the basis of present risk prediction models but fail to identify all individuals at risk. The objective of this study was to investigate if genomic and transcriptional patterns improve prediction of ischemic events in patients with established carotid artery disease. Genotype and gene expression profiles were obtained from carotid plaque tissue (n = 126) and peripheral blood mononuclear cells (n = 97) of patients undergoing carotid endarterectomy. Patients were followed for an average of 44 months, and 25 ischemic events occurred (18 ischemic strokes and 7 myocardial infarctions). Blinded leave-one-out cross-validation on Cox regression coefficients was used to assign gene expression-based risk scores to each patient. When compared with classic risk factors, addition of carotid plaque gene expression-based risk score improved the prediction of future ischemic events from an area under the curve (AUC) of 0.66 to an AUC of 0.79. The inclusion of gene expression risk score from peripheral blood mononuclear cells or from 25 established myocardial infarction risk single nucleotide polymorphisms only exhibited marginal effects on the prediction of ischemic events. Prediction of ischemic events is improved by inclusion of gene expression profiling from carotid endarterectomy tissue compared with prediction on the basis of classic risk markers alone in patients with atherosclerosis. The method may be developed to identify subjects at very high risk of ischemic events.
    Molecular Medicine 02/2012; 18(1):669-75. DOI:10.2119/molmed.2011.00479 · 4.82 Impact Factor

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