Tag Archives: PLoS

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A generalized measurement model to quantify health: the multi-attribute preference response model.
PLoS One. 2013;8(11):e79494
Authors: Krabbe PF
Abstract
After 40 years of deriving … Continue reading →

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MET genetic abnormalities unreliable for patient selection for therapeutic intervention in oropharyngeal squamous cell carcinoma.

PLoS One. 2014;9(1):e84319

Authors: Lacroix L, Post SF, Valent A, Melkane AE, Vielh P, Egile C, Castell C, Larois C, Micallef S, Saulnier P, Goulaouic H, Lefebvre AM, Temam S

Abstract
BACKGROUND: Identification of MET genetic alteration, mutation, or amplification in oropharyngeal squamous cell carcinoma (OPSCC) could lead to development of MET selective kinase inhibitors. The aim of this study was to assess the frequency and prognostic value of MET gene mutation, amplification, and protein expression in primary OPSCC.
METHODS: A retrospective chart review was conducted of patients treated for single primary OPSCC between January 2007 and December 2009. Pre-treatment OPSCC tissue samples were analyzed for MET mutations, gene amplification, and overexpression using Sanger sequencing, FISH analysis, and immunohistochemistry respectively. Univariate and multivariate analyses were used to analyze correlations between molecular abnormalities and patient survival.
RESULTS: 143 patients were included in this study. Six cases (4%) were identified that had a genetic variation, but previously described mutations such as p.Tyr1235Asp (Y1235D) or p.Tyr1230Cys (Y1230C) were not detected. There were 15 high polysomy cases, and only 3 cases met the criteria for true MET amplification, with ≥10% amplified cells per case. Immunohistochemistry evaluation showed 43% of cases were c-MET negative and in 57% c-MET was observed at the tumor cell level. Multivariate analysis showed no significant association between MET mutation, amplification, or expression and survival.
CONCLUSIONS: Our study shows a low frequency of MET mutations and amplification in this cohort of OPSCC. There was no significant correlation between MET mutations, amplification, or expression and patient survival. These results suggest that patient selection based on these MET genetic abnormalities may not be a reliable strategy for therapeutic intervention in OPSCC.

PMID: 24465403 [PubMed – indexed for MEDLINE]

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Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 Deficiency Reduces Insulin Sensitivity in High-Fat Diet-Fed Mice.

PLoS One. 2014;9(9):e106300

Authors: de Boer JF, Dikkers A, Jurdzinski A, von Felden J, Gaestel M, Bavendiek U, Tietge UJ

Abstract
Adipose tissue inflammation is considered an important contributor to insulin resistance. Mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a major downstream target of p38 MAPK and enhances inflammatory processes. In line with the role of MK2 as contributor to inflammation, MK2-/- mice are protected against inflammation in different disease models. Therefore, MK2 is considered an attractive therapeutic target for the treatment of chronic inflammatory diseases. This study tested the impact of MK2-deficiency on high-fat diet (HFD)-induced adipose tissue inflammation and insulin resistance. After feeding MK2-/- and WT control mice a HFD (60% energy from fat) for 24 weeks, body weight was not different between groups. Also, liver weight and the amount of abdominal fat remained unchanged. However, in MK2-/- mice plasma cholesterol levels were significantly increased. Surprisingly, macrophage infiltration in adipose tissue was not altered. However, adipose tissue macrophages were more skewed to the inflammatory M1 phenotype in MK2-/- mice. This differerence in macrophage polarization did however not translate in significantly altered expression levels of Mcp-1, Tnfα and Il6. Glucose and insulin tolerance tests demonstrated that MK2-/- mice had a significantly reduced glucose tolerance and increased insulin resistance. Noteworthy, the expression of the insulin-responsive glucose transporter type 4 (GLUT4) in adipose tissue of MK2-/- mice was reduced by 55% (p<0.05) and 33% (p<0.05) on the mRNA and protein level, respectively, compared to WT mice. In conclusion, HFD-fed MK2-/- display decreased glucose tolerance and increased insulin resistance compared to WT controls. Decreased adipose tissue expression of GLUT4 might contribute to this phenotype. The data obtained in this study indicate that clinical use of MK2 inhibitors has to be evaluated with caution, taking potential metabolic adverse effects into account.

PMID: 25233471 [PubMed – as supplied by publisher]

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Glucose Kinetics in the Collagen-Induced Arthritis Model: An All-in-One Model to Assess Both Efficacy and Metabolic Side Effects of Glucocorticoids.
PLoS One. 2014;9(9):e98684
Authors: Toonen EJ, Laskewitz AJ, van Di… Continue reading →

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Effect of erythropoiesis-stimulating agents on blood pressure in pre-dialysis patients.
PLoS One. 2013;8(12):e84848
Authors: Suttorp MM, Hoekstra T, Mittelman M, Ott I, Franssen CF, Dekker FW
… Continue reading →

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Common and rare EGFR and KRAS mutations in a Dutch non-small-cell lung cancer population and their clinical outcome.

PLoS One. 2013;8(7):e70346

Authors: Kerner GS, Schuuring E, Sietsma J, Hiltermann TJ, Pieterman RM, de Leede GP, van Putten JW, Liesker J, Renkema TE, van Hengel P, Platteel I, Timens W, Groen HJ, CTMM Air Force Consortium

Abstract
INTRODUCTION: In randomly assigned studies with EGFR TKI only a minor proportion of patients with NSCLC have genetically profiled biopsies. Guidelines provide evidence to perform EGFR and KRAS mutation analysis in non-squamous NSCLC. We explored tumor biopsy quality offered for mutation testing, different mutations distribution, and outcome with EGFR TKI.
PATIENT AND METHODS: Clinical data from 8 regional hospitals were studied for patient and tumor characteristics, treatment and overall survival. Biopsies sent to the central laboratory were evaluated for DNA quality and subsequently analyzed for mutations in exons 18-21 of EGFR and exon 2 of KRAS by bidirectional sequence analysis.
RESULTS: Tumors from 442 subsequent patients were analyzed. For 74 patients (17%) tumors were unsuitable for mutation analysis. Thirty-eight patients (10.9%) had EGFR mutations with 79% known activating mutations. One hundred eight patients (30%) had functional KRAS mutations. The mutation spectrum was comparable to the Cosmic database. Following treatment in the first or second line with EGFR TKI median overall survival for patients with EGFR (n = 14), KRAS (n = 14) mutations and wild type EGFR/KRAS (n = 31) was not reached, 20 and 9 months, respectively.
CONCLUSION: One out of every 6 tumor samples was inadequate for mutation analysis. Patients with EGFR activating mutations treated with EGFR-TKI have the longest survival.

PMID: 23922984 [PubMed – indexed for MEDLINE]

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Is Rumination after Bereavement Linked with Loss Avoidance? Evidence from Eye-Tracking.
PLoS One. 2014;9(8):e104980
Authors: Eisma MC, Schut HA, Stroebe MS, van den Bout J, Stroebe W, Boelen PA
Abstract
… Continue reading →

Voice Prosthetic Biofilm Formation and Candida Morphogenic Conversions in Absence and Presence of Different Bacterial Strains and Species on Silicone-Rubber.
PLoS One. 2014;9(8):e104508
Authors: van der Mei HC, Buijs… Continue reading →

Economic Evaluation of Apixaban for the Prevention of Stroke in Non-Valvular Atrial Fibrillation in the Netherlands.

PLoS One. 2014;9(8):e103974

Authors: Stevanović J, Pompen M, Le HH, Rozenbaum MH, Tieleman RG, Postma MJ

Abstract
BACKGROUND: Stroke prevention is the main goal of treating patients with atrial fibrillation (AF). Vitamin-K antagonists (VKAs) present an effective treatment in stroke prevention, however, the risk of bleeding and the requirement for regular coagulation monitoring are limiting their use. Apixaban is a novel oral anticoagulant associated with significantly lower hazard rates for stroke, major bleedings and treatment discontinuations, compared to VKAs.
OBJECTIVE: To estimate the cost-effectiveness of apixaban compared to VKAs in non-valvular AF patients in the Netherlands.
METHODS: Previously published lifetime Markov model using efficacy data from the ARISTOTLE and the AVERROES trial was modified to reflect the use of oral anticoagulants in the Netherlands. Dutch specific costs, baseline population stroke risk and coagulation monitoring levels were incorporated. Univariate, probabilistic sensitivity and scenario analyses on the impact of different coagulation monitoring levels were performed on the incremental cost-effectiveness ratio (ICER).
RESULTS: Treatment with apixaban compared to VKAs resulted in an ICER of €10,576 per quality adjusted life year (QALY). Those findings correspond with lower number of strokes and bleedings associated with the use of apixaban compared to VKAs. Univariate sensitivity analyses revealed model sensitivity to the absolute stroke risk with apixaban and treatment discontinuations risks with apixaban and VKAs. The probability that apixaban is cost-effective at a willingness-to-pay threshold of €20,000/QALY was 68%. Results of the scenario analyses on the impact of different coagulation monitoring levels were quite robust.
CONCLUSIONS: In patients with non-valvular AF, apixaban is likely to be a cost-effective alternative to VKAs in the Netherlands.

PMID: 25093723 [PubMed – as supplied by publisher]

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Associations between lifetime traumatic events and subsequent chronic physical conditions: a cross-national, cross-sectional study.

PLoS One. 2013;8(11):e80573

Authors: Scott KM, Koenen KC, Aguilar-Gaxiola S, Alonso J, Angermeyer MC, Benjet C, Bruffaerts R, Caldas-de-Almeida JM, de Girolamo G, Florescu S, Iwata N, Levinson D, Lim CC, Murphy S, Ormel J, Posada-Villa J, Kessler RC

Abstract
BACKGROUND: Associations between lifetime traumatic event (LTE) exposures and subsequent physical ill-health are well established but it has remained unclear whether these are explained by PTSD or other mental disorders. This study examined this question and investigated whether associations varied by type and number of LTEs, across physical condition outcomes, or across countries.
METHODS: Cross-sectional, face-to-face household surveys of adults (18+) were conducted in 14 countries (n = 38, 051). The Composite International Diagnostic Interview assessed lifetime LTEs and DSM-IV mental disorders. Chronic physical conditions were ascertained by self-report of physician’s diagnosis and year of diagnosis or onset. Survival analyses estimated associations between the number and type of LTEs with the subsequent onset of 11 physical conditions, with and without adjustment for mental disorders.
FINDINGS: A dose-response association was found between increasing number of LTEs and odds of any physical condition onset (OR 1.5 [95% CI: 1.4-1.5] for 1 LTE; 2.1 [2.0-2.3] for 5+ LTEs), independent of all mental disorders. Associations did not vary greatly by type of LTE (except for combat and other war experience), nor across countries. A history of 1 LTE was associated with 7/11 of the physical conditions (ORs 1.3 [1.2-1.5] to 1.7 [1.4-2.0]) and a history of 5+ LTEs was associated with 9/11 physical conditions (ORs 1.8 [1.3-2.4] to 3.6 [2.0-6.5]), the exceptions being cancer and stroke.
CONCLUSIONS: Traumatic events are associated with adverse downstream effects on physical health, independent of PTSD and other mental disorders. Although the associations are modest they have public health implications due to the high prevalence of traumatic events and the range of common physical conditions affected. The effects of traumatic stress are a concern for all medical professionals and researchers, not just mental health specialists.

PMID: 24348911 [PubMed – indexed for MEDLINE]

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Dual role of miR-21 in CD4+ T-cells: activation-induced miR-21 supports survival of memory T-cells and regulates CCR7 expression in naive T-cells.

PLoS One. 2013;8(10):e76217

Authors: Smigielska-Czepiel K, van den Berg A, Jellema P, Slezak-Prochazka I, Maat H, van den Bos H, van der Lei RJ, Kluiver J, Brouwer E, Boots AM, Kroesen BJ

Abstract
Immune cell-type specific miRNA expression patterns have been described but the detailed role of single miRNAs in the function of T-cells remains largely unknown. We investigated the role of miR-21 in the function of primary human CD4+ T-cells. MiR-21 is substantially expressed in T-cells with a memory phenotype, and is robustly upregulated upon αCD3/CD28 activation of both naive and memory T-cells. By inhibiting the endogenous miR-21 function in activated naive and memory T-cells, we showed that miR-21 regulates fundamentally different aspects of T-cell biology, depending on the differentiation status of the T-cell. Stable inhibition of miR-21 function in activated memory T-cells led to growth disadvantage and apoptosis, indicating that the survival of memory T-cells depends on miR-21 function. In contrast, stable inhibition of miR-21 function in activated naive T-cells did not result in growth disadvantage, but led to a significant induction of CCR7 protein expression. Direct interaction between CCR7 and miR-21 was confirmed in a dual luciferase reporter assay. Our data provide evidence for a dual role of miR-21 in CD4+ T cells; Regulation of T-cell survival is confined to activated memory T-cells, while modulation of potential homing properties, through downregulation of CCR7 protein expression, is observed in activated naive T-cells.

PMID: 24098447 [PubMed – indexed for MEDLINE]

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A New Method to Facilitate Valid and Consistent Grading Cardiac Events in Childhood Cancer Survivors Using Medical Records.
PLoS One. 2014;9(7):e100432
Authors: Feijen EL, van der Pal HJ, van Dalen EC, Mulder RL, Bar… Continue reading →

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The presence of modifiable residues in the core peptide part of precursor nisin is not crucial for precursor nisin interactions with NisB- and NisC.
PLoS One. 2013;8(9):e74890
Authors: Khusainov R, … Continue reading →

Association between Exposure to HSV1 and Cognitive Functioning in a General Population of Adolescents. The TRAILS Study.

PLoS One. 2014;9(7):e101549

Authors: Jonker I, Klein HC, Duivis HE, Yolken RH, Rosmalen JG, Schoevers RA

Abstract
BACKGROUND: Infections with different herpes viruses have been associated with cognitive functioning in psychiatric patients and healthy adults. The aim of this study was to find out whether antibodies to different herpes viruses are prospectively associated with cognitive functioning in a general adolescent population.
METHODS: This study was performed in TRAILS, a large prospective general population cohort (N = 1084, 54% female, mean age 16.2 years (SD 0.6)). At age 16, immunoglobulin G antibodies against HSV1, HSV2, CMV and EBV were measured next to high sensitive C-Reactive Protein (hsCRP). Two years later, immediate memory and executive functioning were assessed using the 15 words task and the self ordered pointing task. Multiple linear regression analysis with bootstrapping was performed to study the association between viral infections and cognitive function, adjusting for gender, socioeconomic status, ethnicity, and cannabis use.
RESULTS: Presence of HSV1 antibodies was associated with memory function ((B = -0.272, 95% CI = -0.556 to -0.016, p = 0.047)), while the association with executive functioning did not reach statistical significance (B = 0.560, 95% CI is -0.053 to 1.184, p = 0.075). The level of HSV1 antibodies was associated with both memory function (B = -0.160, 95% CI = -0.280 to -0.039, p = 0.014) and executive functioning (B = 0.296, 95% CI = 0.011 to 0.578, p = 0.046). Other herpes viruses and hsCRP were not associated with cognitive functioning.
CONCLUSIONS: Both presence and level of HSV1 antibodies are prospectively associated with reduced cognitive performance in a large cohort of adolescents.

PMID: 24983885 [PubMed – as supplied by publisher]

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Brain Volumetric Correlates of Autism Spectrum Disorder Symptoms in Attention Deficit/Hyperactivity Disorder.

PLoS One. 2014;9(6):e101130

Authors: O’Dwyer L, Tanner C, van Dongen EV, Greven CU, Bralten J, Zwiers MP, Franke B, Oosterlaan J, Heslenfeld D, Hoekstra P, Hartman CA, Rommelse N, Buitelaar JK

Abstract
Autism spectrum disorder (ASD) symptoms frequently occur in subjects with attention deficit/hyperactivity disorder (ADHD). While there is evidence that both ADHD and ASD have differential structural correlates, no study to date has investigated these structural correlates within a framework that robustly accounts for the phenotypic overlap between the two disorders. The presence of ASD symptoms was measured by the parent-reported Children’s Social and Behavioural Questionnaire (CSBQ) in ADHD subjects (n = 180), their unaffected siblings (n = 118) and healthy controls (n = 146). ADHD symptoms were assessed by a structured interview (K-SADS-PL) and the Conners’ ADHD questionnaires. Whole brain T1-weighted MPRAGE images were acquired and the structural MRI correlates of ASD symptom scores were analysed by modelling ASD symptom scores against white matter (WM) and grey matter (GM) volumes using mixed effects models which controlled for ADHD symptom levels. ASD symptoms were significantly elevated in ADHD subjects relative to both controls and unaffected siblings. ASD scores were predicted by the interaction between WM and GM volumes. Increasing ASD score was associated with greater GM volume. Equivocal results from previous structural studies in ADHD and ASD may be due to the fact that comorbidity has not been taken into account in studies to date. The current findings stress the need to account for issues of ASD comorbidity in ADHD.

PMID: 24979066 [PubMed – as supplied by publisher]

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The Distribution of Dissolved Iron in the West Atlantic Ocean.
PLoS One. 2014;9(6):e101323
Authors: Rijkenberg MJ, Middag R, Laan P, Gerringa LJ, van Aken HM, Schoemann V, de Jong JT, de Baar HJ
Abstract
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Predator-Prey Interactions between Shell-Boring Beetle Larvae and Rock-Dwelling Land Snails.
PLoS One. 2014;9(6):e100366
Authors: Baalbergen E, Helwerda R, Schelfhorst R, Castillo Cajas RF, van Moorsel CH, Kundrata R… Continue reading →

Neural Correlates of Emotion Regulation in Patients with Schizophrenia and Non-Affected Siblings.

PLoS One. 2014;9(6):e99667

Authors: van der Meer L, Swart M, van der Velde J, Pijnenborg G, Wiersma D, Bruggeman R, Aleman A

Abstract
BACKGROUND: Patients with schizophrenia often experience problems regulating their emotions. Non-affected relatives show similar difficulties, although to a lesser extent, and the neural basis of such difficulties remains to be elucidated. In the current paper we investigated whether schizophrenia patients, non-affected siblings and healthy controls (HC) exhibit differences in brain activation during emotion regulation.
METHODS: All subjects (n = 20 per group) performed an emotion regulation task while they were in an fMRI scanner. The task contained two experimental conditions for the down-regulation of emotions (reappraise and suppress), in which IAPS pictures were used to generate a negative affect. We also assessed whether the groups differed in emotion regulation strategies used in daily life by means of the emotion regulation questionnaire (ERQ).
RESULTS: Though the overall negative affect was higher for patients as well as for siblings compared to HC for all conditions, all groups reported decreased negative affect after both regulation conditions. Nonetheless, neuroimaging results showed hypoactivation relative to HC in VLPFC, insula, middle temporal gyrus, caudate and thalamus for patients when reappraising negative pictures. In siblings, the same pattern was evident as in patients, but only in cortical areas.
CONCLUSIONS: Given that all groups performed similarly on the emotion regulation task, but differed in overall negative affect ratings and brain activation, our findings suggest reduced levels of emotion regulation processing in neural circuits in patients with schizophrenia. Notably, this also holds for siblings, albeit to a lesser extent, indicating that it may be part and parcel of a vulnerability for psychosis.

PMID: 24941136 [PubMed – as supplied by publisher]

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Standardized handwriting to assess bradykinesia, micrographia and tremor in Parkinson’s disease.

PLoS One. 2014;9(5):e97614

Authors: Smits EJ, Tolonen AJ, Cluitmans L, van Gils M, Conway BA, Zietsma RC, Leenders KL, Maurits NM

Abstract
OBJECTIVE: To assess whether standardized handwriting can provide quantitative measures to distinguish patients diagnosed with Parkinson’s disease from age- and gender-matched healthy control participants.
DESIGN: Exploratory study. Pen tip trajectories were recorded during circle, spiral and line drawing and repeated character ‘elelelel’ and sentence writing, performed by Parkinson patients and healthy control participants. Parkinson patients were tested after overnight withdrawal of anti-Parkinsonian medication.
SETTING: University Medical Center Groningen, tertiary care, the Netherlands.
PARTICIPANTS: Patients with Parkinson’s disease (n = 10; mean age 69.0 years; 6 male) and healthy controls (n = 10; mean age 68.1 years; 6 male).
INTERVENTIONS: Not applicable.
MAIN OUTCOME MEASURES: Movement time and velocity to detect bradykinesia and the size of writing to detect micrographia. A rest recording to investigate the presence of a rest-tremor, by frequency analysis.
RESULTS: Mean disease duration in the Parkinson group was 4.4 years and the patients were in modified Hoehn-Yahr stages 1-2.5. In general, Parkinson patients were slower than healthy control participants. Median time per repetition, median velocity and median acceleration of the sentence task and median velocity of the elel task differed significantly between Parkinson patients and healthy control participants (all p<0.0014). Parkinson patients also wrote smaller than healthy control participants and the width of the ‘e’ in the elel task was significantly smaller in Parkinson patients compared to healthy control participants (p<0.0014). A rest-tremor was detected in the three patients who were clinically assessed as having rest-tremor.
CONCLUSIONS: This study shows that standardized handwriting can provide objective measures for bradykinesia, tremor and micrographia to distinguish Parkinson patients from healthy control participants.

PMID: 24854199 [PubMed – in process]

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Feasibility of a combined aerobic and strength training program and its effects on cognitive and physical function in institutionalized dementia patients. A pilot study.

PLoS One. 2014;9(5):e97577

Authors: Bossers WJ, Scherder EJ, Boersma F, Hortobágyi T, van der Woude LH, van Heuvelen MJ

Abstract
OBJECTIVES: We examined the feasibility of a combined aerobic and strength training program in institutionalized dementia patients and studied the effects on cognitive and physical function.
METHODS: Thirty-three patients with dementia, recruited from one nursing home, participated in this non-randomized pilot study (25 women; age = 85.2±4.9 years; Mini Mental State Examination = 16.8±4.0). In phase 1 of the study, seventeen patients in the Exercise group (EG) received a combined aerobic and strength training program for six weeks, five times per week, 30 minutes per session, in an individually supervised format and successfully concluded the pre and posttests. In phase 2 of the study, sixteen patients in the Social group (SG) received social visits at the same frequency, duration, and format and successfully concluded the pre and posttests.
RESULTS: Indices of feasibility showed that the recruitment and adherence rate, respectively were 46.2% and 86.3%. All EG patients completed the exercise program according to protocol without adverse events. After the six-week program, no significant differences on cognitive function tests were found between the EG and SG. There was a moderate effect size in favor for the EG for the Visual Memory Span Forward; a visual attention test. There were significant differences between groups in favor for the EG with moderate to large effects for the physical tests Walking Speed (p = .003), Six-Minute Walk Test (p = .031), and isometric quadriceps strength (p = .012).
CONCLUSIONS: The present pilot study showed that it is feasible to conduct a combined aerobic and strength training program in institutionalized patients with dementia. The selective cognitive visual attention improvements and more robust changes in motor function in favor of EG vs. SG could serve as a basis for large randomized clinical trials.
TRIAL REGISTRATION: trialregister.nl 1230.

PMID: 24844772 [PubMed – in process]

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