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  • NARCIS (Royal Netherlands Academy of Arts and Sciences)  (9)
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  • 1
    Language: English
    In: Biology of Reproduction, 2010, Vol.82(1), pp.214-223
    Description: textabstractFormation of the germ cell lineage involves multiple processes, including repression of somatic differentiation and reacquisition of pluripotency as well as a unique epigenetic constitution. The transcriptional regulator Prdm1 has been identified as a main coordinator of this process, controlling...
    Keywords: Ap-2γ ; B Lymphocyte Induced Maturation Protein 1 ; Dna Glycosylase Muty ; Dazl Protein ; Developmental Biology ; Gamete Biology ; Gene Regulation ; Hoxb1 ; Myod1 Protein ; Nanos 3 Protein ; Prdm1 ; Prdm1 Protein ; Primordial Germ Cells ; Somatic Differentiation ; Tcfap2c ; Tcam-2 ; Tcfap2c Protein ; Aminomethyltransferase ; Animal ; Animal Experiment ; Animal Tissue ; Apoptosis ; Article ; Binding Protein ; Biological Marker ; Cell Differentiation ; Controlled Study ; Development And Aging ; Dipeptide Binding Protein ; Embryo ; Embryo Cell ; Embryo Development ; Female ; Gene Expression Regulation ; Germ Cell ; Growth ; Homeobox B1 Protein ; In Vitro Study ; Male ; Membrane Protein ; Mesoderm ; Metabolism ; Mouse ; Mutant ; Nonhuman ; Primordial Germ Cell ; Priority Journal ; Protein Function ; Reproduction ; Transcription Factor ; Transcription Factor Ap 2 ; Transcription Factor Hand 1 ; Transcription Factor Hoxa 1 ; Transcription Factor Tcfap2c ; Transgenic Mouse ; Unclassified Drug ; Upregulation
    ISSN: 00063363
    E-ISSN: 15297268
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  • 2
    Language: English
    In: PLoS ONE, 2010, Vol.5(5), p.e10527
    Description: Antiretroviral therapy (ART) effectively decreases tuberculosis (TB) incidence long-term, but is associated with high TB incidence rates in the first 6 months. We sought to determine the incidence and the long-term effects of TB during ART on HIV treatment outcome, and the risk factors for incident TB during ART in a large urban HIV clinic in Uganda. ; Routinely collected longitudinal clinical data from all patients initiated on first-line ART was retrospectively analysed. 5,982 patients were included with a median baseline CD4+ T cell count (CD4 count) of 117 cells/mm (interquartile range [IQR]; 42, 182). In the first 2 years, there were 336 (5.6%) incident TB events in 10,710 person-years (py) of follow-up (3.14 cases/100pyar [95% CI 2.82–3.49]); incidence rates at 0–3, 3–6, 6–12 and 12–24 months were 11.25 (9.58–13.21), 6.27 (4.99–7.87), 2.47 (1.87–3.36) and 1.02 (0.80–1.31), respectively. Incident TB during ART was independently associated with baseline CD4 count of 〈50 cells/mm (hazard ratio [HR] 1.84 [1.25–2.70],  = 0.002) and male gender (HR 1.68 [1.34–2.11], 〈0.001). After two years on ART, the patients who had developed TB in the first 12 months had a significantly lower median CD4 count increase (184 cells/mm [IQR; 107, 258, n = 118] vs 209 cells/mm [124, 309, n = 2166],  = 0.01), a larger proportion of suboptimal immune reconstitution according to two definitions (increase in CD4 count 〈200 cells/mm: 57.4% vs 46.9%,  = 0.03, and absolute CD4 count 〈200 cells/mm: 30.4 vs 19.9%,  = 0.006), and a higher percentage of immunological failure according to the WHO criteria (13.6% vs 6.5%,  = 0.003). Incident TB during ART was independently associated with poor CD4 count recovery and fulfilling WHO immunogical failure definitions. ; Incident TB during ART occurs most often within 3 months and in patients with CD4 counts less than 50 cells/mm. Incident TB during ART is associated with long-term impairment in immune recovery.
    Keywords: Research Article ; Immunology -- Immune Response ; Virology -- Immunodeficiency Viruses ; Infectious Diseases -- Hiv Infection And Aids ; Public Health And Epidemiology -- Global Health
    E-ISSN: 1932-6203
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  • 3
    In: Clinical Nuclear Medicine, 2012, Vol.37(9), pp.866-871
    Description: PURPOSE: Reconstruction of striatal dopamine transporter (DAT) SPECT is commonly done by filtered back projection (FBP). We investigated if image reconstruction by 3-dimensional ordered-subset expectation maximization (3D-OSEM) with resolution recovery, which has recently become available for clinical routine, provides a relevant improvement. METHODS: I-FP-CIT SPECT studies of 18 patients with normal to severely decreased DAT binding were reconstructed by FBP, 2D-OSEM (without resolution recovery), and 3D-OSEM, each with 2 different filter settings, yielding 3 data set pairs of relatively low and high resolution and noise: FBP with seventh-order Butterworth filter [cutoff frequency, 0.36 Nyquist (FBPlow) and 0.45 Nyquist (FBPhigh)] and OSEM with 8 iterations and 8 subsets (2D-/3D-OSEMlow) and 6 iterations and 16 subsets (2D-/3D-OSEMhigh), each with 8-mm Gaussian filtering. Mean regional counts, variability of counts (coefficient of variation), and binding potential (BPND) were assessed by volume-of-interest analyses of the caudate nucleus, the putamen, and the occipital cortex (reference region). RESULTS: On visual inspection, both 2D- and 3D-OSEM–reconstructed images showed an optimal delineation of striatal structures, whereas variability (noise) of nonspecific cortical I-FP-CIT uptake was lowest (most homogenous) with FBPlow, slightly higher with 2D-/3D-OSEMlow, and notably higher for the other methods. Volume-of-interest analyses revealed no significant differences of counts in the occipital reference region in comparison to FBPlow (reference method). In caudate nucleus, counts and, consequently, BPND values increased significantly with FBPhigh (mean BPND change, +5.2%), 2D-OSEMlow/high (+3.7%/+6.2%), and, most notably, 3D-OSEMlow/high (+11.1%/+14.0%). In the putamen, this effect was less pronounced for FBPhigh (+1.8%) and 3D-OSEMlow/high (+5.6%/+6.8%) and failed to reach statistical significance for 2D-OSEMlow/high (−0.2%/+0.8%). Regression analyses indicated excellent correlations of BPND between FBPlow and all other methods (R 〉 0.97), with the highest regression slopes for 3D-OSEM (1.12–1.16) followed by FBPhigh (1.04–1.06) and then 2D-OSEM (1.01–1.04). The order of the variability of counts in the occipital cortex was as follows: FBPlow (12.5%), 2D-OSEMlow (13.9%), 3D-OSEMlow (14.2%), FBPhigh (15.1%), 2D-OSEMhigh (17.0%), and 3D-OSEMhigh (17.6%). CONCLUSIONS: Three-dimensional OSEM considerably improves DAT SPECT reconstruction by offering an optimal combination of high-resolution delineation of striatal structures, superior recovery of signal and BPND, and sufficiently homogeneous nonspecific tracer uptake of the reference region.
    Keywords: Spect ; Dopamine Transporter ; I-123-Fp-Cit ; Iterative Reconstruction ; Iterative Reconstruction ; Neurotransmission ; Binding;
    ISSN: 0363-9762
    E-ISSN: 15360229
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  • 4
    Source: NARCIS (National Academic Research and Collaborations Information System)
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  • 5
    Language: English
    In: Journal of Nuclear Medicine, 2014, Vol.55(11), pp.1778-1785
    Description: (D)-F-18-fluoromethyltyrosine (D-F-18-FMT), or BAY 86-9596, is a novel F-18-labeled tyrosine derivative rapidly transported by the L-amino acid transporter (LAT-1), with a faster blood pool clearance than the corresponding L-isomer. The aim of this study was to demonstrate the feasibility of tumor detection in patients with non-small cell lung cancer (NSCLC) or head and neck squamous cell cancer (HNSCC) compared with inflammatory and physiologic tissues in direct comparison to F-18-FDG. Methods: 18 patients with biopsy-proven NSCLC (n = 10) or HNSCC (n = 8) were included in this Institutional Review Board-approved, prospective multicenter study. All patients underwent F-18-FDG PET/CT scans within 21 d before D-F-18-FMT PET/CT. For all patients, safety and outcome data were assessed. Results: No adverse reactions were observed related to D-F-18-FMT. Fifty-two lesions were F-18-FDG-positive, and 42 of those were malignant (34 histologically proven and 8 with clinical reference). Thirty-two of the 42 malignant lesions were also D-F-18-FMT-positive, and 10 lesions had no tracer uptake above the level of the blood pool. Overall there were 34 true-positive, 8 true-negative, 10 false-negative, and only 2 false-positive lesions for D-F-18-FMT, whereas F-18-FDG was true-positive in 42 lesions, with 10 false-positive and only 2 false-negative, resulting in a lesion-based detection rate for D-F-18-FMT and F-18-FDG of 77% and 95%, respectively, with an accuracy of 78% for both tracers. A high D-F-18-FMT tumor-to-blood pool ratio had a negative correlation with overall survival (P = 0.050), whereas the F-18-FDG tumor-to-blood pool ratio did not correlate with overall survival. Conclusion: D-F-18-FMT imaging in patients with NSCLC and HNSCC is safe and feasible. The presented preliminary results suggest a lower sensitivity but higher specificity for D-F-18-FMT over F-18-FDG, since there is no D-F-18-FMT uptake in inflammation. This increased specificity may be particularly beneficial in areas with endemic granulomatous disease and may improve clinical management. Further clinical investigations are needed to determine its clinical value and relevance for the prediction of survival prognosis.
    Keywords: D-Amino Acid Transport System ; Lat-1 ; Tumor Staging ; Specificity ; Fdg ; Positron-Emission-Tomography ; Tumor-Imaging Agents ; D-Isomers ; F-18-Fet Pet ; Tyrosine ; Mice ; O-F-18-Fluoromethyl ; Glioma
    ISSN: 0161-5505
    ISSN: 1535-5667
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  • 6
    Language: English
    In: Breast Cancer Research, 2012, Vol. 14(1), p. R33
    Description: Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10(-4)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10(-5), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10(-5)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.
    Keywords: Medical And Health Sciences ; Medicin Och Hälsovetenskap
    ISSN: 1465-542X
    ISSN: 14655411
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  • 7
    Language: English
    In: Human Mutation, April 2012, Vol.33(4), pp.690-702
    Description: Germline mutations in and are associated with increased risks of breast and ovarian cancer. A genome‐wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for and mutation carriers. Four single‐nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 and 7,132 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in carriers; rs10088218 per‐allele hazard ratio (HR) = 0.81 (95% CI: 0.67–0.98) P‐trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21–1.83) P‐trend = 1.8 × 10, rs717852 HR = 1.25 (95% CI: 1.10–1.42) P‐trend = 6.6 × 10, rs9303542 HR = 1.16 (95% CI: 1.02–1.33) P‐trend = 0.026. Two loci were associated with ovarian cancer risk in carriers; rs10088218 per‐allele HR = 0.89 (95% CI: 0.81–0.99) P‐trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10–1.42) P‐trend = 6.1 × 10. The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with and mutations regarding their risk of ovarian cancer. Hum Mutat 33:690–702, 2012. © 2012 Wiley Periodicals, Inc.
    Keywords: Ovarian Cancer ; Brca1 ; Brca2 ; Association ; Snp
    ISSN: 1059-7794
    E-ISSN: 1098-1004
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  • 8
    Language: English
    In: Breast Cancer Research, 2011, Vol. 13(6)
    Description: Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. less thanbrgreater than less thanbrgreater thanMethods: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. less thanbrgreater than less thanbrgreater thanResults: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 x 10(-6)). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. less thanbrgreater than less thanbrgreater thanConclusions: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.
    Keywords: Social Sciences ; Samhällsvetenskap ; Social Sciences ; Samhällsvetenskap
    ISSN: 1465-5411
    E-ISSN: 1465542X
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  • 9
    Language: English
    In: The Lancet Respiratory Medicine, May 2017, Vol.5(5), pp.412-425
    Description: Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors. The APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with , number . Between April 1, 2014, and Jan 31, 2015, 31 127 anaesthetic procedures in 30 874 children with a mean age of 6·35 years (SD 4·50) were included. The incidence of perioperative severe critical events was 5·2% (95% CI 5·0–5·5) with an incidence of respiratory critical events of 3·1% (2·9–3·3). Cardiovascular instability occurred in 1·9% (1·7–2·1), with an immediate poor outcome in 5·4% (3·7–7·5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10 000. This was independent of type of anaesthesia. Age (relative risk 0·88, 95% CI 0·86–0·90; p〈0·0001), medical history, and physical condition (1·60, 1·40–1·82; p〈0·0001) were the major risk factors for a serious critical event. Multivariate analysis revealed evidence for the beneficial effect of years of experience of the most senior anaesthesia team member (0·99, 0·981–0·997; p〈0·0048 for respiratory critical events, and 0·98, 0·97–0·99; p=0·0039 for cardiovascular critical events), rather than the type of health institution or providers. This study highlights a relatively high rate of severe critical events during the anaesthesia management of children for surgical or diagnostic procedures in Europe, and a large variability in the practice of paediatric anaesthesia. These findings are substantial enough to warrant attention from national, regional, and specialist societies to target education of anaesthesiologists and their teams and implement strategies for quality improvement in paediatric anaesthesia. European Society of Anaesthesiology.
    Keywords: Medicine
    ISSN: 2213-2600
    E-ISSN: 2213-2619
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