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  1. Article ; Online: Quantifying apolipoprotein(a) in the era of proteoforms and precision medicine.

    Ruhaak, L R / Cobbaert, C M

    Clinica chimica acta; international journal of clinical chemistry

    2020  Volume 511, Page(s) 260–268

    Abstract: Lipoprotein(a) (Lp(a)) is an independent risk factor in the development of atherosclerotic cardiovascular diseases (ASCVD) and calcific aortic valve disease (CAVD). Lp(a) is an LDL-like particle to which apolipoprotein (a) (apo(a)) is covalently bound. ... ...

    Abstract Lipoprotein(a) (Lp(a)) is an independent risk factor in the development of atherosclerotic cardiovascular diseases (ASCVD) and calcific aortic valve disease (CAVD). Lp(a) is an LDL-like particle to which apolipoprotein (a) (apo(a)) is covalently bound. Apo(a) contains a variable number of kringle IV repeats, a kringle V and a protease domain. Serum/plasma Lp(a) concentrations are traditionally expressed as total particle mass in mg/L. Concern has arisen lately as flawed Lp(a) mass tests have masked its clinical utility. The determinants of variability in Lp(a) composition were investigated, including the apo(a) size polymorphism, post-translational modifications -N- and O-glycosylation- and the lipid:protein ratio. Depending on the number of kringle IV-2 repeats, the theoretical protein content of the Lp(a) particle varies between 30 and 46 (w/w) %, which inescapably confounds Lp(a) mass measurements. The authors advocate that reporting of Lp(a) particle concentrations in mass units is metrologically inappropriate and should be abandoned, as it results in systematically biased Lp(a) results. Enabling technology, such as mass spectrometry, allows unequivocal molecular characterization of the apo(a) measurand(s) and accurate quantitation of apo(a) in molar units, unaffected by apo(a) size polymorphism. To guarantee that Lp(a)/apo(a) tests are fit-for-clinical-purpose, basic metrology principles should be implemented upfront during test development.
    MeSH term(s) Apolipoproteins A/genetics ; Apoprotein(a)/genetics ; Humans ; Kringles ; Lipoprotein(a)/genetics ; Precision Medicine
    Chemical Substances Apolipoproteins A ; Lipoprotein(a) ; Apoprotein(a) (EC 3.4.21.-)
    Language English
    Publishing date 2020-10-13
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 80228-1
    ISSN 1873-3492 ; 0009-8981
    ISSN (online) 1873-3492
    ISSN 0009-8981
    DOI 10.1016/j.cca.2020.10.010
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  2. Article ; Online: Effects of sample matrix in the measurement of antithrombin by LC-MS: A role for immunocapture.

    Kruijt, M / Smit, N P M / van Ham, J J / Cobbaert, C M / Ruhaak, L R

    Journal of mass spectrometry and advances in the clinical lab

    2023  Volume 27, Page(s) 61–65

    Abstract: Introduction: The sample matrix composition, which is greatly affected by the type of blood collection tube used during phlebotomy, is of major importance in laboratory testing as it can influence test results. We developed an LC-MRM-MS test to ... ...

    Abstract Introduction: The sample matrix composition, which is greatly affected by the type of blood collection tube used during phlebotomy, is of major importance in laboratory testing as it can influence test results. We developed an LC-MRM-MS test to molecularly characterize antithrombin in citrate plasma. The test principle differs greatly from traditional laboratory tests and the influence of varying plasma sample matrices is largely unknown.
    Objectives: To identify whether variations in sample matrix affect the LC-MRM-MS test for antithrombin and assess whether sample pre-processing by immunocapture reduces matrix-specific effects.
    Methods: Samples (n = 45) originating from four different blood collection tubes (sodium citrate, lithium heparin, K
    Results: Deming regression analysis of directly processed samples revealed slopes deviating >5% from the line of identity for at least six out of 22 peptides in all matrices. Significant differences between all matrices were found upon analysis by ANOVA for at least 10 peptides. Pre-processing by immunocapture led to slopes within 5% of the line of identity for nearly all peptides of the matrices. Furthermore, significant differences between matrices after immunocapture were only observed for four peptides.
    Conclusion: Variations in the sample matrix affect the measurement of antithrombin by LC-MRM-MS, but observed effects are greatly reduced upon pre-processing by immunocapture.
    Language English
    Publishing date 2023-01-07
    Publishing country Netherlands
    Document type Journal Article
    ISSN 2667-145X
    ISSN (online) 2667-145X
    DOI 10.1016/j.jmsacl.2023.01.002
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  3. Article: High residual cardiovascular risk after lipid-lowering: prime time for Predictive, Preventive, Personalized, Participatory, and Psycho-cognitive medicine.

    Reijnders, E / van der Laarse, A / Jukema, J W / Cobbaert, C M

    Frontiers in cardiovascular medicine

    2023  Volume 10, Page(s) 1264319

    Abstract: As time has come to translate trial results into individualized medical diagnosis and therapy, we analyzed how to minimize residual risk of cardiovascular disease (CVD) by reviewing papers on "residual cardiovascular disease risk". During this review ... ...

    Abstract As time has come to translate trial results into individualized medical diagnosis and therapy, we analyzed how to minimize residual risk of cardiovascular disease (CVD) by reviewing papers on "residual cardiovascular disease risk". During this review process we found 989 papers that started off with residual CVD risk after initiating statin therapy, continued with papers on residual CVD risk after initiating therapy to increase high-density lipoprotein-cholesterol (HDL-C), followed by papers on residual CVD risk after initiating therapy to decrease triglyceride (TG) levels. Later on, papers dealing with elevated levels of lipoprotein remnants and lipoprotein(a) [Lp(a)] reported new risk factors of residual CVD risk. And as new risk factors are being discovered and new therapies are being tested, residual CVD risk will be reduced further. As we move from CVD risk reduction to improvement of patient management, a paradigm shift from a reductionistic approach towards a holistic approach is required. To that purpose, a personalized treatment dependent on the individual's CVD risk factors including lipid profile abnormalities should be configured, along the line of P5 medicine for each individual patient, i.e., with Predictive, Preventive, Personalized, Participatory, and Psycho-cognitive approaches.
    Language English
    Publishing date 2023-10-16
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2781496-8
    ISSN 2297-055X
    ISSN 2297-055X
    DOI 10.3389/fcvm.2023.1264319
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  4. Article ; Online: The addition of the sFlt-1/PlGF ratio to the protein/creatinine ratio in multiple pregnancy: Post-hoc analysis of the PREPARE cohort study.

    Wind, M / Dekker, L / van den Akker-van Marle, M E / Ballieux, B E P B / Cobbaert, C M / Rabelink, T J / van Lith, J M M / Teng, Y K O / Sueters, M

    Pregnancy hypertension

    2024  Volume 36, Page(s) 101111

    Abstract: Objective: To assess the predictive accuracy of the sFlt-1/PlGF ratio cut-off 38 in addition to the standard-of-care spot urine protein/creatinine ratio (PCr) for multiple pregnancies in women with suspected pre-eclampsia.: Study design: Post-hoc ... ...

    Abstract Objective: To assess the predictive accuracy of the sFlt-1/PlGF ratio cut-off 38 in addition to the standard-of-care spot urine protein/creatinine ratio (PCr) for multiple pregnancies in women with suspected pre-eclampsia.
    Study design: Post-hoc analysis of a prospective cohort study.
    Main outcome measures: Primary outcome was the occurrence of pre-eclampsia in one and four weeks after presentation with suspected pre-eclampsia. Test characteristics with 95% confidence intervals (CI) were calculated on pre-eclampsia development in one and four weeks.
    Results: Twenty-three multiple pregnancies with suspected pre-eclampsia between 20 and 37 weeks gestation were included for analysis. Women who eventually developed pre-eclampsia had a significantly higher PCr (34.0 vs. 16.5, p = 0.015), sFlt-1 (17033 vs. 5270 pg/ml, p = 0.047) and sFlt-1/PlGF ratio (99 vs. 25, p = 0.033) at baseline. Furthermore, PCr ≥ 30 and sFlt-1/PlGF ratio > 38 was respectively seen in 1/16 (6.3 %) and 3/16 (18.8 %) of the women who did not develop pre-eclampsia. For predicting pre-eclampsia within one week the sFlt-1/PlGF ratio sensitivity was 75.0 % [95 % CI 19.4-99.4] and the negative predictive value 93.8 % [73.0-98.8], while no pre-eclampsia developed when PCr was < 30. Consequently, the combination of these tests did not lead to an improvement in test characteristics, with non-significant differences in positive predictive value (50.0 % [29.5-70.5] versus 80.0 % [37.3-96.4]) compared to PCr alone for pre-eclampsia development in one week.
    Conclusions: In addition to standard-of-care spot urine PCr measurements, this study has not been able to demonstrate that the sFlt-1/PlGF ratio cut-off 38 is of added value in the prediction of pre-eclampsia in multiple pregnancy.
    Trial registration: Netherlands Trial Register (NL8308).
    Language English
    Publishing date 2024-02-21
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2584464-7
    ISSN 2210-7797 ; 2210-7789
    ISSN (online) 2210-7797
    ISSN 2210-7789
    DOI 10.1016/j.preghy.2024.101111
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  5. Article: Rational selection of a biomarker panel targeting unmet clinical needs in kidney injury.

    van Duijl, T T / Soonawala, D / de Fijter, J W / Ruhaak, L R / Cobbaert, C M

    Clinical proteomics

    2021  Volume 18, Issue 1, Page(s) 10

    Abstract: The pipeline of biomarker translation from bench to bedside is challenging and limited biomarkers have been adopted to routine clinical care. Ideally, biomarker research and development should be driven by unmet clinical needs in health care. To guide ... ...

    Abstract The pipeline of biomarker translation from bench to bedside is challenging and limited biomarkers have been adopted to routine clinical care. Ideally, biomarker research and development should be driven by unmet clinical needs in health care. To guide researchers, clinical chemists and clinicians in their biomarker research, the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) has developed a structured questionnaire in which the clinical gaps in current clinical pathways are identified and desirable performance specifications are predefined. In kidney injury, the high prevalence of the syndrome acute kidney injury (AKI) in the hospital setting has a significant impact on morbidity, patient survival and health care costs, but the use of biomarkers indicating early kidney injury in daily patient care remains limited. Routinely, medical labs measure serum creatinine, which is a functional biomarker, insensitive for detecting early kidney damage and cannot distinguish between renal and prerenal AKI. The perceived unmet clinical needs in kidney injury were identified through the EFLM questionnaire. Nephrologists within our tertiary care hospital emphasized that biomarkers are needed for (1) early diagnosis of in-hospital AKI after a medical insult and in critically ill patients, (2) risk stratification for kidney injury prior to a scheduled (elective) intervention, (3) kidney injury monitoring in patients scheduled to receive nephrotoxic medication and after kidney transplantation and (4) differentiation between prerenal AKI and structural kidney damage. The biomarker search and selection strategy resulted in a rational selection of an eleven-protein urinary panel for kidney injury that target these clinical needs. To assess the clinical utility of the proposed biomarker panel in kidney injury, a multiplexed LC-MS test is now in development for the intended translational research.
    Language English
    Publishing date 2021-02-22
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2205154-5
    ISSN 1542-6416
    ISSN 1542-6416
    DOI 10.1186/s12014-021-09315-z
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    Zs.A 6222: Show issues Location:
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  6. Article ; Online: Clinical value and cost analysis of the sFlt-1/PlGF ratio in addition to the spot urine protein/creatinine ratio in women with suspected pre-eclampsia: PREPARE cohort study.

    Wind, M / van den Akker-van Marle, M E / Ballieux, B E P B / Cobbaert, C M / Rabelink, T J / van Lith, J M M / Teng, Y K O / Sueters, M

    BMC pregnancy and childbirth

    2022  Volume 22, Issue 1, Page(s) 910

    Abstract: Background: This study investigated the clinical value of adding the sFlt-1/PlGF ratio to the spot urine protein/creatinine ratio (PCr) in women with suspected pre-eclampsia.: Methods: This was a prospective cohort study performed in a tertiary ... ...

    Abstract Background: This study investigated the clinical value of adding the sFlt-1/PlGF ratio to the spot urine protein/creatinine ratio (PCr) in women with suspected pre-eclampsia.
    Methods: This was a prospective cohort study performed in a tertiary referral centre. Based on the combination of PCr (< 30) and sFlt-1/PlGF (≤38) results, four groups were described: a double negative result, group A-/-; a negative PCr and positive sFlt-1/PlGF, group B-/+; a positive PCr and negative sFlt-1/PlGF, group C+/-; and a double positive result, group D+/+. The primary outcome was the proportion of false negatives of the combined tests in comparison with PCr alone in the first week after baseline. Secondary, a cost analysis comparing the costs and savings of adding the sFlt-1/PlGF ratio was performed for different follow-up scenarios.
    Results: A total of 199 women were included. Pre-eclampsia in the first week was observed in 2 women (2%) in group A-/-, 12 (26%) in group B-/+, 4 (27%) in group C+/-, and 12 (92%) in group D+/+. The proportion of false negatives of 8.2% [95% CI 4.9-13.3] with the PCr alone was significantly reduced to 1.6% [0.4-5.7] by adding a negative sFlt-1/PlGF ratio. Furthermore, the addition of the sFlt-1/PlGF ratio to the spot urine PCr, with telemonitoring of women at risk, could result in a reduction of 41% admissions and 36% outpatient visits, leading to a cost reduction of €46,- per patient.
    Conclusions: Implementation of the sFlt-1/PlGF ratio in addition to the spot urine PCr, may lead to improved selection of women at low risk and a reduction of hospital care for women with suspected pre-eclampsia.
    Trial registration: Netherlands Trial Register (NL8308).
    MeSH term(s) Female ; Humans ; Pre-Eclampsia/diagnosis ; Cohort Studies ; Prospective Studies ; Netherlands ; Costs and Cost Analysis
    Language English
    Publishing date 2022-12-06
    Publishing country England
    Document type Journal Article
    ZDB-ID 2059869-5
    ISSN 1471-2393 ; 1471-2393
    ISSN (online) 1471-2393
    ISSN 1471-2393
    DOI 10.1186/s12884-022-05254-1
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  7. Article ; Online: IGF-1 and IGF-1 SDS - fit for purpose?

    Kos, S / Cobbaert, C M / Kuijper, T M / Oostdijk, W / Hannema, S E / Wit, J M / Biermasz, N / Ballieux, B E P B

    European journal of endocrinology

    2019  Volume 181, Issue 5, Page(s) L1–L4

    MeSH term(s) Adolescent ; Adult ; Aged ; Biomarkers/blood ; Child ; Child, Preschool ; Female ; Humans ; Insulin-Like Growth Factor I/metabolism ; Male ; Middle Aged ; Reference Standards ; Young Adult
    Chemical Substances Biomarkers ; IGF1 protein, human ; Insulin-Like Growth Factor I (67763-96-6)
    Language English
    Publishing date 2019-09-04
    Publishing country England
    Document type Letter
    ZDB-ID 1183856-5
    ISSN 1479-683X ; 0804-4643
    ISSN (online) 1479-683X
    ISSN 0804-4643
    DOI 10.1530/EJE-19-0458
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  8. Article ; Online: Disease stage and plasma levels of cytokines in Huntington's disease: A 2-year follow-up study.

    Bouwens, J A / van Duijn, E / Cobbaert, C M / Roos, R A C / van der Mast, R C / Giltay, E J

    Movement disorders : official journal of the Movement Disorder Society

    2017  Volume 32, Issue 7, Page(s) 1103–1104

    MeSH term(s) Adult ; Aged ; Cytokines/blood ; Disease Progression ; Female ; Follow-Up Studies ; Humans ; Huntington Disease/blood ; Male ; Middle Aged ; Severity of Illness Index
    Chemical Substances Cytokines
    Language English
    Publishing date 2017-05-29
    Publishing country United States
    Document type Letter
    ZDB-ID 607633-6
    ISSN 1531-8257 ; 0885-3185
    ISSN (online) 1531-8257
    ISSN 0885-3185
    DOI 10.1002/mds.26950
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    Zs.MO 238: Show issues

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  9. Article ; Online: Prediction model for pneumonia in primary care patients with an acute respiratory tract infection: role of symptoms, signs, and biomarkers.

    Groeneveld, G H / van 't Wout, J W / Aarts, N J / van Rooden, C J / Verheij, T J M / Cobbaert, C M / Kuijper, E J / de Vries, J J C / van Dissel, J T

    BMC infectious diseases

    2019  Volume 19, Issue 1, Page(s) 976

    Abstract: Background: Diagnosing pneumonia can be challenging in general practice but is essential to distinguish from other respiratory tract infections because of treatment choice and outcome prediction. We determined predictive signs, symptoms and biomarkers ... ...

    Abstract Background: Diagnosing pneumonia can be challenging in general practice but is essential to distinguish from other respiratory tract infections because of treatment choice and outcome prediction. We determined predictive signs, symptoms and biomarkers for the presence of pneumonia in patients with acute respiratory tract infection in primary care.
    Methods: From March 2012 until May 2016 we did a prospective observational cohort study in three radiology departments in the Leiden-The Hague area, The Netherlands. From adult patients we collected clinical characteristics and biomarkers, chest X ray results and outcome. To assess the predictive value of C-reactive protein (CRP), procalcitonin and midregional pro-adrenomedullin for pneumonia, univariate and multivariate binary logistic regression were used to determine risk factors and to develop a prediction model.
    Results: Two hundred forty-nine patients were included of whom 30 (12%) displayed a consolidation on chest X ray. Absence of runny nose and whether or not a patient felt ill were independent predictors for pneumonia. CRP predicts pneumonia better than the other biomarkers but adding CRP to the clinical model did not improve classification (- 4%); however, CRP helped guidance of the decision which patients should be given antibiotics.
    Conclusions: Adding CRP measurements to a clinical model in selected patients with an acute respiratory infection does not improve prediction of pneumonia, but does help in giving guidance on which patients to treat with antibiotics. Our findings put the use of biomarkers and chest X ray in diagnosing pneumonia and for treatment decisions into some perspective for general practitioners.
    MeSH term(s) Adult ; Aged ; Anti-Bacterial Agents/therapeutic use ; Biomarkers/analysis ; C-Reactive Protein/analysis ; Calcitonin/analysis ; Female ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Netherlands ; Pneumonia/complications ; Pneumonia/diagnosis ; Pneumonia/drug therapy ; Primary Health Care ; Prognosis ; Prospective Studies ; Respiratory Tract Infections/complications ; Respiratory Tract Infections/diagnosis ; Respiratory Tract Infections/drug therapy ; Thorax/diagnostic imaging
    Chemical Substances Anti-Bacterial Agents ; Biomarkers ; Calcitonin (9007-12-9) ; C-Reactive Protein (9007-41-4)
    Language English
    Publishing date 2019-11-20
    Publishing country England
    Document type Journal Article
    ISSN 1471-2334
    ISSN (online) 1471-2334
    DOI 10.1186/s12879-019-4611-1
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  10. Article: Regional differences of HFE (C282Y, H63D) allele frequencies in the Netherlands A model case illustrating the significance of genographics and prehistorical population migration.

    Cobbaert, C M / Delanghe, J / Boer, J M A / Feskens, E J M

    Acta clinica Belgica

    2012  Volume 67, Issue 6, Page(s) 430–435

    Abstract: We investigated HFE C282Y and H63D allele frequencies in three Dutch towns in the Netherlands, as well as their association with cardiovascular disease (CVD) mortality. Study subjects were selected from participants of the Monitoring Project on ... ...

    Abstract We investigated HFE C282Y and H63D allele frequencies in three Dutch towns in the Netherlands, as well as their association with cardiovascular disease (CVD) mortality. Study subjects were selected from participants of the Monitoring Project on Cardiovascular Disease Risk Factors in the Netherlands carried out in Amsterdam, Doetinchem and Maastricht among > 35000 subjects, 20-59 years of age. Mortality follow-up lasted 9 to 13 years. A random sample of the cohort (n = 1075) provided information on the total study population. The random sample and all CVD deaths (n = 301) were genotyped for the C282Y and H63D mutation. Adjusted hazard ratios (HR) for CVD mortality were calculated per genotype. C282Y allele frequencies differed significantly between the towns investigated (p = 0.017), whereas the allele frequencies of H63D were similar (p = 0.141) across towns. In Maastricht we found a C282Y allele frequency of 0.086 compared to 0.055 in Amsterdam and 0.054 in Doetinchem. C282Y and H63D heterozygosity did not predict fatal CVD in either men or women, whereas homozygosity for the H63D mutation increased fatal CVD in women (adjusted HR = 8.5; 95% CI = 2.3-31.1). The unexpected high C282Y allele frequency in Maastricht is in line with the recent evidence of a Celtic origin of citizens from the former southern Netherlands and with prehistorical population migrations revealed in the context of the international Genographic Project, a landmark study of prehistorical human migrations around the globe. We recommend that when designing national screening programmes and national registries for genetic disorders, potential regional prevalence differences should be taken into account.
    MeSH term(s) Adult ; Anthropometry ; Cardiovascular Diseases/genetics ; Cardiovascular Diseases/mortality ; Case-Control Studies ; Female ; Gene Frequency ; Genotype ; Hemochromatosis Protein ; Histocompatibility Antigens Class I/genetics ; Human Migration ; Humans ; Male ; Membrane Proteins/genetics ; Middle Aged ; Molecular Epidemiology ; Mutation ; Netherlands/epidemiology ; Proportional Hazards Models ; Prospective Studies ; Risk Factors
    Chemical Substances HFE protein, human ; Hemochromatosis Protein ; Histocompatibility Antigens Class I ; Membrane Proteins
    Language English
    Publishing date 2012-11
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 390201-8
    ISSN 2295-3337 ; 1784-3286 ; 0001-5512
    ISSN (online) 2295-3337
    ISSN 1784-3286 ; 0001-5512
    DOI 10.2143/ACB.67.6.2062708
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