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Karen?van Eunen Catharina?M.?L.?Volker-Touw Albert?Gerding Aycha?Bleeker Justina?C.?Wolters Willemijn?J.?van Rijt Anne-Claire?M.?F.?Martines Klary?E.?Niezen-Koning Rebecca?M.?Heiner Hjalmar?Permentier Albert?K.?Groen Terry?G.?J.?Derks Barbara?M.?BakkerEmail author 《BMC biology》2016,14(1):107
Background
Defects in genes involved in mitochondrial fatty-acid oxidation (mFAO) reduce the ability of patients to cope with metabolic challenges. mFAO enzymes accept multiple substrates of different chain length, leading to molecular competition among the substrates. Here, we combined computational modeling with quantitative mouse and patient data to investigate whether substrate competition affects pathway robustness in mFAO disorders.Results
First, we used comprehensive biochemical analyses of wild-type mice and mice deficient for medium-chain acyl-CoA dehydrogenase (MCAD) to parameterize a detailed computational model of mFAO. Model simulations predicted that MCAD deficiency would have no effect on the pathway flux at low concentrations of the mFAO substrate palmitoyl-CoA. However, high concentrations of palmitoyl-CoA would induce a decline in flux and an accumulation of intermediate metabolites. We proved computationally that the predicted overload behavior was due to substrate competition in the pathway. Second, to study the clinical relevance of this mechanism, we used patients’ metabolite profiles and generated a humanized version of the computational model. While molecular competition did not affect the plasma metabolite profiles during MCAD deficiency, it was a key factor in explaining the characteristic acylcarnitine profiles of multiple acyl-CoA dehydrogenase deficient patients. The patient-specific computational models allowed us to predict the severity of the disease phenotype, providing a proof of principle for the systems medicine approach.Conclusion
We conclude that substrate competition is at the basis of the physiology seen in patients with mFAO disorders, a finding that may explain why these patients run a risk of a life-threatening metabolic catastrophe.2.
Willemijn L. Eppenga Cornelis Kramers Hieronymus J. Derijks Michel Wensing Jack F. M. Wetzels Peter A. G. M. De Smet 《PloS one》2015,10(3)
Background
The Modification of Diet in Renal Disease (MDRD) formula is widely used in clinical practice to assess the correct drug dose. This formula is based on serum creatinine levels which might be influenced by chronic diseases itself or the effects of the chronic diseases. We conducted a systematic review to determine the validity of the MDRD formula in specific patient populations with renal impairment: elderly, hospitalized and obese patients, patients with cardiovascular disease, cancer, chronic respiratory diseases, diabetes mellitus, liver cirrhosis and human immunodeficiency virus.Methods and Findings
We searched for articles in Pubmed published from January 1999 through January 2014. Selection criteria were (1) patients with a glomerular filtration rate (GFR) < 60 ml/min (/1.73m2), (2) MDRD formula compared with a gold standard and (3) statistical analysis focused on bias, precision and/or accuracy. Data extraction was done by the first author and checked by a second author. A bias of 20% or less, a precision of 30% or less and an accuracy expressed as P30% of 80% or higher were indicators of the validity of the MDRD formula. In total we included 27 studies. The number of patients included ranged from 8 to 1831. The gold standard and measurement method used varied across the studies. For none of the specific patient populations the studies provided sufficient evidence of validity of the MDRD formula regarding the three parameters. For patients with diabetes mellitus and liver cirrhosis, hospitalized patients and elderly with moderate to severe renal impairment we concluded that the MDRD formula is not valid. Limitations of the review are the lack of considering the method of measuring serum creatinine levels and the type of gold standard used.Conclusion
In several specific patient populations with renal impairment the use of the MDRD formula is not valid or has uncertain validity. 相似文献3.
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Bernig T Breunis W Brouwer N Hutchinson A Welch R Roos D Kuijpers T Chanock S 《Human genetics》2005,118(3-4):404-415
Mannose-binding protein (MBL) is a critical component of innate immunity and provides first-line protection against pathogens. Both circulating MBL serum levels and functional activity have been correlated with common genetic variants in the MBL2 gene. Associations between MBL deficiency and severe infections have been reported in immuno-incompetent patients and for autoimmune disorders; however, measured MBL serum levels do not fully correlate with the ‘secretor haplotypes’. Previously, the MBL2 locus was resequenced and determined that a recombination hotspot divides MBL2 into two haplotype blocks. It was sought to investigate whether additional variants, in either block structure could associate with MBL serum levels. Therefore, 31 common variants were analysed across the locus in 212 DNA samples of healthy Caucasian individuals with known MBL serum concentrations. The additional 5′ variants were in strong linkage to the elements of the ‘secretor haplotypes’; functional alleles B, C and D also lie on restricted haplotypes. Four variants in the 3′ block (Ex4-1483T>C, Ex4-1067G>A, Ex4-901G>A and Ex4-710G>A) are components of a distinct haplotype block. The results of this study suggest that additional 5′ variants as well as markers of distinct 3′ haplotype blocks in MBL2 may contribute to circulating protein levels, but further studies are required to confirm these observations. Last, there could be a selective advantage for diversification of the 3′ region of the gene.Electronic Supplementary Material Supplementary material is available for this article at 相似文献
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Meijer WM Werler MM Louik C Hernandez-Diaz S de Jong-van den Berg LT Mitchell AA 《Birth defects research. Part A, Clinical and molecular teratology》2006,76(10):714-717
BACKGROUND: Several studies have suggested a protective effect of folic acid (FA) on congenital heart anomalies. Down syndrome (DS) infants are known to have a high frequency of heart anomalies. Not all children with DS suffer from heart anomalies, which raises the question whether maternal factors might affect the risk of these anomalies. Our objectives were to investigate whether first-trimester FA use protects against heart anomalies among DS children. METHODS: Women with liveborn DS children participating in the Slone Epidemiology Center Birth Defects Study between 1976 and 1997 were included. We performed case-control analyses using DS, with heart anomalies as cases and DS, without heart anomalies as controls. Subanalyses were performed for defects that have been associated with FA in non-DS populations (conotruncal, ventricular septal [VSD]) and for those that are associated with DS (ostium secundum type atrial septal defects [ASD] and endocardial cushion defects [ECD]). Exposure was defined as the use of any FA-containing product for an average of at least 4 days per week during the first 12 weeks of pregnancy, whereas no exposure was defined as no use of FA in these 12 weeks. RESULTS: Of the 223 cases, 110 (49%) were exposed versus 84 (46%) of the 184 controls. After adjustment for possible confounders, no protective effect of FA was found on heart anomalies overall (OR 0.95, 95% CI: 0.61-1.47) nor separately for conotruncal defects, VSDs, ASDs, or ECDs. CONCLUSIONS: Our study does not show a protective effect of FA on heart anomalies among infants with DS. 相似文献
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Periconceptional parental conditions and perimembranous ventricular septal defects in the offspring
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Kim P.J. Wijnands Gerda A. Zeilmaker Willemijn M. Meijer Willem A. Helbing Régine P.M. Steegers‐Theunissen 《Birth defects research. Part A, Clinical and molecular teratology》2014,100(12):944-950
Background: The perimembranous ventricular septal (pVSD) defect is the most common congenital heart disease phenotype. Several parental factors are associated with pVSD risk in the offspring. To contribute to the future prevention of pVSDs, we investigated associations with nongenetic parental conditions. Methods: In a case–control study with standardized data collection at 17 months after birth, 115 parents of a child with pVSD and 484 parents of a healthy child completed questionnaires about periconceptional nongenetic conditions. Univariable and multivariable logistic regression analyses were used to estimate odds ratios (OR) with 95% confidence intervals (95% CI). Results: Complete data were available for 588 families (98%). Maternal risk conditions associated with pVSD offspring were a positive family history of congenital heart disease (OR, 2.61; 95%CI, 0.98–6.91), medication use (OR, 1.80; 95%CI, 1.13–2.85) and advanced age (OR, 1.07; 95%CI, 1.02–1.12). Exposure to phthalates (OR, 1.93; 95%CI, 1.05–3.54) was the only paternal risk condition associated with pVSD offspring. Conclusion: Four periconceptional parental conditions contributed to pVSD risk in the offspring. Couples planning pregnancy should be counseled on these risk conditions which are partially modifiable to contribute to the future prevention of pVSDs. Birth Defects Research (Part A) 100:944–950, 2014. © 2014 Wiley Periodicals, Inc. 相似文献
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H. Susan J. Picavet L. Willemijn Pas Sandra H. van Oostrom Hidde P. van der Ploeg W. M. Monique Verschuren Karin I. Proper 《PloS one》2016,11(1)
Objective
Sedentary behaviors are reported to impose health risks. Since occupational exposure is a major proportion of total sedentary time, we studied the association between occupational sitting and a number of health problems.Methods
From the longitudinal Doetinchem Cohort Study, we selected those working at baseline with complete data (n = 1,509). Participants were examined four times at 5 year-intervals between 1993 and 2012. We characterized occupational sitting as follows: 1) stable sitters and stable non sitters over a 15-year period, based on job characteristics and (2) having a job with a low, moderate or high amount of sitting, based on tertiles of self-reported number of hours per week of occupational sitting, measured at wave 5. Linear and logistic regression models were used. Outcomes were self-reported mental health, low-back or upper extremity pain, and objectively measured cardiometabolic health (overweight, hypertension, hypercholesterolemia).Results
Compared to stable non sitters, a lower risk of chronic upper extremity pain was observed for stable sitters (OR 0.75, 95% CI: 0.57; 1.00) as well as for those in the two upper tertiles for hours of occupational sitting (>4 hr/wk) (OR 0.65; 95%CI 0.50–0.86). For the other health outcomes studied, no significant associations were found with occupational sitting.Conclusion
Our findings do not support the hypothesis that occupational sitting is associated with health problems. The finding that occupational sitting is associated with less upper extremity pain might be due to the association of occupational sitting with less physical load. 相似文献10.
Idema WJ Majer IM Pahan D Oskam L Polinder S Richardus JH 《PLoS neglected tropical diseases》2010,4(11):e874