Dataset Information

Circadian Variation of Plasminogen-Activator-Inhibitor-1 Levels in Children with Meningococcal Sepsis.

ABSTRACT:

Objective

To study whether the circadian variation of plasminogen-activator-inhibitor-1 (PAI-1) levels, with high morning levels, is associated with poor outcome of children with meningococcal sepsis presenting in the morning hours.

Design

Retrospective analysis of prospectively collected clinical and laboratory data.

Setting

Single center study at Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.

Subjects

184 patients aged 3 weeks to 18 years with meningococcal sepsis. In 36 of these children, PAI-1 levels at admission to the PICU were measured in plasma by ELISA.

Interventions

None.

Measurements and main results

Circadian variation was studied by dividing one day in blocks of 6 hours. Patients admitted between 6:00 am and 12:00 am had increased illness severity scores and higher PAI-1 levels (n = 9, median 6912 ng/mL, IQR 5808-15600) compared to patients admitted at night (P = 0.019, n = 9, median 3546 ng/mL, IQR 1668-6118) or in the afternoon (P = 0.007, n = 7, median 4224 ng/mL, IQR 1804-5790). In 184 patients, analysis of circadian variation in relation to outcome showed more deaths, amputations and need for skin grafts in patients admitted to the PICU between 6:00 am and 12:00 am than patients admitted during the rest of the day (P = 0.009).

Conclusions

Circadian variation of PAI-1 levels is present in children with meningococcal sepsis and is associated with illness severity, with a peak level in the morning. Whether circadian variation is an independent risk factor for morbidity and mortality in meningococcal sepsis needs to be explored in future studies.

SUBMITTER: Boeddha NP

PROVIDER: S-EPMC5125643 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Circadian Variation of Plasminogen-Activator-Inhibitor-1 Levels in Children with Meningococcal Sepsis.

Boeddha Navin P NP Driessen Gertjan J GJ Cnossen Marjon H MH Hazelzet Jan A JA Emonts Marieke M

PloS one 20161128 11

<h4>Objective</h4>To study whether the circadian variation of plasminogen-activator-inhibitor-1 (PAI-1) levels, with high morning levels, is associated with poor outcome of children with meningococcal sepsis presenting in the morning hours.<h4>Design</h4>Retrospective analysis of prospectively collected clinical and laboratory data.<h4>Setting</h4>Single center study at Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.<h4>Subjects</h4>184 patients aged 3 weeks to 18 years with m ...[more]

PMID: 27893784

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Project description:BackgroundRecessive mutations in WRN gene eliminate WRN protein function (helicase) and cause Werner syndrome. One of the most important clinical features of Werner syndrome patients are the premature onset and accelerated atherosclerosis process. Studies carried out on polymorphic WRN locus have shown that the alleles 1367R and 1074L confer protection for cardiovascular disease. Given that the levels of plasminogen activator inhibitor type 1 (PAI-1) were found to be significantly increased in Werner syndrome patients, is quiet possible that PAI-1 expression could be under regulation of WRN helicase. Therefore the purpose of this work was to evaluate the role of WRN polymorphism in modulating the expression of PAI-1.MethodsIn order to accomplish our aim, an array of primary cultured fibroblasts from normal adult donors was genotyped for polymorphisms of both the WRN and PAI-1 loci. In addition, steady state levels of WRN and PAI-1 were measured by semi-quantitative RT-PCR assays in such cultures. To search for the potential relationship between the lack of WRN protein and PAI-1 expression, heterozygous cultures of fibroblasts (1367RC/1074LF; WRN genotype) were treated with a molecule of interference RNA against WRN messenger RNA (mRNA).ResultsWe found that, carriers of 1367R and 1074L alleles of WRN shown to have low amounts of PAI-1 in plasma (7.56 +/- 5.02), as compared with carriers of 1367C and 1074F alleles (16.09 +/- 6.03). Moreover, fibroblasts from carriers with these alleles had low expression levels of PAI-1 mRNA. The treatment of heterozygous primary fibroblast cultures (1367RC/1074LF; WRN genotype) with iRNA against WRN mRNA caused PAI-1 overexpression. Treatment with normal PAI-1 inducers (TGFbeta, TNFalpha, or insulin) in these cultures and from those with genotypes 1367CC/1074FF and 1367RR/1074FL resulted in a genotype-dependent PAI-1 expression level.ConclusionOur results suggest that polymorphisms in the WRN gene might have a significant role regulating PAI-1 levels in healthy individuals and "normal states" as well as acute or chronic stress, obesity, aging, acute inflammation, among others, where characteristic high levels of insulin, TNF alpha and TGFbeta, could favor PAI-1 high levels in carriers with polymorphic variants (C and F alleles), beyond the levels reached by carriers with other alleles (R and L alleles).

Dataset Information

Circadian Variation of Plasminogen-Activator-Inhibitor-1 Levels in Children with Meningococcal Sepsis.

Objective

Design

Setting

Subjects

Interventions

Measurements and main results

Conclusions

Publications

Circadian Variation of Plasminogen-Activator-Inhibitor-1 Levels in Children with Meningococcal Sepsis.

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