Activated Protein Synthesis and Suppressed Protein Breakdown Signaling in Skeletal Muscle of Critically Ill Patients

BACKGROUND: Skeletal muscle mass is controlled by myostatin and Akt-dependent signaling on mammalian target of rapamycin (mTOR), glycogen synthase kinase 3β (GSK3β) and forkhead box O (FoxO) pathways, but it is unknown how these pathways are regulated in critically ill human muscle. To describe factors involved in muscle mass regulation, we investigated the phosphorylation and expression of key factors in these protein synthesis and breakdown signaling pathways in thigh skeletal muscle of critically ill intensive care unit (ICU) patients compared with healthy controls. METHODOLOGY/PRINCIPAL FINDINGS: ICU patients were systemically inflamed, moderately hyperglycemic, received insulin therapy, and showed a tendency to lower plasma branched chain amino acids compared with controls. Using Western blotting we measured Akt, GSK3β, mTOR, ribosomal protein S6 kinase (S6k), eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), and muscle ring finger protein 1 (MuRF1); and by RT-PCR we determined mRNA expression of, among others, insulin-like growth factor 1 (IGF-1), FoxO 1, 3 and 4, atrogin1, MuRF1, interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and myostatin. Unexpectedly, in critically ill ICU patients Akt-mTOR-S6k signaling was substantially higher compared with controls. FoxO1 mRNA was higher in patients, whereas FoxO3, atrogin1 and myostatin mRNAs and MuRF1 protein were lower compared with controls. A moderate correlation (r2=0.36, p<0.05) between insulin infusion dose and phosphorylated Akt was demonstrated. CONCLUSIONS/SIGNIFICANCE: We present for the first time muscle protein turnover signaling in critically ill ICU patients, and we show signaling pathway activity towards a stimulation of muscle protein synthesis and a somewhat inhibited proteolysis

Children diagnosed with congenital cardiac malformations at the national university departments of pediatric cardiology: positive predictive values of data in the Danish National Patient Registry

Peter Agergaard1, Anders Hebert2, Jesper Bjerre3, Karina Meden S&amp;oslash;rensen4, Charlotte Olesen3, John Rosendal &amp;Oslash;stergaard31Department of Pediatrics, Viborg Hospital, Viborg, Denmark; 2Department of Pediatrics, Copenhagen University Hospital, Rigshospitalet, Denmark; 3Department of Pediatrics, Aarhus University Hospital, Skejby, Denmark; 4Department of Clinical Biochemistry and Immunology, Statens Serum Institut, Copenhagen, DenmarkIntroduction: The present study was conducted to establish the positive predictive value of congenital cardiac malformation diagnoses registered in the Danish National Patient Registry (NPR), thereby exploring whether the NPR can serve as a valid tool for epidemiologic studies of congenital cardiac malformations.Materials and methods: The study population comprised every individual born from 2000 to 2008 who was registered in the NPR with a congenital cardiac malformation diagnosis and treated at one of the two national departments of pediatric cardiology. Positive predictive values were established comparing NPR information with the clinical record of each individual.Results: A total of 2952 patients with a total of 3536 diagnoses were eligible for validation. Review of their clinical records unveiled no patient without cardiac malformation. In 98% (98%&amp;ndash;99%) of the cases, the NPR diagnosis could be found as the discharge diagnosis in the patient&amp;#39;s clinical record, and in 90% (89%&amp;ndash;91%) of the cases the NPR diagnosis was considered a true reflection of the patient&amp;#39;s actual malformation.Conclusions: Our study verifies that the present study population retrieved from the NPR is a valid tool for epidemiological research within the topic of congenital cardiac malformations, given that the research question is not dependent on a fully established sensitivity of the NPR. Precautions should be made regarding cardiac malformations characterized by low prevalence or poor predictive values, and the reported validity should not be extrapolated beyond the study period.Keywords: congenital cardiac malformation, registry, validatio