This article is available online at http://www.jlr.org uct, formed during storage of cholesterol or artifactually produced during work-up of tissue samples ( 1, 2 ). Enzymatic formation of 25-hydroxycholesterol by rat liver mitochondria was described in 1974 ( 3 ), and it was later shown that 25-hydroxycholesterol is formed as a by-product during cholesterol oxidation by the mitochondrial enzyme sterol 27-hydroxylase in liver in pig ( 4 ) and mouse ( 5 ). In addition to the formation of 25-hydroxycholesterol by sterol 27-hydroxylase (CYP27A1), a specifi c human microsomal cholesterol 25-hydroxylase has been cloned and characterized ( 6 ). This enzyme does not belong to the cytochrome P450 family but is related to the eukaryotic stearoyl-CoA desaturases ( 6 ). Low levels (3-5 ng/ml) of 25-hydroxycholesterol are present in human plasma ( 7 ), but the relative contribution of CYP27A1 and cholesterol 25-hydroxylase to its formation is not known.25-Hydroxycholesterol is a potent regulatory oxysterol and may participate in several aspects of lipid metabolism ( 8 ). A family of oxysterol binding proteins with high affi nity for 25-hydroxycholesterol has been identifi ed ( 9 ). Overexpression of oxysterol binding proteins in Chinese hamster ovary cells resulted in signifi cant changes in genes involved in lipid metabolism ( 10 ). Side chain oxidized oxysterols, such as 25-hydroxycholesterol, have been implicated in the regulation of cholesterol homeostasis for a long time but only recently was the mechanism clarifi ed. These oxysterols bind to proteins called Insigs, thereby blocking the sterol regulatory element binding protein signaling that regulates cholesterol biosynthesis ( 11 ). Furthermore, 25-hydroxycholesterol has been shown to activate the nuclear receptor

Glutathione is quantitatively the most important endogenous scavenger system. Glutathione depletion in skeletal muscle is pronounced following major trauma and sepsis in intensive care unit patients. Also, following elective surgery, glutathione depletion occurs in parallel with a progressive decline in muscle glutamine concentration. The present study was designed to test the hypothesis that glutamine supplementation may counteract glutathione depletion in a human trauma model. A homogeneous group of patients (n = 17) undergoing a standardized surgical procedure were prospectively randomly allocated to receive glutamine (0.56 g x day(-1) x kg(-1)) or placebo as part of isonitrogenous and isocaloric nutrition. Percutaneous muscle biopsies and blood samples were taken pre-operatively and at 24 and 72 h after surgery. The concentrations of muscle glutathione and related amino acids were determined in muscle tissue and plasma. In the control (unsupplemented) subjects, total muscle glutathione had decreased by 47+/-8% and 37+/-11% and reduced glutathione had decreased by 53+/-10% and 45+/-16% respectively at 24 and 72 h after surgery (P < 0.05). In contrast, in the glutamine-supplemented group, no significant post-operative decreases in total or reduced glutathione were seen following surgery. Muscle free glutamine had decreased at 72 h after surgery in both groups, by 41.4+/-14.8% (P < 0.05) in the glutamine-supplemented group and by 46.0+/-14.3% (P < 0.05) in the control group. In conclusion, the present study demonstrates that intravenous glutamine supplementation attenuates glutathione depletion in skeletal muscle in humans following standardized surgical trauma.

This study demonstrates that glutathione remains depleted in whole blood. This contrasts to what has previously been shown in skeletal muscle where a restitution of glutathione concentration is seen.

Background: Venous thrombosis (VT) in children is often associated with a central venous catheter (CVC). We aimed to determine the incidence of VT associated with percutaneous non-tunnelled CVCs in a general paediatric population, and to identify risk factors for VT in this cohort. Methods: Observational, prospective study enrolling consecutive patients at a tertiary multidisciplinary paediatric hospital. A total of 211 percutaneous, non-tunnelled CVCs were analysed. Data regarding potential risk factors for CVCrelated VT were collected. Compression ultrasonography with colour Doppler was used to diagnose VT. Results: Overall, 30.3% of children developed CVC-related VT, with an incidence rate of 29.6 (confidence interval, 22.5e36.9) cases/1000 CVC days. Upper body CVC location, multiple lumen CVCs, and male gender were independent risk factors for VT in multivariate analysis. All upper body VTs were in the internal jugular vein (IJV). The occurrence of CVCrelated VT did not affect length of paediatric ICU or hospital stay. In patients with VT, femoral CVCs, young age, paediatric ICU admission, and a ratio of CVC/vein diameter >0.33 were associated with VT being symptomatic, occlusive, or both. IJV VT was often asymptomatic and non-occlusive. Conclusions: Paediatric non-tunnelled CVCs are frequently complicated by VT. Avoiding IJV CVCs and multiple lumen catheters could potentially reduce the overall risk of VT. However, IJV VT was more likely to be smaller and asymptomatic compared with femoral vein VT. More data are needed on the risk of complications from smaller, asymptomatic VT compared with the group of VT with symptoms or vein occlusion. Femoral vein CVCs and CVC/vein diameter >0.33 could be modifiable risk factors for VT with larger thrombotic mass. Clinical trial registration: ACTRN12615000442505.

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Glutathione is quantitatively the most important endogenous scavenger system. Glutathione depletion in skeletal muscle is pronounced following major trauma and sepsis in intensive care unit patients. Also, following elective surgery, glutathione depletion occurs in parallel with a progressive decline in muscle glutamine concentration. The present study was designed to test the hypothesis that glutamine supplementation may counteract glutathione depletion in a human trauma model. A homogeneous group of patients (n = 17) undergoing a standardized surgical procedure were prospectively randomly allocated to receive glutamine (0.56 g x day(-1) x kg(-1)) or placebo as part of isonitrogenous and isocaloric nutrition. Percutaneous muscle biopsies and blood samples were taken pre-operatively and at 24 and 72 h after surgery. The concentrations of muscle glutathione and related amino acids were determined in muscle tissue and plasma. In the control (unsupplemented) subjects, total muscle glutathione had decreased by 47+/-8% and 37+/-11% and reduced glutathione had decreased by 53+/-10% and 45+/-16% respectively at 24 and 72 h after surgery (P < 0.05). In contrast, in the glutamine-supplemented group, no significant post-operative decreases in total or reduced glutathione were seen following surgery. Muscle free glutamine had decreased at 72 h after surgery in both groups, by 41.4+/-14.8% (P < 0.05) in the glutamine-supplemented group and by 46.0+/-14.3% (P < 0.05) in the control group. In conclusion, the present study demonstrates that intravenous glutamine supplementation attenuates glutathione depletion in skeletal muscle in humans following standardized surgical trauma.

An endotoxin challenge given to healthy volunteers rapidly increases mitochondrial enzyme activity in skeletal muscle. The results of this human model indicate that possibly early during sepsis, mitochondrial activity might be increased in contrast to what has been shown in the later phases of sepsis. It is possible that this early activation leads to exhaustion of the mitochondria and a decreased function later during sepsis.

Children admitted to the PICU following emergency transfers by the specialist paediatric transport team were younger, sicker, received more PICU-specific therapies and had longer PICU LOS than other acutely admitted critically ill patients. This indicates that these transfers were appropriate.