CATCH: A clinical decision rule for the use of computed tomography in children with minor head injury

Background: There is controversy about which children with minor head injury need to undergo computed tomography (CT). We aimed to develop a highly sensitive clinical decision rule for the use of CT in children with minor head injury. Methods: For this multicentre cohort study, we enrolled consecutive children with blunt head trauma presenting with a score of 13-15 on the Glasgow Coma Scale and loss of consciousness, amnesia, disorientation, persistent vomiting or irritability. For each child, staff in the emergency department completed a standardized assessment form before any CT. The main outcomes were need for neurologic intervention and presence of brain injury as determined by CT. We developed a decision rule by using recursive partitioning to combine variables that were both reliable and strongly associated with the outcome measures and thus to find the best combinations of predictor variables that were highly sensitive for detecting the outcome measures with maximal specificity. Results: Among the 3866 patients enrolled (mean age 9.2 years), 95 (2.5%) had a score of 13 on the Glasgow Coma Scale, 282 (7.3%) had a score of 14, and 3489 (90.2%) had a score of 15. CT revealed that 159 (4.1%) had a brain injury, and 24 (0.6%) underwent neurologic intervention. We derived a decision rule for CT of the head consisting of four high-risk factors (failure to reach score of 15 on the Glasgow coma scale within two hours, suspicion of open skull fracture, worsening headache and irritability) and three additional medium-risk factors (large, boggy hematoma of the scalp; signs of basal skull fracture; dangerous mechanism of injury). The high-risk factors were 100.0% sensitive (95% CI 86.2%-100.0%) for predicting the need for neurologic intervention and would require that 30.2% of patients undergo CT. The medium-risk factors resulted in 98.1% sensitivity (95% CI 94.6%-99.4%) for the prediction of brain injury by CT and would require that 52.0% of patients undergo CT. Interpretation: The decision rule developed in this study identifies children at two levels of risk. Once the decision rule has been prospectively validated, it has the potential to standardize and improve the use of CT for children with minor head injury. © 2010 Canadian Medical Association

Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2

Background: Interleukin-1-dependent increases in glycolysis promote allergic airways disease in mice and disruption of pyruvate kinase M2 (PKM2) activity is critical herein. Glutathione-S-transferase P (GSTP) has been implicated in asthma pathogenesis and regulates the oxidation state of proteins via S-glutathionylation. We addressed whether GSTP-dependent S-glutathionylation promotes allergic airways disease by promoting glycolytic reprogramming and whether it involves the disruption of PKM2. Methods: We used house dust mite (HDM) or interleukin-1β in C57BL6/NJ WT or mice that lack GSTP. Airway basal cells were stimulated with interleukin-1β and the selective GSTP inhibitor, TLK199. GSTP and PKM2 were evaluated in sputum samples of asthmatics and healthy controls and incorporated analysis of the U-BIOPRED severe asthma cohort database. Results: Ablation of Gstp decreased total S-glutathionylation and attenuated HDM-induced allergic airways disease and interleukin-1β-mediated inflammation. Gstp deletion or inhibition by TLK199 decreased the interleukin-1β-stimulated secretion of pro-inflammatory mediators and lactate by epithelial cells. 13C-glucose metabolomics showed decreased glycolysis flux at the pyruvate kinase step in response to TLK199. GSTP and PKM2 levels were increased in BAL of HDM-exposed mice as well as in sputum of asthmatics compared to controls. Sputum proteomics and transcriptomics revealed strong correlations between GSTP, PKM2, and the glycolysis pathway in asthma. Conclusions: GSTP contributes to the pathogenesis of allergic airways disease in association with enhanced glycolysis and oxidative disruption of PKM2. Our findings also suggest a PKM2-GSTP-glycolysis signature in asthma that is associated with severe disease

Route of Francisella tularensis infection informs spatiotemporal metabolic reprogramming and inflammation in mice.

Route of exposure to pathogens can inform divergent disease pathogenesis and mortality rates. However, the features that contribute to these differences are not well established. Host metabolism has emerged as a critical element governing susceptibility and the metabolism of tissue exposure sites are unique. Therefore, specific metabolic niches may contribute to the course and outcome of infection depending on route of infection. In the current study, we utilized a combination of imaging and systems metabolomics to map the spatiotemporal dynamics of the host response to intranasal (i.n.) or intradermal (i.d.) infection of mice using the bacterium Francisella tularensis subsp tularensis (FTT). FTT causes lethal disease through these infection routes with similar inoculation doses and replication kinetics, which allowed for isolation of host outcomes independent of bacterial burden. We observed metabolic modifications that were both route dependent and independent. Specifically, i.d. infection resulted in early metabolic reprogramming at the site of infection and draining lymph nodes, whereas the lungs and associated draining lymph nodes were refractory to metabolic reprogramming following i.n. infection. Irrespective of exposure route, FTT promoted metabolic changes in systemic organs prior to colonization, and caused massive dysregulation of host metabolism in these tissues prior to onset of morbidity. Preconditioning infection sites towards a more glycolytic and pro-inflammatory state prior to infection exacerbated FTT replication within the lungs but not intradermal tissue. This enhancement of replication in the lungs was associated with the ability of FTT to limit redox imbalance and alter the pentose phosphate pathway. Together, these studies identify central metabolic features of the lung and dermal compartments that contribute to disease progression and identify potential tissue specific targets that may be exploited for novel therapeutic approaches

PlosONE FT route Metadata Figures 4_5_6_and S4_S5_S6.xlsx

Targeted metabolomics data set used to generate figures 4, 5, 6, and 7 as well as supplemental figures 4, 5, and 6. These data describe the host metabolic response in various tissues following intranasal or intradermal exposure to virulent Francisella tularensis ssp tularensis over time as well as in the context of an preconditioned immunometabolic stimulus.</p

Altered energy metabolism in Fatal Familial Insomnia cerebral organoids is associated with astrogliosis and neuronal dysfunction

Fatal familial insomnia (FFI) is a rare neurodegenerative disease caused by a dominantly inherited single amino acid substitution (D178N) within the prion protein (PrP). No in vitro human brain tissue model for this disease has previously been available. Consequently, how this mutation exerts its damaging effect on brain cells is still unknown. Using CRISPR-Cas9 engineered induced pluripotent stem cells, we made D178N cerebral organoids and compared these with isotype control organoids. We found that, in the absence of other hallmarks of FFI, the D178N organoids exhibited astrogliosis with cellular oxidative stress. Abnormal post-translational processing of PrP was evident but no tissue deposition or propagation of mis-folded PrP isoforms were observed. Neuronal electrophysiological function was compromised and levels of neurotransmitters, particularly acetylcholine and GABA, altered. Underlying these dysfunctions were changes in cellular energy homeostasis, with substantially increased glycolytic and Krebs cycle intermediates, and greater mitochondrial activity. This increased energy demand in D178N organoids was associated with increased mitophagy and depletion of lipid droplets, in turn resulting in shifts of cellular lipid composition. Using a double mutation (178NN) we could confirm that most changes were caused by the presence of the mutation rather than interaction with PrP molecules lacking the mutation. Our data strongly suggests that shifting biosynthetic intermediates and oxidative stress, caused by an imbalance of energy supply and demand, results in astrogliosis with compromised neuronal activity in FFI organoids. They further support that many of the disease associated changes are due to a corruption of PrP function and do not require propagation of PrP mis-folding. Author summary Fatal familial insomnia is a devastating disease characterized by progressively worsening sleep until the brain and body deterioration result in death. Degeneration of brain cells is associated with accumulation of mis-folded proteins called prions. The mis-folding of the prions is caused by a single point mutation, D178N, in the gene encoding the normal precursor protein of the prions, the prion protein. Herein, we have used a human brain model to investigate the how this mutation causes brain cell damage. Our findings show that the mutation causes brain cells to dysfunction without the need for mis-folding into prions. Brain cell dysfunction was associated with stress and abnormal metabolism in such a way as to change critical compounds needed for the brain cells to function correctly. The changes correlate with enhanced wakefulness, which could cause the sleep disturbance. Our data support that many of the disease associated changes are caused by the fatal familial insomnia D178N mutation corrupting prion protein function

GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway

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