Glycolysis and the significance of lactate in traumatic brain injury

In traumatic brain injury (TBI) patients, elevation of the brain extracellular lactate concentration and the lactate/pyruvate ratio are well-recognized, and are associated statistically with unfavorable clinical outcome. Brain extracellular lactate was conventionally regarded as a waste product of glucose, when glucose is metabolized via glycolysis (Embden-Meyerhof-Parnas pathway) to pyruvate, followed by conversion to lactate by the action of lactate dehydrogenase, and export of lactate into the extracellular fluid. In TBI, glycolytic lactate is ascribed to hypoxia or mitochondrial dysfunction, although the precise nature of the latter is incompletely understood. Seemingly in contrast to lactate's association with unfavorable outcome is a growing body of evidence that lactate can be beneficial. The idea that the brain can utilize lactate by feeding into the tricarboxylic acid (TCA) cycle of neurons, first published two decades ago, has become known as the astrocyte-neuron lactate shuttle hypothesis. Direct evidence of brain utilization of lactate was first obtained 5 years ago in a cerebral microdialysis study in TBI patients, where administration of 13C-labeled lactate via the microdialysis catheter and simultaneous collection of the emerging microdialysates, with 13C NMR analysis, revealed 13C labeling in glutamine consistent with lactate utilization via the TCA cycle. This suggests that where neurons are too damaged to utilize the lactate produced from glucose by astrocytes, i.e., uncoupling of neuronal and glial metabolism, high extracellular levels of lactate would accumulate, explaining the association between high lactate and poor outcome. Recently, an intravenous exogenous lactate supplementation study in TBI patients revealed evidence for a beneficial effect judged by surrogate endpoints. Here we review the current state of knowledge about glycolysis and lactate in TBI, how it can be measured in patients, and whether it can be modulated to achieve better clinical outcome.We gratefully acknowledge financial support as follows. Research support: the Medical Research Council (MRC, Grant Nos. G0600986 ID79068 and G1002277 ID98489) and the National Institute for Health Research Biomedical Research Centre (NIHR BRC) Cambridge (Neuroscience Theme; Brain Injury and Repair Theme). Authors' support: KLHC—NIHR BRC Cambridge (Neuroscience Theme; Brain Injury and Repair Theme); IJ—MRC (Grant no. G1002277 ID 98489) and NIHR BRC Cambridge; PJH—NIHR Research Professorship, Academy of Medical Sciences/Health Foundation Senior Surgical Scientist Fellowship, and the NIHR BRC CambridgeThis is the final published version. It first appeared at http://journal.frontiersin.org/article/10.3389/fnins.2015.00112/full#h8

Interrogating and potentiating energy metabolism in the human brain after traumatic brain injury

The pathophysiology of traumatic brain injury (TBI) includes perturbations to energy metabolism. Improving our understanding of cerebral energy metabolism will lead to strategies that improve clinical outcomes. For the studies in my thesis I used microdialysis to deliver carbon-13 labelled substrates to the human brain. I combined this with nuclear magnetic resonance (NMR) spectroscopy of interstitial fluid sampled from the brain to interrogate glucose, lactate and tricarboxylic acid (TCA) cycle metabolism. Study I: I defined the optimal parameters for quantitative proton and carbon-13 NMR of cerebral microdialysates. Study II: I measured baseline microdialysate metabolite concentrations for brain and muscle and investigated the influence of muscle activity and cerebral catheter placement in grey or white matter on metabolite concentrations. Study III: I used 1,2-13C2 glucose to measure glycolysis and pentose phosphate pathway activity. Glycolysis is the dominant lactate-producing pathway but the pentose phosphate pathway also contributes and is increased in some TBI patients. Study IV: I used arterio-venous gradients to measure glucose and lactate delivery to the brain. There are periods after injury when lactate is imported from the circulation despite relatively high brain lactate levels suggesting up-regulation of lactate transport. Study V: I followed the metabolism of 3-13C lactate and demonstrated that lactate is metabolised by the TCA cycle. This occurs in both normal and injured brain but not in muscle. Study VI: I used 2,3-13C2 succinate to investigate the role of the TCA cycle in producing metabolites that are exported into the interstitium. The TCA cycle is found to be a source of lactate. Succinate delivered to the brain improves redox and enhances glutamate uptake into cells. The implications of the findings in my thesis on existing knowledge of cerebral metabolism are discussed. Strategies that might potentiate cerebral metabolism and improve clinical outcomes are suggested.Medical Research Council (Grant no. G1002277 ID 98489) and the National Institute for Health Research Biomedical Research Centre, Cambridge

Status dystonicus resembling the intrathecal baclofen withdrawal syndrome: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Status dystonicus is a rare but life-threatening disorder characterized by increasingly frequent and severe episodes of generalized dystonia that may occur in patients with primary or secondary dystonia. Painful and repetitive spasms interfere with respiration and may cause metabolic disturbances such as hyperpyrexia, dehydration, respiratory insufficiency, and acute renal failure secondary to rhabdomyolysis. Intrathecally administered baclofen, delivered by an implantable pump system, is widely used for the treatment of refractory spasticity. Abrupt cessation of intrathecal baclofen infusion has been associated with a severe withdrawal syndrome comprised of dystonia, autonomic dysfunction, hyperthermia, end-organ failure and sometimes death. The aetiology of this syndrome is not well understood. Status dystonicus describes the episodes of acute and life-threatening generalized dystonia, which occasionally manifest themselves in patients with dystonic syndromes.</p> <p>Case presentation</p> <p>We present the case of a nine-year-old Caucasian boy who experienced a severe episode of status dystonicus with no known cause and clinical features resembling those described in intrathecal baclofen withdrawal. Our patient subsequently underwent the placement of an intrathecal baclofen pump without incident.</p> <p>Conclusion</p> <p>The similarity between the clinical features of the case we present and those reported in connection to abrupt withdrawal of intrathecal baclofen is emphasized. Several drugs, although not intrathecal baclofen withdrawal, have previously been associated with status dystonicus. The similarity between the life-threatening dystonic episode experienced by our patient, and those reported in intrathecal baclofen withdrawal, highlights the possibility that, rather than representing a true physiological withdrawal syndrome, abrupt withdrawal of intrathecal baclofen may simply precipitate an episode of status dystonicus in susceptible individuals. The clinical similarities between the intrathecal baclofen withdrawal syndrome and status dystonicus have not previously been highlighted.</p

The Effects of Political Instability on International Business and Investments in Freetown Since 1991 To 2007

This research explains how political instability affected International business investments in Freetown the capital city of Sierra Leone since 1991-2007. There were a lot of International businesses and Investments in Freetown, but due to the instability faced by the country most of those Investments were affected and closed and it led to the collapse of the country’s economy and it affected other developments like education, Infrastructure, agriculture and medical. The purpose of this paper is to explain how Political Instability affected business continuing strategies and plans, a lot of businesses where unable to continue, both international and local businesses due to the instability in the country especially the ten (10) years civil war, the country was unsafe for business and investments. It also affected inconsistencies in supply chain, sales and distribution. And it affected the safety of human and materials resources in organizations and affected the expansion vision of International Business in the country and those that intended to invest. In this research a qualitative descriptive approach, phenomenology was recommended which focuses on how political instability effected international business investment in Freetown, by the use of documentations and observations. The findings can also been drawn from the background of the Instability in the country, focusing on the capital city Freetown and its effects on International businesses and investments in Freetown. This article will provide significant conclusions and recommendations to governments, feature researchers, Industries, companies, International business and global markets

Glucose metabolism following human traumatic brain injury: methods of assessment and pathophysiological findings.

The pathophysiology of traumatic brain (TBI) injury involves changes to glucose uptake into the brain and its subsequent metabolism. We review the methods used to study cerebral glucose metabolism with a focus on those used in clinical TBI studies. Arterio-venous measurements provide a global measure of glucose uptake into the brain. Microdialysis allows the in vivo sampling of brain extracellular fluid and is well suited to the longitudinal assessment of metabolism after TBI in the clinical setting. A recent novel development is the use of microdialysis to deliver glucose and other energy substrates labelled with carbon-13, which allows the metabolism of glucose and other substrates to be tracked. Positron emission tomography and magnetic resonance spectroscopy allow regional differences in metabolism to be assessed. We summarise the data published from these techniques and review their potential uses in the clinical setting.This is the final published version. It originally appeared at http://dx.doi.org/10.1007/s11011-014-9628-y

Modelling outcomes after paediatric brain injury with admission laboratory values: a machine-learning approach.

BACKGROUND: Severe traumatic brain injury (TBI) is a leading cause of mortality in children, but the accurate prediction of outcomes at the point of admission remains very challenging. Admission laboratory results are a promising potential source of prognostic data, but have not been widely explored in paediatric cohorts. Herein, we use machine-learning methods to analyse 14 different serum parameters together and develop a prognostic model to predict 6-month outcomes in children with severe TBI. METHODS: A retrospective review of patients admitted to Cambridge University Hospital's Paediatric Intensive Care Unit between 2009 and 2013 with a TBI. The data for 14 admission serum parameters were recorded. Logistic regression and a support vector machine (SVM) were trained with these data against dichotimised outcomes from the recorded 6-month Glasgow Outcome Scale. RESULTS: Ninety-four patients were identified. Admission levels of lactate, H+, and glucose were identified as being the most informative of 6-month outcomes. Four different models were produced. The SVM using just the three most informative parameters was the best able to predict favourable outcomes at 6 months (sensitivity = 80%, specificity = 99%). CONCLUSIONS: Our results demonstrate the potential for highly accurate outcome prediction after severe paediatric TBI using admission laboratory data

Increased blood glucose is related to disturbed cerebrovascular pressure reactivity after traumatic brain injury.

BACKGROUND: Increased blood glucose and impaired pressure reactivity (PRx) after traumatic brain injury (TBI) are both known to correlate with unfavorable patient outcome. However, the relationship between these two variables is unknown. METHODS: To test the hypothesis that increased blood glucose leads to increased PRx, we retrospectively analyzed data from 86 traumatic brain injured patients admitted to the Neurocritical Care Unit. Data analyzed included arterial glucose concentration, intracranial pressure (ICP), cerebral perfusion pressure (CPP) and end-tidal CO2. PRx was calculated as the moving correlation coefficient between averaged (10 seconds) arterial blood pressure and ICP. One arterial glucose concentration and one time-aligned PRx value were obtained for each patient, during each day until the fifth day after ictus. RESULTS: Mean arterial glucose concentrations during the first 5 days since ictus were positively correlated with mean PRx (Pearson correlation coefficient = 0.25, p = 0.02). The correlation was strongest on the first day after injury (Pearson correlation coefficient = 0.47, p = 0.008). CONCLUSION: Our preliminary findings indicate that increased blood glucose may impair cerebrovascular reactivity, potentially contributing to a mechanistic link between increased blood glucose and poorer outcome after TBI.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s12028-014-0042-

Glycolysis and the pentose phosphate pathway after human traumatic brain injury: microdialysis studies using 1,2-(13)C2 glucose.

Increased 'anaerobic' glucose metabolism is observed after traumatic brain injury (TBI) attributed to increased glycolysis. An alternative route is the pentose phosphate pathway (PPP), which generates putatively protective and reparative molecules. To compare pathways we employed microdialysis to perfuse 1,2-(13)C2 glucose into the brains of 15 TBI patients and macroscopically normal brain in six patients undergoing surgery for benign tumors, and to simultaneously collect products for nuclear magnetic resonance (NMR) analysis. (13)C enrichment for glycolytic 2,3-(13)C2 lactate was the median 5.4% (interquartile range (IQR) 4.6-7.5%) in TBI brain and 4.2% (2.4-4.4%) in 'normal' brain (P<0.01). The ratio of PPP-derived 3-(13)C lactate to glycolytic 2,3-(13)C2 lactate was median 4.9% (3.6-8.2%) in TBI brain and 6.7% (6.3-8.9%) in 'normal' brain. An inverse relationship was seen for PPP-glycolytic lactate ratio versus PbtO2 (r=-0.5, P=0.04) in TBI brain. Thus, glycolytic lactate production was significantly greater in TBI than 'normal' brain. Several TBI patients exhibited PPP-lactate elevation above the 'normal' range. There was proportionally greater PPP-derived lactate production with decreasing PbtO2. The study raises questions about the roles of the PPP and glycolysis after TBI, and whether they can be manipulated to achieve a better outcome. This study is the first direct comparison of glycolysis and PPP in human brain.We gratefully acknowledge financial support as follows. Study support: Medical Research Council (Grant Nos. G0600986 ID79068 and G1002277 ID98489) and National Institute for Health Research Biomedical Research Centre, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme). Authors’ support: I.J. – Medical Research Council (Grant no. G1002277 ID 98489) and National Institute for Health Research Biomedical Research Centre, Cambridge; K.L.H.C. – National Institute for Health Research Biomedical Research Centre, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme); C.G. – the Canadian Institute of Health Research; A.H. – Medical Research Council/ Royal College of Surgeons of England Clinical Research Training Fellowship (Grant no. G0802251) and Raymond and Beverly Sackler Fellowship; D.K.M. and J.D.P. - National Institute for Health Research Senior Investigator Awards; P.J.H. – National Institute for Health Research Professorship, Academy of Medical Sciences/Health Foundation Senior Surgical Scientist Fellowship.This is the accepted manuscript version. The final version is available from the Nature Publishing Group http://www.nature.com/jcbfm/journal/v35/n1/full/jcbfm2014177a.html