Regional Energy Metabolism Research Articles

Brain Regional Energy Metabolism in Patients with Traumatic Brain Injury: A Cerebral Microdialysis Guided Study.

In traumatic brain injuries (TBI), cerebral microdialysis (CMD)-derived parameters, especially the lactate to pyruvate ratio (LP ratio), have been utilized for cerebral perfusion optimization. The objectives were to identify cerebral ischemia as measured by CMD in TBI patients requiring decompressive craniectomy and to observe the correlation between cerebral perfusion pressure (CPP), intracranial pressure (ICP), and CMD variables in these patients. Our secondary aim was to observe the effect of CPP augmentation on ischemia biomarkers. After the Institute Ethics Committee approvals, seven adult patients requiring decompressive craniectomy following TBI were enrolled and CMD data were obtained prospectively for 72 h. CPP was augmented by 20% with noradrenaline infusion if LP ratio >40. Correlations were done with bootstrapping (n = 500) to obtain the confidence intervals (CI) due to the small sample size. One patient had cerebral ischemia (median LP ratio of 265.5 and median pyruvate of 38 μmol/L), while another patient had non-ischemic mitochondrial dysfunction (median LP ratio 40.7 and median pyruvate 278.5). The coefficients of correlation between the LP ratio with CPP and ICP were r = -0.05 (CI = -0.14-0.03) and r = 0.09 (CI = -0.03-0.24), respectively. The coefficient of correlation between cerebral and blood glucose was r = 0.38, (CI - 0.35-0.14). Only two patients needed CPP augmentation, however, postaugmentation cerebral biochemistry did not change appreciably. CMD can identify cerebral ischemia, however, no correlations were observed between the LP ratio and CPP or ICP. CPP augmentation did not improve cerebral biochemistry. More studies are required to understand and treat cerebral metabolism in TBI.

Changes in bile acid subtypes and long-term successful weight-loss in response to weight-loss diets: The POUNDS lost trial.

Primary bile acids (BAs) are synthesized in the liver and secondary BAs result from intestinal microbial activity. Different subtypes of BAs may be involved in regulating adiposity and energy homeostasis. We examined how changes in circulating BA subtypes induced by weight-loss diets were associated with improvements in adiposity, regional fat deposition and energy metabolism among overweight and obese adults. The study included 551 subjects who participated in a 2-year weight-loss diet intervention trial. Circulating 14 BA subtypes (primary and secondary unconjugated BAs and their taurine-/glycine-conjugates) were measured at baseline and 6months. Associations of changes in BAs with changes in weight, waist circumference, resting energy expenditure (REE), body fat composition and fat distribution were evaluated. Greater decreases in primary BAs (cholate and chenodeoxycholate) and secondary BAs (deoxycholate and lithocholate) and their conjugates (except for glycolithocholate) were associated with more decreases in weight and waist circumference at 6months (P-after-false-discovery-rate-correction [PFDR ]<.05). We found that changes in glycocholate and glycoursodeoxycholate were consistently associated with reductions of general and central adiposity, REE, whole-body fat and visceral adipose tissue (PFDR <.05). Further, the initial (6-month) changes in BA subtypes were differently predictive of successful weight loss over 2years. The decreases in primary and secondary BA subtypes after eating low-calorie weight-loss diets were significantly associated with improving adiposity, fat accumulation and energy metabolism, suggesting that specific BA subtypes would be predictive of long-term successful weight loss and individuals' response to the treatment of weight-loss diets.

Identification of metabolic kinetic patterns in different brain regions using metabolomics methods coupled with various discriminant approaches

Metabolomics is widely used as a powerful technique for identifying metabolic patterns and functions of organs and biological systems. Normally, there are multiple groups/targets involved in data processed by discriminant analysis. This is more common in cerebral studies, as there are always several brain regions involved in neuronal studies or brain metabolic dysfunctions. Furthermore, neuronal activity is highly correlated with cerebral energy metabolism, such as oxidation of glucose, especially for glutamatergic (excitatory) and GABAergic (inhibitory) neuronal activities. Thus, regional cerebral energy metabolism recognition is essential for understanding brain functions. In the current study, ten different brain regions were considered for discrimination analysis. The metabolic kinetics were investigated with 13C enrichments in metabolic products of glucose and measured using the nuclear magnetic spectroscopic method. Multiple discriminative methods were used to construct classification models in order to screen out the best method. After comparing all the applied discriminatory analysis methods, the boost-decision tree method was found to be the best method for classification and every cerebral region exhibited its own metabolic pattern. Finally, the differences in metabolic kinetics among these brain regions were analyzed. We, therefore, concluded that the current technology could also be utilized in other multi-class metabolomics studies and special metabolic kinetic patterns could provide useful information for brain function studies.

Association Between Gray Matter Volume Variations and Energy Utilization in the Brain: Implications for Developmental Stuttering.

Purpose The biological mechanisms underlying developmental stuttering remain unclear. In a previous investigation, we showed that there is significant spatial correspondence between regional gray matter structural anomalies and the expression of genes linked to energy metabolism. In the current study, we sought to further examine the relationship between structural anomalies in the brain in children with persistent stuttering and brain regional energy metabolism. Method High-resolution structural MRI scans were acquired from 26 persistent stuttering and 44 typically developing children. Voxel-based morphometry was used to quantify the between-group gray matter volume (GMV) differences across the whole brain. Group differences in GMV were then compared with published values for the pattern of glucose metabolism measured via F18 fluorodeoxyglucose uptake in the brains of 29 healthy volunteers using positron emission tomography. Results A significant positive correlation between GMV differences and F18 fluorodeoxyglucose uptake was found in the left hemisphere (ρ = .36, p < .01), where speech-motor and language processing are typically localized. No such correlation was observed in the right hemisphere (ρ = .05, p = .70). Conclusions Corroborating our previous gene expression studies, the results of the current study suggest a potential connection between energy metabolism and stuttering. Brain regions with high energy utilization may be particularly vulnerable to anatomical changes associated with stuttering. Such changes may be further exacerbated when there are sharp increases in brain energy utilization, which coincides with the developmental period of rapid speech/language acquisition and the onset of stuttering during childhood. Supplemental Material https://doi.org/10.23641/asha.14110454.

Extension of therapeutic window in ischemic stroke by selective mismatch imaging.

The concept of the ischemic penumbra was formulated on the basis of animal experiments showing functional impairment and electrophysiologic disturbances with decreasing flow to the brain below defined values (the threshold for function) and irreversible tissue damage with blood supply further decreased (the threshold for infarction). The perfusion range between these thresholds was termed the "penumbra," and restitution of flow above the functional threshold was able to reverse the deficits without permanent damage. In further experiments, the dependency of the development of irreversible lesions on the interaction of the severity and the duration of critically reduced blood flow was established, proving that the lower the flow, the shorter the time for efficient reperfusion. As a consequence, infarction develops from the core of ischemia to the areas of less severe hypoperfusion. The translation of this experimental concept as the basis for the efficient treatment of stroke requires methods by which regional flow and energy metabolism can be repeatedly investigated to demonstrate penumbra tissue, which can benefit from therapeutic interventions. Positron emission tomography allows the quantification of regional cerebral blood flow, the regional oxygen extraction fraction, and the regional metabolic rate for oxygen. With these variables, clear definitions of irreversible tissue damage and of critically hypoperfused but potentially salvageable tissue (i.e. the penumbra) in stroke patients can be achieved. However, positron emission tomography is a research tool, and its complex logistics limit clinical routine applications. Perfusion-weighted or diffusion-weighted magnetic resonance imaging is a widely applicable clinical tool, and the "mismatch" between perfusion-weighted and diffusion-weighted abnormalities serves as an indicator of the penumbra. Also computed tomography angiography and computed tomography perfusion imaging can be used to detect areas suspicious of penumbra. The findings with both methods should be validated by positron emission tomography measurements. Several studies included the selection of patients for intravenous thrombolysis on the basis of a perfusion-weighted imaging-diffusion-weighted imaging mismatch or computed tomography perfusion studies. A meta-analysis of several mismatch-based thrombolysis studies of delayed treatment from the DIAS, DIAS-2, DEDAS, EPITHET, and DEFUSE trials revealed increased recanalization. However, this analysis did not confirm an improvement in clinical outcome with delayed thrombolysis. Randomized controlled trials that did enroll patients based on the presence of a target mismatch on multimodal imaging demonstrated a higher benefit of revascularization treatment by comparison with those who did not and demonstrated for the first time that revascularization treatment for occlusion of an internal carotid artery (ICA) or a proximal middle cerebral artery (MCA) was still beneficial from 6 to 24 h after onset among patients in whom the clinical examination and the multimodal brain imaging indicate a persistent penumbra. On this background, the yield of imaging for the selection of patients for a revascularization therapy will be discussed.

Involvement of vascular endothelial growth factor (VEGF) and mitogen-activated protein kinases (MAPK) in the mechanism of neuroleptic drugs.

Recent evidence suggests that the mitogen activated protein kinase (MAPK)-associated signaling pathway in the frontal cortical areas demonstrates abnormal activity in cases of schizophrenia. Moreover, schizophrenia patients often display alterations in the regional cellular energy metabolism and blood flow of the brain; these are shown to parallel changes in angiogenesis primarily mediated by vascular endothelial growth factor (VEGF). The present study examines the differential effects of time-dependent treatment with haloperidol, olanzapine and amisulpride (20μM) on VEGF and MAPK mRNA expression and VEGF level, using the T98 cell line as an example of nerve cells. For the purposes of comparison, the effect of neuroprotective pituitary adenylate cyclase-activating polypeptide (PACAP) on the expression of VEGF mRNA and secretion were also evaluated in this cell model. RT-PCR analysis revealed that all the tested neuroleptics increased VEGF mRNA expression after 72-h incubation; however, only haloperidol and olanzapine also increased the level of VEGF detected by ELISA, and they demonstrated significantly stronger effects than PACAP. Haloperidol and olanzapine, but not amisulpride, decreased MAPK14 mRNA expression in T98G cells after 72-h incubation. The obtained results suggest that haloperidol and olanzapine can trigger the MAPK and VEGF signaling pathway, which may contribute to their neuroprotective mechanism of action.

Altered serum levels of vascular endothelial growth factor in first-episode drug-naïve and chronic medicated schizophrenia

There is much evidence of a relationship between alterations in the brain's regional cellular energy metabolism and blood flow in schizophrenic. Vascular endothelial growth factor (VEGF) plays a role in the pathogenesis of neuropsychiatric illnesses. So, we compared serum VEGF levels in drug-naïve first-episode psychotic (FEP) and chronically medicated schizophrenic to examine if a correlation existed between VEGF and psychopathological symptoms. The serum VEGF levels were assessed in 46 FEP patients, 47 chronic medicated patients and 50 healthy controls. Symptoms of schizophrenia were evaluated with the Positive and Negative Syndrome Scale (PANSS) and sandwich enzyme-linked immunosorbent assay (ELISA) was used to measure serum VEGF levels. VEGF levels were significantly lower in FEP patients compared to both chronically medicated schizophrenic patients and healthy controls, while VEGF levels in chronically medicated patients were markedly higher than in healthy controls. Furthermore, a significant correlation was detected between the levels and the PANSS negative subscale among patient groups. However, no significant correlation was observed between VEGF and clinical variables in patients. This study suggested that imbalanced neurotrophic factors may be associated with the onset of schizophrenia, but subsequent increased VEGF may be related to medication or other factors in disease progression.

Validation of MRI Determination of the Penumbra by PET Measurements in Ischemic Stroke.

The concept of the ischemic penumbra was formulated on the basis of animal experiments showing functional impairment and electrophysiologic disturbances with decreasing flow to the brain below defined values (the threshold for function) and irreversible tissue damage with blood supply further decreased (the threshold for infarction). The perfusion range between these thresholds was termed the "penumbra," and restitution of flow above the functional threshold was able to reverse the deficits without permanent damage. In further experiments, the dependency of the development of irreversible lesions on the interaction of the severity and the duration of critically reduced blood flow was established, proving that the lower the flow, the shorter the time for efficient reperfusion. As a consequence, infarction develops from the core of ischemia to the areas of less severe hypoperfusion. The translation of this experimental concept as the basis for the efficient treatment of stroke requires noninvasive methods with which regional flow and energy metabolism can be repeatedly investigated to demonstrate penumbra tissue, which can benefit from therapeutic interventions. PET allows the quantification of regional cerebral blood flow, the regional oxygen extraction fraction, and the regional metabolic rate for oxygen. With these variables, clear definitions of irreversible tissue damage and of critically hypoperfused but potentially salvageable tissue (i.e., the penumbra) in stroke patients can be achieved. However, PET is a research tool, and its complex logistics limit clinical routine applications. Perfusion-weighted or diffusion-weighted MRI is a widely applicable clinical tool, and the "mismatch" between perfusion-weighted and diffusion-weighted abnormalities serves as an indicator of the penumbra. However, comparative studies of perfusion-weighted or diffusion-weighted MRI and PET have indicated overestimation of the core of irreversible infarction as well as of the penumbra by the MRI modalities. Some of these discrepancies can be explained by the nonselective application of relative perfusion thresholds, which might be improved by more complex analytic procedures. The heterogeneity of the MRI signatures used for the definition of the mismatch are also responsible for disappointing results in the application of perfusion-weighted or diffusion-weighted MRI to the selection of patients for clinical trials. As long as validation of the mismatch selection paradigm is lacking, the use of this paradigm as a surrogate marker of outcome is limited.

Association of serum VEGF levels with prefrontal cortex volume in schizophrenia.

A large body of evidence indicates alterations in brain regional cellular energy metabolism and blood flow in schizophrenia. Among the different molecules regulating blood flow, vascular endothelial growth factor (VEGF) is generally accepted as the major factor involved in the process of angiogenesis. In the present study, we examined whether peripheral VEGF levels correlate with changes in the prefrontal cortex (PFC) volume in patients with schizophrenia and in healthy controls. Whole-blood samples were obtained from 96 people with schizophrenia or schizoaffective disorder and 83 healthy controls. Serum VEGF protein levels were analyzed by enzyme-linked immunosorbent assay, whereas quantitative PCR was performed to measure interleukin-6 (IL-6, a pro-inflammatory marker implicated in schizophrenia) mRNA levels in the blood samples. Structural magnetic resonance imaging scans were obtained using a 3T Achieva scanner on a subset of 59 people with schizophrenia or schizoaffective disorder and 65 healthy controls, and prefrontal volumes were obtained using FreeSurfer software. As compared with healthy controls, individuals with schizophrenia had a significant increase in log-transformed mean serum VEGF levels (t(177)=2.9, P=0.005). A significant inverse correlation (r=-0.40, P=0.002) between serum VEGF and total frontal pole volume was found in patients with schizophrenia/schizoaffective disorder. Moreover, we observed a significant positive association (r=0.24, P=0.03) between serum VEGF and IL-6 mRNA levels in patients with schizophrenia. These findings suggest an association between serum VEGF and inflammation, and that serum VEGF levels are related to structural abnormalities in the PFC of people with schizophrenia.

Hyperperfusion counteracted by transient rapid vasoconstriction followed by long-lasting oligemia induced by cortical spreading depression in anesthetized mice.

Cortical spreading depression (CSD) involves mass depolarization of neurons and glial cells accompanied with changes in regional cerebral blood flow (rCBF) and energy metabolism. To further understand the mechanisms of CBF response, we examined the temporal diametric changes in pial arteries, pial veins, and cortical capillaries. In urethane-anesthetized mice, the diameters of these vessels were measured while simultaneously recording rCBF with a laser Doppler flowmeter. We observed a considerable increase in rCBF during depolarization in CSD induced by application of KCl, accompanied by a transient dip of rCBF with marked vasoconstriction of pial arteries, which resembled the response to pin-prick-induced CSD. Arterial constriction diminished or disappeared during the second and third passages of CSD, whereas the rCBF increase was maintained without a transient dip. Long-lasting oligemia with a decrease in the reciprocal of mean transit time of injected dye and mild constriction of pial arteries was observed after several passages of the CSD wave. These results indicate that CSD-induced rCBF changes consist of initial hyperemia with a transient dip and followed by a long-lasting oligemia, partially corresponding to the diametric changes of pial arteries, and further suggest that vessels other than pial arteries, such as intracortical vessels, are involved.

Stress-Resistant Neural Stem Cells Positively Influence Regional Energy Metabolism After Spinal Cord Injury in Mice

The importance of stem cells to ameliorate the devastating consequences of traumatic injuries in the adult mammalian central nervous system calls for improvements in the capacity of these cells to cope, in particular, with the host response to the injury. We have previously shown, however, that in the acutely traumatized spinal cord local energy metabolism led to decreased ATP levels after neural stem cell (NSC) transplantation. As this might counteract NSC-mediated regenerative processes, we investigated if NSC selected for increased oxidative stress resistance are better suited to preserve local energy content. For this purpose, we exposed wild-type (WT) NSC to hydrogen peroxide prior to transplantation. We demonstrate here that transplantation of WT-NSC into a complete spinal cord compression injury model even lowers the ATP content beyond the level detected in spinal cord injury-control animals. Compared to WT-NSC, stress-resistant (SR) NSC did not lead to a further decrease in ATP content. These differences between WT- and SR-NSC were observed 4h after the lesion with subsequent transplantation. At 24h after lesioning, these differences were no more as obvious. Thus, in contrast to native NSC, transplantation of NSC selected for oxidative stress resistance can positively influence local energy metabolism in the first hours after spinal cord compression. The functional relevance of this observation has to be tested in further experiments.

Comparison Between Cerebral Tissue Oxygen Tension and Energy Metabolism in Experimental Subdural Hematoma

An experimental swine model (n=7) simulating an acute subdural hematoma (ASDH) was employed (1) to explore the relation between the brain tissue oxygenation (PbtO(2)) and the regional cerebral energy metabolism as obtained by microdialysis, and (2) to define the lowest level of PbtO(2) compatible with intact energy metabolism. ASDH was produced by infusion of 7ml of autologous blood (infusion rate 0.5ml/min) by a catheter placed subdurally. PbtO(2) and microdialysis probes were placed symmetrically in the injured ("bad-side") and non-injured ("good-side") hemispheres. Intracranial pressure (ICP) was monitored in the "good-side." ICP, cerebral perfusion pressure (CPP), PbtO(2), glucose, lactate, pyruvate, lactate-pyruvate ratio (LP ratio), glutamate, and glycerol were recorded at baseline (60min) and post trauma (360min). After the creation of the ASDH, PbtO(2) decreased significantly in both the hemispheres (P<0.001). No significant difference was found between the sides post trauma. The LP ratio, glutamate, and glycerol in the "bad-side" increased significantly over the "good-side" where the values remained within the normal limits. A PbtO(2) value below approximately 25mmHg was found to be associated with disturbed energy metabolism in the "bad-side" but not in the "good-side." No correlation was found between the LP ratio and PbtO(2) in either hemisphere. PbtO(2) monitoring accurately describes tissue oxygenation but does not disclose whether the oxygen delivery is sufficient for maintaining cerebral energy metabolism. Accordingly, it may not be possible to define a threshold level for PbtO(2) below which energy failure and permanent tissue damage occurs.

Brain responses to chronic social defeat stress: Effects on regional oxidative metabolism as a function of a hedonic trait, and gene expression in susceptible and resilient rats

Chronic social defeat stress, a depression model in rats, reduced struggling in the forced swimming test dependent on a hedonic trait-stressed rats with high sucrose intake struggled less. Social defeat reduced brain regional energy metabolism, and this effect was also more pronounced in rats with high sucrose intake. A number of changes in gene expression were identified after social defeat stress, most notably the down-regulation of Gsk3b and Map1b. The majority of differences were between stress-susceptible and resilient rats. Conclusively, correlates of inter-individual differences in stress resilience can be identified both at gene expression and oxidative metabolism levels.

Bereitschaftspotential as an indicator of movement preparation in supplementary motor area and motor cortex.

Topographical studies in humans of the Bereitschaftspotential (BP, or readiness potential, as averaged from the electroencephalogram) and the Bereitschaftsmagnetfeld (BM, or readiness magnetic field, as averaged from the magnetoencephalogram) revealed a widespread distribution of motor preparation over both hemispheres even before unilateral movement. This indicates the existence of several generators responsible for the BP, including generators in the ipsilateral hemisphere, which is in agreement with measurements of regional cerebral blood flow or regional cerebral energy metabolism. Nevertheless, two principal generators seem to prevail: (1) An early generator, starting its activity 1s or more before the motor act, with its maximum at the vertex. For this and other reasons, early BP generation probably stems from cortical tissue representing or including the supplementary motor area (SMA). (2) A later generator, starting its activity about 0.5s before the onset of movement and biased towards the contralateral hemisphere (contralateral preponderance of negativity, CPN). For unilateral finger movements the CPN succeeds the BP's initial bilateral symmetry in the later preparation period. Thus, this lateralized BP component probably stems from the primary motor area, MI (area 4, hand representation). While regional cerebral blood flow or regional cerebral energy metabolism show that the SMA is active in conjunction with motor acts, these data do not permit the conclusion that SMA activity precedes motor acts. This can only be shown by the Bereitschaftspotential, which proves that SMA activity occurs before the onset of movement and, what is more, before the onset of MI activity. This important order of events (first SMA, then MI activation) has been elucidated by our BP studies. It gives the SMA an important functional role: the initiation of voluntary movement. The recording of movement-related potentials associated with manual hand-tracking and motor learning points to the SMA and frontal cortex having an important role in these functions.

Nmr spectroscopic analysis of regional brain energy metabolism in manganese neurotoxicity

A central question in manganese neurotoxicity concerns the focal neuronal damage in the globus pallidus. In the present study, we investigated specific pathways of [1-(13)C]glucose as well as of [2-(13)C]acetate in this brain region and the frontal cortex following 4-day manganese treatment by high-resolution NMR spectroscopy. Following administration of 50 mg/kg/day manganese, glutamine concentration in the globus pallidus was decreased to 67% of control values but increased in frontal cortex by 56%. Manganese treatment also caused pronounced changes in glutamine-glutamate-GABA interconversion in which region-selective differences were observed in the isotopomer pattern of GABA compared with that of glutamine when including the astrocyte-specific substrate [2-(13)C]acetate. In particular, decreased (13)C-labeled glutamine, synthesized from [1-(13)C]glucose, paralleled accumulation of (13)C-labeled GABA in globus pallidus but not in frontal cortex. On the other hand, increased synthesis of glutamine from [2-(13)C]acetate showed that GABA accumulation was not due to increased synthesis from astrocytic glutamine. Furthermore, treatment with manganese resulted in a selective decrease in N-acetyl-aspartate in the globus pallidus. These data illustrate the potential importance of alterations in neuronal metabolic function. In particular, neuronal metabolic derangements and regional differences in the ability of astrocytes to fulfill their contribution to the glutamine-glutamate-GABA cycle during the early phase of manganese neurotoxicity may be crucial in determining the severity of cellular injury.

Myocardial hibernation: a delicate balance

The pathophysiology of myocardial hibernation is characterized as a situation of reduced regional contractile function distal to a coronary artery stenosis that recovers after removal of the coronary stenosis. A subacute "downregulation" of contractile function in response to reduced regional myocardial blood flow exists, which normalizes regional energy and substrate metabolism but does not persist for more than 12-24 h. Chronic hibernation develops in response to one or more episodes of myocardial ischemia-reperfusion, possibly progressing from repetitive stunning with normal blood flow to hibernation with reduced blood flow. An upregulation of a protective gene program is seen in hibernating myocardium, putting it into the context of preconditioning. The morphology of hibernating myocardium is characterized by both adaptive and degenerative features.

Assessment of the Lower Limit for Cerebral Perfusion Pressure in Severe Head Injuries by Bedside Monitoring of Regional Energy Metabolism

Assessment of the Lower Limit for Cerebral Perfusion Pressure in Severe Head Injuries by Bedside Monitoring of Regional Energy Metabolism

Effects of continuous venovenous haemofiltration-induced cooling on global haemodynamics, splanchnic oxygen and energy balance in critically ill patients

A number of haemodialysis studies have demonstrated beneficial effects of cooler dialysates on global haemodynamics in chronic dialysis patients. However, the effects of continuous venovenous haemofiltration (CVVH)-induced cooling on regional perfusion and energy metabolism in critically ill septic patients have not been well defined. Nine septic mechanically ventilated patients (age 40-69 years) were investigated during CVVH (ultrafiltration 30-35 ml/kg/h). Baseline data (=WARM 1) were collected when core temperature (Tc) was >37.5 degrees C; the second data set (=COLD) was obtained after 120 min of 'cooling'; and a third set (=WARM 2) was obtained after 120 min of 'rewarming'. During 'warming' (WARM 1 and 2, respectively), both substitution fluids (SFs) and 'returned' blood (RB) were warmed (37 degrees C), whereas during 'cooling', the SFs were at 20 degrees C and RB was not warmed. We measured hepatic venous (HV) haemoglobin oxygen saturation (ShvO(2)), blood gases, lactate and pyruvate. Gastric mucosal PCO(2) (PgmCO(2)) was measured by air tonometry and the gastric mucosal - arterial PCO(2) difference (PCO(2) gap) was calculated. Haemodynamic monitoring was performed with arterial and pulmonary arterial thermodilution catheters. Tcs were significantly altered [WARM 1, 37.9 degrees C (37.6, 38.3); COLD, 36.8 degrees C (36.3, 37.1); WARM 2, 37.5 degrees C (37.0, 38.0); P<0.001; data are median, 25th and 75th percentiles, respectively]. Systemic vascular resistance significantly increased during cooling. As a result, mean arterial pressure increased. Cooling was associated with significant decreases in heart rate, cardiac output, systemic oxygen delivery and consumption. ShvO(2) did not change [WARM 1, 51.0% (44.0, 59.5); COLD, 49.0% (42.0, 58.0); WARM 2, 51.0% (46.0, 57.0); P = NS]. The splanchnic oxygen extraction ratio, the HV lactate to pyruvate ratio, HV acid base status and PCO(2) gap remained unchanged. Mild core cooling induced by CVVH may not affect hepatosplanchnic oxygen and energy balance in septic critically ill patients, even though it affects global haemodynamics.

Regional energy metabolism following short-term neural stem cell transplantation into the injured spinal cord.

Stem cells have been shown to partly restore central nervous system (CNS) function after transplantation into the injured CNS. However, little is known about their influence on acute energy metabolism after spinal cord injury. The present study was designed to analyze regional changes in energy metabolites. Young adult mice were subjected to laminectomy with subsequent hemisection at the L2/3 vertebral level. Immediately thereafter a stable clone of murine neural stem cells (NSCs) was injected into the lesion site. After 4 and 24 h, spinal cords were removed and ATP, glucose, and lactate were analyzed by a bioluminescence approach in serial sections and compared to a laminectomized (intact control), hemisected-only or hemisected vehicle-injected control group. At both time points, ATP content of the hemisected group in the tissue segments adjacent to the lesion was increased when compared to the laminectomized control. At the lesion site ATP content decreased significantly at 24 h in the cell-transplanted group when compared to the laminectomized control group. Glucose content decreased at the lesion site and in segments adjacent to the lesion at both time points and in all experimental groups when compared to the laminectomized control group. Lactate content decreased significantly at 4 h in the caudal segments of the vehicle-injected group and in both adjacent segments of the transplanted group when compared to the laminectomized control. At the lesion site, lactate content decreased significantly at 4 and 24 h in the cell-transplanted group, when compared to the laminectomized control. The area of ATP decline at the lesion site 24 h postinjury was significantly lower in the vehicle control group as compared to the hemisected or transplanted group. The decrease in glucose combined with an increase in ATP in the lesion-adjacent segments may indicate that the tissue responds with an increased use of glucose to support itself with sufficient ATP. The significant decrease in glucose, lactate, and ATP in the cell-transplanted group at 24 h may indicate a high metabolic need of the stem cells. The lower area of ATP decline 24 h after vehicle administration suggests that the vehicle solution washes out toxic mediators, thus ameliorating hemisection-dependent secondary tissue damage.

1,3-Dinitrobenzene Inhibits Mitochondrial Complex II in Rat and Mouse Brainstem and Cortical Astrocytes

1,3-Dinitrobenzene (DNB) produces edematous, glio-vascular lesions that are initially confined to brainstem nuclei with high energy requirements in rats and mice. Perturbation of energy producing processes in the cell is known to induce formation of the mitochondrial permeability transition pore (mtPTP) complex. Selective vulnerability of brainstem astrocytes to DNB is mediated by a 10-fold lower threshold for opening of the cyclosporin A-inhibitable mitochondrial permeability transition (MPT) pore than their cortical counterparts. Other nitrocompounds, such as 3-nitropropionic acid, selectively interfere with regional energy metabolism, including mitochondrial succinate dehydrogenase activity. However, the link between DNB-induced onset of the MPT and disruption of energy producing processes in the astrocyte remains unclear. The effects of DNB on succinate dehydrogenase activity were evaluated in cultured neonatal rat and mouse brainstem and cortical astrocytes. Both histochemical and spectrophotometric assays confirmed significant temporal inhibition of SDH activity in brainstem and cortical astrocytes 0.5, 2 and 5 h following exposure to 100 μM DNB in vitro. Although DNB-induced inhibition of SDH was significantly decreased by CsA pretreatment in brainstem astrocytes after 0.5 and 2 h and with a second pore inhibitor, bongkrekic acid (BKA) after 5 h, both inhibitors failed to reduce inhibition of SDH activity in cortical astrocytes. These data suggest that DNB-induced inhibition of SDH may be independent of differential regional activation of the mtPTP complex in astrocytes and that an unidentified cyclosporin A-inhibitable factor mediates DNB-induced loss of SDH function.