Impaired expression of NADH dehydrogenase subunit 1 and PPARgamma coactivator-1 in skeletal muscle of ZDF rats: restoration by troglitazone.

Type 2 diabetes has been related to a decrease of mitochondrial DNA (mtDNA) content. In this study, we show increased expression of the peroxisome proliferator-activated receptor-alpha (PPARalpha) and its target genes involved in fatty acid metabolism in skeletal muscle of Zucker Diabetic Fatty (ZDF) (fa/fa) rats. In contrast, the mRNA levels of genes involved in glucose transport and utilization (GLUT4 and phosphofructokinase) were decreased, whereas the expression of pyruvate dehydrogenase kinase 4 (PDK-4), which suppresses glucose oxidation, was increased. The shift from glucose to fatty acids as the source of energy in skeletal muscle of ZDF rats was accompanied by a reduction of subunit 1 of complex I (NADH dehydrogenase subunit 1, ND1) and subunit II of complex IV (cytochrome c oxidase II, COII), two genes of the electronic transport chain encoded by mtDNA. The transcript levels of PPARgamma Coactivator 1 (PGC-1) showed a significant reduction. Treatment with troglitazone (30 mg/kg/day) for 15 days reduced insulin values and reversed the increase in PDK-4 mRNA levels, suggesting improved insulin sensitivity. In addition, troglitazone treatment restored ND1 and PGC-1 expression in skeletal muscle. These results suggest that troglitazone may avoid mitochondrial metabolic derangement during the development of diabetes mellitus 2 in skeletal muscle.

Brain spectrin isoforms during development of chick dorsal root ganglion cells in vivo and in vitro

Brain spectrin is one of the major cytoskeletal proteins associated with the plasma membrane. In many tissues this protein occurs in a variety of isoforms, for which at least three have been described in the brain: i) brain spectrin 240/235 is localized in neurons most prominently in axons and is present early during brain development. ii) Brain spectrin 240/235E is immunologicaly related to erythrocyte spectrin and restricted to somato-dendritic regions in neurons and to glia. It appears late in brain development. iii) A third form, brain spectrin 240/ 235A, is found exclusively in astrocytes. In this study we have investigated the appearance and distribution of brain spectrins 240/235 and 240/235E during embryonic chick dorsal root ganglia development in vivo and in vitro. This system provides a unique model due to the lack of dendrites on developing sensory neurons. Both isoforms first appeared at embryonic day 6. Brain spectrin 240/235 increased transiently around embryonic day 10 and 14, and was first expressed in ventrolateral neurons. It was localized abundantly in perikarya and their axons. This somato-axonal distribution pattern found in situ was also observed in vitro. In contrast, brain spectrin 240/235E only slightly increased between E6 and E15 and remained unchanged thereafter. It was localized mainly in small neurons of the mediodorsal area, where it was found as punctate staining in the cytoplasm, forming first a nuclear cap and in subsequent stages becoming distributed evenly throughout cytoplasm. This brain spectrin isoform was absent from axons, both in situ and in vitro. In conclusion, this study suggests i) that brain spectrin 240/235 may contribute towards the outgrowth, elongation and possibly maintenance of axonal processes, ii) that brain spcctrin 240/235E could be involved in the stablization of the cytoarchilecture of cell bodies in a sclected population of ganglion cells, and iii) that isoform expression of brain spectrin 240/235E in DRG cells may depend on environmental factors.

The pressure cooker technique for the treatment of brain AVMs.

Arteriovenous malformations (AVMs) may be cured by injecting liquid embolic agents such as Onyx. Reflux, however, can sometimes be difficult to control and may jeopardize a complete embolization. The pressure cooker technique (PCT) was designed to create an anti-reflux plug by trapping the detachable part of an Onyx-compatible microcatheter with coils and glue in order to obtain wedge-flow conditions, thereby enabling a better understanding of macrofistulous AVMs and a more comprehensive, forceful and controlled Onyx embolization. The PCT might enlarge the range of AVMs amenable to endovascular cure. Three illustrative cases are presented.

Time processing in visual cortices: How the visual brain encodes and keeps track of time

Time is embedded in any sensory experience: the movements of a dance, the rhythm of a piece of music, the words of a speaker are all examples of temporally structured sensory events. In humans, if and how visual cortices perform temporal processing remains unclear. Here we show that both primary visual cortex (V1) and extrastriate area V5/MT are causally involved in encoding and keeping time in memory and that this involvement is independent from low-level visual processing. Most importantly we demonstrate that V1 and V5/MT are functionally linked and temporally synchronized during time encoding whereas they are functionally independent and operate serially (V1 followed by V5/MT) while maintaining temporal information in working memory. These data challenge the traditional view of V1 and V5/MT as visuo-spatial features detectors and highlight the functional contribution and the temporal dynamics of these brain regions in the processing of time in millisecond range. The present project resulted in the paper entitled: 'How the visual brain encodes and keeps track of time' by Paolo Salvioni, Lysiann Kalmbach, Micah Murray and Domenica Bueti that is now submitted for publication to the Journal of Neuroscience.

Predictive value of Glasgow Coma Scale after brain trauma: change in trend over the past ten years.

BACKGROUND: Age and the Glasgow Coma Scale (GCS) score on admission are considered important predictors of outcome after traumatic brain injury. We investigated the predictive value of the GCS in a large group of patients whose computerised multimodal bedside monitoring data had been collected over the previous 10 years. METHODS: Data from 358 subjects with head injury, collected between 1992 and 2001, were analysed retrospectively. Patients were grouped according to year of admission. Glasgow Outcome Scores (GOS) were determined at six months. Spearman's correlation coefficients between GCS and GOS scores were calculated for each year. RESULTS: On average 34 (SD: 7) patients were monitored every year. We found a significant correlation between the GCS and GOS for the first five years (overall 1992-1996: r = 0.41; p<0.00001; n = 183) and consistent lack of correlations from 1997 onwards (overall 1997-2001: r = 0.091; p = 0.226; n = 175). In contrast, correlations between age and GOS were in both time periods significant and similar (r = -0.24 v r = -0.24; p<0.002). CONCLUSIONS: The admission GCS lost its predictive value for outcome in this group of patients from 1997 onwards. The predictive value of the GCS should be carefully reconsidered when building prognostic models incorporating multimodality monitoring after head injury.

Peroxisome proliferator-activated receptor-alpha-null mice have increased white adipose tissue glucose utilization, GLUT4, and fat mass: Role in liver and brain.

Activation of the peroxisome proliferator-activated receptor (PPAR)-alpha increases lipid catabolism and lowers the concentration of circulating lipid, but its role in the control of glucose metabolism is not as clearly established. Here we compared PPARalpha knockout mice with wild type and confirmed that the former developed hypoglycemia during fasting. This was associated with only a slight increase in insulin sensitivity but a dramatic increase in whole-body and adipose tissue glucose use rates in the fasting state. The white sc and visceral fat depots were larger due to an increase in the size and number of adipocytes, and their level of GLUT4 expression was higher and no longer regulated by the fed-to-fast transition. To evaluate whether these adipocyte deregulations were secondary to the absence of PPARalpha from liver, we reexpresssed this transcription factor in the liver of knockout mice using recombinant adenoviruses. Whereas more than 90% of the hepatocytes were infected and PPARalpha expression was restored to normal levels, the whole-body glucose use rate remained elevated. Next, to evaluate whether brain PPARalpha could affect glucose homeostasis, we activated brain PPARalpha in wild-type mice by infusing WY14643 into the lateral ventricle and showed that whole-body glucose use was reduced. Hence, our data show that PPARalpha is involved in the regulation of glucose homeostasis, insulin sensitivity, fat accumulation, and adipose tissue glucose use by a mechanism that does not require PPARalpha expression in the liver. By contrast, activation of PPARalpha in the brain stimulates peripheral glucose use. This suggests that the alteration in adipocyte glucose metabolism in the knockout mice may result from the absence of PPARalpha in the brain.

Hypothermie thérapeutique en traumatologie crânienne grave [Therapeutic hypothermia for severe traumatic brain injury].

Therapeutic hypothermia (TH) is considered a standard of care in the post-resuscitation phase of cardiac arrest. In experimental models of traumatic brain injury (TBI), TH was found to have neuroprotective properties. However, TH failed to demonstrate beneficial effects on neurological outcome in patients with TBI. The absence of benefits of TH uniformly applied in TBI patients should not question the use of TH as a second-tier therapy to treat elevated intracranial pressure. The management of all the practical aspects of TH is a key factor to avoid side effects and to optimize the potential benefit of TH in the treatment of intracranial hypertension. Induction of TH can be achieved with external surface cooling or with intra-vascular devices. The therapeutic target should be set at a 35°C using brain temperature as reference, and should be maintained at least during 48 hours and ideally over the entire period of elevated intracranial pressure. The control of the rewarming phase is crucial to avoid temperature overshooting and should not exceed 1°C/day. Besides its use in the management of intracranial hypertension, therapeutic cooling is also essential to treat hyperthermia in brain-injured patients. In this review, we will discuss the benefit-risk balance and practical aspects of therapeutic temperature management in TBI patients.

Brain tissue segmentation of fetal MR images

We present a segmentation method for fetal brain tissuesof T2w MR images, based on the well known ExpectationMaximization Markov Random Field (EM- MRF) scheme. Ourmain contribution is an intensity model composed of 7Gaussian distribution designed to deal with the largeintensity variability of fetal brain tissues. The secondmain contribution is a 3-steps MRF model that introducesboth local spatial and anatomical priors given by acortical distance map. Preliminary results on 4 subjectsare presented and evaluated in comparison to manualsegmentations showing that our methodology cansuccessfully be applied to such data, dealing with largeintensity variability within brain tissues and partialvolume (PV).

Genetic redox dysregulation induces behavioural deficits in the adult mouse: an animal model for schizophrenia

Background: Glutathione (GSH), a major cellular redox regulator and antioxidant, is decreased in cerebrospinal fluid and prefrontal cortex of schizophrenia patients. The gene of the key GSH-synthesizing enzyme, glutamate-cysteine ligase, modifier (GCLM) subunit, is associated with schizophrenia, suggesting that the deficit in the GSH system is of genetic origin. Using the GCLM knock-out (KO) mouse as model system with 60% decreased brain GSH levels and, thus, strong vulnerability to oxidative stress, we have shown that GSH dysregulation results in abnormal mouse brain morphology (e.g., reduced parvalbumin, PV, immuno-reactivity in frontal areas) and function. Additional oxidative stress, induced by GBR12909 (a dopamine re-uptake inhibitor), enhances morphological changes even further. Aim: In the present study we use the GCLM KO mouse model system, asking now, whether GSH dysregulation also compromises mouse behaviour and cognition. Methods: Male and female wildtype (WT) and GCLM-KO mice are treated with GBR12909 or phosphate buffered saline (PBS) from postnatal day (P) 5 to 10, and are behaviourally tested at P 60 and older. Results: In comparison to WT, KO animals of both sexes are hyperactive in the open field, display more frequent open arm entries on the elevated plus maze, longer float latencies in the Porsolt swim test, and more frequent contacts of novel and familiar objects. Contrary to other reports of animal models with reduced PV immuno-reactivity, GCLM-KO mice display normal rule learning capacity and perform normally on a spatial recognition task. GCLM-KO mice do, however, show a strong deficit in object-recognition after a 15 minutes retention delay. GBR12909 treatment exerts no additional effect. Conclusions: The results suggest that animals with impaired regulation of brain oxidative stress are impulsive and have reduced behavioural control in novel, unpredictable contexts. Moreover, GSH dysregulation seems to induce a selective attentional or stimulus-encoding deficit: despite intensive object exploration, GCLM-KO mice cannot discriminate between novel and familiar objects. In conclusion, the present data indicate that GSH dysregulation may contribute to the manifestation of behavioural and cognitive anomalies that are associated with schizophrenia.

Unconjugated TAT carrier peptide protects against excitotoxicity.

We report in this article for the first time the neuroprotective effects of unconjugated TAT carrier peptide against a mild excitotoxic stimulus both in vitro and in vivo. In view of the widespread use of TAT peptides to deliver neuroprotectants into cells, it is important to know the effects of the carrier itself. Unconjugated TAT carrier protects dissociated cortical neurons against NMDA but not against kainate, suggesting that TAT peptides may interfere with NMDA signaling. Furthermore, a retro-inverso form of the carrier peptide caused a reduction in lesion volume (by about 50%) in a rat neonatal cerebral ischemia model. Thus, even though TAT is designed merely as a carrier, its own pharmacological activity will need to be considered in the analysis of TAT-linked neuroprotectant peptides.

Impact of perinatal factors on continuous early monitoring of brain electrocortical activity in very preterm newborns by amplitude-integrated EEG.

Background:Amplitude-integrated electroencephalogram (aEEG) is increasingly used for neuromonitoring in preterms. We aimed to quantify the effects of gestational age (GA), postnatal age (PNA), and other perinatal factors on the development of aEEG early after birth in very preterm newborns with normal cerebral ultrasounds.Methods:Continuous aEEG was prospectively performed in 96 newborns (mean GA: 29.5 (range: 24.4-31.9) wk, birth weight 1,260 (580-2,120) g) during the first 96 h of life. aEEG tracings were qualitatively (maturity scores) and quantitatively (amplitudes) evaluated using preestablished criteria.Results:A significant increase in all aEEG measures was observed between day 1 and day 4 and for increasing GA (P < 0.001). The effect of PNA on aEEG development was 6.4- to 11.3-fold higher than that of GA. In multivariate regression, GA and PNA were associated with increased qualitative and quantitative aEEG measures, whereas small-for-GA status was independently associated with increased maximum aEEG amplitude (P = 0.003). Morphine administration negatively affected all aEEG measures (P < .05), and caffeine administration negatively affected qualitative aEEG measures (P = 0.02).Conclusion:During the first few days after birth, aEEG activity in very preterm infants significantly develops and is strongly subjected to the effect of PNA. Perinatal factors may alter the early aEEG tracing and interfere with its interpretation.

In vitro biotransformation of the selective serotonin reuptake inhibitor citalopram, its enantiomers and demethylated metabolites by monoamine oxidase in rat and human brain preparations

This study was conducted to identify enzyme systems eventually catalysing a local cerebral metabolism of citalopram, a widely used antidepressant of the selective serotonin reuptake inhibitor type. The metabolism of citalopram, of its enantiomers and demethylated metabolites was investigated in rat brain microsomes and in rat and human brain mitochondria. No cytochrome P-450 mediated transformation was observed in rat brain. By analysing H2O2 formation, monoamine oxidase A activity in rat brain mitochondria could be measured. In rat whole brain and in human frontal cortex, putamen, cerebellum and white matter of five brains monoamine oxidase activity was determined by the stereoselective measurement of the production of citalopram propionate. All substrates were metabolised by both forms of MAO, except in rat brain, where monoamine oxidase B activity could not be detected. Apparent Km and Vmax of S-citalopram biotransformation in human frontal cortex by monoamine oxidase B were found to be 266 microM and 6.0 pmol min(-1) mg(-1) protein and by monoamine oxidase A 856 microM and 6.4 pmol min(-1) mg(-1) protein, respectively. These Km values are in the same range as those for serotonin and dopamine metabolism by monoamine oxidases. Thus, the biotransformation of citalopram in the rat and human brain occurs mainly through monoamine oxidases and not, as in the liver, through cytochrome P-450.

Longitudinal MR assessment of hypoxic ischemic injury in the immature rat brain.

Extremely preterm infants commonly show brain injury with long-term structural and functional consequences. Three-day-old (P3) rat pups share some similarities in terms of cerebral development with the very preterm infant (born at 24-28 weeks of gestation). The aim of this study was to assess longitudinally the cerebral structural and metabolic changes resulting from a moderate neonatal hypoxic ischemic injury in the P3 rat pup using high-field (9.4 T) MRI and localized (1) H magnetic resonance spectroscopy techniques. The rats were scanned longitudinally at P3, P4, P11, and P25. Volumetric measurements showed that the percentage of cortical loss in the long term correlated with size of damage 6 h after hypoxia-ischemia, male pups being more affected than female. The neurochemical profiles revealed an acute decrease of most of metabolite concentrations and an increase in lactate 24 h after hypoxia-ischemia, followed by a recovery phase leading to minor metabolic changes at P25 in spite of an abnormal brain development. Further, the increase of lactate concentration at P4 correlated with the cortical loss at P25, giving insight into the early prediction of long-term cerebral alterations following a moderate hypoxia-ischemia insult that could be of interest in clinical practice.