Pattern of injury with a graded excitotoxic insult and ensuing chronic medial septal damage in the rat brain

Brain damage caused by an acute injury depends on the initial severity of the injury and the time elapsed after the injury. To determine whether these two variables activate common mechanisms, we compared the response of the rat medial septum to insult with a graded series of concentrations of a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) with the time-course effects of a low dose of AMPA. For this purpose we conducted a dose-response study at concentrations of AMPA between 0.27 and 10.8 nmol to measure atrophy of the septal area, losses of cholinergic and GABAergic neurons, astroglial and microglial reactions, and calcification. Cholinergic neurons, whose loss paralleled the degree of septal atrophy produced by AMPA, are more sensitive than GABAergic neurons to the injury produced by AMPA. At doses of AMPA above 2.7 nmol, calcification and the degree of microglial reaction increased only in the GABAergic region of the septal area, whereas atrophy and neuronal loss reached a plateau. We chose the 2.7-nmol dose of AMPA to determine how these parameters were modified between 4 days and 6 months after injection. We found that atrophy and neuronal loss increased progressively through the 6-month study period, whereas astrogliosis ceased to be observed after 1 month, and calcium precipitates were never detected. We conclude that septal damage does not increase with the intensity of an excitotoxic insult. Rather, it progresses continuously after the insult. Because these two situations involve different mechanisms, short-term paradigms are inappropriate for interpreting the pathogenic mechanisms responsible for long-term neurodegenerative processes.

Subthalamic (STN) Deep Brain Stimulation (DBS) in Parkinson's Disease (PD): Correlation Between the Location of the Stimulated Contacts and the Clinical Effects in 14 Patients

Objectives: To correlate the chronic stimulated electrode position on postoperative MRI with the clinical response obtained in PD patients. Material and Method: We retrospectively reviewed 14 consecutive parkinsonian patients who were selected for STN-DBS surgery. Coordinates were determined on an IR T2 MRI coronal section per pendicular to AC-PC plane 3 mm posterior to midcommissural point (MCP) and 12 mm lateral to the midline the inferior aspect of subthalamic region. A CRW stereotactic frame was used for the surgical procedure. A 3D IR T2 MRI was performed postoperatively to determine the location of the stimulated contact in each patient. The clinical results were assessed independently by the neurological team. Results: All but 2 patients had monopolar stimulation. The mean coordinates of the stimulated contacts were: AP ^ ÿ4:23G1:4, Lat ^ 1:12G0:15, Vert ^ ÿ4:1 G2:7 to the MCP. With a mean follow-up of 8 months, all stimulated patients had a significant clinical improvement (preop/postop «ON» UPDRS: 25:8G7:0= 23:3 G8:6; preop/postop «OFF» UPDRS: 50:2G11:4=26:0 G7:8), 60% of them without any antiparkinsonian drug. Conclusion: According to the stereotactic atlas of Schaltenbrand and Warren and the 3D shape of the STN, our results show that our targetting is accurate and almost all the stimulated contacts are comprised in the STN volume. This indicates that MRI is a safe, precise and reproducible procedure for targetting the STN. The location of the stimulated contact within the STN volume is a good predictor of the clinical results.

Tangential migration of neuronal precursors of glutamatergic neurons in the adult mammalian brain.

In a classic model of mammalian brain formation, precursors of principal glutamatergic neurons migrate radially along radial glia fibers whereas GABAergic interneuron precursors migrate tangentially. These migration modes have significant implications for brain function. Here we used clonal lineage tracing of active radial glia-like neural stem cells in the adult mouse dentate gyrus and made the surprising discovery that proliferating neuronal precursors of glutamatergic granule neurons exhibit significant tangential migration along blood vessels, followed by limited radial migration. Genetic birthdating and morphological and molecular analyses pinpointed the neuroblast stage as the main developmental window when tangential migration occurs. We also developed a partial "whole-mount" dentate gyrus preparation and observed a dense plexus of capillaries, with which only neuroblasts, among the entire population of progenitors, are directly associated. Together, these results provide insight into neuronal migration in the adult mammalian nervous system.

Visual performance in preterm infants with brain injuries compared with low-risk preterm infants

Background: Neonatal brain injuries are the main cause of visual deficit produced by damage to posterior visual pathways.While there are several studies of visual function in low-risk preterm infants or older children with brain injuries, research in children of early age is lacking. Aim: To assess several aspects of visual function in preterm infants with brain injuries and to compare them with another group of low-risk preterm infants of the same age. Study design and subjects: Forty-eight preterm infants with brain injuries and 56 low-risk preterm infants. Outcome measures: The ML Leonhardt Battery of Optotypes was used to assess visual functions. This test was previously validated at a post-menstrual age of 40 weeks in newborns and at 30-plus weeks in preterm infants. Results: The group of preterminfants with brain lesions showed a delayed pattern of visual functions in alertness, fixation, visual attention and tracking behavior compared to infants in the healthy preterm group. The differences between both groups, in the visual behaviors analyzed were around 30%. These visual functions could be identified from the first weeks of life. Conclusion: Our results confirm the importance of using a straightforward screening test with preterminfants in order to assess altered visual function, especially in infants with brain injuries. The findings also highlight the need to provide visual stimulation very early on in life.

Identification of Propionibacterium avidum from a breast abscess: an overlooked etiology of clinically significant infections.

We report the case of a 37-year-old previously healthy woman diagnosed with a breast abscess due to Propionibacterium avidum after breast reduction surgery. This case emphasizes the potential pathogenicity and morbidity associated with this commensal skin organism.

Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia.

Many studies indicate a crucial role for the vitamin B12 and folate-dependent enzyme methionine synthase (MS) in brain development and function, but vitamin B12 status in the brain across the lifespan has not been previously investigated. Vitamin B12 (cobalamin, Cbl) exists in multiple forms, including methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl), serving as cofactors for MS and methylmalonylCoA mutase, respectively. We measured levels of five Cbl species in postmortem human frontal cortex of 43 control subjects, from 19 weeks of fetal development through 80 years of age, and 12 autistic and 9 schizophrenic subjects. Total Cbl was significantly lower in older control subjects (> 60 yrs of age), primarily reflecting a >10-fold age-dependent decline in the level of MeCbl. Levels of inactive cyanocobalamin (CNCbl) were remarkably higher in fetal brain samples. In both autistic and schizophrenic subjects MeCbl and AdoCbl levels were more than 3-fold lower than age-matched controls. In autistic subjects lower MeCbl was associated with decreased MS activity and elevated levels of its substrate homocysteine (HCY). Low levels of the antioxidant glutathione (GSH) have been linked to both autism and schizophrenia, and both total Cbl and MeCbl levels were decreased in glutamate-cysteine ligase modulatory subunit knockout (GCLM-KO) mice, which exhibit low GSH levels. Thus our findings reveal a previously unrecognized decrease in brain vitamin B12 status across the lifespan that may reflect an adaptation to increasing antioxidant demand, while accelerated deficits due to GSH deficiency may contribute to neurodevelopmental and neuropsychiatric disorders.

Cell type-specific expression and localization of cytochrome P450 isoforms in tridimensional aggregating rat brain cell cultures.

Within the Predict-IV FP7 project a strategy for measurement of in vitro biokinetics was developed, requiring the characterization of the cellular model used, especially regarding biotransformation, which frequently depends on cytochrome P450 (CYP) activity. The extrahepatic in situ CYP-mediated metabolism is especially relevant in target organ toxicity. In this study, the constitutive mRNA levels and protein localization of different CYP isoforms were investigated in 3D aggregating brain cell cultures. CYP1A1, CYP2B1/B2, CYP2D2/4, CYP2E1 and CYP3A were expressed; CYP1A1 and 2B1 represented almost 80% of the total mRNA content. Double-immunolabeling revealed their presence in astrocytes, in neurons, and to a minor extent in oligodendrocytes, confirming the cell-specific localization of CYPs in the brain. These results together with the recently reported formation of an amiodarone metabolite following repeated exposure suggest that this cell culture system possesses some metabolic potential, most likely contributing to its high performance in neurotoxicological studies and support the use of this model in studying brain neurotoxicity involving mechanisms of toxication/detoxication.

Abcès pulmonaires: évolution dans la prise en charge [Lung abscess: changes in the management?].

L'abcès pulmonaire se présente de manière très pléomorphe selon les germes initialement impliqués. Des symptômes gé­ néraux et une évolution souvent subaiguë sont retrouvés en cas d'aspiration de la flore oropharyngée, chez des patients avec des troubles de l'état de conscience ou de la déglutition. L'infection est très souvent polymicrobienne, avec présence de germes anaérobes dans deux tiers des cas. La prise en charge consiste en un traitement antibiotique prolongé, jusqu'à résolution ou stabilité de l'image radiologique. En cas d'état toxique ou d'absence de drainage bronchique spontané, un drainage de l'abcès est à discuter. Les sanctions chirurgicales sont peu souvent nécessaires et envisagées indépendamment de la taille de l'abcès excepté lors de néoplasie sous-jacente. Lung abscess occurs in very pleomorphic according to germs initially involved. The mechanism commonly found is an aspiration of the oropharyngeal flora in patients with disorders of consciousness or swallowing. The infection is polymicrobial, with presence of anaerobic germs in 2/3 of the cases. The support consists of a prolonged antibiotic treatment, as well as anaerobic until resolution or stability of the radiological image. In case of prolonged toxic state, drainage of the abscess is to be discussed especially if there is no airways drainage. Surgical sanctions is rarely needed regardless of the size of the abscess, unless underlying carcinoma is present.

Clinical neurophysiology in disorders of consciousness: brain function monitoring in the ICU and beyond.

Over the past two decades, electrophysiology has undergone unprecedented changes thanks to technical improvements, which simplify measurement and analysis and allow more compact data storage. This book covers in detail the spectrum of electrophysiology applications in patients with disorders of consciousness. Its content spans from clinical aspects of the management of subjects in the intensive care unit, including EEG, evoked potentials and related implications in terms of prognosis and patient management to research applications in subjects with ongoing consciousness impairment. While the first section provides up-to-date information for the interested clinician, the second part highlights the latest developments in this exciting field. The book comprehensively combines clinical and research information related to neurophysiology in disorder-of- consciousness patients, making it an easily accessible reference for neuro-ICU specialists, epileptologists and clinical neurophysiologists as well as researchers utilizing EEG and event-related potentials.

Brain Connections Associated With Socio-Cognitive Skills in Preterm and Low Birth Weight School Age Children

Identification of neuroimaging biomarkers following extreme prematurity (EP) and intrauterine growth restriction (IUGR) is crucial for understanding their cognitive and behavioral impairments at school age

Automatic Brain Extraction in Fetal MRI using Multi-Atlas-based Segmentation

In fetal brain MRI, most of the high-resolution reconstruction algorithms rely on brain segmentation as a preprocessing step. Manual brain segmentation is however highly time-consuming and therefore not a realistic solution. In this work, we assess on a large dataset the performance of Multiple Atlas Fusion (MAF) strategies to automatically address this problem. Firstly, we show that MAF significantly increase the accuracy of brain segmentation as regards single-atlas strategy. Secondly, we show that MAF compares favorably with the most recent approach (Dice above 0.90). Finally, we show that MAF could in turn provide an enhancement in terms of reconstruction quality.

Distinct roles of NMDA receptors at different stages of granule cell development in the adult brain.

NMDA receptor (NMDAR)-dependent forms of synaptic plasticity are thought to underlie the assembly of developing neuronal circuits and to play a crucial role in learning and memory. It remains unclear how NMDAR might contribute to the wiring of adult-born granule cells (GCs). Here we demonstrate that nascent GCs lacking NMDARs but rescued from apoptosis by overexpressing the pro-survival protein Bcl2 were deficient in spine formation. Insufficient spinogenesis might be a general cause of cell death restricted within the NMDAR-dependent critical time window for GC survival. NMDAR loss also led to enhanced mushroom spine formation and synaptic AMPAR activity throughout the development of newborn GCs. Moreover, similar elevated synapse maturation in the absence of NMDARs was observed in neonate-generated GCs and CA1 pyramidal neurons. Together, these data suggest that NMDAR operates as a molecular monitor for controlling the activity-dependent establishment and maturation rate of synaptic connections between newborn neurons and others.

Islet Brain 1 Protects Insulin Producing Cells against Lipotoxicity.

Chronic intake of saturated free fatty acids is associated with diabetes and may contribute to the impairment of functional beta cell mass. Mitogen activated protein kinase 8 interacting protein 1 also called islet brain 1 (IB1) is a candidate gene for diabetes that is required for beta cell survival and glucose-induced insulin secretion (GSIS). In this study we investigated whether IB1 expression is required for preserving beta cell survival and function in response to palmitate. Chronic exposure of MIN6 and isolated rat islets cells to palmitate led to reduction of the IB1 mRNA and protein content. Diminution of IB1 mRNA and protein level relied on the inducible cAMP early repressor activity and proteasome-mediated degradation, respectively. Suppression of IB1 level mimicked the harmful effects of palmitate on the beta cell survival and GSIS. Conversely, ectopic expression of IB1 counteracted the deleterious effects of palmitate on the beta cell survival and insulin secretion. These findings highlight the importance in preserving the IB1 content for protecting beta cell against lipotoxicity in diabetes.

Robust DNA Methylation in the Clonal Raider Ant Brain.

Social insects are promising model systems for epigenetics due to their immense morphological and behavioral plasticity. Reports that DNA methylation differs between the queen and worker castes in social insects [1-4] have implied a role for DNA methylation in regulating division of labor. To better understand the function of DNA methylation in social insects, we performed whole-genome bisulfite sequencing on brains of the clonal raider ant Cerapachys biroi, whose colonies alternate between reproductive (queen-like) and brood care (worker-like) phases [5]. Many cytosines were methylated in all replicates (on average 29.5% of the methylated cytosines in a given replicate), indicating that a large proportion of the C. biroi brain methylome is robust. Robust DNA methylation occurred preferentially in exonic CpGs of highly and stably expressed genes involved in core functions. Our analyses did not detect any differences in DNA methylation between the queen-like and worker-like phases, suggesting that DNA methylation is not associated with changes in reproduction and behavior in C. biroi. Finally, many cytosines were methylated in one sample only, due to either biological or experimental variation. By applying the statistical methods used in previous studies [1-4, 6] to our data, we show that such sample-specific DNA methylation may underlie the previous findings of queen- and worker-specific methylation. We argue that there is currently no evidence that genome-wide variation in DNA methylation is associated with the queen and worker castes in social insects, and we call for a more careful interpretation of the available data.