Task-induced deactivation from rest extends beyond the default mode brain network

Activity decreases, or deactivations, of midline and parietal cortical brain regions are routinely observed in human functional neuroimaging studies that compare periods of task-based cognitive performance with passive states, such as rest. It is now widely held that such task-induced deactivations index a highly organized"default-mode network" (DMN): a large-scale brain system whose discovery has had broad implications in the study of human brain function and behavior. In this work, we show that common task-induced deactivations from rest also occur outside of the DMN as a function of increased task demand. Fifty healthy adult subjects performed two distinct functional magnetic resonance imaging tasks that were designed to reliably map deactivations from a resting baseline. As primary findings, increases in task demand consistently modulated the regional anatomy of DMN deactivation. At high levels of task demand, robust deactivation was observed in non-DMN regions, most notably, the posterior insular cortex. Deactivation of this region was directly implicated in a performance-based analysis of experienced task difficulty. Together, these findings suggest that task-induced deactivations from rest are not limited to the DMN and extend to brain regions typically associated with integrative sensory and interoceptive processes.

Disruption of embryonic blood-CSF barrier in chick embryos reveals the actual importance of this barrier to control E-CSF composition and homeostasis in early brain development

In vertebrates, early brain development takes place at the expanded anterior end of the neural tube. After closure of the anterior neuropore, the brain wall forms a physiologically sealed cavity that encloses embryonic cerebrospinal fluid (E-CSF), a complex and protein-rich fluid that is initially composed of trapped amniotic fluid. E-CSF has several crucial roles in brain anlagen development. Recently, we reported the presence of transient blood-CSF barrier located in the brain stem lateral to the ventral midline, at the mesencephalon and prosencephalon level, in chick and rat embryos by transporting proteins, water, ions and glucose in a selective manner via transcellular routes. To test the actual relevance of the control of E-CSF composition and homeostasis on early brain development by this embryonic blood-CSF barrier, we block the activity of this barrier by treating the embryos with 6-aminonicotinamide gliotoxin (6-AN). We demonstrate that 6-AN treatment in chick embryos blocks protein transport across the embryonic blood-CSF barrier, and that the disruption of the barrier properties is due to the cease transcellular caveolae transport, as detected by CAV-1 expression cease. We also show that the lack of protein transport across the embryonic blood-CSF barrier influences neuroepithelial cell survival, proliferation and neurogenesis, as monitored by neurepithelial progenitor cells survival, proliferation and neurogenesis. The blockage of embryonic blood-CSF transport also disrupts water influx to the E-CSF, as revealed by an abnormal increase in brain anlagen volume. These experiments contribute to delineate the actual extent of this blood-CSF embryonic barrier controlling E-CSF composition and homeostasis and the actual important of this control for early brain development, as well as to elucidate the mechanism by which proteins and water are transported thought transcellular routes across the neuroectoderm, reinforcing the crucial role of E-CSF for brain development.

The existence of FGFR1-5-HT1A receptor heterocomplexes in midbrain 5-HT neurons of the rat: relevance for neuroplasticity

The ascending midbrain 5-HT neurons to the forebrain may be dysregulated in depression and have a reduced trophic support. With in situ proximity ligation assay (PLA) and supported by coimmunoprecipitation and colocation of the FGFR1 and 5-HT1A immunoreactivities in the midbrain raphe cells, evidence for the existence of FGFR1-5-HT1A receptor heterocomplexes in the dorsal and median raphe nuclei of the Sprague Dawley rat as well as in the rat medullary raphe RN33B cells has been obtained. Especially after combined FGF-2 and 8-OH-DPAT treatment, a marked and significant increase in PLA clusters was found in the RN33B cells. Similar results were reached with the FRET technique in HEK293T cells, where TM-V of the 5HT1A receptor was found to be part of the receptor interface. The combined treatment with FGF-2 and the 5-HT1A agonist also synergistically increased FGFR1 and ERK1/2 phosphorylation in the raphe midline area of the midbrain and the RN33B cells as well as their differentiation, as seen from development of the increased number and length of extensions per cell and their increased 5-HT immunoreactivity. These signaling and differentiation events were dependent on the receptor interface since they were blocked by incubation with TM-V but not by TM-II. Together, the results indicate that the 5-HT1A autoreceptors by being part of a FGFR1-5-HT1A receptor heterocomplex in the midbrain raphe 5-HT nerve cells appear to have a trophic role in the central 5-HT neuron systems in addition to playing a key role in reducing the firing of these neurons

On the existence and function of galanin receptor heteromers in the central nervous system

Galanin receptor (GalR) subtypes 1-3 linked to central galanin neurons may form heteromers with each other and other types of G protein-coupled receptors in the central nervous system (CNS). These heteromers may be one molecular mechanism for galanin peptides and their N-terminal fragments (gal 1-15) to modulate the function of different types of glia-neuronal networks in the CNS, especially the emotional and the cardiovascular networks. GalR-5-HT1A heteromers likely exist with antagonistic GalR-5-HT1A receptor-receptor interactions in the ascending midbrain raphe 5-HT neuron systems and their target regions. They represent a novel target for antidepressant drugs. Evidence is given for the existence of GalR1-5-HT1A heteromers in cellular models with trans-inhibition of the protomer signaling. A GalR1-GalR2 heteromer is proposed to be a galanin N-terminal fragment preferring receptor (1-15) in the CNS. Furthermore, a GalR1-GalR2-5-HT1A heterotrimer is postulated to explain why only galanin (1-15) but not galanin (1-29) can antagonistically modulate the 5-HT1A receptors in the dorsal hippocampus rich in gal fragment binding sites. The results underline a putative role of different types of GalR-5-HT1A heteroreceptor complexes in depression. GalR antagonists may also have therapeutic actions in depression by blocking the antagonistic GalR-NPYY1 receptor interactions in putative GalR-NPYY1 receptor heteromers in the CNS resulting in increases in NPYY1 transmission and antidepressant effects. In contrast the galanin fragment receptor (a postulated GalR1-GalR2 heteromer) appears to be linked to the NPYY2 receptor enhancing the affinity of the NPYY2 binding sites in a putative GalR1-GalR2-NPYY2 heterotrimer. Finally, putative GalR-α2-adrenoreceptor heteromers with antagonistic receptor-receptor interactions may be a widespread mechanism in the CNS for integration of galanin and noradrenaline signals also of likely relevance for depression

The rare cancer network: ongoing studies and future strategy.

The Rare Cancer Network (RCN) was formed in the early 1990's to create a global network that could pool knowledge and resources in the studies of rare malignancies whose infrequency prevented both their study with prospective clinical trials. To date, the RCN has initiated 74 studies resulting in 46 peer reviewed publications. The First International Symposium of the Rare Cancer Network took place in Nice in March of 2014. Status updates and proposals for new studies were heard for fifteen topics. Ongoing studies continue for cardiac sarcomas, thyroid cancers, glomus tumors, and adult medulloblastomas. New proposals were presented at the symposium for primary hepatic lymphoma, solitary fibrous tumors, Rosai-Dorfman disease, tumors of the ampulla of Vater, salivary gland tumors, anorectal melanoma, midline nuclear protein in testes carcinoma, pulmonary lymphoepithelioma-like carcinoma, adenoid cystic carcinoma of the trachea, osteosarcomas of the mandible, and extra-cranial hemangiopericytoma. This manuscript presents the abstracts of those proposals and updates on ongoing studies, as well a brief summary of the vision and future of the RCN.

Nkx2.1-derived astrocytes and neurons together with Slit2 are indispensable for anterior commissure formation.

Guidepost cells present at and surrounding the midline provide guidance cues that orient the growing axons through commissures. Here we show that the transcription factor Nkx2.1 known to control the specification of GABAergic interneurons also regulates the differentiation of astroglia and polydendrocytes within the mouse anterior commissure (AC). Nkx2.1-positive glia were found to originate from three germinal regions of the ventral telencephalon. Nkx2.1-derived glia were observed in and around the AC region by E14.5. Thereafter, a selective cell ablation strategy showed a synergistic role of Nkx2.1-derived cells, both GABAergic interneurons and astroglia, towards the proper formation of the AC. Finally, our results reveal that the Nkx2.1-regulated cells mediate AC axon guidance through the expression of the repellent cue, Slit2. These results bring forth interesting insights about the spatial and temporal origin of midline telencephalic glia, and highlight the importance of neurons and astroglia towards the formation of midline commissures.

Mild guanidinoacetate increase under partial guanidinoacetate methyltransferase deficiency strongly affects brain cell development.

Among cerebral creatine deficiency syndromes, guanidinoacetate methyltransferase (GAMT) deficiency can present the most severe symptoms, and is characterized by neurocognitive dysfunction due to creatine deficiency and accumulation of guanidinoacetate in the brain. So far, every patient was found with negligible GAMT activity. However, GAMT deficiency is thought under-diagnosed, in particular due to unforeseen mutations allowing sufficient residual activity avoiding creatine deficiency, but enough guanidinoacetate accumulation to be toxic. With poorly known GAA-specific neuropathological mechanisms, we developed an RNAi-induced partial GAMT deficiency in organotypic rat brain cell cultures. As expected, the 85% decrease of GAMT protein was insufficient to cause creatine deficiency, but generated guanidinoacetate accumulation causing axonal hypersprouting and decrease in natural apoptosis, followed by induction of non-apoptotic cell death. Specific guanidinoacetate-induced effects were completely prevented by creatine co-treatment. We show that guanidinoacetate accumulation without creatine deficiency is sufficient to affect CNS development, and suggest that additional partial GAMT deficiencies, which may not show the classical brain creatine deficiency, may be discovered through guanidinoacetate measurement.

Induced pluripotent stem cells as a promising tool to study the effect of interleukin-22 in multiple sclerosis

La sclérose en plaques (SEP) est une maladie démyélinisante du système nerveux central (SNC) provoquant des pertes motrices, sensitives et cognitives. La SEP se déclare chez le jeune adulte ayant des prédispositions génétiques, mais semble induite, par des facteurs environnementaux. La SEP touche principalement les femmes et sa prévalence dans les zones à haut risque, tel que la Suisse, est de 0.1%. Bien que son étiologie exacte reste méconnue, nous savons que la maladie est médiée par des lymphocytes T autoréactifs périphériques, qui infiltrent le SNC où ils activent d'autres cellules immunitaires ainsi que les cellules du SNC elles-mêmes, créant un foyer inflammatoire, qui va attaquer et finir par tuer les oligodendrocytes et les neurones. Les épisodes inflammatoires sont entrecoupés par des phases de rémission associées à une guérison partielle des lésions. Cette première phase de la maladie, comprenant des épisodes inflammatoires et de rémissions est appelé SEP récurrente-rémittente (SEP-RR) et touche 90% des patients. Elle évolue, dans deux-tiers des cas, vers une SEP secondaire progressive (SEP-SP), qui est caractérisée par une progression constante de la maladie, associée à une réduction de l'inflammation mais une augmentation de la neurodégénérescence. Les patients souffrants de SEP primaire progressive (SEP-PP) développent directement les symptômes de la phase progressive de la maladie. Les thérapies disponibles ont considérablement amélioré l'évolution de la maladie des patients SEP-RR, en agissant sur une diminution de la réponse immunitaire et donc de l'inflammation. Cependant, ces traitements sont inefficaces chez les patients SEP-SP et SEP-PP, n'agissant pas sur la neurodégénérescence. IL-22, une cytokine sécrétée notoirement par les cellules Th17, a été associée à la SEP en contribuant à la perméabilisation de la barrière hémato-encéphalique et à l'inflammation du SNC, qui sont des étapes clés de la pathogenèse de la maladie. En outre, le gène codant pour un inhibiteur puissant d'IL- 22, 'IL-22 binding protein' (IL-22BP), a été démontré comme un facteur de risque de la SEP. Ces indices nous ont poussés à nous intéresser de plus près au rôle de l'IL-22 dans la SEP. Nous avons pu montrer qu'IL-22 et IL-22BP étaient augmentées dans le sang des patients SEP par rapport à des sujets sains. Nous avons trouvé qu'IL-22 cible spécifiquement les astrocytes dans le SNC et que son récepteur est particulièrement exprimé dans les lésions des patient SEP. Contre toute attente, nous avons pu montrer que l'IL-22 semble soutenir la survie des astrocytes. Cette découverte, suggérant qu'IL-22 serait protecteur pour le SNC et pour la SEP, confirme de récentes publications et ouvre la voie à de potentielles applications thérapeutiques. En parallèle, dans le but de mieux comprendre l'immunopathogenèse de la SEP, nous avons développé les techniques de culture de cellules souches pluripotentes induites (iPSC). Nos iPSC sont dérivées du sang des donneurs et acquièrent toutes les propriétés des cellules souches embryonnaires après induction. Les iPSC peuvent ensuite être différenciées en différents types de cellules, dont les cellules du SNC. Nous avons ainsi pu obtenir avec succès des neurones, dérivés de cellules du sang, en passant par le stade des iPSC. La prochaine étape consiste à générer des cultures d'astrocytes et d'oligodendrocytes et ainsi obtenir les principales cellules du SNC, le but étant de former de véritables 'cerveaux-en-culture'. Cet outil semble particulièrement adapté à l'étude de l'activité de diverses molécules sur les cellules du SNC, comme par exemple l'IL-22 et d'autres molécules ayant un potentiel intérêt thérapeutique au niveau du SNC. Le but ultime étant de développer des co-cultures de cellules du SNC avec des cellules immunitaires autologues, de patients SEP et de sujets sains, afin de mettre en évidence l'attaque des cellules du SNC par des leucocytes autoréactifs. Ce projet prospectif a permis d'accroître nos connaissance sur des aspects immunitaires de la SEP et à pour but de mieux comprendre l'immunopathogenèse de la SEP afin d'élaborer de nouvelles stratégies thérapeutiques. -- La sclérose en plaques est une maladie auto-inflammatoire du système nerveux central conduisant à la destruction de la myéline, indispensable à la conduction nerveuse, et finalement à la mort des neurones eux-mêmes. Cela a pour conséquence des pertes motrices, sensorielles et cognitives, qui ont tendance à s'aggraver au fil de la maladie. Elle se déclare chez le jeune adulte, entre l'âge de 20 et 40 ans, et prédomine chez la femme. En Suisse, environ une personne sur l'OOO est atteinte de sclérose en plaques. Les causes exactes de cette maladie, qui incluent des facteurs génétiques et environnementaux, sont encore mal connues. Des traitements de plus en plus efficaces ont été développés ces dernières années et ont permis de drastiquement améliorer l'évolution de la maladie chez les patients atteints de sclérose en plaques. Cependant, ces traitements ne sont efficaces que sur certaines catégories de patients et peuvent engendrer de lourds effets secondaires. Ces thérapies agissent presque exclusivement sur les cellules du système immunitaire en les désactivant partiellement, mais pas sur les cellules nerveuses, qui sont pourtant celles qui conditionnent le devenir du patient. Le développement de médicaments protégeant ou permettant la régénération des cellules du système nerveux central est donc primordial. L'étude de l'interleukine-22 nous a permis de montrer que cette cytokine ('hormone' du système immunitaire) pouvait cibler spécifiquement les astrocytes, des cellules gliales qui jouent un rôle central dans le maintien de l'équilibre du système nerveux central. Nos recherches ont montré que cette interleukine-22 permettrait une meilleure survie des astrocytes durant la phase aiguë de la maladie et aurait aussi des propriétés neuroprotectrices. En parallèle, nous sommes en train de développer un nouveau modèle in vitro d'étude de la sclérose en plaques grâce à la technologie des cellules souches pluripotentes induites. Ces cellules souches sont induites à partir de cellules du sang du donneur et acquièrent toutes les caractéristiques des cellules souches embryonnaires présentes dans un organisme en formation. Ainsi, ces cellules souches pluripotentes ont, par exemple, la capacité de se différencier en cellules du système nerveux central. Nous avons pu, de cette manière, obtenir des neurones. Le but ultime serait de pouvoir reconstituer une ébauche de cerveau in vitro, en cultivant ensemble différents types de cellules du système nerveux central, afin d'y réaliser des expériences avec des cellules immunitaires du même donneur. Ces travaux ont pour but d'améliorer notre compréhension de la pathogenèse de la sclérose en plaques et de permettre le développement de nouvelles stratégies thérapeutiques. --Multiple sclerosis (MS) is a demyelinating disease of the central nervous system leading to cognitive, sensitive and motor disabilities. MS occurs in genetically predisposed young adults with probable environmental triggers. MS affects predominantly women and its prevalence in high risk area such as Switzerland is 0.1%. Though its exact aetiology remains undetermined, we know that autoreactive T cells from de periphery are reactivated and recruited into the central nervous system (CNS) were they further activate other immune cells and resident cells, creating inflammatory foci, where oligodendrocytes and neurons are insulted and, eventually, killed. Inflammatory episodes, called relapses, are interspersed with remission phases where partial recovery of the lesions occurs. This first phase of the disease, occurring in 90% of the patients, is called relapsing-remitting MS (RR-MS) and is leading, in two-third of the cases, to secondary-progressive MS (SP-MS), where there is a continuous steady progression of the disease, associated with reduced inflammation but increased neurodegeneration. Primary-progressive MS (PP-MS) patients experience directly this progressive phase of the disease. Whereas disease modifying therapies have dramatically ameliorated the disease course of RR-MS patients by dampening immunity and, in turn, inflammation, treatments of SP-MS and PP-MS patients, who suffer primarily from the neurodegenerative aspect of the disease, are still inexistent. IL-22, a pro-inflammatory Th17 cell cytokine, has been associated with MS by participating to blood-brain barrier infiltration and CNS inflammation, which are crucial steps in MS pathogenesis. In addition, the gene coding for IL-22 binding protein (IL-22BP), which is a potent secreted IL-22 inhibitor, has been associated with MS risk. These findings call for further investigation on the role of IL-22 in MS. We detected increased IL-22 and IL-22BP in the blood of MS patients as compared to healthy controls. Acting exclusively on cells of nonhematopoietic origin, we found that IL-22 targets specifically astrocytes in the CNS and that its receptor is highly expressed in the lesion of MS patients. Unexpectedly, we found that IL-22 seems to promote survival of astrocytes. This finding, suggesting that IL-22 might be protective for the CNS in the context of MS, is consistent with recent publications and might open putative therapeutic applications at the CNS level. In parallel, with the aim of better understanding the immunopathogenesis of MS, we developed induced pluripotent stem cell (iPSC) techniques. IPSC are derived from blood cells of the donors and bear embryonic stem cell properties. IPSC can be differentiated into various cell types including CNS cells. We successfully obtained neurons derived from the donor blood cells, through iPSC. We further aim at developing astrocytes and oligodendrocytes cultures to recreate a 'brain-in-a-dish'. This would be a powerful tool to test the activity of various compounds on CNS cells, including IL-22 and other putative neuroprotective drugs. Ultimately, the goal is to develop co-cultures of CNS cells with autologous immune cells of MS patients as well as healthy controls to try to expose evidence of CNS cells targeted by autoreactive leukocytes. This prospective project has increased our knowledge of immune aspects of MS and further aims at better understanding the immunopathology of MS in order to pave the way to the elaboration of new therapeutic strategies.

Brain metastases in gastro-oesophageal adenocarcinoma: insights into the role of the human epidermal growth factor receptor 2 (HER2).

BACKGROUND: Gastro-oesophageal adenocarcinomas rarely metastasize to the central nervous system (CNS). The role of the human epidermal growth factor receptor 2 (HER2) in patients with these cancers and CNS involvement is presently unknown. PATIENTS AND METHODS: A multicentre registry was established to collect data from patients with gastro-oesophageal adenocarcinomas and CNS involvement both retrospectively and prospectively. Inclusion in the study required a predefined clinical data set, a central neuro-radiological or histopathological confirmation of metastatic CNS involvement and central assessment of HER2 by immunohistochemistry (IHC) and in situ hybridisation (ISH). In addition, expression of E-cadherin and DNA mismatch repair (MMR) proteins were assessed by IHC. RESULTS: One hundred patients fulfilled the inclusion criteria. The population's median age was 59 years (interquartile range: 54-68), of which 85 (85%) were male. Twenty-five patients were of Asian and 75 of Caucasian origin. HER2 status was positive in 36% (95% CI: 26.6-46.2) of cases. Median time from initial diagnosis to the development of brain metastases (BMets) or leptomeningeal carcinomatosis (LC) was 9.9 months (95% CI: 8.5-15.0). Median overall survival from diagnosis was 16.9 months (95% CI: 14.0-20.7) and was not related to the HER2 status. E-cadherin loss was observed in 9% of cases and loss of expression in at least one DNA MMR proteins in 6%. CONCLUSIONS: The proportion of a positive HER2 status in patients with gastro-oesophageal adenocarcinoma and CNS involvement was higher than expected. The impact of anti-HER2 therapies should be studied prospectively.

Impact of round-the-clock CSF Gram stain on empirical therapy for suspected central nervous system infections.

The impact of round-the-clock cerebrospinal fluid (CSF) Gram stain on overnight empirical therapy for suspected central nervous system (CNS) infections was investigated. All consecutive overnight CSF Gram stains between 2006 and 2011 were included. The impact of a positive or a negative test on empirical therapy was evaluated and compared to other clinical and biological indications based on institutional guidelines. Bacterial CNS infection was documented in 51/241 suspected cases. Overnight CSF Gram stain was positive in 24/51. Upon validation, there were two false-positive and one false-negative results. The sensitivity and specificity were 41 and 99 %, respectively. All patients but one had other indications for empirical therapy than Gram stain alone. Upon obtaining the Gram result, empirical therapy was modified in 7/24, including the addition of an appropriate agent (1), addition of unnecessary agents (3) and simplification of unnecessary combination therapy (3/11). Among 74 cases with a negative CSF Gram stain and without formal indication for empirical therapy, antibiotics were withheld in only 29. Round-the-clock CSF Gram stain had a low impact on overnight empirical therapy for suspected CNS infections and was associated with several misinterpretation errors. Clinicians showed little confidence in CSF direct examination for simplifying or withholding therapy before definite microbiological results.

Pain-evoked alterations on gingival blood flow and gingival crevicular fluid (GCF) neuropeptide SP and collagenase-2 (MMP-8) levels

Previous studies have demonstrated that clinical pulpal pain can induce the expression of pro-inflammatory neuropeptides in the adjacent gingival crevice fluid (GCF). Vasoactive agents such as substance P (SP) are known to contribute to the inflammatory type of pain and are associated with increased blood flow. More recent animal studies have shown that application of capsaicin on alveolar mucosa provokes pain and neurogenic vasodilatation in the adjacent gingiva. Pain-associated inflammatory reactions may initiate expression of several pro- and anti-inflammatory mediators. Collagenase-2 (MMP-8) has been considered to be the major destructive protease, especially in the periodontitis-affected gingival crevice fluid (GCF). MMP-8 originates mostly from neutrophil leukocytes, the first line of defence cells that exist abundantly in GCF, especially in inflammation. With this background, we wished to clarify the spatial extensions and differences between tooth-pain stimulation and capsaicin-induced neurogenic vasodilatation in human gingiva. Experiments were carried out to study whether tooth stimulation and capsaicin stimulation of alveolar mucosa would induce changes in GCF MMP-8 levels and whether tooth stimulation would release neuropeptide SP in GCF. The experiments were carried out on healthy human volunteers. During the experiments, moderate and high intensity painful tooth stimulation was performed by a constant current tooth stimulator. Moderate tooth stimulation activates A-delta fibres, while high stimulation also activates C-fibres. Painful stimulation of the gingiva was achieved by topical application of capsaicin-moistened filter paper on the mucosal surface. Capsaicin is known to activate selectively nociceptive C-fibres of stimulated tissue. Pain-evoked vasoactive changes in gingivomucosal tissues were mapped by laser Doppler imaging (LDI), which is a sophisticated and non-invasive method for studying e.g. spatial and temporal characteristics of pain- and inflammation-evoked blood flow changes in gingivomucosal tissues. Pain-evoked release of MMP-8 in GCF samples was studied by immunofluorometric assay (IFMA) and Western immunoblotting. The SP levels in GCF were analysed by Enzyme immunoassay (EIA). During the experiments, subjective stimulus-evoked pain responses were determined by a visual analogue pain scale. Unilateral stimulation of alveolar mucosa and attached gingiva by capsaicin evoked a distinct neurogenic vasodilatation in the ipsilateral gingiva, which attenuated rapidly at the midline. Capsaicin stimulation of alveolar mucosa provoked clear inflammatory reactions. In contrast to capsaicin stimuli, tooth stimulation produced symmetrical vasodilatations bilaterally in the gingiva. The ipsilateral responses were significantly smaller during tooth stimulation than during capsaicin stimuli. The current finding – that tooth stimulation evokes bilateral vasodilatation while capsaicin stimulation of the gingiva mainly produces unilateral vasodilatation – emphasises the usefulness of LDI in clarifying spatial features of neurogenic vasoactive changes in the intra-oral tissues. Capsaicin stimulation of the alveolar mucosa induced significant elevations in MMP-8 levels and activation in GCF of the adjacent teeth. During the experiments, no marked changes occurred in MMP-8 levels in the GCF of distantly located teeth. Painful stimulation of the upper incisor provoked elevations in GCF MMP-8 and SP levels of the stimulated tooth. The GCF MMP-8 and SP levels of the non-stimulated teeth were not changed. These results suggest that capsaicin-induced inflammatory reactions in gingivomucosal tissues do not cross the midline in the anterior maxilla. The enhanced reaction found during stimulation of alveolar mucosa indicates that alveolar mucosa is more sensitive to chemical irritants than the attached gingiva. Analysis of these data suggests that capsaicin-evoked neurogenic inflammation in the gingiva can trigger the expression and activation of MMP-8 in GCF of the adjacent teeth. In this study, it is concluded that experimental tooth pain at C-fibre intensity can induce local elevations in MMP-8 and SP levels in GCF. Depending on the role of MMP-8 in inflammation, in addition to surrogated tissue destruction, the elevated MMP-8 in GCF may also reflect accelerated local defensive and anti-inflammatory reactions.

Immunity and inflammation in status epilepticus and its sequelae: possibilities for therapeutic application.

Status epilepticus (SE) is a life-threatening neurological emergency often refractory to available treatment options. It is a very heterogeneous condition in terms of clinical presentation and causes, which besides genetic, vascular and other structural causes also include CNS or severe systemic infections, sudden withdrawal from benzodiazepines or anticonvulsants and rare autoimmune etiologies. Treatment of SE is essentially based on expert opinions and antiepileptic drug treatment per se seems to have no major impact on prognosis. There is, therefore, urgent need of novel therapies that rely upon a better understanding of the basic mechanisms underlying this clinical condition. Accumulating evidence in animal models highlights that inflammation ensuing in the brain during SE may play a determinant role in ongoing seizures and their long-term detrimental consequences, independent of an infection or auto-immune cause; this evidence encourages reconsideration of the treatment flow in SE patients.

Distribution of monocarboxylate transporters in the peripheral nervous system suggests putative roles in lactate shuttling and myelination.

Lactate, a product of glycolysis, has been shown to play a key role in the metabolic support of neurons/axons in the CNS by both astrocytes and oligodendrocytes through monocarboxylate transporters (MCTs). Despite such importance in the CNS, little is known about MCT expression and lactate function in the PNS. Here we show that mouse MCT1, MCT2, and MCT4 are expressed in the PNS. While DRG neurons express MCT1, myelinating Schwann cells (SCs) coexpress MCT1 and MCT4 in a domain-specific fashion, mainly in regions of noncompact myelin. Interestingly, SC-specific downregulation of MCT1 expression in rat neuron/SC cocultures led to increased myelination, while its downregulation in neurons resulted in a decreased amount of neurofilament. Finally, pure rat SCs grown in the presence of lactate exhibited an increase in the level of expression of the main myelin regulator gene Krox20/Egr2 and the myelin gene P0. These data indicate that lactate homeostasis participates in the regulation of the SC myelination program and reveal that similar to CNS, PNS axon-glial metabolic interactions are most likely mediated by MCTs.

Developmental expression of the oligodendrocyte myelin glycoprotein in the mouse telencephalon

The oligodendrocyte myelin glycoprotein is a glycosylphosphatidylinositol-anchored protein expressed by neurons and oligodendrocytes in the CNS. Attempts have been made to identify the functions of the myelin-associated inhibitory proteins (MAIPs) after axonal lesion or in neurodegeneration. However, the developmental roles of some of these proteins and their receptors remain elusive. Recent studies indicate that NgR1 and the recently discovered receptor PirB restrict cortical synaptic plasticity. However, the putative factors that trigger these effects are unknown. Since Nogo-A is mostly associated with the endoplasmic reticulum and MAG appears late during development, the putative participation of OMgp should be considered. Here we examine the pattern of development of OMgp immunoreactive elements during mouse telencephalic development. OMgp immunoreactivity in the developing cortex follows the establishment of the thalamo-cortical barrel-field. At cellular level, we located OMgp neuronal membranes in dendrites and axons as well as in brain synaptosome fractions and axon varicosities. Lastly, the analysis of the barrel-field in OMgp-deficient mice revealed that although thalamo-cortical connections were formed, their targeting in layer IV was altered and numerous axons ectopically invaded layer II-III. Our data support the idea that early-expressed MAIPs play an active role during development and point to OMgp participating in thalamo-cortical connections.

Cerebriforms cells in cerebrum: an unusual finding

Background. Mycosis Fungoides (MF) is the most common cutaneous T-cell lymphoma, and large cell trasformation (tMF) is an adverse prognostic event. Extra-cutaneous dissemination can occur in the course of the disease, but dissemination to the central nervous system (CNS) is uncommon. Moreover, CNS lymphomas are overall rare and most often of B-cell phenotype. We report a case of CNS large T-cell lymphoma presenting as multiple cerebral lesions in a patient with a history of MF. Methods. We report a case of a 33-year-old woman, known since the age of 16 for erythematous plaques thought to be atopic dermatitis, who developed, end 2012, multiple nodular skin lesions and peripheral adenopathies. Two skin lesions were biopsied simultaneously, and diagnosed as MF and tMF. A lymph node biopsy showed dermatopathic changes without lymphoma (Stage IIB). She received local treatment (UVB, PUVA and radiation therapy) and interferon therapy, and experienced almost complete remission. In 2015 neurological symptoms lead to evidence multiple cerebral lesions, suspicious for lymphoma, evaluated by stereotaxic biopsies. We compared histopathological and molecular features of these with previous skin specimens. After negative bone marrow staging biopsy, she was recently started on chemotherapy (MATRIX). Short follow-up shows rapidly worsening clinical conditions. Results. One of the initial skin biopsies showed atypical lymphoid cells with epidermotropism, Pautrier abcesses and CD4+ CD30- phenotype; the other revealed diffuse dermal infiltration by predominantly large cerebriform tumor cells with high proliferative fraction, and CD2−CD3 −CD4+/−CD7−CD30+ALK- EMA- non-cytotoxic immunophenotype. Altogether, these results led us to diagnose MF and tMF, respectively. The brain was infiltrated by large atypical lymphoid cells with cerebriform nuclei, somewhat anaplastic features and perivascular distribution. By immunohistochemistry, tumor cells were highly proliferative, with a CD2−CD3+CD5−CD7+CD30+ activated cytotoxic immunophenotype. A diagnosis of CD30+ cytotoxic peripheral T-cell lymphoma was retained. TRG and TRB clonality analyses revealed clonal rearrangements in skin and CNS biopsies, with identical patterns in both skin specimens but only minimally overlapping profiles when compared to the CNS sample. Der Pathologe 6 ? 2015 | 633 Conclusions. The reported case illustrates an uncommon finding of a CNS T-cell lymphoma in a patient with previous MF, questioning the clonal relationship between the two diseases and challenging the adequate classification of this CNS lymphoma as either a progression or a de novo lymphoma. Despite differences in immunophenotype and clonality patterns, this CNS lymphoma could possibly represent an aggressive divergent evolution of a primary cutaneous T-cell lymphoma. Additional sequencing is ongoing to try to solve the question.