Central Nervous Sytem Research Articles

Cerebral developmental venous anomalies in children with mismatch repair deficiency

Constitutional mismatch repair deficiency (CMMRD) is one of the rare cancer predisposition syndromes. The aim of this study was to evaluate the cerebral developmental venous anomalies in children with central nervous system tumors associated with CMMRD, an area in which there is extremely little experience. Data from children diagnosed with medulloblastoma and high grade central nervous sytem tumor were retrospectively collected. According to the European CMMRD criteria, nine patients were diagnosed as CMMRD syndrome and the others consisted of the group without CMMRD. All radiological examinations of these children were retrospectively reviewed. Whole exome sequencing was performed to index cases` germline DNA. Nine children from four families, six females and three males, were studied. The median age at the first tumor diagnosis was 4.5 years (range, 9 months to 14 years). All CMMRD patients had café au lait spots, but none fulfilled the diagnostic criteria for neurofibromatosis. The patients developed high-grade glial tumor (n: 7) and medulloblastoma (n: 2). The affected genes in the three families were MSH6 [c.478C > T (p.Gln160Ter)], MSH6 [c.2871dupC (p.Phe958LeufsTer5)] and MLH1 [c.236G > A(p.Arg79Lys)], respectively. Seven patients had multiple developmental venous anomalies; six patients had leptomeningeal enhancement; and five patients had cavernomas. None of these findings were present in the group without CMMRD. Constitutional mismatch repair deficiency should be considered when multiple developmental venous anomalies, cavernomas, and leptomeningeal enhancement are detected, especially in patients with café au lait spots.

WHO classification of tumors of the nervous system: preview of the upcoming 5th edition

SummaryIdentification of the underlying genetic and epigenetic alterations in an increasing number of tumors of the nervous system is contributing to a more clinically relevant classification. In the following article, the 7 cIMPACT-NOW publications, which adumbrate the upcoming 5th edition of the WHO Classification of Tumours of the Central Nervous Sytem are summarized.

Anti-inflammatory activity of Jatropha curcas L. in brain glial cells primary cultures

Ethnopharmacological relevanceJatropha curcas L. (Euphorbiaceae), a medicinal plant known in Brazil as “Pinhão Manso”, is highly adaptable, being cultivated in different tropical and subtropical regions of the world. Antimicrobial, antioxidant and antiinflammatory activities have been attributed to different parts of the plant. In the central nervous sytem (CNS), neuroinflammation is mediated by glial cells, mainly by astrocytes and microglia, a process that plays an important role in neurodegenerative diseases and other CNS disorders. In this study, we investigated the anti-inflammatory activity of the methanolic extract obtained from the leaves of J. curcas L. (MEJc) in primary cultures of glial cells submited to inflammatory stimulus. Materials and methodsPrimary cultures of glial cells obtained from the cerebral cortex of neonate Wistar rats were treated with MEJc (0.1–50,000 μg mL-1) and its fractions (FnJc) (0.1 μg mL-1) with or without lipopolysaccharide of Escherichia coli (LPS) (1 μg mL-1). Cell viability was determined with MTT test. Modifications in glial cell morphology were investigated by means of phase contrast microscopy and May-Grünwald staining. The reactivity of astrocytes and microglia were investigated with immunocytochemistry for GFAP, Iba1 and transcription factor NF-kB, as well as with Greiss reaction to determine the nitric oxide (NO) production. ResultsMEJc at 0.1–1000 μg mL-1 was non-toxic to glial cells and the DE50 was 10.794 μg mL-1. The treatment with LPS induced the activation of astrocytes and microglia marked by morphological modifications and changes in the expression of GFAP and Iba1, as well as the increase in NF-kB expression and NO production. Treatment with MEJc inhibited the morphological modifications, changes in GFAP and Iba1 expression, and the increase in NF-kB and NO production induced by LPS. ConclusionThis study demonstrates that the MEJc and its fractions modulate inflammatory response of astrocytes and microglia to LPS and may be considered as a potential therapeutic strategy for neuroinflammation-related diseases.

Choroid Plexus Papilloma with Dandy Walker Variant: Co-existence or Association- A Case Report

Choroid plexus tumors are rare intracranial tumors which account for 0.4-0.6% of all brain tumors. Choroid plexus tumors represent a spectrum of neoplasms derived from papillary epithelium of normal choroid plexus, including well-differentiated papilloma (WHO grade I), intermediate form as atypical Choroid Plexus Papilloma (WHO grade II) and highly aggressive choroid plexus carcinomas (WHO grade III). Though rare, it is responsible for the communicating hydrocephalus in children due to overproduction of cerebrospinal fluid. Due to advances in molecular biology and better understanding of the tumorigenesis of choroid plexus papilloma, now it is established that several genetic syndromes and central nervous sytem abnormalities are associated with this tumor. Here, we reported a case of a 10 months old child who presented with sudden deterioration of consciousness level and after thorough evaluation, diagnosed as a case of Choroid Plexus Papilloma with Dandy Walker Variant. Till date, this is the first reported case of the association/ co-existence of such two conditions which needs further evaluation.
 Bangladesh Med J. 2017 May; 46 (2): 61-65

Advances in risk assessment and prophylaxis for central nervous system relapse in diffuse large B-cell lymphoma.

Central nervous sytem recurrence of diffuse large B-cell lymphoma is an uncommon but devastating event, making identification of patients at high risk for relapse within the central nervous system essential for clinicians. Modern risk stratification includes both clinical and biological features. A validated clinical risk model employing the five traditional International Prognostic Index risk factors plus renal or adrenal involvement can identify a high-risk patient population with a central nervous system recurrence risk of greater than 10%. Lymphoma involvement of certain discrete extranodal sites such as the testis also confers increased risk, even in stage I disease. Adverse biological risk factors for central nervous system relapse include presence of translocations of MYC, BCL2 and/or BCL6, in so-called double- or triple-hit lymphoma. Immunohistochemically detectable co-expression of MYC and BCL2 in the absence of translocations also portends an increased risk of relapse within the central nervous system, particularly in the setting of the activated B-cell-like subtype of diffuse large B-cell lymphoma. The role, method, and timing of prophylactic therapy remain controversial based on the available data. We review both intrathecal and systemic strategies for prophylaxis in high-risk patients. Our preference is for systemic methotrexate in concert with standard chemoimmunotherapy in the majority of cases. Several novel agents have also demonstrated clinical activity in primary and secondary central nervous system lymphoma and warrant future investigation in the prophylactic setting.

An update on meningoencephalomyelitis of unknown aetiology in dogs

Inflammatory diseases of the central nervous system are common causes of neurological dysfunction in the dog and can be grouped into two broad categories; those of infectious and those of unknown aetiology. Μeningoencephalomyelitis of unknown aetiology include non-infectious inflammatory central nervous system diseases in which abnormal findings on magnetic resonance imaging and cerebrospinal fluid analysis indicate inflammatory central nervous system disease, but for which histopathological confirmation has not been reached. Meningoencephalomyelitis of unknown aetiology describes a group of non-infectious inflammatory diseases of the central nervous system. These include the granulomatous meningoencephalomyelitis and the necrotising encephalitis, the latter can be further distinguished into two subtypes: necrotising meningoencephalitis and necrotising leucoencephalitis. Steroid-responsive meningitis-arteritis may be also included to this category and, usually, does not present signs of encephalitis or/and myelitis (except in the chronic form) and is easier diagnosed even without histopathological examination. In most cases of meningoencephalomyelitis of unknown aetiology, a presumptive diagnosis can be achieved by the assessment of case presentation, theneurologic signs, cerebrospinal fluid testing, cross-sectional imaging of the central nervous system and appropriate microbiological tests.Definite diagnosis is achieved with histopathological examination. The underlying cause for these diseases is unknown. The clinical signs in meningoencephalomyelitis of unknown aetiology is variable and depends on which area of the central nervous sytem is affected. Meningoencephalomyelitis is acute in onset, progressive in nature and associated with multifocal to diffuse neuroanatomic localization. Extraneural signs are less common and these usually include pyrexia and peripheral neutrophilia. The differential diagnosis for dogs presented for an acute onset of multifocal central nervous system signs includes genetic abnormalities, metabolic disorders, infectious meningoencephalitis, toxin exposure, stroke and neoplasia.The diagnostic approach includes a complete blood count, a comprehensive chemistry panel, urinalysis, survey radiographs of the thorax plus abdominal ultrasound to rule out systematic disease and metastatic neoplasia, computed-tomography or magnetic reso meningitisnance imaging, cerebrospinal fluid analysis and microbiological tests.When neoplasia is suspected, computed-tomography-guided brain biopsy may be required for the differentiation. Meningoencephalomyelitis of unknown aetiology responds more or less to immunosuppressive therapies, but the prognosis should be guarded to poor with the exception of steroid-responsive meningitisarteritis, for which it is good. Treatment protocols are based on prednisolone, but new immunosuppressive agents have now been added in those to control the diseases and they seem to be effective. However, gold standard protocols have yet to be established.

Effect of oral clonidine premedication on perioperative hemodynamic response-A randomized double blind placebo controlled study

Introduction: Preanesthetic medication forms an integral part of anaesthetic management. Pharmacological and non-pharmacological techniques are tried to achieve anxiolysis and better hemodynamic stability. Clonidine is alpha 2 agonist and acts on central nervous sytem. It is adminstered in various route and oral route is one of them. This study has been designed to study the effect of oral clonidine on perioperative hemodynamics. Aims: To evaluate beneficial effects of oral clonidine in attenuating the haemodynamic responses and comparing with placebo in patients undergoing surgeries under general anaesthesia. Settings and Design: Randomized double blind study. Methods and Material: Two hundred patients were enrolled in this study and studied for 2 years. Randomization was carried out. Four groups, including 50 patients per group were created. Group I (Placebo) received oral tablet ranitidine 150 mg, Group II C2, C3 and C4received oral clonidine 2 µg/kg, 3µg/kg and 4µg/kg body weight respectively. Sedation, anxiolysis and hemodynamic changes were recorded. Statistical analysis used: The statistical significance for categorical variables was determined by chi-square test. For continuous variables two sample t-test was applied. For intra group comparison paired t- test and for inter group comparison unpaired t-test was used. Results were expressed as Mean ± SD (standard deviation). A P value < 0.05 was considered statistically significant. Results: No statistically significant differences concerning demographic data between the groups of patients computed. A significant difference observed with respect to sedation and anxiolysis between all the four groups. The HR response between clonidine (2 µg/kg, 3µg/kg and 4µg/kg) and placebo was very significant at all times (p

Borna disease virus infection in cats: ABCD guidelines on prevention and management.

Borna disease virus (BDV) has a broad host range, affecting primarily horses and sheep, but also cattle, ostriches, cats and dogs. In cats, BDV may cause a non-suppurative meningoencephalomyelitis ('staggering disease'). The mode of transmission is not completely elucidated. Direct and indirect virus transmission is postulated, but BDV is not readily transmitted between cats. Vectors such as ticks may play a role and shrews have been identified as a potential reservoir host. Access to forested areas has been reported to be an important risk factor for staggering disease. It is postulated that BDV may infect nerve endings in the oropharynx and spread via olfactory nerve cells to the central nervous system. A strong T-cell response may contribute to the development of clinical disease. Affected cats develop gait disturbances, ataxia, pain in the lower back and behavioural changes. For diagnostic purposes, detection of viral RNA by reverse transcription PCR in samples collected from cats with clinical signs of Borna disease can be considered diagnostic. Serology is of little value; cats without signs of Borna disease may be seropositive and yet not every cat with BDV infection has detectable levels of antibodies. A hypothesis that BDV infection may be involved in the development of selected neurological disorders in man could not be confirmed. A research group within the German Robert Koch Institute studied the potential health threat of BDV to humans and concluded that BDV was not involved in the aetiology of human psychiatric diseases.

Analyse histologique et moléculaire des métastases cérébrales

The first step in the diagnosis of a metastatic brain lesion is to exclude a primary central nervous sytem tumour, followed by verification or identification of the primary tumor site, in order to guide the clinician to specific therapy. In addition to morphological features, ancillary immunohistochemical study is most effective for the evaluation of a metastatic neoplasm of unknown primary. Although the main principles are same, there are slight variations in the approach to the secondary lesion in the central nervous system versus other regions. Indeed, immunohistochemical approach focuses on the most common tumor types associated with secondary brain colonization: lung cancer, breast cancer and melanoma. Several studies have reported that targeted therapies are capable of reducing brain metastases in melanoma or non-small cell lung cancer, sometimes with a high dramatic response. These results have clearly impacted routine neuropathological practice. It is likely that molecular subtyping of central nervous system metastases will play an increasing role in the future. In accordance with the recommendations of Inca (French national cancer institute), the pathologist develops appropriate strategies for molecular and immunohistochemical analysis, in order to provide results as soon as possible. This article summarizes the diagnosic approach to brain metastases, with a focus on the recent emergence of targeted therapies.

Neuroimmmune interactions of cannabinoids in neurogenesis: focus on interleukin-1β (IL-1β) signalling

Neuroimmune networks and the brain endocannabinoid system contribute to the maintenance of neurogenesis. Activation of cannabinoid receptors suppresses chronic inflammatory responses through the attenuation of pro-inflammatory mediators. Moreover, the endocannabinoid system directs cell fate specification of NSCs (neural stem cells) in the CNS (central nervous system). The aim of our work is to understand better the relationship between the endocannabinoid and the IL-1β (interleukin-1β) associated signalling pathways and NSC biology, in order to develop therapeutical strategies on CNS diseases that may facilitate brain repair. NSCs express functional CB1 and CB2 cannabinoid receptors, DAGLα (diacylglycerol lipase α) and the NSC markers SOX-2 and nestin. We have investigated the role of CB1 and CB2 cannabinoid receptors in the control of NSC proliferation and in the release of immunomodulators [IL-1β and IL-1Ra (IL-1 receptor antagonist)] that control NSC fate decisions. Pharmacological blockade of CB1 and/or CB2 cannabinoid receptors abolish or decrease NSC proliferation, indicating a critical role for both CB1 and CB2 receptors in the proliferation of NSC via IL-1 signalling pathways. Thus the endocannabinoid system, which has neuroprotective and immunomodulatory actions mediated by IL-1 signalling cascades in the brain, could assist the process of proliferation and differentiation of embryonic or adult NSCs, and this may be of therapeutic interest in the emerging field of brain repair.

Gait Abnormalities and Progressive Myelin Degeneration in a New Murine Model of Pelizaeus-Merzbacher Disease with Tandem Genomic Duplication

Pelizaeus-Merzbacher disease (PMD) is a hypomyelinating leukodystrophy caused by mutations of the proteolipid protein 1 gene (PLP1), which is located on the X chromosome and encodes the most abundant protein of myelin in the central nervous sytem. Approximately 60% of PMD cases result from genomic duplications of a region of the X chromosome that includes the entire PLP1 gene. The duplications are typically in a head-to-tail arrangement, and they vary in size and gene content. Although rodent models with extra copies of Plp1 have been developed, none contains an actual genomic rearrangement that resembles those found in PMD patients. We used mutagenic insertion chromosome engineering resources to generate the Plp1dup mouse model by introducing an X chromosome duplication in the mouse genome that contains Plp1 and five neighboring genes that are also commonly duplicated in PMD patients. The Plp1dup mice display progressive gait abnormalities compared with wild-type littermates. The single duplication leads to increased transcript levels of Plp1 and four of the five other duplicated genes over wild-type levels in the brain beginning the second postnatal week. The Plp1dup mice also display altered transcript levels of other important myelin proteins leading to a progressive degeneration of myelin. Our results show that a single duplication of the Plp1 gene leads to a phenotype similar to the pattern seen in human PMD patients with duplications.

Trends in fetal indications for termination of pregnancy between 2002 and 2010 at a tertiary referral centre

We reviewed the data of the termination of pregnancy (TOP) cases between 2002 and 2010 to evaluate the changes in fetal indications for both early and late TOPs in this period. The data of 962 TOP cases were analysed in two groups according to the periods as in 2002-2006 and 2007-2010. The women were also subdivided into two categories according to their gestational age; <23 weeks' gestation (early termination) and ≥23 weeks' gestation (late termination). Four hundred and fifty-eight (47.6%) of TOPs were performed between 2002 and 2006 (Group 1) and 504 (52.3%) were performed between 2007 and 2010 (Group 2). The number of early (<23 weeks) and late (≥23 weeks) terminations were 583 (60.6%) and 379 (39.3%), respectively. The vast majority of anomalies were central nervous sytem malformations (51.8%). They were followed by multiple anomalies (10.2%) and chromosomal anomalies (9.4%). Chromosomal and cardiovascular system anomalies were significantly higher in 2007-2010 in comparison to 2002-2006 (p<0.0001 and p=0.002, respectively). There was no statistically significant difference between the fetal indications that led to early termination compared to those that led to late termination. The distribution of indications for TOP was influenced by the development in prenatal screening policy, resulting in a significant increase in terminations due to chromosomal and cardiovascular system anomalies. Cultural, educational, religious and legal factors cause differences in the indications for TOP as well as the gestational age that TOPS are performed.

The Liver X-Receptor (Lxr) Governs Lipid Homeostasis in Zebrafish during Development

The liver X-receptors (LXRs) act as cholesterol sensors and participate in the regulation of lipid and cholesterol metabolism. The objective of this study was to determine the role of LXR during development using the zebrafish model. By in situ hybridization we showed distinct expression of lxr in the brain and the retina in the developing and adult zebrafish. Lxr ligand activation affected the expression of genes involved in lipid metabolism in zebrafish adult brain and eye as well as in zebrafish embryos. Morpholino knock down of lxr resulted in an overall impaired lipid deposition as determined by oil red O staining particularly in the head and around the eyes, and to significantly elevated levels of both total and free cholesterol in the yolk of lxr morphant embryos. The expression of genes involved in lipid and cholesterol metabolism was also changed in the lxr morphants. Furthermore, alcian blue staining revealed malformation of the pharyngeal skeleton in the lxr morphant. Our data show that lxr is an important component of the regulatory network governing the lipid homeostasis during zebrafish development, which in turn may support a role of lxr for normal development of the central nervous sytem, including the retina.

Pain and immunity

Chronic neuropathic and inflammatory pain is a major public health problem. Nociceptors undergo sensitization, first in peripheral tissues then in the central nervous sytem, via neuroimmune interactions linking neurons, glial cells (microglia and astrocytes), and immune cells. These interactions may either exacerbate or attenuate the pain and inflammation, which normally reach a state of equilibrium. With more powerful or longer lasting stimuli, specific profiles of microglial and, subsequently, astrocytic activation in the dorsal horn play a key role in neuronal plasticity and transition to chronic pain. Recent insights into the interactions between the nervous system and the immune system suggest a large number of potential therapeutic targets that could be influenced either by targeted inhibition or by directing the neuroimmune response toward the antiinflammatory and analgesic end of its spectrum.

Safety Evaluation of Chronic Intrathecal Administration of Idursulfase-IT in Cynomolgus Monkeys

Recombinant human idursulfase, an intravenous enzyme replacement therapy indicated for treatment of somatic symptoms of mucopolysaccharidosis II (Hunter syndrome), is anticipated to have minimal benefit for the cognitive impairment associated with the severe phenotype. Because intrathecal (IT) administration of enzyme replacement therapy for other lysosomal enzyme disorders has shown efficacy in animal models, an IT formulation of idursulfase (idursulfase-IT) and a drug-delivery device (subcutaneous port connected to a lumbar IT catheter) were developed for treating central nervous system (CNS) involvement. In this chronic safety study, cynomolgus monkeys were dosed weekly with IV idursulfase (0.5 mg/kg) and every four weeks with idursulfase-IT (3, 30, and 100 mg) for six months, with device and vehicle controls treated similarly (n = 6, all groups). Necropsies were performed twenty-four hours post-final IT dose or after a recovery period (four weeks post-final dose in vehicle-control, 3 mg, and 100 mg IT groups: n = 6). No clinical signs or gross central nervous system lesions were observed. Compared to controls, more pronounced cellular infiltrates in brain and spinal cord meninges were noted, which largely resolved after the recovery period. Central nervous sytem levels of idursulfase-IT were dose dependent, as determined by enzyme activity and immunohistochemistry. The no-observed-adverse-effect level of idursulfase-IT was 100 mg.

Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway

Inflammation and oxidative stress are thought to promote tissue damage in multiple sclerosis. Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for multiple sclerosis treatment. BG00012 is an oral formulation of dimethylfumarate. In a phase II multiple sclerosis trial, BG00012 demonstrated beneficial effects on relapse rate and magnetic resonance imaging markers indicative of inflammation as well as axonal destruction. First we have studied effects of dimethylfumarate on the disease course, central nervous system, tissue integrity and the molecular mechanism of action in an animal model of chronic multiple sclerosis: myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis in C57BL/6 mice. In the chronic phase of experimental autoimmune encephalomyelitis, preventive or therapeutic application of dimethylfumarate ameliorated the disease course and improved preservation of myelin, axons and neurons. In vitro, the application of fumarates increased murine neuronal survival and protected human or rodent astrocytes against oxidative stress. Application of dimethylfumarate led to stabilization of the transcription factor nuclear factor (erythroid-derived 2)-related factor 2, activation of nuclear factor (erythroid-derived 2)-related factor 2-dependent transcriptional activity and accumulation of NADP(H) quinoline oxidoreductase-1 as a prototypical target gene. Furthermore, the immediate metabolite of dimethylfumarate, monomethylfumarate, leads to direct modification of the inhibitor of nuclear factor (erythroid-derived 2)-related factor 2, Kelch-like ECH-associated protein 1, at cysteine residue 151. In turn, increased levels of nuclear factor (erythroid-derived 2)-related factor 2 and reduced protein nitrosylation were detected in the central nervous sytem of dimethylfumarate-treated mice. Nuclear factor (erythroid-derived 2)-related factor 2 was also upregulated in the spinal cord of autopsy specimens from untreated patients with multiple sclerosis. In dimethylfumarate-treated mice suffering from experimental autoimmune encephalomyelitis, increased immunoreactivity for nuclear factor (erythroid-derived 2)-related factor 2 was detected by confocal microscopy in neurons of the motor cortex and the brainstem as well as in oligodendrocytes and astrocytes. In mice deficient for nuclear factor (erythroid-derived 2)-related factor 2 on the same genetic background, the dimethylfumarate mediated beneficial effects on clinical course, axon preservation and astrocyte activation were almost completely abolished thus proving the functional relevance of this transcription factor for the neuroprotective mechanism of action. We conclude that the ability of dimethylfumarate to activate nuclear factor (erythroid-derived 2)-related factor 2 may offer a novel cytoprotective modality that further augments the natural antioxidant responses in multiple sclerosis tissue and is not yet targeted by other multiple sclerosis therapies.

The chemokine receptor antagonist, TAK‐779, decreased experimental autoimmune encephalomyelitis by reducing inflammatory cell migration into the central nervous system, without affecting T cell function

The C-C chemokine receptor CCR5, and the C-X-C chemokine receptor CXCR3 are involved in the regulation of T cell-mediated immune responses, and in the migration and activation of these cells. To determine whether blockade of these chemokine receptors modulated inflammatory responses in the central nervous sytem (CNS), we investigated the effect of a non-peptide chemokine receptor antagonist, TAK-779, in mice with experimental autoimmune encephalomyelitis (EAE). EAE was induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein (MOG) 35-55. TAK-779 was injected s.c. once a day after immunization. Disease incidence and severity (over 3 weeks) were monitored by histopathological evaluation and FACS assay of inflammatory cells infiltrating into the spinal cord, polymerase chain reaction quantification of mRNA expression, assay of T cell proliferation, by [3H]-thymidine incorporation and cytokine production by enzyme-linked immunosorbent assay. Treatment with TAK-779 reduced incidence and severity of EAE. It strongly inhibited migration of CXCR3/CCR5 bearing CD4+, CD8+ and CD11b+ leukocytes to the CNS. TAK-779 did not reduce proliferation of anti-MOG T cells, the production of IFN-gamma by T cells or CXCR3 expression on T cells. In addition, TAK-779 did not affect production of IL-12 by antigen-presenting cells, CCR5 induction on T cells and the potential of MOG-specific T cells to transfer EAE. TAK-779 restricted the development of MOG-induced EAE. This effect involved reduced migration of inflammatory cells into the CNS without affecting responses of anti-MOG T cells or the ability of MOG-specific T cells to transfer EAE.

Activated Notch pathway proteins and FoxG1 are co‐expressed in Medulloblastoma: correlation with phenotype

Notch pathway activation has been implicated in the negative regulation of neural differentiation in the developing central nervous sytem. Hes 1 and Hes 5 are downstream effectors of the Notch pathway. FoxG1 forms a transcriptional repressor complex with Hes1 and was recently reported as dysregulated in all histologic types of medulloblastoma. We examined 64 medulloblastomas by IHC for nuclear expression of activated Notch‐1, Hes1, and Hes5. Activated Notch‐1, Hes1, and Hes5 expression were detected in all histologic subtypes. Using Spearman correlation (SC) analysis, there was a positive correlation between the expression of activated Notch1 and Hes1 (SC coeff 0.36, p=0.0035) and Hes 5 (SC coeff 0.433, p&lt;0.001). Expression of FoxG1 and Notch1 also showed a weak, but significant positive correlation (SC coeff 0.273, p=0.028).Activated Notch1 expression was higher in the anaplastic subtype (ANOVA on Ranks, Dunn's test, H=12.968, p=0.002). Co‐expression of FoxG1 and Notch pathway effectors is consistent with a putative combined role of FoxG1 and activated Notch pathway in the maintenance of an undiferentiated state in medulloblastoma. In view of the reported association of myc amplification with anaplastic progression and the known Notch‐Wnt signaling pathway crosstalk, the significance of our demonstration of a correlation between Notch1 expression and the anaplastic phenotype remains to be explored.

Birth characteristics and childhood malignant central nervous sytem tumors: The ESCALE study (French Society for Childhood Cancer)

Background: Determining the role of pre- and perinatal factors in the aetiology of childhood malignant central nervous (CNS) tumors, using data from the French national case–control study, ESCALE. Methods: ESCALE included all children in France less than 15 years old with a diagnosis of acute leukaemia, lymphoma, malignant CNS tumor, or neuroblastoma (2003–2004). In all, 209 malignant CNS tumor cases (80% of the eligible cases) and 1681 population-based controls (71%) were included using quotas ensuring frequency matching with the cases by age and gender. Case and control mothers were interviewed using a standardised telephone interview, which elicited birth characteristics, congenital malformation, maternal reproductive history, and use of assisted reproductive technologies for the index child. Results: The cases and controls did not differ in terms of gestational age at birth, birth weight, birth order, breastfeeding, or parental age at birth. There was no association between assisted reproduction for the index child and malignant CNS tumor (OR = 1.1 [0.6–2.2]). A positive association between a maternal history of one miscarriage and malignant CNS tumor was observed (OR = 1.4 [1.0–2.0], p < 0.05), especially for glial cell tumors (other glioma: OR = 2.0 [1.1–3.6]). Conclusion: The results suggest a possible association between a maternal history of one miscarriage and the risk of malignant CNS tumor.

Substrate utilization in sepsis and multiple organ failure

Sepsis and multiple organ failure are characterized by an excessive release of inflammatory mediators and a marked stimulation of stress hormones. These in turn have profound effects on energy and substrate metabolism: energy expenditure is generally increased, and increased lipolysis and fat oxidation are observed. Net protein breakdown occurs and leads to accelerated wasting. Most of these effects can be produced in healthy humans by administration of bacterial endotoxin or by tumor necrosis factor-alpha. Hyperlactatemia is a hallmark of sepsis and critical illness, and its severity is related to mortality. An increased lactate production, possibly secondary to activation of Na-K adenosine 5'-triphosphatase and to muscle mitochondrial dysfunction, is involved. Lactate production by immune cells and wound tissue may also play a role. Long-chain, n-3 polyunsaturated fatty acids have anti-inflammatory effects that may be beneficial in sepsis. They also decrease the stimulation of stress hormones induced by bacterial endotoxin, possibly through an effect exerted at the level of the central nervous sytem. Their use in patients with sepsis does not lead to adverse metabolic effects.