Mutation analysis of the Ras pathway genes<Emphasis Type="Italic"> NRAS</Emphasis>,<Emphasis Type="Italic"> HRAS</Emphasis>,<Emphasis Type="Italic"> KRAS</Emphasis> and<Emphasis Type="Italic"> BRAF</Emphasis> in glioblastomas

Aberrant activation of Ras signaling is a common finding in human glioblastomas. To determine the contribution of Ras gene mutations to this aberration, we screened 94 glioblastomas for mutations in the three Ras family genes NRAS, KRAS and HRAS. All tumors were additionally analyzed for mutations in BRAF, which encodes a Ras-regulated serine/threonine kinase with oncogenic properties. Mutation analysis of the entire coding regions of NRAS and KRAS, as well as the known mutation hot-spot sites in HRAS, identified somatic point mutations in two glioblastomas, both affecting codon 12 of NRAS (c.35G>A, p.G12D). Three additional tumors carried BRAF mutations altering the known hot-spot codon 599 (c.1796T>A, p.V599E). None of these five glioblastomas showed amplification of the EGFR or PDGFRA genes, while three of the tumors, including two with NRAS and one with BRAF mutation, demonstrated PTEN missense mutations or loss of PTEN mRNA expression. Taken together, our data suggest activating mutations in NRAS or BRAF as a molecular alteration that contributes to aberrant Ras signaling in a small fraction of glioblastomas.     

Association study of <Emphasis Type="Italic">interleukin 2</Emphasis> (<Emphasis Type="Italic">IL2</Emphasis>) and <Emphasis Type="Italic">IL4</Emphasis> with schizophrenia in a Japanese population

Interleukin 2 (IL-2) and IL-4 are pleiotropic cytokines regulating Th1/Th2 balance and have a regulatory activity in brain function. Thus these cytokines have been implicated in the pathophysiology of schizophrenia. The latest studies provided controversial results regarding the genetic associations of these cytokines. The functional polymorphisms, IL2-330T/G and IL4-590C/T, were associated with schizophrenia in a German population, although contradictory findings were also reported in a Korean population. To ascertain whether IL2 and IL4 contribute to vulnerability to schizophrenia, we conducted a moderate-scale case-control (536 patients and 510 controls) association study for seven polymorphisms in Japanese subjects. There were no significant associations of these genes with schizophrenia using either single marker or haplotype analyses. The present study suggests that IL2 and IL4 do not contribute to vulnerability to schizophrenia in the Japanese population.     

Sequence analysis of <Emphasis Type="Italic">Drd2</Emphasis>, <Emphasis Type="Italic">Drd4</Emphasis>, and <Emphasis Type="Italic">Dat1</Emphasis> in SHR and WKY rat strains

Background  

The Spontaneously Hypertensive Rat (SHR) shows a number of behaviours that closely parallel those seen in children with attention-deficit hyperactivity disorder. These include motor hyperactivity, excessive responses under a fixed-interval/extinction schedule, difficulty in acquiring operant tasks and increased sensitivity to immediate behavioural reinforcement. As in children with ADHD, the behavioural and cognitive deficits in the SHR are responsive to stimulants, including d-amphetamine and d,l-methylphenidate. The non-hyperactive Wistar Kyoto (WKY) rat strain is often used as a control in behavioural studies of the SHR, and WKY itself has been suggested to be a useful animal model of depression. Numerous studies have shown that dopaminergic neurotransmission is altered between the two strains. Human genetic studies have found associations between several dopaminergic genes and both ADHD and depression.     

<Emphasis Type="Italic">c</Emphasis><Emphasis Type="Italic">-MYC</Emphasis> amplification and expression in astrocytic tumors

Point mutations and genomic multiplications in the α-synuclein (αSYN) gene cause autosomal-dominant Parkinson’s disease. Moreover, αSYN fibrils are the major component of Lewy bodies, the neuropathological hallmarks of Parkinson’s disease and dementia with Lewy bodies as well as of glial cytoplasmic inclusions in multiple system atrophy. These diseases are collectively referred to as α-synucleinopathies. Cellular mechanisms regulating αSYN fibril formation and toxicity are intensely studied in vitro, and in cell culture and diverse animal models. Specific neuropathology was achieved in transgenic mouse models using several promoters to express human wild-type and mutant αSYN in brain regions affected by the various α-synucleinopathies. Somatodendritic accumulation of the transgenic αSYN with neuritic distortions was a common finding. The nigrostriatal dopaminergic projections were surprisingly resistant to α-synucleinopathy in transgenic mice, although they tended to be more vulnerable to neurotoxins. In a few mouse models, αSYN aggregated in an age-dependent manner into genuine fibrillar amyloid. Brain region selective αSYN neuropathology correlated with specific behavioral impairments, such as locomotor dysfunction and cognitive decline. Thus, the αSYN fibrillization process is tightly linked to neuropathology. The role and thus therapeutic potential of post-translational modifications (ubiquitinylation, oxidation, phosphorylation, truncation) and modifier genes on αSYN neuropathology can now be assessed in valid transgenic mouse models of α-synucleinopathies.     

Association of <Emphasis Type="Italic">CILP</Emphasis>, <Emphasis Type="Italic">COL9A2</Emphasis> and <Emphasis Type="Italic">MMP3</Emphasis> Gene Polymorphisms with Lumbar Disc Degeneration in an Indian Population

Lumbar disc degeneration (LDD) is a multifactorial disorder caused by genetic and environmental factors. Polymorphisms in several structural and inflammatory genes like collagens, aggrecan, matrix metalloproteinases are associated with the risk of disc degeneration. In this study, we analyzed the role of a few important single nucleotide polymorphisms in cartilage intermediate layer protein (CILP), collagen 9A2 (COL9A2) and matrix metalloproteinase 3 (MMP3) genes in LDD from an Indian population. Two hundred patients with LDD and 200 healthy controls were recruited for the study. Genotyping was performed by allelic discrimination assay. The rs2073711 polymorphism (CILP gene - GG genotype) was associated with reduced risk of LDD in the Indian population (OR?=?0.43, p?=?0.016). The rs591058 polymorphism (MMP3 gene - TT genotype) is found to be associated with lower risk among women (OR?=?0.34, p?=?0.041). No significant association was found between COL9A2 polymorphism rs7533552 and the risk of LDD. We conclude that the CILP gene polymorphism (rs2073711) is associated with a lower risk of LDD, the MMP3 (rs591058) gene polymorphism is associated with LDD among women, and the TT genotype confers a lower risk of LDD.     

<Emphasis Type="Italic">Clostridium septicum</Emphasis> Pneumocephalus

Background

Spontaneous pneumocephalus in the nontraumatic setting is distinctly unusual. Pneumocephalus from central nervous system infection with Clostridium septicum has been rarely reported, and more commonly reflects a later stage of abscess formation. We present an unusual case of invasive C. septicum infection without an associated diagnosed malignancy presenting with rapidly progressive CNS pathology and resultant early pneumocephalus.

Methods

Medical records, radiologic imaging, and microbiological specimens of a case were reviewed.

Results

A 66-year-old male presented with a history of two witnessed generalized tonic–clonic seizures on awakening. He was found unresponsive at the scene by paramedics and subsequently intubated. There was no reported antecedent symptomatology, such as headache, fever, chills, focal weakness, and speech or gait disturbances. Medical history was remarkable only for diet-controlled hypertension. Computed tomography (CT) head imaging revealed an abnormal right parietal hypodensity. The patient was evaluated per the acute stroke protocol but was not deemed a candidate for intervention or thrombolytic therapy given the uncertainty of his clinical presentation; intravenous antibiotics were administered for possible sepsis. Follow-up CT imaging of the head performed 8 h later revealed right parieto-temporal pneumocephalus with extensive cerebral edema and effacement of basilar cisterns. Neurosurgical intervention was not deemed appropriate given the catastrophic nature of his injury and the patient subsequently expired 14 h after presentation. Blood cultures grew gram-positive rods in three of four bottles identified as C. septicum.

Conclusions

Clostridium septicum is an uncommon and often fatal cause of nontraumatic pneumocephalus. This underscores the need for a high index of clinical suspicion in cases with unexplained pneumocephalus, as early diagnosis remains the key to survival. In survivors of C. septicum infection, subsequent colonoscopy should be considered to exclude undiagnosed or occult gastrointestinal malignancy.

     

<Emphasis Type="Italic">CIC</Emphasis> and <Emphasis Type="Italic">FUBP1</Emphasis> mutations in oligodendrogliomas,oligoastrocytomas and astrocytomas

CIC and FUBP1 mutations have recently been detected in oligodendrogliomas but not in oligoastrocytomas. However, allelic losses in the regions on chromosomal arms 19q and 1p harboring CIC and FUBP1 are a common feature of both, oligodendrogliomas and oligoastrocytomas. To resolve this discrepancy, we analyzed CIC and FUBP1 mutations in a set of primary brain tumors including 18 oligodendrogliomas and 42 oligoastrocytomas. In addition, we analyzed 10 astrocytomas and 16 glioblastomas with allelic losses on 19q as well as a set of 12 medulloblastomas for CIC mutations. CIC mutations were found in 15/18 oligodendrogliomas, 14/42 oligoastrocytomas and 3/10 preselected astrocytomas. With the exception of a single case, all CIC mutations occurred in tumors with combined 1p/19q losses. In contrast to oligodendrogliomas where CIC mutations were always detected along with 1p/19q co-deletion, CIC mutations were only found in 52 % of the 1p/19q co-deleted oligoastrocytomas. FUBP1 mutations were detected in 7/61 tumors, all presenting with CIC mutations. FUBP1 mutations appear to cluster in the DNA binding domain spanning exons 5–14. CIC and FUBP1 mutations exclusively occurred in presence of either IDH1 or IDH2 mutations. Our data confirm CIC and FUBP1 mutations in oligodendrogliomas and demonstrate the presence of these mutations in oligoastrocytomas.     

Significant association of the <Emphasis Type="Italic">arylalkylamine N-acetyltransferase</Emphasis> (<Emphasis Type="Italic">AA-NAT</Emphasis>) gene with delayed sleep phase syndrome

Arylalkylamine N-acetyltransferase (AA-NAT) is a rate-limiting enzyme in melatonin hormone synthesis and participates in daily oscillations of the melatonin level. We studied the association between the AA-NAT gene and delayed sleep phase syndrome (DSPS). Results indicate that there is a significant difference in allele positivity at the single nucleotide polymorphism involved in an amino acid substitution from alanine to threonine at position 129 between patients with DSPS and healthy controls. The frequency of the 129 threonine allele is significantly higher in the patients than in the controls (P=0.0029). The data suggest that AA-NAT could be a susceptibility gene for DSPS. Electronic Publication     

Association study of polymorphisms in synaptic vesicle-associated genes, <Emphasis Type="Italic">SYN2</Emphasis> and <Emphasis Type="Italic">CPLX2</Emphasis>, with schizophrenia

Background  

The occurrence of aberrant functional connectivity in the neuronal circuit is one of the integrative theories of the etiology of schizophrenia. Previous studies have reported that the protein and mRNA levels of the synapsin 2 (SYN2) and complexin 2 (CPLX2) genes were decreased in patients with schizophrenia. Synapsin 2 and complexin 2 are involved in synaptogenesis and the modulation of neurotransmitter release. This report presents a study of the association of polymorphisms of SYN2 and CPLX2 with schizophrenia in the Korean population.     

Regulation of the immediate-early genes <Emphasis Type="Italic">arc</Emphasis> and <Emphasis Type="Italic">zif268</Emphasis> in a mouse operant model of cocaine seeking reinstatement

Reinstatement of extinguished operant responding for drug is an appropriate model of relapse to drug abuse. Due to the difficulty of implementing in mice the procedure of instrumental intravenous self-administration, mechanisms of reinstatement have so far been studied almost exclusively in rats. A mouse model of reinstatement of cocaine seeking has recently been characterized (Soria et al. 2008). The aim of the present study was to assess regional brain activation, as measured by induction of the immediate early genes (IEG) arc and zif268, during priming- or cue-elicited reinstatement of cocaine seeking using this new mouse model and the in situ hybridization technique. We have demonstrated that cue-elicited reinstatement of cocaine seeking was associated with induction of the IEG in the medial prefrontal cortex (prelimbic and infralimbic) and basolateral amygdala. Priming-induced reinstatement produced a more widespread up-regulation of those genes in forebrain regions including medial prefrontal, orbitofrontal and motor cortex, dorsal striatum and basolateral amygdala. These patterns of IEG expression are in agreement with previous results obtained in rats and thus indicate that the new mouse model of reinstatement is functionally equivalent to rat models. That comparability adds to the usefulness of the mouse model as a tool for addressing neurobiological mechanisms of addiction.     

Expression Analysis of <Emphasis Type="Italic">CYFIP1</Emphasis> and <Emphasis Type="Italic">CAMKK2</Emphasis> Genes in the Blood of Epileptic and Schizophrenic Patients

Schizophrenia and epilepsy are two prevalent neurological disorders with high global burden to the society. Genome-wide studies have identified potential underlying causes for these neurological diseases. In the present case-control study, we have assessed expression of CYFIP1 and CAMKK2 genes in the blood samples of epileptic and schizophrenic patients compared with healthy subjects. A total of 180 subjects including 40 epileptic patients, 50 schizophrenic patients, and 90 healthy individuals participated in the study. Expression of the mentioned genes was measured using TaqMan real-time PCR. The results demonstrated a significant upregulation of CYFIP1 gene expression in epileptic patients (P?=?0.029). CAMKK2 was downregulated in female schizophrenic patients compared with female healthy individuals (P?=?0.048). These results may provide new insight into the pathogenesis of epilepsy and schizophrenia and suggest these genes as potential therapeutic targets for these neurological disorders. Future studies should evaluate these results in larger cohorts of patients.     

Variations in <Emphasis Type="Italic">Disrupted</Emphasis>-<Emphasis Type="Italic">in</Emphasis>-<Emphasis Type="Italic">Schizophrenia 1</Emphasis> gene modulate long-term longitudinal differences in cortical thickness in patients with a first-episode of psychosis

Schizophrenia patients typically present a widespread bilateral cortical thinning from the early stages of the illness. However, there is controversy whether this reduction in cortical thickness (CT) is static or progressive over the evolution of the disorder. Disrupted-in-Schizophrenia 1 (DISC1) is one of the main candidates genes for schizophrenia, as it has been found associated to the illness, and to several endophenotypes of the disorder including structural brain differences. This gene is known to be involved in neurodevelopment and brain maturation processes. We therefore hypothesized that variations in this gene modulate different progressions of CT in psychosis. Seventy-nine Caucasian drug-naive patients experiencing a first episode of non-affective psychosis were genotyped for rs6675281 (Leu607Phe) and rs821616 (Ser704Cys) SNPs of the DISC1 gene. Brain MRIs were carried out at baseline and 3 years after initiating the treatment. Other clinical and socio-demographic variables were recorded to rule out possible confounding effects. Patients homozygous for the Leu allele of the rs6675281 SNP had a significant (p?<?0.05) descend in CT over the 3-years period, while those carrying the Phe allele presented an increase in CT. When combining the two SNPs we found a synergic effect on CT progression, presenting those patients homozygous for Leu607 +Ser704 a more pronounced cortical thinning. In conclusion, DISC1 gene variations may modulate the longitudinal changes in cortical thickness in patients suffering from a first episode of non-affective psychosis.     

Update Anti-<Emphasis Type="Italic">N</Emphasis>-Methyl-<Emphasis Type="Italic">D</Emphasis>-Aspartat-Rezeptor-Enzephalitis

Autoimmune encephalitis is a group of autoimmune inflammatory disorders affecting both grey and white matter of the central nervous system. Encephalitis with autoantibodies against the N?methyl-D-aspartate receptor (NMDA-R) is the most frequent autoimmune encephalitis syndrome presenting with a characteristic sequence of psychiatric and neurological symptoms. Treatment necessitates a close interdisciplinary cooperation. This article provides an update on the current knowledge on diagnostic standards, pathogenesis, and treatment strategies for anti-NMDA-R encephalitis from psychiatric and neurological perspectives.     

The complete mitochondrial genomes of two globally invasive ants,the Argentine ant <Emphasis Type="Italic">Linepithema</Emphasis><Emphasis Type="Italic">humile</Emphasis> and the little fire ant <Emphasis Type="Italic">Wasmannia auropunctata</Emphasis>

Ants are among the most widespread and damaging of invasive alien species. Here, we report the complete mitochondrial genomes for two globally invasive ants: the Argentine ant Linepithema humile and the little fire ant Wasmannia auropunctata. The circular genomes of L. humile and W. auropunctata are 15,929 and 16,362 bp in length, respectively, and encode the same typical set of 37 mitochondrial genes (i.e. 13 PCGs, 22 tRNAs and two rRNAs) and one control region. The mitochondrial genome of W. auropunctata harbors a unique gene arrangement (‘rrnS-trnV-CR-trnM-trnI-trnQ-nad2-trnW-trnC-trnY’; the underlines indicate inverted genes) between rrnL and cox1. Phylogenetic analysis largely corroborated the traditional taxonomy, except for L. humile which was found to be more related to those taxa of the subfamilies Formicinae and Myrmicinae than to the consubfamilial Leptomyrmex pallens. Our genomic data can be readily used for genetic assays of these two globally invasive ants.     

Two four-marker haplotypes on 7q36.1 region indicate that the potassium channel gene <Emphasis Type="Italic">HERG1</Emphasis> (<Emphasis Type="Italic">KCNH2</Emphasis>, <Emphasis Type="Italic">Kv11.1</Emphasis>) is related to schizophrenia: a case control study

Background  

The pathobiology of schizophrenia is still unclear. Its current treatment mainly depends on antipsychotic drugs. A leading adverse effect of these medications is the acquired long QT syndrome, which results from the blockade of cardiac HERG1 channels (human ether-a-go-go-related gene potassium channels 1) by antipsychotic agents. The HERG1 channel is encoded by HERG1 (KCNH2, Kv11.1) gene and is most highly expressed in heart and brain. Genetic variations in HERG1 predispose to acquired long QT syndrome. We hypothesized that the blockade of HERG1 channels by antipsychotics might also be significant for their therapeutic mode of action, indicating a novel mechanism in the pathogenesis of schizophrenia.