Erratum to: Childs Nerv Syst DOI 10.1007/s00381-015-2940-y. Unfortunately, one of the authors' name was misspelled in the original publication of this article. Instead of Micheal Söderman, it should ...have been Michael Söderman.
Abstract Herpes simplex encephalitis (HSE) in children is a potentially devastating condition which is occasionally complicated by a clinical relapse. An autoimmune component has long been suspected ...in these relapses and recent findings suggest that antibodies against N-methyl- d -aspartate receptors (NMDARs) may be part of this mechanism. We here report an 11 months old girl with acute HSE and with negative NMDAR antibody serology at presentation who after an initial response to antiviral treatment deteriorated with seizures, abnormal movements, focal neurologic deficits and psychiatric symptoms. We show that this relapse occurred as production of NMDAR antibodies developed and that clinical improvement followed immunotherapy with a concomitant decrease in NMDAR antibody titers in CSF. She also developed a characteristic 15–20 Hz activity over both hemispheres which has been previously described as an electroencephalographic presentation of anti-NMDAR encephalitis. We conclude that relapse or persisting symptoms in HSE in children may represent an immune-mediated mechanism rather than a viral reactivation and that NMDAR antibodies should be analyzed as this may be of importance for the choice of therapy.
Dopamine-containing neurons originating in the ventral tegmental area project primarily to the nucleus accumbens and the prefrontal cortex, forming the mesolimbic and mesocortical systems, ...respectively. Virtually every drug of abuse influences dopamine-mediated neurotransmission by affecting directly or indirectly the activity of these cells. Amphetamine and cocaine, in addition to opioids and nicotine, induce short- and long-term modifications of firing in the dopamine-containing neurons of the ventral mesencephalon. Although exposure to psychostimulants mainly depresses neuronal activity, nicotine and morphine enhance neuronal activity. However, under particular conditions, these drugs could cause different changes of firing. In this article, we propose that changes in the activity of dopamine-containing neurons are related to the processes of addiction. Therefore, we suggest that both the modulation of dopamine release in the extracellular space and transient or enduring changes in the firing of dopamine-containing neurons could be associated with important features of drugs of abuse.
Several studies have indicated that broad genomic characterization of childhood cancer provides diagnostically and/or therapeutically relevant information in selected high-risk cases. However, the ...extent to which such characterization offers clinically actionable data in a prospective broadly inclusive setting remains largely unexplored.
We implemented prospective whole-genome sequencing (WGS) of tumor and germline, complemented by whole-transcriptome sequencing (RNA-Seq) for all children diagnosed with a primary or relapsed solid malignancy in Sweden. Multidisciplinary molecular tumor boards were set up to integrate genomic data in the clinical decision process along with a medicolegal framework enabling secondary use of sequencing data for research purposes.
During the study's first 14 months, 118 solid tumors from 117 patients were subjected to WGS, with complementary RNA-Seq for fusion gene detection in 52 tumors. There was no significant geographic bias in patient enrollment, and the included tumor types reflected the annual national incidence of pediatric solid tumor types. Of the 112 tumors with somatic mutations, 106 (95%) exhibited alterations with a clear clinical correlation. In 46 of 118 tumors (39%), sequencing only corroborated histopathological diagnoses, while in 59 cases (50%), it contributed to additional subclassification or detection of prognostic markers. Potential treatment targets were found in 31 patients (26%), most commonly
mutations/fusions (n = 4), RAS/RAF/MEK/ERK pathway mutations (n = 14),
mutations/fusions (n = 5),
mutations (n = 2), and
gene fusions (n = 2). In one patient, the tumor diagnosis was revised based on sequencing. Clinically relevant germline variants were detected in 8 of 94 patients (8.5%).
Up-front, large-scale genomic characterization of pediatric solid malignancies provides diagnostically valuable data in the majority of patients also in a largely unselected cohort.
Background. AT/RTs are rare aggressive brain tumours, mainly affecting young children. Most cases present with genetic inactivation of SMARCB1, a core member of the SWI/SNF chromatin-remodeling ...complex. We have performed whole exome- and mRNA-sequencing on an early onset AT/RT case for detection of genetic events potentially contributing to the disease. Results. A de novo germline variant in SMARCB1, c.601C>T p.Arg201∗, in combination with somatic deletion of the healthy allele is likely the major tumour causing event. Only seven somatic small scale mutations were discovered (hitting SEPT03, H2BFM, ZIC4, HIST2H2AB, ZIK1, KRTAP6-3, and IFNA8). All were found with subclonal allele frequencies (range 5.7–17%) and none were expressed. However, besides SMARCB1, candidate genes affected by predicted damaging germline variants that were expressed were detected (KDM5C, NUMA1, and PCM1). Analysis of differently expressed genes revealed many dysregulated pathways in the tumour, such as cell cycle, CXCR4 pathway, GPCR-signalling, and neuronal system. FGFR1, CXCR4, and MDK were upregulated and may represent possible drug targets. Conclusion. The loss of SMARCB1 function leads to AT/RT development and deregulated genes and pathways. Additional predisposing events may however contribute. Studies utilizing NGS technologies in larger cohorts will probably identify recurrent genetic and epigenetic alterations and molecular subgroups with implications for clinical practice and development of targeted therapies.
Dopamine (DA) neurones of the ventral mesencephalon are involved in the control of reward related behaviour, cognitive functions and motor performances, and provide a critical site of action for ...major categories of neuropsychiatric drugs, such as antipsychotic agents, dependence producing drugs and anti-Parkinson medication. The midbrain DA neurones are mainly located in the substantia nigra pars compacta (SNPC) and the ventral tegmental area (VTA). Intrinsic membrane properties regulate the activity of these neurones. In fact, they possess several conductances that allow them to fire in a slow pacemaker-like mode. The internal set of membrane currents interact with afferent synaptic inputs which, especially in in vivo conditions, contribute to accelerate or decelerate the firing activity of the cells in accordance with the necessity to optimise the release of dopamine in the terminal fields. In particular, discrete excitatory and inhibitory inputs transform the firing from a low regular into a bursting pattern. The bursting activity promotes dopamine release being very important in cognition and motor performances. In the present paper we review electrophysiological data regarding the role of glutamatergic and cholinergic and GABAergic afferent inputs in regulating the midbrain DAergic neuronal activity.
Patch pipettes were used to record whole-cell synaptic currents under voltage-clamp in dopaminergic neurons in slices of rat substantia nigra pars compacta and ventral tegmental area. We report that ...dihydropyridines (DHPs), L-type Ca2+ channel antagonists, depressed a slow EPSC (EPSCslow) evoked by a train of focally delivered electrical stimuli. In fact, the amplitude of the EPSCslow was reduced by the DHP antagonists nifedipine (1-100 microM), nimodipine (1-100 microM), and isradipine (30 nM-100 microM) in a concentration-dependent and reversible manner. On the other hand, Bay-K 8644 (1 microM), an L-type Ca2+ channel agonist, increased the EPSCslow. The DHPs depressed the EPSCslow only when the high-frequency stimulation that was used to evoke this synaptic current lasted >70 msec. On the other hand, Bay-K 8644 increased the amplitude of the EPSCslow only when it was evoked by a train <70 msec. Moreover, the DHPs did not affect the EPSCfast, the IPSCfast, and the IPSCslow. The inhibition of the EPSCslow caused by the DHPs is attributed to presynaptic mechanisms because (1) the inward current generated by exogenously administered glutamate was not affected and (2) the EPSCslow was reduced to a similar degree even when the activation state of postsynaptic L-type Ca2+ channels was changed by holding the neurons at -100, -60, and +30 mV. Finally, a DHP-sensitive component of the EPSCslow could even be detected after the blockade of N-, Q-, and P-type Ca2+ channels by the combination of omega-conotoxin GVIA, omega-agatoxin IVA, and omega-conotoxin MVIIC. Taken together, these results indicate that under certain patterns of synaptic activity, L-type Ca2+ channels regulate the synaptic release of excitatory amino acids on the dopaminergic neurons of the ventral mesencephalon.
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