Medulloblastoma is a malignant childhood cerebellar tumour comprised of distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. We used single-cell transcriptomics to investigate intra-and inter-tumoural heterogeneity in twenty-five medulloblastomas spanning all molecular subgroups. WNT, SHH, and Group 3 tumours comprised subgroup-specific undifferentiated and differentiated neuronallike malignant populations, whereas Group 4 tumours were exclusively comprised of differentiated neuronal-like neoplastic cells. SHH tumours closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumours exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, whose relative proportions distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide novel insights into the cellular and developmental states underlying subtypespecific medulloblastoma biology. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

OBJECT The object of this study was to identify and quantify predictors of burnout and career satisfaction among US neurosurgeons. METHODS All US members (3247) of the American Association of Neurological Surgeons (AANS) were invited to participate in a survey between September and December 2012. Responses were evaluated through univariate analysis. Factors independently associated with burnout and career satisfaction were determined using multivariable logistic regression. Subgroup analysis of academic and nonacademic neurosurgeons was performed as well. RESULTS The survey response rate was 24% (783 members). The majority of respondents were male, 40–60 years old, in a stable relationship, with children, working in a group or university practice, and trained in a subspecialty. More than 80% of respondents reported being at least somewhat satisfied with their career, and 70% would choose a career in neurosurgery again; however, only 26% of neurosurgeons believed their professional lives would improve in the future, and 52% believed it would worsen. The overall burnout rate was 56.7%. Factors independently associated with both burnout and career satisfaction included achieving a balance between work and life outside the hospital (burnout OR 0.45, satisfaction OR 10.0) and anxiety over future earnings and/or health care reform (burnout OR 1.96, satisfaction OR 0.32). While the burnout rate for nonacademic neurosurgeons (62.9%) was higher than that for academic neurosurgeons (47.7%), academicians who had practiced for over 20 years were less likely to be satisfied with their careers. CONCLUSIONS The rates of burnout and career satisfaction were both high in this survey study of US neurosurgeons. The negative effects of burnout on the lives of surgeons, patients, and their families require further study and probably necessitate the development of interventional programs at local, regional, and even national levels.

A single GAG deletion in Exon 5 of the TOR1A gene is associated with a form of early-onset primary dystonia showing less than 40% penetrance. To provide a framework for cellular and systems study of DYT1 dystonia, we characterized the genetic, behavioral, morphological and neurochemical features of transgenic mice expressing either human wild-type torsinA (hWT) or mutant torsinA (hMT1 and hMT2) and their wild-type (WT) littermates. Relative to human brain, hMT1 mice showed robust neural expression of human torsinA transcript (3.90X). In comparison with WT littermates, hMT1 mice had prolonged traversal times on both square and round raised-beam tasks and more slips on the round raised-beam task. Although there were no effects of genotype on rotarod performance and rope climbing, hMT1 mice exhibited increased hind-base widths in comparison to WT and hWT mice. In contrast to several other mouse models of DYT1 dystonia, we were unable to identify either torsinA-and ubiquitin-positive cytoplasmic inclusion bodies or nuclear bleb formation in hMT1 mice. High-performance liquid chromatography with electrochemical detection was used to determine cerebral cortical, striatal, and cerebellar levels of dopamine (DA), norepinephrine, epinephrine, serotonin, 3, 4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid. Although there were no differences in striatal DA levels between WT and hMT1 mice, DOPAC and HVA concentrations and DA turnover (DOPAC/DA and HVA/DA) were significantly higher in the mutants. Our findings in DYT1 transgenic mice are compatible with previous neuroimaging and postmortem neurochemical studies of human DYT1 dystonia. Increased striatal dopamine turnover in hMT1 mice suggests that the nigrostriatal pathway may be a site of functional neuropathology in DYT1 dystonia.

Object Surgical site infection (SSI) is a serious and costly complication of spinal surgery. There have been several conflicting reports on the use of intrawound vancomycin powder in decreasing SSI in spine surgery. The purpose of this study is to answer the question: “Does intrawound vancomycin powder reduce the rate of SSIs in spine surgery?” Methods A comprehensive search of multiple electronic databases and bibliographies was conducted to identify clinical studies that evaluated the rates of SSI with and without the use of intrawound vancomycin powder in spine surgery. Independent reviewers extracted data and graded the quality of each paper that met inclusion criteria. A random effects meta-analysis was then performed. Results The search identified 9 retrospective cohort studies (Level III evidence) and 1 randomized controlled trial (Level II evidence). There were 2574 cases and 106 infections in the control group (4.1%) and 2518 cases and 33 infections (1.3%) in the treatment group, yielding a pooled absolute risk reduction and relative risk reduction of 2.8% and 68%, respectively. The meta-analysis revealed the use of vancomycin powder to be protective in preventing SSI (relative risk = 0.34, 95% confidence interval 0.17–0.66, p = 0.021). The number needed to treat to prevent 1 SSI was 36. A subgroup analysis found that patients who had implants had a reduced risk of SSI with vancomycin powder (p = 0.023), compared with those who had noninstrumented spinal operations (p = 0.226). Conclusions This meta-analysis suggests that the use of vancomycin powder may be protective against SSI in open spinal surgery; however, the exact population in which it should be used is not clear. This benefit may be most appreciated in higher-risk populations or in facilities with a high baseline rate of infection.

Several members of the tetrahydroisoquinoline (TIQ) family of monoamine alkaloids can be formed from dopamine or its oxidized metabolites and may be involved in the pathogenesis of monoaminergic cell death in Parkinson's disease (PD). Using enantiomeric-selective high-performance liquid chromatography with electrochemical detection and liquid chromatography with tandem mass spectroscopy, the regional concentrations of several TIQ derivatives, including salsolinols, were determined in mouse, rat, normal human, and PD brain. TIQ derivatives were detected in all regions subjected to analysis. In general, salsolinols were present at higher concentrations than TIQ and its benzyl and methyl derivatives, especially in human brain. Moreover, salsolinols were concentrated in areas with increased dopamine synthesis and turnover such as the ventral midbrain and striatum, respectively. A possible consequence of nigrostriatal dopaminergic cell death, significantly lower levels of (R)salsolinol, (S)salsolinol, N-methyl-(R)salsolinol and N-methyl-(S)salsolinol were found in the caudate nuclei of PD in comparison with normal human brain. Our data support the hypothesis of endogenous synthesis of salsolinols and provide evidence for their accumulation in catecholaminergic neurons. Keywords: N-methyl-salsolinol, Parkinson's disease, salsolinol, substantia nigra pars compacta, tetrahydroisoquinoline. Bayerle 1934;Cohen and Collins 1970). Other derivatives can then be generated from SAL via the addition and/or subtraction of methyl groups via transferases . As a result, SAL and a number of its derivatives have been detected in brain tissue (Sjöquist et al. 1982a,b;Musshoff et al. 1999Musshoff et al. , 2000Musshoff et al. , 2003Musshoff et al. , 2005 Tóth et al. 2001;Naoi et al. 2002Naoi et al. , 2004. In addition to endogenous synthesis, TIQ derivatives may also derive from exogenous sources. For example, TIQ and many of its derivatives are natural substances in plants (Rommelspacher and Susilo 1985) and have been detected in certain foods and beverages consumed by humans Duncan and Smythe 1982;Duncan et al. 1984;Makino et al. 1988;Niwa et al. 1989;Collins et al. 1990). Several TIQ derivates have also demonstrated blood-brain permeability (Makino et al. 1988;Thumen et al. 2002;Song et al. 2006). These results, taken together, suggest that, in conjunction with endogenous synthesis, environmental sources may contribute to accumulation of TIQ derivatives in the nervous system.To elucidate the potential role of TIQ neurotoxins in the pathogenesis of idiopathic PD, the tissue concentration of these compounds must be rigorously characterized. Brain distribution studies of TIQ derivatives to date have been largely incomplete, focusing on only a few regions of the brain in a single species and/or involving only a subset of TIQ derivatives, often ignoring enantiomeric considerations. Moreover, stability of TIQ derivatives has been neglected, raising concerns about the validity of previous experimental studies and questions regardin...

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Childhood neurodevelopmental disorders like Angelman syndrome and autism may be the result of underlying defects in neuronal plasticity and ongoing problems with synaptic signaling. Some of these defects may be due to abnormal monoamine levels in different regions of the brain. Ube3a, a gene that causes Angelman syndrome (AS) when maternally deleted and is associated with autism when maternally duplicated has recently been shown to regulate monoamine synthesis in the Drosophila brain. Therefore, we examined monoamine levels in striatum, ventral midbrain, frontal cerebral cortex, cerebellar cortex and hippocampus in Ube3a deficient and Ube3a duplication animals. We found that serotonin (5HT), a monoamine affected in autism, was elevated in the striatum and cortex of AS mice. Dopamine levels were almost uniformly elevated compared to control littermates in the striatum, midbrain and frontal cortex regardless of genotype in Ube3a deficient and Ube3a duplication animals. In the duplication 15q autism mouse model, paternal but not maternal duplication animals showed a decrease in 5HT levels when compared to their wild type littermates, in accordance with previously published data. However, maternal duplication animals show no significant changes in 5HT levels throughout the brain. These abnormal monoamine levels could be responsible for many of the behavioral abnormalities observed in both AS and autism, but further investigation is required to determine if any of these changes are purely dependent on Ube3a levels in the brain.