Longitudinal Assessment of Cortical Excitability in Children and Adolescents With Mild Traumatic Brain Injury and Persistent Post-concussive Symptoms

Introduction: Symptoms following a mild traumatic brain injury (mTBI) usually resolve quickly but may persist past 3 months in up to 15% of children. Mechanisms of mTBI recovery are poorly understood, but may involve alterations in cortical neurophysiology. Transcranial Magnetic Stimulation (TMS) can non-invasively investigate such mechanisms, but the time course of neurophysiological changes in mTBI are unknown.Objective/Hypothesis: To determine the relationship between persistent post-concussive symptoms (PPCS) and altered motor cortex neurophysiology over time.Methods: This was a prospective, longitudinal, controlled cohort study comparing children (8–18 years) with mTBI (symptomatic vs. asymptomatic) groups to controls. Cortical excitability was measured using TMS paradigms at 1 and 2 months post injury. The primary outcome was the cortical silent period (cSP). Secondary outcomes included short interval intracortical inhibition (SICI) and facilitation (SICF), and long-interval cortical inhibition (LICI). Generalized linear mixed model analyses were used to evaluate the effect of group and time on neurophysiological parameters.Results: One hundred seven participants (median age 15.1, 57% female) including 78 (73%) with symptomatic PPCS and 29 with asymptomatic mTBI, were compared to 26 controls. Cortical inhibition (cSP and SICI) was reduced in the symptomatic group compared to asymptomatic group and tended to increase over time. Measures of cortical facilitation (SICF and ICF) were increased in the asymptomatic group and decreased over time. TMS was well tolerated with no serious adverse events.Conclusions: TMS-assessed cortical excitability is altered in children following mild TBI and is dependent on recovery trajectory. Our findings support delayed return to contact sports in children even where clinical symptoms have resolved

The genetic landscape of high-risk neuroblastoma

Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%1. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 cases using a combination of whole exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.60 per megabase (0.48 non-silent), and remarkably few recurrently mutated genes in these tumors. Genes with significant somatic mutation frequencies included ALK (9.2% of cases), PTPN11 (2.9%), ATRX (2.5%, an additional 7.1% had focal deletions), MYCN (1.7%, a recurrent p.Pro44Leu alteration), and NRAS (0.83%). Rare, potentially pathogenic germline variants were significantly enriched in ALK, CHEK2, PINK1, and BARD1. The relative paucity of recurrent somatic mutations in neuroblastoma challenges current therapeutic strategies reliant upon frequently altered oncogenic drivers

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

Longitudinal Assessment of Cortical Excitability in Children and Adolescents With Mild Traumatic Brain Injury and Persistent Post-concussive Symptoms

Introduction: Symptoms following a mild traumatic brain injury (mTBI) usually resolve quickly but may persist past 3 months in up to 15% of children. Mechanisms of mTBI recovery are poorly understood, but may involve alterations in cortical neurophysiology. Transcranial Magnetic Stimulation (TMS) can non-invasively investigate such mechanisms, but the time course of neurophysiological changes in mTBI are unknown.Objective/Hypothesis: To determine the relationship between persistent post-concussive symptoms (PPCS) and altered motor cortex neurophysiology over time.Methods: This was a prospective, longitudinal, controlled cohort study comparing children (8-18 years) with mTBI (symptomatic vs. asymptomatic) groups to controls. Cortical excitability was measured using TMS paradigms at 1 and 2 months post injury. The primary outcome was the cortical silent period (cSP). Secondary outcomes included short interval intracortical inhibition (SICI) and facilitation (SICF), and long-interval cortical inhibition (UCI). Generalized linear mixed model analyses were used to evaluate the effect of group and time on neurophysiological parameters.Results: One hundred seven participants (median age 15.1, 57% female) including 78 (73%) with symptomatic PPCS and 29 with asymptomatic mTBI, were compared to 26 controls. Cortical inhibition (cSP and SICI) was reduced in the symptomatic group compared to asymptomatic group and tended to increase over time. Measures of cortical facilitation (SICF and ICF) were increased in the asymptomatic group and decreased over time. TMS was well tolerated with no serious adverse events.Conclusions: TMS-assessed cortical excitability is altered in children following mild TBI and is dependent on recovery trajectory. Our findings support delayed return to contact sports in children even where clinical symptoms have resolved

Occipital Nerve Blocks for Pediatric Posttraumatic Headache: A Case Series

Posttraumatic headache is one of the most common and disabling symptoms after traumatic brain injury. However, evidence for treating posttraumatic headache is sparse, especially in the pediatric literature. This retrospective chart review evaluated the use of occipital nerve blocks in adolescents treated for posttraumatic headache following mild traumatic brain injury, presenting to the Complex Concussion and Traumatic Brain Injury clinic. Fifteen patients (mean age 15.47; range: 13-17) received occipital nerve block for posttraumatic headache. Follow-up was obtained in 14 patients at 5.57 (standard deviation = 3.52) months postinjury. The headache burden was high, with all except one having headaches 15 or more days per month (median 30, range 10-30). Sixty-four percent reported long-term response to the occipital nerve blocks, with associated improved quality of life and decreased postconcussion symptom scores (P < .05). One patient reported transient allopecia. Occipital nerve blocks are well tolerated and can be helpful in posttraumatic headache

Cortical excitability after pediatric mild traumatic brain injury

Introduction Mild traumatic brain injury (mTBI) outcomes are variable, and 10–15% may suffer from prolonged symptoms beyond 3 months that impair the child's return to normal activities. Neurophysiological mechanisms of mTBI are incompletely understood, particularly in children, but alterations in cortical excitability have been proposed to underlie post-concussion syndrome. Improved understanding is required to advance interventions and improve outcomes. Objective/Hypothesis To determine if cortical excitability is altered in children with mTBI, and its association with clinical symptoms. Methods This was a cross-sectional controlled cohort study. School-aged children (8–18 years) with mTBI were compared to healthy controls. Cortical excitability was measured using multiple TMS paradigms in children with (symptomatic) and without (recovered) persistent symptoms one-month post-injury. Primary outcome was the cortical silent period (cSP), a potential neurophysiological biomarker of GABAergic inhibition. Secondary outcomes included additional TMS neurophysiology, safety and tolerability. Associations between neurophysiology parameters and clinical symptoms were evaluated. Results Fifty-three children with mTBI (55% male; mean age 14.1 SD: 2.4 years; 35 symptomatic and 27 asymptomatic participants) and 28 controls (46% male; mean age 14.3 SD: 3.1 years) were enrolled. cSP duration was similar between groups (F (2, 73)\ua0=\ua00.55, p\ua0=\ua00.582). Log long interval intracortical inhibition (LICI) was reduced in symptomatic participants compared to healthy controls (F (2, 59)\ua0=\ua03.83, p\ua0=\ua00.027). Procedures were well tolerated with no serious adverse events. Conclusions TMS measures of cortical excitability are altered at one month in children with mTBI. Long interval cortical inhibition is decreased in children who remain symptomatic at one month post-injury

A double-blind, placebo-controlled intervention trial of 3 and 10 mg sublingual melatonin for post-concussion syndrome in youths (PLAYGAME): study protocol for a randomized controlled trial

Abstract Background By the age of sixteen, one in five children will sustain a mild traumatic brain injury also known as concussion. Our research found that one in seven school children with mild traumatic brain injury suffer post-concussion syndrome symptoms for three months or longer. Post-concussion syndrome is associated with significant disability in the child and his/her family and yet there are no evidence-based medical treatments available. Melatonin has several potential mechanisms of action that could be useful following mild traumatic brain injury, including neuroprotective effects. The aim of this study is to determine if treatment with melatonin improves post-concussion syndrome in youths following mild traumatic brain injury. Our hypothesis is that treatment of post-concussion syndrome following mild traumatic brain injury with 3 or 10 mg of sublingual melatonin for 28 days will result in a decrease in post-concussion syndrome symptoms compared with placebo. Methods/Design Ninety-nine youths with mild traumatic brain injury, aged between 13 and 18 years, who are symptomatic at 30 days post-injury will be recruited. This study will be conducted as a randomized, double blind, placebo-controlled superiority trial of melatonin. Three parallel treatment groups will be examined with a 1:1:1 allocation: sublingual melatonin 3 mg, sublingual melatonin 10 mg, and sublingual placebo. Participants will receive treatment for 28 days. The primary outcome is a change on the Post-Concussion Symptom Inventory (Parent and Youth). The secondary outcomes will include neurobehavioral function, health-related quality of life and sleep. Neurophysiological and structural markers of change, using magnetic resonance imaging techniques and transcranial magnetic stimulation, will also be investigated. Discussion Melatonin is a safe and well-tolerated agent that has many biological properties that may be useful following a traumatic brain injury. This study will determine whether it is a useful treatment for children with post-concussion syndrome. Recruitment commenced on 4 December 2014. Trial registration This trial was registered on 6 June 2013 at ClinicalTrials.gov. Registration number: NCT01874847

Cerebrale Angiographie bei meningealer Sarkomatose und Karzinomatose

The angiographic findings in a case of metastatic meningeal carcinomatosis and a case of primary meningeal sarcomatosis are presented. The presence of focal arterial narrowing at the base of the brain and/or over the cerebral convexities, with or without a communicating hydrocephalus, may be the important clues to a diagnosis of diffuse meningeal involvement by tumor. In a patient who presents with bizarre and poorly localizing signs and symptoms, when the cerebrospinal fluid analysis does not fully support a diagnosis of meningitis or subarachnoid hemorrhage, and when there is nothing in the history to suggest drug abuse or a systemic collagen disease, the angiographic findings may point to an unexpected diffuse meningeal tumor. Les auteurs rapportent les données angiographiques dans lun cas de carcinomatose méningée métastatique et dans un cas de sarcomatose méningée primitive. La présence de sténoses artérielles localisées à la base du cerveau et/ou au niveau des convexités cérébrales avec ou sans hydrocéphalie communicante peuvent représenter des signes importants en faveur d'un envahissement tumoral méningé diffus. Chez un malade présentant une symptomatologie atypique et mal localisée, lorsque l'examen du liquide céphalo-rachidien ne parle pas franchement en faveur d'une méningite ou d'une hémorragie méningée et lorsque l'anamnèse n'évoque aucune intoxication exogène ni collagénose, les données angiographiques peuvent faire découvrir une tumeur méningée diffuse. In der vorliegenden Arbeit werden die angiographischen Befunde eines Falles einer metastatischen meningealen Karzinomatose und eines Falles einer primären meningealen Sarkomatose geschildert. Dabei läßt sich besonders die umschriebene arterielle Gefäßeinengung an der Basis des Gehirns und/oder über den Konvexitäten beobachten. Dieser Befund kann mit einem Hydrocephalus communicans kombiniert sein. Wenn bei einem Patienten merkwürdige und schlecht lokalisierbare neurologische Symptome vorliegen, wenn durch die Liquoruntersuchung die Diagnose einer Meningitis oder einer Subarachnoidalblutung nicht gesichert werden kann und wenn bei dem Patienten auch kein Drogen-Abusus besteht, ist bei den beschriebenen angiographischen Veränderungen an eine diffuse meningeale Tumorabsiedlung zu denken.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46669/1/234_2004_Article_BF00341592.pd

Ent3p and Ent5p Exhibit Cargo-specific Functions in Trafficking Proteins between the Trans-Golgi Network and the Endosomes in Yeast

The phosphoinositide-binding proteins Ent3p and Ent5p are required for protein transport from the trans-Golgi network (TGN) to the vacuole in Saccharomyces cerevisiae. Both proteins interact with the monomeric clathrin adaptor Gga2p, but Ent5p also interacts with the clathrin adaptor protein 1 (AP-1) complex, which facilitates retention of proteins such as Chs3p at the TGN. When both ENT3 and ENT5 are mutated, Chs3p is diverted from an intracellular reservoir to the cell surface. However, Ent3p and Ent5p are not required for the function of AP-1, but rather they seem to act in parallel with AP-1 to retain proteins such as Chs3p at the TGN. They have all the properties of clathrin adaptors, because they can both bind to clathrin and to cargo proteins. Like AP-1, Ent5p binds to Chs3p, whereas Ent3p facilitates the interaction between Gga2p and the endosomal syntaxin Pep12p. Thus, Ent3p has an additional function in Gga-dependent transport to the late endosome. Ent3p also facilitates the association between Gga2p and clathrin; however, Ent5p can partially substitute for this function. We conclude that the clathrin adaptors AP-1, Ent3p, Ent5p, and the Ggas cooperate in different ways to sort proteins between the TGN and the endosomes