UW Neurological Surgery Recent PubMed Publications

A De Novo Mouse Model of C11orf95-RELA Fusion-Driven Ependymoma Identifies Driver Functions in Addition to NF-κB.

Cell Rep. 2018 06 26;23(13):3787-3797

Authors: Ozawa T, Arora S, Szulzewsky F, Juric-Sekhar G, Miyajima Y, Bolouri H, Yasui Y, Barber J, Kupp R, Dalton J, Jones TS, Nakada M, Kumabe T, Ellison DW, Gilbertson RJ, Holland EC

Abstract
The majority of supratentorial ependymomas (ST-ependymomas) have few mutations but frequently display chromothripsis of chromosome 11q that generates a fusion between C11orf95 and RELA (RELAFUS). Neural stem cells transduced with RELAFUSex vivo form ependymomas when implanted in the brain. These tumors display enhanced NF-κB signaling, suggesting that this aberrant signal is the principal mechanism of oncogenesis. However, it is not known whether RELAFUS is sufficient to drive de novo ependymoma tumorigenesis in the brain and, if so, whether these tumors also arise from neural stem cells. We show that RELAFUS drives ST-ependymoma formation from periventricular neural stem cells in mice and that RELAFUS-induced tumorigenesis is likely dependent on a series of cell signaling pathways in addition to NF-κB.

PMID: 29949764 [PubMed - indexed for MEDLINE]

Identification and characterization of two novel alternatively spliced E2F1 transcripts in the rat CNS.

Mol Cell Neurosci. 2018 10;92:1-11

Authors: Jackson DP, Ting JH, Pozniak PD, Meurice C, Schleidt SS, Dao A, Lee AH, Klinman E, Jordan-Sciutto KL

Abstract
E2F1 is a transcription factor classically known to regulate G0/G1 to S phase progression in the cell cycle. In addition, E2F1 also regulates a wide range of apoptotic genes and thus has been well studied in the context of neuronal death and neurodegenerative diseases. However, its function and regulation in the mature central nervous system are not well understood. Alternative splicing is a well-conserved post-transcriptional mechanism common in cells of the CNS and is necessary to generate diverse functional modifications to RNA or protein products from genes. Heretofore, physiologically significant alternatively spliced E2F1 transcripts have not been reported. In the present study, we report the identification of two novel alternatively spliced E2F1 transcripts: E2F1b, an E2F1 transcript retaining intron 5, and E2F1c, an E2F1 transcript excluding exon 6. These alternatively spliced transcripts are observed in the brain and neural cell types including neurons, astrocytes, and undifferentiated oligodendrocytes. The expression of these E2F1 transcripts is distinct during maturation of primary hippocampal neuroglial cells. Pharmacologically-induced global translation inhibition with cycloheximide, anisomycin or thapsigargin lead to significantly reduced expression of E2F1a, E2F1b and E2F1c. Conversely, increasing neuronal activity by elevating the concentration of potassium chloride selectively increased the expression of E2F1b. Furthermore, experiments expressing these variants in vitro show the transcripts can be translated to generate a protein product. Taken together, our data suggest that the alternatively spliced E2F1 transcript behave differently than the E2F1a transcript, and our results provide a foundation for future investigation of the function of E2F1 splice variants in the CNS.

PMID: 29936143 [PubMed - indexed for MEDLINE]

Angiographic perfusion imaging of intracranial stenting.

J Clin Neurosci. 2018 Feb;48:100-102

Authors: Ene CI, Morton RP, Kelly CM, Levitt MR, Ghodke B

Abstract
Two-dimensional angiographic perfusion imaging (2DAP) is a new technique permitting perfusion imaging during angiography, and has been used to study cerebral vasospasm. Here we report our experience with this technique following angioplasty and stent placement in a patient with symptomatic and medically refractory stenosis of the right supraclinoid internal carotid artery. We found that intraprocedural angiographic perfusion imaging provided real-time and objective evidence of improved cerebral perfusion during intervention. Following treatment, the patient remains symptom-free at last follow-up.

PMID: 29183679 [PubMed - indexed for MEDLINE]

HBsAg mRNA degradation induced by a dihydroquinolizinone compound depends on the HBV posttranscriptional regulatory element.

Antiviral Res. 2018 01;149:191-201

Authors: Zhou T, Block T, Liu F, Kondratowicz AS, Sun L, Rawat S, Branson J, Guo F, Steuer HM, Liang H, Bailey L, Moore C, Wang X, Cuconatti A, Gao M, Lee ACH, Harasym T, Chiu T, Gotchev D, Dorsey B, Rijnbrand R, Sofia MJ

Abstract
In pursuit of novel therapeutics targeting the hepatitis B virus (HBV) infection, we evaluated a dihydroquinolizinone compound (DHQ-1) that in the nanomolar range reduced the production of virion and surface protein (HBsAg) in tissue culture. This compound also showed broad HBV genotype coverage, but was inactive against a panel of DNA and RNA viruses of other species. Oral administration of DHQ-1 in the AAV-HBV mouse model resulted in a significant reduction of serum HBsAg as soon as 4 days following the commencement of treatment. Reduction of HBV markers in both in vitro and in vivo experiments was related to the reduced amount of viral RNA including pre-genomic RNA (pgRNA) and 2.4/2.1 kb HBsAg mRNA. Nuclear run-on and subcellular fractionation experiments indicated that DHQ-1 mediated HBV RNA reduction was the result of accelerated viral RNA degradation in the nucleus, rather than the consequence of inhibition of transcription initiation. Through mutagenesis of HBsAg gene sequences, we found induction of HBsAg mRNA decay by DHQ-1 required the presence of the HBV posttranscriptional regulatory element (HPRE), with a 109 nucleotides sequence within the central region of the HPRE alpha sub-element being the most critical. Taken together, the current study shows that a small molecule can reduce the overall levels of HBV RNA, especially the HBsAg mRNA, and viral surface proteins. This may shed light on the development of a new class of HBV therapeutics.

PMID: 29133129 [PubMed - indexed for MEDLINE]

Expanding the role of stent-retriever endovascular thrombectomy: a case series of free-floating thrombus.

J Neurointerv Surg. 2018 Jun 20;:

Authors: Fitzpatrick N, Motyer R, Gibney B, Duffy S, Murphy S, O'Brien P, Ryan D, Thornton J

Abstract
Carotid artery free-floating thrombus (FFT) is a rare but clinically significant cause of embolic stroke. Treatment has historically been confined to carotid surgery or best medical therapy, with neither option proved to be superior. However, recent advancements in endovascular interventions have heralded a new age of innovative management strategies for vascular disease. We present three distinct cases of stroke secondary to carotid artery FFT, successfully treated with stent retriever endovascular thrombectomy.

PMID: 29925544 [PubMed - as supplied by publisher]

Reagent Validation to Facilitate Experimental Reproducibility.

Curr Protoc Pharmacol. 2018 06;81(1):e40

Authors: Williams M

Abstract
Many results reported in the biomedical research literature cannot be independently reproduced, undermining the basic foundations of science. This overview is intended for researchers who are committed to improving the quality and integrity of biomedical science by raising awareness of both the sources of irreproducibility, and activities specifically targeted to address the issue. The irreproducibility of biomedical research is due to a variety of factors, known and unknown, that markedly influence experimental outcomes. Among the known factors are inadequate training or mentoring, or experimenter incompetence. These may result in flawed experimental design and execution that reflect a lack of planning, leading to an underpowering of a study, an absence of appropriate controls, selective data analysis, inappropriate statistical analysis, and/or investigator bias or fraud. Another frequently overlooked source of irreproducibility is failure to ensure that the equipment used is performing up to manufacturer specifications. Failure to validate/authenticate the experimental reagents is another source of irreproducibility. These include compounds, cell lines, antibodies, and the animal models used in a study. This overview discusses how a lack of validation of research reagents negatively impact experimental reproducibility, and provides guidelines to avoid these pitfalls. © 2018 by John Wiley & Sons, Inc.

PMID: 29927084 [PubMed - indexed for MEDLINE]

Ten years of genome-wide association studies of immune-related diseases.

Clin Transl Immunology. 2018;7(6):e1022

Authors: Ferreira MA

PMID: 29928503 [PubMed]

Consensus statement on concussion in sport-the 5th international conference on concussion in sport held in Berlin, October 2016.

Br J Sports Med. 2017 Jun;51(11):838-847

Authors: McCrory P, Meeuwisse W, Dvořák J, Aubry M, Bailes J, Broglio S, Cantu RC, Cassidy D, Echemendia RJ, Castellani RJ, Davis GA, Ellenbogen R, Emery C, Engebretsen L, Feddermann-Demont N, Giza CC, Guskiewicz KM, Herring S, Iverson GL, Johnston KM, Kissick J, Kutcher J, Leddy JJ, Maddocks D, Makdissi M, Manley GT, McCrea M, Meehan WP, Nagahiro S, Patricios J, Putukian M, Schneider KJ, Sills A, Tator CH, Turner M, Vos PE

PMID: 28446457 [PubMed - indexed for MEDLINE]

Neuropathological and transcriptomic characteristics of the aged brain.

Elife. 2017 Nov 09;6:

Authors: Miller JA, Guillozet-Bongaarts A, Gibbons LE, Postupna N, Renz A, Beller AE, Sunkin SM, Ng L, Rose SE, Smith KA, Szafer A, Barber C, Bertagnolli D, Bickley K, Brouner K, Caldejon S, Chapin M, Chua ML, Coleman NM, Cudaback E, Cuhaciyan C, Dalley RA, Dee N, Desta T, Dolbeare TA, Dotson NI, Fisher M, Gaudreault N, Gee G, Gilbert TL, Goldy J, Griffin F, Habel C, Haradon Z, Hejazinia N, Hellstern LL, Horvath S, Howard K, Howard R, Johal J, Jorstad NL, Josephsen SR, Kuan CL, Lai F, Lee E, Lee F, Lemon T, Li X, Marshall DA, Melchor J, Mukherjee S, Nyhus J, Pendergraft J, Potekhina L, Rha EY, Rice S, Rosen D, Sapru A, Schantz A, Shen E, Sherfield E, Shi S, Sodt AJ, Thatra N, Tieu M, Wilson AM, Montine TJ, Larson EB, Bernard A, Crane PK, Ellenbogen RG, Keene CD, Lein E

Abstract
As more people live longer, age-related neurodegenerative diseases are an increasingly important societal health issue. Treatments targeting specific pathologies such as amyloid beta in Alzheimer's disease (AD) have not led to effective treatments, and there is increasing evidence of a disconnect between traditional pathology and cognitive abilities with advancing age, indicative of individual variation in resilience to pathology. Here, we generated a comprehensive neuropathological, molecular, and transcriptomic characterization of hippocampus and two regions cortex in 107 aged donors (median = 90) from the Adult Changes in Thought (ACT) study as a freely-available resource (http://aging.brain-map.org/). We confirm established associations between AD pathology and dementia, albeit with increased, presumably aging-related variability, and identify sets of co-expressed genes correlated with pathological tau and inflammation markers. Finally, we demonstrate a relationship between dementia and RNA quality, and find common gene signatures, highlighting the importance of properly controlling for RNA quality when studying dementia.

PMID: 29120328 [PubMed - indexed for MEDLINE]

A genotype-specific surgical approach for patients with Pfeiffer syndrome due to W290C pathogenic variant in FGFR2 is associated with improved developmental outcomes and reduced mortality.

Genet Med. 2019 02;21(2):471-476

Authors: Wenger TL, Hopper RA, Rosen A, Tully HM, Cunningham ML, Lee A

Abstract
PURPOSE: Among children with FGFR2-associated Pfeiffer syndrome, those with the W290C pathogenic variant (PV) are reported to have the worst clinical outcomes. Mortality is high, and severe neurocognitive impairment has been reported in all surviving patients. However, it is unclear whether these poor outcomes are an unavoidable consequence of the PV itself, or could be improved with a genotype-specific treatment approach. The purpose of this report is to describe the more intensive surgical approach used for each of the three patients with W290C PV in FGFR2 at our center, all of whom survived and have normal neurocognitive functioning.
METHODS: Retrospective chart review.
RESULTS: In contrast to other patients with Pfeiffer syndrome at our center, all three patients who were subsequently found to have a W290C PV required a similar and more aggressive approach based on early cephalocranial disproportion. In contrast to previously reported W290C cases, each of our three patients survived and demonstrate normal neurocognitive functioning.
CONCLUSION: While previously reported outcomes in W290C-associated Pfeiffer syndrome have been extremely poor, we present three patients who underwent an intensive surgical approach and have normal development. This suggests that a personalized and aggressive surgical approach for children with W290C PV may dramatically improve clinical outcome.

PMID: 29915381 [PubMed - indexed for MEDLINE]

Scoping systematic review on the extent, nature and quality of evidence underlying ophthalmic and paraophthalmic education.

Evid Based Med. 2017 Mar;22(1):23-26

Authors: Williams M, Boohan M, Thurston A

Abstract
BACKGROUND: Effective education of relevant professionals underpins provision of quality eye healthcare.
OBJECTIVES: This scoping systematic review had 2 aims: first to investigate the extent and nature of scholarly output published on ophthalmic and paraophthalmic education, and second to focus on the quality of reporting of randomised controlled trials (RCTs) identified.
STUDY SELECTION: A search strategy was created and applied to PubMed. Any scholarly publications on any aspect of education of those involved in the care of patients with visual problems as the main theme or context was selected. Predefined data were extracted.
FINDINGS: Of 255 studies included, the most common type of scholarly publications were descriptions of an educational innovation, opinion pieces and descriptive studies. RCTs made up 5.5% of the sample. Most of the 14 RCTs failed to report most of the items recommended in the CONSORT guidelines.
CONCLUSIONS: This review highlights the need for investigators, ethical committees and journals to insist on a better quality of RCT conduct than is presently apparent, but also that clinicians should not be blind to the strengths of non-RCT-based studies in the field of education.

PMID: 27993941 [PubMed - indexed for MEDLINE]

Splice variants of the CaV1.3 L-type calcium channel regulate dendritic spine morphology.

Sci Rep. 2016 10 06;6:34528

Authors: Stanika R, Campiglio M, Pinggera A, Lee A, Striessnig J, Flucher BE, Obermair GJ

Abstract
Dendritic spines are the postsynaptic compartments of glutamatergic synapses in the brain. Their number and shape are subject to change in synaptic plasticity and neurological disorders including autism spectrum disorders and Parkinson's disease. The L-type calcium channel CaV1.3 constitutes an important calcium entry pathway implicated in the regulation of spine morphology. Here we investigated the importance of full-length CaV1.3L and two C-terminally truncated splice variants (CaV1.342A and CaV1.343S) and their modulation by densin-180 and shank1b for the morphology of dendritic spines of cultured hippocampal neurons. Live-cell immunofluorescence and super-resolution microscopy of epitope-tagged CaV1.3L revealed its localization at the base-, neck-, and head-region of dendritic spines. Expression of the short splice variants or deletion of the C-terminal PDZ-binding motif in CaV1.3L induced aberrant dendritic spine elongation. Similar morphological alterations were induced by co-expression of densin-180 or shank1b with CaV1.3L and correlated with increased CaV1.3 currents and dendritic calcium signals in transfected neurons. Together, our findings suggest a key role of CaV1.3 in regulating dendritic spine structure. Under physiological conditions it may contribute to the structural plasticity of glutamatergic synapses. Conversely, altered regulation of CaV1.3 channels may provide an important mechanism in the development of postsynaptic aberrations associated with neurodegenerative disorders.

PMID: 27708393 [PubMed - indexed for MEDLINE]

[Prevalence of Dental Caries in Patients with Type 1 Diabetes Mellitus Treated with Multiple Insulin Injections and that of Individuals without Diabetes].

Acta Med Port. 2017 May 31;30(5):402-408

Authors: Machado D, Coelho A, Paula A, Caramelo F, Carrilho F, Barros L, Batista C, Melo M, Ferreira MM, Carrilho E

Abstract
INTRODUCTION: In addition to macro and microvascular complications that are associated with the disease, hyperglycaemia is also a risk factor for several oral complications. The aim of this study is to establish a relationship between dental caries in patients with type 1 diabetes mellitus treated with multiple insulin injections and that of individuals without diabetes. It is also an aim to characterize the oral hygiene habits of this population.
MATERIAL AND METHODS: An observational clinical study of analytical and cross-sectional nature was conducted. Thirty patients with type 1 diabetes mellitus and 30 individuals without diabetes were observed and questioned about information regarding their medical history. Oral examination was conducted according to the standards of the World Health Organization and ICDAS was used for caries detection. Statistical analysis was performed and the significance level was set at 5%.
RESULTS: Patients with diabetes mellitus showed similar caries levels to that of individuals without diabetes. Patients with diabetes mellitus had a higher dental plaque index. Only 10% of the patients having episodes of nocturnal hypoglycaemia brush their teeth after glucose intake.
DISCUSSION: Although there's some controversy in the literature regarding the prevalence of caries in patients with diabetes mellitus, the results are in agreement with a great number of studies. However, patients with diabetes mellitus have a higher plaque index which can be associated with a higher risk for developing certain oral pathologies.
CONCLUSION: No statistically significant association was found between type 1 diabetes mellitus and dental caries.

PMID: 28865505 [PubMed - indexed for MEDLINE]

Contrast-enhanced ultrasound to visualize hemodynamic changes after rodent spinal cord injury.

J Neurosurg Spine. 2018 Sep;29(3):306-313

Authors: Khaing ZZ, Cates LN, DeWees DM, Hannah A, Mourad P, Bruce M, Hofstetter CP

Abstract
OBJECTIVE Traumatic spinal cord injury (tSCI) causes an almost complete loss of blood flow at the site of injury (primary injury) as well as significant hypoperfusion in the penumbra of the injury. Hypoperfusion in the penumbra progresses after injury to the spinal cord and is likely to be a major contributor to progressive cell death of spinal cord tissue that was initially viable (secondary injury). Neuroprotective treatment strategies seek to limit secondary injury. Clinical monitoring of the temporal and spatial patterns of blood flow within the contused spinal cord is currently not feasible. The purpose of the current study was to determine whether ultrafast contrast-enhanced ultrasound (CEUS) Doppler allows for detection of local hemodynamic changes within an injured rodent spinal cord in real time. METHODS A novel ultrafast CEUS Doppler technique was developed utilizing a research ultrasound platform combined with a 15-MHz linear array transducer. Ultrafast plane-wave acquisitions enabled the separation of higher-velocity blood flow in macrocirculation from low-velocity flow within the microcirculation (tissue perfusion). An FDA-approved contrast agent (microbubbles) was used for visualization of local blood flow in real time. CEUS Doppler acquisition protocols were developed to characterize tissue perfusion both during contrast inflow and during the steady-state plateau. A compression injury of the thoracic spinal cord of adult rats was induced using iris forceps. RESULTS High-frequency ultrasound enabled visualization of spinal cord vessels such as anterior spinal arteries as well as central arteries (mean diameter [± SEM] 145.8 ± 10.0 µm; 76.2 ± 4.5 µm, respectively). In the intact spinal cord, ultrafast CEUS Doppler confirmed higher perfusion of the gray matter compared to white matter. Immediately after compression injury of the thoracic rodent spinal cord, spinal cord vessels were disrupted in an area of 1.93 ± 1.14 mm2. Ultrafast CEUS Doppler revealed a topographical map of local tissue hypoperfusion with remarkable spatial resolution. Critical loss of perfusion, defined as less than 40% perfusion compared to the surrounding spared tissue, was seen within an area of 2.21 ± 0.6 mm2. CONCLUSIONS In our current report, we introduce ultrafast CEUS Doppler for monitoring of spinal vascular structure and function in real time. Development and clinical implementation of this type of imaging could have a significant impact on the care of patients with tSCI.

PMID: 29905521 [PubMed - indexed for MEDLINE]

Predictors of Recurrence, Progression, and Retreatment in Basilar Tip Aneurysms: A Location-Controlled Analysis.

Oper Neurosurg (Hagerstown). 2019 04 01;16(4):435-444

Authors: Abecassis IJ, Sen RD, Barber J, Shetty R, Kelly CM, Ghodke BV, Hallam DK, Levitt MR, Kim LJ, Sekhar LN

Abstract
BACKGROUND: Endovascular treatment of intracranial aneurysms is associated with higher rates of recurrence and retreatment, though contemporary rates and risk factors for basilar tip aneurysms (BTAs) are less well-described.
OBJECTIVE: To characterize progression, retreatement, and retreated progression of BTAs treated with microsurgical or endovascular interventions.
METHODS: We retrospectively reviewed records for 141 consecutive BTA patients. We included 158 anterior communicating artery (ACoA) and 118 middle cerebral artery (MCA) aneurysms as controls. Univariate and multivariate analyses were used to calculate rates of progression (recurrence of previously obliterated aneurysms and progression of known residual aneurysm dome or neck), retreatment, and retreated progression. Kaplan-Meier analysis was used to characterize 24-mo event rates for primary outcome prediction.
RESULTS: Of 141 BTA patients, 62.4% were ruptured and 37.6% were unruptured. Average radiographical follow-up was 33 mo. Among ruptured aneurysms treated with clipping, there were 2 rehemorrhages due to recurrence (6.1%), and none in any other cohorts. Overall rates of progression (28.9%), retreatment (28.9%), and retreated progression (24.7%) were not significantly different between surgical and endovascular subgroups, though ruptured aneurysms had higher event rates. Multivariate modeling confirmed rupture status (P = .003, hazard ratio = 0.14) and aneurysm dome width (P = .005, hazard ratio = 1.23) as independent predictors of progression requiring retreatment. In a separate multivariate analysis with ACoA and MCA aneurysms, basilar tip location was an independent predictor of progression, retreatment, and retreated progression.
CONCLUSION: BTAs have higher rates of progression and retreated progression than other aneurysm locations, independent of treatment modality. Rupture status and dome width are risk factors for progression requiring retreatment.

PMID: 29905850 [PubMed - indexed for MEDLINE]

The Relations of Cognitive, Behavioral, and Physical Activity Variables to Depression Severity in Traumatic Brain Injury: Reanalysis of Data From a Randomized Controlled Trial.

J Head Trauma Rehabil. 2017 Sep/Oct;32(5):343-353

Authors: Bombardier CH, Fann JR, Ludman EJ, Vannoy SD, Dyer JR, Barber JK, Temkin NR

Abstract
OBJECTIVE: To explore the relations of cognitive, behavioral, and physical activity variables to depression severity among people with traumatic brain injury (TBI) undergoing a depression treatment trial.
SETTING: Community.
PARTICIPANTS: Adults (N = 88) who sustained complicated mild to severe TBI within the past 10 years, met criteria for major depressive disorder, and completed study measures.
DESIGN: Randomized controlled trial.
METHODS: Participants were randomized to cognitive-behavioral therapy (n = 58) or usual care (n = 42). Outcomes were measured at baseline and 16 weeks. We combined the groups and used regressions to explore the relations among theoretical variables and depression outcomes.
MAIN MEASURES: Depression severity was measured with the Hamilton Depression Rating Scale and Symptom Checklist-20. Theory-based measures were the Dysfunctional Attitudes Scale (DAS), Automatic Thoughts Questionnaire (ATQ), Environmental Rewards Observation Scale (EROS), and the International Physical Activity Questionnaire (IPAQ).
RESULTS: Compared with non-TBI norms, baseline DAS and ATQ scores were high and EROS and IPAQ scores were low. All outcomes improved from baseline to 16 weeks except the DAS. The ATQ was an independent predictor of baseline depression. An increase in EROS scores was correlated with decreased depression.
CONCLUSIONS: Increasing participation in meaningful roles and pleasant activities may be a promising approach to treating depression after TBI.

PMID: 28195952 [PubMed - indexed for MEDLINE]

Anger Self-Management Training for Chronic Moderate to Severe Traumatic Brain Injury: Results of a Randomized Controlled Trial.

J Head Trauma Rehabil. 2017 Sep/Oct;32(5):319-331

Authors: Hart T, Brockway JA, Maiuro RD, Vaccaro M, Fann JR, Mellick D, Harrison-Felix C, Barber J, Temkin N

Abstract
OBJECTIVE: To test efficacy of 8-session, 1:1 treatment, anger self-management training (ASMT), for chronic moderate to severe traumatic brain injury (TBI).
SETTING: Three US outpatient treatment facilities.
PARTICIPANTS: Ninety people with TBI and elevated self-reported anger; 76 significant others (SOs) provided collateral data.
DESIGN: Multicenter randomized controlled trial with 2:1 randomization to ASMT or structurally equivalent comparison treatment, personal readjustment and education (PRE). Primary outcome assessment 1 week posttreatment; 8-week follow-up.
PRIMARY OUTCOME: Response to treatment defined as 1 or more standard deviation change in self-reported anger.
SECONDARY OUTCOMES: SO-rated anger, emotional and behavioral status, satisfaction with life, timing of treatment response, participant and SO-rated global change, and treatment satisfaction.
MAIN MEASURES: State-Trait Anger Expression Inventory-Revised Trait Anger (TA) and Anger Expression-Out (AX-O) subscales; Brief Anger-Aggression Questionnaire (BAAQ); Likert-type ratings of treatment satisfaction, global changes in anger and well-being.
RESULTS: After treatment, ASMT response rate (68%) exceeded that of PRE (47%) on TA but not AX-O or BAAQ; this finding persisted at 8-week follow-up. No significant between-group differences in SO-reported response rates, emotional/behavioral status, or life satisfaction. ASMT participants were more satisfied with treatment and rated global change in anger as significantly better; SO ratings of global change in both anger and well-being were superior for ASMT.
CONCLUSION: ASMT was efficacious and persistent for some aspects of problematic anger. More research is needed to determine optimal dose and essential ingredients of behavioral treatment for anger after TBI.

PMID: 28520666 [PubMed - indexed for MEDLINE]

Sertraline for Major Depression During the Year Following Traumatic Brain Injury: A Randomized Controlled Trial.

J Head Trauma Rehabil. 2017 Sep/Oct;32(5):332-342

Authors: Fann JR, Bombardier CH, Temkin N, Esselman P, Warms C, Barber J, Dikmen S

Abstract
OBJECTIVE: Major depressive disorder (MDD) is common and associated with impaired functioning after traumatic brain injury (TBI). Few placebo-controlled antidepressant trials exist in this population. We evaluated the efficacy and tolerability of sertraline for MDD within 1 year of sustaining a TBI.
SETTING: Level I trauma center.
PARTICIPANTS: Adults with MDD within 1 year of hospitalization for complicated mild to severe TBI.
DESIGN: Randomized, double-blind, placebo-controlled trial.
MAIN MEASURES: Twelve-week treatment response on the 17-item Hamilton Depression Rating Scale. We also assessed symptom improvement and remission.
RESULTS: We randomized 62 participants: 32% sustained a severe TBI, 68% had significant anxiety, 63% had a history of prior MDD, and 69% had a history of alcohol or drug dependence. Depression significantly improved from baseline to 12 weeks in both treatment groups (P < .001). There were no significant differences between the sertraline and placebo groups over 12 weeks on depression severity, response, or remission. The sertraline group had significant improvement on speed of information processing compared with the placebo group (P < .006).
CONCLUSION: Sertraline monotherapy was not superior to placebo for MDD in people with post-acute complicated mild to severe TBI. Research is needed on the effectiveness of interventions that also address the significant psychosocial needs of this population.

PMID: 28520672 [PubMed - indexed for MEDLINE]

Longitudinal Clinical and Neuroimaging Evaluation of Symptomatic Concussion in 10- to 14-year-old Youth Athletes.

J Neurotrauma. 2019 01 15;36(2):264-274

Authors: Mac Donald CL, Barber J, Wright J, Coppel D, De Lacy N, Ottinger S, Peck S, Panks C, Sun S, Zalewski K, Temkin N

Abstract
This study longitudinally assessed 10- to 14-year-old patients with sports and recreational concussion (n = 22) who remained symptomatic 3 to 4weeks post-injury compared with typically developing controls (n = 24). Examination by multi-modal magnetic resonance imaging (MRI) and multi-domain clinical outcome measures was completed at 1-month and 6-months post-injury. Concussion patients showed evidence of improvement by 6-month follow-up in domains of cognitive function, whereas measures of psychological health were less resolved with patients exhibiting sustained symptoms of depression, behavior impairment, and concussion symptoms. Quantitative neuroimaging measures identified measures indicative of chronic injury with regional reductions observed by both volumetric segmentation and white matter fractional anisotropy (FA) from diffusion tensor imaging (DTI). Volumetric reductions (p < 0.01) were observed in the middle anterior and posterior portions of the corpus callosum, and right caudal anterior cingulate cortex of patients, although none held after strict correction. Examination of the FA data identified significant reductions in the left middle frontal gyrus white matter (p = 0.0003). Linear regression analysis on the 6-month depression outcome variable using the initial clinical, demographic, and imaging measures identified the top predictive models to include concussion diagnosis, and initial symptoms of depression, concussion symptoms, and sleep impairment with additional contribution from other measures of mental health, behavior impairment, and quality of life depending on the model (adjusted r-squared = 0.69 indicating strong predictive ability). This study supports further inclusion of mental health rehabilitation and imaging supplementing traditional cognitive rehabilitation strategies employed in these young athletes.

PMID: 29901414 [PubMed - indexed for MEDLINE]

Unique function words characterize genomic proteins.

Proc Natl Acad Sci U S A. 2018 06 26;115(26):6703-6708

Authors: Scaiewicz A, Levitt M

Abstract
Between 2009 and 2016 the number of protein sequences from known species increased 10-fold from 8 million to 85 million. About 80% of these sequences contain at least one region recognized by the conserved domain architecture retrieval tool (CDART) as a sequence motif. Motifs provide clues to biological function but CDART often matches the same region of a protein by two or more profiles. Such synonyms complicate estimates of functional complexity. We do full-linkage clustering of redundant profiles by finding maximum disjoint cliques: Each cluster is replaced by a single representative profile to give what we term a unique function word (UFW). From 2009 to 2016, the number of sequence profiles used by CDART increased by 80%; the number of UFWs increased more slowly by 30%, indicating that the number of UFWs may be saturating. The number of sequences matched by a single UFW (sequences with single domain architectures) increased as slowly as the number of different words, whereas the number of sequences matched by a combination of two or more UFWs in sequences with multiple domain architectures (MDAs) increased at the same rate as the total number of sequences. This combinatorial arrangement of a limited number of UFWs in MDAs accounts for the genomic diversity of protein sequences. Although eukaryotes and prokaryotes use very similar sets of "words" or UFWs (57% shared), the "sentences" (MDAs) are different (1.3% shared).

PMID: 29895692 [PubMed - indexed for MEDLINE]