UW Neurological Surgery Recent PubMed Publications

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]

Dental caries and bacterial load in saliva and dental biofilm of type 1 diabetics on continuous subcutaneous insulin infusion.

J Appl Oral Sci. 2018 Jun 11;26:e20170500

Authors: Coelho A, Paula A, Mota M, Laranjo M, Abrantes M, Carrilho F, Ferreira M, Silva M, Botelho F, Carrilho E

Abstract
OBJECTIVES: Since most of the studies evaluates diabetics on multiple daily injections therapy and continuous subcutaneous insulin infusion may help gain better metabolic control and prevent complications, the objective of this study was to evaluate the prevalence of dental caries, the unstimulated salivary flow rate and the total bacteria load, Streptococcus spp. levels and Lactobacillus spp. levels in saliva and supragingival dental biofilm of type 1 diabetics on insulin pump.
MATERIAL AND METHODS: Sixty patients with type 1 diabetes on insulin pump and 60 nondiabetic individuals were included. The dental caries evaluation was performed using ICDAS and the oral hygiene was assessed according to Greene and Vermillion Simplified Oral Hygiene Index. Unstimulated saliva and supragingival dental biofilm were collected. Total bacteria, Streptococcus spp. and Lactobacillus spp. was quantified by qPCR.
RESULTS: Patients with type 1 diabetes had a higher prevalence of dental caries and filled and missing teeth when compared with the control group. These patients were associated with more risk factors for the development of dental caries, namely a lower unstimulated salivary flow rate and a higher bacterial load in saliva and dental biofilm.
CONCLUSION: Some risk factors related to dental caries were associated with type 1 diabetics. An early diagnosis combined with the evaluation of the risk profile of the diabetic patient is imperative, allowing the dental caries to be analyzed through a perspective of prevention and the patient to be integrated into an individualized oral health program.

PMID: 29898180 [PubMed - indexed for MEDLINE]

Effects of Acute Exposure of Permethrin in Adult and Developing Sprague-Dawley Rats on Acoustic Startle Response and Brain and Plasma Concentrations.

Toxicol Sci. 2018 10 01;165(2):361-371

Authors: Williams MT, Gutierrez A, Vorhees CV

Abstract
Permethrin is a type I (noncyano) pyrethroid that induces tremors at high concentrations and increases acoustic startle responses (ASRs) in adult rodents, however its effects in young rats have been investigated to a limited extent. ASR and tremor were assessed in adult and postnatal day (P)15 Sprague-Dawley rats at oral doses of 60, 90, or 120 mg/kg over an 8 h period. Permethrin increased ASR in adults, regardless of dose, and 20% of the high-dose rats showed tremor at later time points. For the P15 rats all doses induced tremor at all time points, and ASR was increased at 2 h in the 90 and 120 mg/kg groups with a trend in the 60 mg/kg group compared with controls. The 60 mg/kg group showed increased ASR at 4 and 6 h, whereas the 90 mg/kg group showed no differences from the controls at these times. The 120 mg/kg group showed decreased ASR from 4- to 8-h posttreatment. P15 and adult rats both showed plasma and brain cis- and trans-permethrin increases after dosing. After the same dose of permethrin, P15 rats had greater cis- and trans-permethrin in brain and plasma compared with adults. P15 rats had an increased tremor response compared with adults even at comparable brain permethrin concentrations. For ASR, P15 rats responded sooner and showed a biphasic pattern ranging from increased to decreased response as a function of dose and time, unlike adults that only showed increases. Overall, young rats showed greater effects from permethrin compared with adults.

PMID: 29893952 [PubMed - indexed for MEDLINE]

Updating a 2-class attributes sampling plan to account for changes in laboratory methods.

Int J Food Microbiol. 2018 Oct 03;282:24-27

Authors: Williams MS, Ebel ED, Golden NJ

Abstract
Advances in microbiological testing methods have led to faster and less expensive assays. Given these advances, it is logical to employ these assays for use in the sampling plan of an existing microbiological criterion. A change in the performance characteristics of the assay can affect the intended effect of the microbiological criterion. This study describes a method for updating a 2-class attributes sampling plan to account for the different test sensitivity and specificity of a new assay and provides an example based on the replacement of a culture-based assay with a real-time polymerase chain reaction assay.

PMID: 29885974 [PubMed - indexed for MEDLINE]

α2δ-4 Is Required for the Molecular and Structural Organization of Rod and Cone Photoreceptor Synapses.

J Neurosci. 2018 07 04;38(27):6145-6160

Authors: Kerov V, Laird JG, Joiner ML, Knecht S, Soh D, Hagen J, Gardner SH, Gutierrez W, Yoshimatsu T, Bhattarai S, Puthussery T, Artemyev NO, Drack AV, Wong RO, Baker SA, Lee A

Abstract
α2δ-4 is an auxiliary subunit of voltage-gated Cav1.4 L-type channels that regulate the development and mature exocytotic function of the photoreceptor ribbon synapse. In humans, mutations in the CACNA2D4 gene encoding α2δ-4 cause heterogeneous forms of vision impairment in humans, the underlying pathogenic mechanisms of which remain unclear. To investigate the retinal function of α2δ-4, we used genome editing to generate an α2δ-4 knock-out (α2δ-4 KO) mouse. In male and female α2δ-4 KO mice, rod spherules lack ribbons and other synaptic hallmarks early in development. Although the molecular organization of cone synapses is less affected than rod synapses, horizontal and cone bipolar processes extend abnormally in the outer nuclear layer in α2δ-4 KO retina. In reconstructions of α2δ-4 KO cone pedicles by serial block face scanning electron microscopy, ribbons appear normal, except that less than one-third show the expected triadic organization of processes at ribbon sites. The severity of the synaptic defects in α2δ-4 KO mice correlates with a progressive loss of Cav1.4 channels, first in terminals of rods and later cones. Despite the absence of b-waves in electroretinograms, visually guided behavior is evident in α2δ-4 KO mice and better under photopic than scotopic conditions. We conclude that α2δ-4 plays an essential role in maintaining the structural and functional integrity of rod and cone synapses, the disruption of which may contribute to visual impairment in humans with CACNA2D4 mutations.SIGNIFICANCE STATEMENT In the retina, visual information is first communicated by the synapse formed between photoreceptors and second-order neurons. The mechanisms that regulate the structural integrity of this synapse are poorly understood. Here we demonstrate a role for α2δ-4, a subunit of voltage-gated Ca2+ channels, in organizing the structure and function of photoreceptor synapses. We find that presynaptic Ca2+ channels are progressively lost and that rod and cone synapses are disrupted in mice that lack α2δ-4. Our results suggest that alterations in presynaptic Ca2+ signaling and photoreceptor synapse structure may contribute to vision impairment in humans with mutations in the CACNA2D4 gene encoding α2δ-4.

PMID: 29875267 [PubMed - indexed for MEDLINE]

Transcutaneous Electrical Spinal Stimulation Promotes Long-Term Recovery of Upper Extremity Function in Chronic Tetraplegia.

IEEE Trans Neural Syst Rehabil Eng. 2018 06;26(6):1272-1278

Authors: Inanici F, Samejima S, Gad P, Edgerton VR, Hofstetter CP, Moritz CT

Abstract
Upper extremity function is the highest priority of tetraplegics for improving quality of life. We aim to determine the therapeutic potential of transcutaneous electrical spinal cord stimulation for restoration of upper extremity function. We tested the hypothesis that cervical stimulation can facilitate neuroplasticity that results in long-lasting improvement in motor control. A 62-year-old male with C3, incomplete, chronic spinal cord injury (SCI) participated in the study. The intervention comprised three alternating periods: 1) transcutaneous spinal stimulation combined with physical therapy (PT); 2) identical PT only; and 3) a brief combination of stimulation and PT once again. Following four weeks of combined stimulation and physical therapy training, all of the following outcome measurements improved: the Graded Redefined Assessment of Strength, Sensation, and Prehension test score increased 52 points and upper extremity motor score improved 10 points. Pinch strength increased 2- to 7-fold in left and right hands, respectively. Sensation recovered on trunk dermatomes, and overall neurologic level of injury improved from C3 to C4. Most notably, functional gains persisted for over 3 month follow-up without further treatment. These data suggest that noninvasive electrical stimulation of spinal networks can promote neuroplasticity and long-term recovery following SCI.

PMID: 29877852 [PubMed - indexed for MEDLINE]

A model of blood-ammonia homeostasis based on a quantitative analysis of nitrogen metabolism in the multiple organs involved in the production, catabolism, and excretion of ammonia in humans.

Clin Exp Gastroenterol. 2018;11:193-215

Authors: Levitt DG, Levitt MD

Abstract
Increased blood ammonia (NH3) is an important causative factor in hepatic encephalopathy, and clinical treatment of hepatic encephalopathy is focused on lowering NH3. Ammonia is a central element in intraorgan nitrogen (N) transport, and modeling the factors that determine blood-NH3 concentration is complicated by the need to account for a variety of reactions carried out in multiple organs. This review presents a detailed quantitative analysis of the major factors determining blood-NH3 homeostasis - the N metabolism of urea, NH3, and amino acids by the liver, gastrointestinal system, muscle, kidney, and brain - with the ultimate goal of creating a model that allows for prediction of blood-NH3 concentration. Although enormous amounts of NH3 are produced during normal liver amino-acid metabolism, this NH3 is completely captured by the urea cycle and does not contribute to blood NH3. While some systemic NH3 derives from renal and muscle metabolism, the primary site of blood-NH3 production is the gastrointestinal tract, as evidenced by portal vein-NH3 concentrations that are about three times that of systemic blood. Three mechanisms, in order of quantitative importance, release NH3 in the gut: 1) hydrolysis of urea by bacterial urease, 2) bacterial protein deamination, and 3) intestinal mucosal glutamine metabolism. Although the colon is conventionally assumed to be the major site of gut-NH3 production, evidence is reviewed that indicates that the stomach (via Helicobacter pylori metabolism) and small intestine and may be of greater importance. In healthy subjects, most of this gut NH3 is removed by the liver before reaching the systemic circulation. Using a quantitative model, loss of this "first-pass metabolism" due to portal collateral circulation can account for the hyperammonemia observed in chronic liver disease, and there is usually no need to implicate hepatocyte malfunction. In contrast, in acute hepatic necrosis, hyperammonemia results from damaged hepatocytes. Although muscle-NH3 uptake is normally negligible, it can become important in severe hyperammonemia. The NH3-lowering actions of intestinal antibiotics (rifaximin) and lactulose are discussed in detail, with particular emphasis on the seeming lack of importance of the frequently emphasized acidifying action of lactulose in the colon.

PMID: 29872332 [PubMed]

Accuracy of Inferred APOE Genotypes for a Range of Genotyping Arrays and Imputation Reference Panels.

J Alzheimers Dis. 2018;64(1):49-54

Authors: Lupton MK, Medland SE, Gordon SD, Goncalves T, MacGregor S, Mackey DA, Young TL, Duffy DL, Visscher PM, Wray NR, Nyholt DR, Bain L, Ferreira MA, Henders AK, Wallace L, Montgomery GW, Wright MJ, Martin NG

Abstract
Cohort studies investigating aging and dementia require APOE genotyping. We compared directly measured APOE genotypes to 'hard-call' genotypes derived from imputing genome-wide genotyping data from a range of platforms using several imputation panels. Older GWAS arrays imputed to 1000 Genomes Project (1KGP) phases and the Haplotype Reference Consortium (HRC) reference panels were able to achieve concordance rates of over 98% with stringent quality control (hard-call-threshold 0.8). However, this resulted in high levels of missingness (>12% with 1KGP and 5% with HRC). With recent GWAS arrays, concordance of 99% could be obtained with relatively lenient QC, resulting in no missingness.

PMID: 29865051 [PubMed - indexed for MEDLINE]