UW Neurological Surgery Recent PubMed Publications

Nanoparticles That Reshape the Tumor Milieu Create a Therapeutic Window for Effective T-cell Therapy in Solid Malignancies.

Cancer Res. 2018 07 01;78(13):3718-3730

Authors: Zhang F, Stephan SB, Ene CI, Smith TT, Holland EC, Stephan MT

Abstract
A major obstacle to the success rate of chimeric antigen receptor (CAR-) T-cell therapy against solid tumors is the microenvironment antagonistic to T cells that solid tumors create. Conventional checkpoint blockade can silence lymphocyte antisurvival pathways activated by tumors, but because they are systemic, these treatments disrupt immune homeostasis and induce autoimmune side effects. Thus, new technologies are required to remodel the tumor milieu without causing systemic toxicities. Here, we demonstrate that targeted nanocarriers that deliver a combination of immune-modulatory agents can remove protumor cell populations and simultaneously stimulate antitumor effector cells. We administered repeated infusions of lipid nanoparticles coated with the tumor-targeting peptide iRGD and loaded with a combination of a PI3K inhibitor to inhibit immune-suppressive tumor cells and an α-GalCer agonist of therapeutic T cells to synergistically sway the tumor microenvironment of solid tumors from suppressive to stimulatory. This treatment created a therapeutic window of 2 weeks, enabling tumor-specific CAR-T cells to home to the lesion, undergo robust expansion, and trigger tumor regression. CAR-T cells administered outside this therapeutic window had no curative effect. The lipid nanoparticles we used are easy to manufacture in substantial amounts, and we demonstrate that repeated infusions of them are safe. Our technology may therefore provide a practical and low-cost strategy to potentiate many cancer immunotherapies used to treat solid tumors, including T-cell therapy, vaccines, and BITE platforms.Significance: A new nanotechnology approach can promote T-cell therapy for solid tumors. Cancer Res; 78(13); 3718-30. ©2018 AACR.

PMID: 29760047 [PubMed - indexed for MEDLINE]

Successful treatment of direct carotid-cavernous fistula in a patient with Ehlers-Danlos syndrome type IV without arterial puncture: the transvenous triple-overlay embolization (TAILOREd) technique.

BMJ Case Rep. 2017 Aug 18;2017:

Authors: Huynh TJ, Morton RP, Levitt MR, Ghodke BV, Wink O, Hallam DK

Abstract
We report successful transvenous treatment of direct carotid-cavernous fistula in a patient with Ehlers-Danlos syndrome type IV using a novel triple-overlay embolization (TAILOREd) technique without the need for arterial puncture, which is known to be highly risky in this patient group. The TAILOREd technique allowed for successful treatment using preoperative MR angiography as a three-dimensional overlay roadmap combined with cone beam CT and live fluoroscopy, precluding the need for an arterial puncture.

PMID: 28824011 [PubMed - indexed for MEDLINE]

Neural Cotransmission in Spinal Circuits Governing Locomotion.

Trends Neurosci. 2018 May 07;:

Authors: Svensson E, Williams MJ, Schiöth HB

Abstract
Many neuronal circuits contain, or are influenced by, colocalized neurotransmitters, which are suggested to fine-tune circuit function. Much of our knowledge about cotransmission derives from studies in non-mammalian model systems, although a growing number of studies have provided insights into the physiological role of cotransmission in more complex mammalian circuits, including the spinal cord. Here we discuss the current picture of colocalized neurotransmitters in spinal circuits of non-mammalian and mammalian systems, as well as the progression towards understanding of their functional roles. We delineate both evolutionarily conserved and divergent aspects of spinal cotransmission and highlight open questions in the area.

PMID: 29747855 [PubMed - as supplied by publisher]

MicroRNA 21a-5p overexpression impacts mediators of extracellular matrix formation in uterine leiomyoma.

Reprod Biol Endocrinol. 2018 May 11;16(1):46

Authors: Cardozo ER, Foster R, Karmon AE, Lee AE, Gatune LW, Rueda BR, Styer AK

Abstract
BACKGROUND: MicroRNAs (MiR) may promote fibroid development via altered expression of genes involved in cell proliferation and ECM formation, and evidence supports aberrant expression of MicroRNA (MiR) 21a-5p in fibroids. The purpose of this study was to investigate the functional significance of MiR 21a-5p overexpression in the pathobiology of leiomyomata (fibroids).
METHODS: A basic science experimental design using immortalized fibroid and myometrial cell lines derived from patient-matched specimens was used. Stable overexpression of MiR-21a-5p in an immortalized fibroid and patient matched myometrial cell line was achieved through lentiviral vector infection. Main outcome measures were MiR-21-5p overexpression, target gene and protein expression, collagen (COL1A1) production, cell proliferation, cell migration, and cell cycle stages of fibroid and myometrial immortalized cell lines.
RESULTS: MiR-21a-5p was overexpressed to similar levels in fibroid and myometrial cell lines after lentiviral infection. Increased expression of miR-21 resulted in increased gene and protein expression of TGF-β3 in both fibroid and myometrial cells. Changes in expression of the ECM genes Fibronectin, Collagen 1A1, CTGF, Versican and DPT were seen in both fibroid and myometrial cells. Changes were also seen in Matrix Metalloproteinase (MMP) related genes including MMP 2, MMP 9, MMP 11 and Serpine 1 in both fibroid and myometrial cells. MiR-21 upregulation resulted in increased proliferation and migration in fibroid cells compared to myometrial cells.
CONCLUSIONS: MiR-21a-5p overexpression results in changes in the expression of ECM mediators in both fibroid and myometrial cells, and increased cell proliferation in fibroid cells. These finding suggest a potential functional role of MiR-21a-5p in the development of uterine fibroids and warrant further investigation.

PMID: 29747655 [PubMed - indexed for MEDLINE]

In Reply.

J Oral Maxillofac Surg. 2018 08;76(8):1601-1602

Authors: Brandner JS, Rawal YB, Kim LJ, Dillon JK

PMID: 29746841 [PubMed - indexed for MEDLINE]

Amantadine Did Not Positively Impact Cognition in Chronic Traumatic Brain Injury: A Multi-Site, Randomized, Controlled Trial.

J Neurotrauma. 2018 10 01;35(19):2298-2305

Authors: Hammond FM, Sherer M, Malec JF, Zafonte RD, Dikmen S, Bogner J, Bell KR, Barber J, Temkin N

Abstract
Despite limited evidence to support the use of amantadine to enhance cognitive function after traumatic brain injury (TBI), the clinical use for this purpose is highly prevalent and is often based on inferred belief systems. The aim of this study was to assess effect of amantadine on cognition among individuals with a history of TBI and behavioral disturbance using a parallel-group, randomized, double-blind, placebo-controlled trial of amantadine 100 mg twice-daily versus placebo for 60 days. Included in the study were 119 individuals with two or more neuropsychological measures greater than 1 standard deviation below normative means from a larger study of 168 individuals with chronic TBI (>6 months post-injury) and irritability. Cognitive function was measured at treatment days 0, 28, and 60 with a battery of neuropsychological tests. Composite indices were generated: General Cognitive Index (included all measures), a Learning Memory Index (learning/memory measures), and Attention/Processing Speed Index (attention and executive function measures). Repeated-measures analysis of variance revealed statistically significant between-group differences favoring the placebo group at day 28 for General Cognitive Index (p = 0.002) and Learning Memory Index (p = 0.001), but not Attention/Processing Speed Index (p = 0.25), whereas no statistically significant between-group differences were found at day 60. There were no statistically significant between-group differences on adverse events. Cognitive function in individuals with chronic TBI is not improved by amantadine 100 mg twice-daily. In the first 28 days of use, amantadine may impede cognitive processing. However, the effect size was small and mean scores for both groups were generally within expectations for persons with history of complicated mild-to-severe TBI, suggesting that changes observed across assessments may not have functional significance. The use of amantadine to enhance cognitive function is not supported by these findings.

PMID: 29742960 [PubMed - indexed for MEDLINE]

Advances in cellular and integrative control of oxygen homeostasis within the central nervous system.

J Physiol. 2018 08;596(15):3043-3065

Authors: Ramirez JM, Severs LJ, Ramirez SC, Agosto-Marlin IM

Abstract
Mammals must continuously regulate the levels of O2 and CO2 , which is particularly important for the brain. Failure to maintain adequate O2 /CO2 homeostasis has been associated with numerous disorders including sleep apnoea, Rett syndrome and sudden infant death syndrome. But, O2 /CO2 homeostasis poses major regulatory challenges, even in the healthy brain. Neuronal activities change in a differentiated, spatially and temporally complex manner, which is reflected in equally complex changes in O2 demand. This raises important questions: is oxygen sensing an emergent property, locally generated within all active neuronal networks, and/or the property of specialized O2 -sensitive CNS regions? Increasing evidence suggests that the regulation of the brain's redox state involves properties that are intrinsic to many networks, but that specialized regions in the brainstem orchestrate the integrated control of respiratory and cardiovascular functions. Although the levels of O2 in arterial blood and the CNS are very different, neuro-glial interactions and purinergic signalling are critical for both peripheral and CNS chemosensation. Indeed, the specificity of neuroglial interactions seems to determine the differential responses to O2 , CO2 and the changes in pH.

PMID: 29742297 [PubMed - indexed for MEDLINE]

Cardiac-Related Spinal Cord Tissue Motion at the Foramen Magnum is Increased in Patients with Type I Chiari Malformation and Decreases Postdecompression Surgery.

World Neurosurg. 2018 Aug;116:e298-e307

Authors: Lawrence BJ, Luciano M, Tew J, Ellenbogen RG, Oshinski JN, Loth F, Culley AP, Martin BA

Abstract
OBJECTIVE: Type 1 Chiari malformation (CM-I) is a craniospinal disorder historically defined by cerebellar tonsillar position greater than 3-5 mm below the foramen magnum (FM). This definition has come under question because quantitative measurements of cerebellar herniation do not always correspond with symptom severity. Researchers have proposed several additional radiographic diagnostic criteria based on dynamic motion of fluids and/or tissues. The present study objective was to determine if cardiac-related craniocaudal spinal cord tissue displacement is an accurate indicator of the presence of CM-I and if tissue displacement is altered with decompression.
METHODS: A cohort of 20 symptomatic patients underwent decompression surgery. Fifteen healthy volunteers were recruited for comparison with the CM-I group. Axial phase-contrast magnetic resonance imaging (PC-MRI) measurements were collected before and after surgery at the FM with cranial-caudal velocity encoding and 20 frames per cardiac cycle with retrospective reconstruction. Spinal cord motion (SCM) at the FM was quantified based on the peak-to-peak integral of average spinal cord velocity.
RESULTS: Tissue motion for the presurgical group was significantly greater than controls (P = 0.0009). Motion decreased after surgery (P = 0.058) with an effect size of -0.151 mm and a standard error of 0.066 mm. Postoperatively, no statistical difference from controls in bulk displacement at the FM was found (P = 0.200) after post hoc testing using the Tukey adjustment for multiple comparisons.
CONCLUSIONS: These results support SCM measurement by PC-MRI as a possible noninvasive radiographic diagnostic for CM-I. Dynamic measurement of SCM provides unique diagnostic information about CM-I alongside static quantification of tonsillar position and other intracranial morphometrics.

PMID: 29733988 [PubMed - indexed for MEDLINE]

Phytoremediation removal rates of benzene, toluene, and chlorobenzene.

Int J Phytoremediation. 2018 Jun 07;20(7):666-674

Authors: Limmer MA, Wilson J, Westenberg D, Lee A, Siegman M, Burken JG

Abstract
Phytoremediation is a sustainable remedial approach, although performance efficacy is rarely reported. In this study, we assessed a phytoremediation plot treating benzene, toluene, and chlorobenzene. A comparison of the calculated phytoremediation removal rate with estimates of onsite contaminant mass was used to forecast cleanup periods. The investigation demonstrated that substantial microbial degradation was occurring in the subsurface. Estimates of transpiration indicated that the trees planted were removing approximately 240,000 L of water per year. This large quantity of water removal implies substantial removal of contaminant due to large amounts of contaminants in the groundwater; however, these contaminants extensively sorb to the soil, resulting in large quantities of contaminant mass in the subsurface. The total estimate of subsurface contaminant mass was also complicated by the presence of non-aqueous phase liquids (NAPL), additional contaminant masses that were difficult to quantify. These uncertainties of initial contaminant mass at the site result in large uncertainty in the cleanup period, although mean estimates are on the order of decades. Collectively, the model indicates contaminant removal rates on the order of 10-2-100 kg/tree/year. The benefit of the phytoremediation system is relatively sustainable cleanup over the long periods necessary due to the presence of NAPL.

PMID: 29723051 [PubMed - indexed for MEDLINE]

Clinical Characteristics, Sex Differences, and Outcomes in Patients With Normal or Near-Normal Coronary Arteries, Non-Obstructive or Obstructive Coronary Artery Disease.

J Am Heart Assoc. 2018 05 02;7(10):

Authors: Ouellette ML, Löffler AI, Beller GA, Workman VK, Holland E, Bourque JM

Abstract
BACKGROUND: Normal or near-normal coronary arteries (NNCAs) or nonobstructive coronary artery disease (CAD) are found on invasive coronary angiography in ≈55% of patients. Some attribute this to frequent referral of low-risk patients. We sought to identify the referral indications, pretest risk, key clinical characteristics, sex, and outcomes in patients with NNCAs and nonobstructive CAD versus obstructive CAD on nonemergent invasive coronary angiography.
METHODS AND RESULTS: Over 24 months, 925 consecutive patients were classified as having NNCAs (≤20% stenosis), nonobstructive CAD (21-49% stenosis), or obstructive CAD (≥50% stenosis). Outcomes included cardiac death, nonfatal myocardial infarction, and late revasclarization. NNCAs were found in 285 patients (31.0%), nonobstructive CAD in 125 (13.5%), and obstructive CAD in 513 (55.5%). NNCAs or nonobstructive CAD was found in 40.5% with stress ischemia, 27.9% after a non-ST-elevation myocardial infarction, and in 55.5% with stable or unstable angina. More women than men (53.5% versus 37.2%; P<0.001) had NNCAs or nonobstructive CAD across all referral indications. Pretest risk was high and ICA appropriate in 75.5% and 99.2% of patients, respectively. Annual rates of cardiac death or nonfatal myocardial infarction were 1.0%, 1.1%, and 6.7%, respectively, for patients with NNCAs, nonobstructive CAD, and obstructive CAD (P<0.001). No sex differences in outcomes were observed with either NNCAs, nonobstructive CAD, or obstructive CAD (P=0.84).
CONCLUSIONS: Many (44.5%) patients undergoing nonemergent invasive coronary angiography have NNCAs or nonobstructive CAD despite high pretest risk, including ischemia and troponin elevation. Although women had more NNCAs or nonobstructive CAD, there were no differences in event rates by sex. Patients with NNCAs and nonobstructive CAD had very low event rates.

PMID: 29720503 [PubMed - indexed for MEDLINE]

The Dynamic Basis of Respiratory Rhythm Generation: One Breath at a Time.

Annu Rev Neurosci. 2018 07 08;41:475-499

Authors: Ramirez JM, Baertsch NA

Abstract
Rhythmicity is a universal timing mechanism in the brain, and the rhythmogenic mechanisms are generally dynamic. This is illustrated for the neuronal control of breathing, a behavior that occurs as a one-, two-, or three-phase rhythm. Each breath is assembled stochastically, and increasing evidence suggests that each phase can be generated independently by a dedicated excitatory microcircuit. Within each microcircuit, rhythmicity emerges through three entangled mechanisms: ( a) glutamatergic transmission, which is amplified by ( b) intrinsic bursting and opposed by ( c) concurrent inhibition. This rhythmogenic triangle is dynamically tuned by neuromodulators and other network interactions. The ability of coupled oscillators to reconfigure and recombine may allow breathing to remain robust yet plastic enough to conform to nonventilatory behaviors such as vocalization, swallowing, and coughing. Lessons learned from the respiratory network may translate to other highly dynamic and integrated rhythmic systems, if approached one breath at a time.

PMID: 29709210 [PubMed - indexed for MEDLINE]

Ischemic retinal vein occlusion: characterizing the more severe spectrum of retinal vein occlusion.

Surv Ophthalmol. 2018 Nov - Dec;63(6):816-850

Authors: Khayat M, Williams M, Lois N

Abstract
Retinal vein occlusion (RVO)-including central RVO, branch RVO, and hemicentral and hemispheric RVO-is the second most common vascular cause of visual loss, surpassed only by diabetic retinopathy. The presence and extent of retinal ischemia in RVO is associated with a worse prognosis. On this basis, most previously conducted studies considered ischemic retinal vein occlusion (iRVO) and non-iRVO as separate entities based on set thresholds of existing retinal ischemia as determined by fundus fluorescein angiography. Other diagnostic technologies have been used specifically in the differentiation of ischemic central retinal vein occlusion and nonischemic central retinal vein occlusion. To date, there is no fully accepted definition for iRVO. Some clinicians and researchers may favor establishing a clear differentiation between these forms of RVO; others may prefer not to consider iRVO as a separate entity. Whatever the case, retinal ischemia in RVO confers a higher risk of visual loss and neovascular complications; thus, it should be determined as accurately as possible in patients with this disease and be considered in clinical and experimental studies. Most recently conducted clinical trials evaluating new treatments for macular edema secondary to RVO included none or only few patients with iRVO based on previous definitions (i.e., few patients with sizeable areas of retinal ischemia were recruited in these trials), and thus it is unclear whether the results observed in recruited patients could be extrapolated to those with retinal ischemia. There has been scant research aiming at developing and/or testing treatments for retinal ischemia, as well as to prevent new vessel formation as a result of RVO. We provide a detailed review of the knowledge gathered over the years on iRVO, from controversies on its definition and diagnosis to the understanding of its epidemiology, risk factors and pathogenesis, the structural and functional effects of this disease in the eye and its complications, natural history, and outcomes after treatment. In each section, the definition of iRVO used is given so, independently of whether iRVO is considered a separate clinical entity or a more severe end of the spectrum of RVO, the information will be useful to clinicians to determine patient's risk, guide therapeutic decisions, and counsel patients and for researchers to design future studies.

PMID: 29705175 [PubMed - indexed for MEDLINE]

Matching Matched Filtering with Deep Networks for Gravitational-Wave Astronomy.

Phys Rev Lett. 2018 Apr 06;120(14):141103

Authors: Gabbard H, Williams M, Hayes F, Messenger C

Abstract
We report on the construction of a deep convolutional neural network that can reproduce the sensitivity of a matched-filtering search for binary black hole gravitational-wave signals. The standard method for the detection of well-modeled transient gravitational-wave signals is matched filtering. We use only whitened time series of measured gravitational-wave strain as an input, and we train and test on simulated binary black hole signals in synthetic Gaussian noise representative of Advanced LIGO sensitivity. We show that our network can classify signal from noise with a performance that emulates that of match filtering applied to the same data sets when considering the sensitivity defined by receiver-operator characteristics.

PMID: 29694122 [PubMed]

MetaBridge: enabling network-based integrative analysis via direct protein interactors of metabolites.

Bioinformatics. 2018 09 15;34(18):3225-3227

Authors: Hinshaw SJ, Lee AHY, Gill EE, Hancock REW

Abstract
Summary: Here, we present MetaBridge, a tool that collates protein interactors (curated metabolite-enzyme interactions) that influence the levels of specific metabolites including both biosynthetic and degradative enzymes. This enables network-based integrative analysis of metabolomics data with other omics data types. MetaBridge is designed to complement a systems-biology approach to analysis, pairing well with network analysis tools such as NetworkAnalyst.ca, but can be used in any bioinformatics workflow.
Availability and implementation: MetaBridge has been implemented as a web tool at https://www.metabridge.org, and the source code is available at https://github.com/samhinshaw/metabridge_shiny (GNU GPLv3).

PMID: 29688253 [PubMed - indexed for MEDLINE]

Pulmonary exacerbations and acute declines in lung function in patients with cystic fibrosis.

J Cyst Fibros. 2018 07;17(4):496-502

Authors: Wagener JS, Williams MJ, Millar SJ, Morgan WJ, Pasta DJ, Konstan MW

Abstract
BACKGROUND: Patients with cystic fibrosis (CF) who experience acute declines in percent predicted FEV1 (ppFEV1 decreased ≥10% relative to baseline) are often not treated with antibiotics for pulmonary exacerbations (PEx), whereas other patients are treated even when they have not experienced a decline in lung function.
METHODS: We analyzed 2 patient cohorts using 3 years of Epidemiologic Study of CF data. Cohort 1 (12,837 patients) experienced a ≥10% acute decline in ppFEV1 (n = 22,898) and Cohort 2 (10,416 patients) had a clinician-diagnosed PEx (n = 20,731).
RESULTS: 70.7% of ≥10% decline events were treated with antibiotics; with intravenous antibiotics used 67.1% of the time. 32.0% of clinician-diagnosed PEx declined <10%; with intravenous antibiotics used 36.9% of the time.
CONCLUSIONS: A clinician's decision to diagnose a PEx and treat with antibiotics often is not defined by measured lung function: a ≥10% FEV1 decline is not considered an absolute indication of a PEx and the lack of a decline does not contraindicate a PEx. Clinicians appear to use the history of prior PEx plus other variables as factors for diagnosing PEx.

PMID: 29685810 [PubMed - indexed for MEDLINE]

Using a randomized controlled trial to test whether modifications to contingency management improve outcomes for heavy drinkers with serious mental illness.

Contemp Clin Trials. 2018 06;69:92-98

Authors: Oluwoye O, Skalisky J, Burduli E, Chaytor NS, McPherson S, Murphy SM, Herron J, Hirchak K, Burley M, Ries RK, Roll JM, McDonell MG

Abstract
BACKGROUND: In contingency management (CM), individuals receive rewards for alcohol abstinence. CM is associated with reduced alcohol use in adults with co-occurring serious mental illnesses (SMI). Pre-treatment urine ethyl glucuronide (uEtG) levels equivalent to daily heavy drinking (uEtG >349ng/mL) are associated with poor response to CM. Modifications to CM are needed to improve outcomes for non-responders.
AIMS: To determine if pre-treatment heavy drinkers, defined by uEtG, with SMI achieve higher levels of alcohol abstinence when they receive an increased magnitude of reinforcement for abstinence (High-Magnitude CM) or reinforcers for reduced drinking, prior to receiving reinforcers for abstinence (Shaping CM), relative to those who receive typical low-magnitude abstinence based CM (Usual CM). Additionally, variables in the Addictions Neuroclinical Assessment model will be examined as treatment response moderators.
METHODS: Participants (N=400) will be recruited from two urban mental health organizations and complete a 4-week induction period where they will be reinforced for submitting samples for uEtG testing. Participants who attain a mean uEtG >349mg/mL will be randomized to receive either Usual CM, High-Magnitude CM, or Shaping CM for 16weeks. Differences in abstinence, assessed by uEtG, will be examined during treatment and during a 12-month follow-up. Measures of negative emotionality, alcohol reinforcer salience, and executive functioning will be gathered at study intake and used to predict treatment outcomes.
DISCUSSION: This novel approach to CM will use an alcohol biomarker to identify those at risk for treatment non-response and determine if adaptations to CM might improve outcomes for this group.

PMID: 29680318 [PubMed - indexed for MEDLINE]

Eleven loci with new reproducible genetic associations with allergic disease risk.

J Allergy Clin Immunol. 2019 02;143(2):691-699

Authors: Ferreira MAR, Vonk JM, Baurecht H, Marenholz I, Tian C, Hoffman JD, Helmer Q, Tillander A, Ullemar V, Lu Y, Rüschendorf F, 23andMe Research Team, SHARE study, Hinds DA, Hübner N, Weidinger S, Magnusson PKE, Jorgenson E, Lee YA, Boomsma DI, Karlsson R, Almqvist C, Koppelman GH, Paternoster L

Abstract
BACKGROUND: A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever, and eczema. Many more risk loci shared between these common allergic diseases remain to be discovered, which could point to new therapeutic opportunities.
OBJECTIVE: We sought to identify novel risk loci shared between asthma, hay fever, and eczema by applying a gene-based test of association to results from a published GWAS that included data from 360,838 subjects.
METHODS: We used approximate conditional analysis to adjust the results from the published GWAS for the effects of the top risk variants identified in that study. We then analyzed the adjusted GWAS results with the EUGENE gene-based approach, which combines evidence for association with disease risk across regulatory variants identified in different tissues. Novel gene-based associations were followed up in an independent sample of 233,898 subjects from the UK Biobank study.
RESULTS: Of the 19,432 genes tested, 30 had a significant gene-based association at a Bonferroni-corrected P value of 2.5 × 10-6. Of these, 20 were also significantly associated (P < .05/30 = .0016) with disease risk in the replication sample, including 19 that were located in 11 loci not reported to contain allergy risk variants in previous GWASs. Among these were 9 genes with a known function that is directly relevant to allergic disease: FOSL2, VPRBP, IPCEF1, PRR5L, NCF4, APOBR, IL27, ATXN2L, and LAT. For 4 genes (eg, ATXN2L), a genetically determined decrease in gene expression was associated with decreased allergy risk, and therefore drugs that inhibit gene expression or function are predicted to ameliorate disease symptoms. The opposite directional effect was observed for 14 genes, including IL27, a cytokine known to suppress TH2 responses.
CONCLUSION: Using a gene-based approach, we identified 11 risk loci for allergic disease that were not reported in previous GWASs. Functional studies that investigate the contribution of the 19 associated genes to the pathophysiology of allergic disease and assess their therapeutic potential are warranted.

PMID: 29679657 [PubMed - indexed for MEDLINE]

Unmet Rehabilitation Needs After Hospitalization for Traumatic Brain Injury.

Pediatrics. 2018 05;141(5):

Authors: Fuentes MM, Wang J, Haarbauer-Krupa J, Yeates KO, Durbin D, Zonfrillo MR, Jaffe KM, Temkin N, Tulsky D, Bertisch H, Rivara FP

Abstract
OBJECTIVES: In this study, we describe unmet service needs of children hospitalized for traumatic brain injury (TBI) during the first 2 years after injury and examine associations between child, family, and injury-related characteristics and unmet needs in 6 domains (physical therapy, occupational therapy, speech therapy, mental health services, educational services, and physiatry).
METHODS: Prospective cohort study of children age 8 to 18 years old admitted to 6 hospitals with complicated mild or moderate to severe TBI. Service need was based on dysfunction identified via parent-report compared with retrospective baseline at 6, 12, and 24 months. Needs were considered unmet if the child had no therapy services in the previous 4 weeks, no physiatry services since the previous assessment, or no educational services since injury. Analyses were used to compare met and unmet needs for each domain and time point. Generalized multinomial logit models with robust SEs were used to assess factors associated with change in need from pre-injury baseline to each study time point.
RESULTS: Unmet need varied by injury severity, time since injury, and service domain. Unmet need was highest for physiatry, educational services, and speech therapy. Among children with service needs, increased time after TBI and complicated mild TBI were associated with a higher likelihood of unmet rather than met service needs.
CONCLUSIONS: Children hospitalized for TBI have persistent dysfunction with unmet needs across multiple domains. After initial hospitalization, children with TBI should be monitored for functional impairments to improve identification and fulfillment of service needs.

PMID: 29674358 [PubMed - indexed for MEDLINE]

In Reply: Cranial Chordoma: A New Preoperative Grading System.

Neurosurgery. 2018 07 01;83(1):E52-E53

Authors: Brito da Silva H, Sekhar LN

PMID: 29672767 [PubMed - indexed for MEDLINE]

Glucose-regulated protein 78 is essential for cardiac myocyte survival.

Cell Death Differ. 2018 12;25(12):2181-2194

Authors: Wang X, Bi X, Zhang G, Deng Y, Luo X, Xu L, Scherer PE, Ferdous A, Fu G, Gillette TG, Lee AS, Jiang X, Wang ZV

Abstract
Secretory and transmembrane proteins rely on proper function of the secretory pathway for folding, posttranslational modification, assembly, and secretion. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) stimulates the unfolded protein response (UPR), which communicates between the ER and other organelles to enhance ER-folding capacity and restore cellular homeostasis. Glucose-regulated protein of 78 kDa (GRP78), an ER-resident protein chaperone, is a master regulator of all UPR signaling branches. Accumulating studies have established a fundamental role of GRP78 in protein folding, ER stress response, and cell survival. However, role of GRP78 in the heart remains incompletely characterized. Here we showed that embryos lacking GRP78 specifically in cardiac myocytes manifest cardiovascular malformations and die in utero at late gestation. We went further to show that inducible knockout of GRP78 in adult cardiac myocytes causes early mortality due to cardiac cell death and severe decline in heart performance. At the cellular level, we found that loss of GRP78 increases apoptotic cell death, which is accompanied by reduction in AKT signaling and augmentation of production for reactive oxygen species. Importantly, enhancing AKT phosphorylation and activity leads to decreases in oxidative stress and increases in cardiac myocyte survival. Collectively, our results demonstrate an essential role of GRP78 in ensuring normal cardiogenesis and maintaining cardiac contractility and function.

PMID: 29666470 [PubMed - indexed for MEDLINE]