UW Neurological Surgery Recent PubMed Publications

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]

Chlamydia muridarum Genital and Gastrointestinal Infection Tropism Is Mediated by Distinct Chromosomal Factors.

Infect Immun. 2018 07;86(7):

Authors: Morrison SG, Giebel AM, Toh EC, Spencer HJ, Nelson DE, Morrison RP

Abstract
Some members of the genus Chlamydia, including the human pathogen Chlamydia trachomatis, infect multiple tissues, including the genital and gastrointestinal (GI) tracts. However, it is unknown if bacterial targeting to these sites is mediated by multifunctional or distinct chlamydial factors. We previously showed that disruption of individual large clostridial toxin homologs encoded within the Chlamydia muridarum plasticity zone were not critical for murine genital tract infection. Here, we assessed whether cytotoxin genes contribute to C. muridarum GI tropism. Infectivity and shedding of wild-type (WT) C. muridarum and three mutants containing nonsense mutations in different cytotoxin genes, tc0437, tc0438, and tc0439, were compared in mouse genital and GI infection models. One mutant, which had a nonsense mutation in tc0439, was highly attenuated for GI infection and had a GI 50% infectious dose (ID50) that was 1,000 times greater than that of the WT. GI inoculation with this mutant failed to elicit anti-chlamydial antibodies or to protect against subsequent genital tract infection. Genome sequencing of the tc0439 mutant revealed additional chromosomal mutations, and phenotyping of additional mutants suggested that the GI attenuation might be linked to a nonsense mutation in tc0600 The molecular mechanism underlying this dramatic difference in tissue-tropic virulence is not fully understood. However, isolation of these mutants demonstrates that distinct chlamydial chromosomal factors mediate chlamydial tissue tropism and provides a basis for vaccine initiatives to isolate chlamydia strains that are attenuated for genital infection but retain the ability to colonize the GI tract and elicit protective immune responses.

PMID: 29661932 [PubMed - indexed for MEDLINE]

Functions of CaBP1 and CaBP2 in the peripheral auditory system.

Hear Res. 2018 07;364:48-58

Authors: Yang T, Hu N, Pangršič T, Green S, Hansen M, Lee A

Abstract
CaBPs are a family of Ca2+ binding proteins related to calmodulin. Two CaBP family members, CaBP1 and CaBP2, are highly expressed in the cochlea. Here, we investigated the significance of CaBP1 and CaBP2 for hearing in mice lacking expression of these proteins (CaBP1 KO and CaBP2 KO) using auditory brain responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). In CaBP1 KO mice, ABR wave I was larger in amplitude, and shorter in latency and faster in decay, suggestive of enhanced synchrony of auditory nerve fibers. This interpretation was supported by the greater excitability of CaBP1 KO than WT neurons in whole-cell patch clamp recordings of spiral ganglion neurons in culture, and normal presynaptic function of CaBP1 KO IHCs. DPOAEs and ABR thresholds were normal in 4-week old CaBP1 KO mice, but elevated ABR thresholds became evident at 32 kHz at 9 weeks, and at 8 and 16 kHz by 6 months of age. In contrast, CaBP2 KO mice exhibited significant ABR threshold elevations at 4 weeks of age that became more severe in the mid-frequency range by 9 weeks. Though normal at 4 weeks, DPOAEs in CaBP2 KO mice were significantly reduced in the mid-frequency range by 9 weeks. Our results reveal requirements for CaBP1 and CaBP2 in the peripheral auditory system and highlight the diverse modes by which CaBPs influence sensory processing.

PMID: 29661613 [PubMed - indexed for MEDLINE]

Ca2+-Binding Protein 1 Regulates Hippocampal-dependent Memory and Synaptic Plasticity.

Neuroscience. 2018 06 01;380:90-102

Authors: Yang T, Britt JK, Cintrón-Pérez CJ, Vázquez-Rosa E, Tobin KV, Stalker G, Hardie J, Taugher RJ, Wemmie J, Pieper AA, Lee A

Abstract
Ca2+-binding protein 1 (CaBP1) is a Ca2+-sensing protein similar to calmodulin that potently regulates voltage-gated Ca2+ channels. Unlike calmodulin, however, CaBP1 is mainly expressed in neuronal cell-types and enriched in the hippocampus, where its function is unknown. Here, we investigated the role of CaBP1 in hippocampal-dependent behaviors using mice lacking expression of CaBP1 (C-KO). By western blot, the largest CaBP1 splice variant, caldendrin, was detected in hippocampal lysates from wild-type (WT) but not C-KO mice. Compared to WT mice, C-KO mice exhibited mild deficits in spatial learning and memory in both the Barnes maze and in Morris water maze reversal learning. In contextual but not cued fear-conditioning assays, C-KO mice showed greater freezing responses than WT mice. In addition, the number of adult-born neurons in the hippocampus of C-KO mice was ∼40% of that in WT mice, as measured by bromodeoxyuridine labeling. Moreover, hippocampal long-term potentiation was significantly reduced in C-KO mice. We conclude that CaBP1 is required for cellular mechanisms underlying optimal encoding of hippocampal-dependent spatial and fear-related memories.

PMID: 29660444 [PubMed - indexed for MEDLINE]

Control of Excitation/Inhibition Balance in a Hippocampal Circuit by Calcium Sensor Protein Regulation of Presynaptic Calcium Channels.

J Neurosci. 2018 05 02;38(18):4430-4440

Authors: Nanou E, Lee A, Catterall WA

Abstract
Activity-dependent regulation controls the balance of synaptic excitation to inhibition in neural circuits, and disruption of this regulation impairs learning and memory and causes many neurological disorders. The molecular mechanisms underlying short-term synaptic plasticity are incompletely understood, and their role in inhibitory synapses remains uncertain. Here we show that regulation of voltage-gated calcium (Ca2+) channel type 2.1 (CaV2.1) by neuronal Ca2+ sensor (CaS) proteins controls synaptic plasticity and excitation/inhibition balance in a hippocampal circuit. Prevention of CaS protein regulation by introducing the IM-AA mutation in CaV2.1 channels in male and female mice impairs short-term synaptic facilitation at excitatory synapses of CA3 pyramidal neurons onto parvalbumin (PV)-expressing basket cells. In sharp contrast, the IM-AA mutation abolishes rapid synaptic depression in the inhibitory synapses of PV basket cells onto CA1 pyramidal neurons. These results show that CaS protein regulation of facilitation and inactivation of CaV2.1 channels controls the direction of short-term plasticity at these two synapses. Deletion of the CaS protein CaBP1/caldendrin also blocks rapid depression at PV-CA1 synapses, implicating its upregulation of inactivation of CaV2.1 channels in control of short-term synaptic plasticity at this inhibitory synapse. Studies of local-circuit function revealed reduced inhibition of CA1 pyramidal neurons by the disynaptic pathway from CA3 pyramidal cells via PV basket cells and greatly increased excitation/inhibition ratio of the direct excitatory input versus indirect inhibitory input from CA3 pyramidal neurons to CA1 pyramidal neurons. This striking defect in local-circuit function may contribute to the dramatic impairment of spatial learning and memory in IM-AA mice.SIGNIFICANCE STATEMENT Many forms of short-term synaptic plasticity in neuronal circuits rely on regulation of presynaptic voltage-gated Ca2+ (CaV) channels. Regulation of CaV2.1 channels by neuronal calcium sensor (CaS) proteins controls short-term synaptic plasticity. Here we demonstrate a direct link between regulation of CaV2.1 channels and short-term synaptic plasticity in native hippocampal excitatory and inhibitory synapses. We also identify CaBP1/caldendrin as the calcium sensor interacting with CaV2.1 channels to mediate rapid synaptic depression in the inhibitory hippocampal synapses of parvalbumin-expressing basket cells to CA1 pyramidal cells. Disruption of this regulation causes altered short-term plasticity and impaired balance of hippocampal excitatory to inhibitory circuits.

PMID: 29654190 [PubMed - indexed for MEDLINE]

Endoplasmic reticulum stress activates SRC, relocating chaperones to the cell surface where GRP78/CD109 blocks TGF-β signaling.

Proc Natl Acad Sci U S A. 2018 05 01;115(18):E4245-E4254

Authors: Tsai YL, Ha DP, Zhao H, Carlos AJ, Wei S, Pun TK, Wu K, Zandi E, Kelly K, Lee AS

Abstract
The discovery that endoplasmic reticulum (ER) luminal chaperones such as GRP78/BiP can escape to the cell surface upon ER stress where they regulate cell signaling, proliferation, apoptosis, and immunity represents a paradigm shift. Toward deciphering the mechanisms, we report here that, upon ER stress, IRE1α binds to and triggers tyrosine kinase SRC activation, leading to ASAP1 phosphorylation and Golgi accumulation of ASAP1 and Arf1-GTP, resulting in KDEL receptor dispersion from the Golgi and suppression of retrograde transport. At the cell surface, GRP78 binds to and acts in concert with a glycosylphosphatidylinositol-anchored protein, CD109, in blocking TGF-β signaling by promoting the routing of the TGF-β receptor to the caveolae, thereby disrupting its binding to and activation of Smad2. Collectively, we uncover a SRC-mediated signaling cascade that leads to the relocalization of ER chaperones to the cell surface and a mechanism whereby GRP78 counteracts the tumor-suppressor effect of TGF-β.

PMID: 29654145 [PubMed - indexed for MEDLINE]

Intra-session and Inter-day Reliability of the Myon 320 Electromyography System During Sub-maximal Contractions.

Front Physiol. 2018;9:309

Authors: Sorbie GG, Williams MJ, Boyle DW, Gray A, Brouner J, Gibson N, Baker JS, Easton C, Ugbolue UC

Abstract
Electromyography systems are widely used within the field of scientific and clinical practices. The reliability of these systems are paramount when conducting research. The reliability of Myon 320 Surface Electromyography System is yet to be determined. This study aims to determine the intra-session and inter-day reliability of the Myon 320 Surface Electromyography System. Muscle activity from fifteen participants was measured at the anterior deltoid muscle during a bilateral front raise exercise, the vastus lateralis muscle during a squat exercise and the extensor carpi radialis brevis (ECRB) muscle during an isometric handgrip task. Intra-session and inter-day reliability was calculated by intraclass correlation coefficient, standard error of measurement and coefficient of variation (CV). The normalized root mean squared (RMS) surface electromyographic signals produced good intra-session and inter-day testing intraclass correlation coefficient values (range: 0.63-0.97) together with low standard error of measurement (range: 1.49-2.32) and CV (range: 95% Confidence Interval = 0.36-12.71) measures for the dynamic-and-isometric contractions. The findings indicate that the Myon 320 Surface Electromyography System produces good to fair reliability when examining intra-session and inter-day reliability. Findings of the study provide evidence of the reliability of electromyography between trials which is essential during clinical testing.

PMID: 29651252 [PubMed]

Increased HOXA5 expression provides a selective advantage for gain of whole chromosome 7 in IDH wild-type glioblastoma.

Genes Dev. 2018 04 01;32(7-8):512-523

Authors: Cimino PJ, Kim Y, Wu HJ, Alexander J, Wirsching HG, Szulzewsky F, Pitter K, Ozawa T, Wang J, Vazquez J, Arora S, Rabadan R, Levine R, Michor F, Holland EC

Abstract
Glioblastoma is the most frequently occurring and invariably fatal primary brain tumor in adults. The vast majority of glioblastomas is characterized by chromosomal copy number alterations, including gain of whole chromosome 7 and loss of whole chromosome 10. Gain of whole chromosome 7 is an early event in gliomagenesis that occurs in proneural-like precursor cells, which give rise to all isocitrate dehydrogenase (IDH) wild-type glioblastoma transcriptional subtypes. Platelet-derived growth factor A (PDGFA) is one gene on chromosome 7 known to drive gliomagenesis, but, given its location near the end of 7p, there are likely several other genes located along chromosome 7 that select for its increased whole-chromosome copy number within glioblastoma cells. To identify other potential genes that could select for gain of whole chromosome 7, we developed an unbiased bioinformatics approach that identified homeobox A5 (HOXA5) as a gene whose expression correlated with gain of chromosome 7 and a more aggressive phenotype of the resulting glioma. High expression of HOXA5 in glioblastoma was associated with a proneural gene expression pattern and decreased overall survival in both human proneural and PDGF-driven mouse glioblastoma. Furthermore, HOXA5 overexpression promoted cellular proliferation and potentiated radioresistance. We also found enrichment of HOXA5 expression in recurrent human and mouse glioblastoma at first recurrence after radiotherapy. Overall, this study implicates HOXA5 as a chromosome 7-associated gene-level locus that promotes selection for gain of whole chromosome 7 and an aggressive phenotype in glioblastoma.

PMID: 29632085 [PubMed - indexed for MEDLINE]

Developmental manganese, lead, and barren cage exposure have adverse long-term neurocognitive, behavioral and monoamine effects in Sprague-Dawley rats.

Neurotoxicol Teratol. 2018 May - Jun;67:50-64

Authors: Sprowles JLN, Amos-Kroohs RM, Braun AA, Sugimoto C, Vorhees CV, Williams MT

Abstract
Developmental stress, including low socioeconomic status (SES), can induce dysregulation of the hypothalamic-pituitary-adrenal axis and result in long-term changes in stress reactivity. Children in lower SES households experience more stress and are more likely to be exposed to environmental neurotoxins such as lead (Pb) and manganese (Mn) than children in higher SES households. Co-exposure to stress, Pb, and Mn during early development may increase the risk of central nervous system dysfunction compared with unexposed children. To investigate the potential interaction of these factors, Sprague-Dawley rats were bred, and litters born in-house were culled on postnatal day (P)1 to 6 males and 6 females. One male and female within each litter were assigned to one of the following groups: 0 (vehicle), 10 mg/kg Pb, 100 mg/kg Mn, or 10 mg/kg Pb + 100 mg/kg Mn (PbMn), water gavage, and handled only from P4-28 with half the litters reared in cages with standard bedding (29 litters) and half with no bedding (Barren; 27 litters). Mn and PbMn groups had decreased anxiety, reduced acoustic startle, initial open-field hypoactivity, increased activity following (+)-methamphetamine, deficits in egocentric learning in the Cincinnati water maze (CWM), and deficits in latent inhibition conditioning. Pb increased anxiety and reduced open-field activity. Barren-reared rats had decreased anxiety, CWM deficits, increased startle, and initial open-field hyperactivity. Mn, PbMn, Pb Barren-reared groups had impaired Morris water maze performance. Pb altered neostriatal serotonin and norepinephrine, Mn increased hippocampal serotonin in males, Mn + Barren-rearing increased neostriatal serotonin, and Barren-rearing decreased neostriatal dopamine in males. At the doses used here, most effects were in the Mn and PbMn groups. Few interactions between Mn, Pb, and rearing stress were found, indicating that the interaction of these three variables is not as impactful as hypothesized.

PMID: 29631003 [PubMed - indexed for MEDLINE]

Shifting the treatment model for resectable pancreatic cancer.

Lancet Gastroenterol Hepatol. 2018 06;3(6):375-376

Authors: Ko AH

PMID: 29625842 [PubMed - indexed for MEDLINE]

The solution structure of monomeric CCL5 in complex with a doubly sulfated N-terminal segment of CCR5.

FEBS J. 2018 06;285(11):1988-2003

Authors: Abayev M, Rodrigues JPGLM, Srivastava G, Arshava B, Jaremko Ł, Jaremko M, Naider F, Levitt M, Anglister J

Abstract
The inflammatory chemokine CCL5, which binds the chemokine receptor CCR5 in a two-step mechanism so as to activate signaling pathways in hematopoetic cells, plays an important role in immune surveillance, inflammation, and development as well as in several immune system pathologies. The recently published crystal structure of CCR5 bound to a high-affinity variant of CCL5 lacks the N-terminal segment of the receptor that is post-translationally sulfated and is known to be important for high-affinity binding. Here, we report the NMR solution structure of monomeric CCL5 bound to a synthetic doubly sulfated peptide corresponding to the missing first 27 residues of CCR5. Our structures show that two sulfated tyrosine residues, sY10 and sY14, as well as the unsulfated Y15 form a network of strong interactions with a groove on a surface of CCL5 that is formed from evolutionarily conserved basic and hydrophobic amino acids. We then use our NMR structures, in combination with available crystal data, to create an atomic model of full-length wild-type CCR5:CCL5. Our findings reveal the structural determinants involved in the recognition of CCL5 by the CCR5 N terminus. These findings, together with existing structural data, provide a complete structural framework with which to understand the specificity of receptor:chemokine interactions.
DATABASE: Structural data are available in the PDB under the accession number 6FGP.

PMID: 29619777 [PubMed - indexed for MEDLINE]

Microsurgical Resection of a Large Intraventricular Trigonal Tumor: 3-Dimensional Operative Video.

Oper Neurosurg (Hagerstown). 2018 Mar 30;:

Authors: Cheng CY, Shetty R, Sekhar LN

Abstract
A 62-yr-old woman presented with incidentally detected left trigonal mass by magnetic resonance imaging (MRI) performed during workup for left-sided hearing loss and vertigo of 5-yr duration. Due to persistent dizziness, headache, and progressive enlargement of the tumor in follow-up scans, operation was planned. Because the tumor extended superiorly, a superior parietal lobule approach was selected.She underwent a left parietal craniotomy. A strip electrode was used to localize the motor and sensory regions, and neuronavigation was used to confirm the entry site. A small transsulcal corticotomy was performed posterior to a large cortical vein. The tumor was pinkish in color with a well-defined capsule. It was centrally debulked by using curettes, pituitary forceps, and the ultrasonic aspirator. Tumoral blood supply from the choroid plexus and the posterior choroidal vessels were cauterized and divided. Additional blood supply coming from the anterior choroidal vessels was also found and cauterized. After circumferential dissection of the tumor capsule, the tumor was removed completely. The pathology indicated WHO Grade I meningioma. The patient had mild expressive and receptive aphasia postoperatively, but improved progressively. The postoperative MRI showed total resection with no evidence of brain injury. At 3-mo follow-up, the speech was normal; she was independent for all daily activities, but had not yet returned to work (Karnofsky score 80).This 3-D video shows the technical nuances of microsurgical resection of an intraventricular tumor through a narrow brain corridor.Informed consent was obtained from the patient prior to the surgery that included videotaping of the procedure and its distribution for educational purposes. All relevant patient identifiers have also been removed from the video and accompanying radiology slides.

PMID: 29618124 [PubMed - as supplied by publisher]

Physician Time Burden Associated with Querying Prescription Drug Monitoring Programs.

Pain Med. 2018 10 01;19(10):1952-1960

Authors: Bachhuber MA, Saloner B, LaRochelle M, Merlin JS, Maughan BC, Polsky D, Shaparin N, Murphy SM

Abstract
Objective: Prescription drug monitoring programs (PDMPs) enable prescribers to review patient prescription histories, and their use is mandatory in many states. We estimated the cost of physicians retrieving PDMP patient reports compared with a model where a delegate (i.e., administrative staff) retrieves reports.
Methods: We performed a cost analysis with a one-year time horizon, from the perspective of physicians' employers. We obtained specialty-specific estimates of controlled substance prescribing frequency from the National Ambulatory Medical Care Survey, 2012-2014. We defined three PDMP usage cases based on the frequency of queries: comprehensive (before every Schedule II-IV controlled substance prescription), selective (before new Schedule II-IV prescriptions and every six months for continuing medications), and minimal (before new Schedule II or III prescriptions and annually for continuing medications).
Results: The delegate model was less costly for all specialties in the comprehensive usage case and most specialties in the selective usage case, and it was similar to physician model costs in the minimal usage case. Estimated annual costs of the physician model to a large health care system (1,000 full-time equivalent physicians) were $1.6 million for comprehensive usage, $1.1 million for selective usage, and $645,313 for minimal usage. The delegate model was less costly in the comprehensive (savings of $907,283) and selective usage cases (savings of $156,216).
Conclusions: Relying on delegates vs physicians to retrieve reports is less costly in most cases. Automation and integration of PDMP data into electronic health records may reduce costs further. Physicians, health care systems, and states should collaborate to streamline access to PDMPs.

PMID: 29618105 [PubMed - indexed for MEDLINE]

Microvascular Decompression of Facial Nerve and Pexy of the Left Vertebral Artery for Left Hemifacial Spasm: 3-Dimensional Operative Video.

Oper Neurosurg (Hagerstown). 2018 Mar 29;:

Authors: Cheng CY, Shetty R, Martinez V, Sekhar LN

Abstract
A 73-yr-old man presented with intractable left hemifacial spasm of 4 yr duration. Brain magnetic resonance imaging showed significant compression of left facial nerve by the left vertebral artery (VA) and anterior inferior cerebellar artery (AICA).The patient underwent a left retrosigmoid craniotomy and a microvascular decompression of the cranial nerve (CN) VII. Intraoperatively, we found that the distal AICA had a protracted subarcuate extradural course.1 This was relieved by intra/extradural dissection. The left VA and the AICA loop were compressing the root exit zone of CN VII. The VA was mobilized, and pexy into the petrosal dura was done with 8-0 nylon sutures (Ethilon Nylon Suture, Ethicon Inc, a subsidiary of Johnson & Johnson, Somerville, New Jersey). Once this was done, the lateral spread disappeared.2 The AICA loop was decompressed with 2 pieces of Teflon felt (Bard PTFE felt, Bard peripheral Vascular Inc, a subsidiary of CR Bard Inc, Temp, Arizona). After this, wave V of the brainstem auditory evoked potential (BAEP) disappeared completely, with no recovery despite the application of the nicardipine on the internal auditory artery (IAA). The IAA appeared to be stretched by the microvascular decompression. Arachnoidal dissection was done to release the CN VIII and an additional felt piece was placed to elevate the AICA loop; the BAEP recovered completely. The patient had a complete disappearance of the hemifacial spasm postoperatively, and hearing was unchanged.This 3-D video shows the technical nuances of performing a vertebropexy, release of the AICA from its extradural subarcuate course, and the surgical maneuvers in the event of an unexpected change in neuromonitoring response. The suture technique of vertebropexy is preferred to a loop technique, to avoid kinking of the VA.3Informed consent was obtained from the patient prior to the surgery that included videotaping of the procedure and its distribution for educational purposes. All relevant patient identifiers have also been removed from the video and accompanying radiology slides.

PMID: 29617905 [PubMed - as supplied by publisher]

Fewer thromboembolic events after implementation of a venous thromboembolism risk stratification tool.

J Surg Res. 2018 05;225:148-156

Authors: Turrentine FE, Sohn MW, Wilson SL, Stanley C, Novicoff W, Sawyer RG, Williams MD

Abstract
BACKGROUND: Deep venous thrombosis and pulmonary embolus are leading preventable causes of death after surgery. Venous thromboembolism (VTE) prophylaxis management guidelines, with evidenced-based recommendations, are available in the literature. However, over 40% of "at-risk" surgical patients fail to receive appropriate VTE prophylaxis. Decision support-based interventions to reduce venous thromboembolic events were explored.
METHODS: A venous thromboembolic risk stratification tool embedded in the electronic medical record, Epic, linking risk category to venous thromboembolic prophylaxis order sets was created, implemented, and analyzed for general surgery patients. Logistic regression analysis was used to compare rates of venous thromboembolic events before and after the intervention, controlling for age, gender, race, body mass index, inpatient status, transfer status, elective/emergent case status, American Society of Anesthesiologists classification, and wound classification.
RESULTS: Venous thromboembolic events in the preintervention and postintervention periods were 55 (1.25%) and 12 (0.64%), respectively (P = 0.033). All-cause mortality events decreased after intervention from 49 (1.12%) to 14 (0.75%; P = 0.187). Multivariable analyses show that the risk of a venous thromboembolic event after intervention was half (odds ratio = 0.532; 95% confidence interval, 0.284-0.997; P = 0.049) as likely compared to that in the preintervention period. From 2012 to 2015, our institution moved from the ninth decile (poor) to the first decile (best) for the incidence of venous thromboembolic events among 760 National Surgical Quality Improvement Program hospitals across the nation.
CONCLUSIONS: Postoperative thromboembolic events decreased after implementation of a VTE risk stratification tool, linking risk category to venous thromboembolic prophylaxis order sets, embedded in the electronic medical record, Epic.

PMID: 29605025 [PubMed - indexed for MEDLINE]