UW Neurological Surgery Recent PubMed Publications

Microglia Induce PDGFRB Expression in Glioma Cells to Enhance Their Migratory Capacity.

iScience. 2018 Oct 16;9:71-83

Authors: Wallmann T, Zhang XM, Wallerius M, Bolin S, Joly AL, Sobocki C, Leiss L, Jiang Y, Bergh J, Holland EC, Enger PØ, Andersson J, Swartling FJ, Miletic H, Uhrbom L, Harris RA, Rolny C

Abstract
High-grade gliomas (HGGs) are the most aggressive and invasive primary brain tumors. The platelet-derived growth factor (PDGF) signaling pathway drives HGG progression, and enhanced expression of PDGF receptors (PDGFRs) is a well-established aberration in a subset of glioblastomas (GBMs). PDGFRA is expressed in glioma cells, whereas PDGFRB is mostly restricted to the glioma-associated stroma. Here we show that the spatial location of TAMMs correlates with the expansion of a subset of tumor cells that have acquired expression of PDGFRB in both mouse and human low-grade glioma and HCGs. Furthermore, M2-polarized microglia but not bone marrow (BM)-derived macrophages (BMDMs) induced PDGFRB expression in glioma cells and stimulated their migratory capacity. These findings illustrate a heterotypic cross-talk between microglia and glioma cells that may enhance the migratory and invasive capacity of the latter by inducing PDGFRB.

PMID: 30384135 [PubMed - as supplied by publisher]

Epigenetic and Transcriptome Profiling Identifies a Population of Visceral Adipose-Derived Progenitor Cells with the Potential to Differentiate into an Endocrine Pancreatic Lineage.

Cell Transplant. 2019 01;28(1):89-104

Authors: Williams MD, Joglekar MV, Satoor SN, Wong W, Keramidaris E, Rixon A, O'Connell P, Hawthorne WJ, Mitchell GM, Hardikar AA

Abstract
Type 1 diabetes (T1D) is characterized by the loss of insulin-producing β-cells in the pancreas. T1D can be treated using cadaveric islet transplantation, but this therapy is severely limited by a lack of pancreas donors. To develop an alternative cell source for transplantation therapy, we carried out the epigenetic characterization in nine different adult mouse tissues and identified visceral adipose-derived progenitors as a candidate cell population. Chromatin conformation, assessed using chromatin immunoprecipitation (ChIP) sequencing and validated by ChIP-polymerase chain reaction (PCR) at key endocrine pancreatic gene promoters, revealed similarities between visceral fat and endocrine pancreas. Multiple techniques involving quantitative PCR, in-situ PCR, confocal microscopy, and flow cytometry confirmed the presence of measurable (2-1000-fold over detectable limits) pancreatic gene transcripts and mesenchymal progenitor cell markers (CD73, CD90 and CD105; >98%) in visceral adipose tissue-derived mesenchymal cells (AMCs). The differentiation potential of AMCs was explored in transgenic reporter mice expressing green fluorescent protein (GFP) under the regulation of the Pdx1 (pancreatic and duodenal homeobox-1) gene promoter. GFP expression was measured as an index of Pdx1 promoter activity to optimize culture conditions for endocrine pancreatic differentiation. Differentiated AMCs demonstrated their capacity to induce pancreatic endocrine genes as evidenced by increased GFP expression and validated using TaqMan real-time PCR (at least 2-200-fold relative to undifferentiated AMCs). Human AMCs differentiated using optimized protocols continued to produce insulin following transplantation in NOD/SCID mice. Our studies provide a systematic analysis of potential islet progenitor populations using genome-wide profiling studies and characterize visceral adipose-derived cells for replacement therapy in diabetes.

PMID: 30376726 [PubMed - indexed for MEDLINE]

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma.

Oncoimmunology. 2018;7(11):e1507668

Authors: Moyes KW, Davis A, Hoglund V, Haberthur K, Lieberman NA, Kreuser SA, Deutsch GH, Franco S, Locke D, Carleton MO, Gilbertson DG, Simmons R, Winter C, Silber J, Gonzalez-Cuyar LF, Ellenbogen RG, Crane CA

Abstract
Efforts to reduce immunosuppression in the solid tumor microenvironment by blocking the recruitment or polarization of tumor associated macrophages (TAM), or myeloid derived suppressor cells (MDSCs), have gained momentum in recent years. Expanding our knowledge of the immune cell types, cytokines, or recruitment factors that are associated with high-grade disease, both within the tumor and in circulation, is critical to identifying novel targets for immunotherapy. Furthermore, a better understanding of how therapeutic regimens, such as Dexamethasone (Dex), chemotherapy, and radiation, impact these factors will facilitate the design of therapies that can be targeted to the appropriate populations and retain efficacy when administered in combination with standard of care regimens. Here we perform quantitative analysis of tissue microarrays made of samples taken from grades I-III astrocytoma and glioblastoma (GBM, grade IV astrocytoma) to evaluate infiltration of myeloid markers CD163, CD68, CD33, and S100A9. Serum, flow cytometric, and Nanostring analysis allowed us to further elucidate the impact of Dex treatment on systemic biomarkers, circulating cells, and functional markers within tumor tissue. We found that common myeloid markers were elevated in Dex-treated grade I astrocytoma and GBM compared to non-neoplastic brain tissue and grade II-III astrocytomas. Cell frequencies in these samples differed significantly from those in Dex-naïve patients in a pattern that depended on tumor grade. In contrast, observed changes in serum chemokines or circulating monocytes were independent of disease state and were due to Dex treatment alone. Furthermore, these changes seen in blood were often not reflected within the tumor tissue. Conclusions: Our findings highlight the importance of considering perioperative treatment as well as disease grade when assessing novel therapeutic targets or biomarkers of disease.

PMID: 30377570 [PubMed]

Is postoperative Doppler ultrasonography useful for the early detection of asymptomatic pseudoaneurysm and prevention of haemorrhagic complications after partial nephrectomy?

BJU Int. 2018 11;122 Suppl 5:15-21

Authors: Nouhaud FX, Williams M, Arnfield E, Perera ML, Cho J, Esler R, Coughlin G

Abstract
OBJECTIVE: To assess the clinical utility of systematic Doppler ultrasonography (DUS) after robot-assisted partial nephrectomy (PN) for the detection of renal artery pseudoaneurysm (PA) and to allow pre-emptive arterial embolization to reduce the postoperative bleeding risk.
MATERIALS AND METHODS: A retrospective study was conducted including all consecutive patients treated with robot-assisted PN for renal tumours between 2015 and 2017. Every patient underwent renal DUS in the early postoperative period. The presence of PA, arteriovenous malformation or collection on the DUS, as well as the incidence of haemorrhagic complications and need for transfusion/embolization were assessed.
RESULTS: Eighty-three patients were included, with a median (range) age of 58 (19-80) years. The median (range) follow-up was 5 (1-30) months. The mean (±sd) tumour size was 31 (±13.1) mm, the median (range) RENAL nephrometry score was 6 (4-11), and the mean (±sd) warm ischaemia time was 22 (±7) min. A haemostatic agent was used in 12 patients (14.5%). No patient encountered haemorrhagic complications postoperatively, and no patient required transfusion. The median (interquartile range) time to DUS postoperatively was 7 (6-8) days. DUS revealed one asymptomatic PA (1.2%), which was treated with pre-emptive embolization. This was the only patient who encountered a Clavien grade III complication, while 20 patients (24%) had a complication grade I/II.
CONCLUSIONS: No haemorrhagic complications occurred in the present study population, although one asymptomatic PA was found. It was diagnosed early with DUS, allowing pre-emptive management with embolization. These results suggest the potential clinical utility of early postoperative DUS in order to screen for PA to reduce the risk of post-PN haemorrhagic complications.

PMID: 30370984 [PubMed - indexed for MEDLINE]

The "Real" Number of Washington State Adolescents Using Marijuana, and Why: A Misclassification Analysis.

Subst Use Misuse. 2019;54(1):89-96

Authors: Murphy SM, Rosenman R

Abstract
BACKGROUND: Although causality is difficult to establish, the regular use of marijuana has been associated with many adverse physiological and sociological consequences. There is considerable concern regarding marijuana use among adolescents, as the likelihood of adverse consequences increases significantly for this age group. The most comprehensive data for identifying risk factors for adolescent marijuana use is typically self-report, which may be over- or under-reported for a variety of reasons, including stigmatization, peer-pressure, or fear of being discovered.
OBJECTIVES: To identify the prevalence of adolescent marijuana use in Washington State, and the associated risk and protective factors, while controlling for and estimating the extent of misreporting, and its determinants.
METHOD: Data came from the 2014 Washington State Healthy Youth Survey. We accounted for missingness using chained multivariate imputation equations, resulting in 33,320 complete observations. Our model was estimated using a maximum likelihood multiple regression designed to control for systematic misclassification in binary dependent variables.
RESULTS: Approximately 12% of Washington adolescents claimed to have used marijuana in the past 30 days. Our estimates indicate this figure is likely closer to 18%. Determinants of use included use of other substances, gender, age, and measures of deviant social influences, personality/attitude, school and family bonds, bullying, and acquisition ease. Determinants of misreporting included use of other substances, gender, parental education, and family bonds.
CONCLUSIONS: Failing to control for misreporting considerably underestimates the prevalence of marijuana use among adolescents. Our model allows us to better identify at-risk adolescents and inform focused prevention efforts.

PMID: 30362862 [PubMed - indexed for MEDLINE]

A cause of recurrent strokes: carotid webs detected by CT angiogram.

BJR Case Rep. 2018;4(1):20170066

Authors: Smyth H, Byrne D, Hayden D, Eoin K, Murphy S

Abstract
Carotid webs are an uncommon cause of recurrent ischaemic strokes. They are considered a form of fibromuscular dysplasia, possibly developmental in origin, with non-inflammatory and non-atherosclerotic features and a characteristic appearance on CT angiography. They have been described as a thin intraluminal filling defect along the posterior wall of the carotid bulb in oblique sagittal reformats and a septum on axial CT angiography. Here we summarize two cases of ischaemic strokes secondary to carotid webs with characteristic images. Detection and awareness of carotid webs and their imaging features among radiologists and physicians are important as it is associated with a high risk of recurrent cerebrovascular events.

PMID: 30363186 [PubMed]

Towards a non-invasive cardiac arrest monitor: An in vivo pilot study.

Resuscitation. 2019 01;134:76-80

Authors: Kucewicz JC, Salcido DD, Adedipe AA, Truong K, Nichol G, Mourad PD

Abstract
INTRODUCTION: Hemodynamic-guided cardiopulmonary resuscitation (HGCPR) achieves better outcomes than standard resuscitation. Currently, HGCPR requires an invasive procedure, infeasible during resuscitation. Non-invasive measures of blood flow could provide useful hemodynamic guidance to rescuers.
OBJECTIVE: We describe initial efforts to develop a device that detects, analyzes, and measures the velocity of carotid artery blood flow (CABF) towards the brain at pre-arrest baseline ('baseline') and during cardiopulmonary resuscitation, here tested in a swine model of cardiac arrest (CA). A key element of that device consists of non-imaging diagnostic ultrasound, due to its simplicity and small form factor, hence potential for deployment during HGCPR in a bandage placed on the neck.
METHODS: Sixteen mixed-breed domestic swine were sedated, anesthetized and paralyzed, followed by endotracheal intubation and mechanical ventilation. Cardiac arrest was induced with a 3-s 100 mA transthoracic shock or bolus of fentanyl, after which all animals received mechanical CPR. A non-imaging ultrasound probe was manually applied to the neck over the carotid artery to capture CABF during baseline, as verified with diagnostic ultrasound imaging, and during mechanical resuscitation.
RESULTS: We successfully collected CABF measurements at baseline in 14/16 swine and during attempted resuscitation with mechanical chest compression in 5/16 swine. Signal characteristics include peak blood flow both towards (90.4 +/-20.4 cm/s) and away from the brain (-44.2 +/-31.8 cm/s) during resuscitation, each larger than flow towards (41.7+/-14.8 cm/s) and away from brain (-3.0 +/-7.8 cm/s) during baseline.
CONCLUSION: Measurement of CABF before and during CPR in swine with a non-imaging ultrasound probe is feasible before CA and informative when achieved during CPR. For example, observations of reverse flow within the carotid artery during CPR merits further study for its prevalence and effect on resuscitation outcomes. Also, tissue motion represents a significant obstacle for CABF measurement during CPR. Additional work will determine the feasibility and utility of non-imaging ultrasound measurements of CABF during resuscitation.

PMID: 30365974 [PubMed - indexed for MEDLINE]

Reply: Corticosteroids compromise survival in glioblastoma in part through their elevation of blood glucose levels.

Brain. 2017 03 01;140(3):e17

Authors: Weller M, Holland EC, Hambardzumyan D

PMID: 28007996 [PubMed - indexed for MEDLINE]

Whole genome analysis of Yersinia ruckeri isolated over 27 years in Australia and New Zealand reveals geographical endemism over multiple lineages and recent evolution under host selection.

Microb Genom. 2016 11;2(11):e000095

Authors: Barnes AC, Delamare-Deboutteville J, Gudkovs N, Brosnahan C, Morrison R, Carson J

Abstract
Yersinia ruckeri is a salmonid pathogen with widespread distribution in cool-temperate waters including Australia and New Zealand, two isolated environments with recently developed salmonid farming industries. Phylogenetic comparison of 58 isolates from Australia, New Zealand, USA, Chile, Finland and China based on non-recombinant core genome SNPs revealed multiple deep-branching lineages, with a most recent common ancestor estimated at 18 500 years BP (12 355-24 757 95% HPD) and evidence of Australasian endemism. Evolution within the Tasmanian Atlantic salmon serotype O1b lineage has been slow, with 63 SNPs describing the variance over 27 years. Isolates from the prevailing lineage are poorly/non-motile compared to a lineage pre-vaccination, introduced in 1997, which is highly motile but has not been isolated since from epizootics. A non-motile phenotype has arisen independently in Tasmania compared to Europe and USA through a frameshift in fliI, encoding the ATPase of the flagella cluster. We report for the first time lipopolysaccharide O-antigen serotype O2 isolates in Tasmania. This phenotype results from deletion of the O-antigen cluster and consequent loss of high-molecular-weight O-antigen. This phenomenon has occurred independently on three occasions on three continents (Australasia, North America and Asia) as O2 isolates from the USA, China and Tasmania share the O-antigen deletion but occupy distant lineages. Despite the European and North American origins of the Australasian salmonid stocks, the lineages of Y. ruckeri in Australia and New Zealand are distinct from those of the northern hemisphere, suggesting they are pre-existing ancient strains that have emerged and evolved with the introduction of susceptible hosts following European colonization.

PMID: 28348835 [PubMed - indexed for MEDLINE]

Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research.

Lancet Neurol. 2017 12;16(12):987-1048

Authors: Maas AIR, Menon DK, Adelson PD, Andelic N, Bell MJ, Belli A, Bragge P, Brazinova A, Büki A, Chesnut RM, Citerio G, Coburn M, Cooper DJ, Crowder AT, Czeiter E, Czosnyka M, Diaz-Arrastia R, Dreier JP, Duhaime AC, Ercole A, van Essen TA, Feigin VL, Gao G, Giacino J, Gonzalez-Lara LE, Gruen RL, Gupta D, Hartings JA, Hill S, Jiang JY, Ketharanathan N, Kompanje EJO, Lanyon L, Laureys S, Lecky F, Levin H, Lingsma HF, Maegele M, Majdan M, Manley G, Marsteller J, Mascia L, McFadyen C, Mondello S, Newcombe V, Palotie A, Parizel PM, Peul W, Piercy J, Polinder S, Puybasset L, Rasmussen TE, Rossaint R, Smielewski P, Söderberg J, Stanworth SJ, Stein MB, von Steinbüchel N, Stewart W, Steyerberg EW, Stocchetti N, Synnot A, Te Ao B, Tenovuo O, Theadom A, Tibboel D, Videtta W, Wang KKW, Williams WH, Wilson L, Yaffe K, InTBIR Participants and Investigators

PMID: 29122524 [PubMed - indexed for MEDLINE]

Splicing of an automodulatory domain in Cav1.4 Ca2+ channels confers distinct regulation by calmodulin.

J Gen Physiol. 2018 12 03;150(12):1676-1687

Authors: Williams B, Haeseleer F, Lee A

Abstract
Ca2+ influx through Cav1.4 L-type Ca2+ channels supports the sustained release of glutamate from photoreceptor synaptic terminals in darkness, a process that is critical for vision. Consistent with this role, Cav1.4 exhibits weak Ca2+-dependent inactivation (CDI)-a negative feedback regulation mediated by Ca2+-bound calmodulin (CaM). CaM binds to a conserved IQ domain in the proximal C-terminal domain of Cav channels, but in Cav1.4, a C-terminal modulatory domain (CTM) disrupts interactions with CaM. Exon 47 encodes a portion of the CTM and is deleted in a Cav1.4 splice variant (Cav1.4Δex47) that is highly expressed in the human retina. Cav1.4Δex47 exhibits CDI and enhanced voltage-dependent activation, similar to that caused by a mutation that is associated with congenital stationary night blindness type 2, in which the CTM is deleted (K1591X). The presence of CDI and very negative activation thresholds in a naturally occurring variant of Cav1.4 are perplexing considering that these properties are expected to be maladaptive for visual signaling and result in night blindness in the case of K1591X. Here we show that Cav1.4Δex47 and K1591X exhibit fundamental differences in their regulation by CaM. In Cav1.4Δex47, CDI requires both the N-terminal (N lobe) and C-terminal (C lobe) lobes of CaM to bind Ca2+, whereas CDI in K1591X is driven mainly by Ca2+ binding to the C lobe. Moreover, the CaM N lobe causes a Ca2+-dependent enhancement of activation of Cav1.4Δex47 but not K1591X. We conclude that the residual CTM in Cav1.4Δex47 enables a form of CaM N lobe regulation of activation and CDI that is absent in K1591X. Interaction with the N lobe of CaM, which is more sensitive to global elevations in cytosolic Ca2+ than the C lobe, may allow Cav1.4Δex47 to be modulated by a wider range of synaptic Ca2+ concentrations than K1591X; this may distinguish the normal physiological function of Cav1.4Δex47 from the pathological consequences of K1591X.

PMID: 30355583 [PubMed - indexed for MEDLINE]

Acute hemiparesis and status epilepticus following endoscopic esophageal balloon dilation: is it really a stroke?

Clin J Gastroenterol. 2019 Apr;12(2):171-175

Authors: Di Mascio N, MacMathuna P, Murphy S, Kavanagh EC

Abstract
A 68-year-old gentleman was referred for elective upper gastrointestinal endoscopy on a background of dysphagia and esophageal candidiasis. A benign peptic stricture was noted, managed with balloon dilation without apparent immediate complication. At completion, however, the patient became confused and agitated, with no improvement despite the reversal of sedation. Two hours later, with all investigations for suspected complications including perforation, negative, he developed acute left-sided hemiparesis. Urgent computed tomography brain and angiogram were both normal. A diagnosis of acute ischemic stroke was made, and the patient was thrombolysed in the Intensive Care Unit. No improvement of the stroke was observed. Seven hours later, the patient developed generalized tonic-clonic seizures that required phenytoin infusion and subsequent intubation and ventilation. The following morning, magnetic resonance imaging brain did not reveal features of a stroke, but instead diffuse cortical and white matter edema in the right frontal lobe, consistent with atypical, unilateral Posterior Reversible Encephalopathy Syndrome (PRES). Signs and symptoms resolved rapidly over the course of several days, and after one month the patient made a complete clinical and radiological recovery. To our knowledge, this is the only case of PRES to arise in the setting of endoscopy and esophageal dilation.

PMID: 30343464 [PubMed - indexed for MEDLINE]

CCP1 promotes mitochondrial fusion and motility to prevent Purkinje cell neuron loss in pcd mice.

J Cell Biol. 2019 01 07;218(1):206-219

Authors: Gilmore-Hall S, Kuo J, Ward JM, Zahra R, Morrison RS, Perkins G, La Spada AR

Abstract
A perplexing question in neurodegeneration is why different neurons degenerate. The Purkinje cell degeneration (pcd) mouse displays a dramatic phenotype of degeneration of cerebellar Purkinje cells. Loss of CCP1/Nna1 deglutamylation of tubulin accounts for pcd neurodegeneration, but the mechanism is unknown. In this study, we modulated the dosage of fission and fusion genes in a Drosophila melanogaster loss-of-function model and found that mitochondrial fragmentation and disease phenotypes were rescued by reduced Drp1. We observed mitochondrial fragmentation in CCP1 null cells and in neurons from pcd mice, and we documented reduced mitochondrial fusion in cells lacking CCP1. We examined the effect of tubulin hyperglutamylation on microtubule-mediated mitochondrial motility in pcd neurons and noted markedly reduced retrograde axonal transport. Mitochondrial stress promoted Parkin-dependent turnover of CCP1, and CCP1 and Parkin physically interacted. Our results indicate that CCP1 regulates mitochondrial motility through deglutamylation of tubulin and that loss of CCP1-mediated mitochondrial fusion accounts for the exquisite vulnerability of Purkinje neurons in pcd mice.

PMID: 30337352 [PubMed - indexed for MEDLINE]

The impact of marriage on the overall survival of prostate cancer patients: A Surveillance, Epidemiology, and End Results (SEER) analysis.

Can Urol Assoc J. 2018 Oct 15;:

Authors: Liu Y, Xia Q, Xia J, Zhu H, Jiang H, Chen X, Zheng Y, Zhang F, Li S

Abstract
INTRODUCTION: Marital status has long been associated with positive patient outcomes in several malignances; however, little is known about its influence on prostate cancer. We analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database to evaluate whether married patients with prostate cancer had a better prognosis than the unmarried.
METHODS: We identified 824 554 patients diagnosed with prostate cancer between 1973 and 2012 in the SEER database. Using the Cox proportional hazard models, we analyzed the impact of marital status (single, married, divorced/separated, and widowed) on survival after diagnosis with prostate cancer. Chi-square tests were used to analyze the association between marital status and other variables, and the Kaplan-Meier method was used to estimate survival curves.
RESULTS: Married men were more likely to be diagnosed with a lower Gleason score and undergo surgery than patients in the other groups (p<0.001). The married group had a lower risk of mortality caused by prostate cancer than the other groups. The five-year survival rate for married patients was higher than that for patients in the other groups.
CONCLUSIONS: Marital status is a prognostic factor for the survival of prostate cancer patients, as being married was associated with better outcomes.

PMID: 30332597 [PubMed - as supplied by publisher]

Characterization of Host Responses during Pseudomonas aeruginosa Acute Infection in the Lungs and Blood and after Treatment with the Synthetic Immunomodulatory Peptide IDR-1002.

Infect Immun. 2019 01;87(1):

Authors: Wuerth K, Lee AHY, Falsafi R, Gill EE, Hancock REW

Abstract
Pseudomonas aeruginosa is an opportunistic pathogen that causes nosocomial pneumonia and infects patients with cystic fibrosis. P. aeruginosa lung infections are difficult to treat due to bacterial resistance to antibiotics, and strains with multidrug resistance are becoming more prevalent. Here, we examined the use of a small host defense peptide, innate defense regulator 1002 (IDR-1002), in an acute P. aeruginosa lung infection in vivo IDR-1002 significantly reduced the bacterial burden in bronchoalveolar lavage fluid (BALF), as well as MCP-1 in BALF and serum, KC in serum, and interleukin 6 (IL-6) in BALF. Transcriptome sequencing (RNA-Seq) was conducted on lungs and whole blood, and the effects of P. aeruginosa, IDR-1002, and the combination of P. aeruginosa and IDR-1002 were evaluated. Differential gene expression analysis showed that P. aeruginosa increased multiple inflammatory and innate immune pathways, as well as affected hemostasis, matrix metalloproteinases, collagen biosynthesis, and various metabolism pathways in the lungs and/or blood. Infected mice treated with IDR-1002 had significant changes in gene expression compared to untreated infected mice, with fewer differentially expressed genes associated with the inflammatory and innate immune responses to microbial infection, and treatment also affected morphogenesis, certain metabolic pathways, and lymphocyte activation. Overall, these results showed that IDR-1002 was effective in treating P. aeruginosa acute lung infections and associated inflammation.

PMID: 30323028 [PubMed - indexed for MEDLINE]

Adoption of Neutralizing Buffered Peptone Water Coincides with Changes in Apparent Prevalence of Salmonella and Campylobacter of Broiler Rinse Samples.

J Food Prot. 2018 11;81(11):1851-1863

Authors: Williams MS, Ebel ED, Hretz SA, Golden NJ

Abstract
Buffered peptone water is the rinsate commonly used for chicken rinse sampling. A new formulation of buffered peptone water was developed to address concerns about the transfer of antimicrobials, used during poultry slaughter and processing, into the rinsate. This new formulation contains additives to neutralize the antimicrobials, and this neutralizing buffered peptone water replaced the original formulation for all chicken carcass and chicken part sampling programs run by the Food Safety and Inspection Service beginning in July 2016. Our goal was to determine whether the change in rinsate resulted in significant differences in the observed proportion of positive chicken rinse samples for both Salmonella and Campylobacter. This assessment compared sampling results for the 12-month periods before and after implementation. The proportion of carcass samples that tested positive for Salmonella increased from approximately 0.02 to almost 0.06. Concurrently, the proportion of chicken part samples that tested for Campylobacter decreased from 0.15 to 0.04. There were no significant differences associated with neutralizing buffered peptone water for the other two product-pathogen pairs. Further analysis of the effect of the new rinsate on corporations that operate multiple establishments demonstrated that changes in the percent positive rates differed across the corporations, with some corporations being unaffected, while others saw all of the establishments operated by the corporation move from passing to failing the performance standard and vice versa. The results validated earlier concerns that antimicrobial contamination of rinse samples was causing false-negative Salmonella testing results for chicken carcasses. The results also indicate that additional development work may still be required before the rinsate is sufficiently robust for its use in Campylobacter testing.

PMID: 30325223 [PubMed - indexed for MEDLINE]

Predictors of Major Bleeding Among Working-Age Adults with Atrial Fibrillation: Evaluating the Effects of Potential Drug-drug Interactions and Switching from Warfarin to Non-vitamin K Oral Anticoagulants.

Cardiovasc Drugs Ther. 2018 12;32(6):591-600

Authors: Feng X, Sambamoorthi U, Innes K, Castelli G, LeMasters T, Xiong L, Williams MU, Tan X

Abstract
PURPOSE: This study aims to evaluate the associations between switching from warfarin to non-vitamin K oral anticoagulants (NOACs), exposure to potential drug-drug interactions (DDIs), and major bleeding events in working-age adults with atrial fibrillation (AF).
METHODS: We conducted a retrospective cohort study using the claims database of commercially insured working-age adults with AF from 2010 to 2015. Switchers were defined as patients who switched from warfarin to NOAC; non-switchers were defined as those who remained on warfarin. We developed novel methods to calculate the number and proportion of days with potential DDIs with NOAC/warfarin. Multivariate logistic regressions were utilized to evaluate the associations between switching to NOACs, exposure to potential DDIs, and major bleeding events.
RESULTS: Among a total of 4126 patients with AF, we found a significantly lower number of potential DDIs and the average proportion of days with potential DDIs in switchers than non-switchers. The number of potential DDIs (AOR 1.14, 95% CI 1.02-1.27) and the HAS-BLED score (AOR 1.64, 95% CI 1.48-1.82) were significantly and positively associated with the likelihood of a major bleeding event. The proportion of days with potential DDIs was also significantly and positively associated with risk for bleeding (AOR 1.42, 95% CI 1.03, 1.96). We did not find significant associations between switching to NOACs and major bleeding events.
CONCLUSIONS: The number and duration of potential DDIs and patients' comorbidity burden are important factors to consider in the management of bleeding risk in working-age AF adults who take oral anticoagulants.

PMID: 30315487 [PubMed - indexed for MEDLINE]

Effects of Prolonged GRP78 Haploinsufficiency on Organ Homeostasis, Behavior, Cancer and Chemotoxic Resistance in Aged Mice.

Sci Rep. 2017 02 01;7:40919

Authors: Lee AS, Brandhorst S, Rangel DF, Navarrete G, Cohen P, Longo VD, Chen J, Groshen S, Morgan TE, Dubeau L

Abstract
GRP78, a multifunctional protein with potent cytoprotective properties, is an emerging therapeutic target to combat cancer development, progression and drug resistance. The biological consequences of prolonged reduction in expression of this essential chaperone which so far has been studied primarily in young mice, was investigated in older mice, as older individuals are likely to be important recipients of anti-GRP78 therapy. We followed cohorts of Grp78+/+ and Grp78+/- male and female mice up to 2 years of age in three different genetic backgrounds and characterized them with respect to body weight, organ integrity, behavioral and memory performance, cancer, inflammation and chemotoxic response. Our results reveal that body weight, organ development and integrity were not impaired in aged Grp78+/- mice. No significant effect on cancer incidence and inflammation was observed in aging mice. Interestingly, our studies detected some subtle differential trends between the WT and Grp78+/- mice in some test parameters dependent on gender and genetic background. Our studies provide the first evidence that GRP78 haploinsufficiency for up to 2 years of age has no major deleterious effect in rodents of different genetic background, supporting the merit of anti-GRP78 drugs in treatment of cancer and other diseases affecting the elderly.

PMID: 28145503 [PubMed - indexed for MEDLINE]

Retrograde 3D rotational venography (3DRV) for venous sinus stent placement in idiopathic intracranial hypertension.

J Neurointerv Surg. 2018 Aug;10(8):777-779

Authors: Young CC, Morton RP, Ghodke BV, Levitt MR

Abstract
BACKGROUND: Dural venous sinus stenting has emerged as an effective and durable treatment for idiopathic intracranial hypertension (IIH). Improved visualization of the venous sinuses can improve stent placement.
METHODS: We present two cases of IIH treated with venous sinus stenting in which retrograde three-dimensional rotational venography (3DRV) provided superior anatomical details of the venous sinuses for optimal sizing and positioning of stent.
RESULTS: Comparison of pre-stent 3DRV with post-stent contrast-enhanced flat panel detector CT allowed confirmation of stent placement and the result of stenosis dilation.
CONCLUSION: This 3DRV technique provides precise visualization of venous sinus stenosis prior to stenting without the need for arterial cerebral angiography during the treatment course.

PMID: 29175828 [PubMed - indexed for MEDLINE]

Automatic Inference of Sequence from Low-Resolution Crystallographic Data.

Structure. 2018 11 06;26(11):1546-1554.e2

Authors: Ben-Aharon Z, Levitt M, Kalisman N

Abstract
At resolutions worse than 3.5 Å, the electron density is weak or nonexistent at the locations of the side chains. Consequently, the assignment of the protein sequences to their correct positions along the backbone is a difficult problem. In this work, we propose a fully automated computational approach to assign sequence at low resolution. It is based on our surprising observation that standard reciprocal-space indicators, such as the initial unrefined R value, are sensitive enough to detect an erroneous sequence assignment of even a single backbone position. Our approach correctly determines the amino acid type for 15%, 13%, and 9% of the backbone positions in crystallographic datasets with resolutions of 4.0 Å, 4.5 Å, and 5.0 Å, respectively. We implement these findings in an application for threading a sequence onto a backbone structure. For the three resolution ranges, the application threads 83%, 81%, and 64% of the sequences exactly as in the deposited PDB structures.

PMID: 30293812 [PubMed - indexed for MEDLINE]