UW Neurological Surgery Recent PubMed Publications

Subtraction multiphase CT angiography: A new technique for faster detection of intracranial arterial occlusions.

Eur Radiol. 2018 Apr;28(4):1731-1738

Authors: Byrne D, Walsh JP, Sugrue G, Stanley E, Marnane M, Walsh CD, Kelly P, Murphy S, Kavanagh EC, MacMahon PJ

Abstract
OBJECTIVE: To describe and evaluate a novel technical development to improve detection of intracranial vessel occlusions using multiphase CT angiography (MPCTA).
MATERIALS AND METHODS: The institutional ethics committee approved the study. Fifty patients (30 consecutive distal (M2 or smaller) anterior circulation occlusions, ten M1 occlusions, ten cases without occlusion) presenting with suspected AIS who underwent MPCTA were included. Post-processing of MPCTA studies created "subtraction" and "delayed enhancement" (DE) datasets. Initially, non-contrast CT and MPCTA studies for each patient were evaluated. Readers' confidence, speed and sensitivity of detection of intracranial vessel occlusions were recorded. After an interval of at least 4 weeks, readers were provided with post-processed images and studies were re-evaluated.
RESULTS: While the sensitivity of detection of intracranial vessel occlusions was equal for both conventional MPCTA and subMPCTA, the mean time taken to identify a vessel occlusion decreased by 64 % using subMPCTA (16 s vs. 45 s with conventional MPCTA) (p<0.001). In addition, confidence in interpretation improved (from 4.4 to 4.9) using subMPCTA (p<0.001).
CONCLUSION: SubMPCTA is a novel technique that aids in identifying small intracranial vessel occlusions in the suspected AIS patient. SubMPCTA increases confidence in interpretation and reduces the time taken to detect intracranial vessel occlusions.
KEY POINTS: • SubMPCTA processes MPCTA data to better demonstrate intracranial arterial occlusions. • SubMPCTA increases confidence and speed of interpretation of MPCTA studies. • SubMPCTA may aid in rapidly differentiating acute ischaemic stroke from stroke mimics.

PMID: 29134350 [PubMed - indexed for MEDLINE]

Creating a virtual community of practice: an evaluation of ophthalmology-optometry Project ECHO.

Eye (Lond). 2018 12;32(12):1910-1911

Authors: Williams M, Blanco AA, Hogg R, Mahon G, McMullan M, Curran R, Watson M

Abstract

PMID: 30068927 [PubMed - indexed for MEDLINE]

Anesthetics Have Different Effects on the Electrocorticographic Spectra of Wild-type and Mitochondrial Mutant Mice.

Anesthesiology. 2018 10;129(4):744-755

Authors: Carspecken CW, Chanprasert S, Kalume F, Sedensky MM, Morgan PG

Abstract
WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Knockout of the mitochondrial protein Ndufs4 (Ndufs4[KO]) in mice causes hypersensitivity to volatile anesthetics but resistance to ketamine. The authors hypothesized that electrocorticographic changes underlying the responses of Ndufs4(KO) to volatile anesthetics and to ketamine would be similar in mutant and control mice.
METHODS: Electrocorticographic recordings at equipotent volatile anesthetic concentrations were compared between genotypes. In separate studies, control and cell type-specific Ndufs4(KO) mice were anesthetized with intraperitoneal ketamine to determine their ED50s.
RESULTS: Ndufs4 (KO) did not differ from controls in baseline electrocorticography (N = 5). Compared to baseline, controls exposed to isoflurane (EC50) lost power (expressed as mean baseline [µV/Hz]; mean isoflurane [µV/Hz]) in delta (2.45; 0.50), theta (1.41; 0.16), alpha (0.23; 0.05), beta (0.066; 0.016), and gamma (0.020; 0.005) frequency bands (N = 5). Compared to baseline, at their isoflurane EC50, Ndufs4(KO) maintained power in delta (1.08; 1.38), theta (0.36; 0.26), and alpha (0.09; 0.069) frequency bands but decreased in beta (0.041; 0.023) and gamma (0.020; 0.0068) frequency bands (N = 5). Similar results were seen for both genotypes in halothane. Vesicular glutamate transporter 2 (VGLUT2)-specific Ndufs4(KO) mice were markedly resistant to ketamine (ED50; 125 mg/kg) compared to control mice (ED50; 75 mg/kg; N = 6). At their respective ED95s for ketamine, mutant (N = 5) electrocorticography spectra showed a decrease in power in the beta (0.040; 0.020) and gamma (0.035; 0.015) frequency bands not seen in controls (N = 7).
CONCLUSIONS: Significant differences exist between the electrocorticographies of mutant and control mice at equipotent doses for volatile anesthetics and ketamine. The energetic state specifically of excitatory neurons determines the behavioral response to ketamine.

PMID: 30074932 [PubMed - indexed for MEDLINE]

Risk of Major Bleeding with Ibrutinib.

Clin Lymphoma Myeloma Leuk. 2018 11;18(11):755-761

Authors: Mock J, Kunk PR, Palkimas S, Sen JM, Devitt M, Horton B, Portell CA, Williams ME, Maitland H

Abstract
BACKGROUND: The Bruton tyrosine kinase inhibitor, ibrutinib, is an effective therapy against mature B-cell malignancies. Although generally well tolerated, serious bleeding emerged during developmental clinical trials as an unexpected, although uncommon, adverse event. As the use of ibrutinib increases outside of the clinical trial setting and in patients with more comorbidities, the rate of major bleeding could be greater.
MATERIALS AND METHODS: A retrospective analysis the data from all patients at our center and its regional clinics who had been prescribed ibrutinib from January 2012 to May 2016 were reviewed for demographic data, comorbid illnesses, bleeding events, and concurrent medications.
RESULTS: We identified 70 patients. Bleeding of any grade occurred in 56% of patients, mostly grade 1 to 2 bruising and epistaxis. Major bleeding, defined as grade ≥ 3, occurred in 19% of patients, greater than previously reported. Anemia (hemoglobin < 12 g/dL; hazard ratio [HR], 5.0; 95% confidence interval [CI], 1.4-18.2; P = .02) and an elevated international normalized ratio (> 1.5; HR, 9.5; 95% CI, 2.7-33.5; P < .01) at ibrutinib initiation were associated with an increased risk of major bleeding. Of those with major bleeding, most patients were also taking an antiplatelet agent (70%), an anticoagulant (17%), or a CYP 3A4 inhibitor (7%), with 13% taking both antiplatelet and anticoagulant medications. The use of both antiplatelet and anticoagulant therapy significantly increased the risk of a major bleed event (HR, 19.2; 95% CI, 2.3-166.7; P < .01).
CONCLUSION: The results of the present study have demonstrated a greater rate of major bleeding with ibrutinib use in a standard clinical setting than previously reported. Patients with anemia or an elevated international normalized ratio or requiring anticoagulant and/or antiplatelet medications during ibrutinib therapy have a significantly increased risk of major bleeding. Careful consideration of the risks and benefits for this population is needed. The combination of antiplatelet and anticoagulation medications with ibrutinib therapy is of particular concern.

PMID: 30077698 [PubMed - indexed for MEDLINE]

Approaches to closed-loop deep brain stimulation for movement disorders.

Neurosurg Focus. 2018 08;45(2):E2

Authors: Kuo CH, White-Dzuro GA, Ko AL

Abstract
OBJECTIVE Deep brain stimulation (DBS) is a safe and effective therapy for movement disorders, such as Parkinson's disease (PD), essential tremor (ET), and dystonia. There is considerable interest in developing "closed-loop" DBS devices capable of modulating stimulation in response to sensor feedback. In this paper, the authors review related literature and present selected approaches to signal sources and approaches to feedback being considered for deployment in closed-loop systems. METHODS A literature search using the keywords "closed-loop DBS" and "adaptive DBS" was performed in the PubMed database. The search was conducted for all articles published up until March 2018. An in-depth review was not performed for publications not written in the English language, nonhuman studies, or topics other than Parkinson's disease or essential tremor, specifically epilepsy and psychiatric conditions. RESULTS The search returned 256 articles. A total of 71 articles were primary studies in humans, of which 50 focused on treatment of movement disorders. These articles were reviewed with the aim of providing an overview of the features of closed-loop systems, with particular attention paid to signal sources and biomarkers, general approaches to feedback control, and clinical data when available. CONCLUSIONS Closed-loop DBS seeks to employ biomarkers, derived from sensors such as electromyography, electrocorticography, and local field potentials, to provide real-time, patient-responsive therapy for movement disorders. Most studies appear to focus on the treatment of Parkinson's disease. Several approaches hold promise, but additional studies are required to determine which approaches are feasible, efficacious, and efficient.

PMID: 30064321 [PubMed - indexed for MEDLINE]

Anticipating the Direction of Soccer Penalty Shots Depends on the Speed and Technique of the Kick.

Sports (Basel). 2018 Jul 29;6(3):

Authors: Hunter AH, Murphy SC, Angilletta MJ, Wilson RS

Abstract
To succeed at a sport, athletes must manage the biomechanical trade-offs that constrain their performance. Here, we investigate a previously unknown trade-off in soccer: how the speed of a kick makes the outcome more predictable to an opponent. For this analysis, we focused on penalty kicks to build on previous models of factors that influence scoring. More than 700 participants completed an online survey, watching videos of penalty shots from the perspective of a goalkeeper. Participants (ranging in soccer playing experience from never played to professional) watched 60 penalty kicks, each of which was occluded at a particular moment (-0.4 s to 0.0 s) before the kicker contacted the ball. For each kick, participants had to predict shot direction toward the goal (left or right). As expected, predictions became more accurate as time of occlusion approached ball contact. However, the effect of occlusion was more pronounced when players kicked with the side of the foot than when they kicked with the top of the foot (instep). For side-foot kicks, the direction of shots was predicted more accurately for faster kicks, especially when a large portion of the kicker's approach was presented. Given the trade-off between kicking speed and directional predictability, a penalty kicker might benefit from kicking below their maximal speed.

PMID: 30060599 [PubMed]

Early Response Assessment in Pancreatic Ductal Adenocarcinoma Through Integrated PET/MRI.

AJR Am J Roentgenol. 2018 11;211(5):1010-1019

Authors: Wang ZJ, Behr S, Consunji MV, Yeh BM, Ohliger MA, Gao K, Ko AH, Cinar P, Tempero MA, Collisson EA

Abstract
OBJECTIVE: The purpose of this study is to investigate early changes in 18F-FDG PET/MRI metrics after treatment in patients with advanced pancreatic ductal adenocarcinoma (PDAC) and to correlate those changes with eventual tumor response at standard-of-care CT.
SUBJECTS AND METHODS: Thirteen patients with advanced PDAC underwent integrated FDG PET/MRI before and 4 weeks after treatment initiation. Patients were classified as responders or nonresponders according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 at subsequent CT performed 8-12 weeks after treatment initiation. Changes in the primary tumor's maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) determined at PET and apparent diffusion coefficient (ADC) determined at DWI at 4 weeks were compared between responders and nonresponders.
RESULTS: Seven patients had a partial response according to RECIST, and six did not. Responders displayed significantly greater decreases in MTV (p = 0.003) and TLG (p = 0.006) in the primary pancreatic tumor at 4 weeks. Responders also displayed a greater increase in the mean (p = 0.004) and minimum (p = 0.024) ADC of the primary tumors. Tumor size change at 4 weeks was not significantly different between responders and nonresponders (p = 0.11). PET responders enjoyed longer progression-free survival (PFS) (p = 0.0004) and overall survival (OS) (p = 0.013) than did nonresponders, using either a 60% reduction in MTV or 65% reduction in TLG as a threshold. MRI responders had significantly longer PFS (p = 0.0002) and OS (p = 0.027) than did nonresponders, using a 20% increase in either mean or minimum ADC as a threshold.
CONCLUSION: Integrated PET/MRI can provide early response assessment in patients with advanced PDAC, thus potentially allowing early treatment adaptation in nonresponders.

PMID: 30063366 [PubMed - indexed for MEDLINE]

Plasmodium 18S rRNA of intravenously administered sporozoites does not persist in peripheral blood.

Malar J. 2018 Jul 27;17(1):275

Authors: Murphy SC, Ishizuka AS, Billman ZP, Olsen TM, Seilie AM, Chang M, Smith N, Chuenchob V, Chakravarty S, Sim BKL, Kappe SHI, Hoffman SL, Seder RA

Abstract
BACKGROUND: Plasmodium 18S rRNA is a biomarker used to monitor blood-stage infections in malaria clinical trials. Plasmodium sporozoites also express this biomarker, and there is conflicting evidence about how long sporozoite-derived 18S rRNA persists in peripheral blood. If present in blood for an extended timeframe, sporozoite-derived 18S rRNA could complicate use as a blood-stage biomarker.
METHODS: Blood samples from Plasmodium yoelii infected mice were tested for Plasmodium 18S rRNA and their coding genes (rDNA) using sensitive quantitative reverse transcription PCR and quantitative PCR assays, respectively. Blood and tissues from Plasmodium falciparum sporozoite (PfSPZ)-infected rhesus macaques were similarly tested.
RESULTS: In mice, when P. yoelii sporozoite inoculation and blood collection were performed at the same site (tail vein), low level rDNA positivity persisted for 2 days post-infection. Compared to intact parasites with high rRNA-to-rDNA ratios, this low level positivity was accompanied by no increase in rRNA-to-rDNA, indicating detection of residual, non-viable parasite rDNA. When P. yoelii sporozoites were administered via the retro-orbital vein and blood sampled by cardiac puncture, neither P. yoelii 18S rRNA nor rDNA were detected 24 h post-infection. Similarly, there was no P. falciparum 18S rRNA detected in blood of rhesus macaques 3 days after intravenous injection with extremely high doses of PfSPZ. Plasmodium 18S rRNA in the rhesus livers increased by approximately 101-fold from 3 to 6 days post infection, indicating liver-stage proliferation.
CONCLUSIONS: Beyond the first few hours after injection, sporozoite-derived Plasmodium 18S rRNA was not detected in peripheral blood. Diagnostics based on 18S rRNA are unlikely to be confounded by sporozoite inocula in human clinical trials.

PMID: 30053881 [PubMed - in process]

Role of a conserved glutamine in the function of voltage-gated Ca2+ channels revealed by a mutation in human CACNA1D.

J Biol Chem. 2018 09 14;293(37):14444-14454

Authors: Garza-Lopez E, Lopez JA, Hagen J, Sheffer R, Meiner V, Lee A

Abstract
Voltage-gated Cav Ca2+ channels play crucial roles in regulating gene transcription, neuronal excitability, and synaptic transmission. Natural or pathological variations in Cav channels have yielded rich insights into the molecular determinants controlling channel function. Here, we report the consequences of a natural, putatively disease-associated mutation in the CACNA1D gene encoding the pore-forming Cav1.3 α1 subunit. The mutation causes a substitution of a glutamine residue that is highly conserved in the extracellular S1-S2 loop of domain II in all Cav channels with a histidine and was identified by whole-exome sequencing of an individual with moderate hearing impairment, developmental delay, and epilepsy. When introduced into the rat Cav1.3 cDNA, Q558H significantly decreased the density of Ca2+ currents in transfected HEK293T cells. Gating current analyses and cell-surface biotinylation experiments suggested that the smaller current amplitudes caused by Q558H were because of decreased numbers of functional Cav1.3 channels at the cell surface. The substitution also produced more sustained Ca2+ currents by weakening voltage-dependent inactivation. When inserted into the corresponding locus of Cav2.1, the substitution had similar effects as in Cav1.3. However, the substitution introduced in Cav3.1 reduced current density, but had no effects on voltage-dependent inactivation. Our results reveal a critical extracellular determinant of current density for all Cav family members and of voltage-dependent inactivation of Cav1.3 and Cav2.1 channels.

PMID: 30054272 [PubMed - indexed for MEDLINE]

Vitamin D Levels in Patients with Colorectal Cancer Before and After Treatment Initiation.

J Gastrointest Cancer. 2019 Dec;50(4):769-779

Authors: Savoie MB, Paciorek A, Zhang L, Van Blarigan EL, Sommovilla N, Abrams D, Atreya CE, Bergsland EK, Chern H, Kelley RK, Ko A, Laffan A, Sarin A, Varma MG, Venook AP, Van Loon K

Abstract
PURPOSE: We aimed to described 25-hydroxyvitamin D [25(OH)D] levels in newly diagnosed colorectal cancer (CRC) patients and to re-evaluate levels after chemotherapy.
METHODS: Permanent residents of the San Francisco Bay Area with a new CRC diagnosis of any stage were recruited prior to any non-surgical therapy. Serum 25(OH)D levels were measured at time of diagnosis and 6-month follow-up. Supplement use was not restricted. The primary endpoint was the frequency of vitamin D deficiency in patients with newly diagnosed CRC of all stages. The Kruskal-Wallis and Spearman correlation tests were used to evaluate associations of patient characteristics with 25(OH)D levels.
RESULTS: Median 25(OH)D level at baseline was 27.0 ng/mL (range 7.2, 59.0); 65% of patients had insufficient levels (25(OH)D < 30 ng/mL) (n = 94). Race, disease stage, multivitamin use, vitamin D supplementation, and county of residence were associated with baseline 25(OH)D levels (P < 0.05). The median change in 25(OH)D from baseline to 6 months was - 0.7 ng/mL [- 19.4, 51.7] for patients treated with chemotherapy (n = 58) and 1.6 ng/mL [- 6.4, 33.2] for patients who did not receive chemotherapy (n = 19) (P = 0.26). For patients who received vitamin D supplementation during chemotherapy, the median 25(OH)D change was 8.3 ng/mL [- 7.6, 51.7] versus - 1.6 [- 19.4, 24.3] for chemotherapy patients who did not take vitamin D supplements (P = 0.02).
CONCLUSION: Among patients with a new diagnosis of CRC, most patients were found to have 25(OH)D levels consistent with either deficiency or insufficiency. In the subset of patients who received chemotherapy and took a vitamin D supplement, serum 25(OH)D levels increased, suggesting that vitamin D repletion is a feasible intervention during chemotherapy.

PMID: 30058032 [PubMed - indexed for MEDLINE]

Intra-abdominal complications following intestinal anastomoses by suture and staple techniques in dogs.

J Am Vet Med Assoc. 2018 Aug 15;253(4):437-443

Authors: DePompeo CM, Bond L, George YE, Mezzles MJ, Brourman JD, Chandler JC, Murphy SM, Pike F, Mason DR

Abstract
OBJECTIVE To compare the incidence of intra-abdominal complications in dogs following resection and functional end-to-end stapled anastomosis (FEESA) versus anastomosis with an end-to-end sutured technique for treatment of enteric lesions. DESIGN Multicenter, retrospective descriptive cohort study. ANIMALS 180 dogs. PROCEDURES Medical records of dogs undergoing intestinal resection and anastomosis at 3 nonaffiliated private practice specialty centers were retrospectively reviewed. Preoperative clinical variables, indication for surgery, surgical technique (sutured end-to-end anastomosis vs FEESA), and evidence of postoperative anastomosis site leakage (dehiscence) were recorded. Variables of interest were analyzed for associations with dehiscence. RESULTS Dehiscence rates of sutured and stapled anastomoses were 12 of 93 (13%) and 4 of 87 (5%), respectively; odds of postoperative dehiscence were significantly lower for dogs with FEESAs than for dogs with sutured anastomoses (OR, 0.28; 95% confidence interval, 0.09 to 0.94). Among dogs that underwent surgery for treatment of intestinal dehiscence after surgery at another facility, subsequent dehiscence developed in 3 of 5 with sutured anastomoses and 0 of 11 with stapled anastomoses. Dehiscence rates varied significantly among clinics. No other variable was associated with risk of dehiscence. Eleven of 16 dogs with dehiscence were euthanized without additional surgery. Impaction at the anastomosis site was identified months or years after surgery in 3 dogs (4 anastomosis sites) that had FEESAs. CONCLUSIONS AND CLINICAL RELEVANCE Odds for dehiscence were significantly greater for sutured end-to-end anastomoses than FEESAs, and dogs undergoing surgery for previous dehiscence were significantly more likely to experience a subsequent dehiscence with a sutured anastomosis. However, variability of procedure types and dehiscence rates among clinics suggested further research is needed to confirm these findings. Obstruction at the anastomosis site was identified as a potential long-term complication of FEESA.

PMID: 30058972 [PubMed - indexed for MEDLINE]

Aetiology of Eagle syndrome: ossification of the stylohyoid ligament.

QJM. 2018 Jul 28;:

Authors: Morrison RJ, Morrison PJ

PMID: 30060119 [PubMed - as supplied by publisher]

Cortical Brain-Computer Interface for Closed-Loop Deep Brain Stimulation.

IEEE Trans Neural Syst Rehabil Eng. 2017 Nov;25(11):2180-2187

Authors: Herron JA, Thompson MC, Brown T, Chizeck HJ, Ojemann JG, Ko AL

Abstract
Essential tremor is the most common neurological movement disorder. This progressive disease causes uncontrollable rhythmic motions-most often affecting the patient'sdominant upper extremity-thatoccur during volitional movement and make it difficult for the patient to perform everyday tasks. Medication may also become ineffective as the disorder progresses. For many patients, deep brain stimulation (DBS) of the thalamus is an effective means of treating this condition when medication fails. In current use, however, clinicians set the patient's stimulator to apply stimulation at all times-whether it is needed or not. This practice leads to excess power use, and more rapid depletion of batteries that require surgical replacement. In this paper, for the first time, neural sensing of movement (using chronically implanted cortical electrodes) is used to enable or disable stimulation for tremor. Therapeutic stimulation is delivered onlywhen the patient is actively using their effected limb, thereby reducing the total stimulation applied, and potentially extending the lifetime of surgically implanted batteries. This paper, which involves both implanted and external subsystems, paves the way for fully-implanted closed-loop DBS in the future.

PMID: 28541211 [PubMed - indexed for MEDLINE]

Operationalization of the Transition to Comfort Measures Only in the Neurocritical Care Unit: A Quality Improvement Project.

Am J Hosp Palliat Care. 2019 Jan;36(1):38-44

Authors: Lele A, Cheever C, Healey L, Hurley K, Kim LJ, Creutzfeldt CJ

Abstract
INTRODUCTION:: Transition to comfort measures only (CMO) is common in the neurocritical care unit, and close communication between interdisciplinary health-care teams is vital to a smooth transition. We developed and implemented a CMO huddle in an effort to reduce inconsistencies during the process of CMO transition.
METHODS:: The CMO huddle was a multiphase quality improvement project in a neurocritical care unit of a level-1 trauma and comprehensive stroke center. Interdisciplinary critical care clinicians engaged in a huddle during CMO processes and participated in a pre- and postimplementation survey to examine the impact of CMO huddle on communication, missed opportunities, and improvement in knowledge.
RESULTS:: Since the CMO implementation, a total of 131 patients underwent CMO transitions. After implementation of an interdisciplinary CMO huddle, 64.3% of neurocritical care nurses reported that they felt included and involved in CMO process compared to 28% before implementation ( P = .003); 87.9% of all neurocritical care clinicians reported that they felt comfortable participating in CMO discussions compared to 69.8% before ( P < .001); 57.4% of all neurocritical care clinicians reported that the CMO huddle improved communication among neurocritical care clinicians, 51.9% reported reduction in missed opportunities during CMO process, and 21.7% reported witnessing less-than-ideal CMO process compared to 80% before ( P < .001).
CONCLUSIONS:: Implementation of a multidisciplinary huddle in the neuro-intensive care unit before transition to CMO may improve clinician's experience of the end-of-life process through enhanced nursing inclusion and involvement and organized communication with the neurocritical care team.

PMID: 30041532 [PubMed - indexed for MEDLINE]

Editorial: A new definition of postconcussive syndrome.

J Neurosurg. 2016 11;125(5):1204-1205

Authors: Connolly ES, Ellenbogen RG

PMID: 26918480 [PubMed - indexed for MEDLINE]

Suppression of stress induction of the 78-kilodalton glucose regulated protein (GRP78) in cancer by IT-139, an anti-tumor ruthenium small molecule inhibitor.

Oncotarget. 2018 Jul 03;9(51):29698-29714

Authors: Bakewell SJ, Rangel DF, Ha DP, Sethuraman J, Crouse R, Hadley E, Costich TL, Zhou X, Nichols P, Lee AS

Abstract
In many cancers, combination therapy regimens are successfully improving response and survival rates, but the challenges of toxicity remain. GRP78, the master regulator of the unfolded protein response, is emerging as a target that is upregulated in tumors, specifically following treatment, and one that impacts tumor cell survival and disease recurrence. Here, we show IT-139, an antitumor small molecule inhibitor, suppresses induction of GRP78 from different types of endoplasmic reticulum (ER) stress in a variety of cancer cell lines, including those that have acquired therapeutic resistance, but not in the non-cancer cells being tested. We further determined that IT-139 treatment exacerbates ER stress while at the same time suppresses GRP78 induction at the transcriptional level. Our studies revealed a differential effect of IT-139 on chaperone protein family expression at multiple levels in different cancer cell lines. In xenograft studies, IT-139 decreased BRAF inhibitor upregulation of GRP78 expression in the tumor, while having minimal effect on GRP78 expression in the adjacent normal cells. The preferential decrease in GRP78 levels in tumor cells over normal cells, supported by the manageable safety profile seen in the Phase 1 clinical trial, reinforce the value IT-139 brings to combination therapies as it continues its clinical development.

PMID: 30038714 [PubMed]

SIDS Sudden Infant and Early Childhood Death: The Past, the Present and the Future

Book. 2018 05

Authors: Duncan JR, Byard RW

Abstract
The identification of risk factors associated with sudden infant death syndrome (SIDS) has led to significant advances in the prevention of this tragic outcome. The discovery of the prone sleeping position and smoking as two of the major risk factors (1-5) led to worldwide awareness campaigns, such as, for example, the “Back to Sleep” campaign launched in the United States in 1996, and various smoking cessation campaigns (6, 7). These initiatives resulted in a dramatic reduction in the number of children succumbing to SIDS (5, 8). Unfortunately, SIDS still remains the number-one cause of death in infants under 1 year of age in many countries, despite epidemiological and pathological studies that continue to identify additional risk factors, such as hearing deficiencies, or various genetic alterations associated with SIDS (9-11, 12, 13). To parents and families, as well as some health professionals and researchers, the sheer number of suggested risk factors and gene mutations can also be bewildering. The Triple Risk hypothesis by Dr Hannah Kinney and collaborators (14) can partly resolve this confusion. This hypothesis states that SIDS is caused by an incident in which not just one but three risk factors come together to bring an infant into a situation that leads to the sudden death. Specifically, it was proposed that those factors include [1] a vulnerable infant; [2] a critical period of development in homeostatic control; and [3] an exogenous stressor (14, 15). In other words, in the presence of two risk factors, namely being a vulnerable infant in a critical period of development, a third risk factor (e.g. an exogenous stressor) can become the ultimate cause that triggers an irreversible cascade of events leading to the sudden death. The Triple Risk hypothesis also has important practical implications. The awareness campaigns have shown that it is possible to significantly reduce the risk of an infant being exposed to exogenous stressors. A potentially more challenging task is to identify the infant who is particularly vulnerable, which is clearly one of the major tasks for research. A better understanding of the characteristics of a vulnerable infant would facilitate the development of strategies that target a specific vulnerability. Similarly, it will be important for research to identify and recognize the specific developmental conditions that characterize the critical period for SIDS, especially if they are dysregulated, or to target the important developmental and homeostatic mechanisms to prevent the death. This chapter will describe how different risk factors can contribute to the sudden death, the failure to arouse, the specific conditions associated with sleep, and the neuronal networks controlling cardiorespiratory functions and how they contribute to the events leading to sudden death. In this context we will review the physiology and pathophysiology of important brainstem mechanisms that are critical for survival, but that can sometimes fail. Understanding how these brainstem mechanisms interact with endogenous and exogenous mechanisms can also facilitate understanding of the significance of a variety of risk factors known to contribute to SIDS.

PMID: 30035952

Estimates of health utility scores in chronic kidney disease.

Int Urol Nephrol. 2017 Nov;49(11):2043-2049

Authors: Sekercioglu N, Curtis B, Murphy S, Blackhouse G, Barrett B

Abstract
INTRODUCTION: Coverage decisions in publicly funded healthcare systems require a formal, systematic and transparent assessment process for policies related to distribution of resources. The process is complex and employs multiple types of information, such as clinical effectiveness, costs and health utility scores which are used to produce quality-adjusted life years. The purpose of this study was to create health utility scores for CKD patients within the Canadian population.
METHODS: This is a cross-sectional study of CKD patients. We administered the Short-Form 36 Quality of Life Questions to all participants and employed the Short-Form 6 Dimension index to create health utility scores which were created using a set of parametric preference weights, nonparametric preference weights and ordinal health state valuation techniques obtained from a sample of the general population.
RESULTS: Utility values in the dialysis group were lower than in the non-dialysis group. There was a significant relationship between age and health utility scores: As age increases, health utility scores decrease. Diabetes was associated with lower health utility scores in dialysis patients, whereas other covariates did not reach levels of statistical significance in our stepwise regression models. The parametric Bayesian model and standard gamble approach yielded the same results, while the correlation between the nonparametric and parametric methods was above 0.9.
CONCLUSION: Health utility scores were low relative to the general population norm in our study cohort. Longitudinal assessment of CKD patients to capture possible fluctuations in health utility scores may add useful information.

PMID: 28733768 [PubMed - indexed for MEDLINE]

A Randomized, Double-Blinded, Phase II Trial of Gemcitabine and Nab-Paclitaxel Plus Apatorsen or Placebo in Patients with Metastatic Pancreatic Cancer: The RAINIER Trial.

Oncologist. 2017 12;22(12):1427-e129

Authors: Ko AH, Murphy PB, Peyton JD, Shipley DL, Al-Hazzouri A, Rodriguez FA, Womack MS, Xiong HQ, Waterhouse DM, Tempero MA, Guo S, Lane CM, Earwood C, DeBusk LM, Bendell JC

Abstract
LESSONS LEARNED: The addition of the heat shock protein 27 (Hsp27)-targeting antisense oligonucleotide, apatorsen, to a standard first-line chemotherapy regimen did not result in improved survival in unselected patients with metastatic pancreatic cancer.Findings from this trial hint at the possible prognostic and predictive value of serum Hsp27 that may warrant further investigation.
BACKGROUND: This randomized, double-blinded, phase II trial evaluated the efficacy of gemcitabine/nab-paclitaxel plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 (Hsp27) mRNA, or placebo in patients with metastatic pancreatic cancer.
METHODS: Patients were randomized 1:1 to Arm A (gemcitabine/nab-paclitaxel plus apatorsen) or Arm B (gemcitabine/nab-paclitaxel plus placebo). Treatment was administered in 28-day cycles, with restaging every 2 cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and on treatment. The primary endpoint was overall survival (OS).
RESULTS: One hundred thirty-two patients were enrolled, 66 per arm. Cytopenias and fatigue were the most frequent grade 3/4 treatment-related adverse events for both arms. Median progression-free survival (PFS) and OS were 2.7 and 5.3 months, respectively, for arm A, and 3.8 and 6.9 months, respectively, for arm B. Objective response rate was 18% for both arms. Patients with high serum level of Hsp27 represented a poor-prognosis subgroup who may have derived modest benefit from addition of apatorsen.
CONCLUSION: Addition of apatorsen to chemotherapy does not improve outcomes in unselected patients with metastatic pancreatic cancer in the first-line setting, although a trend toward prolonged PFS and OS in patients with high baseline serum Hsp27 suggests this therapy may warrant further evaluation in this subgroup.

PMID: 28935773 [PubMed - indexed for MEDLINE]

Estimated Glomerular Filtration Rate is not Associated with Alzheimer's Disease in a Northern Ireland Cohort.

J Alzheimers Dis. 2017;60(4):1379-1385

Authors: Paterson EN, Williams MA, Passmore P, Silvestri G, MacGillivray TJ, Maxwell AP, McKay GJ

Abstract
BACKGROUND: Alzheimer's disease (AD) prevalence is increasing globally and typically progresses for several years prior to clinical presentation of dementia. Renal dysfunction and vascular disease have been reported in association with dementia in several cross-sectional and longitudinal studies, and may contribute to AD risk. Experimental and observational studies suggest amyloid-β (Aβ) clearance may be impaired in chronic kidney disease (CKD) indicating a mechanism for increased AD risk.
OBJECTIVE: The objective of this study was to compare estimated glomerular filtration rate (eGFR) between individuals with AD and cognitively intact controls, controlling for potential confounding factors.
METHODS: A cross-sectional, case-control study was carried out in 317 cognitively normal participants and 253 cases with a clinical diagnosis of AD in a UK tertiary care dementia clinic. Associations were considered using logistic regression adjusting for confounding variables (age, APOEɛ4 genotype, systolic blood pressure, education (left school at 14), and smoking status).
RESULTS: AD cases were older than cognitively intact controls, had lower MMSE scores, were more likely to have at least one APOEɛ4 allele, had higher rates of smoking, were more likely to be taking aspirin and/or clopidogrel, and had lower blood pressure. We found no significant association between eGFR and AD both before and following adjustment for appropriate confounders.
CONCLUSION: This study failed to find an association between eGFR and AD in a cross-sectional sample study of elderly white individuals.

PMID: 29036821 [PubMed - indexed for MEDLINE]