UW Neurological Surgery Recent PubMed Publications

Both Dietary Ratio of n-6 to n-3 Fatty Acids and Total Dietary Lipid Are Positively Associated with Adiposity and Reproductive Health in Zebrafish.

9 hours 55 minutes ago
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Both Dietary Ratio of n-6 to n-3 Fatty Acids and Total Dietary Lipid Are Positively Associated with Adiposity and Reproductive Health in Zebrafish.

Curr Dev Nutr. 2020 Apr;4(4):nzaa034

Authors: Fowler LA, Dennis-Cornelius LN, Dawson JA, Barry RJ, Davis JL, Powell ML, Yuan Y, Williams MB, Makowsky R, D'Abramo LR, Watts SA

Abstract
Background: Controversial findings have been reported in human and animal studies regarding the influence of n-6 (ω-6) to n-3 (ω-3) fatty acid ratios on obesity and health. Two confounding factors may be related to interactions with other dietary lipid components or sex-specific differences in fatty acid metabolism.
Objective: This study investigated main and interactive effects of total dietary lipid, ratio of n-6 to n-3 fatty acids, and sex on growth, adiposity, and reproductive health in wild-type zebrafish.
Methods: Male and female zebrafish (3 wk old) were fed 9 diets consisting of 3 ratios of n-6 to n-3 fatty acids (1.4:1, 5:1, and 9.5:1) varied within 3 total lipid amounts (80, 110, and 140 g/kg) for 16 wk. Data were then collected on growth, body composition (determined by chemical carcass analysis), and female reproductive success (n = 32 breeding events/diet over 4 wk). Main and interactive effects of dietary lipid and sex were evaluated with regression methods. Significant differences within each dietary lipid component were relative to the intercept/reference group (80 g/kg and 1.4:1 ratio).
Results: Dietary lipid and sex interacted in their effects on body weight (P = 0.015), total body length (P = 0.003), and total lipid mass (P = 0.029); thus, these analyses were stratified by sex. Female spawning success decreased as dietary total lipid and fatty acid ratio increased (P = 0.030 and P = 0.026, respectively). While total egg production was not associated with either dietary lipid component, females fed the 5:1 ratio produced higher proportions of viable embryos compared with the 1.4:1 ratio [median (95% CI): 0.915 (0.863, 0.956) vs 0.819 (0.716, 0.876); P < 0.001].
Conclusions: Further characterization of dietary lipid requirements will help define healthy balances of dietary lipid, while the sex-specific responses to dietary lipid identified in this study may partially explain sex disparities in the development of obesity and its comorbidities.

PMID: 32258992 [PubMed]

Alzheimer's disease beyond amyloid: can the repetitive failures of amyloid-targeted therapeutics inform future approaches to dementia drug discovery?

2 days 10 hours ago
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Alzheimer's disease beyond amyloid: can the repetitive failures of amyloid-targeted therapeutics inform future approaches to dementia drug discovery?

Biochem Pharmacol. 2020 Apr 02;:113945

Authors: Mullane K, Williams M

Abstract
Alzheimer's Disease (AD) therapeutics based on the amyloid hypothesis have repeatedly failed in clinical trials. Together with numerous reports that amyloid is present in brains from aged individuals without cognitive dysfunction, this suggests that the association of amyloid with AD is collateral rather than causal. The preeminence of the amyloid hypothesis has resulted in the 'systematic …thwart[ing of] alternative approaches' to AD/dementia driven by a 'cabal' of amyloid acolytes who have effectively controlled the ideas funded and published, which startups received venture investment and which programs were advanced in biopharmaceutical companies where they consulted. As a result, dementia research is estimated to be 15-30 years behind where it could be with conflicting data ignored in favor of the amyloid dogma and clinical trial failures being ascribed to faulty design or inadequacies in the compound selection process including flawed animal models. Major concerns regarding the precise diagnosis of AD/dementia and conflicting views on the validated status of fluid biomarker assays have resulted in trials that included patients with unknown amyloid pathologies. With the failure of the amyloid approach, emerging data on the role(s) of vascular, mitochondrial and synaptic network dysfunction, infection, diabetes, sleep, hearing loss, the gut microbiome and neuroinflammation/ innate immune function as dementia targets are driving research in new directions bolstered by recent findings on the genetic, omics and systems biology associated with AD/dementia. In moving forward, lessons learnt from the amyloid debacle should be used to enhance the objective identification of AD/dementia therapeutics using a multifactorial disease syndrome.

PMID: 32247851 [PubMed - as supplied by publisher]

Feasibility and safety of transradial access for pediatric neurointerventions.

4 days 10 hours ago
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Feasibility and safety of transradial access for pediatric neurointerventions.

J Neurointerv Surg. 2020 Apr 02;:

Authors: Srinivasan VM, Hadley CC, Prablek M, LoPresti M, Chen SH, Peterson EC, Sweid A, Jabbour P, Young C, Levitt M, Osbun JW, Burkhardt JK, Johnson J, Kan P

Abstract
BACKGROUND: Diagnostic cerebral angiograms are increasingly being performed by transradial access (TRA) in adults, following data from the coronary literature supporting fewer access-site complications. Despite this ongoing trend in neuroangiography, there has been no discussion of its use in the pediatric population. Pediatric TRA has scarcely been described even for coronary or other applications. This is the first dedicated large study of transradial access for neuroangiography in pediatric patients.
METHODS: A multi-institutional series of consecutively performed pediatric transradial angiograms and interventions was collected. This included demographic, procedural, outcomes, and safety data. Data was prospectively recorded and retrospectively analyzed.
RESULTS: Thirty-seven diagnostic angiograms and 24 interventions were performed in 47 pediatric patients. Mean age, height, and weight was 14.1 years, 158.6 cm, and 57.1 kg, respectively. The radial artery measured 2.09+/-0.54 mm distally, and 2.09+/-0.44 mm proximally. Proximal and distal angiography were performed for both diagnostic and interventional application (17 distal angiograms, two distal interventions). Clinically significant vasospasm occurred in eight patients (13.1%). Re-access was successfully performed 11 times in seven patients. Conversion to femoral access occurred in five cases (8.2%). The only access-related complication was a small asymptomatic wrist hematoma after TR band removal.
CONCLUSIONS: Transradial access in pediatric patients is safe and feasible. It can be performed successfully in many cases but carries some unique challenges compared with the adult population. Despite the challenge of higher rates of vasospasm and conversion to femoral access, it is worth exploring further, given the potential benefits.

PMID: 32241922 [PubMed - as supplied by publisher]

Pediatric functional hemispherectomy: operative techniques and complication avoidance.

5 days 10 hours ago
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Pediatric functional hemispherectomy: operative techniques and complication avoidance.

Neurosurg Focus. 2020 Apr 01;48(4):E9

Authors: Young CC, Williams JR, Feroze AH, McGrath M, Ravanpay AC, Ellenbogen RG, Ojemann JG, Hauptman JS

Abstract
Functional hemispherectomy/hemispherotomy is a disconnection procedure for severe medically refractory epilepsy where the seizure foci diffusely localize to one hemisphere. It is an improvement on anatomical hemispherectomy and was first performed by Rasmussen in 1974. Less invasive surgical approaches and refinements have been made to improve seizure freedom and minimize surgical morbidity and complications. Key anatomical structures that are disconnected include the 1) internal capsule and corona radiata, 2) mesial temporal structures, 3) insula, 4) corpus callosum, 5) parietooccipital connection, and 6) frontobasal connection. A stepwise approach is indicated to ensure adequate disconnection and prevent seizure persistence or recurrence. In young pediatric patients, careful patient selection and modern surgical techniques have resulted in > 80% seizure freedom and very good functional outcome. In this report, the authors summarize the history of hemispherectomy and its development and present a graphical guide for this anatomically challenging procedure. The use of the osteoplastic flap to improve outcome and the management of hydrocephalus are discussed.

PMID: 32234987 [PubMed - in process]

DNA methylation profiling identifies a high effect genetic variant for lipoprotein(a) levels.

5 days 10 hours ago
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DNA methylation profiling identifies a high effect genetic variant for lipoprotein(a) levels.

Epigenetics. 2020 Apr 01;:1-10

Authors: Jones GT, Marsman J, Bhat B, Phillips VL, Chatterjee A, Rodger EJ, Williams MJA, van Rij AM, McCormick SPA

Abstract
Changes in whole blood DNA methylation levels at several CpG sites have been associated with circulating blood lipids, specifically high-density lipoprotein and triglycerides. This study performs a discovery and validation epigenome-wide association study (EWAS) for circulating lipoprotein(a) [Lp(a)], an independent risk factor for cardiovascular diseases. Whole-blood DNA methylation profiles were assessed in a cohort of 1020 elderly individuals using the Illumina EPIC array and independent validation in 359 elderly males using the Illumina 450 k array. Plasma Lp(a) was measured using an apolipoprotein(a)-size-independent ELISA. Epigenome-wide rank regression analysis identified and validated a single CpG site, cg17028067 located in intron 1 of the LPA gene, that was significantly associated with plasma Lp(a) levels after correction for multiple testing. Genotyping of the site identified a relatively uncommon SNP (rs76735376, MAF <0.02) at the CpG site that largely explained the observed methylation effect. Rs76735376 is an expression quantitative trait loci for the LPA gene and could affect expression by altering enhancer activity. This EWAS for plasma Lp(a) identified a single CpG site within LPA. This association is due to an uncommon, but highly effective genetic variant, which was not in significant linkage disequilibrium with other variants known to influence Lp(a) levels or apo(a) isoform size. This study highlights the utility of CpG site methylation to identify potentially important genetic associations that would not be readily apparent in a comparable size genetic association study.

PMID: 32237968 [PubMed - as supplied by publisher]

WHO malaria nucleic acid amplification test external quality assessment scheme: results of distribution programmes one to three.

6 days 10 hours ago
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WHO malaria nucleic acid amplification test external quality assessment scheme: results of distribution programmes one to three.

Malar J. 2020 Mar 30;19(1):129

Authors: Cunningham JA, Thomson RM, Murphy SC, de la Paz Ade M, Ding XC, Incardona S, Legrand E, Lucchi NW, Menard D, Nsobya SL, Saez AC, Chiodini PL, Shrivastava J

Abstract
BACKGROUND: The World Health Organization (WHO) recommends parasite-based diagnosis of malaria. In recent years, there has been surge in the use of various kinds of nucleic-acid amplification based tests (NAATs) for detection and identification of Plasmodium spp. to support clinical care in high-resource settings and clinical and epidemiological research worldwide. However, these tests are not without challenges, including lack (or limited use) of standards and lack of reproducibility, due in part to variation in protocols amongst laboratories. Therefore, there is a need for rigorous quality control, including a robust external quality assessment (EQA) scheme targeted towards malaria NAATs. To this effect, the WHO Global Malaria Programme worked with the UK National External Quality Assessment Scheme (UK NEQAS) Parasitology and with technical experts to launch a global NAAT EQA scheme in January 2017.
METHODS: Panels of NAAT EQA specimens containing five major species of human-infecting Plasmodium at various parasite concentrations and negative samples were created in lyophilized blood (LB) and dried blood spot (DBS) formats. Two distributions per year were sent, containing five LB and five DBS specimens. Samples were tested and validated by six expert referee laboratories prior to distribution. Between 37 and 45 laboratories participated in each distribution and submitted results using the online submission portal of UK NEQAS. Participants were scored based on their laboratory's stated capacity to identify Plasmodium species, and individual laboratory reports were sent which included performance comparison with anonymized peers.
RESULTS: Analysis of the first three distributions revealed that the factors that most significantly affected performance were sample format (DBS vs LB), species and parasite density, while laboratory location and the reported methodology used (type of nucleic acid extraction, amplification, or DNA vs RNA target) did not significantly affect performance. Referee laboratories performed better than non-referee laboratories.
CONCLUSIONS: Globally, malaria NAAT assays now inform a range of clinical, epidemiological and research investigations. EQA schemes offer a way for laboratories to assess and improve their performance, which is critical to safeguarding the reliability of data and diagnoses especially in situations where various NAAT methodologies and protocols are in use.

PMID: 32228615 [PubMed - in process]

Tumor endothelial cell up-regulation of IDO1 is an immunosuppressive feed-back mechanism that reduces the response to CD40-stimulating immunotherapy.

6 days 10 hours ago
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Tumor endothelial cell up-regulation of IDO1 is an immunosuppressive feed-back mechanism that reduces the response to CD40-stimulating immunotherapy.

Oncoimmunology. 2020;9(1):1730538

Authors: Georganaki M, Ramachandran M, Tuit S, Núñez NG, Karampatzakis A, Fotaki G, van Hooren L, Huang H, Lugano R, Ulas T, Kaunisto A, Holland EC, Ellmark P, Mangsbo SM, Schultze J, Essand M, Tugues S, Dimberg A

Abstract
CD40-stimulating immunotherapy can elicit potent anti-tumor responses by activating dendritic cells and enhancing T-cell priming. Tumor vessels orchestrate T-cell recruitment during immune response, but the effect of CD40-stimulating immunotherapy on tumor endothelial cells has not been evaluated. Here, we have investigated how tumor endothelial cells transcriptionally respond to CD40-stimulating immunotherapy by isolating tumor endothelial cells from agonistic CD40 mAb- or isotype-treated mice bearing B16-F10 melanoma, and performing RNA-sequencing. Gene set enrichment analysis revealed that agonistic CD40 mAb therapy increased interferon (IFN)-related responses in tumor endothelial cells, including up-regulation of the immunosuppressive enzyme Indoleamine 2, 3-Dioxygenase 1 (IDO1). IDO1 was predominantly expressed in endothelial cells within the tumor microenvironment, and its expression in tumor endothelium was positively correlated to T-cell infiltration and to increased intratumoral expression of IFNγ. In vitro, endothelial cells up-regulated IDO1 in response to T-cell-derived IFNγ, but not in response to CD40-stimulation. Combining agonistic CD40 mAb therapy with the IDO1 inhibitor epacadostat delayed tumor growth in B16-F10 melanoma, associated with increased activation of tumor-infiltrating T-cells. Hereby, we show that the tumor endothelial cells up-regulate IDO1 upon CD40-stimulating immunotherapy in response to increased IFNγ-secretion by T-cells, revealing a novel immunosuppressive feedback mechanism whereby tumor vessels limit T-cell activation.

PMID: 32231867 [PubMed]

Exploring Ethical Concerns About Human Challenge Studies: A Qualitative Study of Controlled Human Malaria Infection Study Participants' Motivations and Attitudes.

1 week ago
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Exploring Ethical Concerns About Human Challenge Studies: A Qualitative Study of Controlled Human Malaria Infection Study Participants' Motivations and Attitudes.

J Empir Res Hum Res Ethics. 2019 02;14(1):49-60

Authors: Kraft SA, Duenas DM, Kublin JG, Shipman KJ, Murphy SC, Shah SK

Abstract
Controlled human malaria infection (CHMI) studies deliberately infect healthy participants with malaria to test interventions faster and more efficiently. Some argue the study design and high payments offered raise ethical concerns about participants' understanding of risks and undue inducement. We conducted baseline and exit interviews with 16 CHMI study participants to explore these concerns. Participants described themes including decision-making tension with friends and family, mixed motivations for participating, low study risks but high burdens, fair compensation, sacrificing values, deceiving researchers, and perceived benefits. Our findings do not support concerns that high payments limit understanding of study risks, but suggest participants may lack appreciation of study burdens, withhold information or engage in deception, and experience conflict with others regarding study participation.

PMID: 30585505 [PubMed - indexed for MEDLINE]

Economic evaluation in the National Drug Abuse Treatment Clinical Trials Network: Past, present, and future.

1 week 2 days ago
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Economic evaluation in the National Drug Abuse Treatment Clinical Trials Network: Past, present, and future.

J Subst Abuse Treat. 2020 Mar;112S:18-27

Authors: Jalali A, Ryan DA, McCollister KE, Marsch LA, Schackman BR, Murphy SM

Abstract
Economic evaluations provide evidence that informs stakeholders on how to efficiently allocate real and financial healthcare resources. The purpose of this study was to review and discuss the integration of economic evaluations into the National Drug Abuse Treatment Clinical Trials Network (CTN) since its inception, as well as expectations for the future of this relationship. A systematic review was performed on published and planned CTN economic evaluations in the CTN dissemination library and PubMed. The well-established Drummond checklist was used to evaluate the comprehensiveness and methodological rigor of published articles. One hundred thirty-eight ancillary, follow-up, or original protocols were reviewed, and 78 potentially relevant published articles were identified. A total number of 14 protocols included an economic evaluation. Of these, 6 protocols were completed, 2 were reported as active, and 6 were reported as in-development at the time of this review. Of the 78 published articles, 9 met the inclusion criteria. As gauged by the Drummond checklist, the quality of CTN published economic evaluations were found to improve over time, and recent published articles were identified as guides to cutting-edge economic research. As the CTN continues to grow and mature, it is imperative that high-quality economic evaluations are incorporated alongside trials in order to maximize the public health impact of the CTN.

PMID: 32220406 [PubMed - in process]

Percutaneous cervical cordotomy for cancer-related pain: national data.

1 week 2 days ago
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Percutaneous cervical cordotomy for cancer-related pain: national data.

BMJ Support Palliat Care. 2020 Mar 27;:

Authors: Poolman M, Makin M, Briggs J, Scofield K, Campkin N, Williams M, Sharma ML, Laird B, Mayland CR, INPIC Group

Abstract
OBJECTIVES: Percutaneous cervical cordotomy (PCC) is an interventional ablative procedure in the armamentarium for cancer pain treatment, but there is limited evidence to support its use. This study aimed to assess the effectiveness and safety of PCC.
METHODS: Analysis was undertaken of the first national (UK) prospective data repository of adult patients with cancer undergoing PCC for pain treatment. The relationship between pain and other outcomes before and after PCC was examined using appropriate statistical methods.
RESULTS: Data on 159 patients' PCCs (performed from 1 January 2012 to 6 June 2017 in three centres) were assessed: median (IQR) age was 66 (58-71) years, 47 (30%) were female. Mesothelioma was the most common primary malignancy (57%). The median (IQR) time from cancer diagnosis to PCC assessment was 13.3 (6.2-23.2) months; PCC to follow-up was 9 (8-25) days; and survival after PCC was 1.3 (0.6-2.8) months. The mean (SD) for 'average pain' using a numerical rating scale was 6 (2) before PCC and 2 (2) at follow-up, and for 'worst pain' 9 (1) and 3 (3), respectively. The median (IQR) reduction in strong opioid dose at follow-up was 50% (34-50). With the exception of 'activity', all health-related quality of life scores (5-level version of EuroQol-5 Dimension) either improved or were stable after PCC. Six patients (4%) had PCC-related adverse events.
CONCLUSIONS: PCC is an effective treatment for cancer pain; however, findings in this study suggest PCC referrals tended to be late in patients' disease trajectories. Further study into earlier treatment and seeking international consensus on PCC outcomes will further enhance opportunities to improve patient care.

PMID: 32220943 [PubMed - as supplied by publisher]

Bilateral Squamosal Suture Craniosynostosis Presenting with Abducens Nerve Palsy and Severe Papilledema.

1 week 3 days ago
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Bilateral Squamosal Suture Craniosynostosis Presenting with Abducens Nerve Palsy and Severe Papilledema.

World Neurosurg. 2020 Mar 23;:

Authors: Cho DY, Evans KN, Weed MC, Lee A, Susarla SM

Abstract
BACKGROUND: Patients with single-suture or minor suture craniosynostosis are typically asymptomatic at early presentation; intervention is aimed at reducing the risk of elevated intracranial pressure and associated developmental sequelae. Patients may be symptomatic in cases of major multi-suture syndromic synostoses or delayed diagnosis. Clinical presentation in this context may include headaches, papilledema, cognitive delay, or behavioral issues. Cranial nerve palsies are atypical symptoms of intracranial hypertension in this patient population.
CASE DESCRIPTION: An 11-month-old otherwise healthy female infant presented with bilateral severe papilledema and left abducens nerve palsy due to non-syndromic near complete bilateral squamosal suture synostosis with associated incomplete sagittal and right lambdoid synostoses. The patient underwent urgent open cranial expansion, with resolution of her papilledema and improvement in eye position and motility.
CONCLUSIONS: Cranial nerve palsies may be presenting symptoms of intracranial hypertension in patients with craniosynostosis. Multi-disciplinary evaluation and treatment is paramount for appropriate management.

PMID: 32217173 [PubMed - as supplied by publisher]

Incorporation of transradial approach in neuroendovascular procedures: defining benchmarks for rates of complications and conversion to femoral access.

1 week 3 days ago
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Incorporation of transradial approach in neuroendovascular procedures: defining benchmarks for rates of complications and conversion to femoral access.

J Neurointerv Surg. 2020 Mar 26;:

Authors: Almallouhi E, Al Kasab S, Sattur MG, Lena J, Jabbour PM, Sweid A, Chalouhi N, Gooch MR, Starke RM, Peterson EC, Yavagal DR, Chen SH, Li Y, Gross BA, Tonetti DA, Zussman BM, Stone JG, Jadhav AP, Jankowitz BT, Young CC, Lim DH, Levitt MR, Osbun JW, Spiotta AM

Abstract
BACKGROUND: The transradial approach (TRA) has gained increasing popularity for neuroendovascular procedures. However, the experience with TRA in neuroangiography is still in early stages in most centers, and the safety and feasibility of this approach have not been well established. The purpose of this study is to report the safety and feasibility of TRA for neuroendovascular procedures.
METHODS: We reviewed charts from six institutions in the USA to include consecutive patients who underwent diagnostic or interventional neuroendovascular procedures through TRA from July 2018 to July 2019. Collected data included baseline characteristics, procedural variables, complications, and whether there was a crossover to transfemoral access.
RESULTS: A total of 2203 patients were included in the study (age 56.1±15.2, 60.8% women). Of these, 1697 (77%) patients underwent diagnostic procedures and 506 (23%) underwent interventional procedures. Successfully completed procedures included aneurysm coiling (n=97), flow diversion (n=89), stent-assisted coiling (n=57), balloon-assisted coiling (n=19), and stroke thrombectomy (n=76). Crossover to femoral access was required in 114 (5.2%). There were no major complications related to the radial access site. Minor complications related to access site were seen in 14 (0.6%) patients.
CONCLUSION: In this early stage of transforming to the 'radial-first' approach for neuroendovascular procedures, TRA was safe with low complication rates for both diagnostic and interventional procedures. A wide range of procedures were completed successfully using TRA.

PMID: 32217626 [PubMed - as supplied by publisher]

Cytotoxic Effects of Zoom® Whitening Product in Human Fibroblasts.

1 week 3 days ago
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Cytotoxic Effects of Zoom® Whitening Product in Human Fibroblasts.

Materials (Basel). 2020 Mar 25;13(7):

Authors: Marto CM, Laranjo M, Paula A, Coelho AS, Abrantes AM, Casalta-Lopes J, Gonçalves AC, Sarmento-Ribeiro AB, Ferreira MM, Cabrita A, Botelho MF, Carrilho E

Abstract
Tooth whitening procedures are increasing; however, side effects can occur, such as damage to pulp cells, by the whitening products. This study aims to assess the cellular effects promoted by a whitening product, namely, the oxidative stress fostered by the active agent hydrogen peroxide, with and without photoactivation. Additionally, if cellular recovery occurred, we intended to determine the time point where cells recover from the tooth whitening induced damage. Human fibroblasts were exposed to hydrogen peroxide, Zoom®, Zoom® + irradiation, and irradiation alone. The following analysis was performed: metabolic activity evaluation by the MTT assay; cell viability, mitochondrial membrane potential, peroxides production, superoxide radical production, and reduced glutathione expression by flow cytometry. We determined the IC50 value for all groups, and a dose-dependent cytotoxic effect was verified. At the times analyzed, hydrogen peroxide groups showed no metabolic activity recovery while a cell recovery was observed after 24 h (Zoom®) and 48 h (Zoom® + irradiation). Cell death was seen in hydrogen peroxide and Zoom® + irradiation groups, mainly by apoptosis, and the irradiation had a cytotoxic effect per se. This in vitro study supports that whitening products with moderate hydrogen peroxide (HP) concentration have a temporary effect on cells, allowing a cellular recovery.

PMID: 32218276 [PubMed - as supplied by publisher]

Aberrant cell migration contributes to defective airway epithelial repair in childhood wheeze.

1 week 6 days ago
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Aberrant cell migration contributes to defective airway epithelial repair in childhood wheeze.

JCI Insight. 2020 Mar 24;:

Authors: Iosifidis T, Sutanto EN, Buckley A, Coleman LA, Gill EE, Lee AH, Ling KM, Hillas J, Looi K, Garratt LW, Martinovich KM, Shaw NC, Montgomery ST, Kicic-Starcevich E, Karpievitch YV, Le Souef P, Laing IA, Vijayasekaran S, Lannigan FJ, Rigby PJ, Hancock RE, Knight D, Stick SM, Kicic A, Waerp OBO, AusREC OBO

Abstract
Abnormal wound repair has been observed in the airway epithelium of patients with chronic respiratory diseases including asthma. Therapies focusing on repairing vulnerable airways, particularly in early life, present an extremely novel treatment strategy. We report defective lower airway epithelial cell repair to strongly associate with common pre-school and school-aged wheezing phenotypes, characterised by aberrant migration patterns and reduced α5β1 integrin expression. Next generation sequencing identified the PI3K/Akt pathway as the top upstream transcriptional regulator of α5β1 integrin, where Akt activation enhanced repair and α5β1 integrin expression in primary cultures from children with wheeze. Conversely, inhibition of PI3K/Akt signaling in primary cultures from children without wheeze reduced α5β1 expression and attenuated repair. Importantly, the FDA-approved drug celecoxib, and its non-COX2-inhibiting analogue dimethyl-celecoxib, stimulated the PI3K/Akt-integrin α5β1 axis and restored airway epithelial repair in cells from children with wheeze. When compared with published clinical datasets the identified transcriptomic signature was also associated with viral-induced wheeze exacerbations highlighting the clinical potential of such therapy. Collectively, these results identify airway epithelial restitution via targeting the PI3K/Akt-integrin axis as a novel therapeutic avenue for childhood wheeze and asthma. We propose that the next step in the therapeutic development process should be a proof-of-concept clinical trial since relevant animal models to test the crucial underlying premise are unavailable.

PMID: 32208383 [PubMed - as supplied by publisher]

Extrusion-Based Bioprinting: Current Standards and Relevancy for Human-Sized Tissue Fabrication.

2 weeks ago
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Extrusion-Based Bioprinting: Current Standards and Relevancy for Human-Sized Tissue Fabrication.

Methods Mol Biol. 2020;2140:65-92

Authors: Willson K, Ke D, Kengla C, Atala A, Murphy SV

Abstract
The field of bioengineering has long pursued the goal of fabricating large-scale tissue constructs for use both in vitro and in vivo. Recent technological advances have indicated that bioprinting will be a key technique in manufacturing these specimens. This chapter aims to provide an overview of what has been achieved to date through the use of microextrusion bioprinters and what major challenges still impede progress. Microextrusion printer configurations will be addressed along with critical design characteristics including nozzle specifications and bioink modifications. Significant challenges within the field with regard to achieving long-term cell viability and vascularization, and current research that shows promise in mitigating these challenges in the near future are discussed. While microextrusion is a broad field with many applications, this chapter aims to provide an overview of the field with a focus on its applications toward human-sized tissue constructs.

PMID: 32207106 [PubMed - in process]

Enhanced transient striatal dopamine release and reuptake in Lphn3 KO rats.

2 weeks 1 day ago
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Enhanced transient striatal dopamine release and reuptake in Lphn3 KO rats.

ACS Chem Neurosci. 2020 Mar 23;:

Authors: Regan SL, Cryan MT, Williams MT, Vorhees CV, Ross AE

Abstract
Latrophilin-3 (LPHN3) is an adhesion G protein coupled receptor involved in regulating neuroplasticity. Variants of LPHN3 are associated with increased risk of attention-deficit hyperactivity disorder. Data from mouse, zebrafish, Drosophila, and rat show that disruption of LPHN3 results in hyperactivity and in the Sprague-Dawley Lphn3 knock-out rat exhibit deficits in learning and memory and changes in dopamine (DA) markers in the neostriatum. To determine the effects of Lphn3 deletion on DA neurotransmission, we compared the concentration, duration, and frequency of DA transients in KO and wildtype rats using fast-scan cyclic voltammetry in brain slices. Lphn3 KO rats showed higher release of DA and the duration and inter-event time were markedly decreased compared with wildtype rats. The data demonstrate that LPHN3 plays a heretofore unrecognized role in DA signaling and may represent a new target for small molecule regulation of DA neurotransmission with translational implications.

PMID: 32203648 [PubMed - as supplied by publisher]

MetaBridge: An Integrative Multi-Omics Tool for Metabolite-Enzyme Mapping.

2 weeks 3 days ago
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MetaBridge: An Integrative Multi-Omics Tool for Metabolite-Enzyme Mapping.

Curr Protoc Bioinformatics. 2020 Jun;70(1):e98

Authors: Blimkie T, Lee AH, Hancock REW

Abstract
MetaBridge is a web-based tool designed to facilitate the integration of metabolomics with other "omics" data types such as transcriptomics and proteomics. It uses data from the MetaCyc metabolic pathway database and the Kyoto Encyclopedia of Genes and Genomes (KEGG) to map metabolite compounds to directly interacting upstream or downstream enzymes in enzymatic reactions and metabolic pathways. The resulting list of enzymes can then be integrated with transcriptomics or proteomics data via protein-protein interaction networks to perform integrative multi-omics analyses. MetaBridge was developed to be intuitive and easy to use, requiring little to no prior computational experience. The protocols described here detail all steps involved in the use of MetaBridge, from preparing input data and performing metabolite mapping to utilizing the results to build a protein-protein interaction network. © 2020 by John Wiley & Sons, Inc. Basic Protocol 1: Mapping metabolite data using MetaCyc identifiers Basic Protocol 2: Mapping metabolite data using KEGG identifiers Support Protocol 1: Converting compound names to HMDB IDs Support Protocol 2: Submitting mapped genes produced by MetaBridge for protein-protein interaction (PPI) network construction.

PMID: 32199034 [PubMed - as supplied by publisher]

Inflammation in Heart Failure: JACC State-of-the-Art Review.

2 weeks 4 days ago
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Inflammation in Heart Failure: JACC State-of-the-Art Review.

J Am Coll Cardiol. 2020 Mar 24;75(11):1324-1340

Authors: Murphy SP, Kakkar R, McCarthy CP, Januzzi JL

Abstract
It has long been observed that heart failure (HF) is associated with measures of systemic inflammation. In recent years, there have been significant advancements in our understanding of how inflammation contributes to the pathogenesis and progression of HF. However, although numerous studies have validated the association between measures of inflammation and HF severity and prognosis, clinical trials of anti-inflammatory therapies have proven mostly unsuccessful. On this backdrop emerges the yet unmet goal of targeting precise phenotypes within the syndrome of HF; if such precise definitions can be realized, and with better understanding of the roles played by specific inflammatory mediators, the expectation is that targeted anti-inflammatory therapies may improve prognosis in patients whose HF is driven by inflammatory pathobiology. Here, the authors describe mechanistic links between inflammation and HF, discuss traditional and novel inflammatory biomarkers, and summarize the latest evidence from clinical trials of anti-inflammatory therapies.

PMID: 32192660 [PubMed - in process]

Slow release oral morphine versus methadone for opioid use disorder in the fentanyl era (pRESTO): Protocol for a non-inferiority randomized clinical trial.

2 weeks 4 days ago
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Slow release oral morphine versus methadone for opioid use disorder in the fentanyl era (pRESTO): Protocol for a non-inferiority randomized clinical trial.

Contemp Clin Trials. 2020 Mar 16;:105993

Authors: Socias ME, Wood E, Dong H, Brar R, Bach P, Murphy SM, Fairbairn N

Abstract
BACKGROUND: North America is facing an unprecedented public health crisis of opioid-related morbidity and mortality, increasingly as a result of the introduction of illicitly manufactured fentanyl into the street drug market. Although the treatment of opioid use disorder (OUD) is a key element in the response to the opioid overdose epidemic, currently available pharmacotherapies (e.g., methadone, buprenorphine) may not be acceptable to or effective in all patients. Available evidence suggests that slow-release oral morphine (SROM) has similar efficacy rates as methadone with respect to promoting abstinence, and with improvements in a number of patient-reported outcomes among persons using heroin. However, little is known about the relative effectiveness and acceptability of SROM compared to methadone in the context of fentanyl use. This study aims to address this research gap.
METHODS: pRESTO is a 24-week, open-label, two arm, non-inferiority, randomized controlled trial comparing SROM versus methadone for the treatment of OUD. Participants will be 298 clinically stable, non-pregnant adults with OUD, recruited from outpatient clinics in Vancouver, Canada, where the majority of the illicit opioids are contaminated with fentanyl. The primary outcome is suppression of illicit opioid use, measured by bi-weekly urine drug screens. Secondary outcomes include: treatment retention, medication safety, overdose events, treatment satisfaction, psychological functioning, changes in drug-related problems, changes in quality of life, opioid cravings, other substance use, and cost-effectiveness.
DISCUSSION: pRESTO will be among the first studies to evaluate treatment options for individuals primarily using synthetic street opioids, providing important evidence to guide treatment strategies for this population.

PMID: 32194251 [PubMed - as supplied by publisher]

Repeated Application of Transcranial Diagnostic Ultrasound Towards the Visual Cortex Induced Illusory Visual Percepts in Healthy Participants.

2 weeks 4 days ago
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Repeated Application of Transcranial Diagnostic Ultrasound Towards the Visual Cortex Induced Illusory Visual Percepts in Healthy Participants.

Front Hum Neurosci. 2020;14:66

Authors: Schimek N, Burke-Conte Z, Abernethy J, Schimek M, Burke-Conte C, Bobola M, Stocco A, Mourad PD

Abstract
Transcranial magnetic stimulation (TMS) of the visual cortex can induce phosphenes as participants look at a visual target. So can non-diagnostic ultrasound (nDU), delivered in a transcranial fashion, while participants have closed their eyes during stimulation. Here, we sought to determine if DU, aimed at the visual cortex, could alter the perception of a visual target. We applied a randomized series of actual or sham DU, transcranially and towards the visual cortex of healthy participants while they stared at a visual target (a white crosshair on a light-blue background), with the ultrasound device placed where TMS elicited phosphenes. These participants observed percepts seven out of ten times, which consisted of extra or extensions of lines relative to the original crosshair, and additional colors, an average of 53.7 ± 2.6% of the time over the course of the experiment. Seven out of ten different participants exposed to sham-only DU observed comparable percepts, but only an average of 36.3 ± 1.9% of the time, a statistically significant difference (p < 0.00001). Moreover, on average, participants exposed to a combination of sham and actual ultrasound reported a net increase of 47.9 percentage points in the likelihood that they would report a percept by the end of the experiment. Our results are consistent with the hypothesis that a random combination of sham-only and actual DU, applied directly over the visual cortex of participants, increased the likelihood that they would observe visual effects, but not the type of effects, with that likelihood increasing over the course of the experiment. From this, we conclude that repeated exposures by DU may make the visual cortex more responsive to stimulation of their visual cortex by the visual target itself. Future studies should identify the biophysical mechanism(s) and neural pathways by which DU, in our hands and others, can generate its observed effects on brain function. These observations, consistent with other's observation of effects of DU stimulation of the human motor cortex and amygdala, as well as the FDA approved nature of DU, may lead to increased use of DU as a means of altering brain function.

PMID: 32194387 [PubMed]

NCBI: db=pubmed; Term="university of washington"[Affiliation] AND neurological surgery AND Browd, Samuel[Full Author Name] OR Chesnut, Randall[Full Author Name] OR Chowdhary, Michelle[Full Author Name] OR Coppel, David[Full Author Name] OR Crane, Courtney[Full Author Name] OR D'Ambrosio, Raimondo[Full Author Name] OR Ellenbogen, Richard[Full Author Name] OR Ferreira, Manuel[Full Author Name] OR Gelfenbeyn, Mikhail[Full Author Name] OR Hofstetter, Christoph[Full Author Name] OR Holland, Eric[Full Author Name] OR Kalume, Franck[Full Author Name] OR Kim, Louis[Full Author Name] OR Ko, Andrew[Full Author Name] OR Lee, Amy[Full Author Name] OR Levitt, Michael[Full Author Name] OR Mac Donald, Christine[Full Author Name] OR Ramirez, Jan Marino[Full Author Name] OR Patel, Anoop[Full Author Name] OR Morrison, Richard[Full Author Name] OR Mourad, Pierre[Full Author Name] OR Murphy, Sean[Full Author Name] OR Ojemann, Jeff[Full Author Name] OR Pridgeon, Jim[Full Author Name] OR Rapport, Richard[Full Author Name] OR Saigal, Rajiv[Full Author Name] OR Sekhar, Laligam[Full Author Name] OR Silber, John[Full Author Name] OR Silbergeld, Daniel [Full Author Name] OR Temkin, Nancy[Full Author Name] OR Williams, Michael[Full Author Name] OR Zhang, Fangyi[Full Author Name]
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