UW Neurological Surgery Recent PubMed Publications

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]

Correcting for Body Surface Area Identifies the True Prevalence of Abdominal Aortic Aneurysm in Screened Women.

Eur J Vasc Endovasc Surg. 2019 02;57(2):221-228

Authors: Jones GT, Sandiford P, Hill GB, Williams MJA, Khashram M, Tilyard MW, Hammond-Tooke GD, Krysa J, van Rij AM

Abstract
OBJECTIVE: Recently, the prevalence of abdominal aortic aneurysm (AAA) using screening strategies based on elevated cardiovascular disease (CVD) risk was reported. AAA was defined as a diameter ≥30 mm, with prevalence of 6.1% and 1.8% in men and women respectively, consistent with the widely reported AAA predominant prevalence in males. Given the obvious differences in body size between sexes this study aimed to re-evaluate the expanded CVD risk based AAA screening dataset to determine the effect of body size on sex specific AAA prevalence.
METHODS: Absolute (26 and 30 mm) and relative (aortic size index [ASI] equals the maximum infrarenal aorta diameter (cm) divided by body surface area (m2), ASI ≥ 1.5) thresholds were used to assess targeted AAA screening groups (n = 4115) and compared with a self reported healthy elderly control group (n = 800).
RESULTS: Male AAA prevalence was the same using either the 30 mm or ASI ≥1.5 aneurysm definitions (5.7%). In females, AAA prevalence was significantly different between the 30 mm (2.4%) and ASI ≥ 1.5 (4.5%) or the 26 mm (4.4%) thresholds.
CONCLUSION: The results suggest the purported male predominance in AAA prevalence is primarily an artefact of body size differences. When aortic size is adjusted for body surface area there is only a modest sex difference in AAA prevalence. This observation has potential implications in the context of the ongoing discussion regarding AAA screening in women.

PMID: 30293889 [PubMed - indexed for MEDLINE]

A generalized multistage approach to oral and nasal intubation in infants with Pierre Robin sequence: A retrospective review.

Paediatr Anaesth. 2018 11;28(11):1029-1034

Authors: Templeton TW, Goenaga-Díaz EJ, Runyan CM, Kiell EP, Lee AJ, Templeton LB

Abstract
BACKGROUND: Airway management in children with Pierre Robin sequence in the infantile period can be challenging and frequently requires specialized approaches.
AIMS: The aim of this study was to review our experience with a multistage approach to oral and nasal intubation in young infants with Pierre Robin sequence.
METHODS: After IRB approval, we reviewed 13 infants with Pierre Robin sequence who underwent a multistage approach to intubation in the operating room for mandibular distractor or gastrostomy tube placement. All patients underwent awake placement of either an LMA-Classic™ #1 or ProSeal™ laryngeal mask airway size #1. General anesthesia was induced with sevoflurane, and patients were relaxed with rocuronium. The laryngeal mask airway was replaced with an air-Q® 1.0. Children were then intubated through the air-Q® 1.0 using a flexible fiberoptic bronchoscope. In cases that required a nasotracheal tube, the oral tube was left in place while a flexible fiberoptic bronchoscope loaded with a similar internal diameter nasal Ring-Adair-Elwyn (RAE) tube was introduced into the nares. Once the scope was in proximity to the glottis, the oral tube was removed and the patient was intubated with the nasal RAE over the fiberscope.
RESULTS: All 13 patients with Pierre Robin sequence were successfully intubated. We observed no periods of desaturation during placement and induction with the LMA-Classic™ or ProSeal™ laryngeal mask airway except in one patient who was in extremis in the neonatal intensive care unit and required emergent transport to the operating room with the laryngeal mask airway in place. We observed several brief periods of desaturation during the apneas associated with fiberoptic intubation.
CONCLUSION: In conclusion, we were able to use a ventilation-driven, multistaged approach using the unique properties of different supraglottic airways to facilitate oral and nasal intubation in 13 infants with Pierre Robin sequence.

PMID: 30284747 [PubMed - indexed for MEDLINE]

Understanding Pancreatic Diseases Using Animated Pancreas Patient: Informing Patients for Better Health Outcomes With Visual Formats of Learning.

Pancreas. 2018 Nov/Dec;47(10):1256-1261

Authors: Munigala S, Gardner TB, OʼReilly EM, Castillo CF, Ko AH, Pleskow D, Mills JB, Vollmer CM, Searle NA, Alsante M, Holt JM, Gelrud A

Abstract
OBJECTIVES: The aim of this study was to evaluate the impact of Animated Pancreas Patient (APP) educational modules (APP website and YouTube) on pancreas education, awareness, and health outcomes.
METHODS: This was a retrospective study of APP metrics data from September 2013 to October 2017. We evaluated audience reach (number of visit sessions, unique visitors, page views) and calculated top views by media type (animation, expert video, patient video, and slide show) and top retention videos from the modules. We also assessed the educational impact through learner feedback survey.
RESULTS: The APP had 1,475,252 views (547,693 unique visitors, 63.1% in United States) during the study period. Most popular topic viewed among the animations was "Role and Anatomy of the Pancreas" (n = 361,116), and most common expert video viewed was "Chronic Pancreatitis: What Foods and Beverages Should I Avoid?" (n = 31,667). Participants who completed the online feedback survey reported knowledge gains and commitments to change.
CONCLUSIONS: Pancreas education in visual formats of learning provided by APP demonstrated wide reach and has substantial potential to inform and impact behaviors of patients and caregivers. Continued efforts should be made to provide patient resources that address health literacy and patient education and respond to patient needs for better quality of life and improved health outcomes in pancreatic diseases.

PMID: 30286013 [PubMed - indexed for MEDLINE]

Lower body negative pressure to safely reduce intracranial pressure.

J Physiol. 2019 01;597(1):237-248

Authors: Petersen LG, Lawley JS, Lilja-Cyron A, Petersen JCG, Howden EJ, Sarma S, Cornwell WK, Zhang R, Whitworth LA, Williams MA, Juhler M, Levine BD

Abstract
KEY POINTS: During long-term missions, some astronauts experience structural and functional changes of the eyes and brain which resemble signs/symptoms experienced by patients with intracranial hypertension. Weightlessness prevents the normal cerebral volume and pressure 'unloading' associated with upright postures on Earth, which may be part of the cerebral and ocular pathophysiology. By placing the lower body in a negative pressure device (LBNP) that pulls fluid away from cranial compartments, we simulated effects of gravity and significantly lowered pressure within the brain parenchyma and ventricle compartments. Application of incremental LBNP demonstrated a non-linear dose-response curve, suggesting 20 mmHg LBNP as the optimal level for reducing pressure in the brain without impairing cerebral perfusion pressure. This non-invasive method of reducing pressure in the brain holds potential as a countermeasure in space as well as having treatment potential for patients on Earth with traumatic brain injury or other pathology leading to intracranial hypertension.
ABSTRACT: Patients with elevated intracranial pressure (ICP) exhibit neuro-ocular symptoms including headache, papilloedema and loss of vision. Some of these symptoms are also present in astronauts during and after prolonged space-flight where lack of gravitational stress prevents daily lowering of ICP associated with upright posture. Lower body negative pressure (LBNP) simulates the effects of gravity by displacing fluid caudally and we hypothesized that LBNP would lower ICP without compromising cerebral perfusion. Ten cerebrally intact volunteers were included: six ambulatory neurosurgical patients with parenchymal ICP-sensors and four former cancer patients with Ommaya-reservoirs to the frontal horn of a lateral ventricle. We applied LBNP while recording ICP and blood pressure while supine, and during simulated intracranial hypertension by 15° head-down tilt. LBNP from 0 to 50 mmHg at increments of 10 mmHg lowered ICP in a non-linear dose-dependent fashion; when supine (n = 10), ICP was decreased from 15 ± 2 mmHg to 14 ± 4, 12 ± 5, 11 ± 4, 10 ± 3 and 9 ± 4 mmHg, respectively (P < 0.0001). Cerebral perfusion pressure (CPP), calculated as mean arterial blood pressure at midbrain level minus ICP, was unchanged (from 70 ± 12 mmHg to 67 ± 9, 69 ± 10, 70 ± 12, 72 ± 13 and 74 ± 15 mmHg; P = 0.02). A 15° head-down tilt (n = 6) increased ICP to 26 ± 4 mmHg, while application of LBNP lowered ICP (to 21 ± 4, 20 ± 4, 18 ± 4, 17 ± 4 and 17 ± 4 mmHg; P < 0.0001) and increased CPP (P < 0.01). An LBNP of 20 mmHg may be the optimal level to lower ICP without impairing CPP to counteract spaceflight-associated neuro-ocular syndrome in astronauts. Furthermore, LBNP holds clinical potential as a safe, non-invasive method for lowering ICP and improving CPP for patients with pathologically elevated ICP on Earth.

PMID: 30286250 [PubMed - indexed for MEDLINE]

The Cost of Nurse-Midwifery Care: Use of Interventions, Resources, and Associated Costs in the Hospital Setting.

Womens Health Issues. 2017 Jul - Aug;27(4):434-440

Authors: Altman MR, Murphy SM, Fitzgerald CE, Andersen HF, Daratha KB

Abstract
INTRODUCTION: Obstetrical care often involves multiple expensive, and often elective, interventions that may increase costs to patients, payers, and the health care system with little effect on patient outcomes. The objectives of this study were to examine the following hospital related outcomes: 1) use of labor and birth interventions, 2) inpatient duration of stay, and 3) total direct health care costs for patients attended by a certified nurse-midwife (CNM) compared with those attended by an obstetrician-gynecologist (OB-GYN), within an environment of safe and high-quality care.
MATERIAL AND METHODS: Electronic health records for 1,441 medically low-risk women who gave birth at a hospital located in the U.S. Pacific Northwest between January and September 2013 were sampled. Multilevel regression and generalized linear models were used for analysis.
RESULTS: Reduced use of selected labor and birth interventions (cesarean delivery, vacuum-assisted delivery, epidural anesthesia, labor induction, and cervical ripening), reduced maternal duration of stay, and reduced overall costs associated with CNM-led care relative to OB-GYN-led care were observed for medically low-risk women in a hospital setting. Maternal and neonatal outcomes were comparable across groups.
CONCLUSIONS: This study supports consideration of increased use of CNMs as providers for the care of women at low risk for complications to decrease costs for the health care system. The use of CNMs to the fullest extent within state-regulated scopes of practice could result in more efficient use of hospital resources.

PMID: 28215984 [PubMed - indexed for MEDLINE]

How early media exposure may affect cognitive function: A review of results from observations in humans and experiments in mice.

Proc Natl Acad Sci U S A. 2018 10 02;115(40):9851-9858

Authors: Christakis DA, Ramirez JSB, Ferguson SM, Ravinder S, Ramirez JM

Abstract
Attention deficit hyperactivity disorder (ADHD) is now among the most commonly diagnosed chronic psychological dysfunctions of childhood. By varying estimates, it has increased by 30% in the past 20 years. Environmental factors that might explain this increase have been explored. One such factor may be audiovisual media exposure during early childhood. Observational studies in humans have linked exposure to fast-paced television in the first 3 years of life with subsequent attentional deficits in later childhood. Although longitudinal and well controlled, the observational nature of these studies precludes definitive conclusions regarding a causal relationship. As experimental studies in humans are neither ethical nor practical, mouse models of excessive sensory stimulation (ESS) during childhood, akin to the enrichment studies that have previously shown benefits of stimulation in rodents, have been developed. Experimental studies using this model have corroborated that ESS leads to cognitive and behavioral deficits, some of which may be potentially detrimental. Given the ubiquity of media during childhood, these findings in humansand rodents perhaps have important implications for public health.

PMID: 30275319 [PubMed - indexed for MEDLINE]

Surgical management of superior petrosal sinus dural arteriovenous fistulae with dominant internal carotid artery supply.

Interv Neuroradiol. 2018 Jun;24(3):331-338

Authors: Stapleton CJ, Patel AP, Walcott BP, Torok CM, Koch MJ, Leslie-Mazwi TM, Rabinov JD, Butler WE, Patel AB

Abstract
Background While technological advances have improved the efficacy of endovascular techniques for tentorial dural arteriovenous fistulae (DAVF), superior petrosal sinus (SPS) DAVF with dominant internal carotid artery (ICA) supply frequently require surgical intervention to achieve a definitive cure. Methods To compare the angiographic and clinical outcomes of endovascular and surgical interventions in patients with SPS DAVF, the records of all patients with tentorial DAVF from August 2010 to November 2015 were reviewed. Results Within this cohort, eight patients with nine SPS DAVF were eligible for evaluation. Five DAVF were initially treated with endovascular embolization, while four underwent surgical occlusion without embolization. Of the SPS DAVF treated with embolization, two (40%) remained occluded on follow-up, while the remaining three (60%) persisted/recurred and required surgical intervention for definitive closure. Of the four SPS DAVF treated with primary surgical occlusion, all four (100%) remained closed on follow-up. In addition, of the three SPS DAVF that persisted/recurred following embolization and required subsequent surgical closure, all three (100%) remained occluded on follow-up. Two (100%) SPS DAVF that were successfully treated with embolization had major or minor external carotid artery supply, while the three (100%) persistent lesions had major ICA supply via the meningohypophyseal trunk (MHT). Three (75%) of the four SPS DAVF treated with primary surgical occlusion had dominant MHT supply. Conclusion Complete endovascular closure of SPS DAVF with dominant ICA supply via the MHT may be difficult to achieve, while upfront surgical intervention is associated with a high rate of complete occlusion.

PMID: 29433364 [PubMed - indexed for MEDLINE]

Impeding DNA Break Repair Enables Oocyte Quality Control.

Mol Cell. 2018 10 18;72(2):211-221.e3

Authors: Qiao H, Rao HBDP, Yun Y, Sandhu S, Fong JH, Sapre M, Nguyen M, Tham A, Van BW, Chng TYH, Lee A, Hunter N

Abstract
Oocyte quality control culls eggs with defects in meiosis. In mouse, oocyte death can be triggered by defects in chromosome synapsis and recombination, which involve repair of DNA double-strand breaks (DSBs) between homologous chromosomes. We show that RNF212, a SUMO ligase required for crossing over, also mediates oocyte quality control. Both physiological apoptosis and wholesale oocyte elimination in meiotic mutants require RNF212. RNF212 sensitizes oocytes to DSB-induced apoptosis within a narrow window as chromosomes desynapse and cells transition into quiescence. Analysis of DNA damage during this transition implies that RNF212 impedes DSB repair. Consistently, RNF212 is required for HORMAD1, a negative regulator of inter-sister recombination, to associate with desynapsing chromosomes. We infer that oocytes impede repair of residual DSBs to retain a "memory" of meiotic defects that enables quality-control processes. These results define the logic of oocyte quality control and suggest RNF212 variants may influence transmission of defective genomes.

PMID: 30270110 [PubMed - indexed for MEDLINE]

A truncating mutation in EPOR leads to hypo-responsiveness to erythropoietin with normal haemoglobin.

Commun Biol. 2018;1:49

Authors: Oskarsson GR, Kristjansson RP, Lee AL, Sveinbjornsson G, Magnusson MK, Ivarsdottir EV, Benonisdottir S, Oddsson A, Davidsson OB, Saemundsdottir J, Halldorsson GH, Arthur J, Arnadottir GA, Masson G, Jensson BO, Holm H, Olafsson I, Onundarson PT, Gudbjartsson DF, Norddahl GL, Thorsteinsdottir U, Sulem P, Stefansson K

Abstract
The cytokine erythropoietin (EPO), signalling through the EPO receptor (EPO-R), is essential for the formation of red blood cells. We performed a genome-wide association study (GWAS) testing 32.5 million sequence variants for association with serum EPO levels in a set of 4187 individuals. We detect an association between a rare and well imputed stop-gained variant rs370865377[A] (p.Gln82Ter) in EPOR, carried by 1 in 550 Icelanders, and increased serum EPO levels (MAF = 0.09%, Effect = 1.47 SD, P = 3.3 × 10-7). We validated these findings by measuring serum EPO levels in 34 additional pairs of carriers and matched controls and found carriers to have 3.23-fold higher EPO levels than controls (P = 1.7 × 10-6; P combined = 1.6 × 10-11). In contrast to previously reported EPOR mutations, p.Gln82Ter does not associate with haemoglobin levels (Effect = -0.045 SD, P = 0.32, N = 273,160), probably due to a compensatory EPO upregulation in response to EPO-R hypo-responsiveness.

PMID: 30271932 [PubMed]

Alzheimer's disease (AD) therapeutics - 2: Beyond amyloid - Re-defining AD and its causality to discover effective therapeutics.

Biochem Pharmacol. 2018 12;158:376-401

Authors: Mullane K, Williams M

Abstract
Compounds targeted for the treatment of Alzheimer's Disease (AD) have consistently failed in clinical trials despite evidence for target engagement and pharmacodynamic activity. This questions the relevance of compounds acting at current AD drug targets - the majority of which reflect the seminal amyloid and, to a far lesser extent, tau hypotheses - and limitations in understanding AD causality as distinct from general dementia. The preeminence of amyloid and tau led to many alternative approaches to AD therapeutics being ignored or underfunded to the extent that their causal versus contributory role in AD remains unknown. These include: neuronal network dysfunction; cerebrovascular disease; chronic, local or systemic inflammation involving the innate immune system; infectious agents including herpes virus and prion proteins; neurotoxic protein accumulation associated with sleep deprivation, circadian rhythm and glymphatic/meningeal lymphatic system and blood-brain-barrier dysfunction; metabolic related diseases including diabetes, obesity hypertension and hypocholesterolemia; mitochondrial dysfunction and environmental factors. As AD has become increasingly recognized as a multifactorial syndrome, a single treatment paradigm is unlikely to work in all patients. However, the biomarkers required to diagnose patients and parse them into mechanism/disease-based sub-groups remain rudimentary and unvalidated as do non-amyloid, non-tau translational animal models. The social and economic impact of AD is also discussed in the context of new FDA regulatory draft guidance and a proposed biomarker-based Framework (re)-defining AD and its stages as part of the larger landscape of treating dementia via the 2013 G8 initiative to identify a disease-modifying therapy for dementia/AD by 2025.

PMID: 30273552 [PubMed - indexed for MEDLINE]

Alzheimer's disease (AD) therapeutics - 1: Repeated clinical failures continue to question the amyloid hypothesis of AD and the current understanding of AD causality.

Biochem Pharmacol. 2018 12;158:359-375

Authors: Mullane K, Williams M

Abstract
Deposits of amyloid plaques and neurofibrillary tangles of aggregated tau in the brain represent key hallmarks of the neurodegenerative disorder, Alzheimer's Disease (AD) and form the basis of the major hypotheses of AD causality. To date, therapeutics that reduce brain amyloid in AD patients have demonstrated no effect in reversing the associated decline in cognition or function indicating that the amyloid hypothesis is either incorrect or that there is a point when the disease becomes independent of Aβ production or is refractory to any type of therapeutic intervention. The clinical failures of inhibitors of tau aggregation, neurotransmitter modulators and drugs repurposed from AD-associated disease indications tend to support this latter viewpoint. Current understanding of AD causality is thus incomplete, a situation that has been compounded by a debate on whether AD is a singularly distinct form of dementia and by the dogmatic promotion of hypotheses over actual clinical data. The latter has repeatedly led to compounds lacking efficacy in Phase II trials being advanced into Phase III where their lack of efficacy is routinely recapitulated. This Commentary, the first of two, discusses amyloid and tau as putative drug targets for AD in the context of the prevalence and economic and social impact of this insidious neurodegenerative disease.

PMID: 30273553 [PubMed - indexed for MEDLINE]

Outcome after myocardial infarction without obstructive coronary artery disease.

Heart. 2019 04;105(7):524-530

Authors: Williams MJA, Barr PR, Lee M, Poppe KK, Kerr AJ

Abstract
OBJECTIVE: The medium-term outcome and cause of death in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) is not well characterised. The aim of this study was to compare mortality and rates of recurrent events in post myocardial infarction (MI) patients with obstructive coronary artery disease (CAD) and in patients with MINOCA compared with an age and sex-matched cohort without cardiovascular disease (CVD).
METHODS: We performed a national cohort study of consecutive patients undergoing coronary angiography for MI during 2 years between 2013 and 2015 from the All New Zealand Acute Coronary Syndrome-Quality Improvement (ANZACS QI) registry. MI patient registry data were linked anonymously to national hospitalisation and mortality records. Age and sex matched patients without known CVD formed the comparison group.
RESULTS: Of the 8305 patients with MI, 897 (10.8%) were classified as MINOCA. Compared with those without known CVD, the adjusted HRs for the primary outcome (all-cause death or recurrent non-fatal MI) were 7.81 (95% CI 6.64 to 9.19, p<0.0001) in those with obstructive CAD and 4.64 (95% CI 3.54 to 6.10, p<0.0001) in those with MINOCA. Kaplan-Meier all-cause mortality at 2 years was 7.9% for those with obstructive CAD, with nearly half being CVD deaths (3.6% CVD deaths and 4.5% non-CVD deaths, respectively). In contrast, MINOCA all-cause mortality was 4.9% with non-CVD death (4.5%) predominating.
CONCLUSIONS: MINOCA is common and has an adverse outcome rate approximately half than that of those with obstructive CAD. The predominant contributor to mortality is non-CVD death. The rate of events in MINOCA is significantly greater than the population without CVD.

PMID: 30269079 [PubMed - indexed for MEDLINE]