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Publication Record


(Na1.5) Variant Functional Perturbation and Clinical Presentation: Variants of a Certain Significance.
Kroncke BM, Glazer AM, Smith DK, Blume JD, Roden DM
(2018) Circ Genom Precis Med 11: e002095
MeSH Terms: Animals, Cell Line, Humans, Models, Genetic, Mutation, NAV1.5 Voltage-Gated Sodium Channel, Penetrance, Probability, Statistics, Nonparametric, Uncertainty
Show Abstract · Added March 26, 2019
BACKGROUND - Accurately predicting the impact of rare nonsynonymous variants on disease risk is an important goal in precision medicine. Variants in the cardiac sodium channel (protein Na1.5; voltage-dependent cardiac Na+ channel) are associated with multiple arrhythmia disorders, including Brugada syndrome and long QT syndrome. Rare variants also occur in ≈1% of unaffected individuals. We hypothesized that in vitro electrophysiological functional parameters explain a statistically significant portion of the variability in disease penetrance.
METHODS - From a comprehensive literature review, we quantified the number of carriers presenting with and without disease for 1712 reported variants. For 356 variants, data were also available for 5 Na1.5 electrophysiological parameters: peak current, late/persistent current, steady-state V1/2 of activation and inactivation, and recovery from inactivation.
RESULTS - We found that peak and late current significantly associate with Brugada syndrome (<0.001; ρ=-0.44; Spearman rank test) and long QT syndrome disease penetrance (<0.001; ρ=0.37). Steady-state V1/2 activation and recovery from inactivation associate significantly with Brugada syndrome and long QT syndrome penetrance, respectively. Continuous estimates of disease penetrance align with the current American College of Medical Genetics classification paradigm.
CONCLUSIONS - Na1.5 in vitro electrophysiological parameters are correlated with Brugada syndrome and long QT syndrome disease risk. Our data emphasize the value of in vitro electrophysiological characterization and incorporating counts of affected and unaffected carriers to aid variant classification. This quantitative analysis of the electrophysiological literature should aid the interpretation of Na1.5 variant electrophysiological abnormalities and help improve Na1.5 variant classification.
© 2018 American Heart Association, Inc.
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10 MeSH Terms
Platelet transfusion does not improve outcomes in patients with brain injury on antiplatelet therapy.
Holzmacher JL, Reynolds C, Patel M, Maluso P, Holland S, Gamsky N, Moore H, Acquista E, Carrick M, Amdur R, Hancock H, Metzler M, Dunn J, Sarani B
(2018) Brain Inj 32: 325-330
MeSH Terms: Aged, Aged, 80 and over, Aspirin, Brain Injuries, Clopidogrel, Female, Humans, Injury Severity Score, Length of Stay, Male, Platelet Aggregation Inhibitors, Platelet Transfusion, Statistics, Nonparametric, Treatment Outcome
Show Abstract · Added June 26, 2018
INTRODUCTION - Platelet dysfunction following traumatic brain injury (TBI) is associated with worse outcomes. The efficacy of platelet transfusion to reverse antiplatelet medication (APM) remains unknown. Thrombelastography platelet mapping (TEG-PM) assesses platelet function. We hypothesize that platelet transfusion can reverse the effects of APM but does not improve outcomes following TBI.
METHODS - An observational study at six US trauma centres was performed. Adult patients on APM with CT evident TBI after blunt injury were enrolled. Demographics, brain CT and TEG-PM results before/after platelet transfusion, length of stay (LOS), and injury severity score (ISS) were abstracted.
RESULTS - Sixty six patients were enrolled (89% aspirin, 50% clopidogrel, 23% dual APM) with 23 patients undergoing platelet transfusion. Transfused patients had significantly higher ISS and admission CT scores. Platelet transfusion significantly reduced platelet inhibition due to aspirin (76.0 ± 30.2% to 52.7 ± 31.5%, p < 0.01), but had a non-significant impact on clopidogrel-associated inhibition (p = 0.07). Platelet transfusion was associated with longer length of stay (7.8 vs. 3.5 days, p < 0.01), but there were no differences in mortality.
CONCLUSION - Platelet transfusion significantly decreases platelet inhibition due to aspirin but is not associated with change in outcomes in patients on APM following TBI.
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14 MeSH Terms
Deformation correction for image guided liver surgery: An intraoperative fidelity assessment.
Clements LW, Collins JA, Weis JA, Simpson AL, Kingham TP, Jarnagin WR, Miga MI
(2017) Surgery 162: 537-547
MeSH Terms: Adult, Aged, Female, Follow-Up Studies, Hepatectomy, Humans, Imaging, Three-Dimensional, Liver, Liver Neoplasms, Male, Middle Aged, Monitoring, Intraoperative, Outcome Assessment (Health Care), Single-Blind Method, Statistics, Nonparametric, Surgery, Computer-Assisted, Treatment Outcome
Show Abstract · Added July 23, 2018
BACKGROUND - Although systems of 3-dimensional image-guided surgery are a valuable adjunct across numerous procedures, differences in organ shape between that reflected in the preoperative image data and the intraoperative state can compromise the fidelity of such guidance based on the image. In this work, we assessed in real time a novel, 3-dimensional image-guided operation platform that incorporates soft tissue deformation.
METHODS - A series of 125 alignment evaluations were performed across 20 patients. During the operation, the surgeon assessed the liver by swabbing an optically tracked stylus over the liver surface and viewing the image-guided operation display. Each patient had approximately 6 intraoperative comparative evaluations. For each assessment, 1 of only 2 types of alignments were considered: conventional rigid and novel deformable. The series of alignment types used was randomized and blinded to the surgeon. The surgeon provided a rating, R, from -3 to +3 for each display compared with the previous display, whereby a negative rating indicated degradation in fidelity and a positive rating an improvement.
RESULTS - A statistical analysis of the series of rating data by the clinician indicated that the surgeons were able to perceive an improvement (defined as a R > 1) of the model-based registration over the rigid registration (P = .01) as well as a degradation (defined as R < -1) when the rigid registration was compared with the novel deformable guidance information (P = .03).
CONCLUSION - This study provides evidence of the benefit of deformation correction in providing an accurate location for the liver for use in image-guided surgery systems.
Copyright © 2017 Elsevier Inc. All rights reserved.
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MeSH Terms
Differential expression of systemic inflammatory mediators in amputees with chronic residual limb pain.
Chamessian A, Van de Ven T, Buchheit T, Hsia HL, McDuffie M, Gamazon ER, Walsh C, Bruehl S, Buckenmaier C', Shaw A
(2017) Pain 158: 68-74
MeSH Terms: Adolescent, Adult, Amputees, Case-Control Studies, Catastrophization, Chronic Pain, Female, Humans, Inflammation Mediators, Male, Pain Measurement, Phantom Limb, Psychometrics, Statistics, Nonparametric, Up-Regulation, Young Adult
Show Abstract · Added April 13, 2017
Chronic postsurgical pain impacts most amputees, with more than half experiencing neuralgic residual limb pain. The transition from normal acute postamputation pain to chronic residual limb pain likely involves both peripheral and central inflammatory mechanisms. As part of the Veterans Integrated Pain Evaluation Research study, we investigated links between systemic inflammatory mediator levels and chronic residual limb pain. Subjects included 36 recent active duty military traumatic amputees with chronic residual limb pain and 40 without clinically significant pain. Blood samples were obtained and plasma concentrations of an array of inflammatory mediators were analyzed. Residual limb pain intensity and pain catastrophizing were assessed to examine associations with inflammatory mediators. Pro-inflammatory mediators including tumor necrosis factor (TNF)-α, TNF-β, interleukin (IL)-8, ICAM-1, Tie2, CRP, and SAA were elevated in patients with chronic residual limb pain. Across all patients, residual limb pain intensity was associated positively with levels of several proinflammatory mediators (IL-8, TNF-α, IL-12, TNF-β, PIGF, Tie2, SAA, and ICAM-1), and inversely with concentrations of the anti-inflammatory mediator IL-13, as well as IL-2 and Eotaxin-3. Pain catastrophizing correlated positively with IL-8, IL-12, TNF-β, PIGF, and ICAM-1, and inversely with IL-13. Significant associations between catastrophizing and residual limb pain intensity were partially mediated by TNF-α, TNF- β, SAA, and ICAM-1 levels. Results suggest that chronic postamputation residual limb pain is associated with excessive inflammatory response to injury or to inadequate resolution of the postinjury inflammatory state. Impact of pain catastrophizing on residual limb pain may be because of part to common underlying inflammatory mechanisms.
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16 MeSH Terms
Activation of Human T Cells in Hypertension: Studies of Humanized Mice and Hypertensive Humans.
Itani HA, McMaster WG, Saleh MA, Nazarewicz RR, Mikolajczyk TP, Kaszuba AM, Konior A, Prejbisz A, Januszewicz A, Norlander AE, Chen W, Bonami RH, Marshall AF, Poffenberger G, Weyand CM, Madhur MS, Moore DJ, Harrison DG, Guzik TJ
(2016) Hypertension 68: 123-32
MeSH Terms: Adult, Analysis of Variance, Angiotensin II, Animals, Antibodies, Monoclonal, Humanized, Cells, Cultured, Chi-Square Distribution, Disease Models, Animal, Humans, Hypertension, Kidney, Lymphocyte Activation, Mice, Middle Aged, Random Allocation, Reference Values, Sampling Studies, Statistics, Nonparametric, T-Lymphocytes, Regulatory
Show Abstract · Added May 25, 2016
Emerging evidence supports an important role for T cells in the genesis of hypertension. Because this work has predominantly been performed in experimental animals, we sought to determine whether human T cells are activated in hypertension. We used a humanized mouse model in which the murine immune system is replaced by the human immune system. Angiotensin II increased systolic pressure to 162 versus 116 mm Hg for sham-treated animals. Flow cytometry of thoracic lymph nodes, thoracic aorta, and kidney revealed increased infiltration of human leukocytes (CD45(+)) and T lymphocytes (CD3(+) and CD4(+)) in response to angiotensin II infusion. Interestingly, there was also an increase in the memory T cells (CD3(+)/CD45RO(+)) in the aortas and lymph nodes. Prevention of hypertension using hydralazine and hydrochlorothiazide prevented the accumulation of T cells in these tissues. Studies of isolated human T cells and monocytes indicated that angiotensin II had no direct effect on cytokine production by T cells or the ability of dendritic cells to drive T-cell proliferation. We also observed an increase in circulating interleukin-17A producing CD4(+) T cells and both CD4(+) and CD8(+) T cells that produce interferon-γ in hypertensive compared with normotensive humans. Thus, human T cells become activated and invade critical end-organ tissues in response to hypertension in a humanized mouse model. This response likely reflects the hypertensive milieu encountered in vivo and is not a direct effect of the hormone angiotensin II.
© 2016 American Heart Association, Inc.
1 Communities
2 Members
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19 MeSH Terms
Association of Arrhythmia-Related Genetic Variants With Phenotypes Documented in Electronic Medical Records.
Van Driest SL, Wells QS, Stallings S, Bush WS, Gordon A, Nickerson DA, Kim JH, Crosslin DR, Jarvik GP, Carrell DS, Ralston JD, Larson EB, Bielinski SJ, Olson JE, Ye Z, Kullo IJ, Abul-Husn NS, Scott SA, Bottinger E, Almoguera B, Connolly J, Chiavacci R, Hakonarson H, Rasmussen-Torvik LJ, Pan V, Persell SD, Smith M, Chisholm RL, Kitchner TE, He MM, Brilliant MH, Wallace JR, Doheny KF, Shoemaker MB, Li R, Manolio TA, Callis TE, Macaya D, Williams MS, Carey D, Kapplinger JD, Ackerman MJ, Ritchie MD, Denny JC, Roden DM
(2016) JAMA 315: 47-57
MeSH Terms: Aged, Aged, 80 and over, Alleles, Arrhythmias, Cardiac, Brugada Syndrome, ERG1 Potassium Channel, Electronic Health Records, Ether-A-Go-Go Potassium Channels, Female, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Genomics, Heterozygote, Humans, Incidental Findings, Laboratories, Male, Middle Aged, Mutation, Missense, NAV1.5 Voltage-Gated Sodium Channel, Phenotype, Prospective Studies, Random Allocation, Statistics, Nonparametric, Young Adult
Show Abstract · Added April 6, 2017
IMPORTANCE - Large-scale DNA sequencing identifies incidental rare variants in established Mendelian disease genes, but the frequency of related clinical phenotypes in unselected patient populations is not well established. Phenotype data from electronic medical records (EMRs) may provide a resource to assess the clinical relevance of rare variants.
OBJECTIVE - To determine the clinical phenotypes from EMRs for individuals with variants designated as pathogenic by expert review in arrhythmia susceptibility genes.
DESIGN, SETTING, AND PARTICIPANTS - This prospective cohort study included 2022 individuals recruited for nonantiarrhythmic drug exposure phenotypes from October 5, 2012, to September 30, 2013, for the Electronic Medical Records and Genomics Network Pharmacogenomics project from 7 US academic medical centers. Variants in SCN5A and KCNH2, disease genes for long QT and Brugada syndromes, were assessed for potential pathogenicity by 3 laboratories with ion channel expertise and by comparison with the ClinVar database. Relevant phenotypes were determined from EMRs, with data available from 2002 (or earlier for some sites) through September 10, 2014.
EXPOSURES - One or more variants designated as pathogenic in SCN5A or KCNH2.
MAIN OUTCOMES AND MEASURES - Arrhythmia or electrocardiographic (ECG) phenotypes defined by International Classification of Diseases, Ninth Revision (ICD-9) codes, ECG data, and manual EMR review.
RESULTS - Among 2022 study participants (median age, 61 years [interquartile range, 56-65 years]; 1118 [55%] female; 1491 [74%] white), a total of 122 rare (minor allele frequency <0.5%) nonsynonymous and splice-site variants in 2 arrhythmia susceptibility genes were identified in 223 individuals (11% of the study cohort). Forty-two variants in 63 participants were designated potentially pathogenic by at least 1 laboratory or ClinVar, with low concordance across laboratories (Cohen κ = 0.26). An ICD-9 code for arrhythmia was found in 11 of 63 (17%) variant carriers vs 264 of 1959 (13%) of those without variants (difference, +4%; 95% CI, -5% to +13%; P = .35). In the 1270 (63%) with ECGs, corrected QT intervals were not different in variant carriers vs those without (median, 429 vs 439 milliseconds; difference, -10 milliseconds; 95% CI, -16 to +3 milliseconds; P = .17). After manual review, 22 of 63 participants (35%) with designated variants had any ECG or arrhythmia phenotype, and only 2 had corrected QT interval longer than 500 milliseconds.
CONCLUSIONS AND RELEVANCE - Among laboratories experienced in genetic testing for cardiac arrhythmia disorders, there was low concordance in designating SCN5A and KCNH2 variants as pathogenic. In an unselected population, the putatively pathogenic genetic variants were not associated with an abnormal phenotype. These findings raise questions about the implications of notifying patients of incidental genetic findings.
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26 MeSH Terms
Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans.
Ramirez CE, Shuey MM, Milne GL, Gilbert K, Hui N, Yu C, Luther JM, Brown NJ
(2014) Prostaglandins Other Lipid Mediat 113-115: 38-44
MeSH Terms: Adult, Arachidonic Acids, Body Mass Index, DNA, Epoxide Hydrolases, Female, Genetic Variation, Genotype, Glucose Clamp Technique, Humans, Insulin, Insulin Resistance, Insulin Secretion, Male, Middle Aged, Polymerase Chain Reaction, Statistics, Nonparametric, Young Adult
Show Abstract · Added October 27, 2014
Epoxyeicosatrienoic acids (EETs) protect against the development of insulin resistance in rodents. EETs are hydrolyzed to less biologically active diols by soluble epoxide hydrolase (encoded for by EPHX2). Functional variants of EPHX2 encode for enzymes with increased (Lys55Arg) or decreased (Arg287Gln) hydrolase activity. This study tested the hypothesis that variants of EPHX2 are associated with insulin sensitivity or secretion in humans. Subjects participating in metabolic phenotyping studies were genotyped. Eighty-five subjects underwent hyperglycemic clamps. There was no relationship between the Lys55Arg genotype and insulin sensitivity or secretion. In contrast, the EPHX2 287Gln variant was associated with higher insulin sensitivity index (p=0.019 controlling for body mass index and metabolic syndrome). Also, there was an interactive effect of EPHX2 Arg287Gln genotype and body mass index on insulin sensitivity index (p=0.029). There was no relationship between EPHX2 Arg287Gln genotype and acute or late-phase glucose-stimulated insulin secretion, but disposition index was higher in 287Gln carriers compared with Arg/Arg (p=0.022). Plasma EETs correlated with insulin sensitivity index (r=0.64, p=0.015 for total EETs) and were decreased in the metabolic syndrome. A genetic variant that results in decreased soluble epoxide hydrolase activity is associated with increased insulin sensitivity, as are higher EETs.
Copyright © 2014 Elsevier Inc. All rights reserved.
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18 MeSH Terms
Elevation of plasma cell-free hemoglobin in pulmonary arterial hypertension.
Brittain EL, Janz DR, Austin ED, Bastarache JA, Wheeler LA, Ware LB, Hemnes AR
(2014) Chest 146: 1478-1485
MeSH Terms: Adult, Aged, Biomarkers, Bone Morphogenetic Protein Receptors, Type II, Case-Control Studies, Female, Hemodynamics, Hemoglobins, Humans, Hypertension, Pulmonary, Kaplan-Meier Estimate, Male, Middle Aged, Plasma Cells, Prognosis, Proportional Hazards Models, Retrospective Studies, Sensitivity and Specificity, Severity of Illness Index, Statistics, Nonparametric, Vascular Resistance
Show Abstract · Added August 8, 2014
BACKGROUND - Cell-free hemoglobin (CFH) is a potent nitric oxide scavenger associated with poor outcomes in several diseases. Pulmonary arterial hypertension (PAH) is characterized by reduced nitric oxide availability. We hypothesized that CFH would be elevated in PAH and would associate with hemodynamics and clinical outcomes.
METHODS - We measured CFH in 200 consecutively evaluated patients with PAH, 16 unaffected bone morphogenetic receptor protein type 2 (BMPR2) mutation carriers, 19 healthy subjects, and 29 patients with pulmonary venous hypertension (PVH). CFH values were tested for association with hemodynamics, time to hospitalization, and death.
RESULTS - CFH was elevated in patients with PAH and BMPR2 carriers compared with healthy subjects and patients with PVH (P ≤ .01 all comparisons). There were no differences in CFH across PAH subtypes. CFH modestly correlated with mean pulmonary artery pressure (ρ = 0.16, P = .03) and pulmonary vascular resistance (ρ = 0.21, P = .01) and inversely with cardiac index (ρ = -0.18, P = .02) in patients with PAH. CFH was not associated with hemodynamic response to nitric oxide or death. Patients with the highest CFH levels had increased risk of PAH-related hospitalization when adjusted for age, sex, and PAH cause (hazard ratio, 1.69; 95% CI ,1.08-2.66; P = .02).
CONCLUSIONS - CFH is elevated in patients with PAH and BMPR2 carriers compared with healthy subjects and patients with PVH. Elevated CFH levels are independently associated with an increased risk of hospitalization. Further study is required to understand the mechanism of CFH elevation and the potential pathologic contribution of CFH in PAH.
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21 MeSH Terms
miR-203 regulates progenitor cell proliferation during adult zebrafish retina regeneration.
Rajaram K, Harding RL, Hyde DR, Patton JG
(2014) Dev Biol 392: 393-403
MeSH Terms: Animals, Blotting, Western, Cell Proliferation, Cloning, Molecular, Electroporation, Flow Cytometry, Gene Expression Regulation, Immunohistochemistry, MicroRNAs, Microinjections, Morpholinos, Real-Time Polymerase Chain Reaction, Regeneration, Retina, Reverse Transcriptase Polymerase Chain Reaction, Statistics, Nonparametric, Stem Cells, Zebrafish
Show Abstract · Added May 27, 2014
Damage of the zebrafish retina triggers a spontaneous regeneration response that is initiated by Müller Glia (MG) dedifferentiation and asymmetric cell division to produce multipotent progenitor cells. Subsequent expansion of the progenitor pool by proliferation is critical for retina regeneration. Pax6b expression in the progenitor cells is necessary for their proliferation, but exact regulation of its expression is unclear. Here, we show that miR-203 is downregulated during regeneration in proliferating progenitor cells. Elevated miR-203 levels inhibit progenitor cell expansion without affecting MG dedifferentiation or progenitor cell generation. Using GFP-reporter assays and gain and loss of function experiments in the retina, we show that miR-203 expression must be suppressed to allow pax6b expression and subsequent progenitor cell proliferation.
Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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18 MeSH Terms
Odorant receptor-mediated sperm activation in disease vector mosquitoes.
Pitts RJ, Liu C, Zhou X, Malpartida JC, Zwiebel LJ
(2014) Proc Natl Acad Sci U S A 111: 2566-71
MeSH Terms: Animals, Anopheles, Biological Assay, Insect Vectors, Male, Receptors, Odorant, Sequence Analysis, RNA, Sperm Capacitation, Sperm Tail, Statistics, Nonparametric, Testis
Show Abstract · Added May 27, 2014
Insects, such as the malaria vector mosquito, Anopheles gambiae, depend upon chemoreceptors to respond to volatiles emitted from a range of environmental sources, most notably blood meal hosts and oviposition sites. A subset of peripheral signaling pathways involved in these insect chemosensory-dependent behaviors requires the activity of heteromeric odorant receptor (OR) ion channel complexes and ligands for numerous A. gambiae ORs (AgOrs) have been identified. Although AgOrs are expressed in nonhead appendages, studies characterizing potential AgOr function in nonolfactory tissues have not been conducted. In the present study, we explore the possibility that AgOrs mediate responses of spermatozoa to endogenous signaling molecules in A. gambiae. In addition to finding AgOr transcript expression in testes, we show that the OR coreceptor, AgOrco, is localized to the flagella of A. gambiae spermatozoa where Orco-specific agonists, antagonists, and other odorant ligands robustly activate flagella beating in an Orco-dependent process. We also demonstrate Orco expression and Orco-mediated activation of spermatozoa in the yellow fever mosquito, Aedes aegypti. Moreover, we find Orco localization in testes across distinct insect taxa and posit that OR-mediated responses in spermatozoa may represent a general characteristic of insect reproduction and an example of convergent evolution.
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11 MeSH Terms