217 results on '"Alexander JJ"'
Search Results
2. Circulating white blood cells and platelets amplify oxidative stress in heart failure
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IJsselmuiden, Alexander JJ, Musters, René JP, de Ruiter, Gijsbert, van Heerebeek, Loek, Alderse-Baas, Frans, van Schilfgaarde, Muriel, Leyte, Anja, Tangelder, Geert-Jan, Laarman, Gerrit J, and Paulus, Walter J
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- 2008
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3. Characterisation of gastroenteritis associated adenoviruses in South Africa
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Moore, P, Steele, AD, Lecatsas, G, and Alexander, JJ
- Abstract
Objective. To analyse adenovirus (Ad) numbers and types associated with paediatric gastro-enteritis in South AfricaSetting. Gauteng, 1994-1996.Methods. A total of 234 paediatric diarrhoeal stool samples were screened for Ad using commercial enzyme-linked iInmunosorbent assays (EUSAs). Adenoviral isolates were typed, where possibie, using restriction enzyme analysis.Results. Ad was detected in 23 (9.8%) specimens, of which 8 (34.8%) were found by subgroup F-specilic EUSA to contain Ad40 or 41. Six of these isolates were typed and 2 could not be typed. Of the remaining 15 specimens, 2 isolates had restriction profiles that did not correspond with known Ads, while 2were identified as Ad31 and 1 as a subgroup CAd. The remaining 10 specimens negative for Ad40/41 were noncultivable and could not be typed.Conclusions. The high percentage of non-eultivable Ads other than Ad40/41 is unusual, and may possibly indicate the prevalence of hexon variants of Ad40/41 or of emerging Ad types in South Africa.
- Published
- 2016
4. C3aR inhibition reduces neurodegeneration in experimental lupus
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Jacob, A., primary, Bao, L., additional, Brorson, J., additional, Quigg, RJ, additional, and Alexander, JJ, additional
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- 2009
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5. Safe and effective direct implantation of a new stent through 5 F. guiding catheters with delivery from the radial artery: initial results of a prospective registry
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IJsselmuiden, Alexander JJ, primary, Cotton, James M, additional, Slagboom, Ton, additional, van der Wieken, Ron, additional, Kiemeneij, Ferdinand, additional, Serruys, Patrick W, additional, and Laarman, GertJan, additional
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- 2003
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6. Pathogenesis of septic encephalopathy.
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Pytel P and Alexander JJ
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- 2009
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7. Primary intimal sarcoma of the aorta associated with a dacron graft and resulting in arterial rupture.
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Alexander JJ, Moawad J, and Cai D
- Abstract
Primary arterial neoplasms are rare lesions which have been most frequently associated with local or constitutional symptomatology, and with distal embolization. Perirenal aortic disruption with pseudoaneurysm formation due to an intimal sarcoma adjacent to a previously placed prosthetic graft is reported in a 66-year-old man. This case supports the premise that the presence of a vascular prosthesis might result in the induction of an arterial wall malignancy. This should be considered when an intraluminal mass is identified in the absence of other arterial pathology. Although the prognosis of these tumors is poor, their preoperative recognition may enhance treatment outcomes. [ABSTRACT FROM AUTHOR]
- Published
- 2006
8. Safe and effective direct implantation of a new stent through 5 F. guiding catheters with delivery from the radial artery: initial results of a prospective registry
- Author
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IJsselmuiden, Alexander JJ, Cotton, James, Slagboom, Ton, van der Wieken, Ron, Kiemeneij, Ferdinand, Serruys, Patrick, and Laarman, GertJan
- Abstract
OBJECTIVES: To evaluate the safety and efficacy of the direct implantation of a new stent via the radial artery through a 5 F. guiding catheter. Background advances in the design of stents and stent delivery systems have facilitated the performance of direct stenting and the use of thinner guiding catheters. METHODS: This registry enrolled prospectively 125 patients (147 lesions, 20.4% AHA/ACC class B2/C) who underwent elective percutaneous coronary revascularization procedures for stable or unstable angina between November 2000 and March 2001. RESULTS: Cannulation of the radial artery was attempted in 92.7% and was successful in 91.0% of cases. Direct stenting was successful in 88.7% of lesions and procedural success was 99.3%. In-hospital major adverse cardiac events occurred in 1.6% of cases (one death, one semi-urgent coronary artery bypass operation). The final rate of successful stent implantation through 5 F. guiding catheters was 96.7%. There were no access-site-related complications. Failure to cross the lesion occurred in 10% of attempts. At a mean follow-up of 7 ± 2.8 months after discharge from hospital, 79% of patients had remained free of angina, and 89% had remained free of ischemic events. CONCLUSIONS: Direct stenting with a new stent design was safe, effective, and could be accomplished through 5 F. guiding catheters with favorable long-term clinical outcomes. (Int J Cardiovasc Intervent 2003; 5: 72-76)
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- 2003
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9. Blood cultures in bacteremia
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Lewis Jf and Alexander Jj
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Male ,medicine.medical_specialty ,Bacteriological Techniques ,medicine.diagnostic_test ,Bacteria ,business.industry ,Infant, Newborn ,General Medicine ,Middle Aged ,medicine.disease ,Hospital records ,Culture Media ,Evaluation Studies as Topic ,Bacteremia ,Internal medicine ,Sepsis ,medicine ,Humans ,Clinical significance ,Blood culture ,Female ,business ,Child - Abstract
Blood cultures in a 700-bed hospital were examined for clinical relevance. During a six-month period 5,154 blood samples were drawn from 1,091 patients. Of the 124 patients with positive blood cultures, 7% had polymicrobic isolates. A review of hospital records for a three-year period revealed 162 charts with adequate documentation for evaluation of bacteremia. An additional 11 charts were found with inappropriately negative blood cultures. Fifteen percent of these patients were found to have polymicrobic isolates. The importance of establishing guidelines and criteria concerning acceptable blood culture practices is detailed.
- Published
- 1982
10. Overnight Refrigeration of Urine Specimens for Culture
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Alexander Jj and Lewis Jf
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Veterinary medicine ,Time Factors ,Refrigeration ,business.industry ,Colony count ,Humans ,Medicine ,General Medicine ,Urine ,business ,Specimen Handling - Abstract
Some authorities state that urine may be refrigerated overnight and still be satisfactory for quantitative bacteriologic evaluation. The papers cited appear to us to be inadequate. Four hundred and fourteen urine cultures were evaluated comparing colony count before and after overnight refrigeration. Overnight refrigeration appears to be a satisfactory means of urine preservation for culture.
- Published
- 1980
11. Neuroimaging-use trends in nonacute pediatric headache before and after clinical practice parameters.
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Graf WD, Kayyali HR, Alexander JJ, Simon SD, and Morriss MC
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- 2008
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12. Developing an Imaging Workforce Pipeline Through an Imaging Trainee Assistant Program.
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Alexander JJ and Chapman E
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- Humans, Workforce, United States, Technology, Radiologic education
- Published
- 2024
13. Complement: Functions, location and implications.
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Kareem S, Jacob A, Mathew J, Quigg RJ, and Alexander JJ
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- Complement System Proteins, Complement Activation
- Abstract
The complement system, an arm of the innate immune system plays a critical role in both health and disease. The complement system is highly complex with dual possibilities, helping or hurting the host, depending on the location and local microenvironment. The traditionally known functions of complement include surveillance, pathogen recognition, immune complex trafficking, processing and pathogen elimination. The noncanonical functions of the complement system include their roles in development, differentiation, local homeostasis and other cellular functions. Complement proteins are present in both, the plasma and on the membranes. Complement activation occurs both extra- and intracellularly, which leads to considerable pleiotropy in their activity. In order to design more desirable and effective therapies, it is important to understand the different functions of complement, and its location-based and tissue-specific responses. This manuscript will provide a brief overview into the complex nature of the complement cascade, outlining some of their complement-independent functions, their effects at different locale, and their implication in disease settings., (© 2023 John Wiley & Sons Ltd.)
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- 2023
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14. Evaluation of FDA Labeling Changes Related to PREA Safety-Waivers.
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Krastein J, Pica-Branco D, Bacho MA, Mulugeta Y, Maynard JW, Alexander JJ, Yao L, and Hausman ED
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- United States, Child, Humans, United States Food and Drug Administration, Pharmaceutical Preparations, Antiviral Agents, Drug Labeling, Biological Products adverse effects
- Abstract
Purpose: The Pediatric Research Equity Act (PREA) gives the US Food and Drug Administration (FDA) authority to require pediatric studies for drug and biologics products under certain circumstances and to waive this requirement in some, or all, pediatric ages. When studies are waived for safety, PREA stipulates the safety issue must be described in labeling. This study assessed the rate of including waiver-related safety information in labeling., Methods: FDA databases were reviewed to determine the number of safety-related pediatric study waivers and issued from December 2003 through August 2020, and corresponding labeling to establish when relevant safety information was included. Descriptive comparisons were conducted across Cohort 1: December 2003-2007, Cohort 2: 2008-2011, Cohort 3: 2012-2015, and Cohort 4: 2016-August 2020., Results: One hundred sixteen safety waivers were issued [Cohort 1 (n = 1); Cohort 2 (n = 38), Cohort 3 (n = 37), and Cohort 4 (n = 40)] for 84 unique drugs or biologics. Most (106 of 116; 91%) waiver-related safety issues were described in labeling [Cohort 1 (1 of 1), Cohort 2 (33 of 38), Cohort 3 (33 of 37), and Cohort 4 (39 of 40)]. Safety waivers were most common in patients ≤ 17 years (n = 40) and least common in patients ≤ 6 months (n = 15). Products for infections (n = 32) were the most common group receiving safety waivers; 17 for non-antiviral anti-infective products including treatments for dermatologic infestations/infections, and 15 for antiviral products., Conclusion: The data confirm that FDA consistently describes waiver-related safety information in drug/biologic product labeling since the inception of PREA in December of 2003., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
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- 2023
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15. Telehealth in PM&R: Past, present, and future in clinical practice and opportunities for translational research.
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Tenforde AS, Alexander JJ, Alexander M, Annaswamy TM, Carr CJ, Chang P, Díaz M, Iaccarino MA, Lewis SB, Millett C, Pandit S, Ramirez CP, Rinaldi R, Roop M, Slocum CS, Tekmyster G, Venesy D, Verduzco-Gutierrez M, Zorowitz RD, and Rowland TR
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- Humans, United States, Translational Research, Biomedical, Delivery of Health Care, Forecasting, Telemedicine, Physical and Rehabilitation Medicine
- Abstract
Telehealth refers to the use of telecommunication devices and other forms of technology to provide services outside of the traditional in-person health care delivery system. Growth in the use of telehealth creates new challenges and opportunities for implementation in clinical practice. The American Academy of Physical Medicine and Rehabilitation (AAPM&R) assembled an expert group to develop a white paper to examine telehealth innovation in Physical Medicine and Rehabilitation (PM&R). The resultant white paper summarizes how telehealth is best used in the field of PM&R while highlighting current knowledge deficits and technological limitations. The report identifies new and transformative opportunities for PM&R to advance translational research related to telehealth and enhance patient care., (© 2023 American Academy of Physical Medicine and Rehabilitation.)
- Published
- 2023
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16. Burnout and Wellness Strategies Used by Academic Physiatry Programs: An Analysis and Perspective From the AAP Chairs Council.
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Steinberg DP, Faurot KR, Thompson KL, Alexander JJ, Braza DW, Cuccurullo S, Herrera J, Sliwa J, and Weiss L
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- Humans, Surveys and Questionnaires, Burnout, Professional prevention & control, Physicians psychology, Medicine, Physical and Rehabilitation Medicine, Physiatrists
- Abstract
Abstract: Physiatrists are at elevated risk of burnout, a work-related exhaustion syndrome resulting from chronic stress associated with emotionally draining work demands. The high reported rate of burnout in physical medicine and rehabilitation led the Association of Academic Physiatrists Chair Council to convene a workgroup to address burnout among academic physical medicine and rehabilitation physicians. The council recognizes that leaders of departments are accountable for all organizational stakeholders, including faculty, trainees, and staff. Department leaders are expected to understand and effectively manage the drivers of burnout among stakeholders. The workgroup identified several opportunities, including identifying and disseminating effective burnout mitigation across US academic medical center physical medicine and rehabilitation programs. As a result, in 2019, a work group conducted a survey of US academic physical medicine and rehabilitation program leaders to ascertain the use of strategies for reducing physician burnout. With the aim of identifying, educating, and advancing the development of effective interventions to address burnout among academic physical medicine and rehabilitation departments, the Association of Academic Physiatrists Chair Council advocates for increased education and utilization of effective strategies aimed at promoting physician well-being across organizational levels (national, organizational, work unit, and individual)., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2023
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17. Corticomuscular Coherence in Children with Unilateral Cerebral Palsy: A Feasibility and Preliminary Protocol Study.
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Gangwani RR, Mark JI, Vaughn RM, Holland H, Thorpe DE, Alexander JJ, Surkar SM, and Cassidy JM
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- Female, Humans, Child, Adolescent, Muscle, Skeletal, Feasibility Studies, Electromyography methods, Electroencephalography methods, Cerebral Palsy, Motor Cortex
- Abstract
Objective This study assessed the feasibility of corticomuscular coherence measurement during a goal-directed task in children with unilateral cerebral palsy while establishing optimal experimental parameters. Methods Participants (Manual Ability Classification System levels I-III) completed a submaximal isometric goal-directed grip task during simultaneous electroencephalography and electromyography (EMG) acquisition. Results All participants (n = 11, 6 females, mean age 11.3 ±2.4 years) completed corticomuscular coherence procedures. Of the 40 trials obtained per extremity, an average of 29 (n = 9) and 27 (n = 10) trials were retained from the more- and less-affected extremities, respectively. Obtaining measurement stability required an average of 28 trials per extremity. Conclusion Findings from this work support the feasibility of corticomuscular coherence measurement in children with unilateral cerebral palsy. Acquiring 28 to 40 corticomuscular coherence trials per extremity is ideal. The experimental parameters established in this work will inform future corticomuscular coherence application in pediatric unilateral cerebral palsy.
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- 2023
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18. Complement: The Road Less Traveled.
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Kemper C, Ferreira VP, Paz JT, Holers VM, Lionakis MS, and Alexander JJ
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- Complement System Proteins, Complement Activation
- Abstract
The complement field has recently experienced a strong resurgence of interest because of the unexpected discovery of new complement functions extending complement's role beyond immunity and pathogen clearance, a growing list of diseases in which complement plays a role, and the proliferation of complement therapeutics. Importantly, although the majority of complement components in the circulation are generated by the liver and activated extracellularly, complement activation unexpectedly also occurs intracellularly across a broad range of cells. Such cell-autonomous complement activation can engage intracellular complement receptors, which then drive noncanonical cell-specific effector functions. Thus, much remains to be discovered about complement biology. In this brief review, we focus on novel noncanonical activities of complement in its "classic areas of operation" (kidney and brain biology, infection, and autoimmunity), with an outlook on the next generation of complement-targeted therapeutics., (Copyright © 2023 by The American Association of Immunologists, Inc.)
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- 2023
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19. Editorial: The complement system in autoimmunity.
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Wu EY, Alexander JJ, and Fukui S
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- Autoimmunity, Complement System Proteins
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Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2022
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20. Macrophage Depletion Reduces Disease Pathology in Factor H-Dependent Immune Complex-Mediated Glomerulonephritis.
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Jacob A, Phelps M, Fraher S, Lopez M, Chang A, Quigg RJ, and Alexander JJ
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- Animals, Apoferritins administration & dosage, Cell Movement, Clodronic Acid administration & dosage, Complement Factor H metabolism, Disease Progression, Fibrosis, Kidney immunology, Kidney pathology, Matrix Metalloproteinase 9 metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Glomerulonephritis immunology, Immune Complex Diseases immunology, Kidney metabolism, Macrophages immunology
- Abstract
Complement factor H (FH) is a key regulator of the alternative pathway of complement, in man and mouse. Earlier, our studies revealed that the absence of FH causes the C57BL6 mouse to become susceptible to chronic serum sickness (CSS) along with an increase in the renal infiltration of macrophages compared to controls. To understand if the increased recruitment of macrophages (M ϕ s) to the kidney was driving inflammation and propagating injury, we examined the effect of M ϕ depletion with clodronate in FH knockout mice with CSS. Eight-week-old FHKO mice were treated with apoferritin (4 mg/mouse) for 5 wks and with either vehicle (PBS) or clodronate (50 mg/kg ip, 3 times/wk for the last 3 weeks). The administration of clodronate decreased monocytes and M ϕ s in the kidneys by >80%. Kidney function assessed by BUN and albumin remained closer to normal on depletion of M ϕ s. Clodronate treatment prevented the alteration in cytokines, TNF α and IL-6, and increase in gene expression of connective tissue growth factor (CTGF), TGF β -1, matrix metalloproteinase-9 (MMP9), fibronectin, laminin, and collagen in FHKO mice with CSS ( P < 0.05). Clodronate treatment led to relative protection from immune complex- (IC-) mediated disease pathology during CSS as assessed by the significantly reduced glomerular pathology (GN) and extracellular matrix. Our results suggest that complement activation is one of the mechanism that regulates the macrophage landscape and thereby fibrosis. The exact mechanism remains to be deciphered. In brief, our data shows that M ϕ s play a critical role in FH-dependent ICGN and M ϕ depletion reduces disease progression., Competing Interests: No conflicts of interest, financial or otherwise, are declared by the authors., (Copyright © 2022 Alexander Jacob et al.)
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- 2022
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21. Local complement factor H protects kidney endothelial cell structure and function.
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Mahajan S, Jacob A, Kelkar A, Chang A, Mcskimming D, Neelamegham S, Quigg RJ, and Alexander JJ
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- Animals, Complement Pathway, Alternative, Endothelial Cells, Humans, Kidney, Mice, Complement Factor H genetics, Kidney Diseases
- Abstract
Factor H (FH) is a critical regulator of the alternative complement pathway and its deficiency or mutation underlie kidney diseases such as dense deposit disease. Since vascular dysfunction is an important facet of kidney disease, maintaining optimal function of the lining endothelial cells is important for vascular health. To investigate the molecular mechanisms that are regulated by FH in endothelial cells, FH deficient and sufficient mouse kidney endothelial cell cultures were established. Endothelial FH deficiency resulted in cytoskeletal remodeling, increased angiogenic potential, loss of cellular layer integrity and increased cell proliferation. FH reconstitution prevented these FH-dependent proliferative changes. Respiratory flux analysis showed reduced basal mitochondrial respiration, ATP production and maximal respiratory capacity in FH deficient endothelial cells, while proton leak remained unaltered. Similar changes were observed in FH deficient human glomerular endothelial cells indicating the translational potential of these studies. Gene expression analysis revealed that the FH-dependent gene changes in mouse kidney endothelial cells include significant upregulation of genes involved in inflammation and the complement system. The transcription factor nuclear factor-kB, that regulates many biological processes, was translocated from the cytoplasm to the nucleus in the absence of FH. Thus, our studies show the functional relevance of intrinsic FH in kidney endothelial cells in man and mouse., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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22. Telehealth: Improving Access to and Quality of Pediatric Health Care.
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Curfman AL, Hackell JM, Herendeen NE, Alexander JJ, Marcin JP, Moskowitz WB, Bodnar CEF, Simon HK, and McSwain SD
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- Adolescent, Child, Child Health Services, Ethnicity, Humans, Pediatricians, Race Factors, Specialization, United States, Health Services Accessibility, Quality of Health Care, Telemedicine
- Abstract
All children and adolescents deserve access to quality health care regardless of their race/ethnicity, health conditions, financial resources, or geographic location. Despite improvements over the past decades, severe disparities in the availability and access to high-quality health care for children and adolescents continue to exist throughout the United States. Economic and racial factors, geographic maldistribution of primary care pediatricians, and limited availability of pediatric medical subspecialists and pediatric surgical specialists all contribute to inequitable access to pediatric care. Robust, comprehensive telehealth coverage is critical to improving pediatric access and quality of care and services, particularly for under-resourced populations., Competing Interests: POTENTIAL CONFLICTS OF INTEREST: Dr Hackell is an expert reviewer and provides testimony to various law firms; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)
- Published
- 2021
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23. Use of a Comprehensive 66-Gene Cholestasis Sequencing Panel in 2171 Cholestatic Infants, Children, and Young Adults.
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Karpen SJ, Kamath BM, Alexander JJ, Ichetovkin I, Rosenthal P, Sokol RJ, Dunn S, Thompson RJ, and Heubi JE
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- Child, Humans, Infant, Infant, Newborn, Mutation, Sequence Analysis, DNA, Young Adult, Cholestasis diagnosis, Cholestasis genetics
- Abstract
Objectives: Cholestasis is caused by a wide variety of etiologies, often genetic in origin. Broad overlap in clinical presentations, particularly in newborns, renders prioritizing diagnostic investigations challenging. In this setting, a timely, comprehensive assessment using a multigene panel by a clinical diagnostic laboratory would likely prove useful. We summarize initial findings from a testing program designed to discover genetic causes of cholestasis., Methods: A neonatal/adult sequencing panel containing 66 genes (originally 57; nine added March 2017) relevant to cholestasis was used. A broad range of eligible patients were enrolled with current/history of cholestasis without an identified cause, or unexplained chronic liver disease. DNA sequencing utilized a custom-designed capture library, and variants were classified and reported as benign, likely benign, variant of unknown significance (VOUS), likely pathogenic (LP), or pathogenic (P), according to the clinical interpretation workflow at EGL Genetics (Tucker, GA)., Results: A total of 2433 samples were submitted between February 2016 and December 2017; 2171 results were reported. Median turnaround time was 21 days. Results from the 2171 subjects (57% <1 year old) included 583 P variants, 79 LP variants, and 3117 VOUS; 166 P/LP variants and 415 VOUS were novel. The panel's overall diagnostic yield was 12% (n = 265/2171) representing 32 genes. The top five genetic diagnoses for the group, in order: JAG1 + NOTCH2 (Alagille syndrome), ABCB11, SERPINA1, ABCB4, and POLG., Conclusions: These findings support the utility of comprehensive rapid multigene testing in diagnosing cholestasis and highlight the evolving understanding of genetic variants contributing to the pathogenesis of cholestasis., Competing Interests: Conflicts of Interest: S.J.K.: Consultant for Albireo, Logic Bio, Intercept, Mirum, and Retrophin, Inc. B.M.K.: Consultant for Albireo, Retrophin, Inc., Shire, Mirum, DCI. J.J.A.: During the course of this study was a consultant for Retrophin, Inc and laboratory director at Emory/EGL. I.I.: During the course of this study was a full-time employee of Retrophin, Inc. P.R.: Consultant for Albireo, Alexion, Alnylam, Audentes, Intercept, and Retrophin, Inc. R.S.: Consultant for Albireo, Alexion, Shire, Mirum, and Retrophin, Inc. S.D.: Full-time employee of Retrophin, Inc. R.T.: Consultant for Retrophin, Inc, Shire, Mirum Albireo, Alnylam, Horizon Pharma, Sana Biotechnology, Qing Bile Therapeutics, and GenerationBio, and has stock options at Qing Bile Therapeutics and GenerationBio. J.E.H.: Equity interest in Asklepion, and consultant for Retrophin, Inc, Shire, Alnylam, Friesland Campina, Mirum, and Nordmark., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)
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- 2021
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24. Epilepsy and Electroencephalographic Abnormalities in SATB2-Associated Syndrome.
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Lewis H, Samanta D, Örsell JL, Bosanko KA, Rowell A, Jones M, Dale RC, Taravath S, Hahn CD, Krishnakumar D, Chagnon S, Keller S, Hagebeuk E, Pathak S, Bebin EM, Arndt DH, Alexander JJ, Mainali G, Coppola G, Maclean J, Sparagana S, McNamara N, Smith DM, Raggio V, Cruz M, Fernández-Jaén A, Kava MP, Emrick L, Fish JL, Vanderver A, Helman G, Pierson TM, and Zarate YA
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- Adolescent, Adult, Age of Onset, Child, Child, Preschool, Electroencephalography, Female, Humans, Infant, Male, Retrospective Studies, Sleep Stages physiology, Syndrome, Young Adult, Epilepsy diagnosis, Epilepsy etiology, Epilepsy genetics, Epilepsy physiopathology, Genetic Diseases, Inborn complications, Genetic Diseases, Inborn diagnosis, Genetic Diseases, Inborn genetics, Genetic Diseases, Inborn physiopathology, Matrix Attachment Region Binding Proteins genetics, Nervous System Malformations diagnosis, Nervous System Malformations etiology, Nervous System Malformations genetics, Nervous System Malformations physiopathology, Sleep Wake Disorders diagnosis, Sleep Wake Disorders etiology, Sleep Wake Disorders genetics, Sleep Wake Disorders physiopathology, Transcription Factors genetics
- Abstract
Background: Seizures are an under-reported feature of the SATB2-associated syndrome phenotype. We describe the electroencephalographic findings and seizure semiology and treatment in a population of individuals with SATB2-associated syndrome., Methods: We performed a retrospective review of 101 individuals with SATB2-associated syndrome who were reported to have had a previous electroencephalographic study to identify those who had at least one reported abnormal result. For completeness, a supplemental survey was distributed to the caregivers and input from the treating neurologist was obtained whenever possible., Results: Forty-one subjects were identified as having at least one prior abnormal electroencephalography. Thirty-eight individuals (93%) had epileptiform discharges, 28 (74%) with central localization. Sleep stages were included as part of the electroencephalographies performed in 31 individuals (76%), and epileptiform activity was recorded during sleep in all instances (100%). Definite clinical seizures were diagnosed in 17 individuals (42%) with a mean age of onset of 3.2 years (four months to six years), and focal seizures were the most common type of seizure observed (42%). Six subjects with definite clinical seizures needed polytherapy (35%). Delayed myelination and/or abnormal white matter hyperintensities were seen on neuroimaging in 19 individuals (61%)., Conclusions: Epileptiform abnormalities are commonly seen in individuals with SATB2-associated syndrome. A baseline electroencephalography that preferably includes sleep stages is recommended during the initial evaluation of all individuals with SATB2-associated syndrome, regardless of clinical suspicion of epilepsy., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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25. Absence of complement factor H reduces physical performance in C57BL6 mice.
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Seldeen KL, Thiyagarajan R, Redae Y, Jacob A, Troen BR, Quigg RJ, and Alexander JJ
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- Actins metabolism, Animals, Complement C3 analysis, Complement C3 genetics, Complement C5a analysis, Complement Factor H metabolism, DNA, Mitochondrial, Gene Expression, Male, Mice, Inbred C57BL, Mice, Knockout, Muscle Fatigue genetics, Muscle Strength genetics, Receptor, Anaphylatoxin C5a genetics, Rotarod Performance Test, Vimentin metabolism, Complement C5a metabolism, Complement Factor H genetics, Muscle, Skeletal metabolism, Physical Endurance genetics, Receptor, Anaphylatoxin C5a metabolism
- Abstract
Complement (C) system is a double edge sword acting as the first line of defense on the one hand and causing aggravation of disease on the other. C activation when unregulated affects different organs including muscle regeneration. However, the effect of factor H (FH), a critical regulator of the alternative C pathway in muscle remains to be studied. FH deficiency results in excessive C activation and generates proinflammatory fragments C5a and C3a as byproducts. C3a and C5a signal through their respective receptors, C5aR and C3aR. In this study, we investigated the role of FH and downstream C5a/C5aR signaling in muscle architecture and function. Using the FH knockout (fh-/-) and fh-/-/C5aR-/double knockout mice we explored the role of C, specifically the alternative C pathway in muscle dysfunction. Substantial C3 and C9 deposits occur along the walls of the fh-/- muscle fibers indicative of unrestricted C activation. Physical performance assessments of the fh-/- mice show reduced grip endurance (76 %), grip strength (14 %) and rotarod balance (36 %) compared to controls. Histological analysis revealed a shift in muscle fiber populations indicated by an increase in glycolytic MHC IIB fibers and reduction in oxidative MHC IIA fibers. Consistent with this finding, mitochondrial DNA (mtDNA) and citrate synthase (CS) expression were both reduced indicating possible reduction in mitochondrial biomass. In addition, our results showed a significant increase in TGFβ expression and altered TGFβ localization in this setting. The architecture of cytoskeletal proteins actin and vimentin in the fh-/- muscle was changed that could lead to contractile weakness and loss of skeletal muscle elasticity. The muscle pathology in fh-/- mice was reduced in fh-/-/C5aR-/- double knockout (DKO) mice, highlighting partial C5aR dependence. Our results for the first time demonstrate an important role of FH in physical performance and skeletal muscle health., (Copyright © 2020 Elsevier GmbH. All rights reserved.)
- Published
- 2020
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26. Double negative T cells, a potential biomarker for systemic lupus erythematosus.
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Alexander JJ, Jacob A, Chang A, Quigg RJ, and Jarvis JN
- Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease that is a challenge to diagnose and treat. There is an urgent need for biomarkers to help define organ involvement, and more effective therapies. A unique population of T cells, the CD3
+ CD4- CD8- (DNeg) cells, is significantly increased in lupus patients. Twenty-seven cases (53%) of pediatric SLE patients had elevated DNeg cells in their peripheral blood, which correlated with kidney function ( R2 = 0.54). Significant infiltration of DNeg cells was observed in both adult and pediatric lupus kidneys by immunofluorescence. For the first time, this study provides direct evidence that DNeg cells facilitate kidney injury in preclinical 8-week-old MRL/ lpr lupus mice. In lupus mice, the increase in DNeg cells tracked with worsening disease and correlated with kidney function ( R2 = 0.85). Our results show that DNeg cells per se can cause kidney dysfunction, increase in number with increase in disease pathology, and could serve as a potential biomarker., (© The Author(s) 2020. Published by Oxford University Press on behalf of West China School of Medicine & West China Hospital of Sichuan University.)- Published
- 2020
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27. Development of a Prospective Real-World Data Clinical Registry of Children and Adolescents With Migraine.
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Hornik CP, Gelfand AA, Szperka CL, Pezzuto T, Utevsky A, Kessel S, McCune S, Alexander JJ, Benjamin DK Jr, and Cohen-Wolkowiez M
- Subjects
- Adolescent, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Male, Mobile Applications, Prospective Studies, Stakeholder Participation, United States, Databases, Factual, Intersectoral Collaboration, Migraine Disorders diagnosis, Registries
- Abstract
Objective: To develop a multicenter, multistakeholder, prospective clinical registry of children and adolescents with migraine to support the collection of real-world data of sufficient quality to support regulatory submissions and provide site-based infrastructure support for future clinical trials., Background: As new migraine treatments come to market, pediatric efficacy and safety trials of these agents are needed. A clinical registry is an ideal regulatory strategy to provide both real-world data and site infrastructure to execute these trials., Design: Multicenter, multistakeholder, prospective real-world data clinical registry of children and adolescents, 4-17 years of age, diagnosed with migraine with or without aura. Participants will be followed for up to 12 months at 3-month intervals, with interval recording of clinical data at study sites and self-reported data via mobile health application, as well as biobanking. We developed electronic case report forms that incorporated routinely collected clinical data with National Institute of Neurological Disorders and Stroke Headache Common Data Elements (Version 2.0). All data are captured in a 21 CFR Part 11 - compliant electronic data capture system - augmented by a real-time, web-based, and customizable data visualization platform. We engaged vendors to provide ancillary biobanking, patient data entry, and data visualization services., Results: We used an iterative and highly collaborative multistakeholder approach to design and implement a streamlined registry protocol with input from all participating US sites. At each design and implementation step, we received input from therapeutic area experts, the US Food and Drug Administration (FDA), the National Institutes of Health, patient and parent advocates, health technology partners, drug developers, and site-based clinical investigators. The registry is governed by a multistakeholder steering committee with representation from sites, industry partners, patient advocates, and a member from the FDA (non-voting with respect to steering committee matters). The multistakeholder and site-driven approach to registry design and execution was highly efficient and resulted in the first patient enrolled within 6 months of concept development., Conclusions: By ensuring regulatory compliant implementation of the registry, we created both a source of real-world data and a multisite platform for the conduct of future clinical trials that can be submitted to regulatory authorities to support inclusion of pediatric data in approved drug labeling. A highly collaborative approach with broad stakeholder engagement at all stages of the registry development was a key to our operational success., (© 2019 American Headache Society.)
- Published
- 2020
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28. Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel.
- Author
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Shen J, Oza AM, Del Castillo I, Duzkale H, Matsunaga T, Pandya A, Kang HP, Mar-Heyming R, Guha S, Moyer K, Lo C, Kenna M, Alexander JJ, Zhang Y, Hirsch Y, Luo M, Cao Y, Wai Choy K, Cheng YF, Avraham KB, Hu X, Garrido G, Moreno-Pelayo MA, Greinwald J, Zhang K, Zeng Y, Brownstein Z, Basel-Salmon L, Davidov B, Frydman M, Weiden T, Nagan N, Willis A, Hemphill SE, Grant AR, Siegert RK, DiStefano MT, Amr SS, Rehm HL, and Abou Tayoun AN
- Subjects
- Alleles, Case-Control Studies, Connexin 26 genetics, Connexins metabolism, Deafness genetics, Female, Hearing Loss, Sensorineural genetics, Humans, Male, Mutation, Polymorphism, Single Nucleotide genetics, Connexins genetics, Hearing Loss genetics
- Abstract
Purpose: Pathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. Therefore, an expert consensus is required for the interpretation of these two variants., Methods: The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Functional, computational, allelic, and segregation data were also obtained. Case-control statistical analyses were performed., Results: The panel reviewed the synthesized information, and classified the p.Met34Thr and p.Val37Ile variants utilizing professional variant interpretation guidelines and professional judgment. We found that p.Met34Thr and p.Val37Ile are significantly overrepresented in hearing loss patients, compared with population controls. Individuals homozygous or compound heterozygous for p.Met34Thr or p.Val37Ile typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for these two variants., Conclusion: Resolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification guidelines, review evidence, and reach a consensus. We concluded that p.Met34Thr and p.Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and incomplete penetrance.
- Published
- 2019
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29. The effect of vitamin E-enhanced cross-linked polyethylene on wear in shoulder arthroplasty-a wear simulator study.
- Author
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Alexander JJ, Bell SN, Coghlan J, Lerf R, and Dallmann F
- Subjects
- Arthroplasty, Replacement, Shoulder instrumentation, Glenoid Cavity, Humans, Humeral Head, Materials Testing, Polyethylenes, Prosthesis Design, Shoulder Prosthesis, Antioxidants, Polyethylene chemistry, Prosthesis Failure, Vitamin E
- Abstract
Background: Wear of the polyethylene glenoid component and subsequent particle-induced osteolysis remains one of the most important modes of failure of total shoulder arthroplasty. Vitamin E is added to polyethylene to act as an antioxidant to stabilize free radicals that exist as a byproduct of irradiation used to induce cross-linking. This study was performed to assess the in vitro performance of vitamin E-enhanced polyethylene compared with conventional polyethylene in a shoulder simulator model., Methods: Vitamin E-enhanced, highly cross-linked glenoid components were compared with conventional ultrahigh-molecular-weight polyethylene glenoids, both articulating with a ceramic humeral head component using a shoulder joint simulator over 500,000 cycles. Unaged and artificially aged comparisons were performed. Volumetric wear was assessed by gravimetric measurement, and wear particle analysis was also subsequently performed., Results: Vitamin E-enhanced polyethylene glenoid components were found to have significantly reduced wear rates compared with conventional polyethylene in both unaged (36% reduction) and artificially aged (49% reduction) comparisons. There were no differences detected in wear particle analysis between the 2 groups., Conclusion: Vitamin E-enhanced polyethylene demonstrates improved wear compared with conventional polyethylene in both unaged and artificially aged comparisons and may have clinically relevant benefits., (Copyright © 2019 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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30. Association of scapholunate dissociation and two-part articular fractures of the distal radius.
- Author
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Sun GTW, MacLean SBM, Alexander JJ, Woodman R, and Bain GI
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Case-Control Studies, Female, Humans, Intra-Articular Fractures classification, Male, Middle Aged, Radius Fractures classification, Retrospective Studies, Tomography, X-Ray Computed, Young Adult, Intra-Articular Fractures diagnostic imaging, Lunate Bone diagnostic imaging, Radius Fractures diagnostic imaging, Scaphoid Bone diagnostic imaging
- Abstract
Scapholunate dissociation may occur in association with distal radial fractures and is easily missed at initial presentation. The aim of this study was to examine variances in the scapholunate distance with respect to subtypes of two-part partial articular distal radial fractures. Axial computed tomography (CT) scans of acute two-part intra-articular radial fractures were assessed retrospectively from 80 patients and compared to 20 controls. From each scan, two images were analysed to identify the scaphoid, lunate and articular fracture line in the distal radius for fracture type categorization. The images were overlaid on a standardized distal radius template and the scapholunate distance measured. Significant increase in the scapholunate distance was noted in fracture subtypes: radial styloid oblique; dorsal ulnar column; sagittal ulnar column; and volar coronal. We conclude that these findings support the need for a higher index of suspicion for scapholunate dissociation in these distal radial fracture subtypes. Level of evidence: III.
- Published
- 2019
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31. The Impact of Suture Caliber and Looped Configurations on the Suture-Tendon Interface in Zone II Flexor Tendon Repair.
- Author
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Bernstein DT, Alexander JJ, Petersen NJ, Lambert BS, Noble PC, and Netscher DT
- Subjects
- Biomechanical Phenomena, Cadaver, Humans, Stress, Mechanical, Tensile Strength, Finger Injuries surgery, Suture Techniques, Sutures, Tendon Injuries surgery
- Abstract
Purpose: To evaluate the impact of suture caliber and looped configurations on the integrity of 4-strand modified Kessler zone II flexor tendon repairs during progressive cyclic loading., Methods: Seventy-two flexor digitorum profundus tendons from 18 fresh human cadaver hands were divided into 4 repair groups. Thirty-six matched tendons underwent repair using either a 4-0 looped or 4-0 single-stranded suture, and an additional 36 tendons underwent 3-0 looped or 3-0 single-stranded repairs. Repair strength was tested by progressive cyclic loading. The force generating 2-mm gap formation, ultimate failure, and the mechanism of failure were recorded for each test. The impact of looped versus single-stranded configurations and the effect of tendon cross-sectional area on repair integrity were analyzed for each suture caliber., Results: There was no statistically significant difference between groups regarding the force to 2-mm gap formation or ultimate failure, and all values exceeded the minimum threshold of 27 N required to withstand an early active range of motion rehabilitation protocol. The use of a 3-0 caliber suture resulted in a significantly higher proportion of repairs failing by suture pullout through the tendon substance, including 63.5% of looped and 38.9% of single-stranded core sutures. By comparison, this occurred in 11.1% of 4-0 looped and 0% of 4-0 single-stranded sutures. Larger tendon cross-sectional areas were associated with more robust repairs, particularly in the 3-0 looped group., Conclusions: In a human cadaver flexor tendon repair model, there was no significant difference in the mean force to failure between all 4 flexor tendon repair constructs under progressive cyclic loading. However, the 3-0 caliber suture failed more frequently by suture pullout, particularly with the use of a looped suture., Clinical Relevance: Four-strand flexor tendon repairs using a 3-0 caliber suture are more prone to early failure by suture pullout under progressive cyclic loading compared with a 4-0 caliber suture., (Copyright © 2019 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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32. SubILM Injection of AAV for Gene Delivery to the Retina.
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Gamlin PD, Alexander JJ, Boye SL, Witherspoon CD, and Boye SE
- Subjects
- Animals, Gene Expression, Genes, Reporter, Injections, Macaca, Microscopy, Fluorescence, Retinal Ganglion Cells metabolism, Transgenes, Dependovirus genetics, Gene Transfer Techniques, Genetic Vectors genetics, Retina metabolism, Transduction, Genetic
- Abstract
Adeno-associated virus (AAV) has emerged as the vector of choice for delivering genes to the retina. Indeed, the first gene therapy to receive FDA approval in the United States is an AAV-based treatment for the inherited retinal disease, Leber congenital amaurosis-2. Voretigene neparvovec (Luxturna™) is delivered to patients via subretinal (SR) injection, an invasive surgical procedure that requires detachment of photoreceptors (PRs) from the retinal pigment epithelium (RPE). It has been reported that subretinal administration of vector under the cone-exclusive fovea leads to a loss of central retinal structure and visual acuity in some patients. Due to its technical difficulty and potential risks, alternatives to SR injection have been explored in primates. Intravitreally (Ivt) delivered AAV transduces inner retina and foveal cones, but with low efficiency. Novel AAV capsid variants identified via rational design or directed evolution have offered only incremental improvements, and have failed to promote pan-inner retinal transduction or significant outer retinal transduction beyond the fovea. Problems with retinal transduction by Ivt-delivered AAV include dilution in the vitreous, potential antibody-mediated neutralization of capsid in this nonimmune privileged space, and the presence of the inner limiting membrane (ILM), a basement membrane separating the vitreous from the neural retina. We have developed an alternative "subILM" injection method that overcomes all three hurdles. Specifically, vector is placed in a surgically induced, hydrodissected space between the ILM and neural retina. We have shown that subILM injection promotes more efficient retinal transduction by AAV than Ivt injection, and results in uniform and extensive transduction of retinal ganglion cells (RGCs) beneath the subILM bleb. We have also demonstrated transduction of Muller glia, ON bipolar cells, and photoreceptors by subILM injection. Our results confirm that the ILM is a major barrier to transduction by AAV in primate retina and that, when it is circumvented, the efficiency and depth to which AAV2 promotes transduction of multiple retinal cell classes is greatly enhanced. Here we describe in detail methods for vector preparation, vector dilution, and subILM injection as performed in macaque (Macaca sp.).
- Published
- 2019
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33. The Role of NETosis in Systemic Lupus Erythematosus.
- Author
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Salemme R, Peralta LN, Meka SH, Pushpanathan N, and Alexander JJ
- Abstract
Systemic lupus erythematosus is an autoimmune disease affecting multiple organs with devastating pathological consequences. Current treatment regimens largely rely on immunosuppressants and corticosteroids to attenuate autoimmune activity. However, such treatments have toxic side effects, often lacks efficacy, and inherently leaves the patient prone to infections, making the discovery of novel biomarkers and therapeutic targets an urgent need. Neutrophil extracellular traps (NETs) that participate in host defense are generated by neutrophils by a process called NETosis. NETs play an important role in the pathogenesis of SLE. In this review, we discuss the current literature regarding the role of NETs in SLE while entertaining the possibility that NETosis could serve as therapeutic targets thereby rendering the treatment more specific and effective in comparison to the current lupus therapy., Competing Interests: Conflict of Interest The authors declare no conflict of interest.
- Published
- 2019
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34. Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients.
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Nallamilli BRR, Chakravorty S, Kesari A, Tanner A, Ankala A, Schneider T, da Silva C, Beadling R, Alexander JJ, Askree SH, Whitt Z, Bean L, Collins C, Khadilkar S, Gaitonde P, Dastur R, Wicklund M, Mozaffar T, Harms M, Rufibach L, Mittal P, and Hegde M
- Abstract
Objective: Limb-girdle muscular dystrophies (LGMDs), one of the most heterogeneous neuromuscular disorders (NMDs), involves predominantly proximal-muscle weakness with >30 genes associated with different subtypes. The clinical-genetic overlap among subtypes and with other NMDs complicate disease-subtype identification lengthening diagnostic process, increases overall costs hindering treatment/clinical-trial recruitment. Currently seven LGMD clinical trials are active but still no gene-therapy-related treatment is available. Till-date no nation-wide large-scale LGMD sequencing program was performed. Our objectives were to understand LGMD genetic basis, different subtypes' relative prevalence across US and investigate underlying disease mechanisms., Methods: A total of 4656 patients with clinically suspected-LGMD across US were recruited to conduct next-generation sequencing (NGS)-based gene-panel testing during June-2015 to June-2017 in CLIA-CAP-certified Emory-Genetics-Laboratory. Thirty-five LGMD-subtypes-associated or LGMD-like other NMD-associated genes were investigated. Main outcomes were diagnostic yield, gene-variant spectrum, and LGMD subtypes' prevalence in a large US LGMD-suspected population., Results: Molecular diagnosis was established in 27% (1259 cases; 95% CI, 26-29%) of the patients with major contributing genes to LGMD phenotypes being: CAPN3 (17%), DYSF (16%), FKRP (9%) and ANO5 (7%). We observed an increased prevalence of genetically confirmed late-onset Pompe disease, DNAJB6- associated LGMD subtype1E and CAPN3 -associated autosomal-dominant LGMDs. Interestingly, we identified a high prevalence of patients with pathogenic variants in more than one LGMD gene suggesting possible synergistic heterozygosity/digenic/multigenic contribution to disease presentation/progression that needs consideration as a part of diagnostic modality., Interpretation: Overall, this study has improved our understanding of the relative prevalence of different LGMD subtypes, their respective genetic etiology, and the changing paradigm of their inheritance modes and novel mechanisms that will allow for improved timely treatment, management, and enrolment of molecularly diagnosed individuals in clinical trials.
- Published
- 2018
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35. Absence of complement factor H alters bone architecture and dynamics.
- Author
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Alexander JJ, Sankaran JS, Seldeen KL, Thiyagarajan R, Jacob A, Quigg RJ, Troen BR, and Judex S
- Subjects
- Actins metabolism, Animals, Biomarkers, Bone Resorption genetics, Bone Resorption metabolism, Bone Resorption pathology, Bone and Bones diagnostic imaging, Bone and Bones pathology, Complement Factor H genetics, Complement Factor H metabolism, Fluorescent Antibody Technique, Immunohistochemistry, Mice, Mice, Knockout, Osteoblasts immunology, Osteoblasts metabolism, Osteoclasts immunology, Osteoclasts metabolism, Phenotype, X-Ray Microtomography, Bone and Bones immunology, Bone and Bones metabolism, Complement Factor H immunology
- Abstract
Complement system is an important arm of the immune system that promotes inflammation. Complement Factor H (FH) is a critical regulator of the alternative complement pathway. Its absence causes pathology in different organs resulting in diseases such as age related macular degeneration and dense deposit disease. Recent studies suggest that the complement system plays a role in bone development and homeostasis. To determine the role of FH in bone architecture, we studied the FH knockout (fh-/-) mice. 3D reconstructions of femur from 16 week old fh-/- mice reveal significant changes, such as decreased BV/TV (4.5%, p < 0.02), trabecular number (22%, p < 0.01), tissue mineral density (16%, p < 0.04), and increased marrow area (16% p < 0.01), compared to their wild type (WT) counterparts. Kidney function and histology remained normal indicating that bone changes occurred prior to kidney dysfunction. Next we examined cultured osteoblasts and osteoclasts isolated from bone marrow. FH is expressed ubiquitously in the osteoblasts and in the cytoplasm of osteoclasts. The changes caused by absence of FH include: increase in number of osteoblasts (362%) and osteoclasts (342%), increase in RNA (180%) and protein expression of cathepsin K and increased osteoclast function (pit formation, 233%). Actin rearrangement in both osteoblasts and osteoclasts was altered, with a loss of integrity of the F-actin ring at the periphery of the osteoclasts. For the first time our studies demonstrate a direct role of FH in the maintenance of bone structure and function and is highlighted as a promising therapeutic target in bone diseases., (Copyright © 2018 Elsevier GmbH. All rights reserved.)
- Published
- 2018
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36. Muscle, myeloid cells, and complement: a complex interaction.
- Author
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Alexander JJ and Quigg RJ
- Subjects
- Muscle, Skeletal, Myeloid Cells, Regeneration, Complement C3a, Monocytes
- Published
- 2018
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37. Epileptic Encephalopathy and Cerebellar Atrophy Resulting from Compound Heterozygous CACNA2D2 Variants.
- Author
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Butler KM, Holt PJ, Milla SS, da Silva C, Alexander JJ, and Escayg A
- Abstract
CACNA2D2 encodes an auxiliary subunit of the voltage-dependent calcium channel. To date, there have only been two reports of individuals with early-infantile epileptic encephalopathy due to CACNA2D2 mutations. In both reports, patients were homozygous for the identified variants. Here, we report a patient with epileptic encephalopathy and cerebellar atrophy who was found to have two novel variants in the CACNA2D2 gene: c.782C>T (p.Pro261Leu) and c.3137T>C (p.Leu1046Pro), by whole-exome sequencing. The variants were shown to be inherited in trans and the unaffected parents were confirmed to be heterozygous carriers. This is the third report of recessive CACNA2D2 variants associated with disease and the first report of compound heterozygous variants. The clinical description of this new case highlights the phenotypic similarities amongst individuals with CACNA2D2 -related disease and suggests that CACNA2D2 should be considered as a differential diagnosis in individuals with cerebellar dysfunction and multiple seizure types that begin in the first year of life.
- Published
- 2018
- Full Text
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38. Blood-brain barrier (BBB) and the complement landscape.
- Author
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Alexander JJ
- Subjects
- Animals, Complement Activation physiology, Humans, Blood-Brain Barrier, Brain, Complement System Proteins
- Abstract
The brain is an immune privileged organ, uniquely placed in the body. Two systems involved in maintaining brain homeostasis and in protecting the brain are the blood-brain barrier (BBB) and the complement system. The BBB is present in the vasculature of the brain and is the dynamic interface between brain and body that regulates what enters and leaves the brain, thereby maintaining the brain microenvironment optimal for brain function. The complement system is ubiquitous, being present systemically and in the brain, both membrane bound and in circulation. It is an important arm of the body's defense that helps maintain homeostasis by eliminating debris and damaged cells, participating in destroying pathogens, promoting inflammation and conveying 'danger signals'. Recent studies reveal that the complement system plays an important role in normal brain development. However, when the complement system is overwhelmed, complement activation could contribute to loss of BBB integrity resulting in brain pathology. Studies support an association between complement proteins and BBB dysfunction, with the mechanisms being slowly unraveled. This review will provide an overview of both these systems, how they intersect and interact with each other., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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39. SLC6A1 variants identified in epilepsy patients reduce γ-aminobutyric acid transport.
- Author
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Mattison KA, Butler KM, Inglis GAS, Dayan O, Boussidan H, Bhambhani V, Philbrook B, da Silva C, Alexander JJ, Kanner BI, and Escayg A
- Subjects
- Cohort Studies, DNA Mutational Analysis, Female, GABA Plasma Membrane Transport Proteins genetics, Genetic Predisposition to Disease genetics, HEK293 Cells, HeLa Cells, Humans, Male, RNA, Messenger metabolism, Transfection, Tritium pharmacokinetics, gamma-Aminobutyric Acid metabolism, Epilepsy genetics, Epilepsy metabolism, GABA Plasma Membrane Transport Proteins metabolism, Gene Expression Regulation genetics, Mutation genetics
- Abstract
Previous reports have identified SLC6A1 variants in patients with generalized epilepsies, such as myoclonic-atonic epilepsy and childhood absence epilepsy. However, to date, none of the identified SLC6A1 variants has been functionally tested for an effect on GAT-1 transporter activity. The purpose of this study was to determine the incidence of SLC6A1 variants in 460 unselected epilepsy patients and to evaluate the impact of the identified variants on γ-aminobutyric acid (GABA)transport. Targeted resequencing was used to screen 460 unselected epilepsy patients for variants in SLC6A1. Five missense variants, one in-frame deletion, one nonsense variant, and one intronic splice-site variant were identified, representing a 1.7% diagnostic yield. Using a [
3 H]-GABA transport assay, the seven identified exonic variants were found to reduce GABA transport activity. A minigene splicing assay revealed that the splice-site variant disrupted canonical splicing of exon 9 in the mRNA transcript, leading to premature protein truncation. These findings demonstrate that SLC6A1 is an important contributor to childhood epilepsy and that reduced GAT-1 function is a common consequence of epilepsy-causing SLC6A1 variants., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)- Published
- 2018
- Full Text
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40. Is exon 8 the most critical or the only dispensable exon of the VCAN gene? Insights into VCAN variants and clinical spectrum of Wagner syndrome.
- Author
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Ankala A, Jain N, Hubbard B, Alexander JJ, and Shankar SP
- Subjects
- Adolescent, Collagen Type II genetics, Exons genetics, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Mutation, Pedigree, Retinal Degeneration diagnosis, Retinal Degeneration physiopathology, Retinal Detachment diagnosis, Retinal Detachment physiopathology, Retinitis Pigmentosa diagnosis, Retinitis Pigmentosa physiopathology, Sequence Deletion genetics, Versicans genetics, Retinal Degeneration genetics, Retinal Detachment genetics, Retinitis Pigmentosa genetics, Versicans deficiency
- Abstract
Wagner syndrome and erosive vitreoretinopathy together constitute the phenotypic continuum of an autosomal dominant vitreoretinopathy, with clinical findings typically isolated to the eye. The disease is caused by pathogenic variants in the VCAN gene and all such variants reported to date are those that plausibly result in haploinsufficiency of exon 8 containing vcan transcripts. Here, we report the molecular findings and long-term follow-up of a 16-year-old female with a history of retinal detachments and pigmentary retinal changes. Next-generation sequencing and microarray analysis of 141 genes established a diagnosis of Wagner syndrome in this individual, by detection of an 11.7 kilobase (kb) deletion encompassing exon 8 of VCAN. In light of the emerging functions and roles of versican protein in human disease, we discuss how variants within exon 8 of the VCAN gene can be compared to those in exon 2 of the COL2A1 gene that cause atypical Stickler syndrome and propose that variants in other regions of the gene can be expected to present with a more systemic disease. The distinctive facial features and atypical gastrointestinal symptoms observed in this long-term follow-up study support the possibility that individuals with VCAN-related vitreoretinopathy may have extra-ocular clinical features., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2018
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41. Moonlighting newborn screening markers: the incidental discovery of a second-tier test for Pompe disease.
- Author
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Tortorelli S, Eckerman JS, Orsini JJ, Stevens C, Hart J, Hall PL, Alexander JJ, Gavrilov D, Oglesbee D, Raymond K, Matern D, and Rinaldo P
- Subjects
- Algorithms, Biomarkers blood, Creatine analysis, Creatine blood, Creatinine analysis, Creatinine blood, Dried Blood Spot Testing methods, Glycogen Storage Disease Type II blood, Humans, Infant, Newborn, Sensitivity and Specificity, alpha-Glucosidases analysis, alpha-Glucosidases blood, Glycogen Storage Disease Type II diagnosis, Neonatal Screening methods
- Abstract
Purpose: To describe a novel biochemical marker in dried blood spots suitable to improve the specificity of newborn screening for Pompe disease., Methods: The new marker is a ratio calculated between the creatine/creatinine (Cre/Crn) ratio as the numerator and the activity of acid α-glucosidase (GAA) as the denominator. Using Collaborative Laboratory Integrated Reports (CLIR), the new marker was incorporated in a dual scatter plot that can achieve almost complete segregation between Pompe disease and false-positive cases., Results: The (Cre/Crn)/GAA ratio was measured in residual dried blood spots of five Pompe cases and was found to be elevated (range 4.41-13.26; 99%ile of neonatal controls: 1.10). Verification was by analysis of 39 blinded specimens that included 10 controls, 24 samples with a definitive classification (16 Pompe, 8 false positives), and 5 with genotypes of uncertain significance. The CLIR tool showed 100% concordance of classification for the 24 known cases. Of the remaining five cases, three p.V222M homozygotes, a benign variant, were classified by CLIR as false positives; two with genotypes of unknown significance, one likely informative, were categorized as Pompe disease., Conclusion: The CLIR tool inclusive of the new ratio could have prevented at least 12 of 13 (92%) false-positive outcomes.
- Published
- 2018
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42. De novo variants in GABRA2 and GABRA5 alter receptor function and contribute to early-onset epilepsy.
- Author
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Butler KM, Moody OA, Schuler E, Coryell J, Alexander JJ, Jenkins A, and Escayg A
- Subjects
- Child, Developmental Disabilities genetics, Epilepsies, Myoclonic physiopathology, Epilepsy genetics, HEK293 Cells, Humans, Mutation, Patch-Clamp Techniques, Receptors, GABA-A metabolism, gamma-Aminobutyric Acid metabolism, Epilepsies, Myoclonic genetics, Receptors, GABA-A genetics
- Abstract
GABAA receptors are ligand-gated anion channels that are important regulators of neuronal inhibition. Mutations in several genes encoding receptor subunits have been identified in patients with various types of epilepsy, ranging from mild febrile seizures to severe epileptic encephalopathy. Using whole-genome sequencing, we identified a novel de novo missense variant in GABRA5 (c.880G > C, p.V294L) in a patient with severe early-onset epilepsy and developmental delay. Targeted resequencing of 279 additional epilepsy patients identified 19 rare variants from nine GABAA receptor genes, including a novel de novo missense variant in GABRA2 (c.875C > A, p.T292K) and a recurrent missense variant in GABRB3 (c.902C > T, p.P301L). Patients with the GABRA2 and GABRB3 variants also presented with severe epilepsy and developmental delay. We evaluated the effects of the GABRA5, GABRA2 and GABRB3 missense variants on receptor function using whole-cell patch-clamp recordings from human embryonic kidney 293T cells expressing appropriate α, β and γ subunits. The GABRA5 p.V294L variant produced receptors that were 10-times more sensitive to GABA but had reduced maximal GABA-evoked current due to increased receptor desensitization. The GABRA2 p.T292K variant reduced channel expression and produced mutant channels that were tonically open, even in the absence of GABA. Receptors containing the GABRB3 p.P301L variant were less sensitive to GABA and produced less GABA-evoked current. These results provide the first functional evidence that de novo variants in the GABRA5 and GABRA2 genes contribute to early-onset epilepsy and developmental delay, and demonstrate that epilepsy can result from reduced neuronal inhibition via a wide range of alterations in GABAA receptor function.
- Published
- 2018
- Full Text
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43. Lupus: The microbiome angle.
- Author
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Yacoub R, Jacob A, Wlaschin J, McGregor M, Quigg RJ, and Alexander JJ
- Subjects
- Animals, Autoimmunity, Homeostasis, Humans, Immune Tolerance, Intestinal Mucosa immunology, Lupus Erythematosus, Systemic immunology, Bacteria, Dysbiosis immunology, Intestinal Mucosa microbiology, Lupus Erythematosus, Systemic microbiology, Microbiota immunology
- Abstract
Microbiota consists of more than 10
14 microorganisms that inhabit different areas of the body including the gastrointestinal tract, mainly the mouth and gut. It includes viruses, fungi, protozoa, archaea and bacteria. The microbiota interacts closely with host leading to a dynamic relationship that results in the biological effects observed. Its diverse genetic material (microbiome) interacts closely with the host immune system and cells, and therefore is closely associated with inflammation, immune tolerance, adaptive immunity and autoimmune diseases. Bacterial microbiota, which is the mostly studied lives in harmony with the host and maintains a symbiotic relationship. Therefore it plays an important role in immunological, metabolic, and neurological aspects and thereby the well-being of the host. Alteration of the homeostatic environment or the dynamic balance of microorganisms can result in dysbiosis or disease. However, does dysbiosis cause disease, aggravate disease or is the result of the disease remains to be defined, it could be a bit of all three factors. More recently, a number of studies demonstrate that these microorganisms could contribute to disease. Alteration of the tightly balanced composition of bacterial microbiota (dysbiosis) leads to exacerbation, rapid progression and worsening of disease states. It is important to identify the 'healthy' microbes that maintain a healthy environment, the 'sensitive' microbes that go awry with disease, the 'bad' microbes that cause disease and the 'therapeutic' microbes that can help rectify the changes. Increased relative abundance of certain bacterial species has been linked to triggering autoimmune diseases. Despite the burgeoning literature in the field, the molecular mechanisms by which the microbiota impacts the body in health and disease remain largely unknown. In this review, we will discuss recent advancements in our understanding of the gut bacterial microbiota associated with inflammatory and immunological processes and the role they play in the autoimmune disease, systemic lupus erythematosus., (Copyright © 2017 Elsevier GmbH. All rights reserved.)- Published
- 2018
- Full Text
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44. Urine oligosaccharide screening by MALDI-TOF for the identification of NGLY1 deficiency.
- Author
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Hall PL, Lam C, Alexander JJ, Asif G, Berry GT, Ferreira C, Freeze HH, Gahl WA, Nickander KK, Sharer JD, Watson CM, Wolfe L, and Raymond KM
- Subjects
- Adolescent, Biomarkers urine, Child, Child, Preschool, Congenital Disorders of Glycosylation urine, Female, Humans, Infant, Male, Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase isolation & purification, Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase urine, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Tandem Mass Spectrometry, Young Adult, Congenital Disorders of Glycosylation diagnosis, Oligosaccharides urine, Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase deficiency
- Abstract
N-glycanase deficiency (NGLY1 deficiency, NGLY1-CDDG), the first autosomal recessive congenital disorder of N-linked deglycosylation (CDDG), is caused by pathogenic variants in NGLY1. The majority of affected individuals have been identified using exome or genome sequencing. To date, no reliable, clinically available biomarkers have been identified. Urine oligosaccharide analysis was included as part of a routine evaluation for possible biomarkers in patients with confirmed NGLY1-CDDG. During the qualitative review of oligosaccharide profiles by an experienced laboratory director an abnormal analyte with a proposed structure of Neu5Ac1Hex1GlcNAc1-Asn was identified in NGLY1-CDDG patient urine samples. The same species has been observed in profiles from individuals affected with aspartylglucosaminuria, although the complete spectra are not identical. Additional studies using tandem mass spectrometry confirmed the analyte's structure. In addition to the known NGLY1-CDDG patients identified by this analysis, a single case was identified in a population referred for clinical testing who subsequently had a diagnosis of NGLY1-CDDG confirmed by molecular testing. Urine oligosaccharide screening by MALDI-TOF MS can identify individuals with NGLY1-CDDG. In addition, this potential biomarker might also be used to monitor the effectiveness of therapeutic options as they become available., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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45. GM2 Activator Deficiency Caused by a Homozygous Exon 2 Deletion in GM2A.
- Author
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Hall PL, Laine R, Alexander JJ, Ankala A, Teot LA, Lidov HGW, and Anselm I
- Abstract
GM2 activator (GM2A) deficiency (OMIM 613109) is a rare lysosomal storage disorder, with onset typically in infancy or early childhood. Clinically, it is almost indistinguishable from Tay-Sachs disease (OMIM 272800) or Sandhoff disease (OMIM 268800); however, traditionally available biochemical screening tests will most likely reveal normal results. We report a 2-year-old male with initially normal development until the age of 9 months, when he presented with developmental delay and regression. Workup at that time was unrevealing; at 15 months, he had abnormal brain MRI findings and a cherry red spot on ophthalmological examination. Family history and all laboratory studies were uninformative. The combination of a cherry red spot and developmental regression was strongly suggestive of a lysosomal storage disorder. Sequence analysis of GM2A did not reveal any pathogenic variants; however, exon 2 of GM2A could not be amplified by PCR, raising suspicion for a large, homozygous deletion. Subsequent copy number analysis confirmed a homozygous deletion of exon 2 in GM2A. This is the first reported case of GM2A deficiency being caused by a whole exon deletion. We describe previously unreported electron microscopy findings in this disease, thus expanding the clinical and variant spectrum for GM2 activator deficiency. These findings demonstrate the increased degree of suspicion required for diagnosis of this rare disorder. Brief Summary: This case of GM2 activator deficiency was caused by a homozygous deletion in GM2A, demonstrating the need to include exon level copy number analysis in any workup to fully exclude this disorder.
- Published
- 2018
- Full Text
- View/download PDF
46. Diagnostic Yield From 339 Epilepsy Patients Screened on a Clinical Gene Panel.
- Author
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Butler KM, da Silva C, Alexander JJ, Hegde M, and Escayg A
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Epilepsy classification, Female, Humans, Infant, Male, Middle Aged, Retrospective Studies, Tripeptidyl-Peptidase 1, Young Adult, Epilepsy diagnosis, Epilepsy genetics, Genetic Predisposition to Disease, Mutation genetics, Pathology, Molecular methods
- Abstract
Background: The contribution of genetic factors to epilepsy has long been recognized and has been estimated to play a role in 70% to 80% of cases. Identification of a pathogenic variant can help families to better cope with the disorder, allows for genetic counseling to determine recurrence risk, and in some cases, can directly influence treatment options. In this study, we determined the diagnostic yield of a clinical gene panel applied to an unselected cohort of epilepsy patients., Methods: Variant reports from 339 clinically referred epilepsy patients screened using a 110-gene panel were retrospectively reviewed. Variants were classified using the American College of Medical Genetics and Genomics guidelines., Results: Pathogenic or likely pathogenic variants were identified in 62 individuals (18%) and potentially causative variants were identified in an additional 21 individuals (6%). Causative and potentially causative variants were most frequently identified in SCN1A (n = 15) and KCNQ2 (n = 10). Other genes in which disease-causing variants were identified in multiple individuals included CDKL5, SCN2A, SCN8A, SCN1B, STXBP1, TPP1, PCDH19, CACNA1A, GABRA1, GRIN2A, SLC2A1, and TSC2. Sixteen additional genes had variants identified in single individuals., Conclusions: We identified 87 variants in 30 different genes that could explain disease, of which 54% were not previously reported. This study confirms the utility of targeted gene panel analysis in epilepsy and highlights several factors to improve the yield of diagnostic genetic testing, including the critical need for clinical phenotype information and parental samples, microarray analysis for whole exon deletions and duplications, and frequent update of panels to incorporate new disease genes., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
47. Immunomodulatory Role of Complement Proteins in the Neuropathology Associated with Opiate Abuse and HIV-1 Co-Morbidity.
- Author
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Mahajan SD, Aalinkeel R, Parikh NU, Jacob A, Cwiklinski K, Sandhu P, Le K, Loftus AW, Schwartz SA, Quigg RJ, and Alexander JJ
- Subjects
- AIDS-Associated Nephropathy epidemiology, Cadaver, Cells, Cultured, Comorbidity, Complement Activation, Cytokines metabolism, HIV Infections epidemiology, Heroin Dependence epidemiology, Humans, Immunomodulation, Microglia pathology, Microglia virology, Up-Regulation, tat Gene Products, Human Immunodeficiency Virus metabolism, AIDS-Associated Nephropathy immunology, Complement System Proteins metabolism, Frontal Lobe metabolism, HIV Infections immunology, HIV-1 physiology, Heroin Dependence immunology, Inflammation Mediators metabolism, Microglia metabolism
- Abstract
The complement system which is a critical mediator of innate immunity plays diverse roles in the neuropathogenesis of HIV-1 infection such as clearing HIV-1 and promoting productive HIV-1 replication. In the development of HIV-1 associated neurological disorders (HAND), there may be an imbalance between complement activation and regulation, which may contribute to the neuronal damage as a consequence of HIV-1 infection. It is well recognized that opiate abuse exacerbates HIV-1 neuropathology, however, little is known about the role of complement proteins in opiate induced neuromodulation, specifically in the presence of co-morbidity such as HIV-1 infection. Complement levels are significantly increased in the HIV-1-infected brain, thus HIV-induced complement synthesis may represent an important mechanism for the pathogenesis of AIDS in the brain, but remains underexplored. Anti-HIV-1 antibodies are able to initiate complement activation in HIV-1 infected CNS cells such as microglia and astrocytes during the course of disease progression; however, this complement activation fails to clear and eradicate HIV-1 from infected cells. In addition, the antiretroviral agents used for HIV therapy cause dysregulation of lipid metabolism, endothelial, and adipocyte cell function, and activation of pro-inflammatory cytokines. We speculate that both HIV-1 and opiates trigger a cytokine-mediated pro-inflammatory stimulus that modulates the complement cascade to exacerbate the virus-induced neurological damage. We examined the expression levels of C1q, SC5b-9, C5L2, C5aR, C3aR, and C9 key members of the complement cascade both in vivo in post mortem brain frontal cortex tissue from patients with HAND who used/did not use heroin, and in vitro using human microglial cultures treated with HIV tat and/or heroin. We observed significant expression of C1q and SC5b-9 by immunofluorescence staining in both the brain cortical and hippocampal region in HAND patients who abused heroin. Additionally, we observed increased gene expression of C5aR, C3aR, and C9 in the brain tissue of both HIV-1 infected patients with HAND who abused and did not abuse heroin, as compared to HIV negative controls. Our results show a significant increase in the expression of complement proteins C9, C5L2, C5aR, and C3aR in HIV transfected microglia and an additional increase in the levels of these complement proteins in heroin-treated HIV transfected microglia. This study highlights the a) potential roles of complement proteins in the pathogenesis of HIV-1-related neurodegenerative disorders; b) the combined effect of an opiate, like heroin, and HIV viral protein like HIV tat on complement proteins in normal human microglial cells and HIV transfected microglial cells. In the context of HAND, targeting selective steps in the complement cascade could help ameliorating the HIV burden in the CNS, thus investigations of complement-related therapeutic approaches for the treatment of HAND are warranted.
- Published
- 2017
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48. Early-Life Epilepsies and the Emerging Role of Genetic Testing.
- Author
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Berg AT, Coryell J, Saneto RP, Grinspan ZM, Alexander JJ, Kekis M, Sullivan JE, Wirrell EC, Shellhaas RA, Mytinger JR, Gaillard WD, Kossoff EH, Valencia I, Knupp KG, Wusthoff C, Keator C, Dobyns WB, Ryan N, Loddenkemper T, Chu CJ, Novotny EJ Jr, and Koh S
- Subjects
- Adolescent, Child, Child, Preschool, Cohort Studies, Female, Follow-Up Studies, Genetic Predisposition to Disease, Humans, Infant, Male, Prospective Studies, United States, Epilepsy genetics, Genetic Testing methods
- Abstract
Importance: Early-life epilepsies are often a consequence of numerous neurodevelopmental disorders, most of which are proving to have genetic origins. The role of genetic testing in the initial evaluation of these epilepsies is not established., Objective: To provide a contemporary account of the patterns of use and diagnostic yield of genetic testing for early-life epilepsies., Design, Setting, and Participants: In this prospective cohort, children with newly diagnosed epilepsy with an onset at less than 3 years of age were recruited from March 1, 2012, to April 30, 2015, from 17 US pediatric hospitals and followed up for 1 year. Of 795 families approached, 775 agreed to participate. Clinical diagnosis of the etiology of epilepsy were characterized based on information available before genetic testing was performed. Added contributions of cytogenetic and gene sequencing investigations were determined., Exposures: Genetic diagnostic testing., Main Outcomes and Measures: Laboratory-confirmed pathogenic variant., Results: Of the 775 patients in the study (367 girls and 408 boys; median age of onset, 7.5 months [interquartile range, 4.2-16.5 months]), 95 (12.3%) had acquired brain injuries. Of the remaining 680 patients, 327 (48.1%) underwent various forms of genetic testing, which identified pathogenic variants in 132 of 327 children (40.4%; 95% CI, 37%-44%): 26 of 59 (44.1%) with karyotyping, 32 of 188 (17.0%) with microarrays, 31 of 114 (27.2%) with epilepsy panels, 11 of 33 (33.3%) with whole exomes, 4 of 20 (20.0%) with mitochondrial panels, and 28 of 94 (29.8%) with other tests. Forty-four variants were identified before initial epilepsy presentation. Apart from dysmorphic syndromes, pathogenic yields were highest for children with tuberous sclerosis complex (9 of 11 [81.8%]), metabolic diseases (11 of 14 [78.6%]), and brain malformations (20 of 61 [32.8%]). A total of 180 of 446 children (40.4%), whose etiology would have remained unknown without genetic testing, underwent some testing. Pathogenic variants were identified in 48 of 180 children (26.7%; 95% CI, 18%-34%). Diagnostic yields were greater than 15% regardless of delay, spasms, and young age. Yields were greater for epilepsy panels (28 of 96 [29.2%]; P < .001) and whole exomes (5 of 18 [27.8%]; P = .02) than for chromosomal microarray (8 of 101 [7.9%])., Conclusions and Relevance: Genetic investigations, particularly broad sequencing methods, have high diagnostic yields in newly diagnosed early-life epilepsies regardless of key clinical features. Thorough genetic investigation emphasizing sequencing tests should be incorporated into the initial evaluation of newly presenting early-life epilepsies and not just reserved for those with severe presentations and poor outcomes.
- Published
- 2017
- Full Text
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49. Optimization of Retinal Gene Therapy for X-Linked Retinitis Pigmentosa Due to RPGR Mutations.
- Author
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Beltran WA, Cideciyan AV, Boye SE, Ye GJ, Iwabe S, Dufour VL, Marinho LF, Swider M, Kosyk MS, Sha J, Boye SL, Peterson JJ, Witherspoon CD, Alexander JJ, Ying GS, Shearman MS, Chulay JD, Hauswirth WW, Gamlin PD, Jacobson SG, and Aguirre GD
- Subjects
- Animals, Dependovirus genetics, Disease Models, Animal, Dogs, G-Protein-Coupled Receptor Kinase 1 genetics, Gene Expression, Gene Order, Genes, Reporter, Genetic Vectors genetics, Humans, Phenotype, Photoreceptor Cells, Vertebrate metabolism, Primates, Promoter Regions, Genetic, Retinitis Pigmentosa diagnosis, Retinitis Pigmentosa therapy, Transduction, Genetic, Transgenes, Vision Tests, Carrier Proteins genetics, Eye Proteins genetics, Genes, X-Linked, Genetic Therapy, Mutation, Retina metabolism, Retinitis Pigmentosa genetics
- Abstract
X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene is an early onset and severe cause of blindness. Successful proof-of-concept studies in a canine model have recently shown that development of a corrective gene therapy for RPGR-XLRP may now be an attainable goal. In preparation for a future clinical trial, we have here optimized the therapeutic AAV vector construct by showing that GRK1 (rather than IRBP) is a more efficient promoter for targeting gene expression to both rods and cones in non-human primates. Two transgenes were used in RPGR mutant (XLPRA2) dogs under the control of the GRK1 promoter. First was the previously developed stabilized human RPGR (hRPGRstb). Second was a new full-length stabilized and codon-optimized human RPGR (hRPGRco). Long-term (>2 years) studies with an AAV2/5 vector carrying hRPGRstb under control of the GRK1 promoter showed rescue of rods and cones from degeneration and retention of vision. Shorter term (3 months) studies demonstrated comparable preservation of photoreceptors in canine eyes treated with an AAV2/5 vector carrying either transgene under the control of the GRK1 promoter. These results provide the critical molecular components (GRK1 promoter, hRPGRco transgene) to now construct a therapeutic viral vector optimized for RPGR-XLRP patients., (Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
50. De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis.
- Author
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Butler KM, da Silva C, Shafir Y, Weisfeld-Adams JD, Alexander JJ, Hegde M, and Escayg A
- Subjects
- Adolescent, Autism Spectrum Disorder genetics, Child, Child, Preschool, Cohort Studies, Female, Genetic Testing, Humans, Infant, Intellectual Disability genetics, Male, Neuromuscular Diseases genetics, Epilepsy genetics, Genetic Predisposition to Disease, Mutation, NAV1.6 Voltage-Gated Sodium Channel genetics
- Abstract
Objectives: To determine the incidence of pathogenic SCN8A variants in a cohort of epilepsy patients referred for clinical genetic testing. We also investigated the contribution of SCN8A to autism spectrum disorder, intellectual disability, and neuromuscular disorders in individuals referred for clinical genetic testing at the same testing laboratory., Methods: Sequence data from 275 epilepsy panels screened by Emory Genetics Laboratory were reviewed for variants in SCN8A. Two additional cases with variants in SCN8A were ascertained from other testing laboratories. Parental samples were tested for variant segregation and clinical histories were examined. SCN8A variants detected from gene panel analyses for autism spectrum disorder, intellectual disability, and neuromuscular disorders were also examined., Results: Five variants in SCN8A were identified in five individuals with epilepsy. Three variants were de novo, one was inherited from an affected parent, and one was inherited from an unaffected parent. Four of the individuals have epilepsy and developmental delay/intellectual disability. The remaining individual has a milder epilepsy presentation without cognitive impairment. We also identified an amino acid substitution at an evolutionarily conserved SCN8A residue in a patient who was screened on the autism spectrum disorder panel. Additionally, we examined the distribution of pathogenic SCN8A variants across the Na
v 1.6 channel and identified four distinct clusters of variants. These clusters are primarily located in regions of the channel that are important for the kinetics of channel inactivation., Conclusions: Variants in SCN8A may be responsible for a spectrum of epilepsies as well as other neurodevelopmental disorders without seizures. The predominant pathogenic mechanism appears to involve disruption of channel inactivation, leading to gain-of-function effects., (Copyright © 2016 Elsevier B.V. All rights reserved.)- Published
- 2017
- Full Text
- View/download PDF
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