89 results on '"Knight EM"'
Search Results
2. Noninvasive predictors of subdural grid seizure localization in children with nonlesional focal epilepsy.
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Kalamangalam GP, Pestana Knight EM, Visweswaran S, Gupta A, Kalamangalam, Giridhar P, Pestana Knight, Elia M, Visweswaran, Shyam, and Gupta, Ajay
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- 2013
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3. Cerebral and systemic infarcts after bronchial artery embolization.
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Pestana Knight EM, Novelli PM, and Joshi SM
- Published
- 2011
4. The effect of caffeine on pregnancy outcome variables.
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Hinds TS, West WL, Knight EM, and Harland BF
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- 1996
5. Nurse staffing and inpatient hospital mortality.
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Knight EM and Knight, Ellis M
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- 2011
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6. Caregiver Perspective of Benefits and Side Effects of Anti-Seizure Medications in CDKL5 Deficiency Disorder from an International Database.
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Wong K, Junaid M, Alexander S, Olson HE, Pestana-Knight EM, Rajaraman RR, Downs J, and Leonard H
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- Humans, Male, Female, Retrospective Studies, Child, Child, Preschool, Adult, Adolescent, Young Adult, Databases, Factual, Spasms, Infantile drug therapy, Infant, Cohort Studies, Anticonvulsants adverse effects, Anticonvulsants administration & dosage, Anticonvulsants therapeutic use, Epileptic Syndromes drug therapy, Seizures drug therapy, Caregivers
- Abstract
Background and Objective: CDKL5 deficiency disorder presents as a challenging condition with early-onset refractory seizures, severe developmental delays, and a range of other neurological symptoms. Our study aimed to explore the benefits and side effects of anti-seizure medications (ASMs) in managing seizures among individuals with CDKL5 deficiency disorder, drawing on data from the International CDKL5 Disorder Database., Methods: Data for this retrospective cohort study were obtained from the International CDKL5 Disorder Database, which contains responses from a baseline questionnaire administered between 2012 and 2022 and a follow-up questionnaire administered between 2018 and 2019. Families of eligible individuals were asked to provide information on ASMs that were previously and currently taken, the dose prescribed, the age at starting the medications, and the age at discontinuation for past medications. The outcome variables of interest were perceived seizure-related benefits for the current and past use of ASMs and caregiver-reported side effects. Rescue medications and infrequently used ASMs were excluded from the analysis. Descriptive statistics were used to summarise the characteristics of the study population., Results: The study included 399 children and adults with CDKL5 deficiency disorder, descriptively analysing the perceived benefits and side effects of 23 unique ASMs based on caregiver reports. The study identified levetiracetam, topiramate, sodium valproate, vigabatrin, phenobarbital and clobazam as the most used ASMs. Notably, cannabidiol showed highly beneficial outcomes with few side effects, whereas levetiracetam and phenobarbital exhibited less favourable benefit-to-side-effect ratios. Dual therapy involving sodium valproate and levetiracetam was only used a small number (n = 5) of times but appeared effective in reducing seizure activity with relatively few side effects. Compared with monotherapy, polytherapy had a relatively higher likelihood of reported side effects than benefits., Conclusions: The study, leveraging a large sample size that exceeds that of previous research, emphasises the complex nature of seizure management in CDKL5 deficiency disorder. Our findings underscore the necessity of ongoing research to optimise treatment strategies, considering both the efficacy of seizure control and the potential for adverse effects. The study also points to the need for future investigations into the therapeutic potential of emerging treatments such as ganaxolone and the unresolved efficacy of cannabis products in seizure management., (© 2024. The Author(s).)
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- 2024
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7. Healthcare utilization and clinical characteristics of genetic epilepsy in electronic health records.
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Boßelmann CM, Ivaniuk A, St John M, Taylor SC, Krishnaswamy G, Milinovich A, Leu C, Gupta A, Pestana-Knight EM, Najm I, and Lal D
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Understanding the clinical characteristics and medical treatment of individuals affected by genetic epilepsies is instrumental in guiding selection for genetic testing, defining the phenotype range of these rare disorders, optimizing patient care pathways and pinpointing unaddressed medical need by quantifying healthcare resource utilization. To date, a matched longitudinal cohort study encompassing the entire spectrum of clinical characteristics and medical treatment from childhood through adolescence has not been performed. We identified individuals with genetic and non-genetic epilepsies and onset at ages 0-5 years by linkage across the Cleveland Clinic Health System. We used natural language processing to extract medical terms and procedures from longitudinal electronic health records and tested for cross-sectional and temporal associations with genetic epilepsy. We implemented a two-stage design: in the discovery cohort, individuals were stratified as being 'likely genetic' or 'non-genetic' by a natural language processing algorithm, and controls did not receive genetic testing. The validation cohort consisted of cases with genetic epilepsy confirmed by manual chart review and an independent set of controls who received negative genetic testing. The discovery and validation cohorts consisted of 503 and 344 individuals with genetic epilepsy and matched controls, respectively. The median age at the first encounter was 0.1 years and 7.9 years at the last encounter, and the mean duration of follow-up was 8.2 years. We extracted 188,295 Unified Medical Language System annotations for statistical analysis across 9659 encounters. Individuals with genetic epilepsy received an earlier epilepsy diagnosis and had more frequent and complex encounters with the healthcare system. Notably, the highest enrichment of encounters compared with the non-genetic groups was found during the transition from paediatric to adult care. Our computational approach could validate established comorbidities of genetic epilepsies, such as behavioural abnormality and intellectual disability. We also revealed novel associations for genitourinary abnormalities (odds ratio 1.91, 95% confidence interval: 1.66-2.20, P = 6.16 × 10
-19 ) linked to a spectrum of underrecognized epilepsy-associated genetic disorders. This case-control study leveraged real-world data to identify novel features associated with the likelihood of a genetic aetiology and quantified the healthcare utilization of genetic epilepsies compared with matched controls. Our results strongly recommend early genetic testing to stratify individuals into specialized care paths, thus improving the clinical management of people with genetic epilepsies., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)- Published
- 2024
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8. CDKL5 Deficiency Disorder: Some Lessons Learned 20 Years After the First Description.
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Pestana Knight EM and Olson HE
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- United States, Humans, Protein Serine-Threonine Kinases genetics, Spasms, Infantile genetics, Epileptic Syndromes genetics
- Abstract
Loss of function variants in the Cyclin-dependent kinase-like 5 gene (CDKL5) causes CDKL5 deficiency disorder (CDD). Most cases of CDD are due to a de novo missense or truncating variants. The CDKL5 gene was discovered in 1998 as part of the genomic mapping of the chromosome Xp22 region that led to the discovery of the serine-threonine kinases STK9. Since then, there have been significant advancements in the description of the disease in humans, the understanding of the pathophysiology, and the management of the disease. There have been many lessons learned since the initial description of the condition in humans in 2003. In this article, we will focus on pathophysiology, clinical manifestations, with particular focus on seizures because of its relevance to the medical practitioners and researchers and guidelines for management. We finalize the manuscript with the voice of the parents and caregivers, as discussed with the 2019 meeting with the Food and Drug Administration., (©AAIDD.)
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- 2024
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9. Recognition of Movement Disorders in Genetic, Developmental, and Epileptic Encephalopathies: More Than Seizures and Neurocognitive Problems.
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Pestana Knight EM
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- Humans, Seizures, Brain Diseases, Movement Disorders, Epilepsy, Generalized
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- 2023
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10. Tizanidine: An overlooked alternative muscle relaxant for older patients.
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Knight EM
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- Humans, Muscles, Clonidine therapeutic use, Muscle Relaxants, Central adverse effects
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- 2023
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11. Historical Overview of Hypsarrhythmia and Its Association to Epileptic Spasms: A Review of the Medical Literature From 1952 to 1982.
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Pestana Knight EM and Mani J
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- Child, Preschool, Humans, Infant, Adrenocorticotropic Hormone therapeutic use, Electroencephalography, Spasm drug therapy, History, 20th Century, Spasms, Infantile therapy
- Abstract
Summary: The initial description of infantile spasms and its association to developmental abnormalities was attributed to Dr. Williams J. West in 1841 but the clinical scenario at the time had also been seen by other physicians. French physician Henry Gastaut proposed the eponym of West syndrome in the 9th Colloquium de Marseille in 1960. The description of hypsarrhythmia in 1952 by Gibbs and Gibbs added the EEG component to the triad of infantile spasms. The hypsarrhythmia discovery led to a sudden interest in understanding the etiology and developing treatments for this devastating disease affecting infants and young children. It was in the 1950s when cases of infantile spasms with absence of hypsarrhythmia were initially observed. Also, the treatment with adrenocorticotrophic hormone was initially reported as efficacious for treating infantile spasms and hypsarrhythmia in the late 1950s. Adrenocorticotrophic hormone remains the best treatment option for these epilepsy types. This article will provide a historical review of knowledge developments about hypsarrhythmia and infantile spasms, emphasizing the period 1952 to 1982. The goal of the article was to highlight clinical elements that were discovered then and remain clinically relevant today., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 by the American Clinical Neurophysiology Society.)
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- 2022
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12. Hypsarrhythmia and Epileptic Spasms: A Look at One Old Epilepsy in the Modern Era.
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Pestana Knight EM
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- Humans, Infant, Anticonvulsants therapeutic use, Spasm drug therapy, Electroencephalography, Spasms, Infantile diagnosis, Epilepsy diagnosis, Epilepsy drug therapy
- Abstract
Competing Interests: The author has no funding or conflicts of interest to disclose.
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- 2022
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13. Patient Empowerment Among Adults With Arthritis: The Case for Emotional Support.
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Carluzzo KL, Knight EM, Schifferdecker KE, Butcher RL, Eakin GS, Eller JA, and Singh JA
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- Adult, Cross-Sectional Studies, Female, Humans, Male, Patient Reported Outcome Measures, Surveys and Questionnaires, Osteoarthritis, Patient Participation
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Objective: This study aimed to identify differences in patient empowerment based on biopsychosocial patient-reported measures, the magnitude of those differences, and which measures best explain differences in patient empowerment., Methods: This was a cross-sectional observational study of 6918 adults with arthritis in the US. Data were collected from March 2019 to March 2020 through the Arthritis Foundation Live Yes! INSIGHTS program. Patient empowerment, measured by the Health Care Empowerment Questionnaire, included 2 scales: Patient Information Seeking and Healthcare Interaction Results. Patient-reported outcomes were measured using the Patient Reported Outcomes Measurement Information System (PROMIS)-29 and PROMIS emotional support scale. ANOVA assessed differences between groups, and Spearman rank correlation assessed correlations between variables. Hierarchical regression analysis determined the contributions of sociodemographic characteristics, arthritis type, and patient-reported health measures in explaining patient empowerment (α = 0.05)., Results: Empowerment was lower among those who were male, older, less educated, or who had lower income, osteoarthritis, less emotional support, or better physical function, although the effect was small-to-negligible for most of these variables in the final regression models. Empowerment did not differ by race/ethnicity in unadjusted or adjusted analysis. In final regression models, emotional support contributed the most to explaining patient empowerment., Conclusion: Emotional support is important for patient empowerment. This suggests that programs that seek to improve patient empowerment should target and measure effects on emotional support., (Copyright © 2022 by the Journal of Rheumatology.)
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- 2022
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14. International Consensus Recommendations for the Assessment and Management of Individuals With CDKL5 Deficiency Disorder.
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Amin S, Monaghan M, Aledo-Serrano A, Bahi-Buisson N, Chin RF, Clarke AJ, Cross JH, Demarest S, Devinsky O, Downs J, Pestana Knight EM, Olson H, Partridge CA, Stuart G, Trivisano M, Zuberi S, and Benke TA
- Abstract
CDKL5 Deficiency Disorder (CDD) is a rare, X-linked dominant condition that causes a developmental and epileptic encephalopathy (DEE). The incidence is between ~ 1:40,000 and 1:60,000 live births. Pathogenic variants in CDKL5 lead to seizures from infancy and severe neurodevelopmental delay. During infancy and childhood, individuals with CDD suffer impairments affecting cognitive, motor, visual, sleep, gastrointestinal and other functions. Here we present the recommendations of international healthcare professionals, experienced in CDD management, to address the multisystem and holistic needs of these individuals. Using a Delphi method, an anonymous survey was administered electronically to an international and multidisciplinary panel of expert clinicians and researchers. To provide summary recommendations, consensus was set, a priori , as >70% agreement for responses. In the absence of large, population-based studies to provide definitive evidence for treatment, we propose recommendations for clinical management, influenced by this proposed threshold for consensus. We believe these recommendations will help standardize, guide and improve the medical care received by individuals with CDD., Competing Interests: JD Consultancy for Marinus, Ultragenyx, Avexis, Anavex, and Newron; any remuneration went to Telethon Kids Institute. MM works as a pediatric researcher with investigator initiated studies funded through industry (PTC Therapeutics). EP is on the advisory board of Marinus Pharmaceuticals and has consulted for Biomarin Pharmaceuticals and Zogenix. JC has acted as an investigator for studies with GW Pharma, Zogenix, Vitaflo, Ovid, Marinius and Stoke Therapeutics. She has been a speaker and on advisory boards for GW Pharma, Biocodex, Zogenix, and Nutricia; all remuneration has been paid to her department. Her research is supported by the National Institute of Health Research (NIHR) Biomedical Research Centre at Great Ormond Street Hospital. She holds as endowed chair at UCL Great Ormond Street Institute of Child Health; she holds grants from NIHR, EPSRC, GOSH Charity, ERUK, the Waterloo Foundation and the Great Ormond Street Hospital Biomedical Research Centre. SA has received funding from GW Pharmaceuticals, Norvartis, PTC Therapeutics, Boston Scientific, Nutricia, UCB, BioMarin, LivaNova, Medtronic, Desitin, Ipsen, CDKL5 UK, TSA and the National Institute for Health Research. HO received consulting fees from Takeda Pharmaceuticals and Zogenix regarding clinical trial design, Ovid Therapeutics regarding clinical trial results, Marinus Pharmaceuticals regarding CDKL5 Deficiency Disorder, and has done consulting for the FOXG1 Research Foundation. TB performed consultancy for Ovid, GW Pharmaceuticals, International Rett Syndrome Foundation, Takeda, Neurogene, Ultragenyx, Zogenix, GrinTherapeutics, Alcyone, Acadia, Neuren and Marinus; Clinical Trials with Acadia, Ovid, GW Pharmaceuticals, Marinus and RSRT; all remuneration has been made to his department. The remaining 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., (Copyright © 2022 Amin, Monaghan, Aledo-Serrano, Bahi-Buisson, Chin, Clarke, Cross, Demarest, Devinsky, Downs, Pestana Knight, Olson, Partridge, Stuart, Trivisano, Zuberi and Benke.)
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- 2022
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15. The Efficacy and Use of a Pocket Card Algorithm in Status Epilepticus Treatment.
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Fesler JR, Belcher AE, Moosa AN, Mays M, Jehi LE, Pestana Knight EM, Lachhwani DK, Alexopoulos AV, Nair DR, and Punia V
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Objective: To determine whether a pocket card treatment algorithm improves the early treatment of status epilepticus and to assess its utilization and retention in clinical practice., Methods: Multidisciplinary care teams participated in video-recorded status epilepticus simulation sessions from 2015 to 2019. In this longitudinal cohort study, we examined the sessions recorded before and after introducing an internally developed, guideline-derived pocket card to determine differences in the adequacy or timeliness of rescue benzodiazepine. Simulation participants were queried 9 months later for submission of a differentiating identification number on each card to assess ongoing availability and utilization., Results: Forty-four teams were included (22 before and 22 after the introduction of the pocket card). The time to rescue therapy was shorter for teams with the pocket card available (84 seconds [64-132]) compared with teams before introduction (144 seconds [100-162]) (U = 94; median difference = -46.9, 95% confidence interval [CI]: -75.9 to -21.9). The adequate dosing did not differ with card availability (odds ratio 1.48, 95% CI: 0.43-5.1). At the 9-month follow-up, 32 participants (65%) completed the survey, with 26 (81%) self-reporting having the pocket card available and 11 (34%) confirming ready access with the identification number. All identification numbers submitted corresponded to the hard copy laminated pocket card, and none to the electronic version., Conclusions: A pocket card is a feasible, effective, and worthwhile educational tool to improve the implementation of updated guidelines for the treatment of status epilepticus., (© 2021 American Academy of Neurology.)
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- 2021
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16. Long-Term Efficacy of Oral Vancomycin Prophylaxis for the Prevention of Clostridium difficile Recurrence.
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Knight EM, Schiller DS, Fulman MK, and Rastogi R
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- Anti-Bacterial Agents therapeutic use, Humans, Recurrence, Retrospective Studies, Vancomycin, Clostridioides difficile, Clostridium Infections drug therapy, Clostridium Infections epidemiology, Clostridium Infections prevention & control
- Abstract
Background: Limited evidence suggests that prophylactic oral vancomycin may be beneficial in preventing Clostridium difficile infection (CDI) recurrence, but long-term efficacy is unknown., Objective: To evaluate the long-term efficacy of oral vancomycin prophylaxis (OVP) in preventing CDI recurrence in subjects who require subsequent antibiotic exposure., Methods: A retrospective cohort study was conducted at a community hospital. A total of 91 subjects with a history of CDI between January 2013 and December 2015 who had a subsequent hospitalization requiring systemic antibiotics within 12 months were evaluated. Thirty-two subjects who received prophylaxis with oral vancomycin were compared to 59 subjects who did not receive prophylaxis., Results: CDI recurrence within 12 months was significantly lower in subjects receiving OVP compared to those who did not receive OVP (6.3% vs 28.8%; odds ratio [OR]: 0.16; 95% confidence interval [CI]: 0.04-0.77; P = .011) including patients whose previous CDI was an initial episode (3.7% [1/27] vs 28.3% [15/53]; OR: 10.3; 95% CI: 1.28-82.6; P = .009)., Conclusion: Use of OVP in subjects with a history of CDI up to 12 months prior to subsequent antibiotic exposure appears to reduce the risk of CDI recurrence for up to 12 months.
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- 2020
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17. An Overview of the Electroencephalographic (EEG) Features of Epilepsy with Eyelid Myoclonia (Jeavons Syndrome).
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Zawar I and Pestana Knight EM
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- Epilepsy, Absence physiopathology, Epilepsy, Reflex physiopathology, Humans, Syndrome, Brain physiopathology, Electroencephalography, Epilepsy, Generalized physiopathology, Eyelids, Myoclonus physiopathology
- Abstract
Epilepsy with eyelid myoclonia or Jeavons Syndrome is a unique idiopathic generalized epilepsy with onset in childhood. It is characterized by eyelid myoclonia which may be associated with absence seizures, eyelid closure-induced epileptiform discharges and/or seizures and photosensitivity. It is frequently underrecognized and misdiagnosed because it may be mistaken for some other type of generalized epilepsy or facial tic disorder. The intent of this narrative review is to focus on existing literature and highlight the distinct electroencephalographic features including characteristic eye movements, associated waveforms, interictal and ictal findings that are suggestive and characteristic of Jeavons Syndrome to aid in timely recognition of this syndrome.
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- 2020
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18. Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review.
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Olson HE, Demarest ST, Pestana-Knight EM, Swanson LC, Iqbal S, Lal D, Leonard H, Cross JH, Devinsky O, and Benke TA
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- Alternative Splicing, Anticonvulsants therapeutic use, Corpus Callosum surgery, Developmental Disabilities etiology, Diet, Ketogenic, Electroencephalography, Gastrointestinal Diseases etiology, Humans, Models, Molecular, Movement Disorders etiology, Mutation, Precision Medicine, Protein Conformation, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases physiology, Vagus Nerve Stimulation, Vision Disorders etiology, Epileptic Syndromes genetics, Epileptic Syndromes pathology, Epileptic Syndromes therapy, Protein Serine-Threonine Kinases deficiency, Spasms, Infantile genetics, Spasms, Infantile pathology, Spasms, Infantile therapy
- Abstract
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental encephalopathy caused by pathogenic variants in the gene CDKL5. This unique disorder includes early infantile onset refractory epilepsy, hypotonia, developmental intellectual and motor disabilities, and cortical visual impairment. We review the clinical presentations and genetic variations in CDD based on a systematic literature review and experience in the CDKL5 Centers of Excellence. We propose minimum diagnostic criteria. Pathogenic variants include deletions, truncations, splice variants, and missense variants. Pathogenic missense variants occur exclusively within the kinase domain or affect splice sites. The CDKL5 protein is widely expressed in the brain, predominantly in neurons, with roles in cell proliferation, neuronal migration, axonal outgrowth, dendritic morphogenesis, and synapse development. The molecular biology of CDD is revealing opportunities in precision therapy, with phase 2 and 3 clinical trials underway or planned to assess disease specific and disease modifying treatments., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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19. Severity Assessment in CDKL5 Deficiency Disorder.
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Demarest S, Pestana-Knight EM, Olson HE, Downs J, Marsh ED, Kaufmann WE, Partridge CA, Leonard H, Gwadry-Sridhar F, Frame KE, Cross JH, Chin RFM, Parikh S, Panzer A, Weisenberg J, Utley K, Jaksha A, Amin S, Khwaja O, Devinsky O, Neul JL, Percy AK, and Benke TA
- Subjects
- Autonomic Nervous System Diseases etiology, Child, Clinical Trials as Topic statistics & numerical data, Cognition Disorders etiology, Delphi Technique, Humans, Movement Disorders etiology, Speech Disorders etiology, Surveys and Questionnaires, Vision Disorders etiology, Epileptic Syndromes complications, Severity of Illness Index, Spasms, Infantile complications, Symptom Assessment methods
- Abstract
Background: Pathologic mutations in cyclin-dependent kinase-like 5 cause CDKL5 deficiency disorder, a genetic syndrome associated with severe epilepsy and cognitive, motor, visual, and autonomic disturbances. This disorder is a relatively common genetic cause of early-life epilepsy. A specific severity assessment is lacking, required to monitor the clinical course and needed to define the natural history and for clinical trial readiness., Methods: A severity assessment was developed based on clinical and research experience from the International Foundation for CDKL5 Research Centers of Excellence consortium and the National Institutes of Health Rett and Rett-Related Disorders Natural History Study consortium. An initial draft severity assessment was presented and reviewed at the annual CDKL5 Forum meeting (Boston, 2017). Subsequently it was iterated through four cycles of a modified Delphi process by a group of clinicians, researchers, industry, patient advisory groups, and parents familiar with this disorder until consensus was achieved. The revised version of the severity assessment was presented for review, comment, and piloting to families at the International Foundation for CDKL5 Research-sponsored family meeting (Colorado, 2018). Final revisions were based on this additional input., Results: The final severity assessment comprised 51 items that comprehensively describe domains of epilepsy; motor; cognition, behavior, vision, and speech; and autonomic functions. Parental ratings of therapy effectiveness and child and family functioning are also included., Conclusions: A severity assessment was rapidly developed with input from multiple stakeholders. Refinement through ongoing validation is required for future clinical trials. The consensus methods employed for the development of severity assessment may be applicable to similar rare disorders., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2019
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20. Variation of the prevalence of pediatric polypharmacy: A scoping review.
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Baker C, Feinstein JA, Ma X, Bolen S, Dawson NV, Golchin N, Horace A, Kleinman LC, Meropol SB, Pestana Knight EM, Winterstein AG, and Bakaki PM
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- Adolescent, Adolescent Health Services, Child, Child Health Services, Female, Global Health, Humans, Male, Pharmacoepidemiology, Pharmacovigilance, Prevalence, Polypharmacy
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Purpose: To examine the range of prevalence of pediatric polypharmacy in literature through a scoping review, focusing on factors that contribute to its heterogeneity in order to improve the design and reporting of quality improvement, pharmacovigilance, and research studies., Methods: We searched Ovid Medline, PubMed, EMBASE, CINAHL, Ovid PsycINFO, Cochrane CENTRAL, and Web of Science Core Collection databases for studies with concepts of children and polypharmacy, along with a hand search of the bibliographies of six reviews and 30 included studies. We extracted information regarding study design, disease conditions, and prevalence of polypharmacy., Results: Two hundred eighty-four studies reported prevalence of polypharmacy. They were more likely to be conducted in North America (37.7%), published after 2010 (44.4%), cross-sectional (67.3%), in outpatient settings (59.5%). Prevalence ranged from 0.9% to 98.4%, median 39.7% (interquartile range [IQR] 22.0%-54.0%). Studies from Asia reported the highest median prevalence of 45.4% (IQR 27.3%-61.0%) while studies from North America reported the lowest median prevalence of 30.4% (IQR 14.7%-50.2%). Prevalence decreased over time: median 45.6% before 2001, 38.1% during 2001 to 2010, and 34% during 2011 to 2017. Studies involving children under 12 years had a higher median prevalence (46.9%) than adolescent studies (33.7%). Inpatient setting studies had a higher median prevalence (50.3%) than studies in outpatient settings (38.8%). Community level samples, higher number and duration of medications defining polypharmacy, and psychotropic medications were associated with lower prevalence., Conclusions: The prevalence of pediatric polypharmacy is high and variable. Studies reporting pediatric polypharmacy should account for context, design, polypharmacy definition, and medications evaluated., (© 2019 John Wiley & Sons, Ltd.)
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- 2019
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21. Defining pediatric polypharmacy: A scoping review.
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Bakaki PM, Horace A, Dawson N, Winterstein A, Waldron J, Staley J, Pestana Knight EM, Meropol SB, Liu R, Johnson H, Golchin N, Feinstein JA, Bolen SD, and Kleinman LC
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- Adolescent, Child, Child, Preschool, Databases, Factual, Drug Therapy, Combination, Humans, Infant, Infant, Newborn, Pediatrics methods, Polypharmacy
- Abstract
Objectives: Lack of consensus regarding the semantics and definitions of pediatric polypharmacy challenges researchers and clinicians alike. We conducted a scoping review to describe definitions and terminology of pediatric polypharmacy., Methods: Medline, PubMed, EMBASE, CINAHL, PsycINFO, Cochrane CENTRAL, and the Web of Science Core Collection databases were searched for English language articles with the concepts of "polypharmacy" and "children". Data were extracted about study characteristics, polypharmacy terms and definitions from qualifying studies, and were synthesized by disease conditions., Results: Out of 4,398 titles, we included 363 studies: 324 (89%) provided numeric definitions, 131 (36%) specified duration of polypharmacy, and 162 (45%) explicitly defined it. Over 81% (n = 295) of the studies defined polypharmacy as two or more medications or therapeutic classes. The most common comprehensive definitions of pediatric polypharmacy included: two or more concurrent medications for ≥1 day (n = 41), two or more concurrent medications for ≥31 days (n = 15), and two or more sequential medications over one year (n = 12). Commonly used terms included polypharmacy, polytherapy, combination pharmacotherapy, average number, and concomitant medications. The term polypharmacy was more common in psychiatry literature while epilepsy literature favored the term polytherapy., Conclusions: Two or more concurrent medications, without duration, for ≥1 day, ≥31 days, or sequentially for one year were the most common definitions of pediatric polypharmacy. We recommend that pediatric polypharmacy studies specify the number of medications or therapeutic classes, if they are concurrent or sequential, and the duration of medications. We propose defining pediatric polypharmacy as "the prescription or consumption of two or more distinct medications for at least one day". The term "polypharmacy" should be included among key words and definitions in manuscripts., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
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22. Arc de cercle as a manifestation of focal epileptic seizures.
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Pestana Knight EM, Grinenko O, Bulacio J, Bingaman W, Gupta A, and Chauvel P
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- 2018
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23. Waveform Window #38: EEG Stages of Neonatal Hypoxic Ischemic Encephalopathy: From Background Suppression to Resolution of Neonatal Seizures.
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Lyutyy Y, Sieciechowicz D, Moosa AN, and Pestana Knight EM
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- Humans, Infant, Newborn, Infant, Newborn, Diseases physiopathology, Seizures physiopathology, Electroencephalography, Hypoxia-Ischemia, Brain physiopathology
- Published
- 2017
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24. Aicardi syndrome: epilepsy surgery as a palliative treatment option for selected patients and pathological findings.
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Podkorytova I, Gupta A, Wyllie E, Moosa A, Bingaman W, Prayson R, and Knight EM
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- Aicardi Syndrome complications, Child, Female, Humans, Palliative Care, Seizures etiology, Aicardi Syndrome surgery, Seizures surgery
- Abstract
The optimal treatment for medically refractory epilepsy in Aicardi syndrome (AS) is still unclear. Palliative surgical treatment, including vagus nerve stimulation and corpus callosotomy, has therefore been used. There is limited data on the role of resective epilepsy surgery as a treatment choice in patients with AS. Here, we describe the seizures, anatomo-pathological findings, and neurodevelopmental outcome of palliative epilepsy surgery in two children with AS who had resective epilepsy surgery at the Cleveland Clinic. The related literature is also reviewed. Case 1 had a left functional hemispherectomy and was free of seizures and hypsarrhythmia for six months after surgery. Her gross motor skills improved after surgery. Outcome at 43 months was 1-3 isolated spasms per day. Case 2 had a right fronto-parietal lobectomy. Her seizures improved in frequency and severity, but remained daily after epilepsy surgery. Neurodevelopment changes included improved alertness and recognition of caregivers. This patient died 21 months after epilepsy surgery of unclear causes. Surgical pathology in both cases showed focal cortical dysplasia associated with other findings, such as nodular heterotopia and polymicrogyria. Epilepsy surgery could be an alternative palliative treatment choice in selective cases of AS, but studies on a larger patient cohort are needed to identify the possible role of surgery in children with AS. The complexity of the pathological findings may offer an explanation for the severity of seizures in AS.
- Published
- 2016
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25. Effective anti-Alzheimer Aβ therapy involves depletion of specific Aβ oligomer subtypes.
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Knight EM, Kim SH, Kottwitz JC, Hatami A, Albay R, Suzuki A, Lublin A, Alberini CM, Klein WL, Szabo P, Relkin NR, Ehrlich M, Glabe CG, Gandy S, and Steele JW
- Abstract
Background: Recent studies have implicated specific assembly subtypes of β-amyloid (Aβ) peptide, specifically soluble oligomers (soAβ) as disease-relevant structures that may underlie memory loss in Alzheimer disease. Removing existing soluble and insoluble Aβ assemblies is thought to be essential for any attempt at stabilizing brain function and slowing cognitive decline in Alzheimer disease. IV immunoglobulin (IVIg) therapies have been shown to contain naturally occurring polyclonal antibodies that recognize conformational neoepitopes of soluble or insoluble Aβ assemblies including soAβ. These naturally occurring polyclonal antibodies have been suggested to underlie the apparent clinical benefits of IVIg. However, direct evidence linking anti-Aβ antibodies to the clinical bioactivity of IVIg has been lacking., Methods: Five-month-old female Dutch APP E693Q mice were treated for 3 months with neat IVIg or with IVIg that had been affinity-depleted over immobilized Aβ conformers in 1 of 2 assembly states. Memory was assessed in a battery of tests followed by quantification of brain soAβ levels using standard anti-soAβ antibodies., Results: We provide evidence that NU4-type soAβ (NU4-soAβ) assemblies accumulate in the brains of Dutch APP E693Q mice and are associated with defects in memory, even in the absence of insoluble Aβ plaques. Memory benefits were associated with depletion from APP E693Q mouse brain of NU4-soAβ and A11-soAβ but not OC-type fibrillar Aβ oligomers., Conclusions: We propose that targeting of specific soAβ assembly subtypes may be an important consideration in the therapeutic and/or prophylactic benefit of anti-Aβ antibody drugs.
- Published
- 2016
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26. Unexpected partial correction of metabolic and behavioral phenotypes of Alzheimer's APP/PSEN1 mice by gene targeting of diabetes/Alzheimer's-related Sorcs1.
- Author
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Knight EM, Ruiz HH, Kim SH, Harte JC, Hsieh W, Glabe C, Klein WL, Attie AD, Buettner C, Ehrlich ME, and Gandy S
- Subjects
- Amino Acids, Branched-Chain blood, Amyloid beta-Peptides blood, Amyloid beta-Protein Precursor genetics, Animals, Body Composition genetics, Diabetes Mellitus, Type 2 etiology, Diabetes Mellitus, Type 2 genetics, Diet, High-Fat adverse effects, Disease Models, Animal, Exploratory Behavior physiology, Female, Glucose Tolerance Test, Humans, Insulin blood, Insulin Resistance, Lipids blood, Male, Maze Learning physiology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation genetics, Phenotype, Presenilin-1 genetics, Receptors, Cell Surface genetics, Sex Factors, Alzheimer Disease complications, Alzheimer Disease genetics, Diabetes Mellitus, Type 2 physiopathology, Receptors, Cell Surface deficiency
- Abstract
Introduction: Insulin resistance and type 2 diabetes mellitus (T2D) are associated with increased risk for cognitive impairment, Alzheimer's disease (AD) and vascular dementia. SORCS1 encodes a protein-sorting molecule genetically linked to both T2D and AD. The association of SORCS1 with both AD and T2D is sexually dimorphic in humans, with both disease associations showing more robust effects in females. Based on published evidence that manipulation of the mouse genome combining multiple genes related to cerebral amyloidosis, to T2D, or both, might provide novel mouse models with exacerbated amyloid and/or diabetes phenotypes, we assessed memory, glucose homeostasis, and brain biochemistry and pathology in male and female wild-type, Sorcs1 -/-, APP/PSEN1, and Sorcs1 -/- X APP/PSEN1 mice., Results: Male mice with either the APP/PSEN1 or Sorcs1 -/- genotype displayed earlier onset and persistent impairment in both learning behavior and glucose homeostasis. Unlike prior examples in the literature, the behavioral and metabolic abnormalities in male mice were not significantly exacerbated when the two disease model mice (Sorcs1 -/- models T2D; APP/PSEN1 models AD) were crossed. However, female Sorcs1 -/- X APP/PSEN1 mice exhibited worse metabolic dysfunction than Sorcs1 -/- knockout mice and worse memory than wild-type mice. The deletion of Sorcs1 from APP/PSEN1 mutant mice led to no obvious changes in brain levels of total or oligomeric amyloid-beta (Aβ) peptide., Conclusions: In general, unexpectedly, there was a trend for gene targeting of Sorcs1-/- to partially mitigate, not exacerbate, the metabolic and amyloid pathologies. These results indicate that crossing AD model mice and T2D model mice may not always cause exacerbation of both the amyloidosis phenotype and the metabolic phenotype and highlight the unexpected pitfalls of creating mixed models of disease.
- Published
- 2016
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27. Electrographic status epilepticus in sleep in an adult with cerebral folate deficiency.
- Author
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Thome U, Klima P, Moosa AN, Gupta A, Parikh S, and Pestana Knight EM
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- 2016
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28. Pre-operative evaluation in pediatric patients with cortical dysplasia.
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Pestana Knight EM, Gonzalez-Martinez J, and Gupta A
- Subjects
- Humans, Infant, Male, Malformations of Cortical Development surgery, Malformations of Cortical Development diagnosis, Pediatrics, Preoperative Care
- Abstract
Introduction: Focal cortical dysplasia (FCD) is an important cause of refractory seizures and catastrophic epilepsy in infants and children who had epilepsy surgery., Aims of the Review: This manuscript will discuss age-related unique clinical characteristics in evaluation of infants and young children because the understanding of these age-related features is critical in selecting children who can benefit from epilepsy surgery. In addition, we will review the non-invasive tools available for the presurgical evaluation of children with FCD and their individual contribution to the formulation of the presurgical hypothesis.
- Published
- 2015
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29. WAVEFORM WINDOW #32: 14 and 6 Hz Positive Spikes: A Normal Variant that Could be Mistaken as Epileptiform.
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Eber C, de Bruyn G, and Knight EM
- Subjects
- Adolescent, Humans, Middle Aged, Brain physiology, Electroencephalography classification
- Published
- 2015
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30. In response: Epilepsy surgery trends in the U.S.-Differences between kids and adults.
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Pestana Knight EM, Schiltz NK, Bakaki PM, Koroukian SM, Lhatoo SD, and Kaiboriboon K
- Subjects
- Female, Humans, Male, Epilepsy surgery, Neurosurgical Procedures
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- 2015
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31. Paroxysmal non-epileptic events in infants and toddlers: A phenomenologic analysis.
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Chen L, Knight EM, Tuxhorn I, Shahid A, and Lüders HO
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- Child, Preschool, Cohort Studies, Diagnosis, Differential, Electroencephalography, Female, Humans, Infant, Infant, Newborn, Male, Retrospective Studies, Video Recording, Arousal, Epilepsy diagnosis, Infant Behavior, Masturbation diagnosis, Nocturnal Myoclonus Syndrome diagnosis
- Abstract
Aim: The aim of this study was to analyze in detail the clinical phenomenology of paroxysmal non-epileptic events (PNEE) in infants and toddlers., Methods: We studied all children aged ≤2 years who were diagnosed with PNEE based on video-electroencephalographic (VEEG) recordings. We analyzed the following four clinical domains of each clinical event: (i) motor manifestations (body/limb jerking, complex motor, and asymmetric limb posturing); (ii) oral/vocal (crying, vocalization, sighing); (iii) behavioral change (arrest of activity, staring); (iv) and autonomic (facial flushing, breath holding)., Results: Thirty-one of 81 (38.3%) infants and toddlers had 38 PNEE recorded during the study period (12 girls and 19 boys, mean age 10.5 months). The predominant clinical features were as follows: motor in 26/38 events, oral/verbal in 14/38 events, behavioral in 11/38 events, and autonomic in 8/38 events. Epileptic seizures and PNEE coexisted in four children (12.9%). Seventeen children (54.8%) had one or more risk factors suggestive of epilepsy. Twelve children (38.7%) had a normal neurologic examination, 10 (32.3%) had developmental delay, and eight (25.8%) had a family history of epilepsy or seizures., Conclusion: VEEG recorded PNEE in nearly 40% of 81 infants and toddlers referred for unclear paroxysmal events in our cohort. Non-epileptic staring spells and benign sleep myoclonus were the most common events recorded, followed by shuddering attacks and infantile masturbation. In addition, greater than one-half of the infants and toddlers had risk factors, raising a concern for epilepsy in the family and prompting the VEEG evaluation, suggesting that paroxysmal non-epileptic seizures may frequently coexist in young children with epilepsy., (© 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.)
- Published
- 2015
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32. Increasing utilization of pediatric epilepsy surgery in the United States between 1997 and 2009.
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Pestana Knight EM, Schiltz NK, Bakaki PM, Koroukian SM, Lhatoo SD, and Kaiboriboon K
- Subjects
- Adolescent, Age Distribution, Child, Child, Preschool, Cross-Sectional Studies, Databases, Factual statistics & numerical data, Epilepsy epidemiology, Female, Humans, Incidence, Infant, Infant, Newborn, Male, Prevalence, Retrospective Studies, United States epidemiology, Epilepsy surgery, Neurosurgical Procedures methods, Neurosurgical Procedures statistics & numerical data, Neurosurgical Procedures trends
- Abstract
Objective: To examine national trends of pediatric epilepsy surgery usage in the United States between 1997 and 2009., Methods: We performed a serial cross-sectional study of pediatric epilepsy surgery using triennial data from the Kids' Inpatient Database from 1997 to 2009. The rates of epilepsy surgery for lobectomies, partial lobectomies, and hemispherectomies in each study year were calculated based on the number of prevalent epilepsy cases in the corresponding year. The age-race-sex adjusted rates of surgeries were also estimated. Mann-Kendall trend test was used to test for changes in the rates of surgeries over time. Multivariable regression analysis was also performed to estimate the effect of time, age, race, and sex on the annual incidence of epilepsy surgery., Results: The rates of pediatric epilepsy surgery increased significantly from 0.85 epilepsy surgeries per 1,000 children with epilepsy in 1997 to 1.44 epilepsy surgeries per 1,000 children with epilepsy in 2009. An increment in the rates of epilepsy surgeries was noted across all age groups, in boys and girls, all races, and all payer types. The rate of increase was lowest in blacks and in children with public insurance. The overall number of surgical cases for each study year was lower than 35% of children who were expected to have surgery, based on the estimates from the Connecticut Study of Epilepsy., Significance: In contrast to adults, pediatric epilepsy surgery numbers have increased significantly in the past decade. However, epilepsy surgery remains an underutilized treatment for children with epilepsy. In addition, black children and those with public insurance continue to face disparities in the receipt of epilepsy surgery., (Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.)
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- 2015
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33. Evidence that small molecule enhancement of β-hexosaminidase activity corrects the behavioral phenotype in Dutch APP(E693Q) mice through reduction of ganglioside-bound Aβ.
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Knight EM, Williams HN, Stevens AC, Kim SH, Kottwitz JC, Morant AD, Steele JW, Klein WL, Yanagisawa K, Boyd RE, Lockhart DJ, Sjoberg ER, Ehrlich ME, Wustman BA, and Gandy S
- Subjects
- Alzheimer Disease genetics, Animals, Blood-Testis Barrier drug effects, Cells, Cultured, Disease Models, Animal, Dose-Response Relationship, Drug, Fibroblasts drug effects, Fibroblasts metabolism, Gangliosides therapeutic use, Humans, Maze Learning drug effects, Mice, Mice, Inbred C57BL, Mutation genetics, Recognition, Psychology drug effects, Time Factors, Alzheimer Disease complications, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor genetics, Antipsychotic Agents therapeutic use, Cognition Disorders drug therapy, Cognition Disorders etiology, Cognition Disorders metabolism, Gangliosides metabolism, beta-N-Acetylhexosaminidases metabolism
- Abstract
Certain mutant Alzheimer's amyloid-β (Aβ) peptides (that is, Dutch mutant APP(E693Q)) form complexes with gangliosides (GAβ). These mutant Aβ peptides may also undergo accelerated aggregation and accumulation upon exposure to GM2 and GM3. We hypothesized that increasing β-hexosaminidase (β-hex) activity would lead to a reduction in GM2 levels, which in turn, would cause a reduction in Aβ aggregation and accumulation. The small molecule OT1001 is a β-hex-targeted pharmacological chaperone with good bioavailability, blood-brain barrier penetration, high selectivity for β-hex and low cytotoxicity. Dutch APP(E693Q) transgenic mice accumulate oligomeric Aβ as they age, as well as Aβ oligomer-dose-dependent anxiety and impaired novel object recognition (NOR). Treatment of Dutch APP(E693Q) mice with OT1001 caused a dose-dependent increase in brain β-hex levels up to threefold over those observed at baseline. OT1001 treatment was associated with reduced anxiety, improved learning behavior in the NOR task and dramatically reduced GAβ accumulation in the subiculum and perirhinal cortex, both of which are brain regions required for normal NOR. Pharmacological chaperones that increase β-hex activity may be useful in reducing accumulation of certain mutant species of Aβ and in preventing the associated behavioral pathology., Competing Interests: Within the past 5 years, SG has held research grants from Baxter Pharmaceuticals and Amicus Therapeutics. SG is also a member of the Data and Safety Monitoring Board for the Pfizer-Janssen Alzheimer's Immunotherapy Alliance. BAW, ACS, DJL, JWS and ERS are employees or shareholders of OrPhi Therapeutics. HNW and REB are employees and shareholders of Amicus Therapeutics.
- Published
- 2015
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34. High-fat diet-induced memory impairment in triple-transgenic Alzheimer's disease (3xTgAD) mice is independent of changes in amyloid and tau pathology.
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Knight EM, Martins IV, Gümüsgöz S, Allan SM, and Lawrence CB
- Subjects
- Adipose Tissue metabolism, Alzheimer Disease metabolism, Alzheimer Disease pathology, Amyloid beta-Peptides metabolism, Animals, Cognition, Disease Models, Animal, Epididymis metabolism, Male, Mice, Mice, Transgenic, Risk, tau Proteins metabolism, Alzheimer Disease etiology, Alzheimer Disease psychology, Brain metabolism, Brain pathology, Diet, High-Fat adverse effects, Memory
- Abstract
Obesity and consumption of a high-fat diet are known to increase the risk of Alzheimer's disease (AD). Diets high in fat also increase disease neuropathology and/or cognitive deficits in AD mouse models. However, the effect of a high-fat diet on both the neuropathology and memory impairments in the triple-transgenic mouse model of AD (3xTgAD) is unknown. Therefore, groups of 2-month-old male 3xTgAD and control (non-Tg) mice were maintained on a high-fat or control diet and memory was assessed at the age of 3-4, 7-8, 11-12, and 15-16 months using a series of behavioral tests. A comparable increase in body weight was observed in non-Tg and 3xTgAD mice after high-fat feeding at all ages tested but a significantly greater increase in epididymal adipose tissue was observed in 3xTgAD mice at the age of 7-8, 11-12, and 15-16 months. A high-fat diet caused memory impairments in non-Tg control mice as early as the age of 3-4 months. In 3xTgAD mice, high-fat consumption led to a reduction in the age of onset and an increase in the extent of memory impairments. Some of these effects of high-fat diet on cognition in non-Tg and 3xTgAD mice were transient, and the age at which cognitive impairment was detected depended on the behavioral test. The effect of high-fat diet on memory in the 3xTgAD mice was independent of changes in AD neuropathology as no significant differences in (plaques, oligomers) or tau neuropathology were observed. An acute increase in microglial activation was seen in high-fat fed 3xTgAD mice at the age of 3-4 months but in non-Tg control mice microglial activation was not observed until the age of 15-16 months. These data indicate therefore that a high-fat diet has rapid and long-lasting negative effects on memory in both control and AD mice that are associated with neuroinflammation, but independent of changes in beta amyloid and tau neuropathology in the AD mice., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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35. Immunomodulation and AD--down but not out.
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Knight EM and Gandy S
- Subjects
- Aged, Alzheimer Disease genetics, Alzheimer Disease immunology, Amyloid beta-Peptides genetics, Amyloid beta-Peptides immunology, Animals, Apolipoprotein E4 genetics, Clinical Trials as Topic, Cognition drug effects, Disease Models, Animal, Humans, Immunomodulation, Mice, Proteolysis drug effects, Alzheimer Disease therapy, Alzheimer Vaccines, Amyloid beta-Peptides metabolism, Antibodies, Monoclonal therapeutic use, Immunoglobulins, Intravenous therapeutic use
- Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia in the elderly. Interventions that remove existing fibrillar and oligomeric amyloid-β (Aβ) are believed to be essential for the success of any attempt at stabilization of brain function and mitigation of cognitive decline. Many of these strategies have focused on Aβ vaccination and administration of anti-Aβ antibodies. Both active and passive immunotherapies have been successful in mouse models, but both have had limited effect in clinical trials. Intravenous immunoglobulin (IVIG) has been proposed as a potential treatment for AD following evidence for behavioral benefit in AD models and cognitive benefit in early phase 1 and phase 2 clinical trials. A phase 3 trial IVIG trial failed to meet its primary outcomes. While there was a statistically significant benefit in moderate stage AD patients who carried an APOE ε4 allele, this stabilization of cognition was evident only on neuropsychological examination. No benefit on activities of daily living was evident, therefore failing to qualify AD as a new indication for IVIG. Identifying the biologically active component (s) responsible for the neuropsychological benefit in APOE ε4-positive AD patients could enable the development of a compound with greater potency that would qualify for FDA (US Food and Drug Administration) registration.
- Published
- 2014
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36. Genome-scale reconstruction of the sigma factor network in Escherichia coli: topology and functional states.
- Author
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Cho BK, Kim D, Knight EM, Zengler K, and Palsson BO
- Subjects
- DNA-Directed RNA Polymerases metabolism, Databases, Genetic, Holoenzymes metabolism, Promoter Regions, Genetic, Protein Binding, Regulon genetics, Transcription Initiation Site, Transcription, Genetic, Escherichia coli genetics, Gene Regulatory Networks, Genome, Bacterial genetics, Sigma Factor chemistry, Sigma Factor metabolism
- Abstract
Background: At the beginning of the transcription process, the RNA polymerase (RNAP) core enzyme requires a σ-factor to recognize the genomic location at which the process initiates. Although the crucial role of σ-factors has long been appreciated and characterized for many individual promoters, we do not yet have a genome-scale assessment of their function., Results: Using multiple genome-scale measurements, we elucidated the network of σ-factor and promoter interactions in Escherichia coli. The reconstructed network includes 4,724 σ-factor-specific promoters corresponding to transcription units (TUs), representing an increase of more than 300% over what has been previously reported. The reconstructed network was used to investigate competition between alternative σ-factors (the σ70 and σ38 regulons), confirming the competition model of σ substitution and negative regulation by alternative σ-factors. Comparison with σ-factor binding in Klebsiella pneumoniae showed that transcriptional regulation of conserved genes in closely related species is unexpectedly divergent., Conclusions: The reconstructed network reveals the regulatory complexity of the promoter architecture in prokaryotic genomes, and opens a path to the direct determination of the systems biology of their transcriptional regulatory networks.
- Published
- 2014
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37. Reduction of synaptojanin 1 accelerates Aβ clearance and attenuates cognitive deterioration in an Alzheimer mouse model.
- Author
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Zhu L, Zhong M, Zhao J, Rhee H, Caesar I, Knight EM, Volpicelli-Daley L, Bustos V, Netzer W, Liu L, Lucast L, Ehrlich ME, Robakis NK, Gandy SE, and Cai D
- Subjects
- Alzheimer Disease genetics, Alzheimer Disease pathology, Amyloid Precursor Protein Secretases genetics, Amyloid Precursor Protein Secretases metabolism, Amyloid beta-Peptides genetics, Animals, Cell Line, Tumor, Disease Models, Animal, Down-Regulation genetics, Gene Knockdown Techniques, Hippocampus pathology, Humans, Lysosomes genetics, Lysosomes metabolism, Mice, Mice, Transgenic, Mutation, Peptide Fragments genetics, Phosphatidylinositol 4,5-Diphosphate genetics, Phosphoric Monoester Hydrolases genetics, Presenilin-1 genetics, Presenilin-1 metabolism, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Hippocampus metabolism, Peptide Fragments metabolism, Phosphatidylinositol 4,5-Diphosphate metabolism, Phosphoric Monoester Hydrolases biosynthesis
- Abstract
Recent studies link synaptojanin 1 (synj1), the main phosphoinositol (4,5)-biphosphate phosphatase (PI(4,5)P2-degrading enzyme) in the brain and synapses, to Alzheimer disease. Here we report a novel mechanism by which synj1 reversely regulates cellular clearance of amyloid-β (Aβ). Genetic down-regulation of synj1 reduces both extracellular and intracellular Aβ levels in N2a cells stably expressing the Swedish mutant of amyloid precursor protein (APP). Moreover, synj1 haploinsufficiency in an Alzheimer disease transgenic mouse model expressing the Swedish mutant APP and the presenilin-1 mutant ΔE9 reduces amyloid plaque load, as well as Aβ40 and Aβ42 levels in hippocampus of 9-month-old animals. Reduced expression of synj1 attenuates cognitive deficits in these transgenic mice. However, reduction of synj1 does not affect levels of full-length APP and the C-terminal fragment, suggesting that Aβ generation by β- and γ-secretase cleavage is not affected. Instead, synj1 knockdown increases Aβ uptake and cellular degradation through accelerated delivery to lysosomes. These effects are partially dependent upon elevated PI(4,5)P2 with synj1 down-regulation. In summary, our data suggest a novel mechanism by which reduction of a PI(4,5)P2-degrading enzyme, synj1, improves amyloid-induced neuropathology and behavior deficits through accelerating cellular Aβ clearance.
- Published
- 2013
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38. Age-related changes in core body temperature and activity in triple-transgenic Alzheimer's disease (3xTgAD) mice.
- Author
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Knight EM, Brown TM, Gümüsgöz S, Smith JC, Waters EJ, Allan SM, and Lawrence CB
- Subjects
- Aging physiology, Alzheimer Disease pathology, Alzheimer Disease psychology, Amyloid beta-Protein Precursor genetics, Animals, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Brain pathology, Brain physiopathology, Circadian Rhythm physiology, Disease Models, Animal, Eating physiology, Humans, Hypothalamus pathology, Hypothalamus physiopathology, Ibuprofen pharmacology, Male, Maze Learning drug effects, Maze Learning physiology, Memory drug effects, Memory physiology, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Transgenic, Neurofibrillary Tangles pathology, Presenilin-1 genetics, tau Proteins genetics, tau Proteins metabolism, Alzheimer Disease genetics, Alzheimer Disease physiopathology, Body Temperature physiology, Motor Activity physiology
- Abstract
Alzheimer's disease (AD) is characterised, not only by cognitive deficits and neuropathological changes, but also by several non-cognitive behavioural symptoms that can lead to a poorer quality of life. Circadian disturbances in core body temperature and physical activity are reported in AD patients, although the cause and consequences of these changes are unknown. We therefore characterised circadian patterns of body temperature and activity in male triple transgenic AD mice (3xTgAD) and non-transgenic (Non-Tg) control mice by remote radiotelemetry. At 4 months of age, daily temperature rhythms were phase advanced and by 6 months of age an increase in mean core body temperature and amplitude of temperature rhythms were observed in 3xTgAD mice. No differences in daily activity rhythms were seen in 4- to 9-month-old 3xTgAD mice, but by 10 months of age an increase in mean daily activity and the amplitude of activity profiles for 3xTgAD mice were detected. At all ages (4-10 months), 3xTgAD mice exhibited greater food intake compared with Non-Tg mice. The changes in temperature did not appear to be solely due to increased food intake and were not cyclooxygenase dependent because the temperature rise was not abolished by chronic ibuprofen treatment. No β-amyloid (Aβ) plaques or neurofibrillary tangles were noted in the hypothalamus of 3xTgAD mice, a key area involved in temperature regulation, although these pathological features were observed in the hippocampus and amygdala of 3xTgAD mice from 10 months of age. These data demonstrate age-dependent changes in core body temperature and activity in 3xTgAD mice that are present before significant AD-related neuropathology and are analogous to those observed in AD patients. The 3xTgAD mouse might therefore be an appropriate model for studying the underlying mechanisms involved in non-cognitive behavioural changes in AD.
- Published
- 2013
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39. Rapid doubling of Alzheimer's amyloid-β40 and 42 levels in brains of mice exposed to a nickel nanoparticle model of air pollution.
- Author
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Kim SH, Knight EM, Saunders EL, Cuevas AK, Popovech M, Chen LC, and Gandy S
- Abstract
Background: Over 20 genetic risk factors have been confirmed to associate with elevated risk for Alzheimer's disease (AD), but the identification of environmental and/or acquired risk factors has been more elusive. At present, recognized acquired risks for AD include traumatic brain injury, hypercholesterolemia, obesity, hypertension, and type 2 diabetes., Methods: Based on reports associating various inhalants with AD pathology, we investigated the possibility that air pollution might contribute to AD risk by exposing wild-type mice to a standard air pollution modeling system employing nickel nanoparticle-enriched atmosphere for 3 hr., Results: Mice exposed to air pollution showed 72-129% increases in brain levels of both amyloid-β peptides Aβ40 and Aβ42, as well as Aβ42/40 (p <0.01)., Conclusions: These effects on elevation of brain Aβ exceed those associated with trisomy 21, a known risk for early onset AD pathology, raising the possibility that clinical importance might be attached. Further work is required to establish the molecular and physiological basis for these phenomena. The rapid, dramatic effect, if verified, would suggest that inhalant exposures should be evaluated for their possible roles in contributing to the environmental risk for common forms of AD.
- Published
- 2012
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40. Obese mice exhibit an altered behavioural and inflammatory response to lipopolysaccharide.
- Author
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Lawrence CB, Brough D, and Knight EM
- Subjects
- Animals, Body Temperature drug effects, Body Weight drug effects, Brain drug effects, Brain metabolism, Cells, Cultured, Cytokines blood, Cytokines metabolism, Diet, High-Fat, Feeding Behavior drug effects, Injections, Intraperitoneal, Lipopolysaccharides administration & dosage, Liver drug effects, Liver metabolism, Macrophages, Peritoneal drug effects, Macrophages, Peritoneal metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Obese, Proto-Oncogene Proteins c-fos metabolism, Spleen drug effects, Spleen metabolism, Behavior, Animal drug effects, Inflammation complications, Inflammation pathology, Lipopolysaccharides pharmacology, Obesity complications, Obesity pathology
- Abstract
Obesity is associated with an increase in the prevalence and severity of infections. Genetic animal models of obesity (ob/ob and db/db mice) display altered centrally-mediated sickness behaviour in response to acute inflammatory stimuli such as lipopolysaccharide (LPS). However, the effect of diet-induced obesity (DIO) on the anorectic and febrile response to LPS in mice is unknown. This study therefore determined how DIO and ob/ob mice respond to a systemic inflammatory challenge. C57BL/6 DIO and ob/ob mice, and their respective controls, were given an intraperitoneal (i.p.) injection of LPS. Compared with controls, DIO and ob/ob mice exhibited an altered febrile response to LPS (100 μg/kg) over 8 hours. LPS caused a greater and more prolonged anorexic effect in DIO compared with control mice and, in ob/ob mice, LPS induced a reduction in food intake and body weight earlier than it did in controls. These effects of LPS in obese mice were also seen after a fixed dose of LPS (5 μg). LPS (100 μg/kg) induced Fos protein expression in several brain nuclei of control mice, with fewer Fos-positive cells observed in the brains of obese mice. An altered inflammatory response to LPS was also observed in obese mice compared with controls: changes in cytokine expression and release were detected in the plasma, spleen, liver and peritoneal macrophages in obese mice. In summary, DIO and ob/ob mice displayed an altered behavioural response and cytokine release to systemic inflammatory challenge. These findings could help explain why obese humans show increased sensitivity to infections.
- Published
- 2012
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41. Gaucher disease: successful treatment of myoclonic status epilepticus with levetiracetam.
- Author
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Vaca GF, Lenz T, Knight EM, and Tuxhorn I
- Subjects
- Adolescent, Electroencephalography, Epilepsies, Myoclonic etiology, Epilepsies, Myoclonic psychology, Gaucher Disease complications, Humans, Levetiracetam, Male, Piracetam therapeutic use, Status Epilepticus etiology, Status Epilepticus psychology, Anticonvulsants therapeutic use, Epilepsies, Myoclonic drug therapy, Gaucher Disease drug therapy, Piracetam analogs & derivatives, Status Epilepticus drug therapy
- Abstract
We present the first reported case of a rapid clinical and electroencephalographic response to intravenous levetiracetam infusion of myoclonic status epilepticus in a patient with progressive myoclonus epilepsy due to Gaucher disease. Under continuous video-EEG monitoring, the clinical myoclonic status and the electrographic ictal discharges resolved within 10 minutes after the infusion was initiated. The patient tolerated the treatment well without any reported side effects. This case suggests that levetiracetam may be a safe, effective, and well tolerated intravenous drug in patients with metabolic myoclonic status epilepticus such as Gaucher disease.
- Published
- 2012
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42. Detailing the optimality of photosynthesis in cyanobacteria through systems biology analysis.
- Author
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Nogales J, Gudmundsson S, Knight EM, Palsson BO, and Thiele I
- Subjects
- Photosynthesis, Synechocystis physiology, Systems Biology
- Abstract
Photosynthesis has recently gained considerable attention for its potential role in the development of renewable energy sources. Optimizing photosynthetic organisms for biomass or biofuel production will therefore require a systems understanding of photosynthetic processes. We reconstructed a high-quality genome-scale metabolic network for Synechocystis sp. PCC6803 that describes key photosynthetic processes in mechanistic detail. We performed an exhaustive in silico analysis of the reconstructed photosynthetic process under different light and inorganic carbon (Ci) conditions as well as under genetic perturbations. Our key results include the following. (i) We identified two main states of the photosynthetic apparatus: a Ci-limited state and a light-limited state. (ii) We discovered nine alternative electron flow pathways that assist the photosynthetic linear electron flow in optimizing the photosynthesis performance. (iii) A high degree of cooperativity between alternative pathways was found to be critical for optimal autotrophic metabolism. Although pathways with high photosynthetic yield exist for optimizing growth under suboptimal light conditions, pathways with low photosynthetic yield guarantee optimal growth under excessive light or Ci limitation. (iv) Photorespiration was found to be essential for the optimal photosynthetic process, clarifying its role in high-light acclimation. Finally, (v) an extremely high photosynthetic robustness drives the optimal autotrophic metabolism at the expense of metabolic versatility and robustness. The results and modeling approach presented here may promote a better understanding of the photosynthetic process. They can also guide bioengineering projects toward optimal biofuel production in photosynthetic organisms.
- Published
- 2012
- Full Text
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43. Hypermetabolism in a triple-transgenic mouse model of Alzheimer's disease.
- Author
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Knight EM, Verkhratsky A, Luckman SM, Allan SM, and Lawrence CB
- Subjects
- Aging metabolism, Animals, Body Weight, Carbon Dioxide metabolism, Disease Models, Animal, Eating, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Oxygen Consumption, Weight Loss, Alzheimer Disease metabolism, Energy Intake, Energy Metabolism
- Abstract
A common feature of Alzheimer's disease (AD) is weight loss, even though there is often an increase in food intake in AD patients. The reasons for this weight loss are unknown, but may be due to increased energy expenditure (metabolic rate) or a reduction in energy intake. This was investigated in the present study, using a triple-transgenic (3xTgAD) mouse model of AD. Two-month-old 3xTgAD mice displayed greater food intake (17%) and body weight (34%) but no difference in metabolic rate, as compared with nontransgenic controls (non-Tg). At 12 months of age, 3xTgAD mice still consumed more food (30%), but their body weight was significantly lower (15%) than non-Tg controls. This reduction in body weight was accompanied by a significant rise in metabolic rate, indicated by greater oxygen consumption (24%) and carbon dioxide production (29%); the effects were also observed in 18-month-old 3xTgAD mice. These data demonstrate for the first time the existence of a hypermetabolic state in an experimental model of AD, but whether this can explain the weight loss observed in AD patients remains to be determined., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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44. Outcome of no resection after long-term subdural electroencephalography evaluation in children with epilepsy.
- Author
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Pestana Knight EM, Loddenkemper T, Lachhwani D, Kotagal P, Wyllie E, Bingaman W, and Gupta A
- Subjects
- Child, Child, Preschool, Female, Follow-Up Studies, Humans, Infant, Male, Paralysis etiology, Patient Selection, Postoperative Complications etiology, Retrospective Studies, Subdural Space, Time, Treatment Outcome, Electrodes, Implanted, Electroencephalography instrumentation, Electroencephalography methods, Epilepsy diagnosis, Epilepsy surgery
- Abstract
Object: The aim of this study was to identify the reasons for and predictors of no resection of the epileptogenic zone in children with epilepsy who had undergone long-term invasive subdural grid electroencephalography (SDG-EEG) evaluation., Methods: The authors retrospectively reviewed the consecutive medical records of children (< 19 years of age) who had undergone SDG-EEG evaluation over a 7-year period (1997-2004). To determine the predictors of no resection, the authors obtained the clinical characteristics and imaging and EEG findings of children who had no resection after long-term invasive SDG-EEG evaluation and compared these data with those in a group of children who did undergo resection. They describe the indications for SDG-EEG evaluation and the reasons for no resection in these patients., Results: Of 66 children who underwent SDG-EEG evaluation, 9 (13.6%) did not undergo subsequent resection (no-resection group; 6 males). Of these 9 patients, 6 (66.7%) had normal neurological examinations and 5 (55.6%) had normal findings on brain MR imaging. Scalp video EEG localized epilepsy to the left hemisphere in 6 of the 9 patients and to the right hemisphere in 2; it was nonlocalizable in 1 of the 9 patients. Indications for SDG-EEG in the no-resection group were ictal onset zone (IOZ) localization (9 of 9 patients), motor cortex localization (5 of 9 patients), and language area localization (4 of 9 patients). Reasons for no resection after SDG-EEG evaluation were the lack of a well-defined IOZ in 5 of 9 patients (4 multifocal IOZs and 1 nonlocalizable IOZ) and anticipated new permanent postoperative neurological deficits in 7 of 9 patients (3 motor, 2 language, and 2 motor and language deficits). Comparison with the resection group (57 patients) demonstrated that postictal Todd paralysis in the dominant hand was the only variable seen more commonly (χ(2) = 4.781, p = 0.029) in the no-resection group (2 [22.2%] of 9 vs 2 [3.5%] of 57 patients). The no-resection group had a larger number of SDG electrode contacts (mean 126. 5 ± 26.98) as compared with the resection group (100.56 ± 25.52; p = 0.010). There were no significant differences in the demographic data, seizure characteristics, scalp and invasive EEG findings, and imaging variables between the resection and no-resection groups., Conclusions: Children who did not undergo resection of the epileptogenic zone after SDG-EEG evaluation were likely to have normal neurological examinations without preexisting neurological deficits, a high probability of a new unacceptable permanent neurological deficit following resection, or multifocal or nonlocalizable IOZs. In comparison with the group that underwent resection after SDG-EEG, a history of Todd paralysis in the dominant hand and arm was the only predictor of no resection following SDG-EEG evaluation. Data in this study will help to better select pediatric patients for SDG-EEG and to counsel families prior to epilepsy surgery.
- Published
- 2011
- Full Text
- View/download PDF
45. RNA polymerase mutants found through adaptive evolution reprogram Escherichia coli for optimal growth in minimal media.
- Author
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Conrad TM, Frazier M, Joyce AR, Cho BK, Knight EM, Lewis NE, Landick R, and Palsson BØ
- Subjects
- Base Sequence, Chromatin Immunoprecipitation, Culture Media chemistry, DNA Primers genetics, Gene Expression Profiling, Gene Knockout Techniques, Kinetics, Molecular Sequence Data, Mutagenesis, Site-Directed, Protein Array Analysis, Sequence Analysis, DNA, Sequence Deletion genetics, Transcription, Genetic physiology, Adaptation, Physiological genetics, DNA-Directed RNA Polymerases genetics, Escherichia coli enzymology, Escherichia coli growth & development, Escherichia coli Proteins genetics, Evolution, Molecular
- Abstract
Specific small deletions within the rpoC gene encoding the β'-subunit of RNA polymerase (RNAP) are found repeatedly after adaptation of Escherichia coli K-12 MG1655 to growth in minimal media. Here we present a multiscale analysis of these mutations. At the physiological level, the mutants grow 60% faster than the parent strain and convert the carbon source 15-35% more efficiently to biomass, but grow about 30% slower than the parent strain in rich medium. At the molecular level, the kinetic parameters of the mutated RNAP were found to be altered, resulting in a 4- to 30-fold decrease in open complex longevity at an rRNA promoter and a ∼10-fold decrease in transcriptional pausing, with consequent increase in transcript elongation rate. At a genome-scale, systems biology level, gene expression changes between the parent strain and adapted RNAP mutants reveal large-scale systematic transcriptional changes that influence specific cellular processes, including strong down-regulation of motility, acid resistance, fimbria, and curlin genes. RNAP genome-binding maps reveal redistribution of RNAP that may facilitate relief of a metabolic bottleneck to growth. These findings suggest that reprogramming the kinetic parameters of RNAP through specific mutations allows regulatory adaptation for optimal growth in new environments.
- Published
- 2010
- Full Text
- View/download PDF
46. Genetic basis of growth adaptation of Escherichia coli after deletion of pgi, a major metabolic gene.
- Author
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Charusanti P, Conrad TM, Knight EM, Venkataraman K, Fong NL, Xie B, Gao Y, and Palsson BØ
- Subjects
- Acetates metabolism, Bacterial Proteins genetics, Clone Cells, Epistasis, Genetic, Escherichia coli enzymology, Gene Knock-In Techniques, Glucose metabolism, Prophages metabolism, Sequence Analysis, DNA, Sigma Factor genetics, Adaptation, Physiological genetics, Escherichia coli genetics, Escherichia coli growth & development, Escherichia coli Proteins genetics, Gene Deletion, Genes, Bacterial genetics, Glucose-6-Phosphate Isomerase genetics, Metabolic Networks and Pathways genetics
- Abstract
Bacterial survival requires adaptation to different environmental perturbations such as exposure to antibiotics, changes in temperature or oxygen levels, DNA damage, and alternative nutrient sources. During adaptation, bacteria often develop beneficial mutations that confer increased fitness in the new environment. Adaptation to the loss of a major non-essential gene product that cripples growth, however, has not been studied at the whole-genome level. We investigated the ability of Escherichia coli K-12 MG1655 to overcome the loss of phosphoglucose isomerase (pgi) by adaptively evolving ten replicates of E. coli lacking pgi for 50 days in glucose M9 minimal medium and by characterizing endpoint clones through whole-genome re-sequencing and phenotype profiling. We found that 1) the growth rates for all ten endpoint clones increased approximately 3-fold over the 50-day period; 2) two to five mutations arose during adaptation, most frequently in the NADH/NADPH transhydrogenases udhA and pntAB and in the stress-associated sigma factor rpoS; and 3) despite similar growth rates, at least three distinct endpoint phenotypes developed as defined by different rates of acetate and formate secretion. These results demonstrate that E. coli can adapt to the loss of a major metabolic gene product with only a handful of mutations and that adaptation can result in multiple, alternative phenotypes., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2010
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47. The transcription unit architecture of the Escherichia coli genome.
- Author
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Cho BK, Zengler K, Qiu Y, Park YS, Knight EM, Barrett CL, Gao Y, and Palsson BØ
- Subjects
- Base Sequence, Binding Sites, DNA-Directed RNA Polymerases metabolism, Gene Expression Profiling, Gene Expression Regulation, Bacterial, High-Throughput Screening Assays, Molecular Sequence Data, Open Reading Frames genetics, Transcription Initiation Site, Escherichia coli genetics, Genome, Bacterial genetics, Transcription, Genetic
- Abstract
Bacterial genomes are organized by structural and functional elements, including promoters, transcription start and termination sites, open reading frames, regulatory noncoding regions, untranslated regions and transcription units. Here, we iteratively integrate high-throughput, genome-wide measurements of RNA polymerase binding locations and mRNA transcript abundance, 5' sequences and translation into proteins to determine the organizational structure of the Escherichia coli K-12 MG1655 genome. Integration of the organizational elements provides an experimentally annotated transcription unit architecture, including alternative transcription start sites, 5' untranslated region, boundaries and open reading frames of each transcription unit. A total of 4,661 transcription units were identified, representing an increase of >530% over current knowledge. This comprehensive transcription unit architecture allows for the elucidation of condition-specific uses of alternative sigma factors at the genome scale. Furthermore, the transcription unit architecture provides a foundation on which to construct genome-scale transcriptional and translational regulatory networks.
- Published
- 2009
- Full Text
- View/download PDF
48. Status epilepticus in Wilson's disease.
- Author
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Pestana Knight EM, Gilman S, and Selwa L
- Subjects
- Brain pathology, Electroencephalography, Functional Laterality, Humans, Liver Cirrhosis complications, Liver Cirrhosis etiology, Liver Cirrhosis physiopathology, Magnetic Resonance Imaging, Male, Middle Aged, Review Literature as Topic, Seizures etiology, Status Epilepticus etiology, Treatment Outcome, Brain physiopathology, Chelating Agents therapeutic use, Hepatolenticular Degeneration complications, Hepatolenticular Degeneration drug therapy, Molybdenum therapeutic use, Seizures physiopathology, Status Epilepticus physiopathology
- Abstract
Rationale: Seizures occur in Wilson's disease (WD), with prevalence figures as high as 4-6% in specialized academic centers, but status epilepticus is rare. We report a patient with WD who developed non-convulsive status epilepticus (SE) during therapy with Tetrathiomolybdate (TTM) and review the last 20 years of the relevant literature., Case Report: A 55 year-old right handed man with WD who had parkinsonian features and hepatic cirrhosis was admitted for seizures. Seizures began on week 4 of treatment with TTM (Phase III Study of Tetrathiomolybdate Dose Regimen in Neurological Wilson's Disease). Seizures were characterized by forced clonic eye, head deviation to the right and right arm posturing followed by unresponsiveness, bilateral eye blinking and right hand automatisms. EEG confirmed frequent left frontal seizures. He developed non-convulsive status epilepticus (NCSE) with electrographic seizures every 5-10 minutes, lasting for 1-2 minutes each. Seizures were controlled within 24 hours with fosphenytoin, midazolam and levetiracetam. Brain MRI showed diffuse atrophy, mineralization of the basal ganglia, and patchy FLAIR increase signal in the left frontal lobe., Literature Review: We found reports of 6 WD patients with SE, two upon presentation of the disease and before copper removing treatment, and four after months to years of treatment with D-penicillamine., Conclusion: SE occurs rarely in WD, and our case is the only one reported to develop SE during treatment with TTM. As the literature documented two patients with WD who developed SE prior to copper deposit treatment, our hypothesis is that seizures in WD can be the result of the progression of the disease or a combination of factors but not necessarily due to its treatment alone.
- Published
- 2009
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49. Gene expression profiling and the use of genome-scale in silico models of Escherichia coli for analysis: providing context for content.
- Author
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Lewis NE, Cho BK, Knight EM, and Palsson BO
- Subjects
- Models, Biological, Escherichia coli genetics, Gene Expression Profiling methods
- Published
- 2009
- Full Text
- View/download PDF
50. Genome-scale reconstruction of the Lrp regulatory network in Escherichia coli.
- Author
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Cho BK, Barrett CL, Knight EM, Park YS, and Palsson BØ
- Subjects
- Escherichia coli metabolism, Escherichia coli Proteins metabolism, Feedback, Physiological, Genomics, Leucine pharmacokinetics, Leucine-Responsive Regulatory Protein metabolism, Nitrogen metabolism, Oligonucleotide Array Sequence Analysis, RNA, Bacterial genetics, Transcription, Genetic, Escherichia coli genetics, Escherichia coli Proteins genetics, Gene Expression Regulation, Bacterial, Gene Regulatory Networks, Genome, Bacterial, Leucine-Responsive Regulatory Protein genetics
- Abstract
Broad-acting transcription factors (TFs) in bacteria form regulons. Here, we present a 4-step method to fully reconstruct the leucine-responsive protein (Lrp) regulon in Escherichia coli K-12 MG 1655 that regulates nitrogen metabolism. Step 1 is composed of obtaining high-resolution ChIP-chip data for Lrp, the RNA polymerase and expression profiles under multiple environmental conditions. We identified 138 unique and reproducible Lrp-binding regions and classified their binding state under different conditions. In the second step, the analysis of these data revealed 6 distinct regulatory modes for individual ORFs. In the third step, we used the functional assignment of the regulated ORFs to reconstruct 4 types of regulatory network motifs around the metabolites that are affected by the corresponding gene products. In the fourth step, we determined how leucine, as a signaling molecule, shifts the regulatory motifs for particular metabolites. The physiological structure that emerges shows the regulatory motifs for different amino acid fall into the traditional classification of amino acid families, thus elucidating the structure and physiological functions of the Lrp-regulon. The same procedure can be applied to other broad-acting TFs, opening the way to full bottom-up reconstruction of the transcriptional regulatory network in bacterial cells.
- Published
- 2008
- Full Text
- View/download PDF
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