104 results on '"Alexander RC"'
Search Results
2. Shaken baby syndrome.
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Alexander RC and Smith WL
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- 1998
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3. Physical and behavioral signs of sexual abuse in infants and toddlers.
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Frasier LD, Barchman V, and Alexander RC
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- 1992
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4. ER records show rise in cocaine use among patients with schizophrenia
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Patkar, AA, Alexander, RC, Lundy, A, and Certa, KM
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Schizophrenics -- Drug use ,Cocaine abuse -- Diagnosis ,Health ,Psychology and mental health ,Diagnosis ,Drug use - Abstract
Cocaine use has increased dramatically among patients with schizophrenia, according to an article published in a recent issue of The American Journal on Addictions. At the same time, amphetamine use [...]
- Published
- 1999
5. Letters to the Editor
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Petrucelli, E, Greenberg, SR, King, AI, Greenberg, SR, Alexander, RC, Sivan, AB, Martin Kaplan, J, Kingston, C, Stoney, DA, Thornton, JI, Lachocki, TM, Church, DF, Pryor, WA, Lowry, WT, Askin, H, Doud, D, Hodgson, BT, Hayward, JS, Fox, GR, Vale, GL, Rawson, RD, Sperber, ND, and Herschaft, EE
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- 1988
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6. To team or not to team: approaches to child abuse.
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Alexander RC
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- 1993
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7. Primary carcinoma of the male urethra
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Alexander Rc
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Male ,medicine.medical_specialty ,business.industry ,Urology ,Carcinoma ,medicine.disease ,Male urethra ,Urethra ,medicine.anatomical_structure ,medicine ,Humans ,business - Published
- 1951
8. QuantiFERON-TB blood testing in the occupational setting.
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Gamsky TE and Alexander RC
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- 2008
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9. A chance to prevent Alzheimer's disease sooner than you think.
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Reiman EM, Cummings JL, Langbaum JB, Mattke S, and Alexander RC
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- Humans, Probability, Alzheimer Disease prevention & control
- Abstract
Competing Interests: EMR declares grants from NIA, Gates Ventures, NOMIS Foundation, Banner Alzheimer's Foundation, and the state of Arizona, and is a PI on some of these grants; co-leads the Alzheimer's Prevention Initiative (API); is co-founder and advisor for ALZPath; is inventor on a patent owned by Banner Health; is a scientific advisor to Alzheon, Aural Analytics, Denali, Retromer Therapeutics, and Vaxxinity; and is an uncompensated advisor to Eli Lilly. JLC declares grants from NIGMS, NINDS, NIA, Alzheimer's Disease Drug Discovery Foundation, Ted and Maria Quirk Endowment, and Joy Chambers-Grundy Endowment; and consultancy to Acadia, Actinogen, Acumen, AlphaCognition, ALZpath, Aprinoia, AriBio, Artery, Biogen, Biohaven, BioVie, BioXcel, Bristol-Myers Squib, Cassava, Cerecin, Diadem, Eisai, GAP Foundation, GemVax, Janssen, Jocasta, Karuna, Lighthouse, Lilly, Lundbeck, LSP/eqt, Merck, NervGen, New Amsterdam, Novo Nordisk, Oligomerix, Optoceutics, Ono, Otsuka, Oxford Brain Diagnostics, Prothena, ReMYND, Roche, Sage Therapeutics, Signant Health, Simcere, sinaptica, Suven, TrueBinding, Vaxxinity, and Wren pharmaceutical, assessment, and investment companies. JBL declares grants from the NIA, NOMIS Foundation, Banner Alzheimer's Foundation, and the state of Arizona; co-leads the API; and has been a consultant to Alector, Biogen, and Denovo Biopharma. SM declares grants from NIA and research contracts to USC from Biogen, C2N, Eisai, Lilly, and Roche/Genentech; is on the board of directors of Senscio Systems; is on the scientific advisory board of AiCure Technologies, ALZPath, and Boston Millennia Partners; and declares speaker and consulting fees from Biogen, C2N, Eisai, Novartis, and Roche/Genentech. RCA is supported by grants from NIA, NOMIS Foundation, and Banner Alzheimer's Foundation; co-leads the API; and is a scientific advisor to Boehringer-Ingelheim, Lundbeck, Novartis, Retromer, Reunion Neuro, Roche, Vigil Neuro, and Cardiff University.
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- 2024
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10. Safety and efficacy of pioglitazone for the delay of cognitive impairment in people at risk of Alzheimer's disease (TOMMORROW): a prognostic biomarker study and a phase 3, randomised, double-blind, placebo-controlled trial.
- Author
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Burns DK, Alexander RC, Welsh-Bohmer KA, Culp M, Chiang C, O'Neil J, Evans RM, Harrigan P, Plassman BL, Burke JR, Wu J, Lutz MW, Haneline S, Schwarz AJ, Schneider LS, Yaffe K, Saunders AM, and Ratti E
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease drug therapy, Alzheimer Disease metabolism, Biomarkers, Pharmacological, Cognitive Dysfunction metabolism, Double-Blind Method, Female, Humans, Male, Pioglitazone metabolism, Prognosis, Risk Factors, Treatment Outcome, Cognitive Dysfunction drug therapy, Pioglitazone therapeutic use, Risk Assessment methods
- Abstract
Background: The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants., Methods: In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65-83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0·8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo (for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0·01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566., Findings: Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3·3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1·0%) of 402 participants at low risk given placebo (hazard ratio 3·26, 99% CI 0·85-12·45; p=0·023). 39 (2·7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3·3%) of 1406 participants at high risk given placebo (hazard ratio 0·80, 99% CI 0·45-1·40; p=0·307). In the safety analysis set, seven (0·5%) of 1531 participants at high risk given pioglitazone died versus 21 (1·4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold., Interpretation: Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies., Funding: Takeda and Zinfandel., Competing Interests: Declaration of interests DKB, CC, SH, and AMS are full-time employees of Zinfandel Pharmaceuticals. AMS has a patent TOMM40 Biomarker Algorithm issued, a patent Low Dose Pioglitazone in mild cognitive impairment issued, and a patent Extended Release Formulation Low Dose Pioglitazone issued. RCA, MC, JO, RME, PH, JW, AJS, and ER were full-time employees of Takeda Pharmaceuticals during study conduct. KAW-B and BLP received funding from Takeda Pharmaceuticals for their work on the project as part of the Neuropsychology Lead Office at Duke University. Outside the submitted work, KAW-B reports personal fees from Biogen and a grant from VeraSci. MWL received consulting fees from Zinfandel Pharmaceuticals. JRB served as a clinical site Principal Investigator and received funding support from Takeda Pharmaceuticals, LSS received personal fees from Takeda Pharmaceuticals during the conduct of the study and served as Chair of the TOMMORROW study Cognitive Impairment Adjudication Committee. Outside of the submitted work, LSS reports grants and personal fees from Eli Lilly, Merck, Roche/Genentech; personal fees from Avraham, Boehringer Ingelheim, Neurim, Neuronix, Cognition, Eisai, Takeda, vTv, Abbott, and Samus; and grants from Biogen, Novartis, Biohaven, and Washington University/ NIA DIAN-TU. KY served as Chair of the Data Safety Monitoring Board and reports personal fees from Alector, Eli Lilly, and the National Institutes for Health outside the submitted work, and serves as a member of the Beeson Scientific Advisory Board and the Global Council on Brain Health., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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11. A 3-way Cross-over Study of Pregabalin, Placebo, and the Histamine 3 Receptor Inverse Agonist AZD5213 in Combination With Pregabalin in Patients With Painful Diabetic Neuropathy and Good Pain-reporting Ability.
- Author
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Alexander RC, Raudibaugh K, Spierings ELH, and Katz N
- Subjects
- Analgesics therapeutic use, Cross-Over Studies, Histamine, Humans, Pain Measurement, Pregabalin therapeutic use, Treatment Outcome, gamma-Aminobutyric Acid therapeutic use, Diabetes Mellitus, Diabetic Neuropathies drug therapy, Neuralgia drug therapy
- Abstract
Objectives: In this study, patients with painful diabetic neuropathy were trained using an experimental pain paradigm in an attempt to enroll a subset of patients who are "pain connoisseurs" and therefore more able to discriminate between active and placebo treatments., Methods: AZD5213, a novel histamine H3 receptor inverse agonist+pregabalin, pregabalin, and placebo were then tested in a 3-period cross-over., Results: The study did not provide any evidence of clinical efficacy for AZD5213 when combined with pregabalin in the treatment of painful diabetic neuropathy., Discussion: The training of study patients in pain reporting and subsequent enrichment with good pain reporters also did not enable the robust detection of the efficacy of pregabalin relative to placebo in a small sample size. Further work is required before recommending the use of "connoisseur" patients in future neuropathic pain studies.
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- 2021
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12. Medical Neglect in Childhood.
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Knox BL, Alexander RC, Luyet FM, and Esernio-Jenssen DD
- Abstract
This introduction provides an overview to the special issues on medical neglect in childhood guest edited by Barbara L. Knox, MD, FAAP, Clinical Professor of Pediatrics, University of Washington School of Medicine, The Children's Hospital at Providence, Medical Director of Alaska Child Abuse Response and Evaluation Services; Randell C. Alexander, MD, PhD, FAAP, Professor and Chief, Division of Child Protection and Forensic Pediatrics at the University of Florida-Jacksonville; Francois M. Luyet, MD, Clinical Assistant Professor, University of Wisconsin School of Medicine and Public Health; and Debra D. Esernio-Jenssen, Professor of Pediatrics at the Morsani College of Medicine USF Health in Tampa, Florida and the Chief of Child Protection Medicine at Lehigh Valley Reilly Children's Hospital. Ten articles are included in this special edition aiming to explore the role of medical neglect in situations commonly encountered by practitioners., (© Springer Nature Switzerland AG 2020.)
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- 2020
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13. A comparative effectiveness trial of two family-based childhood obesity treatment programs in a medically underserved region: Rationale, design & methods.
- Author
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Zoellner JM, You W, Hill JL, Brock DP, Yuhas M, Alexander RC, Price B, and Estabrooks PA
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- Advisory Committees organization & administration, Body Mass Index, Body Weights and Measures, Child, Child, Preschool, Community-Based Participatory Research, Comparative Effectiveness Research, Cost-Benefit Analysis, Diet, Environment, Exercise, Female, Health Behavior, Health Literacy, Health Promotion economics, Humans, Male, Motivation, Overweight therapy, Patient Compliance, Quality of Life, Research Design, Socioeconomic Factors, Family, Health Promotion organization & administration, Healthy Lifestyle, Medically Underserved Area, Pediatric Obesity therapy
- Abstract
While there is a large body of literature documenting the efficacy of family-based childhood obesity (FBCO) treatment interventions, there is little evidence that these interventions have been systematically translated into regular practice - particularly in health disparate regions. To address this research-practice gap, this project was guided by a community advisory board (CAB) and the RE-AIM planning and evaluation framework within a systems-based and community-based participatory research approach. Families with overweight or obese children between 5 and 12 years old, in the medically-underserved Dan River Region, were randomly assigned to one of two FBCO treatment programs (iChoose vs. Family Connections) delivered by local Parks & Recreation staff. Both programs have previously demonstrated clinically meaningful child BMI z-score reductions, but vary in intensity, structure, and implementation demands. Two clinical CAB partners embedded recruitment methods into their regional healthcare organization, using procedures representative to what could be used if either program was taken to scale. The primary effectiveness outcome is child BMI z-scores at 6-months, with additional assessments at 3-months and at 12-months. Secondary goals are to determine: (1) reach into the intended audience; (2) effectiveness on secondary child and parent outcomes; (3) intervention adoption by organizations and staff; (4) fidelity, cost, and capacity for intervention implementation; and (5) maintenance of individual-level changes and organizational-level sustainability. This research addresses literature gaps related to the features within clinical and community settings that could improve both child weight status and the translation of FBCO interventions into typical practice in medically-underserved communities. IDENTIFIERS: Clincialtrials.gov: NCT03245775., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2019
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14. Is High Placebo Response Really a Problem in Depression Trials? A Critical Re-analysis of Depression Studies.
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Whitlock ME, Woodward PW, and Alexander RC
- Abstract
Objective: We investigated the accuracy of the often-stated assumption that placebo nonadditivity and an increasing placebo response are major problems in clinical trials and the cause of a trend for smaller treatment effects observed in clinical trials for major depressive disorder (MDD) in recent years. Method of research: We reviewed data from 122 MDD trials conducted between the years 1983 and 2010 (analyzed originally by Undurraga and Baldessarini in 2012) to determine whether the data support the assumption of placebo additivity. Statistical techniques, such as conventional least squares regression, orthogonal least squares regression and locally weighted loess smoothing, were applied to the data set. Results: Re-analysis of the data set showed the active and placebo responses to be highly correlated, to the degree that would be expected assuming placebo additivity, when random variability in both active and placebo response is considered. Despite the placebo responses in MDD trials increasing up to approximately the year 1998, we found no evidence that it has continued to increase since this date, or that it has been the cause of smaller reported treatment effects in recent years. Conclusion: Attempts to reduce the placebo response are unlikely to increase the treatment effect since they are likely to reduce drug nonspecific effects in the treatment arm by a similar amount. Thus, it should come as no surprise that trial designs set up with the sole purpose of reducing placebo response fail to discernibly benefit our ability to identify new effective treatments., Competing Interests: FUNDING:No funding was provided. DISCLOSURES:The authors have no conflicts of interest relevant to the content of this article., (Copyright © 2019. Matrix Medical Communications. All rights reserved.)
- Published
- 2019
15. Participatory development and pilot testing of iChoose: an adaptation of an evidence-based paediatric weight management program for community implementation.
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Hill JL, Zoellner JM, You W, Brock DJ, Price B, Alexander RC, Frisard M, Brito F, Hou X, and Estabrooks PA
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- Child, Community-Based Participatory Research, Female, Humans, Male, Pilot Projects, Program Evaluation, Evidence-Based Practice organization & administration, Pediatric Obesity prevention & control, Weight Reduction Programs organization & administration
- Abstract
Background: To describe the identification, adaptation, and testing of an evidence-based pediatric weight management program for a health disparate community., Methods: A community advisory board (CAB) of decision-makers and staff from local health care, public health, and recreation organizations engaged with academic partners to select an evidence-based program (EBP) for local implementation. Three EBPs were identified (Traffic Light, Bright Bodies, Golan and colleagues Home Environmental Model) and each EBP was rated on program characteristics, implementation and adaptation, and adoptability. Following selection of the EBP that was rated highest, the POPS-CAB made adaptations based on the program principles described in peer-reviewed publications. The adapted intervention, iChoose, was then pilot tested in 3 iterative phases delivered initially by research partners, then co-delivered by research and community partners, then delivered by community partners. The RE-AIM framework was used to plan and evaluate the iChoose intervention across all waves with assessments at baseline, post program (3 months), and follow-up (6 months)., Results: Bright Bodies rated highest on program characteristics and adoptability (p's < 0.05), while Home Environmental Model rated highest on implementation factors (p < 0.05). Qualitatively, the selection focused on important program characteristics and on matching those characteristics to the potential to fit within the community partner services. The adapted program-iChoose-had 18% reach and with participants that were representative of the target population on age, gender, ethnicity, and race. Effectiveness was demonstrated by modest, but significant reductions in BMI z-scores at post-program compared to baseline (M
Δ = - 0.047; t = - 2.11, p = 0.046). This decrease returned to values similar to baseline 3 months (MΔ = 0.009) after the program was completed. Implementation fidelity was high and implementation fidelity did not differ between community or research delivery agents., Conclusion: The process to help organizations identify and select evidence-based programs appropriate for their community led to consensus on a single EBP. While iChoose was successful in initiating changes in BMI z-scores, could be implemented in a low resource community with fidelity, it was insufficient to lead to sustained child BMI z-scores. In response to these data, maintenance of program effects and delivery are the current focus of the CBPR team.- Published
- 2019
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16. Building and Sustaining Community Capacity to Address Childhood Obesity: A 3-Year Mixed-Methods Case Study of a Community-Academic Advisory Board.
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Brock DP, Estabrooks PA, Hill JL, Barlow ML, Alexander RC, Price BE, Marshall R, and Zoellner JM
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- Child, Humans, Time Factors, Capacity Building methods, Community-Based Participatory Research methods, Pediatric Obesity epidemiology
- Abstract
Guided by a community-based participatory research and systems-based approach, this 3-year mixed-methods case study describes the experiences and capacity development of a Community-Academic Advisory Board (CAB) formed to adapt, implement, and evaluate an evidence-based childhood obesity treatment program in a medically underserved region. The CAB included community, public health, and clinical (n = 9) and academic partners (n = 9). CAB members completed capacity evaluations at 4 points. Partners identified best practices that attributed to the successful execution and continued advancement of project goals. The methodological framework and findings can inform capacity development and sustainability of emergent community-academic collaborations.
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- 2019
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17. The "New Science" of Abusive Head Trauma.
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Lindberg DM, Dubowitz H, Alexander RC, and Reece RM
- Abstract
Claims that new science is changing accepted medical opinion about abusive head injury have been made frequently in the media, legal publications and in legal cases involving abusive head trauma (AHT). This review analyzes recently published scientific articles about AHT to determine whether this new information has led to significant changes in the understanding, evaluation and management of children with suspected AHT. Several specific topics are examined: serious or fatal injuries from short falls; specificity of subdural hematoma for severe trauma; biomechanical explanations for findings; the specificity of retinal hemorrhages; the possibility of cerebral sinus thrombosis presenting with signs similar to AHT; and whether vaccines can produce such findings. We conclude: a) that the overwhelming weight of recent data does not change the fundamental consensus b) that abusive head trauma is a significant source of morbidity and mortality in children c) that subdural hematomas and severe retinal hemorrhages are commonly the result of severe trauma d) that these injuries should prompt an evaluation for abuse when identified in young children without a history of such severe trauma and e) that short falls, cerebral sinus thrombosis and vaccinations are not plausible explanations for findings that raise concern for abusive head trauma., Competing Interests: Conflict of interest statement: The authors have each provided expert witness testimony in cases with alleged child physical abuse.
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- 2019
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18. BACE1 Inhibitor Lanabecestat (AZD3293) in a Phase 1 Study of Healthy Japanese Subjects: Pharmacokinetics and Effects on Plasma and Cerebrospinal Fluid Aβ Peptides.
- Author
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Sakamoto K, Matsuki S, Matsuguma K, Yoshihara T, Uchida N, Azuma F, Russell M, Hughes G, Haeberlein SB, Alexander RC, Eketjäll S, and Kugler AR
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- Adult, Aged, Alzheimer Disease drug therapy, Amyloid Precursor Protein Secretases metabolism, Amyloid beta-Protein Precursor metabolism, Asian People, Brain metabolism, Double-Blind Method, Female, Half-Life, Healthy Volunteers, Humans, Male, Middle Aged, Peptide Fragments metabolism, Young Adult, Amyloid Precursor Protein Secretases antagonists & inhibitors, Amyloid beta-Peptides metabolism, Aspartic Acid Endopeptidases antagonists & inhibitors, Cerebrospinal Fluid metabolism, Imidazoles therapeutic use, Plasma metabolism, Spiro Compounds therapeutic use
- Abstract
Lanabecestat (AZD3293; LY3314814) is an orally active potent inhibitor of human β-secretase 1 in clinical development for the treatment of Alzheimer disease. In this first Japanese clinical study for an Alzheimer disease intervention to include cerebrospinal fluid (CSF) sampling in Japanese elderly healthy subjects, we report the pharmacokinetics and effects on plasma and CSF amyloid-β (Aβ) peptides of lanabecestat in a phase 1 study involving 40 healthy Japanese subjects (NCT02005211). No safety and tolerability concerns were identified in healthy Japanese subjects exposed to lanabecestat up to the highest doses given, which is consistent with observations in a US phase 1 study of lanabecestat. Exposure to lanabecestat was similar for young and elderly subjects and increased in a dose-dependent manner. For elderly subjects, plasma lanabecestat half-life after multiple dosing was 12 to 17 hours (on days 10 and 14). Robust plasma and CSF Aβ peptide reductions were also seen at all doses, with CSF Aβ
42 concentrations reduced by 63% and 79% in the 15- and 50-mg lanabecestat groups, respectively. CSF soluble amyloid-β precursor protein β also decreased following lanabecestat treatment. Suppression of CSF Aβ peptides was similar in elderly healthy Japanese subjects and US patients with mild to moderate Alzheimer disease. Lanabecestat is a promising potentially disease-modifying treatment in phase 3 development for patients with early Alzheimer disease., (© 2017, The American College of Clinical Pharmacology.)- Published
- 2017
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19. The potential efficacy of GABA B antagonists in depression.
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Alexander RC
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- Animals, Depression metabolism, Humans, Receptors, GABA-B metabolism, Treatment Outcome, Depression drug therapy, GABA-B Receptor Antagonists therapeutic use
- Abstract
Evidence for the potential utility of GABA
B antagonists has been assembled from a variety of sources, including clinical experience with the GABAB agonist baclofen, murine genetic GABAB knock-outs, rodent studies of GABAB receptor expression and function following treatment with antidepressant therapies, animal models of depression, and some functional and post mortem data from human subjects. Definitive testing of GABAB antagonists in depression, however, still awaits the development of potent, selective and brain-penetrant compounds for human testing., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
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20. Comparison between semiquantitative and quantitative methods for the assessment of knee synovitis in osteoarthritis using non-enhanced and gadolinium-enhanced MRI.
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Crema MD, Roemer FW, Li L, Alexander RC, Chessell IP, Dudley AD, Karlsten R, Rosen LB, and Guermazi A
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- Aged, Contrast Media therapeutic use, Cross-Sectional Studies, Female, Gadolinium therapeutic use, Humans, Knee Joint diagnostic imaging, Knee Joint pathology, Male, Osteoarthritis, Knee pathology, Synovial Membrane diagnostic imaging, Synovial Membrane pathology, Synovitis pathology, Magnetic Resonance Imaging methods, Osteoarthritis, Knee diagnostic imaging, Synovitis diagnostic imaging
- Abstract
Objective: To compare different semiquantitative and quantitative methods using both non-enhanced and gadolinium-enhanced MRI techniques for the assessment of synovitis in knee osteoarthritis (OA)., Methods: Knees with end-stage clinical OA in patients undergoing total knee replacement surgery were included in this cross-sectional study. MRI was performed on all knees. Standard non-enhanced and gadolinium-enhanced sequences were acquired. Using non-enhanced MRI, we semiquantitatively assessed two features widely used as surrogates for synovitis: effusion-synovitis and Hoffa-synovitis. Using gadolinium-enhanced sequences, we semiquantitatively assessed synovial thickness. We quantitatively evaluated the total synovial volume on the gadolinium-enhanced sequences as well. We assessed the correlations of effusion-synovitis and Hoffa-synovitis with synovial thickness and volume, applying Spearman correlation analysis. The diagnostic performance of both synovitis features on non-enhanced MRI was assessed using synovial thickness on gadolinium-enhanced MRI as the reference., Results: A total of 104 subjects (one knee per subject) were included. Correlations of effusion-synovitis with synovial thickness and volume were r = 0.41 and r = 0.43 (P < .001) r = 0.32 and r = 0.39 (P < .0001)., Conclusion: Using synovial thickness assessed on gadolinium-enhanced sequences as the reference, effusion-synovitis showed superior correlations and sensitivity. Effusion-synovitis should be preferred over Hoffa-synovitis as a surrogate marker for synovial thickening, in studies of knee OA for which gadolinium-enhanced sequences are not available., (Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2017
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21. AZD3293: Pharmacokinetic and Pharmacodynamic Effects in Healthy Subjects and Patients with Alzheimer's Disease.
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Cebers G, Alexander RC, Haeberlein SB, Han D, Goldwater R, Ereshefsky L, Olsson T, Ye N, Rosen L, Russell M, Maltby J, Eketjäll S, and Kugler AR
- Subjects
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Amyloid beta-Peptides blood, Amyloid beta-Peptides cerebrospinal fluid, Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Female, Follow-Up Studies, Food, Healthy Volunteers, Humans, Male, Middle Aged, Neurologic Examination, Peptide Fragments blood, Peptide Fragments cerebrospinal fluid, Time Factors, Young Adult, Alzheimer Disease drug therapy, Antipsychotic Agents pharmacokinetics, Antipsychotic Agents therapeutic use, Imidazoles pharmacokinetics, Imidazoles therapeutic use, Spiro Compounds pharmacokinetics, Spiro Compounds therapeutic use
- Abstract
AZD3293 (LY3314814) is a promising new potentially disease-modifying BACE1 (β-secretase) inhibitor in Phase III clinical development for the treatment of Alzheimer's disease. Reported here are the first two Phase I studies: (1) a single ascending dose study evaluating doses of 1-750 mg with a food-effect component (n = 72), and (2) a 2-week multiple ascending dose study evaluating doses of 15 or 50 mg once daily (QD) or 70 mg once weekly (QW) in elderly subjects (Part 1, n = 31), and 15, 50, or 150 mg QD in patients with mild to moderate Alzheimer's disease (Part 2, n = 16). AZD3293 was generally well tolerated up to the highest doses given. No notable food effects were observed. PK following multiple doses (Part 2) were tmax of 1 to 3 h and mean t1/2 of 16 to 21 h across the 15 to 150 mg dose range. For single doses of ≥5 mg, a ≥70% reduction was observed in mean plasma Aβ40 and Aβ42 concentrations, with prolonged suppression for up to 3 weeks at the highest dose level studied. Following multiple doses, robust reductions in plasma (≥64% at 15 mg and ≥78% at ≥50 mg) and cerebrospinal fluid (≥51% at 15 mg and ≥76% at ≥50 mg) Aβ peptides were seen, including prolonged suppression even with a QW dosing regimen. AZD3293 is the only BACE1 inhibitor for which prolonged suppression of plasma Aβ with a QW dosing schedule has been reported. Two Phase III studies of AZD3293 (AMARANTH, NCT02245737; and DAYBREAK-ALZ, NCT02783573) are now ongoing.
- Published
- 2017
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22. Performance of the G4 Xpert ® MTB/RIF assay for the detection of Mycobacterium tuberculosis and rifampin resistance: a retrospective case-control study of analytical and clinical samples from high- and low-tuberculosis prevalence settings.
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Dharan NJ, Blakemore R, Sloutsky A, Kaur D, Alexander RC, Ghajar M, Musser KA, Escuyer VE, Rowlinson MC, Crowe S, Laniado-Laborin R, Valli E, Nabeta P, Johnson P, and Alland D
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Biological Assay, Case-Control Studies, DNA, Bacterial analysis, Developing Countries, False Positive Reactions, Female, Humans, Male, Microbial Sensitivity Tests, Middle Aged, Mutation, Mycobacterium tuberculosis genetics, Polymerase Chain Reaction methods, Prevalence, Retrospective Studies, Sensitivity and Specificity, Tuberculosis epidemiology, Tuberculosis microbiology, United States epidemiology, Young Adult, Antibiotics, Antitubercular, Drug Resistance, Bacterial genetics, Mycobacterium tuberculosis isolation & purification, Rifampin, Tuberculosis diagnosis
- Abstract
Background: The Xpert
® MTB/RIF (Xpert) assay is a rapid PCR-based assay for the detection of Mycobacterium tuberculosis complex DNA (MTBc) and mutations associated with rifampin resistance (RIF). An updated version introduced in 2011, the G4 Xpert, included modifications to probe B and updated analytic software., Methods: An analytical study was performed to assess Xpert detection of mutations associated with rifampin resistance in rifampin-susceptible and -resistant isolates. A clinical study was performed in which specimens from US and non-US persons suspected of tuberculosis (TB) were tested to determine Xpert performance characteristics. All specimens underwent smear microscopy, mycobacterial culture, conventional drug-susceptibility testing and Xpert testing; DNA from isolates with discordant rifampin resistance results was sequenced., Results: Among 191 laboratory-prepared isolates in the analytical study, Xpert sensitivity for detection of rifampin resistance associated mutations was 97.7% and specificity was 90.8%, which increased to 99.0% after DNA sequencing analysis of the discordant samples. Of the 1,096 subjects in the four clinical studies, 49% were from the US. Overall, Xpert detected MTBc in 439 of 468 culture-positive specimens for a sensitivity of 93.8% (95% confidence interval [CI]: 91.2%-95.7%) and did not detect MTBc in 620 of 628 culture-negative specimens for a specificity of 98.7% (95% CI: 97.5%-99.4%). Sensitivity was 99.7% among smear-positive cases, and 76.1% among smear-negative cases. Non-determinate MTBc detection and false-positive RIF resistance results were low (1.2 and 0.9%, respectively)., Conclusions: The updated Xpert assay retained the high sensitivity and specificity of the previous assay versions and demonstrated low rates of non-determinate and RIF resistance false positive results.- Published
- 2016
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23. AZD3293: A Novel, Orally Active BACE1 Inhibitor with High Potency and Permeability and Markedly Slow Off-Rate Kinetics.
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Eketjäll S, Janson J, Kaspersson K, Bogstedt A, Jeppsson F, Fälting J, Haeberlein SB, Kugler AR, Alexander RC, and Cebers G
- Subjects
- Administration, Oral, Amyloid beta-Peptides metabolism, Animals, Blood Chemical Analysis, Blood-Brain Barrier drug effects, Blood-Brain Barrier enzymology, Brain drug effects, Brain enzymology, Dogs, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Female, Guinea Pigs, Humans, Kinetics, Male, Mice, Inbred C57BL, Peptide Fragments metabolism, Amyloid Precursor Protein Secretases antagonists & inhibitors, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors pharmacokinetics, Imidazoles administration & dosage, Imidazoles pharmacokinetics, Spiro Compounds administration & dosage, Spiro Compounds pharmacokinetics
- Abstract
A growing body of pathological, biomarker, genetic, and mechanistic data suggests that amyloid accumulation, as a result of changes in production, processing, and/or clearance of brain amyloid-β peptide (Aβ) concentrations, plays a key role in the pathogenesis of Alzheimer's disease (AD). Beta-secretase 1 (BACE1) mediates the first step in the processing of amyloid-β protein precursor (AβPP) to Aβ peptides, with the soluble N terminal fragment of AβPP (sAβPPβ) as a direct product, and BACE1 inhibition is an attractive target for therapeutic intervention to reduce the production of Aβ. Here, we report the in vitro and in vivo pharmacological profile of AZD3293, a potent, highly permeable, orally active, blood-brain barrier (BBB) penetrating, BACE1 inhibitor with unique slow off-rate kinetics. The in vitro potency of AZD3293 was demonstrated in several cellular models, including primary cortical neurons. In vivo in mice, guinea pigs, and dogs, AZD3293 displayed significant dose- and time-dependent reductions in plasma, cerebrospinal fluid, and brain concentrations of Aβ40, Aβ42, and sAβPPβ. The in vitro potency of AZD3293 in mouse and guinea pig primary cortical neuronal cells was correlated to the in vivo potency expressed as free AZD3293 concentrations in mouse and guinea pig brains. In mice and dogs, the slow off-rate from BACE1 may have translated into a prolongation of the observed effect beyond the turnover rate of Aβ. The preclinical data strongly support the clinical development of AZD3293, and patients with AD are currently being recruited into a combined Phase 2/3 study to test the disease-modifying properties of AZD3293.
- Published
- 2016
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24. Reversible and Species-Specific Depigmentation Effects of AZD3293, a BACE Inhibitor for the Treatment of Alzheimer's Disease, Are Related to BACE2 Inhibition and Confined to Epidermis and Hair.
- Author
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Cebers G, Lejeune T, Attalla B, Soderberg M, Alexander RC, Budd Haeberlein S, Kugler AR, Ingersoll EW, Platz S, and Scott CW
- Abstract
Background: AZD3293 (also known as LY3314814) is a novel, potent, non-selective BACE1/BACE2 inhibitor currently in Phase 3 clinical development for the treatment of Alzheimer's disease., Objectives: The purpose of these studies was to characterize the effects, putative mechanism, and reversibility of hypopigmentation following treatment with AZD3293 in pigmented Long-Evans rats, Beagle dogs, human cell cultures, and humans., Design: Nonclinical studies were conducted in Long-Evans pigmented rats, and both young and older Beagle dogs using a variety of oral dose levels of AZD3293 or AZD3839 (BACE inhibition reference compound; used in older dogs only) for dosing durations of 13 to 26 weeks. In vitro studies of normal human epidermal melanocytes and reconstituted human epidermis were also conducted. Skin biopsy data from a multiple-dose Phase 1 clinical study of AZD3293 (NCT01795339) are also reported., Setting: Nonclinical in vivo and in vitro studies were conducted in laboratory settings in the US, Canada, and France; the multiple dose clinical study was conducted in a specialized inpatient setting in the US., Participants: Beagle dogs: 13-week study N=36 young (8-10 mo) animals; 39-week study N=64 young animals; and a second 13-week study N=32 older (30-32 mo) animals. Long-Evans rats: N=68 animals. Multiple-dose clinical study: only data for subjects enrolled in Part 2 of this study are included in this report (N=16)., Interventions: AZD3293 was the primary intervention used in these studies. AZD3839, a relatively BACE1-selective reference inhibitor compound was used in one group in the 13 week study in older Beagle dogs and one in vitro assessment. Finally, AZ1340, another relatively BACE1-selective reference inhibitor compound was used only in one in vitro assessment., Measurements: Measurements for the nonclinical studies in dogs and rats included macroscopic observation and assessment of skin biopsies via histopathology, immunochemistry, and electron microscopy. Measurements for the in vitro studies included melanocyte premelanosome protein (PMEL) processing, cytotoxicity, melanin synthesis, Pmel17 labeling, and melanocyte dendricity. Measurements in the clinical study included scoring of melanin content in skin biopsies taken before and after dosing with AZD3293 over 14 days at dose levels up to 150 mg., Results: Depigmentation in rats and dogs was limited to skin, hair, and mucosa with no effects on other pigmented tissues. At a cellular level depigmentation was observed within a week of treatment, whereas the appearance of depigmentation in skin and hair did not become apparent until, at earliest, 4 weeks of treatment. The depigmentation effects were reversible, not associated with degenerative or inflammatory changes, and were dose- and species-dependent in severity. Full recovery of melanization was observed at the microscopic (cellular) level and at least partial recovery was seen in the macroscopic appearance of animals by the end of the 12-week recovery period in both rats and dogs. Interestingly, no changes in melanin production or melanocyte morphology were seen in human primary melanocytes or reconstituted human epidermis in vitro. Finally, there were no changes in melanization level in skin biopsies following 12 days of daily AZD3293 treatment at doses of AZD3293 up to 150 mg/day in human subjects., Conclusions: AZD3293, a novel, potent, non-selective BACE1/BACE2 inhibitor is in development as a potentially disease-modifying treatment for Alzheimer's disease. Chronic nonclinical studies in Beagle dogs and pigmented rats showed macroscopic and microscopic hypopigmentation effects of AZD3293 that were limited to skin, hair, and mucosa. These effects were shown to be reversible in both species. Analysis of data from nonclinical and in vitro studies suggests that hypopigmentation is caused by BACE2 inhibition resulting in accumulation of a premelanosome protein fragment, which interrupts the normal production of melanin. No macroscopic or microscopic reports of hypopigmentation were observed in a Phase 1 clinical study following 13 doses of AZD3293 over 14 days at dose levels up to 150 mg/day. These data suggest that hypopigmentation is species-specific and humans appear to be least sensitive to the depigmentation effect caused by BACE2 inhibition., Competing Interests: Gvido Cebers, MD, PhD: GC was an AstraZeneca employee at the time the primary manuscript work was completed. GC is no longer an employee of AstraZeneca. GC has no financial disclosures. Typhaine Lejeune, DVM, DECVP: TL is an employee of Charles River Laboratories, which conducted in vivo non-clinical studies reported in this paper as a paid contractor for AstraZeneca. TL has no financial disclosures. Bassem Attalla, BS: Dr. BA is an employee of Charles River Laboratories, which conducted in vivo non-clinical studies reported in this paper as a paid contractor for AstraZeneca. BA has no financial disclosures. Magnus Soderberg, MD, PhD: MS is an employee of AstraZeneca and owns AstraZeneca stock. MS has no other financial disclosures. Robert C. Alexander, MD: RCA was an AstraZeneca employee at the time the primary manuscript work was completed. RCA is no longer an employee of AstraZeneca but remains a participant in AstraZeneca’s long term incentive program and owns AstraZeneca stock. RCA is currently an employee of Pfizer. RCA has no other financial disclosures. Samantha Budd Haeberlein, PhD: SBH was an AstraZeneca employee at the time the primary manuscript work was completed. SBA is no longer an employee of AstraZeneca but remains a participant in AstraZeneca’s long term incentive program and owns AstraZeneca stock. SBA is currently an employee of Biogen. SBA has no other financial disclosures. Alan R. Kugler, PhD: ARK was an AstraZeneca employee at the time the primary manuscript work was completed. ARK is no longer an employee of AstraZeneca but remains a participant in AstraZeneca’s long term incentive program and owns AstraZeneca stock. ARK has no other financial disclosures. Evan W. Ingersoll, PhD: EWI was a paid independent contractor for AstraZeneca during the time these studies were conducted and throughout this manuscript development. He provided program management, scientific support, and medical writing services including serving as coordinating editor for this manuscript. EWI has no other financial disclosures. Stefan Platz, DVM, PhD: SP is an AstraZeneca employee, is a participant in AstraZeneca’s long term incentive program, and owns AstraZeneca stock. SP has no other financial disclosures. Clay W. Scott, PhD: CWS is an AstraZeneca employee, is a participant in AstraZeneca’s long term incentive program, and owns AstraZeneca stock. CWS has no other financial disclosures.
- Published
- 2016
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25. Medication Nonadherence, "Professional Subjects," and Apparent Placebo Responders: Overlapping Challenges for Medications Development.
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McCann DJ, Petry NM, Bresell A, Isacsson E, Wilson E, and Alexander RC
- Subjects
- Drug Design, Humans, Mental Disorders drug therapy, Patient Selection, Pharmacokinetics, Research Design, Research Subjects statistics & numerical data, Sample Size, Medication Adherence, Placebo Effect, Randomized Controlled Trials as Topic methods
- Abstract
Nonadherence is a major problem in clinical trials of new medications. To evaluate the extent of nonadherence, this study evaluated pharmacokinetic sampling from 1765 subjects receiving active therapy across 8 psychiatric trials conducted between 2001 and 2011. With nonadherence defined as greater than 50% of plasma samples below the limit of quantification for study drug, the percentage of nonadherent subjects ranged from 12.8% to 39.2%. There was a trend toward increased nonadherence in studies with greater numbers of subjects, but an association with nonadherence was not apparent for other study design parameters or subject characteristics. For 2 trials with multiple recruitment sites in geographical proximity, several subjects attempted to simultaneously enroll at separate site locations. The construct of "professional subjects," those who enroll in trials only for financial gain, is gaining attention, and we therefore modeled the impact of professional subjects on medication efficacy trials. The results indicate that enrollment of professional subjects who are destined to succeed (those who will appear to achieve treatment success regardless of study drug assignment) can substantially increase both the apparent placebo response rate and the sample size requirement for statistical power, while decreasing the observed effect size. The overlapping nature of nonadherence, professional subjects, and placebo response suggests that these issues should be considered and addressed together. Following this approach, we describe a novel clinical trial design to minimize the adverse effects of professional subjects on trial outcomes and discuss methods to monitor adherence.
- Published
- 2015
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26. Rapid detection and differentiation of human noroviruses using RT-PCR coupled to electrospray ionization mass spectrometry.
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Hellberg RS, Li F, Sampath R, Yasuda IJ, Carolan HE, Wolfe JM, Brown MK, Alexander RC, Williams-Hill DM, and Martin WB
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- DNA Primers genetics, Humans, Norovirus genetics, Sensitivity and Specificity, Food Contamination analysis, Norovirus chemistry, Norovirus isolation & purification, Reverse Transcriptase Polymerase Chain Reaction methods, Spectrometry, Mass, Electrospray Ionization methods
- Abstract
The goal of this study was to develop an assay for the detection and differentiation of noroviruses using RT-PCR followed by electrospray ionization mass spectrometry (ESI-MS). Detection of hepatitis A virus was also considered. Thirteen primer pairs were designed for use in this assay and a reference database was created using GenBank sequences and reference norovirus samples. The assay was tested for inclusivity and exclusivity using 160 clinical norovirus samples, 3 samples of hepatitis A virus and 3 other closely related viral strains. Results showed that the assay was able to detect norovirus with a sensitivity of 92% and a specificity of 100%. Norovirus identification at the genogroup level was correct for 98% of samples detected by the assay and for 75% of a subset of samples (n = 32) compared at the genotype level. Identification of norovirus genotypes is expected to improve as more reference samples are added to the database. The assay was also capable of detecting and genotyping hepatitis A virus in all 3 samples tested. Overall, the assay developed here allows for detection and differentiation of noroviruses within one working day and may be used as a tool in surveillance efforts or outbreak investigations., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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27. Clinical pharmacology in the development of new antidepressants: the challenges.
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Alexander RC and Preskorn S
- Subjects
- Animals, Antidepressive Agents pharmacology, Clinical Trials, Phase I as Topic methods, Depression physiopathology, Electroencephalography, Humans, Magnetic Resonance Imaging methods, Pharmacology, Clinical, Antidepressive Agents therapeutic use, Depression drug therapy, Drug Design
- Abstract
Given the lack of fundamental knowledge about the causes and pathophysiology of depression, it is a challenge for Phase I in antidepressant development to efficiently and thoroughly test new drugs. Initiation of Phase I should always be preceded by a careful consideration of what is known about the target and the molecule. While some early indicators of efficacy, such as the Emotional Test Battery, EEG markers, and fMRI correlates of anhedonia are available, further work is needed for their full incorporation in Phase I. Phase I studies of antidepressants should incorporate new measures and methods to the extent possible, and have the freedom to explore new hypotheses and move beyond the predetermined and inflexible study designs of traditional Phase I studies., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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28. Combined NK₁ antagonism and serotonin reuptake inhibition: effects on emotional processing in humans.
- Author
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Harmer CJ, Dawson GR, Dourish CT, Favaron E, Parsons E, Fiore M, Zucchetto M, Bifone A, Poggesi I, Fernandes S, Alexander RC, and Goodwin GM
- Subjects
- Adult, Antidepressive Agents therapeutic use, Citalopram therapeutic use, Double-Blind Method, Facial Expression, Humans, Male, Memory drug effects, Perception drug effects, Recognition, Psychology drug effects, Young Adult, Acetamides therapeutic use, Emotions drug effects, Neurokinin-1 Receptor Antagonists, Piperidines therapeutic use, Selective Serotonin Reuptake Inhibitors therapeutic use
- Abstract
Background: Synergistic effects of NK₁ receptor antagonism combined with serotonin reuptake inhibition have been reported in preclinical models. GSK424887 is a selective competitive antagonist of the human NK₁ receptor and inhibitor of the serotonin transporter. However, its actions in human models of depression have not been assessed., Methods: This study explored the effects of acute administration of GSK424887 compared to placebo in healthy male volunteers. The selective serotonin reuptake inhibitor (SSRI) citalopram was used as a positive control. A battery of emotional processing tasks was given at the peak time of drug effect., Results: GSK424887 enhanced attentional vigilance in the dot-probe task to both positive and negative stimuli. By contrast, citalopram enhanced perception of angry, sad and happy facial expressions and increased positive bias in the facial expression recognition task. Neither drug significantly affected emotion potentiated startle responses or emotional memory., Conclusions: These results suggest that acute administration of GSK424887 modulated some aspects of emotional processing but these effects were not similar to those seen previously with antidepressant agents. This was the first use of the battery of emotional processing tasks in a Phase 1 study. Repeated administration of the test and active control drugs may be needed to reliably characterise their effects.
- Published
- 2013
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29. A randomized, double-blind, crossover comparison of MK-0929 and placebo in the treatment of adults with ADHD.
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Rivkin A, Alexander RC, Knighton J, Hutson PH, Wang XJ, Snavely DB, Rosah T, Watt AP, Reimherr FW, and Adler LA
- Subjects
- Adolescent, Adult, Cross-Over Studies, Dopamine Antagonists pharmacology, Double-Blind Method, Drug Administration Schedule, Female, Humans, Male, Middle Aged, Psychiatric Status Rating Scales, Severity of Illness Index, Treatment Outcome, Attention Deficit Disorder with Hyperactivity drug therapy, Dopamine Antagonists therapeutic use
- Abstract
Objective: Preclinical models, receptor localization, and genetic linkage data support the role of D4 receptors in the etiology of ADHD. This proof-of-concept study was designed to evaluate MK-0929, a selective D4 receptor antagonist as treatment for adult ADHD., Method: A randomized, double-blind, placebo-controlled, crossover study was conducted in adults with primary ADHD. The primary end point was changed from baseline in total score on the Adult ADHD Investigator Symptom Rating Scale following a 4-week treatment regimen. Additional measures included Clinical Global Impression-Severity Scale, Hospital Anxiety and Depression Scale, and Brown Attention Deficit Disorder Scale and D4 genotype analysis., Results: No statistically significant treatment differences were found between MK-0929 and placebo in any of the primary or secondary assessments., Conclusion: Results from this study suggest that blockade of the D4 receptor alone is not efficacious in the treatment of adult ADHD.
- Published
- 2012
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30. Comparative Evaluation of HIV-1 Neutralization in External Secretions and Sera of HIV-1-Infected Women.
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Wei Q, Moldoveanu Z, Huang WQ, Alexander RC, Goepfert PA, and Mestecky J
- Abstract
Objectives: Although human immunodeficiency virus type 1 (HIV-1)-specific antibodies are detectable in external secretions by ELISA and western blot (WB), the presence of HIV-1 neutralizing antibodies is difficult to evaluate due to the low levels of immunoglobulins (Ig) and the presence of humoral factors of innate immunity. The objective of this study was to determine virus neutralization activity and the relative contribution of HIV-1-specific antibodies of various isotypes to virus neutralization in serum/plasma samples, cervicovaginal lavages (CVL), and rectal lavages (RL)., Design: Serum/plasma, CVL, and RL samples were examined by ELISA, WB and HIV-1 neutralization assays. Selected samples were Ig depleted and analyzed for virus neutralization., Results: IgG specific for three HIV-1 ENV antigens was detected in all serum/plasma samples, while IgA to at least one ENV glycoprotein was found at the low levels in 95% samples. Serum/plasma samples had the ability to neutralize at least one of three clade B and two clade C viruses. The neutralizing titers were reduced significantly or became undetectable after IgG removal. In corresponding CVL and RL, HIV-1 ENV-specific IgG antibodies were readily detected compared to IgA. Furthermore, IgG in CVL had greater ability than IgA to reduce virus infectivity. The difference in HIV-1 neutralization before and after Ig depletion was not observed in RL, implying that innate humoral factors were involved in anti-HIV-1 activity., Conclusions: Results demonstrate that HIV-1-specific neutralizing antibodies are almost exclusively of the IgG isotype in serum/plasma and CVL samples. HIV-1-specific binding antibodies detected in RL are not responsible for neutralization activity, suggesting that the antibody-mediated virus neutralization in external secretions should be verified by means of a selective depletion of Ig.
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- 2012
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31. Scarcity or absence of humoral immune responses in the plasma and cervicovaginal lavage fluids of heavily HIV-1-exposed but persistently seronegative women.
- Author
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Mestecky J, Wright PF, Lopalco L, Staats HF, Kozlowski PA, Moldoveanu Z, Alexander RC, Kulhavy R, Pastori C, Maboko L, Riedner G, Zhu Y, Wrinn T, and Hoelscher M
- Subjects
- Adult, Blotting, Western, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunoglobulin A analysis, Immunoglobulin A blood, Immunoglobulin G analysis, Immunoglobulin G blood, Vaginal Douching, Young Adult, HIV Antibodies analysis, HIV Antibodies blood, HIV Infections immunology, HIV-1 immunology, Immunity, Innate, Plasma immunology, Vagina immunology
- Abstract
To address an existing controversy concerning the presence of HIV-1-specific antibodies of the IgA isotype in the female genital tract secretions of highly-exposed but persistently seronegative (HEPSN) women, 41 samples of plasma and cervicovaginal lavage (CVL) fluid were distributed to six laboratories for their blinded evaluation using ELISA with 10 different HIV-1 antigens, chemiluminescence-enhanced Western blots (ECL-WB), and virus neutralization. HIV-specific IgG or IgA antibodies in plasma samples from HEPSN women were absent or detectable only at low levels. In CVL, 11/41 samples displayed low levels of reactivity in ELISA against certain antigens. However, only one sample was positive in two of five laboratories. All but one CVL sample yielded negative results when analyzed by ECL-WB. Viral neutralizing activity was either absent or inconsistently detected in plasma and CVL. Plasma and CVL samples from 26 HIV-1-infected women were used as positive controls. Irrespective of the assays and antigens used, the results generated in all laboratories displayed remarkable concordance in the detection of HIV-1-specific antibodies of the IgG isotype. In contrast, IgA antibodies to HIV-1 antigens were not detected with consistency, and where present, IgA antibodies were at markedly lower levels than IgG. Although HIV-neutralizing activity was detected in plasma of all HIV-1-infected women, only a few of their CVL samples displayed such activity. In conclusion, frequent HIV-1 sexual exposure does not stimulate uniformly detectable mucosal or systemic HIV-1-specific responses, as convincingly documented in the present blindly performed study using a broad variety of immunological assays. Although HIV-1-infection leads to vigorous IgG responses in plasma and CVL, it does not stimulate sustained IgA responses in either fluid.
- Published
- 2011
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32. Methods for evaluation of humoral immune responses in human genital tract secretions.
- Author
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Mestecky J, Alexander RC, Wei Q, and Moldoveanu Z
- Subjects
- Female, HIV Antibodies analysis, Humans, Immunoglobulins blood, Immunoglobulins chemistry, Intestines immunology, Male, Mucous Membrane immunology, Mucous Membrane metabolism, Genitalia, Female immunology, Genitalia, Male immunology, HIV Antibodies immunology, HIV Infections immunology, HIV-1 immunology, Immunity, Humoral
- Abstract
The compilation of epidemiological, virological, and immunological data clearly indicates that HIV-1 infection must be considered primarily as a disease of the mucosal immune system. The earliest and most dramatic alterations of the immune system occur in the mucosal compartment. However, the mucosal immune systems of the genital and intestinal tracts display remarkable immunological differences that must be considered in the evaluation of humoral immune responses in HIV-1-infected individuals or in volunteers immunized with experimental HIV vaccines. In this regard, marked differences in the dominant Ig isotypes, molecular forms of HIV-1-specific antibodies, and their distinct effector functions in the genital versus intestinal tracts must be carefully evaluated and considered in the measurement and interpretation of humoral immune responses. Appropriate controls and alternative immunochemical assays should be used to complement and confirm results generated by ELISA, which are prone to false positivity. Special precautions and rigorous controls must be used in the evaluation of antibody-mediated virus neutralization in external secretions of the genital and intestinal tracts., (© 2010 John Wiley & Sons A/S.)
- Published
- 2011
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33. A new population-enrichment strategy to improve efficiency of placebo-controlled clinical trials of antidepressant drugs.
- Author
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Merlo-Pich E, Alexander RC, Fava M, and Gomeni R
- Subjects
- Computer Simulation, Data Interpretation, Statistical, Databases as Topic, Humans, Multicenter Studies as Topic statistics & numerical data, Placebo Effect, Randomized Controlled Trials as Topic statistics & numerical data, Reproducibility of Results, Treatment Outcome, Antidepressive Agents therapeutic use, Depressive Disorder, Major drug therapy, Multicenter Studies as Topic methods, Patient Selection, Randomized Controlled Trials as Topic methods, Sample Size
- Abstract
The rate-limiting factor in the discovery of novel antidepressants is the inefficient methodology of traditional multicenter randomized clinical trials (RCTs). We applied a model-based approach to a large clinical database (five RCTs in major depressive disorder (MDD), involving 1,837 patients from 124 recruitment centers) with two objectives: (i) to learn about the role of center-specific placebo response in RCT failure and (ii) to apply what is learned to improve the efficiency of RCTs by enhancing the detection of treatment effect (TE). Sensitivity analysis indicated that center-specific placebo response was the most relevant predictor of RCT failure. To reduce the statistical "noise" generated by centers with nonplausible, excessively high/low placebo responses, we developed an enrichment-window strategy. Clinical trial simulation was used to assess the enrichment strategy applied before the standard statistical analysis, resulting in an overall reduction in failure of RCTs from ~50 to ~10%.
- Published
- 2010
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34. Antibody-mediated protection and the mucosal immune system of the genital tract: relevance to vaccine design.
- Author
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Mestecky J, Raska M, Novak J, Alexander RC, and Moldoveanu Z
- Subjects
- Animals, Bacterial Vaccines administration & dosage, Humans, Viral Vaccines administration & dosage, Antibodies immunology, Bacterial Vaccines immunology, Immunity, Mucosal immunology, Urogenital System immunology, Viral Vaccines immunology
- Abstract
Mucosal tissues of the genital tracts and the distal intestinal tract are portals of entry for infectious agents of sexually transmitted diseases, including HIV-1. Although the genital and intestinal tracts share a common embryologic origin and remain in anatomical proximity, these two sites display remarkably different immunologic features, including the levels, isotypes and molecular forms of immunoglobulins, and magnitudes and qualities of humoral and cellular immune responses. Thus, viral and bacterial infections of the genital tract or intravaginal immunizations induce, in the absence of mucosal adjuvants, minimal immune responses. Consequently, to induce relevant immune responses in the genital tract, alternative immunization routes have been explored, including systemic, intranasal, oral, or rectal immunization and their combinations. In limited studies performed in animals, systemic immunization with a subsequent mucosal (intranasal) immunization proved to be effective in the induction of humoral immune responses in genital tract secretions. The approaches have been explored to a limited extent in humans., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2010
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35. Plasma protein biomarkers for depression and schizophrenia by multi analyte profiling of case-control collections.
- Author
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Domenici E, Willé DR, Tozzi F, Prokopenko I, Miller S, McKeown A, Brittain C, Rujescu D, Giegling I, Turck CW, Holsboer F, Bullmore ET, Middleton L, Merlo-Pich E, Alexander RC, and Muglia P
- Subjects
- Case-Control Studies, Depressive Disorder diagnosis, Humans, Multivariate Analysis, Proteins classification, Schizophrenia diagnosis, Biomarkers blood, Depressive Disorder blood, Proteins analysis, Proteomics methods, Schizophrenia blood
- Abstract
Despite significant research efforts aimed at understanding the neurobiological underpinnings of psychiatric disorders, the diagnosis and the evaluation of treatment of these disorders are still based solely on relatively subjective assessment of symptoms. Therefore, biological markers which could improve the current classification of psychiatry disorders, and in perspective stratify patients on a biological basis into more homogeneous clinically distinct subgroups, are highly needed. In order to identify novel candidate biological markers for major depression and schizophrenia, we have applied a focused proteomic approach using plasma samples from a large case-control collection. Patients were diagnosed according to DSM criteria using structured interviews and a number of additional clinical variables and demographic information were assessed. Plasma samples from 245 depressed patients, 229 schizophrenic patients and 254 controls were submitted to multi analyte profiling allowing the evaluation of up to 79 proteins, including a series of cytokines, chemokines and neurotrophins previously suggested to be involved in the pathophysiology of depression and schizophrenia. Univariate data analysis showed more significant p-values than would be expected by chance and highlighted several proteins belonging to pathways or mechanisms previously suspected to be involved in the pathophysiology of major depression or schizophrenia, such as insulin and MMP-9 for depression, and BDNF, EGF and a number of chemokines for schizophrenia. Multivariate analysis was carried out to improve the differentiation of cases from controls and identify the most informative panel of markers. The results illustrate the potential of plasma biomarker profiling for psychiatric disorders, when conducted in large collections. The study highlighted a set of analytes as candidate biomarker signatures for depression and schizophrenia, warranting further investigation in independent collections.
- Published
- 2010
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36. Mucosal immunology of the genital and gastrointestinal tracts and HIV-1 infection.
- Author
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Mestecky J, Moldoveanu Z, Smith PD, Hel Z, and Alexander RC
- Subjects
- Female, Gastrointestinal Tract virology, Genitalia virology, HIV Antibodies metabolism, HIV Antigens immunology, HIV Infections physiopathology, HIV-1 pathogenicity, Humans, Immunity, Humoral, Male, Gastrointestinal Tract immunology, Genitalia immunology, HIV Infections immunology, HIV-1 immunology, Immunity, Mucosal
- Abstract
The male and female genital tracts are protected by a local immune system that displays features distinguishing them from other mucosal sites. In contrast to the intestinal tract, where locally produced IgA is the dominant Ig, secretions of the male and female genital tract contain predominantly IgG of both local and systemic origin. Genital tract tissues also lack mucosal lymphoepithelial inductive sites analogous to intestinal Peyer's patches; consequently, local immunization or infections with sexually transmitted pathogens induce low immune responses. Human immunodeficiency virus 1 (HIV-1) infection must be primarily considered as a mucosal disease with extensive involvement of the systemic immune compartment. Although the majority of infections is acquired through the genital mucosa, a high rate of virus replication and profound CD4(+) T cell depletion occurs in the intestinal mucosa and other mucosal tissues shortly after infection. Evaluation of HIV-specific antibodies in sera and external secretions, including vaginal washes and semen, unexpectedly revealed a selective lack of IgA responses. Moreover, specific antibody-secreting cells in peripheral blood were of the IgG isotype, even in mucosally infected individuals. Whether humoral responses to previously or newly encountered antigens are compromised in HIV-1-infected persons is under current investigation.
- Published
- 2009
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37. Shaken baby syndrome and a baby's cry.
- Author
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Talvik I, Alexander RC, and Talvik T
- Subjects
- Female, Humans, Incidence, Infant, Infant, Newborn, Male, Prospective Studies, Retrospective Studies, Risk Factors, Shaken Baby Syndrome complications, Child Abuse, Crying, Shaken Baby Syndrome epidemiology, Violence
- Abstract
The aim of this study was to investigate the relationship between crying of an infant and inflicted head injury by shaking and/or impact. During the period between January 1, 1997 and December 31, 2003, 26 cases of shaken baby syndrome (SBS) were identified in Estonia. The incidence of SBS was 28.7 per 100,000 children under 1 year of age during the whole study period. In this group there were four children from twin pairs: two twin boys and a girl from a twin pair and a boy from another twin pair. This represents 15.4% of the 26 cases. Twins in Estonia represent 2.12% of infant births. The mean age on admission was 3.9 months. According to outpatient records almost all parents (88.5%) in the study group (23/26) had contacted their family physicians and other specialists because of excessive crying or irritability of the baby prior to the admission to the hospital with SBS or death. We found that the time curve of crying was similar to the curve of highest incidence of cases of SBS except the crying curve began earlier. CONCLUSION. Our data confirm that the families with twins are at additional risk for SBS and parent's complaints of excessive crying of their infants should be taken as signal that parents need to be carefully counselled.
- Published
- 2008
- Full Text
- View/download PDF
38. 5' transcript replacement in vitro catalyzed by a group I intron-derived ribozyme.
- Author
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Alexander RC, Baum DA, and Testa SM
- Subjects
- Base Sequence, Catalysis, Exons genetics, Genes, ras genetics, Guanosine Monophosphate genetics, Hydrolysis, Models, Chemical, Mutagenesis, Site-Directed, Pneumocystis carinii enzymology, Pneumocystis carinii genetics, RNA, Catalytic chemistry, RNA, Fungal chemistry, 5' Untranslated Regions genetics, Introns genetics, RNA Splicing, RNA, Catalytic genetics, RNA, Fungal genetics
- Abstract
Group I intron-derived ribozymes can perform a variety of catalytic reactions, including the replacement of the 3' end of a mutant RNA transcript with a corrected version of the transcript [Sullenger, B. A., and Cech, T. R. (1994) Nature 371, 619-622]. We now demonstrate in vitro that a ribozyme, derived from a Pneumocystis carinii group I intron, can replace the 5' end of a targeted exogenous RNA with an endogenous RNA. Our model system is a short synthetic mimic of a k-ras transcript, in which substitution mutations at codon 12 are implicated in a host of cancer types. In these experiments, yields of up to 70% were obtained. We analyzed the length dependence of two molecular contacts, P9.0 and P10, that occur between the ribozyme and the exogenous k-ras mimic, and determined that longer, and thus more stable, interactions result in higher product yields. Furthermore, the length of the loop region L1 can substantially influence the yield and the rate of the reaction. These results are a further demonstration that group I intron-derived ribozymes are quite malleable in terms of intermolecular recognition and catalysis, and that these properties can be exploited in developing potentially useful biochemical tools.
- Published
- 2005
- Full Text
- View/download PDF
39. Canonical nucleosides can be utilized by T4 DNA ligase as universal template bases at ligation junctions.
- Author
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Alexander RC, Johnson AK, Thorpe JA, Gevedon T, and Testa SM
- Subjects
- Bacteriophage T4 enzymology, Base Pair Mismatch, Base Sequence, Kinetics, Oligonucleotides chemistry, Oligonucleotides metabolism, Templates, Genetic, DNA Ligases metabolism, Genetic Techniques, Nucleosides metabolism
- Abstract
T4 DNA ligase catalyzes the template-dependent ligation of DNA. Using T4 DNA ligase under specific experimental conditions, we demonstrate that each of the four canonical nucleosides, centrally located on a template molecule such that they flank the site of ligation, can direct the ligation of nucleic acids regardless of the identity of the terminal nucleosides being covalently joined. This universal templating capability extends to those positions adjacent to the ligation junction. This is the first report, irrespective of the ligation method used or the identity of the template nucleosides (including analogs), which shows that nucleosides can act essentially as universal templates at ligation junctions in vitro. The canonical nucleosides do, however, differ in their ability to template sequence- independent ligations, with thymidine and guanosine being equally effective, yet more effective than adenosine and cytidine. Results indicate that hybridization strength surrounding the ligation junction is an important factor. The implications of this previously undiscovered property of T4 DNA ligase with canonical nucleosides are discussed.
- Published
- 2003
- Full Text
- View/download PDF
40. Poverty and child abuse: suffer the children.
- Author
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Alexander RC and Johnson MC
- Subjects
- Child, Humans, Nervous System growth & development, Socioeconomic Factors, Child Abuse statistics & numerical data, Poverty
- Published
- 2000
41. Changing patterns of illicit substance use among schizophrenic patients: 1984-1996.
- Author
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Patkar AA, Alexander RC, Lundy A, and Certa KM
- Subjects
- Adult, Catchment Area, Health, Female, Humans, Male, Psychiatric Status Rating Scales, Retrospective Studies, Substance-Related Disorders urine, Urban Population, Illicit Drugs, Schizophrenia complications, Substance-Related Disorders complications, Substance-Related Disorders diagnosis
- Abstract
Over 1,700 psychiatric emergency room visits of schizophrenic and schizoaffective patients between 1984 and 1996 were reviewed, and urine drug screens (UDS) were recorded. Illicit drug use increased significantly over the 12-year period, with a large increase for cocaine (0% to 73% of positive UDS), a decline for amphetamines (60% to 0%), and a small increase for marijuana (0% to 27%). Opiate and sedative use remained unchanged. The results support the impression that cocaine use increased dramatically among urban schizophrenic patients beginning in 1988 and continuing to the present. Furthermore, cocaine seems to have replaced amphetamines as the preferred drug of abuse among schizophrenic persons following the crack epidemic.
- Published
- 1999
- Full Text
- View/download PDF
42. American Academy of Pediatrics. Committee on Child Abuse and Neglect and Committee on Community Health Services. Investigation and review of unexpected infant and child deaths.
- Author
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Kairys SW, Alexander RC, Block RW, Everett VD, Hymel KP, Johnson CF, Kanda MB, Malinkovich P, Bell WC, Cora-Bramble D, DuPlessis HM, Handal GA, Holmberg RE, Lavin A, Tayloe DT Jr, Varrasso DA, and Wood DL
- Subjects
- Adolescent, Child, Child, Preschool, Forensic Medicine standards, Humans, Infant, Interprofessional Relations, Pediatrics, Autopsy, Cause of Death, Child Abuse diagnosis
- Abstract
Although there is a continuing need for timely review of child deaths, no uniform system exists for investigation in the United States. Investigation of a death that is traumatic, unexpected, obscure, suspicious, or otherwise unexplained in a child younger than 18 years requires a scene investigation and an autopsy. Review of these deaths requires the participation of pediatricians and other professionals, usually as a child death review team. An appropriately constituted team should evaluate the death investigation process, review difficult cases, and compile child death statistics.
- Published
- 1999
43. Recombinant retrovirus vectors for the expression of MHC class II heterodimers.
- Author
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Shimada H, Alexander RC, Germana S, Sachs DH, and LeGuern C
- Subjects
- Animals, Blotting, Northern, Blotting, Southern, Flow Cytometry, Gene Transfer Techniques, HLA-DQ alpha-Chains, HLA-DQ beta-Chains, Immune Tolerance, Plasmids genetics, RNA, Viral analysis, Swine, Swine, Miniature, Transcription, Genetic, Transduction, Genetic, Transfection, DNA, Recombinant genetics, DNA, Viral genetics, Genetic Vectors genetics, HLA-DQ Antigens genetics, Retroviridae genetics
- Abstract
Class II antigens are critical in determining the fate of vascularized allografts across major histocompatibility differences. We have recently developed a new approach to induce transplantation tolerance in miniature swine by creating MHC class II antigen "molecular chimerism" in bone marrow cells of potential recipients through retrovirus-mediated gene transfer. As part of this project, the ability of a recombinant double-expression vector (ZQ32N) to express MHC class II DQA and DQB was investigated. Flow cytometry analyses of ZQ32N transfected virus-producer cells demonstrated the cell surface expression of DQa/DQb heterodimers, thus suggesting a correct transcription, translation, and transport of the swine polypeptides to the cell surface. The analyses of RNA isolated from virus particles produced from ZQ32N transfected virus-producer cells indicated the DQ sequences to be correctly packaged. However, the DQ-negative cells transduced with the ZQ32N retrovirus did not show any DQ-retrovirus surface expression. Southern and Northern blot analyses of ZQ32N transfected and transduced cells strongly suggested DNA rearrangements and deletions which could account for transgene expression loss. An analysis of transduced cell genomes suggested DNA recombinations targeted to homologous sequences within the recombinant provirus. The implications of the sequence instability in designing vectors for gene therapy of organ transplantation are discussed.
- Published
- 1999
- Full Text
- View/download PDF
44. Schizencephaly associated with psychosis.
- Author
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Alexander RC, Patkar AA, Lapointe JS, Flynn SW, and Honer WG
- Subjects
- Adult, Female, Frontal Lobe pathology, Humans, Intellectual Disability diagnosis, Magnetic Resonance Imaging, Male, Septum Pellucidum abnormalities, Wechsler Scales, Frontal Lobe abnormalities, Psychotic Disorders etiology, Psychotic Disorders psychology
- Abstract
Schizencephaly is a rare disorder of brain development resulting in the formation of abnormal unilateral or bilateral clefts in the cerebral hemispheres. It is often accompanied by partial seizures, mental retardation, and hemiparesis. Two patients are described with clear psychotic symptoms with either unilateral or bilateral schizencephaly. The implications of the association between schizencephaly and psychosis in these patients for understanding the biology of the psychoses are discussed.
- Published
- 1997
- Full Text
- View/download PDF
45. Neurosyphilis occurring in a patient with schizophrenia: a cautionary tale.
- Author
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Patkar AA, Peng AT, and Alexander RC
- Subjects
- Ambulatory Care, Comorbidity, Diagnosis, Differential, Female, Humans, Middle Aged, Neurologic Examination, Neurosyphilis epidemiology, Schizophrenia epidemiology, Syphilis Serodiagnosis, Neurosyphilis diagnosis, Schizophrenia diagnosis
- Published
- 1997
- Full Text
- View/download PDF
46. Quantitative trait loci contributing to phencyclidine-induced and amphetamine-induced locomotor behavior in inbred mice.
- Author
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Alexander RC, Wright R, and Freed W
- Subjects
- Animals, Female, Genetic Markers, Mice, Mice, Inbred Strains, Amphetamine pharmacology, Central Nervous System Stimulants pharmacology, Excitatory Amino Acid Antagonists pharmacology, Motor Activity drug effects, Motor Activity genetics, Phencyclidine pharmacology
- Abstract
Phencyclidine (PCP) and amphetamine (AMP) can induce psychotic syndromes in humans, whereas administration of these drugs to mice results in behavioral activation that is influenced by genetic factors. Quantitative trait loci (QTL) underlying genetic differences in response to PCP and AMP in mice were provisionally identified by correlating allelic variation at known marker loci in the BXD series of recombinant inbred (RI) mice and its progenitors (C57BL/6J and DBA/2J inbred strains) with the locomotor response of each strain to PCP and AMP. Total distance traveled for individual mice from each of the 26 BXD RI and two progenitor strains was measured after injections of normal saline and 7.5 mg/kg i.p. injection of PCP. This procedure was repeated after 1 week, using 5.0 mg/kg of AMP, instead of PCP. Markers significantly (p < .01) correlated with response to PCP map to murine chromosomes 1, 14, and 15. Response to amphetamine was correlated with markers mapping to chromosomes 4, 5, 6, 8, 14, and 18. Identification of the QTL underlying PCP-induced and AMP-induced behavior in mice may provide clues into the complicated genetics of psychosis in humans.
- Published
- 1996
- Full Text
- View/download PDF
47. Parotid gland swelling with clozapine.
- Author
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Patkar AA and Alexander RC
- Subjects
- Adult, Humans, Male, Schizophrenia, Paranoid drug therapy, Antipsychotic Agents adverse effects, Clozapine adverse effects, Edema chemically induced, Parotid Diseases chemically induced
- Published
- 1996
48. Investigating abuse in the asymptomatic twin.
- Author
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Alexander RC and Smith WL
- Subjects
- Humans, Infant, Battered Child Syndrome diagnosis, Child Abuse diagnosis, Diseases in Twins diagnosis
- Published
- 1996
- Full Text
- View/download PDF
49. Further evidence for a quantitative trait locus on murine chromosome 10 controlling morphine preference in inbred mice.
- Author
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Alexander RC, Heydt D, Ferraro TN, Vogel W, and Berrettini WH
- Subjects
- Animals, Mice, Phenotype, Chromosome Mapping, Consummatory Behavior, Mice, Inbred C57BL genetics, Mice, Inbred DBA genetics, Morphine
- Published
- 1996
- Full Text
- View/download PDF
50. Current and emerging concepts in child abuse.
- Author
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Alexander RC
- Subjects
- Adult, Child, Child Abuse, Sexual, Humans, Child Abuse prevention & control
- Abstract
Within the three decades since Henry Kempe first popularized the concept of "the battered child syndrome," much has been learned not only about physical abuse but also neglect and sexual abuse. More recently, physicians with an interest in child abuse have expanded their focus to include child death review and other prevention strategies. Despite the increasing specialization of child abuse evaluation and management, all physicians working with children are likely to encounter child abuse in their practice. In 1994, more than 3.1 million reports of child abuse were made, of which more than 1 million had enough evidence to substantiate the allegations. Approximately one-half of all substantiated child abuse reports were for neglect. Physical abuse was involved in 21% and sexual abuse in about 11%. In 3% of the cases, the newer category of mental injury (emotional abuse/neglect) also was present. Despite the increase in the reporting of child abuse, the percentage of adults who have experienced child maltreatment (approximately 25% to 33%) probably has not changed significantly during this century. Most people who are victims of child abuse still never come to the overt attention of physicians, social workers, or other professionals, but the hidden emotional consequences have a considerable impact on the mental and medical health care systems. This article will briefly review the following three major categories of child abuse to highlight some of the thinking behind recent advances: Neglect; Physical Abuse; and Sexual Abuse. We will also discuss Prevention.
- Published
- 1995
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