287 results on '"Gill, Michael"'
Search Results
102. DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia.
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Hannon, Eilis, Dempster, Emma L., Mansell, Georgina, Burrage, Joe, Bass, Nick, Bohlken, Marc M., Corvin, Aiden, Curtis, Charles J., Dempster, David, Di Forti, Marta, Dinan, Timothy G., Donohoe, Gary, Gaughran, Fiona, Gill, Michael, Gillespie, Amy, Gunasinghe, Cerisse, Hulshoff, Hilleke E., Hultman, Christina M., Johansson, Viktoria, and Kahn, René S.
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DNA methylation , *GUT microbiome , *LABORATORY mice , *SCHIZOPHRENIA , *PSYCHOSES , *GLYCANS - Abstract
Genes encoding glycosyltransferases can be under relatively high selection pressure, likely due to the involvement of the glycans synthesized in host-microbe interactions. Here, we used mice as an experimental model system to investigate whether loss of α−1,3-galactosyltransferase gene (GGTA1) function and Galα1-3Galβ1-4GlcNAcβ1-R (αGal) glycan expression affects host-microbiota interactions, as might have occurred during primate evolution. We found that Ggta1 deletion shaped the composition of the gut microbiota. This occurred via an immunoglobulin (Ig)-dependent mechanism, associated with targeting of αGal-expressing bacteria by IgA. Systemic infection with an Ig-shaped microbiota inoculum elicited a less severe form of sepsis compared to infection with non-Ig-shaped microbiota. This suggests that in the absence of host αGal, antibodies can shape the microbiota towards lower pathogenicity. Given the fitness cost imposed by bacterial sepsis, we infer that the observed reduction in microbiota pathogenicity upon Ggta1 deletion in mice may have contributed to increase the frequency of GGTA1 loss-of-function mutations in ancestral primates that gave rise to humans. [ABSTRACT FROM AUTHOR]
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- 2021
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103. COVID‐19 Crisis Reduces Free Tropospheric Ozone Across the Northern Hemisphere.
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Steinbrecht, Wolfgang, Kubistin, Dagmar, Plass‐Dülmer, Christian, Davies, Jonathan, Tarasick, David W., Gathen, Peter von der, Deckelmann, Holger, Jepsen, Nis, Kivi, Rigel, Lyall, Norrie, Palm, Matthias, Notholt, Justus, Kois, Bogumil, Oelsner, Peter, Allaart, Marc, Piters, Ankie, Gill, Michael, Van Malderen, Roeland, Delcloo, Andy W., and Sussmann, Ralf
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TROPOSPHERIC ozone , *COVID-19 pandemic , *PHOTOCHEMICAL smog , *OZONE layer , *OZONE layer depletion , *ATMOSPHERIC composition , *COVID-19 - Abstract
Throughout spring and summer 2020, ozone stations in the northern extratropics recorded unusually low ozone in the free troposphere. From April to August, and from 1 to 8 kilometers altitude, ozone was on average 7% (≈4 nmol/mol) below the 2000–2020 climatological mean. Such low ozone, over several months, and at so many stations, has not been observed in any previous year since at least 2000. Atmospheric composition analyses from the Copernicus Atmosphere Monitoring Service and simulations from the NASA GMI model indicate that the large 2020 springtime ozone depletion in the Arctic stratosphere contributed less than one‐quarter of the observed tropospheric anomaly. The observed anomaly is consistent with recent chemistry‐climate model simulations, which assume emissions reductions similar to those caused by the COVID‐19 crisis. COVID‐19 related emissions reductions appear to be the major cause for the observed reduced free tropospheric ozone in 2020. Plain Language Summary: Worldwide actions to contain the COVID‐19 virus have closed factories, grounded airplanes, and have generally reduced travel and transportation. Less fuel was burnt, and less exhaust was emitted into the atmosphere. Due to these measures, the concentration of nitrogen oxides and volatile organic compounds (VOCs) decreased in the atmosphere. These substances are important for photochemical production and destruction of ozone in the atmosphere. In clean or mildly polluted air, reducing nitrogen oxides and/or VOCs will reduce the photochemical production of ozone and result in less ozone. In heavily polluted air, in contrast, reducing nitrogen oxides can increase ozone concentrations, because less nitrogen oxide is available to destroy ozone. In this study, we use data from three types of ozone instruments, but mostly from ozonesondes on weather balloons. The sondes fly from the ground up to 30 kilometers altitude. In the first 8 km, we find significantly reduced ozone concentrations in the northern extratropics during spring and summer of 2020, less than in any other year since at least 2000. We suggest that reduced emissions due to the COVID‐19 crisis have lowered photochemical ozone production and have caused the observed ozone reductions in the troposphere. Key Points: In spring and summer 2020, stations in the northern extratropics report on average 7% (4 nmol/mol) less tropospheric ozone than normalSuch low tropospheric ozone, over several months, and at so many sites, has not been observed in any previous year since at least 2000Most of the reduction in tropospheric ozone in 2020 is likely due to emissions reductions related to the COVID‐19 pandemic [ABSTRACT FROM AUTHOR]
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- 2021
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104. Childhood trauma, parental bonding, and social cognition in patients with schizophrenia and healthy adults.
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Rokita, Karolina I., Dauvermann, Maria R., Mothersill, David, Holleran, Laurena, Holland, Jessica, Costello, Laura, Cullen, Caroline, Kane, Ruán, McKernan, Declan, Morris, Derek W., Kelly, John, Gill, Michael, Corvin, Aiden, Hallahan, Brian, McDonald, Colm, and Donohoe, Gary
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SOCIAL perception , *PEOPLE with schizophrenia , *EMOTION recognition , *COGNITIVE development , *THEORY of mind - Abstract
Objective: This study investigated associations between childhood trauma, parental bonding, and social cognition (i.e., Theory of Mind and emotion recognition) in patients with schizophrenia and healthy adults. Methods: Using cross‐sectional data, we examined the recollections of childhood trauma experiences and social cognitive abilities in 74 patients with schizophrenia and 116 healthy adults. Results: Patients had significantly higher scores compared with healthy participants on childhood trauma, and lower scores on parental bonding and social cognitive measures. Physical neglect was found to be the strongest predictor of emotion recognition impairments in both groups. Optimal parental bonding attenuated the impact of childhood trauma on emotion recognition. Conclusion: The present study provides evidence of an association between physical neglect and emotion recognition in patients with schizophrenia and healthy individuals and shows that both childhood trauma and parental bonding may influence social cognitive development. Psychosocial interventions should be developed to prevent and mitigate the long‐term effects of childhood adversities. [ABSTRACT FROM AUTHOR]
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- 2021
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105. Long-term potentiation is independent of the C-tail of the GluA1 AMPA receptor subunit.
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Díaz-Alonso, Javier, Morishita, Wade, Incontro, Salvatore, Simms, Jeffrey, Holtzman, Julia, Gill, Michael, Mucke, Lennart, Malenka, Robert C., and Nicoll, Roger A.
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AMPA receptors , *SPATIAL memory - Abstract
We tested the proposal that the C-terminal domain (CTD) of the AMPAR subunit GluA1 is required for LTP. We found that a knock-in mouse lacking the CTD of GluA1 expresses normal LTP and spatial memory, assayed by the Morris water maze. Our results support a model in which LTP generates synaptic slots, which capture passively diffusing AMPARs. [ABSTRACT FROM AUTHOR]
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- 2020
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106. Detecting schizophrenia at the level of the individual: relative diagnostic value of whole-brain images, connectome-wide functional connectivity and graph-based metrics.
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Lei, Du, Pinaya, Walter H. L., van Amelsvoort, Therese, Marcelis, Machteld, Donohoe, Gary, Mothersill, David O., Corvin, Aiden, Gill, Michael, Vieira, Sandra, Huang, Xiaoqi, Lui, Su, Scarpazza, Cristina, Young, Jonathan, Arango, Celso, Bullmore, Edward, Qiyong, Gong, McGuire, Philip, and Mechelli, Andrea
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DIAGNOSIS of schizophrenia , *BRAIN mapping , *DIAGNOSTIC imaging , *MACHINE learning , *MAGNETIC resonance imaging , *COMPUTERS in medicine , *LOGISTIC regression analysis , *NEURAL pathways , *DESCRIPTIVE statistics - Abstract
Background: Previous studies using resting-state functional neuroimaging have revealed alterations in whole-brain images, connectome-wide functional connectivity and graph-based metrics in groups of patients with schizophrenia relative to groups of healthy controls. However, it is unclear which of these measures best captures the neural correlates of this disorder at the level of the individual patient. Methods: Here we investigated the relative diagnostic value of these measures. A total of 295 patients with schizophrenia and 452 healthy controls were investigated using resting-state functional Magnetic Resonance Imaging at five research centres. Connectome-wide functional networks were constructed by thresholding correlation matrices of 90 brain regions, and their topological properties were analyzed using graph theory-based methods. Single-subject classification was performed using three machine learning (ML) approaches associated with varying degrees of complexity and abstraction, namely logistic regression, support vector machine and deep learning technology. Results: Connectome-wide functional connectivity allowed single-subject classification of patients and controls with higher accuracy (average: 81%) than both whole-brain images (average: 53%) and graph-based metrics (average: 69%). Classification based on connectome-wide functional connectivity was driven by a distributed bilateral network including the thalamus and temporal regions. Conclusion: These results were replicated across the three employed ML approaches. Connectome-wide functional connectivity permits differentiation of patients with schizophrenia from healthy controls at single-subject level with greater accuracy; this pattern of results is consistent with the 'dysconnectivity hypothesis' of schizophrenia, which states that the neural basis of the disorder is best understood in terms of system-level functional connectivity alterations. [ABSTRACT FROM AUTHOR]
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- 2020
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107. Prevalence of N-Methyl-d-Aspartate Receptor antibody (NMDAR-Ab) encephalitis in patients with first episode psychosis and treatment resistant schizophrenia on clozapine, a population based study.
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Kelleher, Eric, McNamara, Patricia, Dunne, Jean, Fitzmaurice, Brian, Heron, Elizabeth A., Whitty, Peter, Walsh, Richard, Mooney, Christina, Hogan, Denise, Conlon, Niall, Gill, Michael, Vincent, Angela, Doherty, Colin P., and Corvin, Aiden
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ANTI-NMDA receptor encephalitis , *METHYL aspartate receptors , *RECEPTOR antibodies , *ENCEPHALITIS , *MENTAL health services , *SERODIAGNOSIS , *DRUG therapy for psychoses , *AUTOANTIBODIES , *RESEARCH , *PSYCHOSES , *RESEARCH methodology , *RETROSPECTIVE studies , *CELL receptors , *MEDICAL cooperation , *EVALUATION research , *COMPARATIVE studies , *CLOZAPINE , *DISEASE prevalence , *EPIDEMIOLOGICAL research - Abstract
Introduction: N-methyl-d-aspartate receptor antibody (NMDAR-Ab) encephalitis consensus criteria has recently been defined. We aimed to examine the prevalence of NMDAR-Ab encephalitis in patients with first episode psychosis (FEP) and treatment resistant schizophrenia (TRS) on clozapine, using clinical investigations, antibody testing and to retrospectively apply diagnostic consensus criteria.Methods: Adult (18-65 years old) cases of FEP meeting inclusion criteria were recruited over three years and assessed using the Structured Clinical Interview for DSM-IV disorders (SCID). NMDAR-Ab was identified using a live cell-based assay (L-CBA). Seropositive cases were clinically investigated for features of encephalitis including neuro-imaging, EEG and CSF where possible. Serum was retested using immunohistochemistry (IHC) as part of diagnostic criteria guidelines. A cohort of patients with TRS was also recruited.Results: 112 FEP patients were recruited over 3 years. NMDAR-Ab seroprevalence was 4/112 (3.5%) cases. One case (<1%) was diagnosed with definite NMDAR-Ab encephalitis and treated with immunotherapy. One of the three other seropositive cases met criteria for probable encephalitis. However all three were ultimately diagnosed with mood disorders with psychotic features. None have developed neurological features at three year follow up. 1/100 (1%) of patients with TRS was 100 patients with TRS were recruited. One case (1%) seropositive for NMDAR-Ab but did not meet criteria for encephalitis.Conclusions: NMDAR-Ab encephalitis as defined by consensus guidelines occured rarely in psychiatric services in this study. Further studies are needed to establish pathogenicity of serum NMDAR-Ab antibodies. Psychiatric services should be aware of the clinical features of encephalitis. [ABSTRACT FROM AUTHOR]- Published
- 2020
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108. No association between TPH2 gene polymorphisms and ADHD in a UK sample
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Sheehan, Karen, Hawi, Ziarih, Gill, Michael, and Kent, Lindsey
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TRYPTOPHAN , *ENZYMES , *SEROTONIN , *BRAIN , *BIOMARKERS , *ATTENTION-deficit hyperactivity disorder - Abstract
Abstract: Tryptophan Hydroxylase 2 (TPH2) is the rate-limiting enzyme in the biosynthesis of serotonin which is exclusively expressed in the brain. Recent molecular studies reported significant association between markers mapped to TPH2 and psychiatric conditions including ADHD. We have examined four single nucleotide polymorphisms (SNPs) two of which (rs1843809, rs1386493) were reported to associate with ADHD in an Irish ADHD sample. Transmission disequilibrium analysis revealed no significant association between any of these markers and ADHD. Dividing by the sex of the transmitting parent has also failed to replicate the previously reported paternal over-transmission of the associated alleles to ADHD probands. A larger sample size will be required to clarify if TPH2 alleles are or are not associated with ADHD. [Copyright &y& Elsevier]
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- 2007
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109. Reply to Joober and Sengupta.
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Segurado, Ricardo, Hawi, Ziarih, and Gill, Michael
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LETTERS to the editor , *ATTENTION-deficit hyperactivity disorder - Abstract
A letter to the editor is presented in response to the article "Parent-of-origin effect and risk for attention-deficit/hyperactivity disorder: Balancing the evidence against bias and chance findings," by Ridha Joober and Sarojini Sengupta in the present issue of the journal.
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- 2006
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110. A Preliminary Study on the Abundance, Seasonality, and Sampling Patterns of Amblyomma americanum (Acari: Ixodidae) in Central Missouri.
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Grasing, Michael J., Grasing, Kenneth W., Martz, Katherine E., Gill, Michael M., Khan, Usna A., and Sempertegui-Sosa, Carolina D.
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IXODIDAE , *MITES , *AMBLYOMMA , *DRY ice , *RHIPICEPHALUS , *TICKS - Abstract
Amblyomma americanum (Ixodida: Ixodidae) is Missouri's most common tick species and a carrier of bacterial pathogens. The objectives of this study were to analyze tick abundance and seasonality in two locations in central Missouri, to compare the effectiveness of dragging and dry ice trap sampling methods for collecting A. americanum in the field, and to analyze tick developmental stage collection pattern. We collected ticks from Knob Noster State Park, in Johnson County, Missouri and Mark Twain National Forest, in Boone County, Missouri. On eight dates from May to November, we collected ticks simultaneously at both locations, using dry ice traps and drag sampling. Of the 7,475 collected ticks, 99.7% were A. americanum. We found the most larvae in August and September, the most nymphs in June and July, and the most adults in June. Drag sampling collected more nymphs at Columbia than Knob Noster on one sampling date in the late summer. Abundance did not differ between locations at any other time point, regardless of developmental stage or sampling method. Compared to the drag method, significantly more nymphs and adults were identified using the dry ice trap sampling method. Additionally, we found that nymphs and adults were more likely to be found in the same areas of the sampling locations, but neither larvae and adults nor nymphs and larvae followed this relationship. Our findings demonstrate a strong seasonality of A. americanum in Missouri and support dry ice trapping as an effective sampling method for collecting all of its life stages. [ABSTRACT FROM AUTHOR]
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- 2020
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111. Principles of Psychiatric Genetics.
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GILL, MICHAEL
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GENETICS , *PSYCHIATRY - Published
- 2014
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112. Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer’s disease.
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Baker, Emily, Sims, Rebecca, Leonenko, Ganna, Frizzati, Aura, Harwood, Janet C., Grozeva, Detelina, null, null, Morgan, Kevin, Passmore, Peter, Holmes, Clive, Powell, John, Brayne, Carol, Gill, Michael, Mead, Simon, Bossù, Paola, Spalletta, Gianfranco, Goate, Alison M., Cruchaga, Carlos, Maier, Wolfgang, and Heun, Reinhard
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ALZHEIMER'S disease , *SINGLE nucleotide polymorphisms , *GENES , *CIRCADIAN rhythms , *MOLECULAR genetics , *CHOLESTEROL metabolism - Abstract
Late onset Alzheimer’s disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer’s disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer’s Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer’s cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10−6), RORA (p = 7.4 × 10−7) and ZNF423 (p = 2.1 × 10−6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer’s disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer’s disease-specific protein network and is likely involved with centrosomes and DNA damage repair. [ABSTRACT FROM AUTHOR]
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- 2019
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113. Building a supportive framework for brain research in Ireland: Inaugural position paper of the Irish Brain Council.
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Rogers, Mags, Boland, Barry, Clarke, Sarah, Craven, Audrey, Fassbender, Catherine, Gill, Michael, Hardiman, Orla, Henshall, David C., Lynch, Tim, Mitchell, Kevin, Pender, Niall, Rogan, Carol, and Roche, Richard A. P.
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APHASIA , *BRAIN , *AMYOTROPHIC lateral sclerosis , *SPINAL muscular atrophy - Published
- 2019
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114. Targeted Sequencing of 10,198 Samples Confirms Abnormalities in Neuronal Activity and Implicates Voltage-Gated Sodium Channels in Schizophrenia Pathogenesis.
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Rees, Elliott, Carrera, Noa, Morgan, Joanne, Hambridge, Kirsty, Escott-Price, Valentina, Pocklington, Andrew J., Richards, Alexander L., Pardiñas, Antonio F., McDonald, Colm, Donohoe, Gary, Morris, Derek W., Kenny, Elaine, Kelleher, Eric, Gill, Michael, Corvin, Aiden, Kirov, George, Walters, James T.R., Holmans, Peter, Owen, Michael J., and O'Donovan, Michael C.
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SODIUM channels , *CALCIUM channels , *HUMAN abnormalities , *SCHIZOPHRENIA , *GENOMES - Abstract
Abstract Background Sequencing studies have pointed to the involvement in schizophrenia of rare coding variants in neuronally expressed genes, including activity-regulated cytoskeleton-associated protein (ARC) and N -methyl-D-aspartate receptor (NMDAR) complexes; however, larger samples are required to reveal novel genes and specific biological mechanisms. Methods We sequenced 187 genes, selected for prior evidence of association with schizophrenia, in a new dataset of 5207 cases and 4991 controls. Included among these genes were members of ARC and NMDAR postsynaptic protein complexes, as well as voltage-gated sodium and calcium channels. We performed a rare variant meta-analysis with published sequencing data for a total of 11,319 cases, 15,854 controls, and 1136 trios. Results While no individual gene was significantly associated with schizophrenia after genome-wide correction for multiple testing, we strengthen the evidence that rare exonic variants in the ARC (p = 4.0 × 10–4) and NMDAR (p = 1.7 × 10–5) synaptic complexes are risk factors for schizophrenia. In addition, we found that loss-of-function variants and missense variants at paralog-conserved sites were enriched in voltage-gated sodium channels, particularly the alpha subunits (p = 8.6 × 10–4). Conclusions In one of the largest sequencing studies of schizophrenia to date, we provide novel evidence that multiple voltage-gated sodium channels are involved in schizophrenia pathogenesis and confirm the involvement of ARC and NMDAR postsynaptic complexes. [ABSTRACT FROM AUTHOR]
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- 2019
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115. Reduced Cancer Survival Among Adults With HIV and AIDS-Defining Illnesses Despite No Difference in Cancer Stage at Diagnosis.
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Grover, Surbhi MD, MPH, Desir, Fidel MPH, Jing, Yuezhou MS, Bhatia, Rohini K. BA, Trifiletti, Daniel M. MD, Swisher-McClure, Samuel MD, Kobie, Julie PhD, Moore, Richard D. MD, MHS, Rabkin, Charles S. MD, MSc, Silverberg, Michael J. PhD, MPH, Salters, Kate PhD, Mathews, William Christopher MD, MSPH, Gill, Michael John MB, ChB, MS, Thorne, Jennifer E. MD, PhD, Castilho, Jessica MD, MPH, Kitahata, Mari M. MD, MPH, Justice, Amy MD, PhD, Horberg, Michael A. MD, Achenbach, Chad J. MD, MPH, and Mayor, Angel M. MD
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Background: It is not known whether immune dysfunction is associated with increased risk of death after cancer diagnosis in persons with HIV (PWH). AIDS-defining illness (ADI) can signal significant immunosuppression. Our objective was to determine differences in cancer stage and mortality rates in PWH with and without history of ADI. Methods: PWH with anal, oropharynx, cervical, lung cancers, or Hodgkin lymphoma diagnoses from January 2000 to December 2009 in the North American AIDS Cohort Collaboration on Research and Design were included. Results: Among 81,865 PWH, 814 had diagnoses included in the study; 341 (39%) had a history of ADI at time of cancer diagnosis. For each cancer type, stage at diagnosis did not differ by ADI (P > 0.05). Mortality and survival estimates for cervical cancer were limited by n = 5 diagnoses. Adjusted mortality rate ratios showed a 30%-70% increase in mortality among those with ADI for all cancer diagnoses, although only lung cancer was statistically significant. Survival after lung cancer diagnosis was poorer in PWH with ADI vs. without (P = 0.0001); the probability of survival was also poorer in those with ADI at, or before other cancers although not statistically significant. Conclusions: PWH with a history of ADI at lung cancer diagnosis had higher mortality and poorer survival after diagnosis compared to those without. Although not statistically significant, the findings of increased mortality and decreased survival among those with ADI (vs. without) were consistent for all other cancers, suggesting the need for further investigations into the role of HIV-related immune suppression and cancer outcomes. [ABSTRACT FROM AUTHOR]
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- 2018
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116. The Science of The Psychiatric Genomics Consortium (Part 1).
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Sullivan, Patrick, Levinson, Douglas, and Gill, Michael
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CONSORTIA , *GENOMICS , *HISTORY of psychiatry - Abstract
Overall Abstract On the advice of the Jerusalem organizers, the Psychiatric Genomics Consortium (PGC) is submitting two symposia which are meant to occur on the same afternoon. The PGC, now in its ninth year, is one of the most innovative experiments in the history of psychiatry. We have unified much of the field to enable rapid progress in elucidating the genetic basis of psychiatric disorders. We have 900+ investigators from 40+ countries and >400K subjects. The PGC has published 17 main papers plus 31 secondary analysis/methods development papers. Due to our open-source approach, there are 75+ papers that use PGC results, and numerous groups are using our findings to direct basic and applied research (including therapeutic development). Large amounts of new data will be available to the PGC in the next five years. We have developed a rigorous set of approaches that are yielding discoveries for all of the initial five disorders (which led to adding four new disorders). We thus have the unique opportunity to rapidly and efficiently increase our knowledge of common and rare variation in order to understand the causes and comorbidities of major psychiatric disorders. Our overarching goal is to identify “actionable” variation via the empirical evaluation of the etiological, clinical, nosological, therapeutic, and biological significance of our genomic findings. In Part 1, we provide a "big picture" overview of where we've been and where we are (Sklar) followed by a description of the just awarded "PGC3" grant (Sullivan). This is followed by updates of the current status and future plans for the key PGC groups: ADHD and ASD (Børglum from iPSYCH), bipolar disorder (Kelsoe), eating disorders (Bulik), and MDD (Levinson). [ABSTRACT FROM AUTHOR]
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- 2017
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117. Sex‐based differences in antiretroviral therapy initiation, switching and treatment interruptions: global overview from the International Epidemiologic Databases to Evaluate AIDS (IeDEA).
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Giles, Michelle L., Achhra, Amit C., Abraham, Alison G., Haas, Andreas D., Gill, Michael John, Lee, Man Po, Luque, Marco, McGowan, Catherine, Cornell, Morna, Braitstein, Paula, de Rekeneire, Nathalie, Becquet, Renaud, Wools‐Kaloustian, Kara, and Law, Matthew
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HIGHLY active antiretroviral therapy , *ANTIRETROVIRAL agents , *HIV infections , *THERAPEUTICS , *HIV-positive persons , *HIV , *DIAGNOSIS of HIV infections - Abstract
Abstract: Introduction: In 2015, the World Health Organization recommended that all HIV‐infected individuals consider ART initiation as soon as possible after diagnosis. Sex differences in choice of initial ART regimen, indications for switching, time to switching and choice of second‐line regimens have not been well described. The aims of this study were to describe first‐line ART and CD4 count at ART initiation by sex, calendar year and region, and to analyse time to change or interruption in first‐line ART, according to sex in each region. Methods: Participating cohorts included: Southern, East and West Africa (IeDEA‐Africa), North America (NA‐ACCORD), Caribbean, Central/South America (CCASAnet) and Asia‐Pacific including Australia (IeDEA Asia‐Pacific). The primary outcomes analysed for each region and according to sex were choice of initial ART, time to switching and time to discontinuation of the first‐line regimen. Results and Discussion: The combined cohort data set comprised of 715,252 participants across seven regions from low‐ to high‐income settings. The median CD4 count at treatment initiation was lower in men compared with women in nearly all regions and time periods. Women from North America and Southern Africa were more likely to switch ART compared to men (p < 0.001) with approximately 90% of women reporting a major change after 10 years in North America. Overall, after 8 years on ART, >50% of HIV‐ positive men and women from Southern Africa, East Africa, South and Central America remained on their original regimen. Men were more likely to have a treatment interruption compared with women in low‐ and middle‐income countries from the Asia/Pacific region (p < 0.001) as were men from Southern Africa (p < 0.001). Greater than 75% of men and women did not report a treatment interruption after 10 years on ART from all regions except North America and Southern Africa. Conclusions: There are regional variations in the ART regimen commenced at baseline and rates of major change and treatment interruption according to sex. Some of this is likely to reflect changes in local and international antiretroviral guideline recommendations but other sex‐specific factors such as pregnancy may contribute to these differences. [ABSTRACT FROM AUTHOR]
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- 2018
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118. Optoacoustics delineates murine breast cancer models displaying angiogenesis and vascular mimicry.
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Quiros-Gonzalez, Isabel, Tomaszewski, Michal R, Aitken, Sarah J., Ansel-Bollepalli, Laura, McDuffus, Leigh-Ann, Gill, Michael, Hacker, Lina, Brunker, Joanna, and Bohndiek, Sarah E.
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BREAST tumor diagnosis , *ANIMAL experimentation , *BREAST tumors , *CELL lines , *COMPARATIVE studies , *DRUG monitoring , *RESEARCH methodology , *MEDICAL cooperation , *MICE , *RESEARCH , *RESEARCH funding , *SOUND , *TOMOGRAPHY , *TUMOR classification , *EVALUATION research , *OXYGEN consumption , *PATHOLOGIC neovascularization - Abstract
Background: Optoacoustic tomography (OT) of breast tumour oxygenation is a promising new technique, currently in clinical trials, which may help to determine disease stage and therapeutic response. However, the ability of OT to distinguish breast tumours displaying different vascular characteristics has yet to be established. The aim of the study is to prove OT as a sensitive technique for differentiating breast tumour models with manifestly different vasculatures.Methods: Multispectral OT (MSOT) was performed in oestrogen-dependent (MCF-7) and oestrogen-independent (MDA-MB-231) orthotopic breast cancer xenografts. Total haemoglobin (THb) and oxygen saturation (SO2MSOT) were calculated. Pathological and biochemical evaluation of the tumour vascular phenotype was performed for validation.Results: MCF-7 tumours show SO2MSOT similar to healthy tissue in both rim and core, despite significantly lower THb in the core. MDA-MB-231 tumours show markedly lower SO2MSOT with a significant rim-core disparity. Ex vivo analysis revealed that MCF-7 tumours contain fewer blood vessels (CD31+) that are more mature (CD31+/aSMA+) than MDA-MB-231. MCF-7 presented higher levels of stromal VEGF and iNOS, with increased NO serum levels. The vasculogenic process observed in MCF-7 was consistent with angiogenesis, while MDA-MB-231 appeared to rely more on vascular mimicry.Conclusions: OT is sensitive to differences in the vascular phenotypes of our breast cancer models. [ABSTRACT FROM AUTHOR]- Published
- 2018
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119. Istradefylline reduces memory deficits in aging mice with amyloid pathology.
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Orr, Anna G., Lo, Iris, Schumacher, Heike, Ho, Kaitlyn, Gill, Michael, Guo, Weikun, Kim, Daniel H., Knox, Anthony, Saito, Takashi, Saido, Takaomi C., Simms, Jeffrey, Toddes, Carlee, Wang, Xin, Yu, Gui-Qiu, and Mucke, Lennart
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ADENOSINES , *CELL receptors , *NEUROLOGICAL disorders , *ALZHEIMER'S disease , *ASTROCYTES - Abstract
Adenosine A 2A receptors are putative therapeutic targets for neurological disorders. The adenosine A 2A receptor antagonist istradefylline is approved in Japan for Parkinson's disease and is being tested in clinical trials for this condition elsewhere. A 2A receptors on neurons and astrocytes may contribute to Alzheimer's disease (AD) by impairing memory. However, it is not known whether istradefylline enhances cognitive function in aging animals with AD-like amyloid plaque pathology. Here, we show that elevated levels of Aβ, C-terminal fragments of the amyloid precursor protein (APP), or amyloid plaques, but not overexpression of APP per se, increase astrocytic A 2A receptor levels in the hippocampus and neocortex of aging mice. Moreover, in amyloid plaque-bearing mice, low-dose istradefylline treatment enhanced spatial memory and habituation, supporting the conclusion that, within a well-defined dose range, A 2A receptor blockers might help counteract memory problems in patients with Alzheimer's disease. [ABSTRACT FROM AUTHOR]
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- 2018
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120. Increased non-AIDS mortality among persons with AIDS-defining events after antiretroviral therapy initiation.
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Pettit, April C, Giganti, Mark J, Ingle, Suzanne M, May, Margaret T, Shepherd, Bryan E, Gill, Michael J, Fätkenheuer, Gerd, Abgrall, Sophie, Saag, Michael S, Del Amo, Julia, Justice, Amy C, Miro, Jose M, Cavasinni, Matthias, Dabis, François, Monforte, Antonella D, Reiss, Peter, Guest, Jodie, Moore, David, Shepherd, Leah, and Obel, Niels
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MORTALITY of AIDS patients , *ANTIRETROVIRAL agents , *HIV infections , *THERAPEUTICS , *CAUSES of death , *DISEASE risk factors - Abstract
INTRODUCTION: HIV-1 infection leads to chronic inflammation and to an increased risk of non-AIDS mortality. Our objective was to determine whether AIDS-defining events (ADEs) were associated with increased overall and cause-specific non-AIDS related mortality after antiretroviral therapy (ART) initiation. METHODS: We included HIV treatment-naïve adults from the Antiretroviral Therapy Cohort Collaboration (ART-CC) who initiated ART from 1996 to 2014. Causes of death were assigned using the Coding Causes of Death in HIV (CoDe) protocol. The adjusted hazard ratio (aHR) for overall and cause-specific non-AIDS mortality among those with an ADE (all ADEs, tuberculosis (TB), Pneumocystis jiroveci pneumonia (PJP), and non-Hodgkin's lymphoma (NHL)) compared to those without an ADE was estimated using a marginal structural model. RESULTS: The adjusted hazard of overall non-AIDS mortality was higher among those with any ADE compared to those without any ADE (aHR 2.21, 95% confidence interval (CI) 2.00 to 2.43). The adjusted hazard of each of the cause-specific non-AIDS related deaths were higher among those with any ADE compared to those without, except metabolic deaths (malignancy aHR 2.59 (95% CI 2.13 to 3.14), accident/suicide/overdose aHR 1.37 (95% CI 1.05 to 1.79), cardiovascular aHR 1.95 (95% CI 1.54 to 2.48), infection aHR (95% CI 1.68 to 2.81), hepatic aHR 2.09 (95% CI 1.61 to 2.72), respiratory aHR 4.28 (95% CI 2.67 to 6.88), renal aHR 5.81 (95% CI 2.69 to 12.56) and central nervous aHR 1.53 (95% CI 1.18 to 5.44)). The risk of overall and cause-specific non-AIDS mortality differed depending on the specific ADE of interest (TB, PJP, NHL). CONCLUSIONS: In this large multi-centre cohort collaboration with standardized assignment of causes of death, non-AIDS mortality was twice as high among patients with an ADE compared to without an ADE. However, non-AIDS related mortality after an ADE depended on the ADE of interest. Although there may be unmeasured confounders, these findings suggest that a common pathway may be independently driving both ADEs and NADE mortality. While prevention of ADEs may reduce subsequent death due to NADEs following ART initiation, modification of risk factors for NADE mortality remains important after ADE survival. [ABSTRACT FROM AUTHOR]
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- 2018
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121. Genetics of schizophrenia: A consensus paper of the WFSBP Task Force on Genetics.
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Giegling, Ina, Hosak, Ladislav, Mössner, Rainald, Serretti, Alessandro, Bellivier, Frank, Claes, Stephan, Collier, David A., Corrales, Alejo, DeLisi, Lynn E., Gallo, Carla, Gill, Michael, Kennedy, James L., Leboyer, Marion, Maier, Wolfgang, Marquez, Miguel, Massat, Isabelle, Mors, Ole, Muglia, Pierandrea, Nöthen, Markus M., and Ospina-Duque, Jorge
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GENETICS of schizophrenia , *DNA copy number variations , *TASK performance , *LOCUS (Genetics) , *NUCLEOTIDE sequencing , *DELETION mutation - Abstract
Objectives:Schizophrenia is a severe psychiatric disease affecting about 1% of the general population. The relative contribution of genetic factors has been estimated to be up to 80%. The mode of inheritance is complex, non-Mendelian, and in most cases involving the combined action of large numbers of genes. Methods:This review summarises recent efforts to identify genetic variants associated with schizophrenia detected, e.g., through genome-wide association studies, studies on copy-number variants or next-generation sequencing. Results:A large, new body of evidence on genetics of schizophrenia has accumulated over recent years. Many new robustly associated genetic loci have been detected. Furthermore, there is consensus that at least a dozen microdeletions and microduplications contribute to the disease. Genetic overlap between schizophrenia, other psychiatric disorders, and neurodevelopmental syndromes raised new questions regarding the current classification of psychiatric and neurodevelopmental diseases. Conclusions:Future studies will address especially the functional characterisation of genetic variants. This will hopefully open the doors to our understanding of the pathophysiology of schizophrenia and other related diseases. Complementary, integrated systems biology approaches to genomics, transcriptomics, proteomics and metabolomics may also play crucial roles in enabling a precision medicine approach to the treatment of individual patients. [ABSTRACT FROM PUBLISHER]
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- 2017
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122. A Flow-Based Model of the HIV Care Continuum in the United States.
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Gonsalves, Gregg S., Paltiel, A. David, Cleary, Paul D., Gill, Michael J., Kitahata, Mari M., Rebeiro, Peter F., Silverberg, Michael J., Horberg, Michael, Abraham, Alison G., Althoff, Keri N., Moore, Richard, Bosch, Ronald J., Tian Tang, Hall, H. Irene, and Kaplan, Edward H.
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Background: Understanding the flow of patients through the continuum of HIV care is critical to determine how best to intervene so that the proportion of HIV-infected persons who are on antiretroviral treatment and virally suppressed is as large as possible. Methods: Using immunological and virological data from the Centers for Disease Control and Prevention and the North American AIDS Cohort Collaboration on Research and Design from 2009 to 2012, we estimated the distribution of time spent in and dropout probability from each stage in the continuum of HIV care. We used these estimates to develop a queueing model for the expected number of patients found in each stage of the cascade. Results: HIV-infected individuals spend an average of about 3.1 months after HIV diagnosis before being linked to care, or dropping out of that stage of the continuum with a probability of 8%. Those who link to care wait an additional 3.7 months on average before getting their second set of laboratory results (indicating engagement in care) or dropping out of care with probability of almost 6%. Those engaged in care spent an average of almost 1 year before achieving viral suppression on antiretroviral therapy or dropping out with average probability 13%. For patients who achieved viral suppression, the average time suppressed on antiretroviral therapy was an average of 4.5 years. Conclusions: Interventions should be targeted to more rapidly identifying newly infected individuals, and increasing the fraction of those engaged in care that achieves viral suppression. [ABSTRACT FROM AUTHOR]
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- 2017
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123. Occurrence and co-occurrence of hallucinations by modality in schizophrenia-spectrum disorders.
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McCarthy-Jones, Simon, Smailes, David, Corvin, Aiden, Gill, Michael, Morris, Derek W., Dinan, Timothy G., Murphy, Kieran C., Anthony O′Neill, F., Waddington, John L., Australian Schizophrenia Research Bank, null, Donohoe, Gary, and Dudley, Robert
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HALLUCINATIONS , *SCHIZOPHRENIA , *CHRONIC diseases , *HEARING disorders , *SMELL disorders - Abstract
It is not only unclear why hallucinations in schizophrenia occur with different prevalence by modality, but also to what extent they do. Reliable prevalence estimates of hallucinations by modality in schizophrenia are currently lacking, particularly for non-auditory hallucinations. Studies have also tended to report lifetime, not point prevalence by modality. This study assessed the prevalence and co-occurrence of hallucinations, for both lifetime and point prevalence, across the auditory, visual, olfactory, and tactile modalities, in people diagnosed with chronic schizophrenia-spectrum disorders in Ireland (N=693) and Australia (N=218). Lifetime prevalence was 64–80% auditory, 23–31% visual, 9–19% tactile, and 6–10% olfactory. Past month prevalence was 23–27% auditory, 5–8% visual, 4–7% tactile, and 2% olfactory. The majority of participants had only hallucinated in one modality, with this nearly always being the auditory. Approximately one-third had hallucinated in two modalities, most commonly the auditory and visual. Most currently hallucinating patients also hallucinated in a single modality, again, nearly always the auditory. Whereas 30–37% of patients with lifetime auditory hallucinations had experienced visual hallucinations, 83–97% of patients with experience of visual hallucinations had experienced auditory hallucinations. These findings help delineate the modality distribution of hallucinations in schizophrenia, and provide an explanatory target for theoretical models. [ABSTRACT FROM AUTHOR]
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- 2017
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124. Further evidence of alerted default network connectivity and association with theory of mind ability in schizophrenia.
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Mothersill, Omar, Tangney, Noreen, Morris, Derek W., McCarthy, Hazel, Frodl, Thomas, Gill, Michael, Corvin, Aiden, and Donohoe, Gary
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THOUGHT & thinking , *MENTAL illness , *SCHIZOPHRENIA , *FUNCTIONAL magnetic resonance imaging , *PATHOLOGICAL psychology , *BRAIN mapping , *CEREBRAL cortex , *SENSORY perception , *PSYCHOSES - Abstract
Background: Resting-state functional magnetic resonance imaging (rs-fMRI) has repeatedly shown evidence of altered functional connectivity of large-scale networks in schizophrenia. The relationship between these connectivity changes and behaviour (e.g. symptoms, neuropsychological performance) remains unclear.Methods: Functional connectivity in 27 patients with schizophrenia or schizoaffective disorder, and 25 age and gender matched healthy controls was examined using rs-fMRI. Based on seed regions from previous studies, we examined functional connectivity of the default, cognitive control, affective and attention networks. Effects of symptom severity and theory of mind performance on functional connectivity were also examined.Results: Patients showed increased connectivity between key nodes of the default network including the precuneus and medial prefrontal cortex compared to controls (p<0.01, FWE-corrected). Increasing positive symptoms and increasing theory of mind performance were both associated with altered connectivity of default regions within the patient group (p<0.01, FWE-corrected).Discussion: This study confirms previous findings of default hyper-connectivity in schizophrenia spectrum patients and reveals an association between altered default connectivity and positive symptom severity. As a novel find, this study also shows that default connectivity is correlated to and predictive of theory of mind performance. Extending these findings by examining the effects of emerging social cognition treatments on both default connectivity and theory of mind performance is now an important goal for research. [ABSTRACT FROM AUTHOR]- Published
- 2017
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125. Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response.
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Fabbri, Chiara, Hosak, Ladislav, Mössner, Rainald, Giegling, Ina, Mandelli, Laura, Bellivier, Frank, Claes, Stephan, Collier, David A., Corrales, Alejo, Delisi, Lynn E., Gallo, Carla, Gill, Michael, Kennedy, James L., Leboyer, Marion, Lisoway, Amanda, Maier, Wolfgang, Marquez, Miguel, Massat, Isabelle, Mors, Ole, and Muglia, Pierandrea
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MENTAL depression , *THERAPEUTICS , *ANTIDEPRESSANTS , *EPIGENETICS , *GENE expression , *GENETIC polymorphisms - Abstract
Major depressive disorder (MDD) is a heritable disease with a heavy personal and socio-economic burden. Antidepressants of different classes are prescribed to treat MDD, but reliable and reproducible markers of efficacy are not available for clinical use. Further complicating treatment, the diagnosis of MDD is not guided by objective criteria, resulting in the risk of under- or overtreatment. A number of markers of MDD and antidepressant response have been investigated at the genetic, epigenetic, gene expression and protein levels. Polymorphisms in genes involved in antidepressant metabolism (cytochrome P450 isoenzymes), antidepressant transport (ABCB1), glucocorticoid signalling (FKBP5) and serotonin neurotransmission (SLC6A4andHTR2A) were among those included in the first pharmacogenetic assays that have been tested for clinical applicability. The results of these investigations were encouraging when examining patient-outcome improvement. Furthermore, a nine-serum biomarker panel (includingBDNF, cortisol and soluble TNF-α receptor type II) showed good sensitivity and specificity in differentiating between MDD and healthy controls. These first diagnostic and response-predictive tests for MDD provided a source of optimism for future clinical applications. However, such findings should be considered very carefully because their benefit/cost ratio and clinical indications were not clearly demonstrated. Future tests may include combinations of different types of biomarkers and be specific for MDD subtypes or pathological dimensions. [ABSTRACT FROM PUBLISHER]
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- 2017
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126. Cause-Specific Mortality in HIV-Positive Patients Who Survived Ten Years after Starting Antiretroviral Therapy.
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Trickey, Adam, May, Margaret T., Vehreschild, Janne, Obel, Niels, Gill, Michael John, Crane, Heidi, Boesecke, Christoph, Samji, Hasina, Grabar, Sophie, Cazanave, Charles, Cavassini, Matthias, Shepherd, Leah, d’Arminio Monforte, Antonella, Smit, Colette, Saag, Michael, Lampe, Fiona, Hernando, Vicky, Montero, Marta, Zangerle, Robert, and Justice, Amy C.
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HIV infections , *THERAPEUTICS , *ANTIRETROVIRAL agents , *DEATH rate , *VIRAL replication , *CD4 lymphocyte count - Abstract
Objectives: To estimate mortality rates and prognostic factors in HIV-positive patients who started combination antiretroviral therapy between 1996–1999 and survived for more than ten years. Methods: We used data from 18 European and North American HIV cohort studies contributing to the Antiretroviral Therapy Cohort Collaboration. We followed up patients from ten years after start of combination antiretroviral therapy. We estimated overall and cause-specific mortality rate ratios for age, sex, transmission through injection drug use, AIDS, CD4 count and HIV-1 RNA. Results: During 50,593 person years 656/13,011 (5%) patients died. Older age, male sex, injecting drug use transmission, AIDS, and low CD4 count and detectable viral replication ten years after starting combination antiretroviral therapy were associated with higher subsequent mortality. CD4 count at ART start did not predict mortality in models adjusted for patient characteristics ten years after start of antiretroviral therapy. The most frequent causes of death (among 340 classified) were non-AIDS cancer, AIDS, cardiovascular, and liver-related disease. Older age was strongly associated with cardiovascular mortality, injecting drug use transmission with non-AIDS infection and liver-related mortality, and low CD4 and detectable viral replication ten years after starting antiretroviral therapy with AIDS mortality. Five-year mortality risk was <5% in 60% of all patients, and in 30% of those aged over 60 years. Conclusions: Viral replication, lower CD4 count, prior AIDS, and transmission via injecting drug use continue to predict higher all-cause and AIDS-related mortality in patients treated with combination antiretroviral therapy for over a decade. Deaths from AIDS and non-AIDS infection are less frequent than deaths from other non-AIDS causes. [ABSTRACT FROM AUTHOR]
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- 2016
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127. LIMITATIONS OF OPT-OUT HIV SCREENING AND MOTHER--CHILD HIV TRANSMISSION.
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Siemieniuk, Reed A. C., Jadavji, Taj, Gill, Michael John, Hughes, Christine A., Zuk, Dalyce, Foisy, Michelle, Robinson, Joan, Singh, Ameeta E., and Houston, Stan
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LETTERS to the editor , *PRENATAL diagnosis - Abstract
A letter to the editor and a response from the authors of the article "Prenatal Screening and Perinatal HIV Transmission in Northern Alberta" in a 2009 issue is presented.
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- 2010
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128. Evaluation of cardiac function in unrestrained dogs and monkeys using left ventricular dP/dt.
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Buchanan, Lewis V., Warner, William A., Arthur, Susan R., Gleason, Carol R., Lewen, Geoff, Levesque, Paul C., and Gill, Michael W.
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HEART function tests , *BIOTELEMETRY , *CONTROL groups , *DRUG development , *LABORATORY dogs , *LABORATORY monkeys , *CARDIAC contraction - Abstract
Introduction Preclinical assessment for alterations in cardiac ventricular function for drug candidates has not been a focus of ICH S7b guidelines for cardiovascular safety studies, but there is growing interest given that the cardiovascular risk is associated with positive and negative inotropes. Methods From 2003 through 2013, 163 telemetry studies with left-ventricular function analyses were conducted in dogs and monkeys at Bristol Myers Squibb (BMS) in support for drug development programs. The ability of the telemetry system to detect changes in cardiac contractility was verified with positive control agents pimobendan and atenolol. Control data from a subset of studies were analyzed to determine dP/dt reference range values, and minimum detectable mean differences (control vs. treated) for statistical significance. Results Median minimum detectable differences for dogs ranged from 14 to 21% for positive dP/dt and 11 to 21% for negative dP/dt. For monkeys, median minimum detectable differences were 25 and 14% for positive and negative dP/dt, respectively. For BMS programs, 15 drug candidates were identified that produced primary effects on contractility. Changes in contractility that were associated with, and potentially secondary to, drug-related effects on heart rate or systemic blood pressure were observed with an additional 29 drug candidates. Discussion Changes in contractility have been observed in large animals during drug development studies at BMS over the past 10 years. Model sensitivity has been demonstrated and a dP/dt beat-to-beat cloud analysis tool has been developed to help distinguish primary effects from those potentially secondary to systemic hemodynamic changes. [ABSTRACT FROM AUTHOR]
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- 2016
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129. Mortality According to CD4 Count at Start of Combination Antiretroviral Therapy Among HIV-infected Patients Followed for up to 15 Years After Start of Treatment: Collaborative Cohort Study.
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May, Margaret T., Vehreschild, Jorg-Janne, Trickey, Adam, Obel, Niels, Reiss, Peter, Bonnet, Fabrice, Mary-Krause, Murielle, Samji, Hasina, Cavassini, Matthias, John Gill, Michael, Shepherd, Leah C., Crane, Heidi M., d’Arminio Monforte, Antonella, Burkholder, Greer A., Johnson, Margaret M., Sobrino-Vegas, Paz, Domingo, Pere, Zangerle, Robert, Justice, Amy C., and Sterling, Timothy R.
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Background. CD4 count at start of combination antiretroviral therapy (ART) is strongly associated with short-term survival, but its association with longer-term survival is less well characterized. Methods. We estimated mortality rates (MRs) by time since start of ART (<0.5, 0.5–0.9, 1–2.9, 3–4.9, 5–9.9, and ≥10 years) among patients from 18 European and North American cohorts who started ART during 1996–2001. Piecewise exponential models stratified by cohort were used to estimate crude and adjusted (for sex, age, transmission risk, period of starting ART [1996–1997, 1998–1999, 2000–2001], and AIDS and human immunodeficiency virus type 1 RNA at baseline) mortality rate ratios (MRRs) by CD4 count at start of ART (0–49, 50–99, 100–199, 200–349, 350–499, ≥500 cells/µL) overall and separately according to time since start of ART. Results. A total of 6344 of 37 496 patients died during 359 219 years of follow-up. The MR per 1000 person-years was 32.8 (95% confidence interval [CI], 30.2–35.5) during the first 6 months, declining to 16.0 (95% CI, 15.4–16.8) during 5–9.9 years and 14.2 (95% CI, 13.3–15.1) after 10 years’ duration of ART. During the first year of ART, there was a strong inverse association of CD4 count at start of ART with mortality. This diminished over the next 4 years. The adjusted MRR per CD4 group was 0.97 (95% CI, .94–1.00; P = .054) and 1.02 (95% CI, .98–1.07; P = .32) among patients followed for 5–9.9 and ≥10 years, respectively. Conclusions. After surviving 5 years of ART, the mortality of patients who started ART with low baseline CD4 count converged with mortality of patients with intermediate and high baseline CD4 counts. [ABSTRACT FROM AUTHOR]
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- 2016
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130. Expression of nuclear Methyl-CpG binding protein 2 (Mecp2) is dependent on neuronal stimulation and application of Insulin-like growth factor 1.
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Tropea, Daniela, Mortimer, Niall, Bellini, Stefania, Molinos, Ines, Sanfeliu, Albert, Shovlin, Stephen, McAllister, Donna, Gill, Michael, Mitchell, Kevin, and Corvin, Aiden
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RETT syndrome , *NEURAL stimulation , *SOMATOMEDIN C , *NEUROPLASTICITY , *DNA-binding proteins - Abstract
Methyl-CpG binding protein 2 (MECP2) is a chromosome-binding protein that regulates the development and maintenance of brain circuits. Altered function of the protein product of MECP2 plays an important role in the etiology of many neurodevelopmental disorders. Mutations involving a loss of function are implicated in the etiology of Rett syndrome, intellectual disability, psychosis and severe encephalopathy. Conversely, MECP2 duplications have been identified in autism and intellectual disability. MECP2 action is dependent on neuronal function, as the DNA binding is modulated by activity, and it is phosphorylated in response to stimulation. Although MECP2 is considered a major risk factor for neurodevelopmental disorders, and it is a mediator of activity-dependent mechanisms, the expression levels in response to neuronal activity have never been measured. We studied the expression of Mecp2 protein and RNA in mice neuronal cultures in response to different stimulation conditions and in the presence of insulin-like growth factor1 (IGF1): a growth factor involved in brain development and plasticity. The stimulation protocols were selected according to their ability to induce different forms of synaptic plasticity: rapid depolarization, feed-forward plasticity (LTP, LTD) and feedback forms of plasticity (TTX, KCl). We find a significant reduction of Mecp2 protein nuclear expression in neurons in response to stimuli that induce a potentiation of neuronal response, suggesting that Mecp2 protein expression is modulated by neuronal activation. Application of IGF1 to the cultures induces an increase in the expression of Mecp2 transcript and nuclear Mecp2 protein in neurons. These results show that Mecp2 is responsive to neuronal stimulation and IGF1, and different stimuli have different effects on Mecp2 expression; this differential response may have downstream effects on functional mechanisms regulating brain development and plasticity. [ABSTRACT FROM AUTHOR]
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- 2016
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131. Illness Severity, Social and Cognitive Ability, and EEG Analysis of Ten Patients with Rett Syndrome Treated with Mecasermin (Recombinant Human IGF-1).
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Pini, Giorgio, Congiu, Laura, Benincasa, Alberto, DiMarco, Pietro, Bigoni, Stefania, Dyer, Adam H., Mortimer, Niall, Della-Chiesa, Andrea, O’Leary, Sean, McNamara, Rachel, Mitchell, Kevin J., Gill, Michael, and Tropea, Daniela
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RETT syndrome , *SOMATOMEDIN C , *PSYCHOMOTOR disorders , *COGNITIVE ability , *ELECTROENCEPHALOGRAPHY , *THERAPEUTICS - Abstract
Rett Syndrome (RTT) is a severe neurodevelopmental disorder characterized by an apparently normal development followed by an arrest and subsequent regression of cognitive and psychomotor abilities. At present, RTT has no definitive cure and the treatment of RTT represents a largely unmet clinical need. Following partial elucidation of the underlying neurobiology of RTT, a new treatment has been proposed, Mecasermin (recombinant human Insulin-Like Growth Factor 1), which, in addition to impressive evidence from preclinical murine models of RTT, has demonstrated safety in human studies of patients with RTT. The present clinical study examines the disease severity as assessed by clinicians (International Scoring System: ISS), social and cognitive ability assessed by two blinded, independent observers (RSS: Rett Severity Score), and changes in brain activity (EEG) parameters of ten patients with classic RTT and ten untreated patients matched for age and clinical severity. Significant improvement in both the ISS (p=0.0106) and RSS (p=0.0274) was found in patients treated with IGF1 in comparison to untreated patients. Analysis of the novel RSS also suggests that patients treated with IGF1 have a greater endurance to social and cognitive testing. The present clinical study adds significant preliminary evidence for the use of IGF-1 in the treatment of RTT and other disorders of the autism spectrum. [ABSTRACT FROM AUTHOR]
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- 2016
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132. Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with attention deficit hyperactivity disorder.
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Tong, Janette, McKinley, Leigh-Anne, Cummins, Tarrant D.R., Johnson, Beth, Matthews, Natasha, Vance, Alasdair, Heussler, Helen, Gill, Michael, Kent, Lindsey, Bellgrove, Mark A., and Hawi, Ziarih
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ATTENTION-deficit hyperactivity disorder , *BEHAVIOR disorders , *NEUROTRANSMITTERS , *GENETIC polymorphism research , *LUCIFERASE genetics , *GENETICS - Abstract
Objectives. Dysregulation in neurotransmitter signalling has been implicated in the aetiology of attention deficit hyperactivity disorder (ADHD). Polymorphisms of the gene encoding dopamine beta hydroxylase (DBH) have been reported to be associated with ADHD; however, small sample sizes have led to inconsistency. Methods. We conducted transmission disequilibrium test analysis in 794 nuclear families to examine the relationship between DBH and ADHD. The effects of the ADHD-associated polymorphisms on gene expression were assessed by luciferase reporter assays in a human neuroblastoma cell line, SH-SY5Y. Results. A SNP within the 3′ untranslated region of DBH rs129882 showed a significant association with ADHD (χ2 = 9.71, p = 0.0018, OR = 1.37). This association remained significant after Bonferroni correction for multiple testing (p = 0.02). Further, allelic variation in rs129882 significantly impacted luciferase expression. Specifically, the C allele of the ADHD-associated rs129882 SNP produced a 2-fold decrease (p < 0.001) in luciferase activity. Conclusions. These data demonstrate for the first time that a DBH gene variant, rs129882, which confers risk to ADHD is also associated with reduced in vitro gene expression. Reduced DBH expression would be consistent with decreased conversion of dopamine to noradrenaline and thus with a relative hypo-noradrenergic state in ADHD. [ABSTRACT FROM AUTHOR]
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- 2015
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133. Common polygenic variation enhances risk prediction for Alzheimer's disease.
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Escott-Price, Valentina, Sims, Rebecca, Bannister, Christian, Harold, Denise, Vronskaya, Maria, Majounie, Elisa, Badarinarayan, Nandini, Morgan, Kevin, Passmore, Peter, Holmes, Clive, Powell, John, Brayne, Carol, Gill, Michael, Mead, Simon, Goate, Alison, Cruchaga, Carlos, Lambert, Jean-Charles, van Duijn, Cornelia, Maier, Wolfgang, and Ramirez, Alfredo
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ALZHEIMER'S disease risk factors , *MONOGENIC & polygenic inheritance (Genetics) , *GENOTYPES , *ALLELES , *RECEIVER operating characteristic curves , *CLINICAL trials , *ALZHEIMER'S disease , *APOLIPOPROTEINS , *DISEASE susceptibility , *GENETICS , *RESEARCH funding , *GENETIC testing , *LOGISTIC regression analysis , *RELATIVE medical risk , *CASE-control method , *SEQUENCE analysis - Abstract
The identification of subjects at high risk for Alzheimer's disease is important for prognosis and early intervention. We investigated the polygenic architecture of Alzheimer's disease and the accuracy of Alzheimer's disease prediction models, including and excluding the polygenic component in the model. This study used genotype data from the powerful dataset comprising 17 008 cases and 37 154 controls obtained from the International Genomics of Alzheimer's Project (IGAP). Polygenic score analysis tested whether the alleles identified to associate with disease in one sample set were significantly enriched in the cases relative to the controls in an independent sample. The disease prediction accuracy was investigated in a subset of the IGAP data, a sample of 3049 cases and 1554 controls (for whom APOE genotype data were available) by means of sensitivity, specificity, area under the receiver operating characteristic curve (AUC) and positive and negative predictive values. We observed significant evidence for a polygenic component enriched in Alzheimer's disease (P = 4.9 × 10(-26)). This enrichment remained significant after APOE and other genome-wide associated regions were excluded (P = 3.4 × 10(-19)). The best prediction accuracy AUC = 78.2% (95% confidence interval 77-80%) was achieved by a logistic regression model with APOE, the polygenic score, sex and age as predictors. In conclusion, Alzheimer's disease has a significant polygenic component, which has predictive utility for Alzheimer's disease risk and could be a valuable research tool complementing experimental designs, including preventative clinical trials, stem cell selection and high/low risk clinical studies. In modelling a range of sample disease prevalences, we found that polygenic scores almost doubles case prediction from chance with increased prediction at polygenic extremes. [ABSTRACT FROM AUTHOR]
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- 2015
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134. Impaired reward processing in the human prefrontal cortex distinguishes between persistent and remittent attention deficit hyperactivity disorder.
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Wetterling, Friedrich, McCarthy, Hazel, Tozzi, Leonardo, Skokauskas, Norbert, O'Doherty, John P., Mulligan, Aisling, Meaney, James, Fagan, Andrew J., Gill, Michael, and Frodl, Thomas
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Symptoms of attention deficit hyperactivity disorder (ADHD) in children often persist into adulthood and can lead to severe antisocial behavior. However, to-date it remains unclear whether neuro-functional abnormalities cause ADHD, which in turn can then provide a marker of persistent ADHD. Using event-related functional magnetic resonance imaging (fMRI), we measured blood oxygenation level dependent (BOLD) signal changes in subjects during a reversal learning task in which choice of the correct stimulus led to a probabilistically determined 'monetary' reward or punishment. Participants were diagnosed with ADHD during their childhood ( N = 32) and were paired with age, gender, and education matched healthy controls ( N = 32). Reassessment of the ADHD group as adults resulted in a split between either persistent (persisters, N = 17) or remitted ADHDs (remitters, N = 15). All three groups showed significantly decreased activation in the medial prefrontal cortex (PFC) and the left striatum during punished correct responses, however only remitters and controls presented significant psycho-physiological interaction between these fronto-striatal reward and outcome valence networks. Comparing persisters to remitters and controls showed significantly inverted responses to punishment ( P < 0.05, family-wise error corrected) in left PFC region. Interestingly, the decreased activation shown after punishment was located in different areas of the PFC for remitters compared with controls, suggesting that remitters might have learned compensation strategies to overcome their ADHD symptoms. Thus, fMRI helps understanding the neuro-functional basis of ADHD related behavior differences and differentiates between persistent and remittent ADHD. Hum Brain Mapp 36:4648-4663, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
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- 2015
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135. Treatment outcomes with telaprevir-based therapy for HIV/hepatitis C coinfected patients are comparable with hepatitis C monoinfected patients.
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O'Neil, Conar R., Pang, Jack X. Q., Lee, Samuel S., Swain, Mark G., Burak, Kelly W., Klein, Patricia, Myers, Robert P., Kapler, Jeff, Gill, Michael J., Labrie, Martin, and Coffin, Carla S.
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TELAPREVIR , *HIV - Abstract
A letter to the editor is presented in response to the article related to the treatment of telaprevir-based therapy for HIV/hepatitis C coinfected patients.
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- 2015
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136. DNA methylation of the serotonin transporter gene (SLC6A4) is associated with brain function involved in processing emotional stimuli.
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Frodl, Thomas, Szyf, Moshe, Carballedo, Angela, Ly, Victoria, Dymov, Sergiy, Vaisheva, Farida, Morris, Derek, Fahey, Ciara, Meaney, James, Gill, Michael, and Booij, Linda
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BRAIN physiology , *DNA , *ANALYSIS of covariance , *CHI-squared test , *MENTAL depression , *EMOTIONS , *GENES , *REGRESSION analysis , *RESEARCH funding , *SEROTONIN , *STATISTICS , *DATA analysis , *CASE-control method , *DATA analysis software , *DESCRIPTIVE statistics , *PHYSIOLOGY - Abstract
Background: The aim of the present study was to investigate the association of fMRI blood oxygen--level dependent (BOLD) reactivity with the level of epigenetic methylation of SLC6A4 in blood DNA from a sample of healthy participants and patients with major depressive disorder (MDD). Methods: We investigated patients with MDD and healthy controls using fMRI and an emotional attention-shifting task. We assessed site-specific DNA methylation of a previously characterized SLC6A4 region in peripheral blood DNA using pyro-sequencing. Results: Our study involved 25 patients with MDD and 35 healthy controls. Activation in the anterior insula elicited by negative emotional content was significantly positively associated with the degree of SLC6A4 methylation. Significantly negative associations were observed between activation in the posterior insula and the degree of SLC6A4 methylation when judging the geometry of pictures after seeing negative in contrast to positive emotional stimuli. Healthy controls with a high degree of SLC6A4 methylation depicted significantly more activity elicited by positive stimuli in limbic regions and more activity elicited by negative stimuli in limbic as well as cognitive control regions than those with a low degree of SLC6A4 methylation. Limitations: It is impossible to measure methylation directly in the brain and thus we assessed peripheral methylation of SLC6A4. Since the association was cross-sectional, no conclusion about cause and effect can be drawn. Conclusion: Our study provides further support to the hypothesis that particular DNA methylation states that are associated with brain function during emotion processing are detectable in the periphery. [ABSTRACT FROM AUTHOR]
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- 2015
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137. TH75. SEQUENCING STUDY OF A CONSANGUINEOUS PEDIGREE WITH A HIGH LOAD OF SCHIZOPHRENIA.
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Ryan, Niamh, Ormond, Cathal, Bulaeva, Kazima, Heron, Elizabeth, Gill, Michael, and Corvin, Aiden
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SCHIZOPHRENIA , *GENEALOGY - Published
- 2021
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138. TU74. A CO-SEGREGATION ANALYSIS OF ULTRA-RARE VARIANTS IN FAMILIES MULTIPLY AFFECTED BY SCHIZOPHRENIA USING WHOLE GENOME SEQUENCING.
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Ormond, Cathal, Ryan, Niamh M, Byerley, William, Heron, Elizabeth A, Gill, Michael, and Corvin, Aiden
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WHOLE genome sequencing , *EXOMES , *SCHIZOPHRENIA , *FAMILIES - Published
- 2021
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139. Injection Drug Use and Hepatitis C as Risk Factors for Mortality in HIV-Infected Individuals: The Antiretroviral Therapy Cohort Collaboration.
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May, Margaret T., Justice, Amy C., Birnie, Kate, Ingle, Suzanne M., Smit, Colette, Smith, Colette, Neau, Didier, Guiguet, Marguerite, Schwarze-Zander, Carolynne, Moreno, Santiago, Guest, Jodie L., Monforte, Antonella d'Arminio, Tural, Cristina, Gill, Michael J., Bregenzer, Andrea, Kirk, Ole, Saag, Michael, Sterling, Timothy R., Crane, Heidi M., and Sterne, Jonathan A. C.
- Published
- 2015
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140. Impact of Age on Retention in Care and Viral Suppression.
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Yehia, Baligh R., Rebeiro, Peter, Althoff, Keri N., Agwu, Allison L., Horberg, Michael A., Samji, Hasina, Napravnik, Sonia, Mayer, Kenneth, Tedaldi, Ellen, Silverberg, Michael J., Thorne, Jennifer E., Burchell, Ann N., Rourke, Sean B., Rachlis, Anita, Mayor, Angel, Gill, Michael J., Zinski, Anne, Ohl, Michael, Anastos, Kathryn, and Abraham, Alison G.
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- 2015
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141. A genetic risk score combining 32 SNPs is associated with body mass index and improves obesity prediction in people with major depressive disorder.
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Chi-Fa Hung, Breen, Gerome, Czamara, Darina, Corre, Tanguy, Wolf, Christiane, Kloiber, Stefan, Bergmann, Sven, Craddock, Nick, Gill, Michael, Holsboer, Florian, Jones, Lisa, Jones, Ian, Korszun, Ania, Kutalik, Zoltan, Lucae, Susanne, Maier, Wolfgang, Mors, Ole, Owen, Michael J., Rice, John, and Rietschel, Marcella
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OBESITY risk factors , *SINGLE nucleotide polymorphisms , *BODY mass index , *OBESITY genetics - Abstract
Background: Obesity is strongly associated with major depressive disorder (MDD) and various other diseases. Genome-wide association studies have identified multiple risk loci robustly associated with body mass index (BMI). In this study, we aimed to investigate whether a genetic risk score (GRS) combining multiple BMI risk loci might have utility in prediction of obesity in patients with MDD. Methods: Linear and logistic regression models were conducted to predict BMI and obesity, respectively, in three independent large case-control studies of major depression (Radiant, GSK-Munich, PsyCoLaus). The analyses were first performed in the whole sample and then separately in depressed cases and controls. An unweighted GRS was calculated by summation of the number of risk alleles. A weighted GRS was calculated as the sum of risk alleles at each locus multiplied by their effect sizes. Receiver operating characteristic (ROC) analysis was used to compare the discriminatory ability of predictors of obesity. Results: In the discovery phase, a total of 2,521 participants (1,895 depressed patients and 626 controls) were included from the Radiant study. Both unweighted and weighted GRS were highly associated with BMI (P <0.001) but explained only a modest amount of variance. Adding 'traditional' risk factors to GRS significantly improved the predictive ability with the area under the curve (AUC) in the ROC analysis, increasing from 0.58 to 0.66 (95% CI, 0.62-0.68; χ² = 27.68; P <0.0001). Although there was no formal evidence of interaction between depression status and GRS, there was further improvement in AUC in the ROC analysis when depression status was added to the model (AUC = 0.71; 95% CI, 0.68-0.73; χ² = 28.64; P <0.0001). We further found that the GRS accounted for more variance of BMI in depressed patients than in healthy controls. Again, GRS discriminated obesity better in depressed patients compared to healthy controls. We later replicated these analyses in two independent samples (GSK-Munich and PsyCoLaus) and found similar results. Conclusions: A GRS proved to be a highly significant predictor of obesity in people with MDD but accounted for only modest amount of variance. Nevertheless, as more risk loci are identified, combining a GRS approach with information on non-genetic risk factors could become a useful strategy in identifying MDD patients at higher risk of developing obesity. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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142. Lessons learned from ten years of distance learning outreach.
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Locatis, Craig, Gaines, Cynthia, Wei-Li Liu, Gill, Michael, and Ackerman, Michael
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ALTERNATIVE education , *ASIANS , *BLACK people , *HISPANIC Americans , *HIGH school students , *NATIVE Americans , *VIDEOCONFERENCING , *VOCATIONAL guidance , *TEACHING methods - Abstract
Objective: The study tested the efficacy of providing distance learning with real-time videoconferencing to broaden high school student knowledge of health careers. Methods: A pilot program was tried out and extended over ten years to include other schools in four different time zones and the National Library of Medicine. Survey results, site visits, and continued school participation were used as effectiveness indicators. Student ratings, site visits, and ongoing discussions were used to evaluate critical factors in the program. Results: Nine program factors contributed to success. Conclusions: Synchronous communication can be effective for outreach to special populations given appropriate infrastructure, technology, program design, and implementation. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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143. DNA Methylation of the Serotonin Transporter Gene in Peripheral Cells and Stress-Related Changes in Hippocampal Volume: A Study in Depressed Patients and Healthy Controls.
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Booij, Linda, Szyf, Moshe, Carballedo, Angela, Frey, Eva-Maria, Morris, Derek, Dymov, Sergiy, Vaisheva, Farida, Ly, Victoria, Fahey, Ciara, Meaney, James, Gill, Michael, and Frodl, Thomas
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SEROTONIN transporters , *HIPPOCAMPUS physiology , *DEPRESSED persons , *ETIOLOGY of diseases , *NEURAL development , *PATHOLOGICAL psychology - Abstract
Serotonin plays an important role in the etiology of depression. Serotonin is also crucial for brain development. For instance, animal studies have demonstrated that early disruptions in the serotonin system affect brain development and emotion regulation in later life. A plausible explanation is that environmental stressors reprogram the serotonin system through epigenetic processes by altering serotonin system gene expression. This in turn may affect brain development, including the hippocampus, a region with dense serotonergic innervations and important in stress-regulation. The aim of this study was to test whether greater DNA methylation in specific CpG sites at the serotonin transporter promoter in peripheral cells is associated with childhood trauma, depression, and smaller hippocampal volume. We were particularly interested in those CpG sites whose state of methylation in peripheral cells had previously been associated with in vivo measures of brain serotonin synthesis. Thirty-three adults with Major Depressive Disorder (MDD) (23 females) and 36 matched healthy controls (21 females) were included in the study. Depressive symptoms, childhood trauma, and high-resolution structural MRI for hippocampal volume were assessed. Site-specific serotonin transporter methylation was assessed using pyrosequencing. Childhood trauma, being male, and smaller hippocampal volume were independently associated with greater peripheral serotonin transporter methylation. Greater serotonin transporter methylation in the depressed group was observed only in SSRI-treated patients. These results suggest that serotonin transporter methylation may be involved in physiological gene-environment interaction in the development of stress-related brain alterations. The results provide some indications that site-specific serotonin transporter methylation may be a biomarker for serotonin-associated stress-related psychopathology. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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144. The DEAH-box Helicase Dhr1 Dissociates U3 from the Pre-rRNA to Promote Formation of the Central Pseudoknot.
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Sardana, Richa, Liu, Xin, Granneman, Sander, Zhu, Jieyi, Gill, Michael, Papoulas, Ophelia, Marcotte, Edward M., Tollervey, David, Correll, Carl C., and Johnson, Arlen W.
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EUKARYOTES , *PROTEIN folding , *PROTEIN synthesis , *RIBOSOMES , *RIBOSOMAL proteins , *HELICASES - Abstract
In eukaryotes, the highly conserved U3 small nucleolar RNA (snoRNA) base-pairs to multiple sites in the pre-ribosomal RNA (pre-rRNA) to promote early cleavage and folding events. Binding of the U3 box A region to the pre-rRNA is mutually exclusive with folding of the central pseudoknot (CPK), a universally conserved rRNA structure of the small ribosomal subunit essential for protein synthesis. Here, we report that the DEAH-box helicase Dhr1 (Ecm16) is responsible for displacing U3. An active site mutant of Dhr1 blocked release of U3 from the pre-ribosome, thereby trapping a pre-40S particle. This particle had not yet achieved its mature structure because it contained U3, pre-rRNA, and a number of early-acting ribosome synthesis factors but noticeably lacked ribosomal proteins (r-proteins) that surround the CPK. Dhr1 was cross-linked in vivo to the pre-rRNA and to U3 sequences flanking regions that base-pair to the pre-rRNA including those that form the CPK. Point mutations in the box A region of U3 suppressed a cold-sensitive mutation of Dhr1, strongly indicating that U3 is an in vivo substrate of Dhr1. To support the conclusions derived from in vivo analysis we showed that Dhr1 unwinds U3-18S duplexes in vitro by using a mechanism reminiscent of DEAD box proteins. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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145. BDNF Val66 Met genotype interacts with childhood adversity and influences the formation of hippocampal subfields.
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Frodl, Thomas, Skokauskas, Norbert, Frey, Eva‐Maria, Morris, Derek, Gill, Michael, and Carballedo, Angela
- Abstract
Childhood stress and genetic factors like the Val66MET polymorphism of the brain derived neurotrophic factor (BDNF) gene are associated with a higher risk for developing major depressive disorder (MDD) and might also influence hippocampal changes. The aim of this study was to determine which hippocampal dentate gyrus and cornu ammonis subfields are altered in MDD compared to healthy controls and which subfields are affected by the BDNF Val66Met polymorphism and child adversity. Adult patients with MDD and healthy matched controls underwent high-resolution magnetic resonance imaging. Automatic segmentation using the programme FreeSurfer was used to segment the hippocampal subfields dentate gyrus (DG/CA4), CA1 and CA2/3. The history of possible childhood adversity was assessed using the Childhood Trauma Questionnaire and the Val66Met BDNF SNP (rs6265) genotypes were obtained. Patients with MDD had significantly smaller CA4/DG and CA2/3 volumes compared to healthy controls. Furthermore, there was a significant interactive effect of BDNF allele and childhood adversity on CA2/3 and CA4/DG volumes. Met allele carriers without childhood adversity had larger and with childhood adversity smaller CA4/DG and CA2/3 volumes than Val-allele homozygotes. Our results highlight stress by gene interactions as relevant for hippocampal volume reductions, in particular for the subfield CA2/3 and dentate gyrus. Hum Brain Mapp 35:5776-5783, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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146. Expression of glucocorticoid inducible genes is associated with reductions in cornu ammonis and dentate gyrus volumes in patients with major depressive disorder.
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Cicchetti, Dante, Natsuaki, Misaki N., Frodl, Thomas, Carballedo, Angela, Frey, Eva-Maria, O'Keane, Veronica, Skokauskas, Norbert, Morris, Derrek, Gill, Michael, Hughes, Martina Mary, Harkin, Andrew, and Connor, Thomas
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GENE expression , *DENTATE gyrus , *GLUCOCORTICOIDS , *HIPPOCAMPUS physiology , *DEPRESSED persons , *MESSENGER RNA , *PEOPLE with mental illness , *PHYSIOLOGY - Abstract
Alterations of the glucocorticoid system and of hippocampal volumes have consistently been reported in patients with major depressive disorders (MDD). The aim of the present study was to investigate whether the messenger RNA (mRNA) expression of glucocorticoid inducible genes is associated with changes in the cornu ammonis (CA) and dentate gyrus subfields. Forty-three patients with MDD and 43 healthy controls were recruited and investigated with high resolution magnetic resonance imaging. Hippocampal subfields were measured using freesurfer. Measurement of whole blood mRNA expression of glucocorticoid inducible genes serum and glucocorticoid-regulated kinase 1 (SGK1), FK506 binding protein 5 (FKBP5), and glucocorticoid induced leucine zipper (GILZ) was performed. Patients with MDD had significantly smaller volumes of CA1, CA2/3, CA4/DG, and subiculum compared to healthy controls. In the regression analysis, the factor diagnosis had a significant moderating effect on the association of SGK1 and hippocampal volumes. Patients with low expression of SGK1 had significantly smaller CA2/3 and CA4/DG volumes compared to patients with high expression of SGK1 mRNA and to healthy controls with low/high expression of SGK1, respectively. Therefore, a lack of mRNA expression of glucocorticoid inducible genes in patients with MDD that seems to correspond to a blunted cortisol response is associated with smaller hippocampal CA and dentate gyrus volumes. SGK1 seems to be particularly relevant for stress-related mental disorders. [ABSTRACT FROM PUBLISHER]
- Published
- 2014
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147. The phenotypic manifestations of rare CNVs in schizophrenia.
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Merikangas, Alison K., Segurado, Ricardo, Cormican, Paul, Heron, Elizabeth A., Anney, Richard J.L., Moore, Susan, Kelleher, Eric, Hargreaves, April, Anderson-Schmidt, Heike, Gill, Michael, Gallagher, Louise, and Corvin, Aiden
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SCHIZOPHRENIA , *DNA copy number variations , *DISEASE susceptibility , *NEURODEVELOPMENTAL treatment , *DELETION mutation , *FAMILY history (Medicine) - Abstract
There is compelling evidence for the role of copy number variants (CNVs) in schizophrenia susceptibility, and it has been estimated that up to 2–3% of schizophrenia cases may carry rare CNVs. Despite evidence that these events are associated with an increased risk across categorical neurodevelopmental disorders, there is limited understanding of the impact of CNVs on the core features of disorders like schizophrenia. Our objective was to evaluate associations between rare CNVs in differentially brain expressed (BE) genes and the core features and clinical correlates of schizophrenia. The sample included 386 cases of Irish ancestry with a diagnosis of schizophrenia, at least one rare CNV impacting any gene, and a core set of phenotypic measures. Statistically significant associations between deletions in differentially BE genes were found for family history of mental illness (decreased prevalence of all CNVs and deletions, unadjusted and adjusted) and for paternal age (increase in deletions only, unadjusted, among those with later ages at birth of patient). The strong effect of a lack of a family history on BE genes suggests that CNVs may comprise one pathway to schizophrenia, whereas a positive family history could index other genetic mechanisms that increase schizophrenia vulnerability. To our knowledge, this is the first investigation of the association between genome-wide CNVs and risk factors and sub-phenotypic features of schizophrenia beyond cognitive function. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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148. Altered medial prefrontal activity during dynamic face processing in schizophrenia spectrum patients.
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Mothersill, Omar, Morris, Derek W., Kelly, Sinead, Rose, Emma Jane, Bokde, Arun, Reilly, Richard, Gill, Michael, Corvin, Aiden P., and Donohoe, Gary
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SCHIZOPHRENIA treatment , *PREFRONTAL cortex , *FACE perception , *FUNCTIONAL magnetic resonance imaging , *HEALTH outcome assessment , *COGNITIVE ability - Abstract
Background Processing the emotional content of faces is recognised as a key deficit of schizophrenia, associated with poorer functional outcomes and possibly contributing to the severity of clinical symptoms such as paranoia. At the neural level, fMRI studies have reported altered limbic activity in response to facial stimuli. However, previous studies may be limited by the use of cognitively demanding tasks and static facial stimuli. To address these issues, the current study used a face processing task involving both passive face viewing and dynamic social stimuli. Such a task may (1) lack the potentially confounding effects of high cognitive demands and (2) show higher ecological validity. Methods Functional MRI was used to examine neural activity in 25 patients with a DSM-IV diagnosis of schizophrenia/schizoaffective disorder and 21 age- and gender-matched healthy controls while they participated in a face processing task, which involved viewing videos of angry and neutral facial expressions, and a non-biological baseline condition. Results While viewing faces, patients showed significantly weaker deactivation of the medial prefrontal cortex, including the anterior cingulate, and decreased activation in the left cerebellum, compared to controls. Patients also showed weaker medial prefrontal deactivation while viewing the angry faces relative to baseline. Discussion Given that the anterior cingulate plays a role in processing negative emotion, weaker deactivation of this region in patients while viewing faces may contribute to an increased perception of social threat. Future studies examining the neurobiology of social cognition in schizophrenia using fMRI may help establish targets for treatment interventions. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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149. Cheers & Jeers.
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Schoneman, Jim, Hnatuk, Bill, Gill, Michael, Evans, Phil, Zimmerman, Larry, Zook, Kevin, Proctor, Dan, DeMatthews, Barry, Hugill, Ed, Ready, Steven, and Batcho, Andy
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LETTERS to the editor , *FISHING , *HUNTING , *OUTDOOR recreation , *HUNTERS - Abstract
Several letters to the editor are presented in response to articles in previous issues including "Horn of the Hunter," by David E. Petzal, "The Ultimate Summer Gig," and "Casting a Spell," by Bill Heavey.
- Published
- 2011
150. PERCUTANEOUS ECMO-ASSOCIATED HARLEQUIN (NORTH-SOUTH) SYNDROME FOLLOWING V-A ECMO INITIATION.
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Karan, Abhinav, Mgbemena, Okechukwu, Rollini, Fabiana, Al-Turk, Bashar, Liu, Kevin, Rivas, Jose, Dhruva, Pooja, Peterson, Alexa, Rwigema, Jean-Christophe, Durgin, Kevin, Gill, Michael, Shiber, Joseph, Kochuba, Matthew, Madbak, Firas, Yorkgitis, Brian, and Skarupa, David
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SYNDROMES - Published
- 2022
- Full Text
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