Publications by authors named "Jacqueline Harris"

28 Publications

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Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.

Authors:
Sarah E Sheppard Ian M Campbell Margaret H Harr Nina Gold Dong Li Hans T Bjornsson Julie S Cohen Jill A Fahrner Ali Fatemi Jacqueline R Harris Catherine Nowak Cathy A Stevens Katheryn Grand Margaret Au John M Graham Pedro A Sanchez-Lara Miguel Del Campo Marilyn C Jones Omar Abdul-Rahman Fowzan S Alkuraya Jennifer A Bassetti Katherine Bergstrom Elizabeth Bhoj Sarah Dugan Julie D Kaplan Nada Derar Karen W Gripp Natalie Hauser A Micheil Innes Beth Keena Neslida Kodra Rebecca Miller Beverly Nelson Malgorzata J Nowaczyk Zuhair Rahbeeni Shay Ben-Shachar Joseph T Shieh Anne Slavotinek Andrew K Sobering Mary-Alice Abbott Dawn C Allain Louise Amlie-Wolf Ping Yee Billie Au Emma Bedoukian Geoffrey Beek James Barry Janet Berg Jonathan A Bernstein Cheryl Cytrynbaum Brian Hon-Yin Chung Sarah Donoghue Naghmeh Dorrani Alison Eaton Josue A Flores-Daboub Holly Dubbs Carolyn A Felix Chin-To Fong Jasmine Lee Fong Fung Balram Gangaram Amy Goldstein Rotem Greenberg Thoa K Ha Joseph Hersh Kosuke Izumi Staci Kallish Elijah Kravets Pui-Yan Kwok Rebekah K Jobling Amy E Knight Johnson Jessica Kushner Bo Hoon Lee Brooke Levin Kristin Lindstrom Kandamurugu Manickam Rebecca Mardach Elizabeth McCormick D Ross McLeod Frank D Mentch Kelly Minks Colleen Muraresku Stanley F Nelson Patrizia Porazzi Pavel N Pichurin Nina N Powell-Hamilton Zoe Powis Alyssa Ritter Caleb Rogers Luis Rohena Carey Ronspies Audrey Schroeder Zornitza Stark Lois Starr Joan Stoler Pim Suwannarat Milen Velinov Rosanna Weksberg Yael Wilnai Neda Zadeh Dina J Zand Marni J Falk Hakon Hakonarson Elaine H Zackai Fabiola Quintero-Rivera

Am J Med Genet A 2021 Mar 30. Epub 2021 Mar 30.

Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.
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http://dx.doi.org/10.1002/ajmg.a.62124DOI Listing
March 2021

Characterization of an unbalanced translocation causing 3q28qter duplication and 10q26.2qter deletion in a patient with global developmental delay and self-injury.

Cold Spring Harb Mol Case Stud 2020 Dec 17;6(6). Epub 2020 Dec 17.

Program in Human Genetics, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.

Chromosomal structural variation can cause severe neurodevelopmental and neuropsychiatric phenotypes. Here we present a nonverbal female adolescent with severe stereotypic movement disorder with severe problem behavior (e.g., self-injurious behavior, aggression, and disruptive and destructive behaviors), autism spectrum disorder, severe intellectual disability, attention deficit hyperactivity disorder, and global developmental delay. Previous cytogenetic analysis revealed balanced translocations present in the patient's apparently normal mother. We hypothesized the presence of unbalanced translocations in the patient due to maternal history of spontaneous abortions. Whole-genome sequencing and whole-genome optical mapping, complementary next-generation genomic technologies capable of the accurate and robust detection of structural variants, identified t(3;10), t(10;14), and t(3;14) three-way balanced translocations in the mother and der(10)t(3;14;10) and der(14)t(3;14;10) translocations in the patient. Instead of a t(3;10), she inherited a normal maternal copy of Chromosome 3, resulting in an unbalanced state of a 3q28qter duplication and 10q26.2qter deletion. Copy-imbalanced genes in one or both of these regions, such as , , and , may contribute to the patient's phenotype that spans neurodevelopmental, musculoskeletal, and psychiatric domains, with the possible contribution of a maternally inherited 15q13.2q13.3 deletion.
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http://dx.doi.org/10.1101/mcs.a005884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784495PMC
December 2020

Structural covariance pattern abnormalities of insula in major depressive disorder: A CAN-BIND study report.

Prog Neuropsychopharmacol Biol Psychiatry 2020 Dec 6:110194. Epub 2020 Dec 6.

Non-Invasive Neurostimulation Therapies (NINET) Laboratory, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Background And Methods: Investigation of the insula may inform understanding of the etiopathogenesis of major depressive disorder (MDD). In the present study, we introduced a novel gray matter volume (GMV) based structural covariance technique, and applied it to a multi-centre study of insular subregions of 157 patients with MDD and 93 healthy controls from the Canadian Biomarker Integration Network in Depression (CAN-BIND, https://www.canbind.ca/). Specifically, we divided the unilateral insula into three subregions, and investigated their coupling with whole-brain GMV-based structural brain networks (SBNs). We compared between-group difference of the structural coupling patterns between the insular subregions and SBNs.

Results: The insula was divided into three subregions, including an anterior one, a superior-posterior one and an inferior-posterior one. In the comparison between MDD patients and controls we found that patients' right anterior insula showed increased inter-network coupling with the default mode network, and it showed decreased inter-network coupling with the central executive network; whereas patients' right ventral-posterior insula showed decreased inter-network coupling with the default mode network, and it showed increased inter-network coupling with the central executive network. We also demonstrated that patients' loading parameters of the right ventral-posterior insular structural covariance negatively correlated with their suicidal ideation scores; and controls' loading parameters of the right ventral-posterior insular structural covariance positively correlated with their motor and psychomotor speed scores, whereas these phenomena were not found in patients. Additionally, we did not find significant inter-network coupling between the whole-brain SBNs, including salience network, default mode network, and central executive network.

Conclusions: Our work proposed a novel technique to investigate the structural covariance coupling between large-scale structural covariance networks, and provided further evidence that MDD is a system-level disorder that shows disrupted structural coupling between brain networks.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110194DOI Listing
December 2020

Clinical, behavioral, and neural measures of reward processing correlate with escitalopram response in depression: a Canadian Biomarker Integration Network in Depression (CAN-BIND-1) Report.

Neuropsychopharmacology 2020 07;45(8):1390-1397

Institute of Medical Science, University of Toronto, Toronto, ON, Canada.

Anhedonia is thought to reflect deficits in reward processing that are associated with abnormal activity in mesocorticolimbic brain regions. It is expressed clinically as a deficit in the interest or pleasure in daily activities. More severe anhedonia in major depressive disorder (MDD) is a negative predictor of antidepressant response. It is unknown, however, whether the pathophysiology of anhedonia represents a viable avenue for identifying biological markers of antidepressant treatment response. Therefore, this study aimed to examine the relationships between reward processing and response to antidepressant treatment using clinical, behavioral, and functional neuroimaging measures. Eighty-seven participants in the first Canadian Biomarker Integration Network in Depression (CAN-BIND-1) protocol received 8 weeks of open-label escitalopram. Clinical correlates of reward processing were assessed at baseline using validated scales to measure anhedonia, and a monetary incentive delay (MID) task during functional neuroimaging was completed at baseline and after 2 weeks of treatment. Response to escitalopram was associated with significantly lower self-reported deficits in reward processing at baseline. Activity during the reward anticipation, but not the reward consumption, phase of the MID task was correlated with clinical response to escitalopram at week 8. Early (baseline to week 2) increases in frontostriatal connectivity during reward anticipation significantly correlated with reduction in depressive symptoms after 8 weeks of treatment. Escitalopram response is associated with clinical and neuroimaging correlates of reward processing. These results represent an important contribution towards identifying and integrating biological, behavioral, and clinical correlates of treatment response. ClinicalTrials.gov: NCT01655706.
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http://dx.doi.org/10.1038/s41386-020-0688-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297974PMC
July 2020

An investigation of cortical thickness and antidepressant response in major depressive disorder: A CAN-BIND study report.

Neuroimage Clin 2020 13;25:102178. Epub 2020 Jan 13.

Neuroscience Graduate Program, McMaster University, Hamilton, ON, Canada; Mood Disorders Program and Women's Health Concerns Clinic, St. Joseph's Healthcare Hamilton, Hamilton, ON, Canada; Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada. Electronic address:

Major depressive disorder (MDD) is considered a highly heterogeneous clinical and neurobiological mental disorder. We employed a novel layered treatment design to investigate whether cortical thickness features at baseline differentiated treatment responders from non-responders after 8 and 16 weeks of a standardized sequential antidepressant treatment. Secondary analyses examined baseline differences between MDD and controls as a replication analysis and longitudinal changes in thickness after 8 weeks of escitalopram treatment. 181 MDD and 95 healthy comparison (HC) participants were studied. After 8 weeks of escitalopram treatment (10-20 mg/d, flexible dosage), responders (>50% decrease in Montgomery-Åsberg Depression Scale score) were continued on escitalopram; non-responders received adjunctive aripiprazole (2-10 mg/d, flexible dosage). MDD participants were classified into subgroups according to their response profiles at weeks 8 and 16. Baseline group differences in cortical thickness were analyzed with FreeSurfer between HC and MDD groups as well as between response groups. Two-stage longitudinal processing was used to investigate 8-week escitalopram treatment-related changes in cortical thickness. Compared to HC, the MDD group exhibited thinner cortex in the left rostral middle frontal cortex [MNI(X,Y,Z=-29,9,54.5,-7.7); CWP=0.0002]. No baseline differences in cortical thickness were observed between responders and non-responders based on week-8 or week-16 response profile. No changes in cortical thickness was observed after 8 weeks of escitalopram monotherapy. In a two-step 16-week sequential clinical trial we found that baseline cortical thickness does not appear to be associated to clinical response to pharmacotherapy at 8 or 16 weeks.
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http://dx.doi.org/10.1016/j.nicl.2020.102178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011077PMC
January 2021

Reliability of a functional magnetic resonance imaging task of emotional conflict in healthy participants.

Hum Brain Mapp 2020 04 3;41(6):1400-1415. Epub 2019 Dec 3.

Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Task-based functional neuroimaging methods are increasingly being used to identify biomarkers of treatment response in psychiatric disorders. To facilitate meaningful interpretation of neural correlates of tasks and their potential changes with treatment over time, understanding the reliability of the blood-oxygen-level dependent (BOLD) signal of such tasks is essential. We assessed test-retest reliability of an emotional conflict task in healthy participants collected as part of the Canadian Biomarker Integration Network in Depression. Data for 36 participants, scanned at three time points (weeks 0, 2, and 8) were analyzed, and intra-class correlation coefficients (ICC) were used to quantify reliability. We observed moderate reliability (median ICC values between 0.5 and 0.6), within occipital, parietal, and temporal regions, specifically for conditions of lower cognitive complexity, that is, face, congruent or incongruent trials. For these conditions, activation was also observed within frontal and sub-cortical regions, however, their reliability was poor (median ICC < 0.2). Clinically relevant prognostic markers based on task-based fMRI require high predictive accuracy at an individual level. For this to be achieved, reliability of BOLD responses needs to be high. We have shown that reliability of the BOLD response to an emotional conflict task in healthy individuals is moderate. Implications of these findings to further inform studies of treatment effects and biomarker discovery are discussed.
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http://dx.doi.org/10.1002/hbm.24883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267954PMC
April 2020

Escitalopram ameliorates differences in neural activity between healthy comparison and major depressive disorder groups on an fMRI Emotional conflict task: A CAN-BIND-1 study.

J Affect Disord 2020 03 13;264:414-424. Epub 2019 Nov 13.

Neuroscience Graduate Program, McMaster University, Hamilton, ON, Canada; Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada; Department of Psychology Neuroscience & Behaviour, McMaster University, Hamilton, ON, Canada. Electronic address:

Background: Identifying objective biomarkers can assist in predicting remission/non-remission to treatment, improving remission rates, and reducing illness burden in major depressive disorder (MDD).

Methods: Sixteen MDD 8-week remitters (MDD-8), twelve 16-week remitters (MDD-16), 14 non-remitters (MDD-NR) and 30 healthy comparison participants (HC) completed a functional magnetic resonance imaging emotional conflict task at baseline, prior to treatment with escitalopram, and 8 weeks after treatment initiation. Patients were followed 16 weeks to assess remitter status.

Results: All groups demonstrated emotional Stroop in reaction time (RT) at baseline and Week 8. There were no baseline differences between HC and MDD-8, MDD-16, or MDD-NR in RT or accuracy. By Week 8, MDD-8 demonstrated poorer accuracy compared to HC. Compared to HC, the baseline blood-oxygen level dependent (BOLD) signal was decreased in MDD-8 in brain-stem and thalamus; in MDD-16 in lateral occipital cortex, middle temporal gyrus, and cuneal cortex; in MDD-NR in lingual and occipital fusiform gyri, thalamus, putamen, caudate, cingulate gyrus, insula, cuneal cortex, and middle temporal gyrus. By Week 8, there were no BOLD activity differences between MDD groups and HC.

Limitations: The Emotional Conflict Task lacks a neutral (non-emotional) condition, restricting interpretation of how mood may influence perception of non-emotionally valenced stimuli.

Conclusions: The Emotional Conflict Task is not an objective biomarker for remission trajectory in patients with MDD receiving escitalopram treatment. Escitalopram may have influenced emotion recognition in MDD groups in terms of augmented accuracy and BOLD signal in response to an Emotional Conflict Task, following 8 weeks of escitalopram treatment.
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http://dx.doi.org/10.1016/j.jad.2019.11.068DOI Listing
March 2020

De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder.

Genet Med 2020 03 14;22(3):538-546. Epub 2019 Nov 14.

Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.

Purpose: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292).

Methods: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships.

Results: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment.

Conclusion: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.
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http://dx.doi.org/10.1038/s41436-019-0693-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060121PMC
March 2020

Hippocampal tail volume as a predictive biomarker of antidepressant treatment outcomes in patients with major depressive disorder: a CAN-BIND report.

Neuropsychopharmacology 2020 01 14;45(2):283-291. Epub 2019 Oct 14.

Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Finding a clinically useful neuroimaging biomarker that can predict treatment response in patients with major depressive disorder (MDD) is challenging, in part because of poor reproducibility and generalizability of findings across studies. Previous work has suggested that posterior hippocampal volumes in depressed patients may be associated with antidepressant treatment outcomes. The primary purpose of this investigation was to examine further whether posterior hippocampal volumes predict remission following antidepressant treatment. Magnetic resonance imaging (MRI) scans from 196 patients with MDD and 110 healthy participants were obtained as part of the first study in the Canadian Biomarker Integration Network in Depression program (CAN-BIND 1) in which patients were treated for 16 weeks with open-label medication. Hippocampal volumes were measured using both a manual segmentation protocol and FreeSurfer 6.0. Baseline hippocampal tail (Ht) volumes were significantly smaller in patients with depression compared to healthy participants. Larger baseline Ht volumes were positively associated with remission status at weeks 8 and 16. Participants who achieved early sustained remission had significantly greater Ht volumes compared to those who did not achieve remission by week 16. Ht volume is a prognostic biomarker for antidepressant treatment outcomes in patients with MDD.
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http://dx.doi.org/10.1038/s41386-019-0542-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901577PMC
January 2020

Evaluating the Clinical Outcomes of Parotid Hemangiomas in the Pediatric Patient Population.

Ear Nose Throat J 2019 Sep 29:145561319877760. Epub 2019 Sep 29.

Surgical Outcomes Center for Kids, Vanderbilt University Medical Center, Nashville, TN, USA.

Introduction: Infantile hemangiomas (IHs) are the most common tumor of the parotid gland in children; however, there is no standard protocol for the treatment of IH. The generally accepted practice is to begin the patient on β-blocker therapy if there are no contraindications.

Objective: The purpose of this study is to better understand the challenges and successes of management of pediatric patients with parotid IH.

Methods: This retrospective study analyzed 15 patients diagnosed with parotid IH from 2009 to 2016 who were cared for at a tertiary care center. Demographic information, lesion characteristics, and treatment course were obtained through patient chart review.

Results: Fifteen pediatric patients with parotid IH were evaluated. The female:male ratio was 4:1; the average age of diagnosis was 8.75 months. Most lesions were greater than 3 cm in their widest dimension (73.3%), and 13 patients underwent imaging to further clarify the parotid mass in their clinical workup. Fourteen patients began treatment with propranolol; 10 patients saw complete resolution of their IH (66.7%) and 3 had a partial response to β-blocker therapy (20%). After discontinuation of propranolol, 2 patients had regrowth 2 to 3 months later after regression and were restarted on therapy. The average duration of treatment was 9.9 ± 8.45 months. The known adverse effects of propranolol-hypoglycemia, hypotension, bradycardia, and bronchospasm-were not observed in any patient.

Conclusion: In the treatment of parotid IH, propranolol is the generally accepted first-line therapy, as compared to corticosteroid or interferon α injections of years past. Parotid hemangiomas, however, have a lower response rate to propranolol and a similar recurrence rate compared to IH at other sites. The treatment duration necessary tends to be longer. Future studies will aim at identifying and evaluating potential predictors of outcomes to help inform the management of parotid hemangiomas.
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http://dx.doi.org/10.1177/0145561319877760DOI Listing
September 2019

White Matter Indices of Medication Response in Major Depression: A Diffusion Tensor Imaging Study.

Biol Psychiatry Cogn Neurosci Neuroimaging 2019 10 12;4(10):913-924. Epub 2019 Jun 12.

Department of Psychology, Neuroscience & Behavior, McMaster University, Hamilton, Ontario, Canada; Imaging Research Center, St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada. Electronic address:

Background: While response to antidepressants in major depressive disorder is difficult to predict, characterizing the organization and integrity of white matter in the brain with diffusion tensor imaging (DTI) may provide the means to distinguish between antidepressant responders and nonresponders.

Methods: DTI data were collected at 6 sites (Canadian Biomarker Integration Network in Depression-1 [CAN-BIND-1 study]) from 200 (127 women) depressed and 112 (71 women) healthy participants at 3 time points: at baseline, 2 weeks, and 8 weeks following initiation of selective serotonin reuptake inhibitor treatment. Therapeutic response was established by a 50% reduction of symptoms at 8 weeks. Analysis on responders, nonresponders, and control subjects yielded 4 scalar metrics: fractional anisotropy and mean, axial, and radial diffusivity. Region-of-interest analysis was carried out on 40 white matter regions using a skeletonization approach. Mixed-effects regression was incorporated to test temporal trends.

Results: The data acquired at baseline showed that axial diffusivity in the external capsule, which overlaps the superior longitudinal fasciculus, was significantly associated with medication response. Regression analysis revealed further baseline differences of responders compared with nonresponders in the cingulum regions, sagittal stratum, and corona radiata. Additional group differences relative to control subjects were seen in the internal capsule, posterior thalamic radiation, and uncinate fasciculus. Most effect sizes were moderate (near 0.5), with a maximum of 0.76 in the cingulum-hippocampus region. No temporal changes in DTI metrics were observed over the 8-week study period.

Conclusions: Several DTI measures of altered white matter specifically distinguished medication responders and nonresponders at baseline and show promise for predicting treatment response in depression.
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http://dx.doi.org/10.1016/j.bpsc.2019.05.016DOI Listing
October 2019

Reduced accuracy accompanied by reduced neural activity during the performance of an emotional conflict task by unmedicated patients with major depression: A CAN-BIND fMRI study.

J Affect Disord 2019 10 6;257:765-773. Epub 2019 Jul 6.

Neuroscience Graduate Program, McMaster University, Hamilton, ON, Canada; Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada; Department of Psychology Neuroscience & Behaviour, McMaster University, Hamilton, ON, Canada. Electronic address:

Methods: We studied 48 MDD and 30 HC who performed an emotional conflict task in a functional magnetic resonance imaging (fMRI) scanner.

Results: On the emotional conflict task, MDD and HC demonstrated a robust emotional Stroop effect in reaction time and accuracy. Overall, accuracy was lower in MDD compared to HC with no significant reaction time differences. The fMRI data indicated lower BOLD activation in MDD compared to HC on comparisons of all trials, congruent, incongruent, and incongruent > congruent trials in regions including right inferior temporal gyrus, lateral occipital cortex, and occipital fusiform gyrus. Behavioural and neuroimaging data indicated no group differences in fearful versus happy face processing.

Limitations: Inclusion of a neutral condition may have provided a valuable contrast to how MDD and HC process stimuli without emotional valence compared to stimuli with a strong emotional valence.

Conclusions: MDD and HC demonstrated a robust emotional Stroop effect. Compared to HC, MDD demonstrated an overall reduced accuracy on the emotional conflict task and reduced BOLD activity in regions important for face perception and emotion information processing, with no differences in responding to fearful versus happy faces. These findings provide support for the theory of emotion context insensitivity in individuals with depression.
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http://dx.doi.org/10.1016/j.jad.2019.07.037DOI Listing
October 2019

Vigabatrin as a Targeted Treatment of GABA Receptor-Related Epileptic Encephalopathy.

Pediatr Neurol 2019 10 18;99:82-84. Epub 2019 Apr 18.

Kennedy Krieger Institute, Baltimore, Maryland.

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http://dx.doi.org/10.1016/j.pediatrneurol.2019.04.005DOI Listing
October 2019

Testing a deep convolutional neural network for automated hippocampus segmentation in a longitudinal sample of healthy participants.

Neuroimage 2019 08 7;197:589-597. Epub 2019 May 7.

Department of Psychiatry, University of Calgary, Calgary, AB, Canada.

Subtle changes in hippocampal volumes may occur during both physiological and pathophysiological processes in the human brain. Assessing hippocampal volumes manually is a time-consuming procedure, however, creating a need for automated segmentation methods that are both fast and reliable over time. Segmentation algorithms that employ deep convolutional neural networks (CNN) have emerged as a promising solution for large longitudinal neuroimaging studies. However, for these novel algorithms to be useful in clinical studies, the accuracy and reproducibility should be established on independent datasets. Here, we evaluate the performance of a CNN-based hippocampal segmentation algorithm that was developed by Thyreau and colleagues - Hippodeep. We compared its segmentation outputs to manual segmentation and FreeSurfer 6.0 in a sample of 200 healthy participants scanned repeatedly at seven sites across Canada, as part of the Canadian Biomarker Integration Network in Depression consortium. The algorithm demonstrated high levels of stability and reproducibility of volumetric measures across all time points compared to the other two techniques. Although more rigorous testing in clinical populations is necessary, this approach holds promise as a viable option for tracking volumetric changes in longitudinal neuroimaging studies.
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http://dx.doi.org/10.1016/j.neuroimage.2019.05.017DOI Listing
August 2019

Outcomes of Nasal Septal Perforation Repair Using Combined Temporoparietal Fascia Graft and Polydioxanone Plate Construct.

JAMA Facial Plast Surg 2019 Jul;21(4):319-326

Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee.

Importance: Numerous techniques are used for septal perforation repair, yet success rates remain variable. Few studies have evaluated the effectiveness of interposition grafts of polydioxanone plates combined with a temporoparietal fascia graft for septal perforation repair.

Objective: To investigate and describe the use of interposition grafts of polydioxanone plates combined with a temporoparietal fascia graft for septal perforation repair and the expansion of this technique to patients with more challenging comorbidities, including granulomatosis with polyangiitis.

Design, Setting, And Participants: A retrospective medical record review was performed of patients who underwent septal perforation repair using interposition grafts of polydioxanone plates combined with a temporoparietal fascia graft from January 1, 2015, to July 1, 2018, at Vanderbilt University Medical Center and from January 1, 2017, to July 1, 2018, at the University of Iowa.

Intervention: All patients underwent septal perforation repair with interposition grafts of polydioxanone plates and a temporoparietal fascia graft.

Main Outcomes And Measures: Assessing closure of septal perforation was the primary outcome. Secondary outcomes were resolution of presenting symptoms of septal perforation, area of perforation, length of postoperative stent and silastic sheeting placement, postoperative complications and resolution, and duration of follow-up. Preoperative and postoperative Nasal Obstruction Symptom Evaluation (NOSE) scores were assessed.

Results: A total of 17 patients (12 women and 5 men; mean [SD] age, 45 [15] years) were included. The causes of perforations were iatrogenic (9 [53%]), rheumatologic (2 [12%]), and unknown or idiopathic (6 [35%]). Patients most commonly presented with nasal crusting (12 [71%]), whistling (9 [53%]), nasal obstruction (9 [53%]), and epistaxis (5 [29%]). Mean (SD) perforation size was 0.99 (1.04) cm2. Mean (SD) postoperative follow-up was 6.1 (4.1) months. A total of 15 patients (88%) had complete resolution of presenting symptoms at last follow-up. All perforations were closed with overlying mucosa at the most recent follow-up examination. Nine of 17 patients completed both preoperative and postoperative NOSE. There was a significant difference between the mean (SD) preoperative and postoperative NOSE scores (62.78 [27.74] vs 17.78 [15.83]; P = .004).

Conclusions And Relevance: Repair of symptomatic nasal septal perforations using a temporoparietal fascia graft combined with a polydioxanone plate was associated with positive outcomes. Repair of septal perforations caused by rheumatologic disease, including granulomatosis with polyangiitis, can be considered for repair using this technique. Resolution of symptoms appeared to be clinically more meaningful in evaluation of septal perforation repair than rate of perforation closure, and the NOSE scale has the potential to serve as an objective corroboration to patient-reported postoperative outcomes.

Level Of Evidence: 4.
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http://dx.doi.org/10.1001/jamafacial.2019.0020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583828PMC
July 2019

The Canadian Biomarker Integration Network in Depression (CAN-BIND): magnetic resonance imaging protocols

J Psychiatry Neurosci 2019 07;44(4):223-236

From the Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, Alta., Canada (MacQueen, Hassel, Addington, Sharma); the Rotman Research Institute, Baycrest, and Department of Medical Biophysics, University of Toronto, Toronto, Ont., Canada (Arnott, Zamyadi, Strother); the Department of Psychology, Queen’s University, Kingston, Ont., Canada (Bowie, Harkness, Milev); the Department of Radiology, University of Calgary, Calgary, Alta., Canada (Bray, Lebel); the Alberta Children’s Hospital Research Institute, Calgary, Alta., Canada (Bray, Lebel); the Child and Adolescent Imaging Research (CAIR) Program, Calgary, Alta., Canada (Bray, Lebel); the Department of Psychology, Neuroscience and Behaviour, McMaster University, and St. Joseph’s Healthcare Hamilton, Hamilton, Ont., Canada (Hall); the Krembil Research Institute and Centre for Mental Health, University Health Network, Toronto, Ont., Canada (Downar); the Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ont., Canada (Downar); the Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Ont., Canada (Downar, Müller, Rizvi, Rotzinger, Kennedy); the Department of Psychiatry, Krembil Research Centre, University Health Network, University of Toronto, Toronto, Ont., Canada (Foster, Rotzinger, Kennedy); the Department of Psychiatry and Behavioural Neurosciences, McMaster University, and St. Joseph’s Healthcare Hamilton, Hamilton, Ont., Canada (Foster, Frey); the Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, Ont., Canada (Goldstein); the Departments of Psychiatry and Pharmacology, Faculty of Medicine, University of Toronto, Toronto, Ont., Canada (Goldstein); the Department of Computer Science, University of Alberta, Edmonton, Alta., Canada (Harris); the University of British Columbia and Vancouver Coastal Health Authority, Vancouver, B.C., Canada (Lam, Vila-Rodriguez); the Department of Psychiatry, Queen’s University and Providence Care Hospital, Kingston, Ont., Canada (Milev, Soares); the Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ont., Canada (Müller); the Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA (Parikh); the Arthur Sommer Rotenberg Suicide and Depression Studies Program, Li Ka Shing Knowledge Institute and St. Michael’s Hospital, Toronto, Ont., Canada (Rizvi); the Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ont., Canada (Rizvi); the Department of Psychiatry, St. Michael’s Hospital, University of Toronto, Toronto, Ont., Canada (Rotzinger, Soares, Yu); McGill University, Montréal, Que., Canada (Turecki); the Douglas Mental Health University Institute, Frank B. Common, Montréal, Que., Canada (Turecki); and the Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ont., Canada (Kennedy).

Studies of clinical populations that combine MRI data generated at multiple sites are increasingly common. The Canadian Biomarker Integration Network in Depression (CAN-BIND; www.canbind.ca) is a national depression research program that includes multimodal neuroimaging collected at several sites across Canada. The purpose of the current paper is to provide detailed information on the imaging protocols used in a number of CAN-BIND studies. The CAN-BIND program implemented a series of platform-specific MRI protocols, including a suite of prescribed structural and functional MRI sequences supported by real-time monitoring for adherence and quality control. The imaging data are retained in an established informatics and databasing platform. Approximately 1300 participants are being recruited, including almost 1000 with depression. These include participants treated with antidepressant medications, transcranial magnetic stimulation, cognitive behavioural therapy and cognitive remediation therapy. Our ability to analyze the large number of imaging variables available may be limited by the sample size of the substudies. The CAN-BIND program includes a multimodal imaging database supported by extensive clinical, demographic, neuropsychological and biological data from people with major depression. It is a resource for Canadian investigators who are interested in understanding whether aspects of neuroimaging — alone or in combination with other variables — can predict the outcomes of various treatment modalities.
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http://dx.doi.org/10.1503/jpn.180036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606427PMC
July 2019

Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.

Authors:
Benjamin Cogné Sophie Ehresmann Eliane Beauregard-Lacroix Justine Rousseau Thomas Besnard Thomas Garcia Slavé Petrovski Shiri Avni Kirsty McWalter Patrick R Blackburn Stephan J Sanders Kévin Uguen Jacqueline Harris Julie S Cohen Moira Blyth Anna Lehman Jonathan Berg Mindy H Li Usha Kini Shelagh Joss Charlotte von der Lippe Christopher T Gordon Jennifer B Humberson Laurie Robak Daryl A Scott Vernon R Sutton Cara M Skraban Jennifer J Johnston Annapurna Poduri Magnus Nordenskjöld Vandana Shashi Erica H Gerkes Ernie M H F Bongers Christian Gilissen Yuri A Zarate Malin Kvarnung Kevin P Lally Peggy A Kulch Brina Daniels Andres Hernandez-Garcia Nicholas Stong Julie McGaughran Kyle Retterer Kristian Tveten Jennifer Sullivan Madeleine R Geisheker Asbjorg Stray-Pedersen Jennifer M Tarpinian Eric W Klee Julie C Sapp Jacob Zyskind Øystein L Holla Emma Bedoukian Francesca Filippini Anne Guimier Arnaud Picard Øyvind L Busk Jaya Punetha Rolph Pfundt Anna Lindstrand Ann Nordgren Fayth Kalb Megha Desai Ashley Harmon Ebanks Shalini N Jhangiani Tammie Dewan Zeynep H Coban Akdemir Aida Telegrafi Elaine H Zackai Amber Begtrup Xiaofei Song Annick Toutain Ingrid M Wentzensen Sylvie Odent Dominique Bonneau Xénia Latypova Wallid Deb Sylvia Redon Frédéric Bilan Marine Legendre Caitlin Troyer Kerri Whitlock Oana Caluseriu Marine I Murphree Pavel N Pichurin Katherine Agre Ralitza Gavrilova Tuula Rinne Meredith Park Catherine Shain Erin L Heinzen Rui Xiao Jeanne Amiel Stanislas Lyonnet Bertrand Isidor Leslie G Biesecker Dan Lowenstein Jennifer E Posey Anne-Sophie Denommé-Pichon Claude Férec Xiang-Jiao Yang Jill A Rosenfeld Brigitte Gilbert-Dussardier Séverine Audebert-Bellanger Richard Redon Holly A F Stessman Christoffer Nellaker Yaping Yang James R Lupski David B Goldstein Evan E Eichler Francois Bolduc Stéphane Bézieau Sébastien Küry Philippe M Campeau

Am J Hum Genet 2019 03 28;104(3):530-541. Epub 2019 Feb 28.

Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, University of Montreal, Montreal, QC H3T1J4, Canada. Electronic address:

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.
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http://dx.doi.org/10.1016/j.ajhg.2019.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407527PMC
March 2019

Disrupted epigenetics in the Sotos syndrome neurobehavioral phenotype.

Curr Opin Psychiatry 2019 03;32(2):55-59

Department of Pediatrics.

Purpose Of Review: Sotos syndrome is among a growing list of disorders resulting from mutations in epigenetic machinery genes. These Mendelian disorders of the epigenetic machinery (MDEMs) exhibit phenotypic overlap broadly characterized by intellectual disability and atypical growth and behaviors. Manifestations of Sotos syndrome include a distinct facial appearance, overgrowth, intellectual disability, and behavioral issues. Herein we review key aspects of Sotos syndrome, focusing on the neurobehavioral phenotype. Additionally, we highlight recent advances in our understanding of molecular pathogenesis implicating epigenetic mechanisms.

Recent Findings: Increasing evidence suggests MDEMs account for ∼19% of intellectual disability and ∼45% of overgrowth combined with intellectual disability, with Sotos syndrome constituting most of the latter. Although the genetic cause of Sotos syndrome, disruption of the histone methyltransferase writer NSD1, is well established, recent studies have further delineated the neurobehavioral phenotype and provided insight into disease pathogenesis. Explicitly, NSD1 target genes accounting for a subset of Sotos syndrome features and a specific DNA methylation signature have been identified.

Summary: Sotos syndrome is, therefore, a genetic disorder with epigenetic consequences. Its characteristic neurobehavioral phenotype and those of related MDEMs illustrate the essential role epigenetic mechanisms play in neurologic development. Improvement in our understanding of molecular pathogenesis has important implications for development of diagnostic tests and therapeutic interventions.
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http://dx.doi.org/10.1097/YCO.0000000000000481DOI Listing
March 2019

Viewpoint: A perfect example of a new-fashioned GP.

Br J Gen Pract 2018 01;68(666):26

Meadowcroft Surgery, Jackson Road, Aylesbury, HP19 9EX, UK. E-mail:

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http://dx.doi.org/10.3399/bjgp17X694181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737293PMC
January 2018

Books: The Fatal Tree: A Practical Guide to 18th-Century Criminality.

Br J Gen Pract 2017 10;67(663):468

Meadowcroft Surgery, Aylesbury. E-mail:

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http://dx.doi.org/10.3399/bjgp17X692933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604820PMC
October 2017

Discovery of phenotypic networks from genotypic association studies with application to obesity.

Int J Data Min Bioinform 2015 ;12(2):129-43

Genome-wide Association Studies (GWAS) have resulted in many discovered risk variants for several obesity-related traits. However, before clinical relevance of these discoveries can be achieved, molecular or physiological mechanisms of these risk variants needs to be discovered. One strategy is to perform data mining of phenotypically-rich data sources such as those present in dbGAP (database of Genotypes and Phenotypes) for hypothesis generation. Here we propose a technique that combines the power of existing Bayesian Network (BN) learning algorithms with the statistical rigour of Structural Equation Modelling (SEM) to produce an overall phenotypic network discovery system with optimal properties. We illustrate our method using the analysis of a candidate SNP data set from the AMERICO sample, a multi-ethnic cross-sectional cohort of roughly 300 children with detailed obesity-related phenotypes. We demonstrate our approach by showing genetic mechanisms for three obesity-related SNPs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657437PMC
http://dx.doi.org/10.1504/ijdmb.2015.069414DOI Listing
November 2015

High dose folic acid supplementation of rats alters synaptic transmission and seizure susceptibility in offspring.

Sci Rep 2013 ;3:1465

Complexity Science Group, Department of Physics and Astronomy, Faculty of Science, University of Calgary, Calgary, AB, Canada.

Maternal folic acid supplementation is essential to reduce the risk of neural tube defects. We hypothesize that high levels of folic acid throughout gestation may produce neural networks more susceptible to seizure in offspring. We hence administered large doses of folic acid to rats before and during gestation and found their offspring had a 42% decrease in their seizure threshold. In vitro, acute application of folic acid or its metabolite 4Hfolate to neurons induced hyper-excitability and bursting. Cultured neuronal networks which develop in the presence of a low concentration (50 nM) of 4Hfolate had reduced capacity to stabilize their network dynamics after a burst of high-frequency activity, and an increase in the frequency of mEPSCs. Networks reared in the presence of the folic acid metabolite 5M4Hfolate developed a spontaneous, distinctive bursting pattern, and both metabolites produced an increase in synaptic density.
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http://dx.doi.org/10.1038/srep01465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598003PMC
September 2013

A Hybrid Bayesian Network/Structural Equation (BN/SEM) Modeling Approach for Detecting Physiological Networks for Obesity-related Genetic Variants.

Proceedings (IEEE Int Conf Bioinformatics Biomed) 2011 :696-702

Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham.

GWAS studies have been successful in finding genetic determinants of obesity. To translate discovered genetic variants into new therapies or prevention strategies, molecular or physiological mechanisms need to be discovered. One strategy is to perform data mining of data sets with detailed phenotypic data, such as those present in dbGAP (database of Genotypes and Phenotypes) for hypothesis generation. We propose a novel technique that combines the power and computational efficiency of existing Bayesian Network (BN) learning algorithms with the statistical rigor of Structural Equation Modeling (SEM) to produce an overall system that searches the space of potential networks and evaluates promising candidates using standard SEM model selection criteria. We demonstrate our method using the analysis of a candidate SNP data set from the AMERICO sample, a multi-ethnic cross-sectional cohort of roughly three hundred children with detailed obesity-related phenotypes. We demonstrate our approach by showing genetic mechanisms for three obesity-related SNPs.
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http://dx.doi.org/10.1109/BIBMW.2011.6112455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272699PMC
January 2011

Expression signature of IFN/STAT1 signaling genes predicts poor survival outcome in glioblastoma multiforme in a subtype-specific manner.

PLoS One 2012 5;7(1):e29653. Epub 2012 Jan 5.

Department of Biostatistics (Section on Statistical Genetics), University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

Previous reports have implicated an induction of genes in IFN/STAT1 (Interferon/STAT1) signaling in radiation resistant and prosurvival tumor phenotypes in a number of cancer cell lines, and we have hypothesized that upregulation of these genes may be predictive of poor survival outcome and/or treatment response in Glioblastoma Multiforme (GBM) patients. We have developed a list of 8 genes related to IFN/STAT1 that we hypothesize to be predictive of poor survival in GBM patients. Our working hypothesis that over-expression of this gene signature predicts poor survival outcome in GBM patients was confirmed, and in addition, it was demonstrated that the survival model was highly subtype-dependent, with strong dependence in the Proneural subtype and no detected dependence in the Classical and Mesenchymal subtypes. We developed a specific multi-gene survival model for the Proneural subtype in the TCGA (the Cancer Genome Atlas) discovery set which we have validated in the TCGA validation set. In addition, we have performed network analysis in the form of Bayesian Network discovery and Ingenuity Pathway Analysis to further dissect the underlying biology of this gene signature in the etiology of GBM. We theorize that the strong predictive value of the IFN/STAT1 gene signature in the Proneural subtype may be due to chemotherapy and/or radiation resistance induced through prolonged constitutive signaling of these genes during the course of the illness. The results of this study have implications both for better prediction models for survival outcome in GBM and for improved understanding of the underlying subtype-specific molecular mechanisms for GBM tumor progression and treatment response.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0029653PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3252343PMC
May 2012

Using protein abundance to indicate underlying mRNA expression levels in E.coli: an SEM modelling approach.

Int J Comput Biol Drug Des 2011 24;4(4):387-95. Epub 2011 Dec 24.

Department of Biostatistics, University of Alabama, Birmingham, AL 35294, USA.

Do steady-state protein levels accurately predict mRNA levels? Based on the central dogma (DNA RNA protein) current protein levels are representative of mRNA present at an earlier time. However, most cellular mRNA protein comparative studies try to relate steady-state protein levels to current mRNA levels in cells. Protein steady-states are more correctly related to protein production, protein degradation and other complex cellular conditions. Using Structural Equation Modelling (SEM) we relate linear protein measurements to latent mRNA in E.coli. This method can be used to find the optimal protein measurements that explain underlying mRNA expression, and better understand the proteomic and transcriptomic relationship in E.coli gene expression.
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http://dx.doi.org/10.1504/IJCBDD.2011.044445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272697PMC
April 2012

Associations of obesity genes with obesity-related outcomes in multiethnic children.

Arch Med Res 2011 Aug 31;42(6):509-14. Epub 2011 Oct 31.

Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, 1530 Third Avenue South, Birmingham, AL 35294-3360, USA.

Background And Aims: Genome-wide association studies (GWAS) have identified several loci that are associated with body mass index (BMI = kg/m(2)). However, little is known regarding whether the genetic basis of BMI differs among children of diverse racial/ethnic backgrounds, how the cumulative effect of these genes influences weight, or the contribution of these variants to body composition. This study examined the association between 17 GWAS-identified loci located in 16 genes and body-composition phenotypes in a multiethnic pediatric sample and evaluated the association of a composite genetic risk score with these phenotypes.

Methods: Anthropometric measures of BMI, waist circumference and waist-to-hip ratio were obtained in a sample of 298 children. Lean and fat mass were obtained from dual-energy X-ray absorptiometry (DXA). Genotypes of 17 single nucleotide polymorphisms (SNPs) were tested for association with the phenotypic measures, adjusted by standard covariates and estimates of genetic admixture.

Results: Both SNPs rs8050136 and rs9939609 in FTO were associated with BMI and waist circumference in a direction opposite to that observed among adults, and an inverse association was detected between the risk variant in MC4R and total lean body mass. Lean body mass mediated the association between TMEM18 and BMI. The association between the genetic risk score and body composition differed according to ethnic/racial classification.

Conclusions: Our findings suggest that genetic associations with BMI among children are different from those in adults, that some loci may operate through lean body mass, and that genetic risk scores will not have universal applicability across ethnic/racial groups.
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http://dx.doi.org/10.1016/j.arcmed.2011.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3541020PMC
August 2011

The TRIM5{alpha} genotype of rhesus macaques affects acquisition of simian immunodeficiency virus SIVsmE660 infection after repeated limiting-dose intrarectal challenge.

J Virol 2011 Sep 6;85(18):9637-40. Epub 2011 Jul 6.

AIDS Vaccine Research Laboratory, 555 Science Dr., Madison, WI 53711, USA.

It has recently been shown that polymorphism at the rhesus macaque TRIM5 locus can affect simian immunodeficiency virus (SIV) replication. Here we show that TRIM5 alleles can also affect acquisition of SIVsmE660. Animals coexpressing the TRIM5(TFP) and TRIM5(CypA) alleles took significantly longer to become infected with SIVsmE660, but not SIVmac239, after repeated limiting-dose intrarectal challenge than did animals expressing other TRIM5 allele combinations. Our results indicate that the TRIM5 alleles can be a barrier to productive infection and that this should be taken into account when designing acquisition studies using SIVsmE660 or related viruses.
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http://dx.doi.org/10.1128/JVI.05074-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165772PMC
September 2011

Recurrent spontaneous coronary artery dissection: A case report and review of the literature.

Int J Angiol 2007 ;16(3):109-12

Departments of Cardiology.

Spontaneous coronary artery dissection is a rare cause of acute coronary syndrome. Recurrent spontaneous dissection is even more rare. A case of recurrent coronary artery dissection is reported and the literature is reviewed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2733024PMC
http://dx.doi.org/10.1055/s-0031-1278260DOI Listing
August 2012