Arts & Sciences Brown School McKelvey School Medicine Weekly Publications

WashU weekly Neuroscience publications

“Repeated neonatal isoflurane exposures in the mouse induce apoptotic degenerative changes in the brain and relatively mild long-term behavioral deficits” (2019) Scientific Reports

Repeated neonatal isoflurane exposures in the mouse induce apoptotic degenerative changes in the brain and relatively mild long-term behavioral deficits
(2019) Scientific Reports, 9 (1), art. no. 2779, . 

Maloney, S.E.a d f , Yuede, C.M.a b , Creeley, C.E.c , Williams, S.L.a , Huffman, J.N.a , Taylor, G.T.d , Noguchi, K.N.a f , Wozniak, D.F.a e f

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Psychology, State University of New York at Fredonia, Fredonia, NY 14063, United States
d Department of Psychology, University of Missouri – St. Louis, St. Louis, MO 63121, United States
e Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States
f Intellectual and Developmental Disabilities Research Center, Washington University, St. Louis, MO, United States

Abstract
Epidemiological studies suggest exposures to anesthetic agents and/or sedative drugs (AASDs) in children under three years old, or pregnant women during the third trimester, may adversely affect brain development. Evidence suggests lengthy or repeated AASD exposures are associated with increased risk of neurobehavioral deficits. Animal models have been valuable in determining the type of acute damage in the developing brain induced by AASD exposures, as well as in elucidating long-term functional consequences. Few studies examining very early exposure to AASDs suggest this may be a critical period for inducing long-term functional consequences, but the impact of repeated exposures at these ages has not yet been assessed. To address this, we exposed mouse pups to a prototypical general anesthetic, isoflurane (ISO, 1.5% for 3 hr), at three early postnatal ages (P3, P5 and P7). We quantified the acute neuroapoptotic response to a single versus repeated exposure, and found age- and brain region-specific effects. We also found that repeated early exposures to ISO induced subtle, sex-specific disruptions to activity levels, motor coordination, anxiety-related behavior and social preference. Our findings provide evidence that repeated ISO exposures may induce behavioral disturbances that are subtle in nature following early repeated exposures to a single AASD. © 2019, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Cavitation dose painting for focused ultrasound-induced blood-brain barrier disruption” (2019) Scientific Reports

Cavitation dose painting for focused ultrasound-induced blood-brain barrier disruption
(2019) Scientific Reports, 9 (1), art. no. 2840, . 

Yang, Y.a , Zhang, X.b , Ye, D.c , Laforest, R.b , Williamson, J.d , Liu, Y.b , Chen, H.a d

a Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO 63130, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO 63110, United States
c Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, Saint Louis, MO 63130, United States
d Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63108, United States

Abstract
Focused ultrasound combined with microbubble for blood-brain barrier disruption (FUS-BBBD) is a promising technique for noninvasive and localized brain drug delivery. This study demonstrates that passive cavitation imaging (PCI) is capable of predicting the location and concentration of nanoclusters delivered by FUS-BBBD. During FUS-BBBD treatment of mice, the acoustic emissions from FUS-activated microbubbles were passively detected by an ultrasound imaging system and processed offline using a frequency-domain PCI algorithm. After the FUS treatment, radiolabeled gold nanoclusters, 64 Cu-AuNCs, were intravenously injected into the mice and imaged by positron emission tomography/computed tomography (PET/CT). The centers of the stable cavitation dose (SCD) maps obtained by PCI and the corresponding centers of the 64 Cu-AuNCs concentration maps obtained by PET coincided within 0.3 ± 0.4 mm and 1.6 ± 1.1 mm in the transverse and axial directions of the FUS beam, respectively. The SCD maps were found to be linearly correlated with the 64 Cu-AuNCs concentration maps on a pixel-by-pixel level. These findings suggest that SCD maps can spatially “paint” the delivered nanocluster concentration, a technique that we named as cavitation dose painting. This PCI-based cavitation dose painting technique in combination with FUS-BBBD opens new horizons in spatially targeted and modulated brain drug delivery. © 2019, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Sodium-activated potassium channels shape peripheral auditory function and activity of the primary auditory neurons in mice” (2019) Scientific Reports

Sodium-activated potassium channels shape peripheral auditory function and activity of the primary auditory neurons in mice
(2019) Scientific Reports, 9 (1), art. no. 2573, . 

Reijntjes, D.O.J.a , Lee, J.H.b , Park, S.b , Schubert, N.M.A.a , van Tuinen, M.a , Vijayakumar, S.c , Jones, T.A.c , Jones, S.M.c , Gratton, M.A.d , Xia, X.-M.d , Yamoah, E.N.b , Pyott, S.J.a

a University of Groningen, University Medical Center Groningen, Groningen, Department of Otorhinolaryngology and Head/Neck Surgery, Groningen, 9713GZ, Netherlands
b Department of Physiology and Cell Biology, Program in Communication and Sensory Sciences, School of Medicine, University of Nevada Reno, Reno, NV 89557, United States
c University of Nebraska Lincoln, Department of Special Education and Communication Disorders, 304B Barkley Memorial Center, Lincoln, NE 68583, United States
d Departments of Otorhinolaryngology Head and Neck Surgery and Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Potassium (K + ) channels shape the response properties of neurons. Although enormous progress has been made to characterize K + channels in the primary auditory neurons, the molecular identities of many of these channels and their contributions to hearing in vivo remain unknown. Using a combination of RNA sequencing and single molecule fluorescent in situ hybridization, we localized expression of transcripts encoding the sodium-activated potassium channels K Na 1.1 (SLO2.2/Slack) and K Na 1.2 (SLO2.1/Slick) to the primary auditory neurons (spiral ganglion neurons, SGNs). To examine the contribution of these channels to function of the SGNs in vivo, we measured auditory brainstem responses in K Na 1.1/1.2 double knockout (DKO) mice. Although auditory brainstem response (wave I) thresholds were not altered, the amplitudes of suprathreshold responses were reduced in DKO mice. This reduction in amplitude occurred despite normal numbers and molecular architecture of the SGNs and their synapses with the inner hair cells. Patch clamp electrophysiology of SGNs isolated from DKO mice displayed altered membrane properties, including reduced action potential thresholds and amplitudes. These findings show that K Na 1 channel activity is essential for normal cochlear function and suggest that early forms of hearing loss may result from physiological changes in the activity of the primary auditory neurons. © 2019, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Posterior reversible encephalopathy syndrome with isolated infratentorial involvement: A case report” (2019) Radiology Case Reports

Posterior reversible encephalopathy syndrome with isolated infratentorial involvement: A case report
(2019) Radiology Case Reports, 14 (5), pp. 576-580. 

Samara, A.a , Berry, B.b , Ghannam, M.b

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
b Neurology Department, University of Minnesota, Minneapolis, MN, United States

Abstract
Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiological entity of acute neurological symptoms associated with characteristic MRI finding. Vasogenic edema in the white matter of parieto-occipital regions is the classical MRI findings. Spinal cord involvement in PRES is extremely rare and frequently underrecognized condition. Recently, a variant-type PRES with isolated involvement of infratentorial structures is getting more attention. Herein, we present a case of hypertensive emergency and associated radiological features of PRES with isolated involvement of the brain stem, cerebellum, and spinal cord. © 2019 The Authors

Author Keywords
Hypertensive emergency;  Infratentorial structures;  Posterior reversible encephalopathy syndrome;  Spinal cord involvement

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Rationale and methods for a multicenter clinical trial assessing exercise and intensive vascular risk reduction in preventing dementia (rrAD Study)” (2019) Contemporary Clinical Trials

Rationale and methods for a multicenter clinical trial assessing exercise and intensive vascular risk reduction in preventing dementia (rrAD Study)
(2019) Contemporary Clinical Trials, 79, pp. 44-54. 

Szabo-Reed, A.N.a b , Vidoni, E.a c , Binder, E.F.d , Burns, J.a c , Cullum, C.M.e f , Gahan, W.P.g , Gupta, A.a b , Hynan, L.S.e h , Kerwin, D.R.i j , Rossetti, H.e , Stowe, A.M.k , Vongpatanasin, W.g , Zhu, D.C.l , Zhang, R.f i , Keller, J.N.g

a KU Alzheimer’s Disease Center, Fairway, KS, United States
b Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, United States
c Department of Neurology, University of Kansas Medical Center, Kansas City, KS, United States
d Department of Internal Medicine, Division of Geriatrics & Nutritional Science, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
e Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, United States
f Department of Neurology & Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX, United States
g Institute for Dementia Research and Prevention, Pennington Biomedical Research Center, Baton Rouge, LA, United States
h Department of Clinical Sciences, UT Southwestern Medical Center, Dallas, TX, United States
i Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, Dallas, United States
j Kerwin Research Center and Memory Care, Dallas, TX, United States
k Department of Neurology, University of Kentucky, Lexington, KY, United States
l Department for Radiology, Michigan State University, East Lansing, MI, United States

Abstract
Alzheimer’s Disease (AD) is an age-related disease with modifiable risk factors such as hypertension, hypercholesterolemia, obesity, and physical inactivity influencing the onset and progression. There is however, no direct evidence that reducing these risk factors prevents or slows AD. The Risk Reduction for Alzheimer’s Disease (rrAD) trial is designed to study the independent and combined effects of intensive pharmacological control of blood pressure and cholesterol and exercise training on neurocognitive function. Six hundred and forty cognitively normal older adults age 60 to 85 years with hypertension and increased risk for dementia will be enrolled. Participants are randomized into one of four intervention group for two years: usual care, Intensive Reduction of Vascular Risk factors (IRVR) with blood pressure and cholesterol reduction, exercise training (EX), and IRVR+EX. Neurocognitive function is measured at baseline, 6, 12, 18, and 24 months; brain MRIs are obtained at baseline and 24 months. We hypothesize that both IRVR and EX will improve global cognitive function, while IRVR+EX will provide a greater benefit than either IRVR or EX alone. We also hypothesize that IRVR and EX will slow brain atrophy, improve brain structural and functional connectivity, and improve brain perfusion. Finally, we will explore the mechanisms by which study interventions impact neurocognition and brain. If rrAD interventions are shown to be safe, practical, and successful, our study will have a significant impact on reducing the risks of AD in older adults. NCT Registration: NCT02913664 © 2019

Author Keywords
Alzheimer’s disease;  Brain structure;  Cognition;  Exercise;  Reduction of vascular risk factors

Document Type: Article
Publication Stage: Final
Source: Scopus

“The subjective-objective deficit paradox in schizotypy extends to emotion regulation and awareness” (2019) Journal of Psychiatric Research

The subjective-objective deficit paradox in schizotypy extends to emotion regulation and awareness
(2019) Journal of Psychiatric Research, 111, pp. 160-168. 

Li, L.Y.a , Karcher, N.R.b , Kerns, J.G.c , Fung, C.K.a , Martin, E.A.a

a Department of Psychological Science, University of California, Irvine, Irvine, CA, United States
b Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
c Department of Psychological Sciences, University of Missouri, Columbia, MO, United States

Abstract
There is an emerging subjective-objective deficit paradox in schizotypy. Individuals with schizotypy report severe subjective complaints in several key functional domains commensurate with that of individuals with schizophrenia. However, objective assessments of the same domains show relatively intact performance. We examined whether this subjective-objective deficit paradox extends to two closely linked affective processes: emotion regulation and awareness. Individuals with elevated social anhedonia (SocAnh; n = 61) and elevated perceptual aberration/magical ideation (PerMag; n = 73) were compared to control participants (n = 81) on subjective and objective measures of emotion regulation and awareness. Subjective measures included self-report questionnaires assessing regulatory ability, attention to emotion, and emotional clarity. Implicit emotion regulation was assessed by the Emotion Regulation-Implicit Association Test (ER-IAT) while objective emotional awareness was assessed by the Levels of Emotional Awareness Scale (LEAS), a performance-based test. Results showed that both SocAnh and PerMag groups reported notable deficits in almost all subjective measures relative to controls (composite ds > 0.55). In contrast, performance on ER-IAT and LEAS was very similar to controls (composite ds < 0.11). The current study suggests that the subjective-objective deficit paradox extends to emotion regulation and awareness, highlighting the importance of higher-order cognitive bias in understanding emotional abnormalities in schizotypy. © 2019 Elsevier Ltd

Author Keywords
Emotion regulation;  Emotional awareness;  Magical ideation;  Perceptual aberration;  Schizotypy;  Social anhedonia

Document Type: Article
Publication Stage: Final
Source: Scopus

“Maternal Depression and Stress in the Neonatal Intensive Care Unit: Associations With Mother−Child Interactions at Age 5 Years” (2019) Journal of the American Academy of Child and Adolescent Psychiatry

Maternal Depression and Stress in the Neonatal Intensive Care Unit: Associations With Mother−Child Interactions at Age 5 Years
(2019) Journal of the American Academy of Child and Adolescent Psychiatry, 58 (3), pp. 350-358.e2. 

Gerstein, E.D.a , Njoroge, W.F.M.b , Paul, R.A.c , Smyser, C.D.c , Rogers, C.E.c

a University of Missouri-St. LouisMO, United States
b Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States
c Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective: Previous studies suggest that maternal postpartum mental health issues may have an impact on parenting and child development in preterm infants, but have often not measured symptomatology in the neonatal intensive care unit (NICU) or followed families through early childhood. This study examines how maternal depressive symptoms and stress in the NICU are related to parenting behaviors at age 5 years, in mothers of children born very preterm (at ≤30 weeks’ gestation). Method: This longitudinal study followed a diverse sample of 74 very preterm children and their mothers. Maternal depression and stress were assessed in the NICU. At age 5, mother−child dyads were observed and coded for maternal intrusiveness, negativity, sensitivity, and positivity. Other covariates, including maternal and child intelligence, maternal education, income-to-needs ratio, maternal depression at age 5 years, and child sex were included in multivariate analyses. Results: The interaction between maternal NICU stress and NICU depression for intrusiveness and negativity indicates that greater NICU depression was associated with more intrusiveness under medium or high levels of NICU stress, and more negativity under high levels of NICU stress. Furthermore, greater NICU depression was associated with less sensitivity, over and above other covariates. Conclusion: Findings suggest that early maternal peripartum depression and stress in the NICU can have lasting impacts on multiple parenting behaviors, highlighting the need for screening and targeted interventions in the NICU. © 2018 American Academy of Child and Adolescent Psychiatry

Author Keywords
depression;  NICU;  parent-child interactions;  parenting;  preterm

Document Type: Article
Publication Stage: Final
Source: Scopus

“Health care professionals’ perspectives on physical activity within the Ugandan mental health care system” (2019) Mental Health and Physical Activity

Health care professionals’ perspectives on physical activity within the Ugandan mental health care system
(2019) Mental Health and Physical Activity, 16, pp. 1-7. 

Mugisha, J.a b , De Hert, M.c , Knizek, B.L.d , Kwiringira, J.a , Kinyanda, E.e f g , Byansi, W.l , van Winkel, R.c h , Myin-Germeys, I.h , Stubbs, B.i j , Vancampfort, D.c k

a Kyambogo University, Department of Sociology and Social Administration, Kampala, Uganda
b Butabika National Referral and Mental Health Hospital, Kampala, Uganda
c University Psychiatric Centre KU Leuven, Kortenberg, Belgium
d Norwegian University of Science and Technology, Faculty of Medicine and Health Sciences, Trondheim, Norway
e MRC/UVRI, Uganda Research Unit on AIDS, Entebbe, Uganda
f Department of Psychiatry, Makerere College of Health Sciences, Kampala, Uganda
g Senior Welcome Trust Fellowship, London, United Kingdom
h KU Leuven Centre of Contextual Psychiatry, Leuven, Belgium
i Physiotherapy Department, South London and Maudsley NHS Foundation Trust, Denmark Hill, London, SE5 8AZ, United Kingdom
j Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom
k KU Leuven Department of Rehabilitation Sciences, Leuven, Belgium
l Brown School of Social Work, Washington University, St. Louis, United States

Abstract
Background: Mental health care systems in Africa are faced with a high burden of mental disorders. There is need to explore evidence-based, scalable interventions to compliment the “traditional” health care system. Physical activity (PA) can augment the effectiveness of existing programs. However, little is known about the perspectives of health care professionals on PA. Understanding this is key to implementation. Methods: This was a qualitative exploratory study based on 13 key informant interviews among experienced health care professionals working at Butabika National Referral and Teaching Hospital, Uganda. Data was analyzed through content thematic analysis. Results: Participants reported PA benefits were: improved individual competences and engagement, social reintegration and reduced family and community burden. Self-stigma, lack of community support, lack of infrastructure and equipment, lack of monitoring capacity, human resource challenges and a focus solely on pharmacotherapy were among the most reported barriers to application of PA in management of mental health problems. Conclusion: Despite the high level of understanding of PA among health care professionals, PA promotion largely depends on implementation of strategies to deal with community and health systems barriers. Although patients need to be empowered to deal with their individual barriers, greater support and action is needed by policy makers. Public health programs should support PA through community engagement and social re-integration programs. The government should promote a holistic mental health care perspective and provide adequate infrastructural and human resources to support PA in the existing primary and mental health care systems. © 2019

Author Keywords
Community;  Exercise;  Physical activity;  Stigma

Document Type: Article
Publication Stage: Final
Source: Scopus

“Prevalence of Axonal Sensory Neuropathy With IgM Binding to Trisulfated Heparin Disaccharide in Patients With Fibromyalgia” (2019) Journal of clinical neuromuscular disease

Prevalence of Axonal Sensory Neuropathy With IgM Binding to Trisulfated Heparin Disaccharide in Patients With Fibromyalgia
(2019) Journal of clinical neuromuscular disease, 20 (3), pp. 103-110. 

Malik, A.a , Lopate, G.b , Hayat, G.a , Jones, J.a , Atluri, R.a , Malo, B.b , Pestronk, A.b

a Saint Louis University, Saint Louis, MO, United States
b Washington University in Saint Louis, Saint Louis, MO, United States

Abstract
OBJECTIVE: To assess the intraepidermal nerve fiber density in patients diagnosed with fibromyalgia (FM) and to evaluate the role of IgM binding to trisulfated heparin disaccharide (TS-HDS) in these patients. METHODS: FM is a poorly understood pain disorder with several proposed pathophysiologic mechanisms. It is characterized by widespread pain, fatigue, and sleep abnormalities. Small fiber neuropathy (SFN) has been proposed as an underlying mechanism, and patients with FM have been shown to have a reduction in the intraepidermal nerve fiber density. An underlying inflammatory process that could be a result of autoimmune phenomena has also been suggested. Non-length-dependent SFN (NLDSFN) has been shown to have a higher incidence of autoimmune disease. Twenty-two patients with established diagnosis of FM underwent skin biopsy at 2 sites; 10 cm above the lateral malleolus and 10 cm above the patella. Serum IgM binding to TS-HDS was assayed using an ELISA method. RESULTS: A total of 5/22 patients had positive TS-HDS antibodies; of these, 4 had NLDSFN (P = 0.0393). Comparison with a control group at Washington University showed no significant difference in percentage with TS-HDS antibodies (P = 0.41). When compared with Washington University database of skin biopsy, there was a trend for an increased percentage of NLDSFN in patients with FM (P = 0.06). CONCLUSIONS: This study further supports the hypothesis that a subgroup of patients with FM has SFN. We suggest a correlation between the presence of NLDSFN and TS-HDS antibodies.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Repetitive Concussive and Subconcussive Injury in a Human Tau Mouse Model Results in Chronic Cognitive Dysfunction and Disruption of White Matter Tracts, but Not Tau Pathology” (2019) Journal of Neurotrauma

Repetitive Concussive and Subconcussive Injury in a Human Tau Mouse Model Results in Chronic Cognitive Dysfunction and Disruption of White Matter Tracts, but Not Tau Pathology
(2019) Journal of Neurotrauma, 36 (5), pp. 735-755. 

Gangolli, M.a , Benetatos, J.b , Esparza, T.J.c , Fountain, E.M.c , Seneviratne, S.c , Brody, D.L.c

a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 20814-4799, United States
b Queensland Brain Institute, University of Queensland, St. Lucia, Australia
c Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Due to the unmet need for a means to study chronic traumatic encephalopathy (CTE) in vivo, there have been numerous efforts to develop an animal model of this progressive tauopathy. However, there is currently no consensus in the field on an injury model that consistently reproduces the neuropathological and behavioral features of CTE. We have implemented a repetitive Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) injury paradigm in human transgenic (hTau) mice. Animals were subjected to daily subconcussive or concussive injuries for 20 days and tested acutely, 3 months, and 12 months post-injury for deficits in social behavior, anxiety, spatial learning and memory, and depressive behavior. Animals also were assessed for chronic tau pathology, astrogliosis, and white matter degeneration. Repetitive concussive injury caused acute deficits in Morris water maze performance, including reduced swimming speed and increased distance to the platform during visible and hidden platform phases that persisted during the subacute and chronic time-points following injury. We found evidence of white matter disruption in animals injured with subconcussive and concussive injuries, with the most severe disruption occurring in the repetitive concussive injury group. Severity of white matter disruption in the corpus callosum was moderately correlated with swimming speed, while white matter disruption in the fimbria showed weak but significant correlation with worse performance during probe trial. There was no evidence of tau pathology or astrogliosis in sham or injured animals. In summary, we show that repetitive brain injury produces persistent behavioral abnormalities as late as 1 year post-injury that may be related to chronic white matter disruption, although the relationship with CTE remains to be determined. © Copyright 2019, Mary Ann Liebert, Inc., publishers 2019.

Author Keywords
chronic behavior;  concussive;  subconcussive;  white matter injury

Document Type: Article
Publication Stage: Final
Source: Scopus

“Crossover to Bilateral Repetitive Transcranial Magnetic Stimulation: A Potential Strategy When Patients Are Not Responding to Unilateral Left-Sided High-Frequency Repetitive Transcranial Magnetic Stimulation” (2019) Journal of ECT

Crossover to Bilateral Repetitive Transcranial Magnetic Stimulation: A Potential Strategy When Patients Are Not Responding to Unilateral Left-Sided High-Frequency Repetitive Transcranial Magnetic Stimulation
(2019) Journal of ECT, 35 (1), pp. 3-5. 

Cristancho, P.a , Trapp, N.T.b , Siddiqi, S.H.a c , Dixon, D.a , Miller, J.P.d , Lenze, E.J.a

a Department of Psychiatry, Healthy Mind Lab, School of Medicine, Washington University in St Louis, St Louis, MO, United States
b University of Iowa Hospital and Clinics, Iowa City, IA, United States
c Department of Neurology, McLean Hospital and Harvard Medical School, Boston, MA, United States
d Division of Biostatistics, School of Medicine, Washington University in St Louis, St Louis, MO, United States

Abstract
Clinical trials using left-sided repetitive transcranial magnetic stimulation (rTMS) report remission rates of 14% to 32.6%. A large percentage of patients would not achieve remission with standard rTMS treatment. The question of what clinicians should do when a patient is not responding to standard high-frequency (HF) left-sided rTMS remains unanswered. This prospective case series examines whether crossover to bilateral stimulation enhances antidepressant outcomes in patients not responding to unilateral rTMS. Patients in a major depressive episode received an rTMS clinical protocol of 4 to 6 weeks’ duration. Stimulation began with HF rTMS (10 Hz) over the left dorsolateral prefrontal cortex (range, 3000-5000 pulses per session). A total of 17 patients without sufficient clinical improvement early in their rTMS course received 1-Hz rTMS (range, 600-1200 pps) over the right dorsolateral prefrontal cortex (added to the HF left-sided stimulation). Hamilton Depression Rating Scale scores decreased from 13.9 ± 3.9 (mean ± SD) from the start of augmentation to 12.2 ± 5.8 at the end of acute treatment, a 1.7-point change, Cohen d effect size =-0.35, 95% confidence interval,-1.01 to-0.34, suggesting improvement. Remission rate in this sample was 24% (4/17). This case series indicates that crossover to bilateral stimulation is a feasible and potentially effective strategy when patients are not improving with standard rTMS. A randomized controlled trial comparing crossover versus standard rTMS is needed to determine the efficacy of this paradigm. © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Author Keywords
antidepressant;  augmentation;  depression;  rTMS;  slow frequency;  slow rTMS

Document Type: Article
Publication Stage: Final
Source: Scopus

“Provocative testing in patients with jackhammer esophagus: evidence for altered neural control” (2019) American journal of physiology. Gastrointestinal and liver physiology

Provocative testing in patients with jackhammer esophagus: evidence for altered neural control
(2019) American journal of physiology. Gastrointestinal and liver physiology, 316 (3), pp. G397-G403. 

Mauro, A.a b , Quader, F.c , Tolone, S.d , Savarino, E.e , De Bortoli, N.f , Franchina, M.a b , Gyawali, C.P.c , Penagini, R.a b

a Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
b Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
c Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, United States
d Division of General and Bariatric Surgery, Department of Surgery, Second University of Naples, Naples, Italy
e Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
f Division of Gastroenterology, Department of Translational Research and New Technology in Medicine and Surgery, University of Pisa, Cisanello Hospital, Pisa, Italy

Abstract
Jackhammer esophagus (JE) is a hypercontractile disorder, the pathogenesis of which is incompletely understood. Multiple rapid swallows (MRS) and rapid drink challenge (RDC) are complementary tests used during high-resolution manometry (HRM) that evaluate inhibitory and excitatory neuromuscular function and latent obstruction, respectively. Our aim was to evaluate esophageal pathophysiology using MRS and RDC in 83 JE patients (28 men; median age: 63 yr; IQR: 54-70 yr). Twenty-one healthy subjects (11 men; median age: 28 yr; range: 26-30 yr) were used as a control group. All patients underwent solid-state HRM with ten 5-ml single swallows (SS) and one to three 10-ml MRS; 34 patients also underwent RDC. Data are shown as median (interquartile range). Abnormal motor inhibition was noted during at least one MRS test in 48% of JE patients compared with 29% of controls ( P = 0.29). Mean distal contractile integral (DCI) after MRS was significantly lower than after SS [6,028 (3,678-9,267) mmHg·cm·s vs. 7,514 (6,238-9,197) mmHg·cm·s, P = 0.02], as was highest DCI ( P < 0.0001). Consequently, 66% of JE patients had no contraction reserve. At least one variable of obstruction during RDC (performed in 34 patients) was outside the normal range in 25 (74%) of JE patients. Both highest DCI after SS and pressure gradient across the esophagogastric junction (EGJ) during RDC were higher in patients with dysphagia versus those without ( P = 0.04 and 0.01, respectively). Our data suggest altered neural control in JE patients with heterogeneity in inhibitory function. Furthermore, some patients had latent EGJ obstruction during RDC, which correlated with the presence of dysphagia. NEW & NOTEWORTHY Presence of abnormal inhibition was observed during multiple rapid swallows (MRS) in some but not all patients with jackhammer esophagus (JE). Unlike healthy subjects, JE patients were more strongly stimulated after single swallows than after MRS. An obstructive pattern was frequently observed during rapid drink challenge (RDC) and was related to presence of dysphagia. MRS and RDC during high-resolution manometry are useful to show individual pathophysiological patterns in JE and may guide optimal therapeutic strategies.

Author Keywords
dysphagia;  high-resolution manometry;  jackhammer esophagus;  multiple rapid swallows;  rapid drink challenge

Document Type: Article
Publication Stage: Final
Source: Scopus

“Prevalence of 3 Healthy Lifestyle Behaviors Among US Adults With and Without History of Stroke” (2019) Preventing chronic disease

Prevalence of 3 Healthy Lifestyle Behaviors Among US Adults With and Without History of Stroke
(2019) Preventing chronic disease, 16, p. E23. 

Bailey, R.R.a , Phad, A.b , McGrath, R.c , Tabak, R.b , Haire-Joshu, D.b

a Ryan R. Bailey, OTR/L, Washington University in St Louis, Brown School, Campus Box 1196 ,One Brookings Dr, St Louis, MO 63110, United States
b Washington University in St Louis, St Louis, MO, United States
c North Dakota State University, Fargo, ND, United States

Abstract
INTRODUCTION: Engaging in healthy lifestyle behaviors decreases risk for cardiometabolic complications, which is of particular concern for stroke survivors whose history of stroke (HOS) increases cardiometabolic risk. Population-based estimates of healthy behaviors in adults with HOS are lacking but could be used to inform research, policy, and health care practice. The objective of this study was to calculate and compare population-based estimates of the prevalence of consuming 1 or more fruit and 1 or more vegetable daily, meeting weekly aerobic physical activity recommendations, having a body mass index (BMI) of less than 25 kg/m2, and the number of healthy behaviors among US adults with and without HOS. METHODS: We used data from the 2015 Behavioral Risk Factor Surveillance System. Weighted and age-adjusted (to the 2000 US standard population) prevalence estimates and adjusted odds ratios (AORs, adjusted for demographic variables) were computed for study variables. RESULTS: Adults with HOS were less likely than adults without HOS to consume 1 or more fruit and 1 or more vegetable daily (AOR = 0.85; 95% confidence interval [CI], 0.79-0.91), meet weekly aerobic physical activity recommendations (AOR = 0.72; 95% CI, 0.67-0.78), and engage in 2 (AOR = 0.86; 95% CI, 0.79-0.94) or 3 (AOR = 0.73; 95% CI, 0.64-0.82) healthy behaviors. Adults with HOS were more likely to engage in 0 healthy behaviors (AOR = 1.26; 95% CI, 1.16-1.37). Having a BMI of less than 25 kg/m2 and engaging in 1 healthy behavior were similar between groups. CONCLUSION: Prevalence of individual and total number of healthy behaviors was lower in adults with HOS for several healthy behaviors. Future research, policy, and health care practice is needed to promote healthy behaviors in adults with HOS.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Evolution of clinical trials in multiple sclerosis” (2019) Therapeutic Advances in Neurological Disorders

Evolution of clinical trials in multiple sclerosis
(2019) Therapeutic Advances in Neurological Disorders, 12, . 

Zhang, Y.a , Salter, A.b , Wallström, E.c , Cutter, G.d , Stüve, O.e f

a Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, United States
b Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
c Sanofi Genzyme, Neuro and Gene Therapy, Cambridge, MA, United States
d Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States
e Neurology Section, North Texas Health Care System, Medical Service, 4500 South Lancaster Rd, Dallas, TX 75216, United States
f Department of Neurology, Klinikum rechts der Isar, Technische Universität, München, Germany

Abstract
Clinical trials have advanced the treatment of multiple sclerosis (MS) by demonstrating the safety and efficacy of disease-modifying therapies (DMTs). This review discusses major changes to MS clinical trials in the era of DMTs. As treatment options for MS continue to increase, patients in modern MS trials present earlier and with milder disease compared with historic MS populations. While placebo-controlled trials for some questions may still be relevant, DMT trials in relapsing–remitting MS (RRMS) are no longer ethical. The replacement of the placebo arm by an active comparator arm in trials have raised the cost of trials by requiring larger sample sizes to detect on-study changes in treatment effects. Efforts to improve trial efficiency in RRMS have focused on exploring adaptive designs and relying on sensitive magnetic resonance imaging measures of disease activity. In trials for progressive forms of MS (PMS), the lack of sensitive outcome measures that can be used in shorter-term trials have delayed the development of effective treatments. Recent shifting of the focus to advancing trials in PMS has identified paraclinical outcome measurements with improved potential, and the testing of agents for neuroprotection and remyelination is in progress. © The Author(s), 2019.

Author Keywords
clinical trials;  diagnostic criteria;  multiple sclerosis;  outcome measure;  progressive multiple sclerosis;  trial design

Document Type: Review
Publication Stage: Final
Source: Scopus

“Network Restructuring Control for Conic Invariance with Application to Neural Networks” (2019) Proceedings of the IEEE Conference on Decision and Control

Network Restructuring Control for Conic Invariance with Application to Neural Networks
(2019) Proceedings of the IEEE Conference on Decision and Control, 2018-December, art. no. 8618729, pp. 2704-2709. 

Singh, M.F.a , Ching, S.b

a Departments of Neuroscience Psychology, Electrical and Systems Engineering, Washington University in St. Louis, United States
b Department of Electrical and Systems Engineering and Biomedical Engineering, Washington University in St. Louis, United States

Abstract
Recent advances in the study of artificial and biological neural networks support the power of dynamic representations-computing with information stored as nontrivial limit-sets rather than fixed-point attractors. Understanding and manipulating these computations in nonlinear networks requires a theory of control for abstract objective functions. Towards this end, we consider two properties of limit-sets: their topological dimension and orientation (covariance) in phase space and combine these abstract properties into a single well-defined objective: conic control-invariant sets in the derivative space (i.e., the vector field). Real-world applications, such as neural-medicine, constrain which control laws are feasible with less-invasive controllers being preferable. To this end, we derive a feedback control-law for conic invariance which corresponds to constrained restructuring of the network connections as might occur with pharmacological intervention (as opposed to a physically separate control unit). We demonstrate the ease and efficacy of the technique in controlling the orientation and dimension of limit sets in high-dimensional neural networks. © 2018 IEEE.

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus

“Visualizing the Heterogeneity of Retinal Microglia” (2019) Immunity

Visualizing the Heterogeneity of Retinal Microglia
(2019) Immunity, . 

Lin, J.B.a , Apte, R.S.a b c

a Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
b Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
In this issue of Immunity, O’Koren et al. (2019) report that murine retinal microglia are long lived and are divided into two spatially and functionally distinct niches in the retina. In models of retinal neurodegeneration, retinal microglia migrate to the subretinal space, an inducible disease-associated niche, where they are neuroprotective. © 2019 Elsevier Inc.

In this issue of Immunity, O’Koren et al. (2019) report that murine retinal microglia are long lived and are divided into two spatially and functionally distinct niches in the retina. In models of retinal neurodegeneration, retinal microglia migrate to the subretinal space, an inducible disease-associated niche, where they are neuroprotective. © 2019 Elsevier Inc.

Document Type: Short Survey
Publication Stage: Article in Press
Source: Scopus

“Identification of common genetic risk variants for autism spectrum disorder” (2019) Nature Genetics

Identification of common genetic risk variants for autism spectrum disorder
(2019) Nature Genetics, . Cited 1 time.

Grove, J.a b c d , Ripke, S.e f g , Als, T.D.a b c , Mattheisen, M.a b c h i , Walters, R.K.e f , Won, H.j k , Pallesen, J.a b c , Agerbo, E.a l m , Andreassen, O.A.n o , Anney, R.p , Awashti, S.g , Belliveau, R.f , Bettella, F.n o , Buxbaum, J.D.q r s t , Bybjerg-Grauholm, J.a u , Bækvad-Hansen, M.a u , Cerrato, F.f , Chambert, K.f , Christensen, J.H.a b c , Churchhouse, C.e f v , Dellenvall, K.w , Demontis, D.a b c , De Rubeis, S.q r , Devlin, B.x , Djurovic, S.n y , Dumont, A.L.f , Goldstein, J.I.e f v , Hansen, C.S.a u z , Hauberg, M.E.a b c , Hollegaard, M.V.a u , Hope, S.n aa , Howrigan, D.P.e f , Huang, H.e f , Hultman, C.M.w , Klei, L.x , Maller, J.f ab ac , Martin, J.f p w , Martin, A.R.e f v , Moran, J.L.f , Nyegaard, M.a b c , Nærland, T.n ad , Palmer, D.S.e f , Palotie, A.e f v ae , Pedersen, C.B.a l m , Pedersen, M.G.a l m , dPoterba, T.e f v , Poulsen, J.B.a u , Pourcain, B.S.af ag ah , Qvist, P.a b c , Rehnström, K.ai , Reichenberg, A.q r s , Reichert, J.q r , Robinson, E.B.e f aj , Roeder, K.ak al , Roussos, P.r am an ao , Saemundsen, E.ap , Sandin, S.q r w , Satterstrom, F.K.e f v , Davey Smith, G.ag aq , Stefansson, H.ar , Steinberg, S.ar , Stevens, C.R.f , Sullivan, P.F.j w as , Turley, P.e f , Walters, G.B.ar at , Xu, X.q r , Wray, N.R.ba bb , Trzaskowski, M.ba , Byrne, E.M.ba , Abdellaoui, A.bc , Adams, M.J.bd , Air, T.M.be , Andlauer, T.F.M.bf bg , Bacanu, S.-A.bh , Beekman, A.T.F.bi , Bigdeli, T.B.bh bj , Binder, E.B.bf bk , Blackwood, D.H.R.bd , Bryois, J.w , Buttenschøn, H.N.a b bl , Cai, N.bm bn , Castelao, E.bo , Clarke, T.-K.bd , Coleman, J.R.I.bp , Colodro-Conde, L.bq , Couvy-Duchesne, B.br bs , Craddock, N.bt , Crawford, G.E.bu bv , Davies, G.bw , Deary, I.J.bw , Degenhardt, F.bx by , Derks, E.M.bq , Direk, N.bz ca , Dolan, C.V.bc , Dunn, E.C.f cb cc , Eley, T.C.bp , Escott-Price, V.cd , Kiadeh, F.F.H.ce , Finucane, H.K.aj cf , Forstner, A.J.bx by cg ch , Frank, J.ci , Gaspar, H.A.bp , Gill, M.cj , Goes, F.S.ck , Gordon, S.D.bq , Hall, L.S.bd cl , Hansen, T.F.cm cn co , Herms, S.bx by ch , Hickie, I.B.cp , Hoffmann, P.bx by ch , Homuth, G.cq , Horn, C.cr , Hottenga, J.-J.bc , Ising, M.cs , Jansen, R.bi , Jorgenson, E.ct , Knowles, J.A.cu , Kohane, I.S.cv cw cx , Kraft, J.cy , Kretzschmar, W.W.cz , Krogh, J.da , Kutalik, Z.db dc , Li, Y.cz , Lind, P.A.bq , MacIntyre, D.J.dd de , MacKinnon, D.F.ck , Maier, R.M.bb , Maier, W.df , Marchini, J.dg , Mbarek, H.bc , McGrath, P.dh , McGuffin, P.bp , Medland, S.E.bq , Mehta, D.bb di , Middeldorp, C.M.bc dj dk , Mihailov, E.dl , Milaneschi, Y.bi , Milani, L.dl , Mondimore, F.M.ck , Montgomery, G.W.ba , Mostafavi, S.dm dn , Mullins, N.bp , Nauck, M.do dp , Ng, B.dn , Nivard, M.G.bc , Nyholt, D.R.dq , O’Reilly, P.F.bp , Oskarsson, H.dr , Owen, M.J.p , Painter, J.N.bq , Peterson, R.E.bh ds , Pettersson, E.w , Peyrot, W.J.bi , Pistis, G.bo , Posthuma, D.dt du , Quiroz, J.A.dv , Rice, J.P.dw , Riley, B.P.bh , Rivera, M.bp dx , Mirza, S.S.bz , Schoevers, R.dy , Schulte, E.C.dz ea , Shen, L.ct , Shi, J.eb , Shyn, S.I.ec , Sigurdsson, E.ed , Sinnamon, G.C.B.ee , Smit, J.H.bi , Smith, D.J.ef , Streit, F.ci , Strohmaier, J.ci , Tansey, K.E.eg , Teismann, H.eh , Teumer, A.ei , Thompson, W.a n o cn ej , Thomson, P.A.ek , Thorgeirsson, T.E.el , Traylor, M.em , Treutlein, J.ci , Trubetskoy, V.cy , Uitterlinden, A.G.en , Umbricht, D.eo , Van der Auwera, S.ep , van Hemert, A.M.eq , Viktorin, A.w , Visscher, P.M.ba bb , Wang, Y.a n o cn , Webb, B.T.ds , Weinsheimer, S.M.a cn , Wellmann, J.eh , Willemsen, G.bc , Witt, S.H.ci , Wu, Y.ba , Xi, H.S.er , Yang, J.bb es , Zhang, F.ba , Arolt, V.et , Baune, B.T.be , Berger, K.eh , Boomsma, D.I.bc , Cichon, S.bx ch eu ev , Dannlowski, U.et , de Geus, E.J.C.bc ew , DePaulo, J.R.ck , Domenici, E.ex , Domschke, K.ey , Esko, T.v dl , Grabe, H.J.ep , Hamilton, S.P.ez , Hayward, C.fa , Heath, A.C.dw , Kendler, K.S.bh , Kloiber, S.cs fb fc , Lewis, G.fd , Li, Q.S.fe , Lucae, S.cs , Madden, P.A.F.dw , Magnusson, P.K.w , Martin, N.G.bq , McIntosh, A.M.bd bw , Metspalu, A.dl ff , Müller-Myhsok, B.bf bg fg , Nöthen, M.M.bx by , O’Donovan, M.C.p , Paciga, S.A.fh , Pedersen, N.L.w , Penninx, B.W.J.H.bi , Perlis, R.H.cb fi , Porteous, D.J.ek , Potash, J.B.fj , Preisig, M.bo , Rietschel, M.ci , Schaefer, C.ct , Schulze, T.G.ci ck ea fk fl , Smoller, J.W.f cb cc , Tiemeier, H.bz fm fn , Uher, R.fo , Völzke, H.ei , Weissman, M.M.dh fp , Lewis, C.M.bp fq , Levinson, D.F.fr , Breen, G.bp fs , Agee, M.ft , Alipanahi, B.ft , Auton, A.ft , Bell, R.K.ft , Bryc, K.ft , Elson, S.L.ft , Fontanillas, P.ft , Furlotte, N.A.ft , Hromatka, B.S.ft , Huber, K.E.ft , Kleinman, A.ft , Litterman, N.K.ft , McIntyre, M.H.ft , Mountain, J.L.ft , Noblin, E.S.ft , Northover, C.A.M.ft , Pitts, S.J.ft , Sathirapongsasuti, J.F.ft , Sazonova, O.V.ft , Shelton, J.F.ft , Shringarpure, S.ft , Tung, J.Y.ft , Vacic, V.ft , Wilson, C.H.ft , Stefansson, K.ar at , Geschwind, D.H.au av aw , Nordentoft, M.a ax , Hougaard, D.M.a u , Werge, T.a z ay , Mors, O.a az , Mortensen, P.B.a b l m , Neale, B.M.e f v , Daly, M.J.e f v ae , Børglum, A.D.a b c , Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortiumfu , BUPGENfu , Major Depressive Disorder Working Group of the Psychiatric Genomics Consortiumfv , 23andMe Research Teamfv

a The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark
b Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark
c Department of Biomedicine–Human Genetics, Aarhus University, Aarhus, Denmark
d Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
e Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
f Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, United States
g Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin, Berlin, Germany
h Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany
i Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
j Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
k UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
l National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark
m Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark
n NORMENT-KG Jebsen Centre for Psychosis Research, University of Oslo, Oslo, Norway
o Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
p MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
q Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, United States
r Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States
s Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
t Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
u Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
v Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, United States
w Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
x Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
y Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
z Institute of Biological Psychiatry, MHC SctHans, Mental Health Services, Copenhagen, Denmark
aa Department of Neurohabilitation, Oslo University Hospital, Oslo, Norway
ab Genomics plc, Oxford, United Kingdom
ac Vertex Pharmaceuticals, Abingdon, United Kingdom
ad NevSom, Department of Rare Disorders and Disabilities, , Oslo University Hospital, Oslo, Norway
ae Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
af Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, Netherlands
ag MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
ah Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands
ai Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom
aj Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
ak Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, United States
al Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA, United States
am Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
an Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
ao Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, NY, United States
ap The State Diagnostic and Counselling Centre, Kópavogur, Iceland
aq Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
ar deCODE genetics/Amgen, Reykjavík, Iceland
as Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
at Faculty of Medicine, University of Iceland, Reykjavik, Iceland
au Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
av Center for Autism Research and Treatment and Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, United States
aw Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
ax Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark
ay Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
az Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark
ba Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
bb Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia
bc Department of Biological Psychology & EMGO+ Institute for Health and Care Research, Vrije Universiteit, Amsterdam, Amsterdam, Netherlands
bd Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom
be Discipline of Psychiatry, University of Adelaide, Adelaide, SA, Australia
bf Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
bg Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
bh Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States
bi Department of Psychiatry, Vrije Universiteit Medical Center and GGZ inGeest, Amsterdam, Netherlands
bj Virginia Institute for Psychiatric and Behavior Genetics, Richmond, VA, United States
bk Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
bl Department of Clinical Medicine, Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark
bm Human Genetics, Wellcome Trust Sanger Institute, Cambridge, United Kingdom
bn Statistical genomics and systems genetics, European Bioinformatics Institute (EMBL-EBI), Cambridge, United Kingdom
bo Department of Psychiatry, University Hospital of Lausanne, Prilly, Switzerland
bp MRC Social Genetic and Developmental Psychiatry Centre, King’s College London, London, United Kingdom
bq Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
br Centre for Advanced Imaging, University of Queensland, Saint Lucia, QLD, Australia
bs Queensland Brain Institute, University of Queensland, Saint Lucia, QLD, Australia
bt Psychological Medicine, Cardiff University, Cardiff, United Kingdom
bu Center for Genomic and Computational Biology, Duke University, Durham, NC, United States
bv Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC, United States
bw Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
bx Institute of Human Genetics, University of Bonn, Bonn, Germany
by Life&Brain Center, Department of Genomics, University of Bonn, Bonn, Germany
bz Epidemiology, Erasmus MC, Rotterdam, Netherlands
ca Psychiatry, Dokuz Eylul University School Of Medicine, Izmir, Turkey
cb Department of Psychiatry, Massachusetts General Hospital, Boston, MA, United States
cc Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, MA, United States
cd Neuroscience and Mental Health, Cardiff University, Cardiff, United Kingdom
ce Bioinformatics, University of British Columbia, Vancouver, BC, Canada
cf Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA, United States
cg Department of Psychiatry (UPK), University of Basel, Basel, Switzerland
ch Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland
ci Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty, Mannheim, Heidelberg University, Mannheim, Baden-Württemberg, Germany
cj Department of Psychiatry, Trinity College Dublin, Dublin, Ireland
ck Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, United States
cl Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
cm Danish Headache Centre, Department of Neurology, Rigshospitalet, Glostrup, Denmark
cn Institute of Biological Psychiatry, Mental Health Center SctHans, Mental Health Services Capital Region of Denmark, Copenhagen, Denmark
co iPSYCH, Lundbeck Foundation Initiative for Psychiatric Research, Copenhagen, Denmark
cp Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia
cq Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Mecklenburg-Vorpommern, Germany
cr Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, FHoffmann-La Roche Ltd, Basel, Switzerland
cs Max Planck Institute of Psychiatry, Munich, Germany
ct Division of Research, Kaiser Permanente Northern California, Oakland, CA, United States
cu Psychiatry & The Behavioral Sciences, University of Southern California, Los Angeles, CA, United States
cv Department of Biomedical Informatics, Harvard Medical School, Boston, MA, United States
cw Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
cx Informatics Program, Boston Children’s Hospital, Boston, MA, United States
cy Department of Psychiatry and Psychotherapy, Universitätsmedizin Berlin Campus Charité Mitte, Berlin, Germany
cz Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
da Department of Endocrinology at Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark
db Institute of Social and Preventive Medicine (IUMSP), University Hospital of Lausanne, Lausanne, Switzerland
dc Swiss Institute of Bioinformatics, Lausanne, Switzerland
dd Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
de Mental Health, NHS 24, Glasgow, United Kingdom
df Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany
dg Statistics, University of Oxford, Oxford, United Kingdom
dh Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, United States
di School of Psychology and Counseling, Queensland University of Technology, Brisbane, QLD, Australia
dj Child and Youth Mental Health Service, Children’s Health Queensland Hospital and Health Service, South Brisbane, QLD, Australia
dk Child Health Research Centre, University of Queensland, Brisbane, QLD, Australia
dl Estonian Genome Center, University of Tartu, Tartu, Estonia
dm Medical Genetics, University of British Columbia, Vancouver, BC, Canada
dn Statistics, University of British Columbia, Vancouver, BC, Canada
do DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, University Medicine, University Medicine Greifswald, Greifswald, Germany
dp Institute of Clinical Chemistry and Laboratory Medicine, University Medicine, Greifswald, Germany
dq Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
dr Humus, Reykjavik, Iceland
ds Virginia Institute for Psychiatric & Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
dt Clinical Genetics, Vrije Universiteit Medical Center, Amsterdam, Netherlands
du Complex Trait Genetics, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
dv Solid Biosciences, Boston, MA, United States
dw Department of Psychiatry, Washington University in Saint Louis School of Medicine, Saint Louis, MO, United States
dx Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain
dy Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
dz Department of Psychiatry and Psychotherapy, Medical Center of the University of Munich, Campus Innenstadt, Munich, Germany
ea Institute of Psychiatric Phenomics and Genomics (IPPG), Medical Center of the University of Munich, Campus Innenstadt, Munich, Germany
eb Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
ec Behavioral Health Services, Kaiser Permanente Washington, Seattle, WA, United States
ed Faculty of Medicine, Department of Psychiatry, University of Iceland, Reykjavik, Iceland
ee School of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia
ef Institute of Health and Wellbeing, University of Glasgow, Glasgow, United Kingdom
eg College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom
eh Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany
ei Institute for Community Medicine, University Medicine, Greifswald, Germany
ej Department of Psychiatry, University of California, San Diego, San Diego, CA, United States
ek Medical Genetics Section, CGEM, IGMM, University of Edinburgh, Edinburgh, United Kingdom
el deCODE Genetics/Amgen, Reykjavik, Iceland
em Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
en Internal Medicine, Erasmus MC, Rotterdam, Netherlands
eo Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases Discovery & Translational Medicine Area, Roche Innovation Center Basel, FHoffmann-La Roche Ltd, Basel, Switzerland
ep Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
eq Department of Psychiatry, Leiden University Medical Center, Leiden, Netherlands
er Computational Sciences Center of Emphasis, Pfizer Global Research and Development, Cambridge, MA, United States
es Institute for Molecular Bioscience, Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia
et Department of Psychiatry, University of Münster, Münster, Germany
eu Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
ev Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany
ew Amsterdam Public Health Institute, Vrije Universiteit Medical Center, Amsterdam, Netherlands
ex Centre for Integrative Biology, Università degli Studi di Trento, Trento, Trentino-Alto Adige, Italy
ey Department of Psychiatry and Psychotherapy, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
ez Psychiatry, Kaiser Permanente Northern California, San Francisco, CA, United States
fa Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
fb Department of Psychiatry, University of Toronto, Toronto, ON, Canada
fc Centre for Addiction and Mental Health, Toronto, ON, Canada
fd Division of Psychiatry, University College London, London, United Kingdom
fe Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, NJ, United States
ff Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
fg University of Liverpool, Liverpool, United Kingdom
fh Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Groton, CT, United States
fi Psychiatry, Harvard Medical School, Boston, MA, United States
fj Psychiatry, University of Iowa, Iowa City, IA, United States
fk Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany
fl Human Genetics Branch, NIMH Division of Intramural Research Programs, Bethesda, MD, United States
fm Child and Adolescent Psychiatry, Erasmus MC, Rotterdam, Netherlands
fn Psychiatry, Erasmus MC, Rotterdam, Netherlands
fo Psychiatry, Dalhousie University, Halifax, NS, Canada
fp Division of Epidemiology, New York State Psychiatric Institute, New York, NY, United States
fq Department of Medical & Molecular Genetics, King’s College London, London, United Kingdom
fr Psychiatry & Behavioral Sciences, Stanford University, Stanford, CA, United States
fs NIHR BRC for Mental Health, King’s College London, London, United Kingdom
ft 23andMe, Inc., Mountain View, CA, United States

Abstract
Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Novel neurosteroid hypnotic blocks T-type calcium channel-dependent rebound burst firing and suppresses long-term potentiation in the rat subiculum” (2019) British Journal of Anaesthesia

Novel neurosteroid hypnotic blocks T-type calcium channel-dependent rebound burst firing and suppresses long-term potentiation in the rat subiculum
(2019) British Journal of Anaesthesia, . 

Joksimovic, S.M.a , Izumi, Y.b c , Joksimovic, S.L.a , Tesic, V.a , Krishnan, K.d , Asnake, B.e , Jevtovic-Todorovic, V.a , Covey, D.F.c d , Zorumski, C.F.b c , Todorovic, S.M.a

a Department of Anesthesiology, University of Colorado, School of Medicine, Aurora, CO, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States
d Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Anesthesiology and Pain Medicine, University of California, Davis, CA, United States

Abstract
Background: Hypnotics and general anaesthetics impair memory by altering hippocampal synaptic plasticity. We recently reported on a neurosteroid analogue with potent hypnotic activity [(3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile; 3β-OH], which does not cause developmental neurotoxicity in rat pups. Here, we investigated the effects of 3β-OH on neuronal excitability in the subiculum, the major output structure of the hippocampal formation, and synaptic plasticity at two key hippocampal synapses in juvenile rats. Methods: Biophysical properties of isolated T-type calcium currents (T-currents) in the rat subiculum were investigated using acute slice preparations. Subicular T-type calcium channel (T-channel) subtype mRNA expression was compared using qRT–PCR. Using electrophysiological recordings, we examined the effects of 3β-OH and an endogenous neuroactive steroid, allopregnanolone (Allo), on T-currents and burst firing properties of subicular neurones, and on the long-term potentiation (LTP) in CA3-CA1 and CA1-subiculum pathways. Results: Biophysical and molecular studies confirmed that Ca V 3.1 channels represent the dominant T-channel isoform in the subiculum of juvenile rats. 3β-OH and Allo inhibited rebound burst firing by decreasing the amplitude of T-currents in a voltage-dependent manner with similar potency, with 30–80% inhibition. Both neurosteroids suppressed LTP at the CA1-subiculum, but not at the CA3-CA1 Schaffer collateral synapse. Conclusions: Neurosteroid effects on T-channels modulate hippocampal output and provide possible molecular mechanisms for the amnestic action of the novel hypnotic 3β-OH. Effects on T-channels in the subiculum provide a novel target for amnestic effects of hypnotics. © 2019 British Journal of Anaesthesia

Author Keywords
amnesia;  general anaesthetic;  hippocampus;  neurosteroid;  subiculum;  synaptic plasticity;  T-type calcium channels

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Influence of Environmental Factors on Social Participation Post-Stroke” (2019) Behavioural neurology

Influence of Environmental Factors on Social Participation Post-Stroke
(2019) Behavioural neurology, 2019, p. 2606039. 

Foley, E.L.a , Nicholas, M.L.b , Baum, C.M.c , Connor, L.T.a

a Department of Occupational Therapy, MGH Institute of Health Professions, Boston MA, United States
b Department of Communication Sciences and Disorders, MGH Institute of Health Professions, Boston MA, United States
c Program in Occupational Therapy and Departments of Neurology & Social Work, Washington University in St. Louis, St. Louis MO, United States

Abstract
Objectives: For rehabilitation professionals to adequately address meaningful participation in social activities with their patients after a stroke, there must be a better understanding of neurobehavior, that is, how neurological impairment and its sequelae and environmental factors support or limit social participation. The current study examines how stroke severity (NIH Stroke Scale), its impact on perceived mobility (Stroke Impact Scale mobility domain), and the environment (MOS Social Support-Positive Social Interactions scale and Measure of Stroke Environment receptivity and built environment domains) influence social participation (Activity Card Sort: ACS). Methods: A correlational, cross-sectional design examined the relationships among neurological impairment, perceived limitations in activity, environmental factors, and social participation. Participants included 48 individuals who were at least 6 months post-stroke both with aphasia (N = 22) and without aphasia (N = 26) living in the community for whom all measures were available for analysis. Results: No differences in social participation were found between those with and without aphasia, though both groups reported a large (25-30%) decline in participating in their prestroke social activities. For the ACS Social Domain activities and ACS Partner to Do With activities (percent retained), 37% and 35% of the variance, respectively, was accounted for by the predictor variables, with only MOS Social Support making an independent contribution to social participation. In this sample, neurological impairment was not a significant correlate of social participation. Additionally, perceived mobility and the built environment were not found to independently predict participation in social activities. Conclusions: Perceived social support was found to predict social participation in individuals living in the community 6 months or greater post-stroke. Focusing on social support during post-stroke rehabilitation may provide an avenue for increased social participation and more successful community reintegration.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Transplant and risk of Parkinson disease” (2019) Parkinsonism and Related Disorders

Transplant and risk of Parkinson disease
(2019) Parkinsonism and Related Disorders, . 

Fan, J.a , Searles Nielsen, S.a , Faust, I.M.a , Racette, B.A.a b

a Washington University School of Medicine, Department of Neurology, 660 S. Euclid Ave, Campus Box 8111, St. Louis, MO 63110, United States
b University of the Witwatersrand, School of Public Health, Faculty of Health Sciences, 27 Saint Andrews Road, Johannesburg, South Africa

Abstract
Introduction: The pathophysiology of Parkinson’s disease (PD) remains unclear, but growing evidence supports a role of neuroinflammation. The purpose of this study was to investigate the association between tissue transplantation and PD risk, given the importance of immunosuppressants in post-transplant management. Methods: We performed a case-control study among Medicare beneficiaries age 66–90 using claims from 2004 to 2009. We used International Classification of Diseases, Ninth Edition (ICD-9) and Current Procedural Terminology (CPT) codes to identify PD (89,790 incident cases, 118,095 population-based controls) and history of tissue transplant (kidney, heart, liver, lung, and bone marrow). We investigated risk of PD in relation to tissue transplant in logistic regression models, adjusting for age, sex, race, smoking, and overall use of medical care. Results: Beneficiaries who had received a tissue transplant at least five years prior to PD diagnosis or reference had a lower risk of PD (odds ratio [OR] 0.63, 95% confidence interval [CI] 0.53, 0.75) than those without tissue transplant. This inverse association was observed for kidney (OR 0.63, 95% CI 0.47, 0.84), heart (OR 0.58, 95% CI 0.40, 0.83), lung (OR 0.41, 95% CI 0.21, 0.77), and bone marrow (OR 0.57, 95% 0.38, 0.85) transplants. Associations were attenuated, but remained, following adjustment for indications for the respective type of transplant. Liver transplant was not associated with PD risk. Conclusions: Patients undergoing tissue transplant may have a lower risk of developing PD than the general population. Further studies are needed to determine if this association is causal and if immunosuppressants mediate this association. © 2019 Elsevier Ltd

Author Keywords
Kidney transplant;  Liver transplant;  Lung transplant;  Parkinson’s disease

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Twice-weekly glucocorticosteroids in infants and young boys with Duchenne muscular dystrophy” (2019) Muscle and Nerve

Twice-weekly glucocorticosteroids in infants and young boys with Duchenne muscular dystrophy
(2019) Muscle and Nerve, . 

Connolly, A.M.a b , Zaidman, C.M.a b , Golumbek, P.T.a b , Cradock, M.M.b , Flanigan, K.M.c , Kuntz, N.L.d , Finkel, R.S.e , McDonald, C.M.f , Iannaccone, S.T.g , Anand, P.a , Siener, C.A.a , Florence, J.M.a , Lowes, L.P.c , Alfano, L.N.c , Johnson, L.B.f , Nicorici, A.f , Nelson, L.L.g , Mendell, J.R.c , for the MDA DMD Clinical Research Networkh

a Department of Neurology, Washington University School of Medicine in Saint Louis, St Louis, MO 63110, United States
b Department of Pediatrics, Washington University School of Medicine in Saint Louis, St Louis, MO, United States
c Department of Pediatrics, Nationwide Children’s Hospital, Ohio State University, Columbus, OH, United States
d Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
e Department of Pediatrics, Nemours Children’s Hospital, Orlando, FL, United States
f Department of Physical Medicine and Rehabilitation, University of California, Davis Medical Center, Sacramento, CA, United States
g Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, United States

Abstract
Introduction: Glucocorticosteroids (GC) are effective in slowing weakness in boys with Duchenne muscular dystrophy (DMD). Methods: This is a multisite, 1-year, open-label trial of twice-weekly prednisolone (5 mg/kg/dose) in infants/young boys (0.4–2.4 years) with DMD. We compared changes in Bayley III Scales of Infant Development (Bayley-III) with untreated boys followed for 1 year (historical control cohort [HCC]). Twenty-three of 25 participants completed the study. Results: Treated boys gained an average of 0.5 points on the Bayley-III gross motor scaled score (GMSS) compared with the HCC who, on average, declined 1.3 points (P = 0.03). All boys maintained linear growth, and none developed Cushingoid features. Excessive weight gain occurred in 13 of 23 (56%) boys. Discussion: This study provides evidence that twice-weekly GC is well tolerated in infants and young boys with DMD and improves GMSS. Excessive weight gain is a potential risk. Longer follow-up is required to determine whether early GC initiation is feasible in most infants/boys with DMD. Muscle Nerve, 2019. © 2019 Wiley Periodicals, Inc.

Author Keywords
Bayley-III Scales of Infant and Toddler Development;  DMD;  Duchenne muscular dystrophy;  GC;  infants;  twice-weekly glucocorticosteroid

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Development of hair cell phenotype and calyx nerve terminals in the neonatal mouse utricle” (2019) Journal of Comparative Neurology

Development of hair cell phenotype and calyx nerve terminals in the neonatal mouse utricle
(2019) Journal of Comparative Neurology, . 

Warchol, M.E.a , Massoodnia, R.b e , Pujol, R.b c , Cox, B.C.d , Stone, J.S.b

a Department of Otolaryngology, Washington University, St Louis, MO, United States
b Department of Otolaryngology-Head and Neck Surgery and the Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, WA, United States
c INSERM Unit 1051, Institute of Neuroscience, University of Montpellier, Montpellier, France
d Departments of Pharmacology and Surgery, Division of Otolaryngology, Southern Illinois University School of Medicine, Springfield, IL, United States
e Newport-Mesa Audiology Balance and Ear Institute, 500 Old Newport Blvd Suite 101, Newport Beach, CA 92663, United States

Abstract
The vestibular organs of reptiles, birds, and mammals possess Type I and Type II sensory hair cells, which have distinct morphologies, physiology, and innervation. Little is known about how vestibular hair cells adopt a Type I or Type II identity or acquire proper innervation. One distinguishing marker is the transcription factor Sox2, which is expressed in all developing hair cells but persists only in Type II hair cells in maturity. We examined Sox2 expression and formation of afferent nerve terminals in mouse utricles between postnatal days 0 (P0) and P17. Between P3 and P14, many hair cells lost Sox2 immunoreactivity and the density of calyceal afferent nerve terminals (specific to Type I hair cells) increased in all regions of the utricle. At early time points, many calyces enclosed Sox2-labeled hair cells, while some Sox2-negative hair cells within the striola had not yet developed a calyx. These observations indicate that calyx maturation is not temporally correlated with loss of Sox2 expression in Type I hair cells. To determine which type(s) of hair cells are formed postnatally, we fate-mapped neonatal supporting cells by injecting Plp-CreER T2 :Rosa26 tdTomato mice with tamoxifen at P2 and P3. At P9, tdTomato-positive hair cells were immature and not classifiable by type. At P30, tdTomato-positive hair cells increased 1.8-fold compared to P9, and 91% of tdTomato-labeled hair cells were Type II. Our findings show that most neonatally-derived hair cells become Type II, and many Type I hair cells (formed before P2) downregulate Sox2 and acquire calyces between P0 and P14. © 2019 Wiley Periodicals, Inc.

Author Keywords
afferent;  calyx;  hair cell;  RRID AB_10015251;  RRID AB_177520;  RRID AB_2286684;  RRID AB_2721321;  RRID AB_531793;  Sox2;  type I;  type II;  vestibular

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Protein oligomerization as a metabolic control mechanism: Application to apoE” (2019) Protein Science

Protein oligomerization as a metabolic control mechanism: Application to apoE
(2019) Protein Science, . 

Frieden, C.

Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
It has been estimated that 30%–50% of proteins self-assemble to form complexes consisting of multiple copies of themselves. If there is a functional difference between different molecular weight forms and if these forms interconvert on a reasonable time scale then oligomerization could be an important metabolic control mechanism. The example given here is of apoE for which the oligomerization process is measured in minutes to hours and the monomer binds lipids while the tetramer does not. Examination of the literature reveals few reports on the rate constants that control the interconversion of different molecular weight forms. Perhaps it is time to collect such data. © 2019 The Protein Society

Author Keywords
kinetics;  lipid binding;  metabolism

Document Type: Article
Publication Stage: Article in Press
Source: Scopus