36 results on '"Anne Venner"'
Search Results
2. Orexin neurons inhibit sleep to promote arousal
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Roberto De Luca, Stefano Nardone, Kevin P. Grace, Anne Venner, Michela Cristofolini, Sathyajit S. Bandaru, Lauren T. Sohn, Dong Kong, Takatoshi Mochizuki, Bianca Viberti, Lin Zhu, Antonino Zito, Thomas E. Scammell, Clifford B. Saper, Bradford B. Lowell, Patrick M. Fuller, and Elda Arrigoni
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Science - Abstract
Sleep and wakefulness is stabilized by a population of orexin-expressing neurons. In this study, the authors demonstrate how these neurons drive arousal by silencing sleep-promoting neurons in the ventrolateral preoptic nucleus.
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- 2022
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3. Suprachiasmatic VIP neurons are required for normal circadian rhythmicity and comprised of molecularly distinct subpopulations
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William D. Todd, Anne Venner, Christelle Anaclet, Rebecca Y. Broadhurst, Roberto De Luca, Sathyajit S. Bandaru, Lindsay Issokson, Lauren M. Hablitz, Olga Cravetchi, Elda Arrigoni, John N. Campbell, Charles N. Allen, David P. Olson, and Patrick M. Fuller
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Science - Abstract
Cell groups in the hypothalamic suprachiasmatic clock contribute to the genesis of circadian rhythms. The authors identified two populations of vasoactive intestinal polypeptide-expressing neurons in the suprachiasmatic nucleus which regulate locomotor circadian rhythm in mice.
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- 2020
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- View/download PDF
4. Role of serotonergic dorsal raphe neurons in hypercapnia-induced arousals
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Satvinder Kaur, Roberto De Luca, Mudasir A. Khanday, Sathyajit S. Bandaru, Renner C. Thomas, Rebecca Y. Broadhurst, Anne Venner, William D. Todd, Patrick M. Fuller, Elda Arrigoni, and Clifford B. Saper
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Science - Abstract
Dorsal raphe 5HT(DRSert) neurons regulate arousal from hypercapnia by their projections to the neurons in the external lateral parabrachial nucleus (PBel) that are glutamatergic and also express calcitonin gene related peptide (PBelCGRP). The DRSert input to the PBel modulates the arousal system to rising levels of blood CO2, and may be mediated by 5HT2a receptors on the PBelCGRP neurons.
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- 2020
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5. Supramammillary glutamate neurons are a key node of the arousal system
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Nigel P. Pedersen, Loris Ferrari, Anne Venner, Joshua L. Wang, Stephen B. G. Abbott, Nina Vujovic, Elda Arrigoni, Clifford B. Saper, and Patrick M. Fuller
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Science - Abstract
Supramammillary nucleus (SuM) neurons have been studied in the context of REM sleep but their possible role in mediating wakefulness is not known. Here the authors elucidate the distinct functional contributions of three subpopulations in the SuM on electrographical and behavioral arousal in mice using genetically targeted approaches.
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- 2017
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- View/download PDF
6. Tilt-table Echocardiography Unmasks Early Diastolic Dysfunction in Patients With Hemoglobinopathies
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Kandice Mah, Kelvin Chow, Richard B. Thompson, Aisha Bruce, Norazah Zahari, Nee S. Khoo, Edythe B Tham, and Mary Anne Venner
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Male ,medicine.medical_specialty ,Thalassemia ,Diastole ,Cardiomyopathy ,Ventricular Dysfunction, Left ,03 medical and health sciences ,0302 clinical medicine ,Cardiac magnetic resonance imaging ,Internal medicine ,Humans ,Medicine ,Child ,medicine.diagnostic_test ,business.industry ,Hematology ,Prognosis ,medicine.disease ,Sickle cell anemia ,Hemoglobinopathies ,Preload ,Hemoglobinopathy ,Oncology ,Echocardiography ,Case-Control Studies ,030220 oncology & carcinogenesis ,Heart failure ,Pediatrics, Perinatology and Child Health ,cardiovascular system ,Cardiology ,Female ,business ,Follow-Up Studies ,030215 immunology - Abstract
Individuals with hemoglobinopathy (sickle cell anemia and thalassemia major) are at risk for cardiac complications such as heart failure and cardiomyopathy. Diastolic dysfunction is known to precede systolic dysfunction in many cardiac diseases. This study sought to determine whether changes in left atrial (LA) function during manipulation of cardiac preload by tilt-table echocardiography can unmask subclinical diastolic dysfunction in pediatric patients with hemoglobinopathies. Eleven sickle cell anemia, 9 transfusion-dependent thalassemia major, and 10 control subjects underwent tilt-table echocardiogram in the supine (loading) and 30-degree upright (unloading) positions and cardiac magnetic resonance imaging (MRI). Echocardiography assessed LA and left ventricular (LV) strain, strain rate, mitral inflow, and annular velocities. MRI assessed LV function, myocardial T1 and T2* for iron deposition. Both thalassemia major and sickle cell anemia patients had normal LV function and no evidence of cardiac iron deposition on MRI T2* measurements. During cardiac loading, controls appropriately increased LA conduit (P=0.002) and reservoir strain (P=0.002), mitral e' velocity (P
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- 2020
7. Lateral septum modulates cortical state to tune responsivity to threat stimuli
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Mariko Hashimoto, Salvador Ignacio Brito, Anne Venner, Amanda Loren Pasqualini, Tracy Lulu Yang, David Allen, Patrick Michael Fuller, and Todd Erryl Anthony
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Neurons ,Neuroscience [CP] ,Medical Physiology ,Neurosciences ,Brain ,neural circuit ,Fear ,Basic Behavioral and Social Science ,General Biochemistry, Genetics and Molecular Biology ,calcium imaging ,Mice ,viral tracing ,looming ,Behavioral and Social Science ,Animals ,Attention ,Biochemistry and Cell Biology ,sleep ,optogenetics - Abstract
Sudden unexpected environmental changes capture attention and, when perceived as potentially dangerous, evoke defensive behavioral states. Perturbations of the lateral septum (LS) can produce extreme hyperdefensiveness even to innocuous stimuli, but how this structure influences stimulus-evoked defensive responses and threat perception remains unclear. Here, we show that Crhr2-expressing neurons in mouse LS exhibit phasic activation upon detection of threatening but not rewarding stimuli. Threat-stimulus-driven activity predicts the probability but not vigor or type of defensive behavior evoked. Although necessary for and sufficient to potentiate stimulus-triggered defensive responses, LSCrhr2 neurons do not promote specific behaviors. Rather, their stimulation elicits negative valence and physiological arousal. Moreover, LSCrhr2 activity tracks brain state fluctuations and drives cortical activation and rapid awakening in the absence of threat. Together, our findings suggest that LS directs bottom-up modulation of cortical function to evoke preparatory defensive internal states and selectively enhance responsivity to threat-related stimuli.
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- 2022
8. Reassessing the Role of Histaminergic Tuberomammillary Neurons in Arousal Control
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Takatoshi Mochizuki, Anne Venner, Elda Arrigoni, Christelle Anaclet, Clifford B. Saper, Thomas E. Scammell, Patrick M. Fuller, and Roberto De Luca
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Male ,0301 basic medicine ,Vesicular Inhibitory Amino Acid Transport Proteins ,Glutamate decarboxylase ,Action Potentials ,Inbred C57BL ,Medical and Health Sciences ,Mice ,0302 clinical medicine ,EEG/EMG ,Research Articles ,gamma-Aminobutyric Acid ,Neurons ,Glutamate Decarboxylase ,wake ,General Neuroscience ,Chemogenetics ,medicine.anatomical_structure ,Hypothalamus ,GABAergic ,Arousal ,Sleep Research ,Tuberomammillary nucleus ,Histamine ,Biology ,Optogenetics ,03 medical and health sciences ,Rare Diseases ,Behavioral and Social Science ,medicine ,Animals ,sleep ,optogenetics ,histidine decarboxylase ,Neurology & Neurosurgery ,Hypothalamic Area ,Psychology and Cognitive Sciences ,Neurosciences ,Histaminergic ,Lateral ,Mice, Inbred C57BL ,030104 developmental biology ,nervous system ,Hypothalamic Area, Lateral ,chemogenetics ,Sleep ,Neuroscience ,030217 neurology & neurosurgery - Abstract
The histaminergic neurons of the tuberomammillary nucleus (TMNHDC) of the posterior hypothalamus have long been implicated in promoting arousal. More recently, a role for GABAergic signaling by the TMNHDCneurons in arousal control has been proposed. Here, we investigated the effects of selective chronic disruption of GABA synthesis (via genetic deletion of the GABA synthesis enzyme, glutamic acid decarboxylase 67) or GABAergic transmission (via genetic deletion of the vesicular GABA transporter (VGAT)) in the TMNHDCneurons on sleep–wake in male mice. We also examined the effects of acute chemogenetic activation and optogenetic inhibition of TMNHDCneurons upon arousal in male mice. Unexpectedly, we found that neither disruption of GABA synthesis nor GABAergic transmission altered hourly sleep–wake quantities, perhaps because very few TMNHDCneurons coexpressed VGAT. Acute chemogenetic activation of TMNHDCneurons did not increase arousal levels above baseline but did enhance vigilance when the mice were exposed to a behavioral cage change challenge. Similarly, acute optogenetic inhibition had little effect upon baseline levels of arousal. In conclusion, we could not identify a role for GABA release by TMNHDCneurons in arousal control. Further, if TMNHDCneurons do release GABA, the mechanism by which they do so remains unclear. Our findings support the view that TMNHDCneurons may be important for enhancing arousal under certain conditions, such as exposure to a novel environment, but play only a minor role in behavioral and EEG arousal under baseline conditions.SIGNIFICANCE STATEMENTThe histaminergic neurons of the tuberomammillary nucleus of the hypothalamus (TMNHDC) have long been thought to promote arousal. Additionally, TMNHDCneurons may counter-regulate the wake-promoting effects of histamine through co-release of the inhibitory neurotransmitter, GABA. Here, we show that impairing GABA signaling from TMNHDCneurons does not impact sleep–wake amounts and that few TMNHDCneurons contain the vesicular GABA transporter, which is presumably required to release GABA. We further show that acute activation or inhibition of TMNHDCneurons has limited effects upon baseline arousal levels and that activation enhances vigilance during a behavioral challenge. Counter to general belief, our findings support the view that TMNHDCneurons are neither necessary nor sufficient for the initiation and maintenance of arousal under baseline conditions.
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- 2019
9. 'A complex interface: Exploring sickle cell disease from a parent’s perspective, after moving from Sub-Saharan Africa to North America'
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Mandeep Plaha, Mary Anne Venner, Maria Mayan, Adrienne Witol, Haley Greenslade, Tatjana Alvadj-Korenic, and Aisha Bruce
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Male ,Gerontology ,Canada ,congenital, hereditary, and neonatal diseases and abnormalities ,Sub saharan ,African descent ,Anemia, Sickle Cell ,Disease ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Humans ,Medicine ,cardiovascular diseases ,030212 general & internal medicine ,Africa South of the Sahara ,business.industry ,Perspective (graphical) ,Hematology ,Emigration and Immigration ,medicine.disease ,Chronic disease ,Hemoglobinopathy ,Oncology ,030220 oncology & carcinogenesis ,Pediatrics, Perinatology and Child Health ,Female ,business ,Psychosocial - Abstract
Sickle cell disease (SCD) is an inherited, multi-system, chronic disease with the highest prevalence affecting people of Sub-Saharan African descent. While major advances in SCD care have occurred over the last few decades in many African countries these advances are not readily available. Prior literature from Ghana and Kenya describe stigma, despair, and economic burden as well as hope when a child has SCD. When people migrate to North America with a child with SCD it is unknown whether their perception of the disease changes. We asked, "How do immigrant parents of children with SCD from Sub-Saharan Africa perceive, and manage the disease in the context of western medical care?"The research question was explored with qualitative methodology, specifically focused ethnography. Semi-structured interviews were conducted with parent(s). The interviews were audio recorded, transcribed, and open coded. Rigor was determined through methodological coherence, appropriate and sufficient sampling, and iterative data collection and analysis.Twelve interviews were conducted. Identified themes are as follows: memories of SCD in Africa, the emotional journey towards acceptance, and parental approach to care for their child.Healthcare providers should be responsive to an immigrant families' needs and not expect linear progression of emotional acceptance to the diagnosis. Healthcare providers patience with the process helps establish trust, works to facilitate and encourage hope and acknowledges the strength of the families, and their dedication to their family member. Healthcare providers should acknowledge parents' sources of support (religion/family) and ensure parents are aware of medical advances.
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- 2018
10. Suprachiasmatic VIP neurons are required for normal circadian rhythmicity and comprised of molecularly distinct subpopulations
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David P. Olson, John N. Campbell, Elda Arrigoni, Lindsay Issokson, William D. Todd, Rebecca Y. Broadhurst, Olga Cravetchi, Charles N. Allen, Christelle Anaclet, Sathyajit S. Bandaru, Roberto De Luca, Lauren M. Hablitz, Patrick M. Fuller, and Anne Venner
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0301 basic medicine ,Science ,1.1 Normal biological development and functioning ,Cell ,General Physics and Astronomy ,02 engineering and technology ,Biology ,Locomotor activity ,Brain mapping ,Circadian mechanisms ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Mice ,Rhythm ,Underpinning research ,Vasoactive ,Circadian Clocks ,Genetics ,medicine ,Animals ,Circadian rhythm ,lcsh:Science ,Neurons ,Brain Mapping ,Multidisciplinary ,Suprachiasmatic nucleus ,Neurosciences ,General Chemistry ,Behavioral state ,021001 nanoscience & nanotechnology ,Circadian Rhythm ,Optogenetics ,Mental Health ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Circadian regulation ,Neurological ,lcsh:Q ,Suprachiasmatic Nucleus ,Sleep Research ,0210 nano-technology ,Neuroscience ,Locomotion - Abstract
The hypothalamic suprachiasmatic (SCN) clock contains several neurochemically defined cell groups that contribute to the genesis of circadian rhythms. Using cell-specific and genetically targeted approaches we have confirmed an indispensable role for vasoactive intestinal polypeptide-expressing SCN (SCNVIP) neurons, including their molecular clock, in generating the mammalian locomotor activity (LMA) circadian rhythm. Optogenetic-assisted circuit mapping revealed functional, di-synaptic connectivity between SCNVIP neurons and dorsomedial hypothalamic neurons, providing a circuit substrate by which SCNVIP neurons may regulate LMA rhythms. In vivo photometry revealed that while SCNVIP neurons are acutely responsive to light, their activity is otherwise behavioral state invariant. Single-nuclei RNA-sequencing revealed that SCNVIP neurons comprise two transcriptionally distinct subtypes, including putative pacemaker and non-pacemaker populations. Altogether, our work establishes necessity of SCNVIP neurons for the LMA circadian rhythm, elucidates organization of circadian outflow from and modulatory input to SCNVIP cells, and demonstrates a subpopulation-level molecular heterogeneity that suggests distinct functions for specific SCNVIP subtypes., Cell groups in the hypothalamic suprachiasmatic clock contribute to the genesis of circadian rhythms. The authors identified two populations of vasoactive intestinal polypeptide-expressing neurons in the suprachiasmatic nucleus which regulate locomotor circadian rhythm in mice.
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- 2020
11. Role of serotonergic dorsal raphe neurons in hypercapnia-induced arousals
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Elda Arrigoni, Clifford B. Saper, Satvinder Kaur, Renner C. Thomas, Anne Venner, Roberto De Luca, William D. Todd, Patrick M. Fuller, Rebecca Y. Broadhurst, Mudasir Ahmad Khanday, and Sathyajit S. Bandaru
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Male ,0301 basic medicine ,General Physics and Astronomy ,Transgenic ,Hypercapnia ,Mice ,0302 clinical medicine ,2.1 Biological and endogenous factors ,Aetiology ,lcsh:Science ,Lung ,Serotonin Plasma Membrane Transport Proteins ,Multidisciplinary ,Parabrachial Nucleus ,Brainstem ,Arousal ,Sleep Research ,Serotonergic Neurons ,Dorsal Raphe Nucleus ,Serotonin ,Science ,Calcitonin Gene-Related Peptide ,Mice, Transgenic ,Optogenetics ,Calcitonin gene-related peptide ,Biology ,Serotonergic ,Neural circuits ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Glutamatergic ,Dorsal raphe nucleus ,Behavioral and Social Science ,Animals ,Lateral parabrachial nucleus ,Wakefulness ,Animal ,Neurosciences ,General Chemistry ,Carbon Dioxide ,Disease Models, Animal ,030104 developmental biology ,nervous system ,Disease Models ,lcsh:Q ,Neuroscience ,030217 neurology & neurosurgery ,Brain Stem - Abstract
During obstructive sleep apnea, elevation of CO2 during apneas contributes to awakening and restoring airway patency. We previously found that glutamatergic neurons in the external lateral parabrachial nucleus (PBel) containing calcitonin gene related peptide (PBelCGRP neurons) are critical for causing arousal during hypercapnia. However, others found that genetic deletion of serotonin (5HT) neurons in the brainstem also prevented arousal from hypercapnia. To examine interactions between the two systems, we showed that dorsal raphe (DR) 5HT neurons selectively targeted the PBel. Either genetically directed deletion or acute optogenetic silencing of DRSert neurons dramatically increased the latency of mice to arouse during hypercapnia, as did silencing DRSert terminals in the PBel. This effect was mediated by 5HT2a receptors which are expressed by PBelCGRP neurons. Our results indicate that the serotonergic input from the DR to the PBel via 5HT2a receptors is critical for modulating the sensitivity of the PBelCGRP neurons that cause arousal to rising levels of blood CO2., Dorsal raphe 5HT(DRSert) neurons regulate arousal from hypercapnia by their projections to the neurons in the external lateral parabrachial nucleus (PBel) that are glutamatergic and also express calcitonin gene related peptide (PBelCGRP). The DRSert input to the PBel modulates the arousal system to rising levels of blood CO2, and may be mediated by 5HT2a receptors on the PBelCGRP neurons.
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- 2020
12. A hypothalamic circuit for the circadian control of aggression
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Joshua L. Wang, Henning Fenselau, Rebecca Y. Broadhurst, William D. Todd, Natalia L. S. Machado, David P. Olson, Bradford B. Lowell, Clifford B. Saper, Satvinder Kaur, Anne Venner, Patrick M. Fuller, Rong Zhang, and Timothy Lynagh
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0301 basic medicine ,Male ,Circadian clock ,Hypothalamus ,Optogenetics ,Biology ,Inbred C57BL ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Postsynaptic potential ,Neural Pathways ,medicine ,Biological neural network ,Acquired Cognitive Impairment ,Psychology ,Animals ,Circadian rhythm ,gamma-Aminobutyric Acid ,Brain Mapping ,Neurology & Neurosurgery ,Suprachiasmatic nucleus ,Aggression ,General Neuroscience ,Neurosciences ,Excitatory Postsynaptic Potentials ,Brain Disorders ,Circadian Rhythm ,Mice, Inbred C57BL ,030104 developmental biology ,nervous system ,Ventromedial Hypothalamic Nucleus ,Neurological ,Dementia ,Cognitive Sciences ,Suprachiasmatic Nucleus ,medicine.symptom ,Sleep Research ,Corticosterone ,Neuroscience ,030217 neurology & neurosurgery ,Paraventricular Hypothalamic Nucleus ,Vasoactive Intestinal Peptide - Abstract
'Sundowning' in dementia and Alzheimer's disease is characterized by early-evening agitation and aggression. While such periodicity suggests a circadian origin, whether the circadian clock directly regulates aggressive behavior is unknown. We demonstrate that a daily rhythm in aggression propensity in male mice is gated by GABAergic subparaventricular zone (SPZGABA) neurons, the major postsynaptic targets of the central circadian clock, the suprachiasmatic nucleus. Optogenetic mapping revealed that SPZGABA neurons receive input from vasoactive intestinal polypeptide suprachiasmatic nucleus neurons and innervate neurons in the ventrolateral part of the ventromedial hypothalamus (VMH), which is known to regulate aggression. Additionally, VMH-projecting dorsal SPZ neurons are more active during early day than early night, and acute chemogenetic inhibition of SPZGABA transmission phase-dependently increases aggression. Finally, SPZGABA-recipient central VMH neurons directly innervate ventrolateral VMH neurons, and activation of this intra-VMH circuit drove attack behavior. Altogether, we reveal a functional polysynaptic circuit by which the suprachiasmatic nucleus clock regulates aggression.
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- 2018
13. Supramammillary glutamate neurons are a key node of the arousal system
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Stephen B. G. Abbott, Loris L. Ferrari, Joshua L. Wang, Clifford B. Saper, Nigel P. Pedersen, Nina Vujovic, Anne Venner, Elda Arrigoni, and Patrick M. Fuller
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0301 basic medicine ,Male ,Hypothalamus, Posterior ,Vesicular Inhibitory Amino Acid Transport Proteins ,General Physics and Astronomy ,Stimulation ,Nitric Oxide Synthase Type I ,Transgenic ,Mice ,0302 clinical medicine ,Theta Rhythm ,lcsh:Science ,Mice, Knockout ,Neurons ,Multidisciplinary ,biology ,Chemistry ,Glutamate receptor ,Nitric oxide synthase ,Hypothalamus ,Neurological ,Wakefulness ,Sleep Research ,Arousal ,Cell type ,Knockout ,Science ,Glutamic Acid ,Sleep, REM ,Mice, Transgenic ,Posterior ,Optogenetics ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Behavioral and Social Science ,Animals ,Neurosciences ,General Chemistry ,030104 developmental biology ,nervous system ,REM ,biology.protein ,Vesicular Glutamate Transport Protein 2 ,lcsh:Q ,Sleep ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Basic and clinical observations suggest that the caudal hypothalamus comprises a key node of the ascending arousal system, but the cell types underlying this are not fully understood. Here we report that glutamate-releasing neurons of the supramammillary region (SuMvglut2) produce sustained behavioral and EEG arousal when chemogenetically activated. This effect is nearly abolished following selective genetic disruption of glutamate release from SuMvglut2 neurons. Inhibition of SuMvglut2 neurons decreases and fragments wake, also suppressing theta and gamma frequency EEG activity. SuMvglut2 neurons include a subpopulation containing both glutamate and GABA (SuMvgat/vglut2) and another also expressing nitric oxide synthase (SuMNos1/Vglut2). Activation of SuMvgat/vglut2 neurons produces minimal wake and optogenetic stimulation of SuMvgat/vglut2 terminals elicits monosynaptic release of both glutamate and GABA onto dentate granule cells. Activation of SuMNos1/Vglut2 neurons potently drives wakefulness, whereas inhibition reduces REM sleep theta activity. These results identify SuMvglut2 neurons as a key node of the wake−sleep regulatory system., Supramammillary nucleus (SuM) neurons have been studied in the context of REM sleep but their possible role in mediating wakefulness is not known. Here the authors elucidate the distinct functional contributions of three subpopulations in the SuM on electrographical and behavioral arousal in mice using genetically targeted approaches.
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- 2017
14. 074 Basal Forebrain GABAergic Neurons Promote Arousal by Disinhibiting the Orexin Neurons via Local GABAergic Interneurons
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Kevin P. Grace, Elda Arrigoni, Patrick M. Fuller, Loris L. Ferrari, Anne Venner, Roberto De Luca, and Michela Cristofolini
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Basal forebrain ,nervous system ,Physiology (medical) ,medicine ,GABAergic ,Neurology (clinical) ,Biology ,Optogenetics ,Neuroscience ,gamma-Aminobutyric acid ,Arousal ,medicine.drug ,Orexin - Abstract
Introduction Optogenetic and chemogenetic studies have shown that activation of basal forebrain (BF) GABAergic neurons rapidly wakes up mice from non-REM (NREM) sleep. These wake-promoting responses have been attributed to BF GABAergic neurons projecting to the cerebral cortex and more specifically to the inhibition of cortical fast-spiking interneurons. Tracing studies have however found that BF GABAergic neurons also densely innervate the lateral hypothalamus (LH) perifornical area, although the role of this pathway in behavioral state control remains mostly unexplored. Methods We conducted in vivo and in vitro optogenetic studies. We selectively expressed channelrhodopsin-2 (ChR2) in BF GABAergic neurons by injecting a cre-dependent viral vector encoding for ChR2 into the BF of VGAT-cre mice. We photostimulated the BF GABAergic input to the LH with optical fibers placed into the LH of EEG instrumented mice. For in vitro recordings we expressed ChR2 in BF GABAergic neurons and we fluorescently labeled orexin or LH GABAergic neurons. We recorded in brain slices from identified orexin neurons or GABA neurons while photostimulating the BF GABAergic input. Results Optogenetic stimulation of the BF GABAergic fibers in the LH produced rapid arousals from NREM sleep. The same stimulation however did not wake up the mice if they were in REM sleep. We conducted additional studies in brain slices to identify the postsynaptic neurons in the LH targeted by the BF GABAergic input. We found that while optogenetic stimulation of the BF GABAergic input did not produce opto-evoked synaptic responses in the orexin neurons, it produced short-latency opto-evoked inhibitory postsynaptic currents (IPSCs) in LH GABAergic neurons. These opto-evoked IPSCs were GABAA receptor-mediated and were maintained in tetrodotoxin (TTX) indicating monosynaptic connectivity. We have previously found that orexin neurons are inhibited by local LH GABAergic neurons. Our hypothesis is that these local GABAergic interneurons are the target of the BF GABAergic arousal input. Conclusion BF GABAergic neurons drive arousal through projections to the LH. We propose that this arousal response is due to the inhibition of local GABAergic interneurons which in turn disinhibit the LH wake-promoting neurons including the orexin neurons. Support (if any) NS091126 and HL149630
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- 2021
15. Selective activation of serotoninergic dorsal raphe neurons facilitates sleep through anxiolysis
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Anne Venner, Patrick M. Fuller, William D. Todd, Lauren T Sohn, and Rebecca Y. Broadhurst
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Dorsal Raphe Nucleus ,Elevated plus maze ,medicine.drug_class ,Population ,Basic Science of Sleep and Circadian Rhythms ,Serotonergic ,Anxiolytic ,Open field ,Arousal ,03 medical and health sciences ,0302 clinical medicine ,Dorsal raphe nucleus ,Physiology (medical) ,Medicine ,Wakefulness ,education ,030304 developmental biology ,0303 health sciences ,education.field_of_study ,business.industry ,Neurology (clinical) ,Sleep ,business ,Neuroscience ,030217 neurology & neurosurgery ,Serotonergic Neurons - Abstract
A role for the brain’s serotoninergic (5HT) system in the regulation of sleep and wakefulness has been long suggested. Yet, previous studies employing pharmacological, lesion and genetically driven approaches have produced inconsistent findings, leaving 5HT’s role in sleep-wake regulation incompletely understood. Here we sought to define the specific contribution of 5HT neurons within the dorsal raphe nucleus (DRN5HT) to sleep and arousal control. To do this, we employed a chemogenetic strategy to selectively and acutely activate DRN5HT neurons and monitored sleep-wake using electroencephalogram recordings. We additionally assessed indices of anxiety using the open field and elevated plus maze behavioral tests and employed telemetric-based recordings to test effects of acute DRN5HT activation on body temperature and locomotor activity. Our findings indicate that the DRN5HT cell population may not modulate sleep-wake per se, but rather that its activation has apparent anxiolytic properties, suggesting the more nuanced view that DRN5HT neurons are sleep permissive under circumstances that produce anxiety or stress.
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- 2019
16. Non-Crh glutamatergic neurons in Barrington’s nucleus control micturition via glutamatergic afferents from the midbrain and hypothalamus
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Rachel A. Ross, Anne Venner, Reina Kobayashi, Lin Zhu, Joel C. Geerling, Elda Arrigoni, Veronique G.J.M. VanderHorst, John C. Mathai, Anne M.J. Verstegen, Nataliya Klymko, and Mark L. Zeidel
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Male ,0301 basic medicine ,genetic structures ,Corticotropin-Releasing Hormone ,Urinary Bladder ,Hypothalamus ,Urination ,Optogenetics ,Biology ,Periaqueductal gray ,General Biochemistry, Genetics and Molecular Biology ,Article ,Barrington's Nucleus ,Mice ,03 medical and health sciences ,Glutamatergic ,0302 clinical medicine ,Mesencephalon ,medicine ,Biological neural network ,Animals ,Humans ,Neurons, Afferent ,Axon ,Spinal Cord Injuries ,Neurons ,medicine.diagnostic_test ,Cystometry ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Spinal Cord ,Female ,Neuron ,General Agricultural and Biological Sciences ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Lower urinary tract symptoms (LUTS) are exceptionally common and debilitating, and are likely caused or exacerbated by dysfunction of neural circuits controlling bladder function. An incomplete understanding of neural control of bladder function limits our ability to clinically address LUTS. Barrington’s nucleus (Bar) provides descending control of bladder and sphincter function, and its glutamatergic neurons expressing corticotropin releasing hormone (Bar(Crh/Vglut2)) are implicated in bladder control. However, it remains unclear whether this subset of Bar neurons are necessary for voiding, and the broader circuitry providing input to this control center remains largely unknown. Here we examine the contribution to micturition behavior of Bar(Crh/Vglut2) neurons relative to the overall Bar(Vglut2) population. First, we identify robust, excitatory synaptic input to Bar. Glutamatergic axons from the periaqueductal gray (PAG) and lateral hypothalamic area (LHA) intensely innervate and are functionally connected to Bar, and optogenetic stimulation of these axon terminals reliably provokes voiding. Similarly, optogenetic stimulation of Bar(Vglut2) neurons triggers voiding, whereas stimulating the Bar(Crh/Vglut2) subpopulation causes bladder contraction, typically without voiding. Next, we genetically ablate either Bar(Vglut2) or Bar(Crh/Vglut2) neurons and found that only Bar(Vglut2) ablation replicates the profound urinary retention produced by conventional lesions in this region. Fiber photometry recordings reveal that Bar(Vglut2) neuron activity precedes increased bladder pressure, while activity of Bar(Crh/Vglut2) is phase-delayed. Finally, deleting Crh from Bar neurons has no effect on voiding and related bladder physiology. Our results help identify the circuitry that modulates Bar neuron activity, and identify subtypes that may serve different roles in micturition.
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- 2019
17. An Inhibitory Lateral Hypothalamic-Preoptic Circuit Mediates Rapid Arousals from Sleep
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Anne Venner, Lauren T. Sohn, Patrick M. Fuller, Elda Arrigoni, Anne M.J. Verstegen, Roberto De Luca, and Sathyajit S. Bandaru
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0301 basic medicine ,Male ,Hypothalamus ,Optogenetics ,Biology ,Inhibitory postsynaptic potential ,General Biochemistry, Genetics and Molecular Biology ,Arousal ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Postsynaptic potential ,Sleep Disorders, Circadian Rhythm ,medicine ,Animals ,Galanin ,GABAergic Neurons ,Wakefulness ,Neurons ,Brain ,Electroencephalography ,Preoptic Area ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Hypothalamic Area, Lateral ,GABAergic ,Female ,General Agricultural and Biological Sciences ,Sleep ,Neuroscience ,Nucleus ,030217 neurology & neurosurgery - Abstract
Summary Among the neuronal populations implicated in sleep-wake control, the ventrolateral preoptic (VLPO) nucleus has emerged as a key sleep-promoting center. However, the synaptic drives that regulate the VLPO to control arousal levels in vivo have not to date been identified. Here, we show that sleep-promoting galaninergic neurons within the VLPO nucleus, defined pharmacologically and by single-cell transcript analysis, are postsynaptic targets of lateral hypothalamic GABAergic (LHGABA) neurons and that activation of this pathway in vivo rapidly drives wakefulness. Ca2+ imaging from LHGABA neurons indicate that they are both wake and rapid eye movement (REM)-sleep active. Consistent with the potent arousal-promoting property of the LHGABA → VLPO pathway, presynaptic inputs to LHGABA neurons originate from several canonical stress- and arousal-related network nodes. This work represents the first demonstration that direct synaptic inhibition of the VLPO area can suppress sleep-promoting neurons to rapidly promote arousal.
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- 2019
18. Newly identified sleep–wake and circadian circuits as potential therapeutic targets
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Hannah E. Bowrey, William D. Todd, Satvinder Kaur, Anne Venner, Christelle Anaclet, Ada Eban-Rothschild, and Jimmy J. Fraigne
- Subjects
Sleep Wake Disorders ,medicine.medical_specialty ,Hypothalamus ,Rapid eye movement sleep ,Sleep, REM ,Basic Science of Sleep and Circadian Rhythms ,Optogenetics ,Sleep medicine ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,Animals ,Humans ,Medicine ,Circadian rhythm ,GABAergic Neurons ,Wakefulness ,Neurons ,Synucleinopathies ,business.industry ,Sleep apnea ,Chemogenetics ,medicine.disease ,Circadian Rhythm ,3. Good health ,Ventral tegmental area ,medicine.anatomical_structure ,030228 respiratory system ,Neurology (clinical) ,Nerve Net ,Sleep ,business ,Neuroscience ,030217 neurology & neurosurgery ,Brain Stem - Abstract
Optogenetics and chemogenetics are powerful tools, allowing the specific activation or inhibition of targeted neuronal subpopulations. Application of these techniques to sleep and circadian research has resulted in the unveiling of several neuronal populations that are involved in sleep–wake control, and allowed a comprehensive interrogation of the circuitry through which these nodes are coordinated to orchestrate the sleep–wake cycle. In this review, we discuss six recently described sleep–wake and circadian circuits that show promise as therapeutic targets for sleep medicine. The parafacial zone (PZ) and the ventral tegmental area (VTA) are potential druggable targets for the treatment of insomnia. The brainstem circuit underlying rapid eye movement sleep behavior disorder (RBD) offers new possibilities for treating RBD and neurodegenerative synucleinopathies, whereas the parabrachial nucleus, as a nexus linking arousal state control and breathing, is a promising target for developing treatments for sleep apnea. Therapies that act upon the hypothalamic circuitry underlying the circadian regulation of aggression or the photic regulation of arousal and mood pathway carry enormous potential for helping to reduce the socioeconomic burden of neuropsychiatric and neurodegenerative disorders on society. Intriguingly, the development of chemogenetics as a therapeutic strategy is now well underway and such an approach has the capacity to lead to more focused and less invasive therapies for treating sleep–wake disorders and related comorbidities.
- Published
- 2019
19. A Novel Population of Wake-Promoting GABAergic Neurons in the Ventral Lateral Hypothalamus
- Author
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Clifford B. Saper, Anne Venner, Rebecca Y. Broadhurst, Patrick M. Fuller, and Christelle Anaclet
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Lateral hypothalamus ,Vesicular Inhibitory Amino Acid Transport Proteins ,Population ,Gene Expression ,Biology ,Periaqueductal gray ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,GABAergic Neurons ,Wakefulness ,education ,education.field_of_study ,Preoptic area ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,nervous system ,Hypothalamic Area, Lateral ,GABAergic ,Locus coeruleus ,General Agricultural and Biological Sciences ,Tuberomammillary nucleus ,Neuroscience ,030217 neurology & neurosurgery - Abstract
The largest synaptic input to the sleep-promoting ventrolateral preoptic area (VLPO) [1] arises from the lateral hypothalamus [2], a brain area associated with arousal [3-5]. However, the neurochemical identity of the majority of these VLPO-projecting neurons within the lateral hypothalamus (LH), as well as their function in the arousal network, remains unknown. Herein we describe a population of VLPO-projecting neurons in the LH that express the vesicular GABA transporter (VGAT; a marker for GABA-releasing neurons). In addition to the VLPO, these neurons also project to several other established sleep and arousal nodes, including the tuberomammillary nucleus, ventral periaqueductal gray, and locus coeruleus. Selective and acute chemogenetic activation of LH VGAT(+) neurons was profoundly wake promoting, whereas acute inhibition increased sleep. Because of its direct and massive inputs to the VLPO, this population may play a particularly important role in sleep-wake switching.
- Published
- 2016
20. 0163 Investigating the Role of Vasoactive Intestinal Peptide-Containing Neurons of the Ventromedal Preoptic Area in Sleep-Wake Control
- Author
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Patrick M. Fuller and Anne Venner
- Subjects
Preoptic area ,medicine.medical_specialty ,Endocrinology ,business.industry ,Physiology (medical) ,Internal medicine ,Sleep wake ,Vasoactive intestinal peptide ,medicine ,Neurology (clinical) ,business - Abstract
Introduction A role for vasoactive intestinal peptide (VIP) in promoting rapid eye movement (REM) sleep has been suggested, but the anatomical location of the neurons that release VIP to promote REM sleep has not been identified. Here, we investigated the role of VIP-containing cell groups in the ventromedial preoptic area (VMPOVIP) in sleep-wake regulation. The VMPO has also previously been implicated in thermoregulation and the febrile response. Methods We first investigated the native firing activity of VMPOVIP neurons, over repeated sleep-wake cycles, using in vivo fiber photometry in VIP-ires-Cre mice. We next examined the afferent and efferent profile of this cell group using conditional retrograde (pseudotyped modified rabies) and anterograde (adeno-associated viral vector-based) tracers. We finally utilized a chemogenetic strategy to selectively activate VMPOVIP neurons cells while monitoring electroencephalogram/electromyogram activity and core body temperature, in order to determine their role in sleep-wake and thermoregulatory control. Results We found that VMPOVIP cells were predominantly and strikingly REM-active, that they received many synaptic inputs from surrounding hypothalamic regions (including the ventromedial hypothalamus, dorsomedial hypothalamus and the arcuate nucleus), and that they targeted established sleep-wake nodes, such as the ventrolateral preoptic nucleus, tuberomammillary nucleus, lateral hypothalamus and ventrolateral periaqueductal gray area. To our surprise, chemogenetic activation of the VMPOVIP cell population had little effect upon all measures of sleep-wake analysed and no effect upon core body temperature. Conclusion We conclude that VMPOVIP neurons do not promote REM sleep per se. However, their REM-active profile and anatomical connectivity suggest that these neurons may play a functional role in generating certain cardinal features of REM sleep, which is an active focus of on-going research in our laboratory. Support SRSF CDA #016-JP-17 to A.V. and NS073613, NS092652 and NS103161 to P.M.
- Published
- 2020
21. An overview of sleep–wake circuitry
- Author
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Patrick M. Fuller and Anne Venner
- Subjects
medicine.medical_specialty ,Sleep wake ,medicine ,Audiology ,Psychology - Abstract
How and when we wake and sleep are under the control of incredibly complex neural circuitry, consisting of neuronal populations (or nodes), neurotransmitters, and pathways that form orchestrated wake- or sleep-promoting networks. When any aspect of this neural circuitry is impaired (e.g. disease) or altered by external factors (e.g. stress), sleep and wake can be disrupted, sometimes quite profoundly. As one example, selective loss of orexin neurons in the lateral hypothalamus results in the sleep disorder narcolepsy. While our understanding of how discrete circuit elements in the brain work together to regulate wake and sleep remains incomplete, the relatively recent development of genetically driven tools and techniques has enabled a far more detailed understanding of the functional and structural basis of this circuitry. In this chapter, we review the current state of our understanding of the brain circuitry regulating sleep and wake, including how disruption of discrete circuit elements underlies a myriad of sleep- and wake-disorders.
- Published
- 2018
22. National Emergency Cards for Sickle Cell Disease: A Survey on Usefulness from the Patient Perspective
- Author
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Lauren Bolster, Aisha Bruce, Michelle Dang, Catherine Corriveau-Bourque, Maria McGrath, Hatoon Ezzat, Ghazi S. Alotaibi, and Mary Anne Venner
- Subjects
Response rate (survey) ,medicine.medical_specialty ,business.industry ,Immunology ,Specialty ,Cell Biology ,Hematology ,Emergency department ,medicine.disease ,Biochemistry ,Proxy (climate) ,Hemophilias ,Intervention (counseling) ,Acute care ,Honorarium ,medicine ,Medical emergency ,business - Abstract
Patients with Sickle Cell Disease (SCD) frequently present for emergency care with pain or fever. The rate of emergency visits/year is between 2-4 per patient every year with 12% of patients visiting the emergency 4 or more times/year1. National medical organizations in Canada and the United States recommend pain therapy within 30 minutes of arriving to the emergency department2,3. Feedback from patients in Canada reflected a lack of awareness of the medical community regarding the disease and optimal management. As a response Canadian Haemoglobinopathy Association2 (CanHaem), created the "Sickle Cell Disease Emergency Wallet Cards" which were inspired from the successful Hemophilia "Factor First Card4". The goal of the cards was to provide simple care instructions to an emergency responder and facilitate timely care for patients in crisis. These wallet cards have recommendations for treatment of pain and fever within 30 minutes, patient's diagnosis, program contact details, and patient's individual pain plan. The cards have been in circulation for 4 years. The purpose of this study was to determine if the cards are used by parents and patients as intended. Research Questions: 1.Are the CanHaem Cards used by patients and families? 2. Do patients find the card helpful in facilitating their care delivery? Methods: The surveys were administered to patients and/or proxies. Prior to survey distribution three parents/patients have verified the utility of the questions, the content and the readability of the survey. The survey was translated into French/Arabic by two independent translators per language. It was distributed in Alberta and British Columbia, Canada in specialty clinics known to use the cards. The University of Alberta Ethics Board deemed the project a quality improvement initiative and the ARECCI tool: A pRoject Ethics Community Consensus Initiative was completed prior to quality improvement project start. Results: 140/184 participants completed the survey. The response rate: 76%. Demographics: 91% province of Alberta. Proxy: 49%; Patients: 51%. The majority of respondents were female: 54%, median age: 37 years (range 16-84 years). See graphs 1-4 below: 72.3% felt the card was helpful in their care. 78.6% carry the physical card (purse, wallet, and diaper bag), while 10.7% have a picture on their phone, 9.3% don't carry the card, 7.1% state they never received a card. The majority (63.6%) show the card at first contact in emergency, 48.9% felt staff read the card. Total of 68 comments. 67.6% of comments were positive: "Sense of security"; "Get us in to see the doctor faster..." Neutral comments (22%) ranged from requests for lamination to provider response to the card being variable "sometimes it is faster and sometime(s) doesn't really change anything". Finally, 10% were negative reflecting long wait times "Good concept, the idea itself is great. Execution... could be improved greatly", and requests for more information on the card. Conclusion: In Canada, SCD is an uncommon disease and many healthcare providers may not be aware of national and international guidelines regarding acute presentations. To help facilitate knowledge transfer and to aid communication with emergency services, CanHaem created wallet cards as a Canada-wide initiative. This survey demonstrates the patient/parent perspective of the emergency cards. Eighty-nine percent of patients/proxies carried the card (either digitally or physically) and 63% showed the card in the acute care setting. The discrepancy between those who carry the card and those who show it may reflect that numerous respondents stated they had not required emergency care since receiving the card as well some respondents were "carried away by the pain and forget to use the card". Comments revealed a sense of security and patient's appreciation for having the card available to them indicating the value of card to patients. The card demonstrates a simple and low cost intervention to facilitate emergency care for hemoglobinopathy patients. References: 1. Paulukonis ST et al. Emergency department utilization by Californians with sickle cell disease. Ped Blood and Ca 2017. doi: 1002/pbc.26390 2. CanHaem https://www.canhaem.org/healthcare-professionals/ 3. Evidence-Based Management of Sickle Cell Disease: Expert Panel, 2014. 4. Canadian Hemophilia Society. Stop the Bleeding. https://www.hemophilia.ca/files/ER%20CARD%20E_%20Jan%2009.pdf Figure Disclosures Ezzat: Novartis: Honoraria, Speakers Bureau; ApoPharma: Research Funding.
- Published
- 2019
23. Genetic Activation, Inactivation, and Deletion Reveal a Limited And Nuanced Role for Somatostatin-Containing Basal Forebrain Neurons in Behavioral State Control
- Author
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Roberto De Luca, Michael Lazarus, Patrick M. Fuller, Olga Malyshevskaya, Christelle Anaclet, Elda Arrigoni, and Anne Venner
- Subjects
0301 basic medicine ,Male ,Aging ,Vesicular Inhibitory Amino Acid Transport Proteins ,Electroencephalography ,Neurodegenerative ,Sleep, Slow-Wave ,Medical and Health Sciences ,Mice ,0302 clinical medicine ,arousal ,EEG ,Research Articles ,Neurons ,Basal forebrain ,Behavior, Animal ,medicine.diagnostic_test ,General Neuroscience ,AAV ,Sleep in non-human animals ,Neurological ,Wakefulness ,Female ,Somatostatin ,Sleep Research ,psychological phenomena and processes ,Transcriptional Activation ,Genotype ,Basal Forebrain ,Optogenetics ,Biology ,optogenetic ,Non-rapid eye movement sleep ,Basic Behavioral and Social Science ,Arousal ,03 medical and health sciences ,Behavioral and Social Science ,medicine ,Animals ,diphtheria ,Behavior ,Neurology & Neurosurgery ,Animal ,Psychology and Cognitive Sciences ,Neurosciences ,Electrophysiological Phenomena ,Electrophysiology ,030104 developmental biology ,nervous system ,Slow-Wave ,DREADD ,Sleep ,Neuroscience ,030217 neurology & neurosurgery ,Gene Deletion - Abstract
Recent studies have identified an especially important role for basal forebrain GABAergic (BFVGAT) neurons in the regulation of behavioral waking and fast cortical rhythms associated with cognition. However, BFVGATneurons comprise several neurochemically and anatomically distinct subpopulations, including parvalbumin-containing BFVGATneurons and somatostatin-containing BFVGATneurons (BFSOMneurons), and it was recently reported that optogenetic activation of BFSOMneurons increases the probability of a wakefulness to non-rapid-eye movement (NREM) sleep transition when stimulated during the rest period of the animal. This finding was unexpected given that most BFSOMneurons are not NREM sleep active and that central administration of the synthetic somatostatin analog, octreotide, suppresses NREM sleep or increases REM sleep. Here we used a combination of genetically driven chemogenetic and optogenetic activation, chemogenetic inhibition, and ablation approaches to further explore thein vivorole of BFSOMneurons in arousal control. Our findings indicate that acute activation or inhibition of BFSOMneurons is neither wakefulness nor NREM sleep promoting and is without significant effect on the EEG, and that chronic loss of these neurons is without effect on total 24 h sleep amounts, although a small but significant increase in waking was observed in the lesioned mice during the early active period. Ourin vitrocell recordings further reveal electrophysiological heterogeneity in BFSOMneurons, specifically suggesting at least two distinct subpopulations. Together, our data support the more nuanced view that BFSOMneurons are electrically heterogeneous and are not NREM sleep or wake promoting per se, but may exert, in particular during the early active period, a modest inhibitory influence on arousal circuitry.SIGNIFICANCE STATEMENTThe cellular basal forebrain (BF) is a highly complex area of the brain that is implicated in a wide range of higher-level neurobiological processes, including regulating and maintaining normal levels of electrocortical and behavioral arousal. The respectivein vivoroles of BF cell populations and their neurotransmitter systems in the regulation of electrocortical and behavioral arousal remains incompletely understood. Here we seek to define the neurobiological contribution of GABAergic somatostatin-containing BF neurons to arousal control. Understanding the respective contribution of BF cell populations to arousal control may provide critical insight into the pathogenesis of a host of neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, schizophrenia, and the cognitive impairments of normal aging.
- Published
- 2018
24. Basal forebrain control of wakefulness and cortical rhythms
- Author
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Elda Arrigoni, Anne Venner, Patrick M. Fuller, Loris L. Ferrari, Christelle Anaclet, Caroline E. Bass, and Nigel P. Pedersen
- Subjects
Aging ,Basal Forebrain ,General Physics and Astronomy ,Sleep, REM ,Glutamic Acid ,Biology ,Neurodegenerative ,Alzheimer's Disease ,Basic Behavioral and Social Science ,General Biochemistry, Genetics and Molecular Biology ,Article ,Glutamatergic ,Mice ,Behavioral and Social Science ,medicine ,Acquired Cognitive Impairment ,Animals ,Cholinergic neuron ,Wakefulness ,GABAergic Neurons ,Cerebral Cortex ,Neurons ,Basal forebrain ,Multidisciplinary ,Neurosciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Electroencephalography ,General Chemistry ,Immunohistochemistry ,Brain Waves ,Cholinergic Neurons ,Brain Disorders ,medicine.anatomical_structure ,Cerebral cortex ,REM ,Forebrain ,Neurological ,GABAergic ,Cholinergic ,Dementia ,Sleep ,Sleep Research ,Neuroscience ,Proto-Oncogene Proteins c-fos - Abstract
Wakefulness, along with fast cortical rhythms and associated cognition, depend on the basal forebrain (BF). BF cholinergic cell loss in dementia and the sedative effect of anti-cholinergic drugs have long implicated these neurons as important for cognition and wakefulness. The BF also contains intermingled inhibitory GABAergic and excitatory glutamatergic cell groups whose exact neurobiological roles are unclear. Here we show that genetically targeted chemogenetic activation of BF cholinergic or glutamatergic neurons in behaving mice produced significant effects on state consolidation and/or the electroencephalogram but had no effect on total wake. Similar activation of BF GABAergic neurons produced sustained wakefulness and high-frequency cortical rhythms, whereas chemogenetic inhibition increased sleep. Our findings reveal a major contribution of BF GABAergic neurons to wakefulness and the fast cortical rhythms associated with cognition. These findings may be clinically applicable to manipulations aimed at increasing forebrain activation in dementia and the minimally conscious state., The mammalian basal forebrain controls cortical rhythm and wake-sleep. Anaclet et al. use genetically-targeted chemogenetic systems to activate or inhibit cholinergic, glutamatergic or GABAergic neurons in this region, and reveal their contributions to behavioral and electrocortical arousal in behaving mice.
- Published
- 2015
25. Dichotomous cellular properties of mouse orexin/hypocretin neurons
- Author
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David A. Knowles, Anne Venner, Denis Burdakov, Cornelia Schöne, and Mahesh M. Karnani
- Subjects
Nervous system ,0303 health sciences ,Cell type ,education.field_of_study ,Physiology ,Population ,AMPA receptor ,Biology ,Orexin ,Sholl analysis ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,nervous system ,Excitatory postsynaptic potential ,medicine ,education ,Nucleus ,Neuroscience ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Hypothalamic hypocretin/orexin (Hcrt/Orx) neurons recently emerged as critical regulators of sleep–wake cycles, reward seeking and body energy balance. However, at the level of cellular and network properties, it remains unclear whether Hcrt/Orx neurons are one homogeneous population, or whether there are several distinct types of Hcrt/Orx cells. Here, we collated diverse structural and functional information about individual Hcrt/Orx neurons in mouse brain slices, by combining patch-clamp analysis of spike firing, membrane currents and synaptic inputs with confocal imaging of cell shape and subsequent 3-dimensional Sholl analysis of dendritic architecture. Statistical cluster analysis of intrinsic firing properties revealed that Hcrt/Orx neurons fall into two distinct types. These two cell types also differ in the complexity of their dendritic arbour, the strength of AMPA and GABAA receptor-mediated synaptic drive that they receive, and the density of low-threshold, 4-aminopyridine-sensitive, transient K+ current. Our results provide quantitative evidence that, at the cellular level, the mouse Hcrt/Orx system is composed of two classes of neurons with different firing properties, morphologies and synaptic input organization.
- Published
- 2011
26. Direct and indirect control of orexin/hypocretin neurons by glycine receptors
- Author
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Lise T. Jensen, Denis Burdakov, Mahesh M. Karnani, Anne Venner, and Lars Fugger
- Subjects
0303 health sciences ,medicine.medical_specialty ,Physiology ,Glutamate receptor ,Strychnine ,Biology ,Inhibitory postsynaptic potential ,gamma-Aminobutyric acid ,Orexin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,chemistry ,Postsynaptic potential ,Internal medicine ,medicine ,Excitatory postsynaptic potential ,Glycine receptor ,Neuroscience ,030217 neurology & neurosurgery ,030304 developmental biology ,medicine.drug - Abstract
Hypothalamic hypocretin/orexin (hcrt/orx) neurons promote arousal and reward seeking, while reduction in their activity has been linked to narcolepsy, obesity and depression. However, the mechanisms influencing the activity of hcrt/orx networks in situ are not fully understood. Here we show that glycine, a neurotransmitter best known for its actions in the brainstem and spinal cord, elicits dose dependent postsynaptic Cl⁻ currents in hcrt/orx cells in acute mouse brain slices. The effect was blocked by the glycine receptor (GLyR) antagonist strychnine and mimicked by the GlyR agonist alanine. Postsynaptic GlyRs on hcrt/orx cells remained functional during both early postnatal and adult periods, and gramicidin-perforated patch-clamp recordings revealed that they progressively switch from excitatory to inhibitory during the first two postnatal weeks. The pharmacological profile of the glycine response suggested that developed hcrt/orx neurons contain α/β-heteromeric GlyRs that lack α2-subunits, whereas α2-subunits, whereas α2-subunits are present in early postnatal hcrt/orx neurons. All postsynaptic currents (PSCs) in developed hcrt/orx cells were blocked by inhibitors of GABA and glutamate receptors, with no evidence of GlyR-mediated PSCs. However, the frequency but not amplitude of miniature PSCs was reduced by strychnine and increased by glycine in ~50% of hcrt/orx neurons. Together, these results provide the first evidence for functional GlyRs in identified hcrt/orx circuits and suggest that the activity of developed hcrt/orx cells is regulated by two GlyR pools: inhibitory extrasynaptic GlyRs located on all hcrt/orx cells and excitatory GlyRs located on presynaptic terminals contacting some hcrt/orx cells.
- Published
- 2011
27. 0160 The Role of Dorsal Raphe Neurons in Sleep and Wakefulness
- Author
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Patrick M. Fuller, Anne Venner, and R Y Broadhurst
- Subjects
Dorsal raphe nucleus ,business.industry ,Physiology (medical) ,Medicine ,Wakefulness ,Neurology (clinical) ,business ,Neuroscience ,Sleep in non-human animals - Published
- 2018
28. 0062 Functional and Anatomical Characterization of Lateral Hypothalamic GABA Arousal Circuitry
- Author
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R De Luca, Anne Venner, Elda Arrigoni, and Patrick M. Fuller
- Subjects
Chemistry ,Physiology (medical) ,Neurology (clinical) ,Neuroscience ,Arousal - Published
- 2018
29. A Genetically Defined Circuit for Arousal from Sleep during Hypercapnia
- Author
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Stephen Thankachan, Daniel Kroeger, Elda Arrigoni, Andrew Wellman, Michael Lazarus, Clifford B. Saper, Satvinder Kaur, Joshua L. Wang, Loris L. Ferrari, Patrick M. Fuller, and Anne Venner
- Subjects
0301 basic medicine ,Patch-Clamp Techniques ,Inbred C57BL ,Hypercapnia ,apne ,Mice ,0302 clinical medicine ,arousal ,Psychology ,Lung ,Neurons ,Respiration ,General Neuroscience ,Sleep apnea ,Electroencephalography ,calcitonin gene related peptide ,Cognitive Sciences ,Wakefulness ,Arousal ,Sleep Research ,medicine.medical_specialty ,Calcitonin Gene-Related Peptide ,Optogenetics ,Calcitonin gene-related peptide ,parabrachial neurons ,Article ,03 medical and health sciences ,Glutamatergic ,Prosencephalon ,Sleep Apnea Syndromes ,Internal medicine ,Behavioral and Social Science ,medicine ,Biological neural network ,Animals ,Lateral parabrachial nucleus ,sleep ,optogenetics ,Neurology & Neurosurgery ,Electromyography ,Neurosciences ,Carbon Dioxide ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Acoustic Stimulation ,chemogenetics ,Nerve Net ,Sleep ,Neuroscience ,030217 neurology & neurosurgery - Abstract
The precise neural circuitry that mediates arousal during sleep apnea is not known. We previously found that glutamatergic neurons in the external lateral parabrachial nucleus (PBel) play a critical role in arousal to elevated CO2 or hypoxia. Because many of the PBel neurons that respond to CO2 express calcitonin gene-related peptide (CGRP), we hypothesized that CGRP may provide a molecular identifier of the CO2 arousal circuit. Here, we report that selective chemogenetic and optogenetic activation of PBelCGRP neurons caused wakefulness, whereas optogenetic inhibition of PBelCGRP neurons prevented arousal to CO2, but not to an acoustic tone or shaking. Optogenetic inhibition of PBelCGRP terminals identified a network of forebrain sites under the control of a PBelCGRP switch that is necessary to arouse animals from hypercapnia. Our findings define a novel cellular target for interventions that may prevent sleep fragmentation and the attendant cardiovascular and cognitive consequences seen in obstructive sleep apnea. VIDEO ABSTRACT.
- Published
- 2017
30. 0160 WAKE PROMOTION BY SUPRAMAMMILLARY NITRIC OXIDE NEURONS CRITICALLY DEPENDS ON GLUTAMATE RELEASE
- Author
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Clifford B. Saper, Nigel P. Pedersen, Patrick M. Fuller, and Anne Venner
- Subjects
medicine.diagnostic_test ,biology ,Glutamate receptor ,Electroencephalography ,Sleep in non-human animals ,Nitric oxide ,Arousal ,Nitric oxide synthase ,chemistry.chemical_compound ,chemistry ,Physiology (medical) ,medicine ,biology.protein ,Wakefulness ,Neurology (clinical) ,Neuroscience - Published
- 2017
31. How Do New Immigrant Families (African Continent) with a Child with Sickle Cell Disease (SCD) Experience the Western Medical System?
- Author
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Mary Anne Venner, Mandeep Plaha, Aisha Bruce, Haley Greenslade, and Adrienne D. Witol
- Subjects
Research ethics ,Social stigma ,business.industry ,Immunology ,Language barrier ,Extended family ,Stigma (botany) ,Context (language use) ,Cell Biology ,Hematology ,Biochemistry ,Social support ,Nursing ,Health care ,Medicine ,business - Abstract
INTRODUCTION: New immigrant families from continental Africa account for an increasing proportion of pediatric patients with Sickle Cell Disease (SCD) in Canada and North America. As families enter the western medical system they face a myriad of tests and medications as well they encounter language barriers, endless forms and large teams. Previous experiences with healthcare also influence families' expectations and adjustment.There is no published data exploring the experiences of these families to help guide practice. Resources such as the Canadian Pediatric Society guide on immigrant health are not specific to SCD. We set out to examine cultural sensitivity methodologically in order to improve delivery of care. Research Questions: What are newcomer families' experiences with SCD in Canada and their home country?What are the prevailing values and beliefs related to SCD that shape the attitude and behaviors of newcomer families?How do newcomer families perceivethe current delivery of medical care (the barriers and the facilitators)? METHODS: Focused ethnography was used to understand the socio-cultural context in which newcomer families from Africa experience their child's SCD; to explore their perspectives, beliefs, how they manage daily life and experience the western medical system. A sample size of12-15 participants was selected to reach saturation.Participants were selected using purposeful and convenience sampling and semi-structured interviews were held with the primary caregiver(s) with use of aninterpreter if needed. Research Ethics Board approved. RESULTS: Saturation was reached at 10 families and 12 were interviewed due to recruiting methods. Demographics:12 caregivers (N=8 females; N=4 males); most were in their forties and from Congo, Nigeria or Liberia. The majority had 3 or more children, were married and employed. The majority did not have extended family within the region. Languages spoken at home were English, French, Yoruba, Swahili orMoorie. They immigrated to Canada between 2002 and 2015 For themes see table 1. CONCLUSIONS: Participants' attitude, perception and knowledge about SCD were profoundly affected by their experiences in their countries of origin. These mostly negative experiences (seeing children suffering without appropriate medical care; observing social stigma, etc.) were deeply embedded and determined their response to SCD in their children. 1. Practice guideline: Allow for sufficient time and provision oftranslation services to explore the families' experience with stigma within country of residence and origin as well as embedded in the healthcare system and the community. Despite the prevalence of SCD in their home countries the diagnosis was a surprise. The path towards acceptance was slow, emotionally convoluted and not linear. Acceptance of the diagnosis is a process and devastating in the context of previous experiences. 2. Practice guideline: Review diagnostic information early and have easily accessible information about SCD available for parents/family network. This information will also need to be reviewed with the child at key developmental time periods. SCD has a dominant impact on life causing renegotiation of all relationships: spousal, family, community, co-workers and school staff. Managing SCD influenced daily routines imposing structure which was disrupted for hospitalizations. Families were reluctant to leave children unattended in the hospital and thus sacrificed personal and employment goals. Social support is limited and families cope alone.Families tend to seek practical support and deny the desire for emotional support. 3. Practice guideline: 3a)Screen for potential isolation and explore whether other caretakers are aware of diagnosis and disease specific care 3b) Given the tendency to deny emotional support needs, lack of nearby extended family and the stigma in the community setting up networks that provide both practical and instrumental support could be meaningful and more likely utilized resources. The life-long complexity of SCD creates anxiety for the child's life expectancy. Families trust in medical expertise, improvements in medical treatments and their faith/religious beliefs are foundations for hope. 4. Practice guideline: HCP working with families should ensure awareness of clinical advances and develop means to easily share knowledge as it will strengthen hope for the future. Table 1 Table 1. Disclosures Bruce: Novartis: Consultancy, Honoraria; Apopharma: Consultancy.
- Published
- 2016
32. Orexin neurons as conditional glucosensors: paradoxical regulation of sugar sensing by intracellular fuels
- Author
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Anne, Venner, Mahesh M, Karnani, J Antonio, Gonzalez, Lise T, Jensen, Lars, Fugger, and Denis, Burdakov
- Subjects
Neurons ,Orexins ,Patch-Clamp Techniques ,Fluoroacetates ,Neuropeptides ,Intracellular Signaling Peptides and Proteins ,Brain ,Neuroscience: Behavioural/Systems/Cognitive ,Mice, Transgenic ,Mitochondrial Proton-Translocating ATPases ,Mice ,Adenosine Triphosphate ,Glucose ,Pyruvic Acid ,Animals ,Oligomycins ,Lactic Acid ,Energy Metabolism - Abstract
Central orexin/hypocretin neurons promote wakefulness, feeding and reward-seeking, and control blood glucose levels by regulating sympathetic outflow to the periphery. Glucose itself directly suppresses the electrical activity and cytosolic calcium levels of orexin cells. Recent in vitro studies suggested that glucose inhibition of orexin cells may be mechanistically unusual, because it persists under conditions where glucose metabolism is unlikely. To investigate this further, and to clarify whether background metabolic state regulates orexin cell glucosensing, here we analysed glucose responses of orexin cells in mouse brain slices, in the presence and absence of metabolic inhibitors and physiological energy substrates. Consistent with their documented insensitivity to glucokinase inhibitors, the glucose responses of orexin cells persisted in the presence of the mitochondrial poison oligomycin or the glial toxin fluoroacetate. Unexpectedly, in the presence of oligomycin, the magnitude of the glucose response was significantly enhanced. In turn, 2-deoxyglucose, a non-metabolizable glucose analogue, elicited larger responses than glucose. Conversely, intracellular pyruvate dose-dependently suppressed the glucose responses, an effect that was blocked by oligomycin. The glucose responses were also suppressed by intracellular lactate and ATP. Our new data suggest that other energy substrates not only fail to mimic the orexin glucose response, but paradoxically suppress it in a metabolism-dependent manner. We propose that this unexpected intrinsic property of orexin cells allows them to act as 'conditional glucosensors' that preferentially respond to glucose during reduced background energy levels.
- Published
- 2011
33. Direct and indirect control of orexin/hypocretin neurons by glycine receptors
- Author
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Mahesh M, Karnani, Anne, Venner, Lise T, Jensen, Lars, Fugger, and Denis, Burdakov
- Subjects
Aging ,Patch-Clamp Techniques ,Green Fluorescent Proteins ,Glycine ,Hypothalamus ,Glutamic Acid ,Mice, Transgenic ,Benzothiadiazines ,Membrane Potentials ,GABA Antagonists ,Mice ,Receptors, Glycine ,Receptors, GABA ,Chloride Channels ,Animals ,Picrotoxin ,gamma-Aminobutyric Acid ,6-Cyano-7-nitroquinoxaline-2,3-dione ,Neurons ,Orexins ,Alanine ,Neuropeptides ,Intracellular Signaling Peptides and Proteins ,Strychnine ,Synaptic Potentials ,Electrophysiological Phenomena ,Pyridazines ,Animals, Newborn ,Receptors, Glutamate ,Neuroscience - Abstract
Hypothalamic hypocretin/orexin (hcrt/orx) neurons promote arousal and reward seeking, while reduction in their activity has been linked to narcolepsy, obesity and depression. However, the mechanisms influencing the activity of hcrt/orx networks in situ are not fully understood. Here we show that glycine, a neurotransmitter best known for its actions in the brainstem and spinal cord, elicits dose dependent postsynaptic Cl⁻ currents in hcrt/orx cells in acute mouse brain slices. The effect was blocked by the glycine receptor (GLyR) antagonist strychnine and mimicked by the GlyR agonist alanine. Postsynaptic GlyRs on hcrt/orx cells remained functional during both early postnatal and adult periods, and gramicidin-perforated patch-clamp recordings revealed that they progressively switch from excitatory to inhibitory during the first two postnatal weeks. The pharmacological profile of the glycine response suggested that developed hcrt/orx neurons contain α/β-heteromeric GlyRs that lack α2-subunits, whereas α2-subunits, whereas α2-subunits are present in early postnatal hcrt/orx neurons. All postsynaptic currents (PSCs) in developed hcrt/orx cells were blocked by inhibitors of GABA and glutamate receptors, with no evidence of GlyR-mediated PSCs. However, the frequency but not amplitude of miniature PSCs was reduced by strychnine and increased by glycine in ~50% of hcrt/orx neurons. Together, these results provide the first evidence for functional GlyRs in identified hcrt/orx circuits and suggest that the activity of developed hcrt/orx cells is regulated by two GlyR pools: inhibitory extrasynaptic GlyRs located on all hcrt/orx cells and excitatory GlyRs located on presynaptic terminals contacting some hcrt/orx cells.
- Published
- 2010
34. Removal of Codeine in Pediatric Oncology: A Qualitative Evaluation of Sucess and Attitudes
- Author
-
Mary Anne Venner, Jennifer Shepherd, Mark Belletrutti, Karina Black, Marcel Romanick, and Shirley Perry
- Subjects
medicine.medical_specialty ,Practice change ,business.industry ,Pediatrics, Perinatology and Child Health ,Codeine ,Pediatric oncology ,Medicine ,business ,Intensive care medicine ,medicine.drug - Published
- 2012
35. Book Reviews
- Author
-
Roberta A. Smith, Anne Venner, and Linda Tinsley
- Subjects
Biochemistry (medical) ,Clinical Biochemistry - Published
- 1998
36. Improving quality of transcutaneous bilirubin measurements: Value of in-house developed quality control
- Author
-
Heather Anne Paul, Brenda Joanne Adams, and Allison Anne Venner
- Subjects
Hyperbilirubinemia ,POCT ,Quality ,Quality control ,Transcutaneous bilirubin ,Medicine (General) ,R5-920 ,Chemistry ,QD1-999 - Abstract
Objectives: Quality assurance (QA) plays an integral role in Point of Care Testing (POCT) programs. Quality control (QC) is an important QA program component to ensure high quality results and enhanced patient care. The measurement of transcutaneous bilirubin (TcB) in the POCT setting is an essential part of newborn care in Alberta, Canada. However, there is currently no available commercial QC material for TcB meters. An in-house developed QC material has been in use within a single TcB POCT program within Alberta. The objective of this study was to determine the performance of this QC material by other POCT staff and clinical end-users to assess whether its use could be expanded. Design and methods: Two levels of QC material were measured by POCT staff and clinical end-users across 12 different sites using the Dräger Jaundice Meter JM-103® and JM-105® meters. Results: The performance of the QC material was acceptable when tested by POCT staff, was stable and reliable over time, and had an acceptable CV (≤8%). However, the data does not support use of the QC material by clinical end-users. Conclusions: The use of the QC material could be expanded into other TcB settings for use by POCT staff. Additional training and experience with the QC material by end-users is needed to facilitate QC use in the clinical setting.
- Published
- 2021
- Full Text
- View/download PDF
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