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1.
PLoS Biol ; 22(5): e3002596, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38718086

RESUMEN

Autism spectrum disorders (ASD) frequently accompany macrocephaly, which often involves hydrocephalic enlargement of brain ventricles. Katnal2 is a microtubule-regulatory protein strongly linked to ASD, but it remains unclear whether Katnal2 knockout (KO) in mice leads to microtubule- and ASD-related molecular, synaptic, brain, and behavioral phenotypes. We found that Katnal2-KO mice display ASD-like social communication deficits and age-dependent progressive ventricular enlargements. The latter involves increased length and beating frequency of motile cilia on ependymal cells lining ventricles. Katnal2-KO hippocampal neurons surrounded by enlarged lateral ventricles show progressive synaptic deficits that correlate with ASD-like transcriptomic changes involving synaptic gene down-regulation. Importantly, early postnatal Katnal2 re-expression prevents ciliary, ventricular, and behavioral phenotypes in Katnal2-KO adults, suggesting a causal relationship and a potential treatment. Therefore, Katnal2 negatively regulates ependymal ciliary function and its deletion in mice leads to ependymal ciliary hyperfunction and hydrocephalus accompanying ASD-related behavioral, synaptic, and transcriptomic changes.


Asunto(s)
Trastorno del Espectro Autista , Cilios , Epéndimo , Ratones Noqueados , Fenotipo , Animales , Masculino , Ratones , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/fisiopatología , Conducta Animal , Cilios/metabolismo , Modelos Animales de Enfermedad , Epéndimo/metabolismo , Hipocampo/metabolismo , Hidrocefalia/genética , Hidrocefalia/metabolismo , Hidrocefalia/patología , Hidrocefalia/fisiopatología , Katanina/metabolismo , Katanina/genética , Ratones Endogámicos C57BL , Neuronas/metabolismo , Sinapsis/metabolismo , Transcriptoma/genética
2.
Proc Natl Acad Sci U S A ; 120(28): e2219231120, 2023 07 11.
Artículo en Inglés | MEDLINE | ID: mdl-37399389

RESUMEN

Real-time monitoring of various neurochemicals with high spatial resolution in multiple brain regions in vivo can elucidate neural circuits related to various brain diseases. However, previous systems for monitoring neurochemicals have limitations in observing multiple neurochemicals without crosstalk in real time, and these methods cannot record electrical activity, which is essential for investigating neural circuits. Here, we present a real-time bimodal (RTBM) neural probe that uses monolithically integrated biosensors and multiple shanks to study the connectivity of neural circuits by measuring multiple neurochemicals and electrical neural activity in real time. Using the RTBM probe, we demonstrate concurrent measurements of four neurochemicals-glucose, lactate, choline, and glutamate without cross-talking each other-and electrical activity in real time in vivo. Additionally, we show the functional connectivity between the medial prefrontal cortex and mediodorsal thalamus through the simultaneous measurement of chemical and electrical signals. We expect that our device will contribute to not only elucidating the role of neurochemicals in neural circuits related to brain functions but also developing drugs for various brain diseases related to neurochemicals.


Asunto(s)
Encefalopatías , Encéfalo , Humanos , Encéfalo/fisiología , Fenómenos Electrofisiológicos , Ácido Glutámico , Electrofisiología
3.
EMBO J ; 39(11): e104150, 2020 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-32347567

RESUMEN

Alternative splicing regulates trans-synaptic adhesions and synapse development, but supporting in vivo evidence is limited. PTPδ, a receptor tyrosine phosphatase adhering to multiple synaptic adhesion molecules, is associated with various neuropsychiatric disorders; however, its in vivo functions remain unclear. Here, we show that PTPδ is mainly present at excitatory presynaptic sites by endogenous PTPδ tagging. Global PTPδ deletion in mice leads to input-specific decreases in excitatory synapse development and strength. This involves tyrosine dephosphorylation and synaptic loss of IL1RAPL1, a postsynaptic partner of PTPδ requiring the PTPδ-meA splice insert for binding. Importantly, PTPδ-mutant mice lacking the PTPδ-meA insert, and thus lacking the PTPδ interaction with IL1RAPL1 but not other postsynaptic partners, recapitulate biochemical and synaptic phenotypes of global PTPδ-mutant mice. Behaviorally, both global and meA-specific PTPδ-mutant mice display abnormal sleep behavior and non-REM rhythms. Therefore, alternative splicing in PTPδ regulates excitatory synapse development and sleep by modulating a specific trans-synaptic adhesion.


Asunto(s)
Proteína Accesoria del Receptor de Interleucina-1/metabolismo , Proteínas Tirosina Fosfatasas/metabolismo , Fases del Sueño , Sinapsis/metabolismo , Animales , Proteína Accesoria del Receptor de Interleucina-1/genética , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Proteínas Tirosina Fosfatasas/genética , Sinapsis/genética
4.
Mol Psychiatry ; 28(8): 3548-3562, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37365244

RESUMEN

ADNP syndrome, involving the ADNP transcription factor of the SWI/SNF chromatin-remodeling complex, is characterized by developmental delay, intellectual disability, and autism spectrum disorders (ASD). Although Adnp-haploinsufficient (Adnp-HT) mice display various phenotypic deficits, whether these mice display abnormal synaptic functions remain poorly understood. Here, we report synaptic plasticity deficits associated with cognitive inflexibility and CaMKIIα hyperactivity in Adnp-HT mice. These mice show impaired and inflexible contextual learning and memory, additional to social deficits, long after the juvenile-stage decrease of ADNP protein levels to ~10% of the newborn level. The adult Adnp-HT hippocampus shows hyperphosphorylated CaMKIIα and its substrates, including SynGAP1, and excessive long-term potentiation that is normalized by CaMKIIα inhibition. Therefore, Adnp haploinsufficiency in mice leads to cognitive inflexibility involving CaMKIIα hyperphosphorylation and excessive LTP in adults long after its marked expressional decrease in juveniles.


Asunto(s)
Trastorno Autístico , Discapacidad Intelectual , Ratones , Animales , Proteínas del Tejido Nervioso/metabolismo , Plasticidad Neuronal/genética , Potenciación a Largo Plazo/genética , Trastorno Autístico/metabolismo , Cognición , Proteínas de Homeodominio/metabolismo
5.
Can J Neurol Sci ; : 1-7, 2024 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-38235823

RESUMEN

OBJECTIVE: Management of primary headache (PHA) varies across emergency departments (ED), yet there is widespread agreement that computed tomography (CT) scans are overused. This study assessed emergency physicians' (EPs) PHA management and their attitudes towards head CT ordering. METHODS: A cross-sectional study was undertaken with EPs from one Canadian center. Drivers of physicians' perceptions regarding the appropriateness of CT ordering for patients with PHA were explored. RESULTS: A total of 73 EPs (70% males; 48% with <10 years of practice) participated in the study. Most EPs (88%) did not order investigations for moderate-severe primary headaches; however, CT was the common investigation (47%) for headaches that did not improve. Computed tomography ordering was frequently motivated by the need for specialist consultation (64%) or admission (64%). A small proportion (27%) believed patients usually/frequently expected a scan. Nearly half of EPs (48%) identified patient imaging expectations/requests as a barrier to reducing CT ordering. Emergency physicians with CCFP (EM) certification were less likely to perceive CT ordering for patients with PHA as appropriate. Conversely, those who identified the possibility of missing a condition as a major barrier to limiting their CT use were more likely to perceive CT ordering for patients with PHA as appropriate. CONCLUSIONS: Emergency physicians reported consistency and evidence-based medical management. They highlighted the complexities of limiting CT ordering and both their level of training and their perceived barriers for limiting CT ordering seem to be influencing their attitudes. Further studies could elucidate these and other factors influencing their practice.

6.
Inj Prev ; 29(6): 537-544, 2023 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-37507213

RESUMEN

OBJECTIVE: This systematic review aimed to identify research involving adults presenting to the emergency department (ED) with a concussion to document the reporting of sex and/or gender according to the Canadian Institutes of Health Research (CIHR) guidelines, the prevalence of sex and gender-based analysis (SGBA) and to summarise sex and/or gender-based differences in ED presentation, management and outcomes. DESIGN: Systematic review. METHODS: Electronic databases and grey literature were searched to identify studies that recruited adult patients with concussion from the ED. Two independent reviewers identified eligible studies, assessed quality and extracted data. A descriptive summary of the evidence was generated, and sex and/or gender reporting was examined for accuracy according to standardised criteria. RESULTS: Overall, 126 studies were included in the analyses. A total of 80 (64%) studies reported sex and/or gender as demographic information, of which 51 (64%) included sex and/or gender in their analysis; however, 2 (3%) studies focused on an SGBA. Sex was more accurately reported in alignment with CIHR definitions than gender (94% vs 12%; p<0.0001). In total, 25 studies used an SGBA for outcomes of interest. Males and females experience different causes of concussion, 60% of studies documented that females had less frequent CT scanning while in the ED, and 57% of studies reported that postconcussion syndrome was more prevalent in females and women. CONCLUSION: This systematic review highlighted that sex is reported more accurately than gender, approximately half of studies did not report either sex and/or gender as demographic information, and one-third of studies did not include SGBA. There were important sex and gender differences in the cause, ED presentation, management and outcomes of concussions. PROSPERO REGISTRATION NUMBER: CRD42021258613.


Asunto(s)
Conmoción Encefálica , Masculino , Adulto , Humanos , Femenino , Canadá/epidemiología , Conmoción Encefálica/epidemiología , Conmoción Encefálica/terapia , Servicio de Urgencia en Hospital , Factores Sexuales , Prevalencia
7.
Biochem Biophys Res Commun ; 586: 114-120, 2022 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-34839189

RESUMEN

Prepulse inhibition (PPI) is a neurophysiological finding that is decreased in schizophrenia patients and has been used in pathophysiology studies of schizophrenia and the development of antipsychotic drugs. PPI is affected by several drugs including amphetamine, ketamine, and nicotinic agents, and it is reported that several brain regions and modulatory neurotransmitters are involved in PPI. Here we showed that mice with IRSp53 deletion in each dopaminergic, cholinergic, oxytocinergic, and serotoninergic modulatory neurons showed a decrease in PPI. Other than PPI, there were no other behavioral changes among IRSp53 deletion mice. Through this study, we could reconfirm that dysfunction of each modulatory neuron such as dopamine, acetylcholine, oxytocin, and serotonin can result in PPI impairment, and it should be considered that PPI could be broadly affected by changes in one of a certain kind of modulatory neurons.


Asunto(s)
Encéfalo/metabolismo , Neuronas Colinérgicas/metabolismo , Neuronas Dopaminérgicas/metabolismo , Proteínas del Tejido Nervioso/genética , Inhibición Prepulso , Neuronas Serotoninérgicas/metabolismo , Acetilcolina/metabolismo , Animales , Encéfalo/patología , Mapeo Encefálico , Neuronas Colinérgicas/patología , Dopamina/metabolismo , Neuronas Dopaminérgicas/patología , Eliminación de Gen , Genes Reporteros , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/deficiencia , Ruido , Oxitocina/metabolismo , Reflejo de Sobresalto , Neuronas Serotoninérgicas/patología , Serotonina/metabolismo
8.
PLoS Biol ; 17(6): e2005326, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31166939

RESUMEN

Netrin-G ligand-3 (NGL-3) is a postsynaptic adhesion molecule known to directly interact with the excitatory postsynaptic scaffolding protein postsynaptic density-95 (PSD-95) and trans-synaptically with leukocyte common antigen-related (LAR) family receptor tyrosine phosphatases to regulate presynaptic differentiation. Although NGL-3 has been implicated in the regulation of excitatory synapse development by in vitro studies, whether it regulates synapse development or function, or any other features of brain development and function, is not known. Here, we report that mice lacking NGL-3 (Ngl3-/- mice) show markedly suppressed normal brain development and postnatal survival and growth. A change of the genetic background of mice from pure to hybrid minimized these developmental effects but modestly suppressed N-methyl-D-aspartate (NMDA) receptor (NMDAR)-mediated synaptic transmission in the hippocampus without affecting synapse development, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR)-mediated basal transmission, and presynaptic release. Intriguingly, long-term depression (LTD) was near-completely abolished in Ngl3-/- mice, and the Akt/glycogen synthase kinase 3ß (GSK3ß) signaling pathway, known to suppress LTD, was abnormally enhanced. In addition, pharmacological inhibition of Akt, but not activation of NMDARs, normalized the suppressed LTD in Ngl3-/- mice, suggesting that Akt hyperactivity suppresses LTD. Ngl3-/- mice displayed several behavioral abnormalities, including hyperactivity, anxiolytic-like behavior, impaired spatial memory, and enhanced seizure susceptibility. Among them, the hyperactivity was rapidly improved by pharmacological NMDAR activation. These results suggest that NGL-3 regulates brain development, Akt/GSK3ß signaling, LTD, and locomotive and cognitive behaviors.


Asunto(s)
Encéfalo/embriología , Encéfalo/crecimiento & desarrollo , Proteínas Ligadas a GPI/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Animales , Encéfalo/metabolismo , Proteínas Ligadas a GPI/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hipocampo/metabolismo , Ligandos , Depresión Sináptica a Largo Plazo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Netrinas/metabolismo , Plasticidad Neuronal , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transducción de Señal , Sinapsis/metabolismo , Sinapsis/fisiología , Transmisión Sináptica
9.
EMBO Rep ; 21(2): e48097, 2020 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-31782602

RESUMEN

TMEM16A, a Ca2+ -activated Cl- channel, is known to modulate the excitability of various types of cells; however, its function in central neurons is largely unknown. Here, we show the specific expression of TMEM16A in the medial habenula (mHb) via RNAscope in situ hybridization, immunohistochemistry, and electrophysiology. When TMEM16A is ablated in the mHb cholinergic neurons (TMEM16A cKO mice), the slope of after-hyperpolarization of spontaneous action potentials decreases and the firing frequency is reduced. Reduced mHb activity also decreases the activity of the interpeduncular nucleus (IPN). Moreover, TMEM16A cKO mice display anxiogenic behaviors and deficits in social interaction without despair-like phenotypes or cognitive dysfunctions. Finally, chemogenetic inhibition of mHb cholinergic neurons using the DREADD (Designer Receptors Exclusively Activated by Designer Drugs) approach reveals similar behavioral phenotypes to those of TMEM16A cKO mice. We conclude that TMEM16A plays a key role in anxiety-related behaviors regulated by mHb cholinergic neurons and could be a potential therapeutic target against anxiety-related disorders.


Asunto(s)
Habénula , Animales , Ansiedad/genética , Neuronas Colinérgicas , Ratones , Ratones Endogámicos C57BL
10.
Clin J Sport Med ; 32(5): e469-e477, 2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-36083333

RESUMEN

OBJECTIVE: To document the occurrence and recovery outcomes of sports-related concussions (SRCs) presenting to the Emergency Department (ED) in a community-based sample. DESIGN: A prospective observational cohort study was conducted in 3 Canadian hospitals. SETTING: Emergency Department. PATIENTS: Adults (≥17 years) presenting with a concussion to participating EDs with a Glasgow Coma Scale score ≥13 were recruited. INTERVENTIONS: Patient demographics (eg, age and sex), clinical characteristics (eg, history of depression or anxiety), injury characteristics (eg, injury mechanisms and loss of consciousness and duration), and ED management and outcomes (eg, imaging, consultations, and ED length of stay) were collected. MAIN OUTCOME MEASURES: Patients' self-reported persistent concussion symptoms, return to physical activity status, and health-related quality of life at 30 and 90 days after ED discharge. RESULTS: Overall, 248 patients were enrolled, and 25% had a SRC. Patients with SRCs were younger and reported more physical activity before the event. Although most of the patients with SRCs returned to their normal physical activities at 30 days, postconcussive symptoms persisted in 40% at 90 days of follow-up. After adjustment, there was no significant association between SRCs and persistent symptoms; however, patients with concussion from motor vehicle collisions were more likely to have persistent symptoms. CONCLUSION: Although physically active individuals may recover faster after a concussion, patients returning to their physical activities before full resolution of symptoms are at higher risk of persistent symptoms and further injury. Patient-clinician communications and tailored recommendations should be encouraged to guide appropriate acute management of concussions.


Asunto(s)
Traumatismos en Atletas , Conmoción Encefálica , Adulto , Traumatismos en Atletas/diagnóstico , Traumatismos en Atletas/epidemiología , Traumatismos en Atletas/terapia , Conmoción Encefálica/diagnóstico , Conmoción Encefálica/epidemiología , Conmoción Encefálica/terapia , Canadá/epidemiología , Servicio de Urgencia en Hospital , Humanos , Estudios Prospectivos , Calidad de Vida
11.
Glia ; 69(4): 1037-1052, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33300228

RESUMEN

The brain has an intrinsic capacity to repair injury, but the specific mechanisms are largely unknown. In this study, we found that, despite their incipient death, damaged neurons play a key repair role with the help of monocytes infiltrated from blood. Monocytes phagocytosed damaged and/or dying neurons that expressed osteopontin (OPN), with possible subsequent activation of their inflammasome pathway, resulting in pyroptosis. During this process, monocytes released CD63-positive exosome-like vesicles containing OPN. Importantly, following the exosome-like vesicles, neuron and astrocyte processes elongated toward the injury core. In addition, exosomes prepared from the injured brain contained OPN, and enhanced neurite outgrowth of cultured neurons in an OPN-dependent manner. Thus, our results introduce the concept that neurons in the injured brain that are destined to die perceive the stressful condition and begin the regeneration processes through induction of OPN, ultimately executing the repair process with the help of monocytes recruited from the circulation.


Asunto(s)
Monocitos , Osteopontina , Encéfalo/metabolismo , Monocitos/metabolismo , Neuronas/metabolismo , Osteopontina/metabolismo , Fagocitosis
12.
J Neurosci ; 38(26): 5872-5887, 2018 06 27.
Artículo en Inglés | MEDLINE | ID: mdl-29798891

RESUMEN

SALM1 (SALM (synaptic adhesion-like molecule), also known as LRFN2 (leucine rich repeat and fibronectin type III domain containing), is a postsynaptic density (PSD)-95-interacting synaptic adhesion molecule implicated in the regulation of NMDA receptor (NMDAR) clustering largely based on in vitro data, although its in vivo functions remain unclear. Here, we found that mice lacking SALM1/LRFN2 (Lrfn2-/- mice) show a normal density of excitatory synapses but altered excitatory synaptic function, including enhanced NMDAR-dependent synaptic transmission but suppressed NMDAR-dependent synaptic plasticity in the hippocampal CA1 region. Unexpectedly, SALM1 expression was detected in both glutamatergic and GABAergic neurons and Lrfn2-/- CA1 pyramidal neurons showed decreases in the density of inhibitory synapses and the frequency of spontaneous inhibitory synaptic transmission. Behaviorally, ultrasonic vocalization was suppressed in Lrfn2-/- pups separated from their mothers and acoustic startle was enhanced, but locomotion, anxiety-like behavior, social interaction, repetitive behaviors, and learning and memory were largely normal in adult male Lrfn2-/- mice. These results suggest that SALM1/LRFN2 regulates excitatory synapse function, inhibitory synapse development, and social communication and startle behaviors in mice.SIGNIFICANCE STATEMENT Synaptic adhesion molecules regulate synapse development and function, which govern neural circuit and brain functions. The SALM/LRFN (synaptic adhesion-like molecule/leucine rich repeat and fibronectin type III domain containing) family of synaptic adhesion proteins consists of five known members for which the in vivo functions are largely unknown. Here, we characterized mice lacking SALM1/LRFN2 (SALM1 KO) known to associate with NMDA receptors (NMDARs) and found that these mice showed altered NMDAR-dependent synaptic transmission and plasticity, as expected, but unexpectedly also exhibited suppressed inhibitory synapse development and synaptic transmission. Behaviorally, SALM1 KO pups showed suppressed ultrasonic vocalization upon separation from their mothers and SALM1 KO adults showed enhanced responses to loud acoustic stimuli. These results suggest that SALM1/LRFN2 regulates excitatory synapse function, inhibitory synapse development, social communication, and acoustic startle behavior.


Asunto(s)
Glicoproteínas de Membrana/fisiología , Proteínas del Tejido Nervioso/fisiología , Plasticidad Neuronal/fisiología , Células Piramidales/fisiología , Reflejo de Sobresalto/fisiología , Vocalización Animal/fisiología , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Conducta Social , Sinapsis/fisiología , Transmisión Sináptica/fisiología
13.
Magn Reson Med ; 81(5): 3124-3137, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30549088

RESUMEN

PURPOSE: To develop a correction method for the effects of the magnetic susceptibility of fat (χFat ) on the calculation of venous oxygen saturation (SvO2 ). THEORY: The magnetic field shifts associated with the magnetic susceptibility of deoxyhemoglobin can be used to estimate SvO2 , a measure of oxygen extraction and metabolism. However, the distinct magnetic susceptibility of fat surrounding targeted veins will give rise to magnetic field perturbations that will extend into the vein and surrounding tissues, potentially confounding the calculation of SvO2 . METHODS: Multi-echo modified Dixon fat-water separated imaging was used to quantify fat-water distributions around the superficial femoral vein (venous return from the lower leg). Fat fraction images were used to generate χFat images, to calculate and remove the associated fat-susceptibility-induced magnetic field shifts before the estimation of SvO2 . This approach was evaluated at rest and with plantar flexion exercise to evaluate calf muscle oxygen extraction in 10 healthy subjects. RESULTS: The presence of fat around the vein resulted in complex magnetic field shifts and errors in estimated SvO2 . Corrected resting SvO2 values were significantly larger than those measured with conventional methods, at rest (72.6 ± 11.0% vs. 65.2 ± 12.2%, P < 0.05) and post-exercise (37.4 ± 12.3% vs. 31.7 ± 12.7%, P < 0.05), with larger errors in individuals and/or regions with increased fat volumes. Estimation and removal of the field-effects from χFat enabled the use of fat tissues for the measurement and removal of the background magnetic field. CONCLUSIONS: The magnetic susceptibility effects of fat can confound SvO2 estimation, but the susceptibility field effects can estimated and removed with the use of modified Dixon fat-water separated imaging.


Asunto(s)
Vena Femoral/diagnóstico por imagen , Hemoglobinas/química , Imagen por Resonancia Magnética , Músculo Esquelético/diagnóstico por imagen , Oximetría , Oxígeno/metabolismo , Adulto , Ejercicio Físico , Femenino , Análisis de Fourier , Voluntarios Sanos , Humanos , Campos Magnéticos , Magnetismo , Masculino , Fantasmas de Imagen
15.
Int J Mol Sci ; 21(1)2019 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-31861806

RESUMEN

Developmentally regulated GTP-binding protein 2 (DRG2) was first identified in the central nervous system of mice. However, the physiological function of DRG2 in the brain remains largely unknown. Here, we demonstrated that knocking out DRG2 impairs the function of dopamine neurons in mice. DRG2 was strongly expressed in the neurons of the dopaminergic system such as those in the striatum (Str), ventral tegmental area (VTA), and substantia nigra (SN), and on neuronal cell bodies in high-density regions such as the hippocampus (HIP), cerebellum, and cerebral cortex in the mouse brain. DRG2 knockout (KO) mice displayed defects in motor function in motor coordination and rotarod tests and increased anxiety. However, unexpectedly, DRG2 depletion did not affect the dopamine (DA) neuron population in the SN, Str, or VTA region or dopamine synthesis in the Str region. We further demonstrated that dopamine release was significantly diminished in the Str region of DRG2 KO mice and that treatment of DRG2 KO mice with l-3,4-dihydroxyphenylalanine (L-DOPA), a dopamine precursor, rescued the behavioral motor deficiency in DRG2 KO mice as observed with the rotarod test. This is the first report to identify DRG2 as a key regulator of dopamine release from dopamine neurons in the mouse brain.


Asunto(s)
Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Proteínas de Unión al GTP/genética , Trastornos Motores/genética , Animales , Ansiedad/genética , Ansiedad/metabolismo , Cuerpo Estriado/citología , Neuronas Dopaminérgicas/citología , Neuronas Dopaminérgicas/metabolismo , Proteínas de Unión al GTP/análisis , Proteínas de Unión al GTP/metabolismo , Eliminación de Gen , Ratones , Ratones Noqueados , Trastornos Motores/metabolismo
16.
N Y State Dent J ; 80(5): 40-5, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25672077

RESUMEN

In the years 2007 to 2011, faculty, pediatric dental residents and dental students lead by New York University College of Dentistry and Healthcare International Reachout, Inc., traveled to the Hoolebury School, Saint Ann Parish, Jamaica, where they provided treatment to 172 children. The service project focused on dental health promotion, education and prevention. Although not a randomized controlled trial, the statistical evidence from records of treatment received and the presence of decay strongly suggests the positive benefit of repeat dental visits and the placement of sealants on permanent molars in these children.


Asunto(s)
Caries Dental/prevención & control , Cariostáticos/uso terapéutico , Niño , Preescolar , Índice CPO , Restauración Dental Permanente , Fluoruros Tópicos/uso terapéutico , Educación en Salud Dental , Promoción de la Salud , Humanos , Jamaica , Misiones Médicas , Evaluación de Necesidades , New York , Salud Bucal , Higiene Bucal/educación , Selladores de Fosas y Fisuras/uso terapéutico , Estudios Retrospectivos , Extracción Dental
17.
Int J Emerg Med ; 17(1): 110, 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39227764

RESUMEN

BACKGROUND: Bleeding in early pregnancy is a common emergency department (ED) presentation. Although variability in approaches has been demonstrated, research is relatively uncommon on practices and outcomes. This study investigated the influence of clinical pattern of care, utility, and contribution of pelvic examination aimed at diagnosing and managing bleeding in early pregnancy at three Canadian EDs. METHODS: After obtaining informed consent, data were collected from adult women who were pregnant and from treating ED physicians using a structured questionnaire. We defined the change in management based on the initial clinical plan at the time of the initial physician assessment in the ED and any subsequent changes made after the pelvic examination was performed. Patient telephone follow-up was supplemented by linking with provincial administrative data for births. Univariable and multivariable binary logistic regression analyses were performed to identify factors associated with a change in patient management following pelvic examination in the ED. RESULTS: Overall, 200 women were enrolled. The mean age was 31 years, patients had been bleeding for a median of 1 day and stayed in the ED for a median of 5 h. Of these, 166 (83.0%) received a pelvic examination, including speculum examination and/or bimanual palpation. Pregnancy outcome data were available for 192 pregnancies; 107 (56%) experienced a miscarriage. Factors significantly associated with a change in management after pelvic examination in the univariate logistic regression analysis were brown/dark-red bleeding per vaginam (physician determined), tachycardia, right lower quadrant tenderness, and bimanual palpation. In the multivariate logistic regression analysis, brown/dark-red bleeding per vaginam was independently associated with a reduced likelihood of a change in management after pelvic examination (aOR = 0.37; 95% CI: 0.14-0.98). CONCLUSION: Among women presenting to the ED with bleeding in early pregnancy prior to 20 weeks gestation, only brown/dark-red vaginal bleeding, potentially indicative of bleeding resolution, significantly independently influenced the baseline odds of a change in management after pelvic examination. Until the debate on the utility of pelvic examination in the ED for this presentation is resolved, physician preferences and shared decision making with patients should guide practice regarding speculum examination/bimanual palpation for the management of bleeding in early pregnancy.

18.
PLoS One ; 19(10): e0309767, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39436875

RESUMEN

In recent years, there has been an increase in the use of accelerated diagnostic protocols (ADPs) and high-sensitivity troponin assays (hsTn) for the assessment of chest pain in emergency departments (EDs). This study aimed to quantitatively summarize the operational and clinical outcomes of ADPs implemented for patients with suspected cardiac chest pain. To be considered eligible for inclusion, studies must have implemented some form of ADP within the ED for evaluating adult (age ≥18 years) patients presenting with chest pain using Tn assays. The primary outcome was ED length of stay (LOS). Secondary outcomes included the proportion of patients admitted and the proportion with 30-day major adverse cardiac events (MACE). Thirty-seven articles involving 404,566 patients met the inclusion criteria, including five randomized controlled trials (RCTs) and 32 observational studies. A significant reduction in total ED LOS was reported in 22 observational studies and four RCTs. Emergency departments with longer baseline ED LOS showed significantly larger reductions in LOS after ADP implementation. This observed association persisted after adjusting for both the change in serial Tn measurement interval and transition from conventional Tn assay to an hsTn assay (ß = -0.26; 95% CI, -0.43 to -0.10). Three studies reported an increase in the proportion of patients admitted after introducing an ADP, one of which was significant while 15 studies reported a significant decrease in admission proportion. There was moderate heterogeneity among the 13 studies that reported MACE proportions, with a non-significant pooled risk ratio of 0.95 (95% CI, 0.86-1.04). Implementation of ADPs for chest pain presentations decreases ED LOS, most noticeably within sites with a high baseline LOS; this decreased LOS is seen even in the absence of any change in troponin assay type. The decrease in LOS occurred alongside reductions in hospital admissions, while not increasing MACE. The observed benefits translated across multiple countries and health regions.


Asunto(s)
Dolor en el Pecho , Servicio de Urgencia en Hospital , Tiempo de Internación , Humanos , Dolor en el Pecho/diagnóstico , Troponina/sangre
19.
CJC Open ; 6(7): 915-924, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39026624

RESUMEN

Background: This study strove to assess the impact of the implementation of an accelerated diagnostic protocol (ADP), using shortened serial-testing intervals and a conventional troponin I (c-TnI) test, on emergency department (ED) length of stay (LOS). Methods: This retrospective cohort study included adults (aged ≥ 18 years) presenting to a Canadian ED with a primary complaint of cardiac chest pain between January 14, 2017 and January 15, 2019. For non-high-risk patients, the troponin delta timing decreased from 6 hours to 3 hours, and a different conventional troponin I level cut-point was implemented on January 15, 2018. The primary outcome was ED LOS. Secondary outcomes included disposition status, consultation proportions, and major adverse cardiac events within 30 days. Results: A total of 3133 patient interactions were included. Although the overall decrease in median ED LOS was not significant (P = 0.074), a significant reduction occurred in ED LOS (-33 minutes; 95% confidence interval: -53.6 to -12.4 minutes) among patients who were discharged in the post-ADP group. Consultations were unchanged between groups (36.1% before vs 33.8% after; P = 0.17). The major adverse cardiac events outcomes were unchanged across cohorts (15.9% vs 15.3%; P = 0.62). Conclusions: The implementation of an ADP, with a conventional troponin I test, for cardiac chest pain in a Canadian ED was not associated with a significant reduction of LOS for all patients; however, a significant reduction occurred for patients who were discharged, and the strategy appears safe.


Contexte: Cette étude visait à évaluer les répercussions de la mise en œuvre d'un protocole de diagnostic accéléré avec intervalles plus courts entre les épreuves séquentielles et dosage classique de la troponine I sur la durée du séjour à l'urgence. Méthodologie: Cette étude de cohortes rétrospective a été menée chez des adultes (âgés de 18 ans ou plus) qui se sont présentés à l'urgence d'un hôpital canadien principalement pour une douleur thoracique cardiaque entre le 14 janvier 2017 et le 15 janvier 2019. Chez les patients qui n'étaient pas exposés à un risque élevé, l'intervalle de dosage de la troponine (delta) est passé de 6 heures à 3 heures, et une nouvelle valeur seuil a été utilisée pour le dosage classique de la troponine I à compter du 15 janvier 2018. Le critère d'évaluation principal était la durée du séjour à l'urgence. Les critères d'évaluation secondaires comprenaient le statut au moment de la sortie, les proportions de consultation et les événements cardiovasculaires indésirables majeurs dans les 30 jours. Résultats: Au total, 3 133 interactions avec des patients ont été incluses. Bien que la diminution globale de la durée médiane du séjour à l'urgence n'ait pas été significative (p = 0,074), une réduction significative du séjour à l'urgence (-33 minutes; intervalle de confiance à 95 % : -53,6 à -12,4 minutes) a été observée chez les patients ayant reçu leur congé appartenant au groupe dans lequel le protocole de diagnostic accéléré a été mis en œuvre. Les consultations étaient inchangées entre les groupes (36,1 % avant vs 33,8 % après; p = 0,17). Les résultats relatifs aux événements cardiovasculaires indésirables majeurs sont demeurés inchangés dans les cohortes (15,9 % vs 15,3 %; p = 0,62). Conclusions: La mise en œuvre d'un protocole de diagnostic accéléré, avec un dosage classique de la troponine I, en cas de douleur thoracique d'origine cardiaque, à l'urgence d'un établissement canadien ne s'est pas traduite par une réduction significative du séjour à l'urgence chez tous les patients. Une réduction significative a néanmoins été observée chez les patients qui ont reçu leur congé, et la stratégie s'est avérée sûre.

20.
Jt Comm J Qual Patient Saf ; 50(11): 784-790, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39289143

RESUMEN

BACKGROUND: Mucosal barrier injury central line-associated bloodstream infections (MBI-CLABSIs) remain a challenge among the pediatric cancer population. These infections commonly occur by oral or gastrointestinal (GI) bacteria translocating through impaired gut or oral mucosa. Although strategies to prevent gut MBI-CLABSIs are well characterized, oral pathogen prevention strategies are lacking. METHODS: The authors' oncodental collaboration quality improvement project, which included two Plan-Do-Study-Act (PDSA) cycles, aimed to improve MBI-CLABSI rates and oral care adherence on a pediatric hematopoietic stem cell transplant (HSCT) unit. PDSA cycle 1 integrated dental residents into existing rounds every third week to screen for dental, gum, and mucosal disease and provide targeted education to patients and families. PDSA cycle 2 implemented a novel oral health educator (OHE) role in which a trained dental hygienist rounded four days per week. Monthly MBI-CLABSI rates and oral care adherence were followed from December 2020 to May 2021 (baseline), June 2021 to March 2022 (PDSA cycle 1), and April 2022 to December 2022 (PDSA cycle 2). Qualitative surveys captured patient and family perception, and a cost savings analysis was completed. RESULTS: A 58.8% reduction in MBI-CLABSI rate (events per 1,000 central venous line days) was detected (baseline: 5.1; PDSA cycle 2: 2.1), oral care adherence improved 41.7% (baseline: 60.9%; PDSA cycle 2: 86.3%), 100% of patients found it beneficial to receive oral care demonstrations, and an annual cost savings of $541,000 was estimated. CONCLUSION: Direct patient outcomes have measurably improved. This project suggests the implementation of an OHE in pediatric HSCT inpatient units may be valuable to patients and families and may be a cost-effective way to reduce MBI-CLABSIs resulting from oral pathogens.


Asunto(s)
Infecciones Relacionadas con Catéteres , Trasplante de Células Madre Hematopoyéticas , Mejoramiento de la Calidad , Humanos , Mejoramiento de la Calidad/organización & administración , Infecciones Relacionadas con Catéteres/prevención & control , Salud Bucal , Niño
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