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1.
Ann Neurol ; 95(3): 576-582, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38038962

RESUMO

OBJECTIVE: Telestroke (TS) service has been shown to improve stroke diagnosis timing and accuracy, facilitate treatment decisions, and decrease interfacility transfers. Expanding TS service to inpatient units at the community hospital provides an opportunity to follow up on stroke patients and optimize medical management. This study examines the outcome of expanding TS coverage from acute emergency room triage to incorporate inpatient consultation. METHODS: We studied the effect of expanding TS to inpatient consultation service at 19 regional hospitals affiliated with Promedica Stroke Network. We analyzed data pre- and post-TS expansion. We reviewed changes in TS utilization, admission rate, thrombolytic therapy, patient transfer rate, and diagnosis accuracy. RESULTS: Between January 2018 and June 2022, a total of 9,756 patients were evaluated in our stroke network (4,705 in pre- and 5,051 in the post-TS expansion). In the post-TS expansion period, stroke patients' admission at the spoke hospital increased from 18/month to 40/month, and for TIA from 11/month to 16/month. TS cart use increased from 12% to 35.2%. Patient transfers to hub hospital decreased by 31%. TS service expansion did not affect intravenous thrombolytic therapy rate or door-to-needle time. There was no difference in length of stay or readmission rate, and the patients at the spoke hospitals had a higher rate of home discharge 57.38% compared with 52.58% at hub hospital. INTERPRETATION: Telestroke service expansion to inpatient units helped decrease transfers and retain patients in their communities, increased stroke and TIA diagnosis accuracy, and did not compromise patients' hospitalization or outcome. ANN NEUROL 2024;95:576-582.


Assuntos
Ataque Isquêmico Transitório , Acidente Vascular Cerebral , Telemedicina , Humanos , Ativador de Plasminogênio Tecidual , Hospitais Comunitários , Ataque Isquêmico Transitório/tratamento farmacológico , Fatores de Tempo , Acidente Vascular Cerebral/terapia , Acidente Vascular Cerebral/tratamento farmacológico , Fibrinolíticos/efeitos adversos , Terapia Trombolítica/efeitos adversos , Resultado do Tratamento
2.
Neurosci Bull ; 30(4): 569-83, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24968808

RESUMO

Precise modulation of the cytoskeleton is involved in a variety of cellular processes including cell division, migration, polarity, and adhesion. In developing post-mitotic neurons, extracellular guidance cues not only trigger signaling cascades that act at a distance to indirectly regulate microtubule distribution, and assembly and disassembly in the growth cone, but also directly modulate microtubule stability and dynamics through coupling of guidance receptors with microtubules to control growth-cone turning. Microtubule-associated proteins including classical microtubule-associated proteins and microtubule plus-end tracking proteins are required for modulating microtubule dynamics to influence growth-cone steering. Multiple key signaling components, such as calcium, small GTPases, glycogen synthase kinase-3ß, and c-Jun N-terminal kinase, link upstream signal cascades to microtubule stability and dynamics in the growth cone to control axon outgrowth and projection. Understanding the functions and regulation of microtubule dynamics in the growth cone provides new insights into the molecular mechanisms of axon guidance.


Assuntos
Axônios/metabolismo , Cones de Crescimento/metabolismo , Microtúbulos/metabolismo , Transdução de Sinais , Animais , Axônios/ultraestrutura , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Fatores de Crescimento Neural/metabolismo , Tubulina (Proteína)/metabolismo
3.
J Cell Sci ; 126(Pt 14): 3070-81, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23641072

RESUMO

The coupling of axon guidance cues, such as netrin-1, to microtubule (MT) dynamics is essential for growth cone navigation in the developing nervous system. However, whether axon guidance signaling regulates MT dynamics directly or indirectly is unclear. Here, we report that TUBB3, the most dynamic ß-tubulin isoform in neurons, directly interacts with the netrin receptor DCC, and that netrin-1 induces this interaction in primary neurons. TUBB3 colocalizes with DCC in the growth cones of primary neurons and MT dynamics is required for netrin-1-promoted association of TUBB3 with DCC. Netrin-1 not only increases co-sedimentation of DCC with polymerized MT, but also promotes MT dynamics in the growth cone. Knocking down TUBB3 inhibits netrin-1-induced MT dynamics, axon outgrowth and attraction in vitro and causes defects in commissural axon projection in the embryo. These results indicate that TUBB3 directly links netrin signaling pathways to MT dynamics and plays an important role in guiding commissural axons in vivo.


Assuntos
Axônios/metabolismo , Microtúbulos/metabolismo , Fatores de Crescimento Neural/metabolismo , Receptores de Superfície Celular/metabolismo , Tubulina (Proteína)/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Processos de Crescimento Celular/genética , Embrião de Galinha , Receptor DCC , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Espaço Intracelular , Camundongos , Fatores de Crescimento Neural/farmacologia , Netrina-1 , Neurônios/metabolismo , Ligação Proteica/genética , Transporte Proteico/genética , RNA Interferente Pequeno/genética , Transdução de Sinais/genética , Medula Espinal/metabolismo , Transgenes/genética , Tubulina (Proteína)/genética , Proteínas Supressoras de Tumor/farmacologia
4.
J Biol Chem ; 288(3): 1883-95, 2013 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-23223444

RESUMO

The JNK family of MAPKs is involved in a large variety of physiological and pathological processes in brain development, such as neural survival, migration, and polarity as well as axon regeneration. However, whether JNK activation is involved in axon guidance remains unknown. Here, we provide evidence indicating the JNK pathway is required for Netrin signaling in the developing nervous system. Netrin-1 increased JNK1, not JNK2 or JNK3, activity in the presence of deleted in colorectal cancer (DCC) or Down syndrome cell adhesion molecule (DSCAM), and expression of both of them further enhanced Netrin-1-induced JNK1 activity in vitro. Inhibition of JNK signaling either by a JNK inhibitor, SP600125, or expression of a dominant negative form of MKK4, a JNK upstream activator, blocked Netrin-1-induced JNK1 activation in HEK293 cells. Netrin-1 increased endogenous JNK activity in primary neurons. Netrin-1-induced JNK activation was inhibited either by the JNK inhibitor or an anti-DCC function-blocking antibody. Combination of the anti-DCC function-blocking antibody with expression of DSCAM shRNA in primary neurons totally abolished Netrin-1-induced JNK activation, whereas knockdown of DSCAM partially inhibited the Netrin-1 effect. In the developing spinal cord, phospho-JNK was strongly expressed in commissural axons before and as they crossed the floor plate, and Netrin-1 stimulation dramatically increased the level of endogenous phospho-JNK in commissural axon growth cones. Inhibition of JNK signaling either by JNK1 RNA interference (RNAi) or the JNK inhibitor suppressed Netrin-1-induced neurite outgrowth and axon attraction. Knockdown of JNK1 in ovo caused defects in spinal cord commissural axon projection and pathfinding. Our study reveals that JNK1 is important in the coordination of DCC and DSCAM in Netrin-mediated attractive signaling.


Assuntos
Axônios/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Proteína Quinase 8 Ativada por Mitógeno/genética , Fatores de Crescimento Neural/genética , Medula Espinal/metabolismo , Proteínas Supressoras de Tumor/genética , Animais , Antracenos/farmacologia , Axônios/efeitos dos fármacos , Moléculas de Adesão Celular/antagonistas & inibidores , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Embrião de Galinha , Receptor DCC , Embrião de Mamíferos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Células HEK293 , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , MAP Quinase Quinase 4/antagonistas & inibidores , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Camundongos , Proteína Quinase 8 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Fatores de Crescimento Neural/antagonistas & inibidores , Fatores de Crescimento Neural/metabolismo , Netrina-1 , Cultura Primária de Células , Inibidores de Proteínas Quinases/farmacologia , RNA Interferente Pequeno/genética , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/crescimento & desenvolvimento , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/metabolismo
5.
J Biol Chem ; 287(32): 27126-38, 2012 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-22685302

RESUMO

In the developing nervous system, neuronal growth cones explore the extracellular environment for guidance cues, which can guide them along specific trajectories toward their targets. Netrin-1, a bifunctional guidance cue, binds to deleted in colorectal cancer (DCC) and DSCAM mediating axon attraction, and UNC5 mediating axon repulsion. Here, we show that DSCAM interacts with UNC5C and this interaction is stimulated by netrin-1 in primary cortical neurons and postnatal cerebellar granule cells. DSCAM partially co-localized with UNC5C in primary neurons and brain tissues. Netrin-1 induces axon growth cone collapse of mouse cerebellum external granule layer (EGL) cells, and the knockdown of DSCAM or UNC5C by specific shRNAs or blocking their signaling by overexpressing dominant negative mutants suppresses netrin-1-induced growth cone collapse. Similarly, the simultaneous knockdown of DSCAM and UNC5C also blocks netrin-1-induced growth cone collapse in EGL cells. Netrin-1 increases tyrosine phosphorylation of endogenous DSCAM, UNC5C, FAK, Fyn, and PAK1, and promotes complex formation of DSCAM with these signaling molecules in primary postnatal cerebellar neurons. Inhibition of Src family kinases efficiently reduces the interaction of DSCAM with UNC5C, FAK, Fyn, and PAK1 and tyrosine phosphorylation of these proteins as well as growth cone collapse of mouse EGL cells induced by netrin-1. The knockdown of DSCAM inhibits netrin-induced tyrosine phosphorylation of UNC5C and Fyn as well as the interaction of UNC5C with Fyn. The double knockdown of both receptors abolishes the induction of Fyn tyrosine phosphorylation by netrin-1. Our study reveals the first evidence that DSCAM coordinates with UNC5C in netrin-1 repulsion.


Assuntos
Moléculas de Adesão Celular/metabolismo , Cones de Crescimento/patologia , Fatores de Crescimento Neural/metabolismo , Receptores de Superfície Celular/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Western Blotting , Células Cultivadas , Primers do DNA , Camundongos , Receptores de Netrina , Netrina-1 , Transdução de Sinais , Quinases da Família src/metabolismo
6.
Epilepsy Res ; 99(3): 293-305, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22245138

RESUMO

Hypoxia regulates neuronal ion channels, sometimes resulting in seizures. We evaluated the effects of brief sustained hypoxia (1% O(2), 4h) on voltage-gated calcium channels (VGCCs) in cultured rat primary cortical neurons. High-voltage activated (HVA) Ca(2+) currents were acquired immediately after hypoxic exposure or after 48h recovery in 95% air/5% CO(2). Maximal Ca(2+) current density increased 1.5-fold immediately after hypoxia, but reverted to baseline after 48h normoxia. This enhancement was primarily due to an increase in L-type VGCC activity, since nimodipine-insensitive residual Ca(2+) currents were unchanged. The half-maximal potentials of activation and steady-state inactivation were unchanged. The calcineurin inhibitors FK-506 (in the recording pipette) or cyclosporine A (during hypoxia) prevented the post-hypoxic increase in HVA Ca(2+) currents, while rapamycin and okadaic acid did not. L-type VGCCs were the source of Ca(2+) for calcineurin activation, as nimodipine during hypoxia prevented post-hypoxic enhancement. Hypoxia transiently potentiated L-type VGCC currents via calcineurin, suggesting a positive feedback loop to amplify neuronal calcium signaling that may contribute to seizure generation.


Assuntos
Calcineurina/fisiologia , Canais de Cálcio Tipo L/fisiologia , Córtex Cerebral/fisiologia , Neurônios/fisiologia , Animais , Inibidores de Calcineurina , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/fisiologia , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Tacrolimo/farmacologia
7.
BMC Genomics ; 9: 284, 2008 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-18549495

RESUMO

BACKGROUND: Genomes possess different levels of non-randomness, in particular, an inhomogeneity in their nucleotide composition. Inhomogeneity is manifest from the short-range where neighboring nucleotides influence the choice of base at a site, to the long-range, commonly known as isochores, where a particular base composition can span millions of nucleotides. A separate genomic issue that has yet to be thoroughly elucidated is the role that RNA secondary structure (SS) plays in gene expression. RESULTS: We present novel data and approaches that show that a mid-range inhomogeneity (~30 to 1000 nt) not only exists in mammalian genomes but is also significantly associated with strong RNA SS. A whole-genome bioinformatics investigation of local SS in a set of 11,315 non-redundant human pre-mRNA sequences has been carried out. Four distinct components of these molecules (5'-UTRs, exons, introns and 3'-UTRs) were considered separately, since they differ in overall nucleotide composition, sequence motifs and periodicities. For each pre-mRNA component, the abundance of strong local SS (< -25 kcal/mol) was a factor of two to ten greater than a random expectation model. The randomization process preserves the short-range inhomogeneity of the corresponding natural sequences, thus, eliminating short-range signals as possible contributors to any observed phenomena. CONCLUSION: We demonstrate that the excess of strong local SS in pre-mRNAs is linked to the little explored phenomenon of genomic mid-range inhomogeneity (MRI). MRI is an interdependence between nucleotide choice and base composition over a distance of 20-1000 nt. Additionally, we have created a public computational resource to support further study of genomic MRI.


Assuntos
Conformação de Ácido Nucleico , Precursores de RNA/química , Precursores de RNA/genética , Regiões 3' não Traduzidas/química , Regiões 3' não Traduzidas/genética , Regiões 5' não Traduzidas/química , Regiões 5' não Traduzidas/genética , Algoritmos , Animais , Composição de Bases , Sequência de Bases , Cromossomos Humanos Par 17/química , Cromossomos Humanos Par 17/genética , Biologia Computacional , DNA Intergênico/química , DNA Intergênico/genética , Éxons/genética , Genoma Humano , Humanos , Íntrons/genética , Dados de Sequência Molecular , Termodinâmica
9.
J Neurosci ; 27(2): 299-303, 2007 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-17215389

RESUMO

The medial septum and diagonal band of Broca (MSDB) are major afferents to the hippocampus and are important for learning, memory, and hippocampal theta rhythm. In the present study, we assessed the effect of cholinergic or noncholinergic MSDB lesions on the sequential learning of different goal locations in the same environment, a type of task that is proposed to require hippocampal theta rhythm. Rats were administered saline, 192-IgG saporin (SAP), or kainic acid (KA) into the MSDB and then behaviorally tested. On any day, a single arm of a radial maze was rewarded with food, but the location of this rewarded arm changed between days. As in previous studies, intraseptal SAP reduced the number of cholinergic neurons although sparing GABAergic septohippocampal neurons. KA had the reverse effect, reducing GABAergic septohippocampal neurons and sparing cholinergic neurons. KA, but not SAP, impaired performance on the repeated acquisition task. Saline and SAP rats showed rapid within-session learning, whereas KA rats were much slower to learn the goal location. Performance on a 30 min retention trial was also impaired, although this may be attributable to incomplete acquisition. These findings provide evidence that noncholinergic, but not cholinergic, MSDB neurons are important in helping the animal deal with high loads of memory interference, and provides partial support for the idea that hippocampal theta rhythm is involved.


Assuntos
Fibras Colinérgicas/fisiologia , Aprendizagem em Labirinto/fisiologia , Septo do Cérebro/fisiologia , Comportamento Espacial/fisiologia , Animais , Masculino , Desempenho Psicomotor/fisiologia , Ratos , Ratos Long-Evans
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