RESUMEN
PURPOSE: The efficacy of the 1-h bundle for emergency department (ED) patients with suspected sepsis, which includes lactate measurement, blood culture, broad-spectrum antibiotics administration, administration of 30 mL/kg crystalloid fluid for hypotension or lactate ≥ 4 mmol/L, remains controversial. METHODS: We carried out a pragmatic stepped-wedge cluster-randomized trial in 23 EDs in France and Spain. Adult patients with Sepsis-3 criteria or a quick sequential organ failure assessment (SOFA) score ≥ 2 or a lactate > 2 mmol/L were eligible. The intervention was the implementation of the 1-h sepsis bundle. The primary outcome was in-hospital mortality truncated at 28 days. Secondary outcomes included volume of fluid resuscitation at 24 h, acute heart failure at 24 h, SOFA score at 72 h, intensive care unit (ICU) length of stay, number of days on mechanical ventilation or renal replacement therapy, vasopressor free days, unnecessary antibiotic administration, and mortality at 28 days. 1148 patients were planned to be analysed; the study period ended after 873 patients were included. RESULTS: 872 patients (mean age 66, 42% female) were analyzed: 387 (44.4%) in the intervention group and 485 (55.6%) in the control group. Median SOFA score was 3 [1-5]. Median time to antibiotic administration was 40 min in the intervention group vs 113 min in the control group (difference - 73 [95% confidence interval (CI) - 93 to - 53]). There was a significantly higher rate, volume, and shorter time to fluid resuscitation within 3 h in the intervention group. There were 47 (12.1%) in-hospital deaths in the intervention group compared to 61 (12.6%) in the control group (difference in percentage - 0.4 [95% CI - 5.1 to 4.2], adjusted relative risk (aRR) 0.81 [95% CI 0.48 to 1.39]). There were no differences between groups for other secondary endpoints. CONCLUSIONS: Among patients with suspected sepsis in the ED, the implementation of the 1-h sepsis bundle was not associated with significant difference in in-hospital mortality. However, this study may be underpowered to report a statistically significant difference between groups.
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Servicio de Urgencia en Hospital , Fluidoterapia , Mortalidad Hospitalaria , Sepsis , Humanos , Femenino , Masculino , Sepsis/mortalidad , Sepsis/terapia , Sepsis/tratamiento farmacológico , Anciano , Servicio de Urgencia en Hospital/estadística & datos numéricos , Persona de Mediana Edad , Francia/epidemiología , Fluidoterapia/métodos , Puntuaciones en la Disfunción de Órganos , Paquetes de Atención al Paciente/métodos , Paquetes de Atención al Paciente/normas , Paquetes de Atención al Paciente/estadística & datos numéricos , Antibacterianos/uso terapéutico , España/epidemiología , Unidades de Cuidados Intensivos/estadística & datos numéricos , Unidades de Cuidados Intensivos/organización & administración , Tiempo de Internación/estadística & datos numéricosRESUMEN
OBJECTIVE: To evaluate the feasibility of lung ultrasonography (LUS) performed by novice users' general practitioners (GPs) in diagnosing lower respiratory tract infections (LRTIs) in primary health care settings. DESIGN: A prospective interventional multicenter study (December 2019-March 2020). SETTINGS AND SUBJECTS: Patients aged >3 months, suspected of having LRTI consulting in three different general practices (GPs) (rural, semirural and urban) in France. MAIN OUTCOME MEASURES: Feasibility of LUS by GPs was assessed by (1) the proportion of patients where LUS was not performed, (2) technical breakdowns, (3) interpretability of images by GPs, (4) examination duration and (5) patient perception and acceptability. RESULTS: A total of 151 patients were recruited, and GPs performed LUS for 111 (73.5%) patients (LUS group). In 99.1% (n = 110) of cases, GPs indicated that they were able to interpret images. The median [IQR] exam duration was 4 [3-5] minutes. LRTI was diagnosed in 70.3% and 60% of patients in the LUS and no-LUS groups, respectively (p = .43). After LUS, GPs changed their diagnosis from 'other' to 'LRTI' in six cases (+5.4%, p < .001), prescribed antibiotics for five patients (+4.5%, p = .164) and complementary chest imaging for 10 patients (+9%, p < .001). Patient stress was reported in 1.8% of cases, 81.7% of patients declared that they better understood the diagnosis, and 82% of patients thought that the GP diagnosis was more reliable after LUS. CONCLUSIONS: LUS by GPs using handheld devices is a feasible diagnostic tool in primary health care for LRTI symptoms, demonstrating both effectiveness and positive patient reception. TRIAL REGISTRATION NUMBER: Clinicaltrial.gov: NCT04602234, 20/10/2020.
RESUMEN
The main objective of this work was to develop a tool to assist the activation of a helicopter emergency medical service (HEMS) for the SAMU 14. We opted for a methodology based on "guidelines of good professional practice." Simple consensus was used. A multidisciplinary working group (pilots, medical regulation assistants, doctors) was created. Subgroup meetings (pilots, medical regulation assistants, doctors) developed subparts of the tool. The assembly of the tool's subparts was reviewed by the working group and then by an independent reading group. This work enabled the consensual creation of a tool to support the use of the helicopter emergency medical service (HEMS) for the SAMU 14. It is composed of maps, a protocol, and a written procedure of activation. This methodology by "simple consensus" allowed the development of a tool rationalizing the activation of the helicopter emergency medical service (HEMS) for the SAMU 14. It was the first work of this type within the SAMU 14. This simple and transposable methodology could be used in other emergency centers or for other multidisciplinary protocols.
L'objectif principal de ce travail était la création d'un outil d'aide au déclenchement d'un SMUR héliporté au SAMU 14. Nous avons opté pour une méthodologie type « recommandations de bonnes pratiques professionnelles ¼ (RBPP). Le consensus simple a été utilisé. Un groupe de travail multidisciplinaire (pilotes, assistant de régulation médicale [ARM], médecins) a été créé. Des réunions en sous-groupe (pilote, ARM et médecins) ont permis d'élaborer des sous-parties de l'outil. L'assemblage des sous-parties de l'outil a été relu par le groupe de travail puis par un groupe de lecture autonome et validé en réunion de service. Ce travail a permis la création consensuelle d'un outil d'aide à l'emploi du vecteur héliporté en SMUR primaire au sein du SAMU 14. Il est composé de cartes, d'une fiche réflexe et d'une procédure écrite de déclenchement. Cette méthodologie par consensus simple a permis la création d'un outil rationalisant le déclenchement du vecteur héliporté pour le SAMU 14. Il s'agissait du premier travail de ce type au SAMU 14. Cette méthodologie simple et transposable pourrait être utilisée dans d'autres centres 15 ou pour d'autres protocoles multidisciplinaires.
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Ambulancias Aéreas , Servicios Médicos de Urgencia , Humanos , Consenso , Aeronaves , Técnicos Medios en SaludRESUMEN
Importance: Tracheal intubation is recommended for coma patients and those with severe brain injury, but its use in patients with decreased levels of consciousness from acute poisoning is uncertain. Objective: To determine the effect of intubation withholding vs routine practice on clinical outcomes of comatose patients with acute poisoning and a Glasgow Coma Scale score less than 9. Design, Setting, and Participants: This was a multicenter, randomized trial conducted in 20 emergency departments and 1 intensive care unit (ICU) that included comatose patients with suspected acute poisoning and a Glasgow Coma Scale score less than 9 in France between May 16, 2021, and April 12, 2023, and followed up until May 12, 2023. Intervention: Patients were randomized to undergo conservative airway strategy of intubation withholding vs routine practice. Main Outcomes and Measures: The primary outcome was a hierarchical composite end point of in-hospital death, length of ICU stay, and length of hospital stay. Key secondary outcomes included adverse events resulting from intubation as well as pneumonia within 48 hours. Results: Among the 225 included patients (mean age, 33 years; 38% female), 116 were in the intervention group and 109 in the control group, with respective proportions of intubations of 16% and 58%. No patients died during the in-hospital stay. There was a significant clinical benefit for the primary end point in the intervention group, with a win ratio of 1.85 (95% CI, 1.33 to 2.58). In the intervention group, there was a lower proportion with any adverse event (6% vs 14.7%; absolute risk difference, 8.6% [95% CI, -16.6% to -0.7%]) compared with the control group, and pneumonia occurred in 8 (6.9%) and 16 (14.7%) patients, respectively (absolute risk difference, -7.8% [95% CI, -15.9% to 0.3%]). Conclusions and Relevance: Among comatose patients with suspected acute poisoning, a conservative strategy of withholding intubation was associated with a greater clinical benefit for the composite end point of in-hospital death, length of ICU stay, and length of hospital stay. Trial Registration: ClinicalTrials.gov Identifier: NCT04653597.
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Coma , Neumonía , Humanos , Femenino , Adulto , Masculino , Coma/etiología , Coma/terapia , Mortalidad Hospitalaria , Intubación Intratraqueal , Servicio de Urgencia en HospitalRESUMEN
BACKGROUND: Recently, validated clinical decision rules have been developed that avoid unnecessary use of computed tomographic pulmonary angiography (CTPA) in patients with suspected pulmonary embolism (PE) in the emergency department (ED). OBJECTIVE: To measure any resulting change in CTPA use for suspected PE. DESIGN: Retrospective analysis. SETTING: 26 European EDs in 6 countries. PATIENTS: Patients with CTPA performed for suspected PE in the ED during the first 7 days of each odd month between January 2015 and December 2019. MEASUREMENTS: The primary end points were the CTPAs done for suspected PE in the ED and the number of PEs diagnosed in the ED each year adjusted to an annual census of 100 000 ED visits. Temporal trends were estimated using generalized linear mixed regression models. RESULTS: 8970 CTPAs were included (median age, 63 years; 56% female). Statistically significant temporal trends for more frequent use of CTPA (836 per 100 000 ED visits in 2015 vs. 1112 in 2019; P < 0.001), more diagnosed PEs (138 per 100 000 in 2015 vs. 164 in 2019; P = 0.028), a higher proportion of low-risk PEs (annual percent change [APC], 13.8% [95% CI, 2.6% to 30.1%]) with more ambulatory management (APC, 19.3% [CI, 4.1% to 45.1%]), and a lower proportion of intensive care unit admissions (APC, -8.9% [CI, -17.1% to -0.3%]) were observed. LIMITATION: Data were limited to 7 days every 2 months. CONCLUSION: Despite the recent validation of clinical decision rules to limit the use of CTPA, an increase in the CTPA rate along with more diagnosed PEs and especially low-risk PEs were instead observed. PRIMARY FUNDING SOURCE: None specific for this study.
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Embolia Pulmonar , Tomografía Computarizada por Rayos X , Humanos , Femenino , Persona de Mediana Edad , Masculino , Estudios Retrospectivos , Embolia Pulmonar/diagnóstico por imagen , Servicio de Urgencia en Hospital , AngiografíaRESUMEN
The main objective of this work was to develop a tool to assist the activation of a helicopter emergency medical service (HEMS) for the SAMU 14. We opted for a methodology based on "guidelines of good professional practice." Simple consensus was used. A multidisciplinary working group (pilots, medical regulation assistants, doctors) was created. Subgroup meetings (pilots, medical regulation assistants, doctors) developed subparts of the tool. The assembly of the tool's subparts was reviewed by the working group and then by an independent reading group. This work enabled the consensual creation of a tool to support the use of the helicopter emergency medical service (HEMS) for the SAMU 14. It is composed of maps, a protocol, and a written procedure of activation. This methodology by "simple consensus" allowed the development of a tool rationalizing the activation of the helicopter emergency medical service (HEMS) for the SAMU 14. It was the first work of this type within the SAMU 14. This simple and transposable methodology could be used in other emergency centers or for other multidisciplinary protocols.
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Ambulancias Aéreas , Servicios Médicos de Urgencia , Humanos , Consenso , Aeronaves , Técnicos Medios en SaludRESUMEN
OBJECTIVES: Acute triage is needed to prioritize care and achieve optimal resource allocation in busy emergency departments. The main objective is to compare the FRench Emergency Nurse Classification in Hospital scale (FRENCH) to the American scale Emergency Severity Index (ESI). Secondary objectives are to compare for each scale the over and under-triage, the triage matching to the gold standard and the inter-individual sorting reproducibility between the nurses. METHODS: This is a prospective observational study conducting among the nursing staffs and nursing students, selected from Caen University College Hospital and Lisieux Hospital Center emergency departments between two months. Each group individually rank 60 referent clinical cases composed by scales designers. An assessment of scale practicality is collected after for each tool. The collected parameters are analyzed by a Cohen kappa concordance test (κ). RESULTS: With 8151 triage results of gold standard scenarios sorting in two scales by the same nurses, the FRENCH scale seems to give better triage results than the US ESI scale (nurse: FRENCH 60% and ESI 53%, p = 0.003 ; nursing students: FRENCH 49% and ESI 42%, p < 0.001). In the two groups ESI has also a big tendency to under-sort (p = 0.01), particularly for the most severe patients (p < 0.01). The interobserver sorting concordance for any experience gives good results for the FRENCH and the ESI without any difference (nurses : FRENCH KPQ=0.72 ESI KPQ=0.78; p = 0.32 ; students KPQ=0.44 KPQ=0.55; p = 0.22). CONCLUSION: The ESI and FRENCH scales comparison on 8151 sorting results shows direct validity in favor of FRENCH one and similar interobserver agreement for both scales.
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Servicio de Urgencia en Hospital , Triaje , Humanos , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , Triaje/métodos , Estudios ProspectivosRESUMEN
Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a neuropsychiatric disease characterized by an antibody-mediated autoimmune response against NMDAR. Recent studies have shown that anti-NMDAR antibodies are involved in the pathophysiology of the disease. However, the upstream immune and inflammatory processes responsible for this pathogenic response are still poorly understood. Here, we immunized mice against the region of NMDA receptor containing the N368/G369 amino acids, previously implicated in a pathogenic response. This paradigm induced encephalopathy characterized by blood-brain barrier opening, periventricular T2-MRI hyperintensities and IgG deposits into the brain parenchyma. Two weeks after immunization, mice developed clinical symptoms reminiscent of encephalitis: anxiety- and depressive-like behaviours, spatial memory impairment (without motor disorders) and increased sensitivity to seizures. This response occurred independently of overt T-cell recruitment. However, it was associated with B220+ (B cell) infiltration towards the ventricles, where they differentiated into CD138+ cells (plasmocytes). Interestingly, these B cells originated from peripheral lymphoid organs (spleen and cervical lymphoid nodes). Finally, blocking the B-cell response using a depleting cocktail of antibodies reduced the severity of symptoms in encephalitis mice. This study demonstrates that the B-cell response can lead to an autoimmune reaction against NMDAR that drives encephalitis-like behavioural impairments. It also provides a relevant platform for dissecting encephalitogenic mechanisms in an animal model, and enables the testing of therapeutic strategies targeting the immune system in anti-NMDAR encephalitis.
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Autoanticuerpos/sangre , Linfocitos B/metabolismo , Encefalitis/sangre , Enfermedad de Hashimoto/sangre , Proteínas del Tejido Nervioso/toxicidad , Animales , Autoanticuerpos/inmunología , Linfocitos B/inmunología , Encefalitis/inducido químicamente , Encefalitis/inmunología , Enfermedad de Hashimoto/inducido químicamente , Enfermedad de Hashimoto/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/inmunología , Receptores de N-Metil-D-Aspartato/inmunologíaRESUMEN
Increase in blood-brain barrier (BBB) permeability is a crucial step in neuroinflammatory processes. We previously showed that N Methyl D Aspartate Receptor (NMDARs), expressed on cerebral endothelial cells forming the BBB, regulate immune cell infiltration across this barrier in the mouse. Here, we describe the mechanism responsible for the action of NMDARs on BBB permeabilization. We report that mouse CNS endothelial NMDARs display the regulatory GluN3A subunit. This composition confers to NMDARs' unconventional properties: these receptors do not induce Ca2+ influx but rather show nonionotropic properties. In inflammatory conditions, costimulation of human brain endothelial cells by NMDA agonists (NMDA or glycine) and the serine protease tissue plasminogen activator, previously shown to potentiate NMDAR activity, induces metabotropic signaling via the Rho/ROCK pathway. This pathway leads to an increase in permeability via phosphorylation of myosin light chain and subsequent shrinkage of human brain endothelial cells. Together, these data draw a link between NMDARs and the cytoskeleton in brain endothelial cells that regulates BBB permeability in inflammatory conditions.SIGNIFICANCE STATEMENT The authors describe how NMDARs expressed on endothelial cells regulate blood-brain barrier function via myosin light chain phosphorylation and increase in permeability. They report that these non-neuronal NMDARs display distinct structural, functional, and pharmacological features than their neuronal counterparts.
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Barrera Hematoencefálica/metabolismo , Células Endoteliales/metabolismo , Miosinas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas de Unión al GTP rho/metabolismo , Quinasas Asociadas a rho/metabolismo , Animales , Barrera Hematoencefálica/efectos de los fármacos , Línea Celular , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Células Endoteliales/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/farmacología , Masculino , Ratones , N-Metilaspartato/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Permeabilidad , Fosforilación/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/agonistas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Activador de Tejido Plasminógeno/farmacología , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
An alteration of parenchymal cerebrospinal fluid circulation (CSF) has been proposed to take part in the pathophysiology of multiple sclerosis. By using an intragate T1-weighted high-resolution MRI of the spinal cord of freely breathing mice injected with a gadolinium chelate in the cisterna magna, we show that a parenchymal CSF circulation exists in the spinal cord, in addition to that originally described in the brain. In experimental autoimmune encephalomyelitis, a model of multiple sclerosis, we show a reduction of parenchymal CSF circulation specifically in the spinal cord but not in the brain.
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Líquido Cefalorraquídeo/fisiología , Encefalomielitis Autoinmune Experimental/fisiopatología , Tejido Parenquimatoso/fisiopatología , Médula Espinal/fisiopatología , Animales , Encéfalo/fisiopatología , Cisterna Magna/efectos de los fármacos , Medios de Contraste/administración & dosificación , Femenino , Verde de Indocianina/administración & dosificación , Imagen por Resonancia Magnética , Meglumina/administración & dosificación , Ratones , Esclerosis Múltiple/fisiopatología , Compuestos Organometálicos/administración & dosificaciónRESUMEN
New strategies for detecting disease activity in multiple sclerosis are being investigated to ameliorate diagnosis and follow-up of patients. Today, although magnetic resonance imaging (MRI) is widely used to diagnose and monitor multiple sclerosis, no imaging tools exist to predict the evolution of disease and the efficacy of therapeutic strategies. Here, we show that molecular MRI targeting the endothelial adhesion molecule P-selectin unmasks the pathological events that take place in the spinal cord of mice subjected to chronic or relapsing experimental autoimmune encephalomyelitis. This approach provides a quantitative spatiotemporal follow-up of disease course in relation to clinical manifestations. Moreover, it predicts relapse in asymptomatic mice and remission in symptomatic animals. Future molecular MRI targeting P-selectin may be used to improve diagnosis, follow-up of treatment, and management of relapse/remission cycles in multiple sclerosis patients by providing information currently inaccessible through conventional MRI techniques.
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Imagen por Resonancia Magnética/métodos , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Animales , Barrera Hematoencefálica/diagnóstico por imagen , Encéfalo/patología , Medios de Contraste , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Encefalomielitis Autoinmune Experimental/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/metabolismo , Selectina-P/metabolismo , Recurrencia , Médula Espinal/patologíaRESUMEN
BACKGROUND: The ability of oligodendrocyte progenitor cells (OPCs) to give raise to myelin forming cells during developmental myelination, normal adult physiology and post-lesion remyelination in white matter depends on factors which govern their proliferation, migration and differentiation. Tissue plasminogen activator (tPA) is a serine protease expressed in the central nervous system (CNS), where it regulates cell fate. In particular, tPA has been reported to protect oligodendrocytes from apoptosis and to facilitate the migration of neurons. Here, we investigated whether tPA can also participate in the migration of OPCs during CNS development and during remyelination after focal white matter lesion. METHODS: OPC migration was estimated by immunohistological analysis in spinal cord and corpus callosum during development in mice embryos (E13 to P0) and after white matter lesion induced by the stereotactic injection of lysolecithin in adult mice (1 to 21 days post injection). Migration was compared in these conditions between wild type and tPA knock-out animals. The action of tPA was further investigated in an in vitro chemokinesis assay. RESULTS: OPC migration along vessels is delayed in tPA knock-out mice during development and during remyelination. tPA enhances OPC migration via an effect dependent on the activation of epidermal growth factor receptor. CONCLUSION: Endogenous tPA facilitates the migration of OPCs during development and during remyelination after white matter lesion by the virtue of its epidermal growth factor-like domain.
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Diferenciación Celular/efectos de los fármacos , Sistema Nervioso Central/crecimiento & desarrollo , Células-Madre Neurales/efectos de los fármacos , Oligodendroglía/efectos de los fármacos , Activador de Tejido Plasminógeno/farmacología , Animales , Lesiones Encefálicas/patología , Movimiento Celular/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Cuerpo Calloso/efectos de los fármacos , Cuerpo Calloso/patología , Embrión de Mamíferos , Factor de Crecimiento Epidérmico , Imagenología Tridimensional , Immunoblotting , Inmunohistoquímica , Imagen por Resonancia Magnética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Vaina de Mielina/efectos de los fármacos , Células-Madre Neurales/citología , Oligodendroglía/citología , Sustancia Blanca/efectos de los fármacosRESUMEN
N-methyl-d-aspartate receptors (NMDARs) are ion channels whose synaptic versus extrasynaptic localization critically influences their functions. This distribution of NMDARs is highly dependent on their lateral diffusion at the cell membrane. Each obligatory subunit of NMDARs (GluN1 and GluN2) contains two extracellular clamshell-like domains with an agonist-binding domain and a distal N-terminal domain (NTD). To date, the roles and dynamics of the NTD of the GluN1 subunit in NMDAR allosteric signaling remain poorly understood. Using single nanoparticle tracking in mouse neurons, we demonstrate that the extracellular neuronal protease tissue-type plasminogen activator (tPA), well known to have a role in the synaptic plasticity and neuronal survival, leads to a selective increase of the surface dynamics and subsequent diffusion of extrasynaptic NMDARs. This process explains the previously reported ability of tPA to promote NMDAR-mediated calcium influx. In parallel, we developed a monoclonal antibody capable of specifically blocking the interaction of tPA with the NTD of the GluN1 subunit of NMDAR. Using this original approach, we demonstrate that the tPA binds the NTD of the GluN1 subunit at a lysine in position 178. Accordingly, when applied to mouse neurons, our selected antibody (named Glunomab) leads to a selective reduction of the tPA-mediated surface dynamics of extrasynaptic NMDARs, subsequent signaling and neurotoxicity, both in vitro and in vivo. Altogether, we demonstrate that the tPA is a ligand of the NTD of the obligatory GluN1 subunit of NMDAR acting as a modulator of their dynamic distribution at the neuronal surface and subsequent signaling.
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Membrana Celular/metabolismo , Neuronas/citología , Neuronas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/metabolismo , Activador de Tejido Plasminógeno/farmacología , Animales , Anticuerpos Monoclonales/farmacología , Calcio/metabolismo , Muerte Celular/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Difusión , Fibrinolisina/farmacología , Células HEK293 , Humanos , Lisina/metabolismo , Masculino , Ratones Endogámicos BALB C , Neuronas/efectos de los fármacos , Neurotoxinas/toxicidad , Dominios Proteicos , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/química , Transducción de Señal/efectos de los fármacos , Sinapsis/efectos de los fármacosRESUMEN
Research advances support the idea that excessive activation of the glutamatergic pathway plays an important part in the pathophysiology of multiple sclerosis. Beyond the well established direct toxic effects on neurons, additional sites of glutamate-induced cell damage have been described, including effects in oligodendrocytes, astrocytes, endothelial cells, and immune cells. Such toxic effects could provide a link between various pathological aspects of multiple sclerosis, such as axonal damage, oligodendrocyte cell death, demyelination, autoimmunity, and blood-brain barrier dysfunction. Understanding of the mechanisms underlying glutamate toxicity in multiple sclerosis could help in the development of new approaches for diagnosis, treatment, and follow-up in patients with this debilitating disease. While several clinical trials of glutamatergic modulators have had disappointing results, our growing understanding suggests that there is reason to remain optimistic about the therapeutic potential of these drugs.
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Biomarcadores/metabolismo , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Ácido Glutámico/metabolismo , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/metabolismo , HumanosRESUMEN
Multiple sclerosis is among the most common causes of neurological disability in young adults. Here we provide the preclinical proof of concept of the benefit of a novel strategy of treatment for multiple sclerosis targeting neuroendothelial N-methyl-D-aspartate glutamate receptors. We designed a monoclonal antibody against N-methyl-D-aspartate receptors, which targets a regulatory site of the GluN1 subunit of N-methyl-D-aspartate receptor sensitive to the protease tissue plasminogen activator. This antibody reverted the effect of tissue plasminogen activator on N-methyl-D-aspartate receptor function without affecting basal N-methyl-D-aspartate receptor activity (n = 21, P < 0.01). This antibody bound N-methyl-D-aspartate receptors on the luminal surface of neurovascular endothelium in human tissues and in mouse, at the vicinity of tight junctions of the blood-spinal cord barrier. Noteworthy, it reduced human leucocyte transmigration in an in vitro model of the blood-brain barrier (n = 12, P < 0.05). When injected during the effector phase of MOG-induced experimental autoimmune encephalomyelitis (n = 24), it blocked the progression of neurological impairments, reducing cumulative clinical score (P < 0.001) and mean peak score (P < 0.001). This effect was observed in wild-type animals but not in tissue plasminogen activator knock-out animals (n = 10). This therapeutic effect was associated to a preservation of the blood-spinal cord barrier (n = 6, P < 0.001), leading to reduced leucocyte infiltration (n = 6, P < 0.001). Overall, this study unveils a critical function of endothelial N-methyl-D-aspartate receptor in multiple sclerosis, and highlights the therapeutic potential of strategies targeting the protease-regulated site of N-methyl-D-aspartate receptor.
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Barrera Hematoencefálica/metabolismo , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Antagonistas de Aminoácidos Excitadores/farmacología , Proteínas del Tejido Nervioso/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Activador de Tejido Plasminógeno/metabolismo , Animales , Células Endoteliales , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
BACKGROUND AND PURPOSE: The debate over the fact that experimental drugs proposed for the treatment of stroke fail in the translation to the clinical situation has attracted considerable attention in the literature. In this context, we present a retrospective pooled analysis of a large data set from preclinical studies, to examine the effects of early versus late administration of intravenous recombinant tissue-type plasminogen activator. METHODS: We collected data from 26 individual studies from 9 international centers (13 researchers; 716 animals) that compared recombinant tissue-type plasminogen activator with controls, in a unique mouse model of thromboembolic stroke induced by an in situ injection of thrombin into the middle cerebral artery. Studies were classified into early (<3 hours) versus late (≥3 hours) drug administration. Final infarct volumes, assessed by histology or magnetic resonance imaging, were compared in each study, and the absolute differences were pooled in a random-effect meta-analysis. The influence of time of administration was tested. RESULTS: When compared with saline controls, early recombinant tissue-type plasminogen activator administration was associated with a significant benefit (absolute difference, -6.63 mm(3); 95% confidence interval, -9.08 to -4.17; I(2)=76%), whereas late recombinant tissue-type plasminogen activator treatment showed a deleterious effect (+5.06 mm(3); 95% confidence interval, +2.78 to +7.34; I(2)=42%; Pint<0.00001). Results remained unchanged after subgroup analyses. CONCLUSIONS: Our results provide the basis needed for the design of future preclinical studies on recanalization therapies using this model of thromboembolic stroke in mice. The power analysis reveals that a multicenter trial would require 123 animals per group instead of 40 for a single-center trial.