RESUMEN
To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1-11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely.
Asunto(s)
Lesiones Encefálicas , COVID-19 , Humanos , Estudios de Seguimiento , Citocinas , COVID-19/complicaciones , Sueroterapia para COVID-19 , Autoanticuerpos , Mediadores de Inflamación , Biomarcadores , Proteína Ácida Fibrilar de la GlíaRESUMEN
COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.
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Lesiones Encefálicas , COVID-19 , Gripe Humana , Humanos , Proteínas de Neurofilamentos , COVID-19/complicaciones , Biomarcadores , Autoanticuerpos , InmunidadRESUMEN
Cholinergic tone is high during wake and rapid eye movement sleep and lower during slow wave sleep (SWS). Nevertheless, the low tone of acetylcholine during SWS modulates sharp wave ripple incidence in the hippocampus and slow wave activity in the neocortex. Linking the hippocampus and neocortex, the medial entorhinal cortex (mEC) regulates the coupling between these structures during SWS, alternating between silent Down states and active Up states, which outlast neocortical ones. Here, we investigated how low physiological concentrations of acetylcholine (ACh; 100-500 nM) modulate Up and Down states in a mEC slice preparation. We find that ACh has a dual effect on mEC activity: it prolongs apparent Up state duration as recorded in individual cells and decreases the total synaptic charge transfer, without affecting the duration of detectable synaptic activity. The overall outcome of ACh application is excitatory and we show that ACh increases Up state incidence via muscarinic receptor activation. The mean firing rate of principal neurons increased in around half of the cells while the other half showed a decrease in firing rate. Using two-photon calcium imaging of population activity, we found that population-wide network events are more frequent and rhythmic during ACh and confirmed that ACh modulates cell participation in these network events, consistent with a role for cholinergic modulation in regulating information flow between the hippocampus and neocortex during SWS.
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Corteza Entorrinal , Neocórtex , Potenciales de Acción , Animales , Colinérgicos , Hipocampo , RatonesRESUMEN
This report describes a case of a 62-year-old man who developed Foix-Chavany-Marie syndrome subsequent to traumatic brain injury. The initial presentation of the syndrome was profound loss of voluntary control of orofacial muscles, causing a loss of speech and impairment of swallow. Over subsequent months, a remarkable recovery of these functions was observed. The natural history of FCMS in this case was favourable, with good improvement in function over months. Furthermore, the pattern of bilateral opercular injury was more readily recognised on MRI than on CT, supporting the role of MRI in cases of traumatic brain injury.
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Lesiones Traumáticas del Encéfalo/complicaciones , Trastornos de Deglución/etiología , Disartria/etiología , Parálisis Facial/etiología , Trastornos de Deglución/diagnóstico por imagen , Trastornos de Deglución/patología , Disartria/diagnóstico por imagen , Disartria/patología , Parálisis Facial/diagnóstico por imagen , Parálisis Facial/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Lóbulo Temporal/diagnóstico por imagen , Lóbulo Temporal/patologíaRESUMEN
BACKGROUND: Pouchitis is the most frequent complication after ileal pouch-anal anastomosis for refractory ulcerative colitis. A non-standardized preventative treatment exists. Sulfasalazine has proved effective in acute pouchitis therapy. AIMS: The aim of this study was to retrospectively evaluate the effect of sulfasalazine in primary prophylaxis of pouchitis after proctocolectomy with ileal pouch-anal anastomosis. METHODS: Data files of patients who underwent total proctocolectomy with ileal pouch-anal anastomosis for refractory ulcerative colitis and/or dysplasia from January 2007 to December 2014, with a follow-up until August 2015, were analyzed. After closure of loop ileostomy, on a voluntary basis, patients received a primary prophylaxis of pouchitis with sulfasalazine (2000 mg per day) continually until acute pouchitis flare and/or drop out due to side effects. RESULTS: Follow-up data were available for 51 of the 55 surgical patients. Median follow-up time was 68 months (range 10-104). Thirty postoperative complications occurred in 25 patients. 45% of patients developed pouchitis. Sulfasalazine prophylaxis was administered in 39.2% of patients; 15% of the these developed pouchitis versus 64.5% (20/31) of the non-sulfasalazine patients (p < 0.001). Pouchitis-free survival curves were 90.55 months in sulfasalazine patients and 44.46 in non-sulfasalazine patients (log-rank test p = 0.001, Breslow p = 0.001). CONCLUSION: Sulfasalazine may be potentially administered in pouchitis prophylaxis after proctocolectomy with ileal pouch-anal anastomosis, but large prospectively controlled trials are needed.
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Canal Anal/cirugía , Colitis Ulcerosa/cirugía , Reservorios Cólicos/efectos adversos , Reservoritis/prevención & control , Proctocolectomía Restauradora/efectos adversos , Sulfasalazina/uso terapéutico , Adolescente , Adulto , Anciano , Anastomosis Quirúrgica/efectos adversos , Anastomosis Quirúrgica/tendencias , Reservorios Cólicos/tendencias , Femenino , Estudios de Seguimiento , Fármacos Gastrointestinales/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Reservoritis/etiología , Proctocolectomía Restauradora/tendencias , Estudios Prospectivos , Estudios Retrospectivos , Adulto JovenRESUMEN
The medial entorhinal cortex (mEC) is a key structure which controls the communication between the hippocampus and the neocortex. During slow-wave sleep, it stands out from other cortical regions by exhibiting persistent activity that outlasts neocortical Up states, decoupling the entorhinal cortex-hippocampal interaction from the neocortex. Here, we compared the mechanisms involved in the maintenance of the Up state in the barrel cortex (BC) and mEC using whole cell recordings in acute mouse brain slices. Bath application of an NMDA receptor antagonist abolished Up states in the BC, and reduced the incidence but not the duration of Up states in the mEC. Conversely, blockade of kainate receptors decreased Up state duration in the mEC, but not in the BC. Voltage clamp recordings demonstrated the presence of a non-NMDA glutamate receptor-mediated slow excitatory postsynaptic current, sensitive to the selective kainate receptor antagonist UBP-302, in layer III neurons of the mEC, which was not observed in the BC. Moreover, we found that kainate receptor-mediated currents assist in recovery back to the Up state membrane potential following a current-induced hyperpolarisation of individual cells in the mEC. Finally, we were able to generate Up state activity in a network model of exponential integrate-and-fire neurons only supported by AMPA and kainate receptor-mediated currents. We propose that synaptic kainate receptors are responsible for the unique properties of mEC Up states.
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Potenciales de Acción/fisiología , Corteza Entorrinal/fisiología , Neocórtex/fisiología , Red Nerviosa/fisiología , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Técnicas de Cultivo de Órganos , Receptores de Ácido Kaínico/fisiología , Receptores de N-Metil-D-Aspartato/fisiologíaAsunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad Veno-Oclusiva Hepática/diagnóstico por imagen , Tioguanina/efectos adversos , Deprescripciones , Enfermedad Veno-Oclusiva Hepática/inducido químicamente , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Remisión EspontáneaAsunto(s)
Colitis Ulcerosa , Complejo de Antígeno L1 de Leucocito , Biomarcadores , Enfermedad Crónica , Heces , Humanos , RecurrenciaRESUMEN
Inflammatory bowel diseases have a natural course characterized by alternating periods of remission and relapse. Disease flares occur in a random way and are currently unpredictable for the most part. Predictors of benign or unfavourable clinical course are required to facilitate treatment decisions and to avoid overtreatment. The present article provides a literature review of the current evidence on the main clinical, genetic, endoscopic, histologic, serologic and fecal markers to predict aggressiveness of inflammatory bowel disease and discuss their prognostic role, both in Crohn's disease and ulcerative colitis. No single marker seems to be reliable alone as a flare predictor, even in light of promising evidence regarding the role of fecal markers, in particular fecal calprotectin, which has reported good results recently. In order to improve our daily clinical practice, validated prognostic scores should be elaborated, integrating clinical and biological markers of prognosis. Finally, we propose an algorithm considering clinical history and biological markers to intercept patients with high risk of clinical relapse.