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Leber hereditary optic neuropathy is a mitochondrial disease mainly due to pathologic mutations in mitochondrial genes related to the respiratory complex I of the oxidative phosphorylation system. Genetic, physiological, and environmental factors modulate the penetrance of these mutations. We report two patients suffering from this disease and harboring a m.15950G > A mutation in the mitochondrial DNA-encoded gene for the threonine transfer RNA. We also provide evidences supporting the pathogenicity of this mutation.
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Atrofia Óptica Hereditaria de Leber , ADN Mitocondrial/genética , Complejo I de Transporte de Electrón/genética , Humanos , Mutación , Atrofia Óptica Hereditaria de Leber/genética , Atrofia Óptica Hereditaria de Leber/patología , ARN de Transferencia/genéticaRESUMEN
BACKGROUND: It is suggested that neuroinflammation, in which activated microglial cells play a relevant role, contributes to the development of Parkinson's disease (PD). Consequently, the modulation of microglial activation is a potential therapeutic target to be taken into account to act against the dopaminergic neurodegeneration occurring in this neurological disorder. Several soluble and membrane-associated inhibitory mechanisms contribute to maintaining microglial cells in a quiescent/surveillant phenotype in physiological conditions. However, the presence of activated microglial cells in the brain in PD patients suggests that these mechanisms have been somehow overloaded. We focused our interest on one of the membrane-associated mechanisms, the CD200-CD200R1 ligand-receptor pair. METHODS: The acute MPTP experimental mouse model of PD was used to study the temporal pattern of mRNA expression of CD200 and CD200R1 in the context of MPTP-induced dopaminergic neurodegeneration and neuroinflammation. Dopaminergic damage was assessed by tyrosine hydroxylase (TH) immunoreactivity, and neuroinflammation was evaluated by the mRNA expression of inflammatory markers and IBA1 and GFAP immunohistochemistry. The effect of the modulation of the CD200-CD200R1 system on MPTP-induced damage was determined by using a CD200R1 agonist or CD200 KO mice. RESULTS: MPTP administration resulted in a progressive decrease in TH-positive fibres in the striatum and TH-positive neurons in the substantia nigra pars compacta, which were accompanied by transient astrogliosis, microgliosis and expression of pro- and anti-inflammatory markers. CD200 mRNA levels rapidly decreased in the ventral midbrain after MPTP treatment, while a transient decrease of CD200R1 mRNA expression was repeatedly observed in this brain area at earlier and later phases. By contrast, a transient increase in CD200R1 expression was observed in striatum. The administration of a CD200R1 agonist resulted in the inhibition of MPTP-induced dopaminergic neurodegeneration, while microglial cells showed signs of earlier activation in CD200-deficient mice. CONCLUSIONS: Collectively, these findings provide evidence for a correlation between CD200-CD200R1 alterations, glial activation and neuronal loss. CD200R1 stimulation reduces MPTP-induced loss of dopaminergic neurons, and CD200 deficiency results in earlier microglial activation, suggesting that the potentiation of CD200R1 signalling is a possible approach to controlling neuroinflammation and neuronal death in PD.
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Sistemas de Liberación de Medicamentos/métodos , Microglía/metabolismo , Receptores de Orexina/deficiencia , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/metabolismo , Animales , Femenino , Inmunoglobulina G/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/efectos de los fármacos , Receptores de Orexina/agonistas , Receptores de Orexina/genética , Trastornos Parkinsonianos/inducido químicamenteRESUMEN
ß-Catenin, the core element of the Wnt/ß-catenin pathway, is a multifunctional and evolutionarily conserved protein which performs essential roles in a variety of developmental and homeostatic processes. Despite its crucial roles, the mechanisms that control its context-specific functions in time and space remain largely unknown. The Wnt/ß-catenin pathway has been extensively studied in planarians, flatworms with the ability to regenerate and remodel the whole body, providing a 'whole animal' developmental framework to approach this question. Here we identify a C-terminally truncated ß-catenin (ß-catenin4), generated by gene duplication, that is required for planarian photoreceptor cell specification. Our results indicate that the role of ß-catenin4 is to modulate the activity of ß-catenin1, the planarian ß-catenin involved in Wnt signal transduction in the nucleus, mediated by the transcription factor TCF-2. This inhibitory form of ß-catenin, expressed in specific cell types, would provide a novel mechanism to modulate nuclear ß-catenin signaling levels. Genomic searches and in vitro analysis suggest that the existence of a C-terminally truncated form of ß-catenin could be an evolutionarily conserved mechanism to achieve a fine-tuned regulation of Wnt/ß-catenin signaling in specific cellular contexts.
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Planarias/fisiología , Vía de Señalización Wnt , beta Catenina/metabolismo , Animales , Proteínas del Dominio Armadillo/genética , Proteínas del Dominio Armadillo/metabolismo , Evolución Molecular , Homeostasis , Modelos Biológicos , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Células Fotorreceptoras de Invertebrados/fisiología , Planarias/genética , Planarias/crecimiento & desarrollo , Dominios y Motivos de Interacción de Proteínas , Regeneración , Factores de Transcripción TCF/genética , Factores de Transcripción TCF/metabolismo , beta Catenina/antagonistas & inhibidores , beta Catenina/genética , gamma Catenina/genética , gamma Catenina/metabolismoAsunto(s)
COVID-19/terapia , Hospitales Públicos/organización & administración , Hospitales de Enseñanza/organización & administración , Hospitales Urbanos/organización & administración , Transferencia de Pacientes , Anciano , Femenino , Capacidad de Camas en Hospitales , Humanos , Masculino , Persona de Mediana Edad , Cuarentena , SARS-CoV-2 , Índice de Severidad de la Enfermedad , EspañaRESUMEN
Objective: We present a case of multiple tumefactive demyelinating lesions (TDLs) emerging 24 months after the second cycle of alemtuzumab treatment. Methods: A woman with relapsing-remitting multiple sclerosis (MS) discontinued fingolimod treatment due to gestational desire, which resulted in a severe disease exacerbation. Alemtuzumab was initiated, accompanied by regular clinical, radiological, and immunological monitoring. Results: She relapsed prior to the second cycle, exhibiting 12 T1Gd+ lesions, and peripheral blood showed an increase in B-cells and a decrease in T-cells. At 24 months following the second cycle, she developed cognitive impairment and multiple T1Gd+ lesions, including TDLs, were evident on the brain MRI. We found not only an increase in B-cells but also in Th1 central memory cells. Th1/Th17 cells increased 3 months before the detection of TDLs. Conclusions: TDLs can appear 24 months after the second cycle of alemtuzumab treatment in MS. The increase in Th1/Th17 cells could be a candidate biomarker for TDLs in alemtuzumab-treated MS patients.
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Alemtuzumab , Biomarcadores , Imagen por Resonancia Magnética , Esclerosis Múltiple Recurrente-Remitente , Humanos , Alemtuzumab/efectos adversos , Alemtuzumab/uso terapéutico , Femenino , Adulto , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/inmunología , Células Th17/inmunología , Células TH1/inmunología , Linfocitos B/inmunología , Linfocitos B/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encéfalo/inmunologíaRESUMEN
Microglia, the main resident immune cells in the central nervous system, are implicated in the pathogenesis of various neurological disorders. Much of our knowledge on microglial biology was obtained using rodent microglial cultures. To understand the role of microglia in human disease, reliable in vitro models of human microglia are necessary. Monocyte-derived microglia-like cells (MDMi) are a promising approach. This study aimed to characterize MDMi cells generated from adult human monocytes using granulocyte-macrophage colony-stimulating factor and interleukin-34. To this end, 49 independent cultures of MDMI were prepared, and various methodological and functional studies were performed. We show that with this protocol, adult human monocytes develop into microglia-like cells, a coating is unnecessary, and high cell density seeding is preferable. When compared to monocytes, MDMi upregulate the expression of many, but not all, microglial markers, indicating that, although these cells display a microglia-like phenotype, they cannot be considered bona fide human microglia. At the functional level, MDMi phagocytose α-synuclein aggregates and responds to lipopolysaccharide (LPS) by nuclear translocation of the transcription factor nuclear factor-kappaB (NFkappaB) and the upregulation of proinflammatory genes. Finally, a long-lasting silencing of the transcription factor CCAAT/enhancer protein ß (C/EBPß) was achieved by small interfering RNA, resulting in the subsequent downregulation of proinflammatory genes. This supports the hypothesis that C/EBPß plays a key role in proinflammatory gene program activation in human microglia. Altogether, this study sheds new light on the properties of MDMi cells and supports these cells as a promising in vitro model for studying adult human microglia-like cells.
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Objective: The modified Centers for Disease Control and Prevention (mCDC) criteria have been proposed for diagnosing and managing stroke-associated pneumonia (SAP). The objective was to investigate the impact of SAP on stroke outcome depending on whether or not it conforms to mCDC criteria. Our secondary objective was to identify the responsible factors for antibiotic initiation in stroke patients. Methods: We conducted a prospective, multicenter, observational study of ischemic stroke patients with moderate to severe stroke (NIHSS≥4) admitted within 24 h. For 7 days, mCDC criteria were assessed daily, and infections and antibiotics were recorded. Pneumonias were divided into those fulfilling mCDC criteria (mCDC-SAP) or not (other pneumonias, OPn). The effect of each type of pneumonia on 3-month outcome was evaluated in separated logistic regression models. Factors associated with antibiotic initiation were explored using a random forest analysis. Results: Of the 342 patients studied, infections were diagnosed in 72 (21.6%), including 39 (11.7%) cases of pneumonia. Of them, 25 (7.5%) fulfilled mCDC criteria. Antibiotics were used in 92% of mCDC-SAP and 64.3% of OPn. In logistic regression analysis, mCDC-SAP, but not OPn, was an independent predictor of poor outcome [OR, 4.939 (1.022-23.868)]. The random forest analysis revealed that fever had the highest importance for antibiotic initiation. Interpretation: The mCDC criteria might be useful for detecting clinically relevant SAP, which is associated with poor outcomes. Isolated signs of infection were more important for antibiotic initiation than compliance with pre-defined criteria. Therefore, adherence to mCDC criteria might result in antibiotic saving without compromising clinical outcome.
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Background: Circadian variations in the timing of the onset of stroke symptoms have been described, showing a morning excess of cardiovascular risk. To date, no differences have been found between stroke subtype and time distribution throughout the day. The present study aims to compare the seasonal and circadian rhythm of symptoms onset in ischemic, hemorrhagic, and stroke mimic patients. Methods: This study was conducted prospectively at a hospital and involved a cohort of stroke alert patients from 2018 to 2021. Stroke subtypes were classified as ischemic stroke, intracerebral hemorrhage (ICH), transient ischemic attack (TIA), and stroke mimic. Clinical variables were recorded, and each patient was assigned to a 4-h interval of the day according to the time of onset of symptoms; unwitnessed stroke patients were analyzed separately. Seasonal changes in stroke distribution were analyzed at 3-month intervals. Results: A total of 2,348 patients were included in this analysis (ischemic 67%, ICH 13%, mimic 16%, and TIA 3%). Regardless of stroke subtype, most of the patients were distributed between 08-12 h and 12-16 h. Significant differences were found in the time distribution depending on stroke subtype, with ICH predominating in the 4-8 h period (dawn), most of which were hypertensive, TIA in the 12-16 h period (afternoon), and stroke mimic in the 20 h period (evening). The ischemic stroke was evenly distributed throughout the different periods of the day. There were no differences in the seasonal pattern between different stroke subtypes, with winter being the one that accumulated the most cases. Conclusion: The present study showed different circadian patterns of stroke subtypes, with a predominance of ICH at dawn and stroke mimic in the afternoon. The stroke circadian rhythm resembles previous studies, with a higher incidence in the morning and a second peak in the afternoon.
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Malignant psoas syndrome is a rare and under-recognised entity with a life expectancy of months. Its presentation is characterised by refractory back pain, which is a red flag that should raise suspicion about the condition. We present a case of a man who presented with refractory back pain and bilateral hydronephrosis without hydroureter who had no evident initial obstruction and showed stent-placement failure. Three months later, a recurrence of colorectal cancer associated with malignant psoas syndrome was diagnosed. We review the current literature on malignant psoas syndrome and hydronephrosis in relation to the presentation of cancer.
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Neoplasias Colorrectales , Hidronefrosis , Síndrome Neuroléptico Maligno , Dolor Intratable , Masculino , Humanos , Hidronefrosis/diagnóstico por imagen , Hidronefrosis/etiología , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/diagnóstico , Dolor de EspaldaRESUMEN
Neuroinflammation, in which activated microglia are involved, appears to contribute to the development of Parkinson's disease (PD). However, the role of microglial activation and the mechanisms governing this process remain uncertain. We focused on one inhibitory mechanism involved in the control of microglial activation, the microglia inhibitory receptor CD200R1, and its ligand CD200, mainly expressed by neurons. The human CD200R1 gene encodes two membrane-associated and two soluble protein isoforms and the human CD200 gene encodes full-length proteins (CD200full) but also truncated (CD200tr) proteins which act as CD200R1 antagonists. Little is known about their expression in the human brain under pathological conditions. We used human peripheral blood monocytes and monocyte-derived microglia-like cells from control subjects to characterize the expression of the CD200R1 mRNA variants, which showed stimulus-specific responses. We provide evidence of increased CD200R1 (mRNA variants and protein isoforms) and CD200 expression (CD200tr mRNA) in brain tissue of PD patients, mainly in the hippocampus, as well as increased CD200 expression (CD200full and CD200tr mRNAs) in iPSCs-derived dopaminergic neurons generated from skin fibroblasts of PD patients. Our results suggest that CD200-CD200R1 signalling is altered in PD, which may affect the microglial function and constitute a potential target in therapeutic strategies for PD.
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Aim: Mesoporous silica particles (MSPs) are broadly used drug delivery carriers. In this study, the authors analyzed the responses to MSPs of astrocytes and microglia, the two main cellular players in neuroinflammation. Materials & methods: Primary murine cortical mixed glial cultures were treated with rhodamine B-labeled MSPs. Results: MSPs are avidly internalized by microglial cells and remain inside the cells for at least 14 days. Despite this, MSPs do not affect glial cell viability or morphology, basal metabolic activity or oxidative stress. MSPs also do not affect mRNA levels of key proinflammatory genes; however, in combination with lipopolysaccharide, they significantly increase extracellular IL-1ß levels. Conclusion: These results suggest that MSPs could be novel tools for specific drug delivery to microglial cells.
Mesoporous silica particles (MSPs) are broadly used drug delivery carriers. In this study, the authors analyzed the responses of two types of brain cells, astrocytes and microglia, to MSPs. Mouse astrocytes and microglia were kept alive in cultures and were treated with MSPs that were labeled with a red fluorescent agent to facilitate visualization under the microscope. MSPs are avidly internalized by microglial cells and remain inside the cells for at least 14 days. Despite this, MSPs do not affect glial cell viability or morphology, basal metabolic activity or oxidative stress. When given alone, MSPs do not affect mRNA levels of key proinflammatory genes. However, MSPs given in combination with lipopolysaccharide, a strong proinflammatory agent, significantly increase extracellular levels of IL-1ß, one of the proinflammatory mediators studied. These results suggest that MSPs could be novel tools for specific drug delivery to microglial cells.
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Microglía , Dióxido de Silicio , Animales , Ratones , Dióxido de Silicio/metabolismo , Lipopolisacáridos/metabolismo , Astrocitos , ARN Mensajero , Células CultivadasRESUMEN
Exposure to pesticides such as rotenone is a risk factor for Parkinson's disease. Dopaminergic neurons are especially sensitive to the toxicity of compounds that inhibit the mitochondrial respiratory chain such as rotenone and 1-methyl-4-phenylpyridinium (MPP+). However, there is scarce information on their effects on glia. To evaluate whether these neurotoxicants affect the immune response of glia, primary mouse mixed glial and microglial cultures were treated with interleukin (IL) 4 in the absence and presence of MPP+ or rotenone. Using qRTPCR or western blot, we determined the expression of anti-inflammatory markers, the CD200R1 microglial receptor and its ligand CD200, and genes regulating glycolysis and oxidative metabolism. ATP and lactate levels were additionally determined as an index of cell metabolism. Microglial phagocytosis was also evaluated. MPP+ and rotenone clearly abrogated the IL4-induced expression of anti-inflammatory markers in mixed glial cultures. CD200 and CD200R1 expression and microglia phagocytosis were also affected by the neurotoxicants. Changes in the mRNA expression of the molecules regulating glycolysis and oxidative metabolism, as well as in ATP levels and lactate release suggested that metabolic reprogramming in response to MPP+ and rotenone differs between microglial and mixed glial cultures. These findings support the hypothesis that parkinsonian neurotoxicants may impair brain immune response altering glial cell metabolism.
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1-Metil-4-fenilpiridinio/toxicidad , Antígenos CD/metabolismo , Interleucina-4/metabolismo , Glicoproteínas de Membrana/metabolismo , Microglía/efectos de los fármacos , Plaguicidas/toxicidad , Adenosina Trifosfato/metabolismo , Animales , Células Cultivadas , Femenino , Ácido Láctico/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , FagocitosisRESUMEN
In the case of Parkinson's disease (PD), epidemiological studies have reported that pesticide exposure is a risk factor for its pathology. It has been suggested that some chemical agents, such as rotenone and paraquat, that inhibit the mitochondrial respiratory chain (in the same way as the PD mimetic toxin 1-methyl-4-phenylpyridinium, MPP+) are involved in the development of PD. However, although the neurotoxic effect of such compounds has been widely reported using in vivo and in vitro experimental approaches, their direct effect on the glial cells remains poorly characterized. In addition, the extent to which these toxins interfere with the immune response of the glial cells, is also underexplored. We used mouse primary mixed glial and microglial cultures to study the effect of MPP+ and rotenone on glial activation, in the absence and the presence of a pro-inflammatory stimulus (lipopolysaccharide plus interferon-γ, LPS+IFN-γ). We determined the mRNA expression of the effector molecules that participate in the inflammatory response (pro-inflammatory cytokines and enzymes), as well as the nitric oxide (NO) and cytokine production. We also studied the phagocytic activity of the microglial cells. In addition, we evaluated the metabolic changes associated with the observed effects, through the measurement of adenosine triphosphate (ATP) production and the expression of genes involved in the control of metabolic pathways. We observed that exposure of the glial cultures to the neurotoxins, especially rotenone, impaired the pro-inflammatory response induced by LPS/IFN-γ. MPP+ and rotenone also impaired the phagocytic activity of the microglial cells, and this effect was potentiated in the presence of LPS/IFN-γ. The deficit in ATP production that was detected, mainly in MPP+ and rotenone-treated mixed glial cultures, may be responsible for the effects observed. These results show that the response of glial cells to a pro-inflammatory challenge is altered in the presence of toxins inhibiting mitochondrial respiratory chain activity, suggesting that the glial immune response is impaired by such agents. This may have relevant consequences for brain function and the central nervous system's (CNS's) response to insults.
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Background and objectives The aim of this study was to assess the reliability and validity of the Bush Francis Catatonia Screening Instrument and Bush Francis Catatonia Rating Scale Spain Version (BFCSI-SV and BFCRS-SV) using the ICD-11 and DSM-5 diagnostic criteria as well as other catatonia scales. Methods One hundred patients were admitted to the inpatient psychiatry unit at Hospital Universitari Germans Trias I Pujol and two psychiatrists administered the BFCRS-SV to the first 10 patients to assess inter-rater reliability. The BFCRS-SV, BFCSI-SV, Modified Rogers Scale (MRS), Abnormal Involuntary Movement Scales, Barnes Akathisia Rating Scale, and Modified Simpson-Angus Scale were then employed. Results The results showed that 27% of patients had catatonia using the DSM-5 diagnostic criteria. Additionally, 51% of patients had 2 or more BFCRSI-SV items (Sensitivity: 100%; Specificity: 67.12%). The alpha coefficient values were 0.80 and 0.84 for the BFCSI-SV and BFCRS-SV, respectively, and the intraclass correlation coefficient values were 0.902 and 0.903. The area under the ROC curve was 0.971 and 0.96, and the instruments had a strong positive correlation with the DSM-5 score, ICD-11 score, and MRS. The study identified a three-factor model comprising the inhibition, excitement, and parakinetic dimensions. Conclusions Overall, the results suggest that the BFCSI-SV and BFCRS-SV are valid and reliable tools for the diagnosis of catatonia, especially when using a cut-off score of 5 or higher for the BFCSI-SV and 7 or higher for the BFCRS-SV. (AU)