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In neonates with hypoxic-ischemic encephalopathy (HIE), neuroprotection mediated by therapeutic hypothermia (TH) is the standard of care in developed nations; however TH may be not beneficial or contraindicated in developing world. Moreover, in most of the clinical trials, hypothermic neuroprotection was incomplete because many infants still die or suffer significant neurological sequelae. Therefore, finding innovative, neuroprotective compounds for this encephalopathy represents an important and urgent need. In reference to the recent review by Zhou , ACS Chem. Neurosci. 2023 14, 1-9, in this viewpoint, we discuss the therapeutic role of ketone bodies and thiamine in neonatal HIE, their possible synergistic effect, and how these micronutrients may provide additive neuroprotection to TH and improve safer and effective treatment strategies also helpful in low-middle-income countries.
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Hipotermia Inducida , Hipoxia-Isquemia Encefálica , Recién Nacido , Lactante , Humanos , Hipoxia-Isquemia Encefálica/terapia , Neuroprotección , Resultado del TratamientoRESUMEN
Alexander's disease (AxD) is a rare, usually relentlessly progressive disorder of astroglial cells in the central nervous system related to mutations in the gene encoding the type III intermediate filament protein, glial fibrillary acidic protein (GFAP). The pathophysiology of AxD is only partially understood. Available data indicate that an excessive GFAP gene expression may play a role. In particular, a "threshold hypothesis" has been reported, suggesting that mutant GFAP representing about 20% of the total cellular GFAP should be sufficient to cause disease. Thus, strategies based on reducing cellular mutant GFAP protein levels and/or activating biological processes involved in the correct protein folding could be effective in counteracting the toxic effect of misfolded GFAP. Considering that clomipramine (CLM), which has been selected by a wide small molecules screening as the greatest inhibitory potential drug against GFAP expression, is contraindicated because of its proconvulsant activity in the infantile form of AxD, which is also characterized by the occurrence of epileptic seizures, two powerful antiepileptic agents, carbamazepine (CBZ) and phenytoin (PHT), which share specific stereochemical features in common with CLM, were taken into consideration in a reliable in vitro model of AxD. In the present work, we document for the first time that CBZ and PHT have a definite inhibitory effect on pathological GFAP cellular expression and folding. Moreover, we confirm previous results of a similar beneficial effect of CLM. In addition, we have demonstrated that CBZ and CLM play a refolding effect on mutant GFAP proteins, likely ascribed at the induction of CRYAB expression, resulting in the decrease of mutant GFAP aggregates formation. As CBZ and PHT are currently approved for use in humans, their documented effects on pathological GFAP cellular expression and folding may indicate a potential therapeutic role as disease-modifying agents of these drugs in the clinical management of AxD, particularly in AxD patients with focal epilepsy with and without secondary generalization.
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Interleukin 2 (IL-2) is considered a key player in exacerbating multiple sclerosis (MS). Therapies targeting its receptor have been developed; however, a resolution of the disease and side effects are still an issue of concern. The involvement of other factors, such as Mycobacterium avium subspecies paratuberculosis (MAP) and envelope protein derived from human endogenous retrovirus type W (HERV-Wenv), in MS pathogenesis has been recently suggested. Here, we investigated the levels of antibodies (Abs) directed against IL-2 and HERV-Wenv in 108 MS patients, 34 patients affected by neuromyelitis optica spectrum disorder (NMOSD), and 137 healthy controls (HCs). Our results show increased levels of Abs specific to IL-2 and HERV-Wenv-su antigens in MS vs. HCs (p < 0.0001 for IL-2, p = 0.0004 for HERV-Wenv) and significantly decreased levels in NMOSD vs. MS. The assessment of different 12-month-long therapies on Abs against IL-2, HERV-Wenv, and MAP lipoarabinomannan (LAM) demonstrated the strongest effect on anti-LAM Abs (p = 0.018), a slight reduction of anti-IL-2 Abs, and small variations for anti-HERV-Wenv Abs. These results highlight the conclusion that the impact of therapy is more correlated with selected epitopes than with the therapeutic agent. Screening for anti-IL-2 and anti-HERV-Wenv Abs has a potential as additional future practice to distinguish between symptomatically similar MS and NMOSD.
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A point mutation (P56S) in the gene-encoding vesicle-associated membrane-protein-associated protein B (VAPB) leads to an autosomal-dominant form of amyotrophic lateral sclerosis (ALS), classified as ALS-8. The mutant VAPB is characterized by ER-associated aggregates that lead to a complete reorganization of ER structures. Growing evidences suggest VAPB involvement in ALS pathomechanisms. In fact, numerous studies demonstrated VAPB alteration also in sporadic ALS (sALS) and showed the presence of its aggregates when others ALS-related gene are mutant. Recently, the identification of new biomarkers in peripheral blood mononuclear cells (PBMCs) has been proposed as a good noninvasive option for studying ALS. Here, we evaluated VAPB as a possible ALS pathologic marker analyzing PBMCs of sALS patients. Immunofluorescence analysis (IFA) showed a peculiar pattern of VAPB aggregates in sALS, not evident in healthy control (HC) subjects and in Parkinson's disease (PD) PBMCs. This specific pattern led us to suppose that VAPB could be misfolded in sALS. The data indirectly confirmed by flow cytometry assay (FCA) showed a reduction of VAPB fluorescent signals in sALS. However, our observations were not associated with the presence of a genetic mutation or altered gene expression of VAPB. Our study brings further evidences of the VAPB role in ALS as a diagnostic biomarker.
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Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Retículo Endoplásmico/metabolismo , Agregado de Proteínas , Proteínas de Transporte Vesicular/metabolismo , Anciano , Biomarcadores/metabolismo , Femenino , Fibroblastos/metabolismo , Fluorescencia , Células HeLa , Humanos , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Modelos Biológicos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Piel/patología , Proteínas de Transporte Vesicular/genéticaRESUMEN
OBJECTIVE: To determine the diagnostic relevance of myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) in CSF of seronegative cases by retrospectively analyzing consecutive time-matched CSF of 80 MOG-Ab-seronegative patients with demyelinating disease. METHODS: The cohort included 44 patients with NMOSD and related disorders and 36 patients with multiple sclerosis (MS). Two independent neurologists blinded to diagnosis analyzed MOG-Abs by live cell-based immunofluorescence assay with goat anti-human immunoglobulin (Ig) G (whole molecule) antibody. Sera were tested at dilutions of 1:20 and 1:40, and a cutoff of 1:160 was considered for serum positivity. CSF specimens were tested undiluted and at 1:2 dilution with further titrations in case of positivity. Anti-IgG-Fc and anti-IgM-µ secondary antibodies were used to confirm the exclusive presence of MOG-IgG in positive cases. CSF of 13 MOG-Abs seropositive cases and 36 patients with neurodegenerative conditions was analyzed as controls. RESULTS: Three seronegative cases had CSF MOG-Abs (4% of the whole cohort or 7% of cases excluding patients with MS, in which MOG-Abs seem to lack diagnostic relevance). In particular, 2 patients with neuromyelitis optica spectrum disorder (NMOSD) and 1 with acute disseminated encephalomyelitis had MOG-Abs in CSF. Analysis with anti-IgG-Fc and anti-IgM confirmed the exclusive presence of MOG-IgG in the CSF of these patients. Among the control group, MOG-Abs were detectable in the CSF of 8 of 13 MOG-Ab-seropositive cases and in none of the patients with neurodegenerative disorders. CONCLUSION: Although serum is the optimal specimen for MOG-Ab testing, analyzing CSF could improve diagnostic sensitivity in seronegative patients. This observation has relevant diagnostic impact and might provide novel insight into the biological mechanisms of MOG-Ab synthesis.
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Acuaporina 4/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Esclerosis Múltiple/diagnóstico , Glicoproteína Mielina-Oligodendrócito/inmunología , Neuromielitis Óptica/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/inmunología , Neuromielitis Óptica/sangre , Neuromielitis Óptica/líquido cefalorraquídeo , Neuromielitis Óptica/inmunología , Estudios Retrospectivos , Adulto JovenAsunto(s)
Mano , Dolor de Cuello/diagnóstico , Enfermedad de Parkinson/diagnóstico , Temblor/diagnóstico , alfa-Sinucleína , Diagnóstico Diferencial , Mano/patología , Humanos , Masculino , Persona de Mediana Edad , Dolor de Cuello/etiología , Dolor de Cuello/genética , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/genética , Temblor/etiología , Temblor/genética , alfa-Sinucleína/genéticaAsunto(s)
Enfermedades Desmielinizantes/sangre , Enfermedades Desmielinizantes/diagnóstico , Esclerosis Múltiple/sangre , Esclerosis Múltiple/diagnóstico , Glicoproteína Mielina-Oligodendrócito/inmunología , Proteínas de Neurofilamentos/sangre , Adolescente , Adulto , Factores de Edad , Anciano , Anticuerpos/sangre , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Estudios de Casos y Controles , Niño , Enfermedades Desmielinizantes/líquido cefalorraquídeo , Enfermedades Desmielinizantes/inmunología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/inmunología , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Neuroimagen , Adulto JovenRESUMEN
Circulating and cerebrospinal fluid (CSF) neurofilament light chain (NfL) levels represent a reliable indicator of disease activity and axonal damage in different neuroinflammatory conditions. Recently, high CSF NfL levels have been detected in active autoimmune encephalitis, as opposed to significant lower levels after clinical improvement. The aim of the present study was to evaluate serum and CSF NfL concentration in patients with autoimmune encephalitis and to analyse the association between NfL levels and clinical, MRI, and CSF data. We retrospectively included 25 patients with neurological syndromes associated with autoantibodies to neuronal cell surface antigens and we collected clinical, MRI, CSF, and follow-up data. Using an ultrasensitive method (Simoa, Quanterix), we measured NfL levels in serum and CSF samples of all patients and in 25 sera of healthy controls. Serum NfL levels were higher in all cases, including 20 patients with inflammatory MRI/CSF features and 5 non-inflammatory cases (median 16.9 pg/ml, range 4.5-90) than in controls (median 6.9 pg/ml, range 2.7-12.8; p < 0.001). A correlation between serum and CSF NfL levels was found (r = 0.461, p = 0.023), whereas no significant association was observed between NfL levels and clinical, MRI/CSF inflammatory burden, and antibody type. In the 13 available follow-up samples, correlation between disease activity and NfL values was also observed. In conclusion, NfL levels are significantly increased in the serum of patients with antibody-mediated encephalitis, independently of the MRI/CSF inflammatory profile. These findings support the presence of ongoing axonal damage and suggest the co-occurrence of different mechanisms for neuronal/axonal involvement in antibody-associated CNS syndromes.
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Encefalitis/sangre , Encefalitis/líquido cefalorraquídeo , Enfermedad de Hashimoto/sangre , Enfermedad de Hashimoto/líquido cefalorraquídeo , Proteínas de Neurofilamentos/sangre , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Niño , Preescolar , Encefalitis/diagnóstico por imagen , Femenino , Estudios de Seguimiento , Enfermedad de Hashimoto/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Transcutaneous trigeminal nerve stimulation (TNS) has antiepileptic effects in patients with drug-resistant epilepsy (DRE). However, whether and how TNS is able to modulate the electroencephalogram (EEG) background activity in patients with DRE is still unknown. OBJECTIVES: To investigate the effect of short-term TNS on EEG background activity in DRE by qualitative and quantitative analyses. METHODS: Twenty-nine DRE patients participated in the study. Twenty-two were randomly divided into a "sham-TNS" or "real-TNS" group; seven patients underwent stimulation of the median nerve (MNS) at the wrist. Real-TNS was delivered bilaterally to the infraorbital nerve (trains of 1-20â¯mA, 120â¯Hz, cyclic modality for 20â¯min). The sham-TNS protocol mimicked the real-TNS one but at a zero intensity. For MNS, the same parameters as real-TNS were used. EEG was continuously acquired for 40â¯min: 10' pre, 20' during and 10' post stimulation. EEG was visually inspected for interictal epileptiform discharge (IEDs) changes and processed by spectral analysis for changes in mean frequency and absolute power of each frequency band. RESULTS: A significant increase of EEG absolute alpha power was observed during real-TNS compared with the sham-TNS (F34,680â¯=â¯1.748; pâ¯=â¯0.006). Conversely, no significant effects were noticed either for quantitative analysis of other frequency bands or for IEDs detection. MNS proved unable to modulate EEG activity. CONCLUSIONS: Short-term TNS induces an acute and specific effect on background EEG of DRE by increasing the absolute alpha band power. EEG alpha rhythm enhancement may index a cortical functional inhibition and act as a seizure-preventing mechanism.
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Epilepsia Refractaria/fisiopatología , Epilepsia Refractaria/terapia , Electroencefalografía/métodos , Estimulación Eléctrica Transcutánea del Nervio/métodos , Nervio Trigémino/fisiología , Adulto , Anciano , Epilepsia Refractaria/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Parkinson's disease is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons of the substantia nigra pars compacta with a reduction of dopamine concentration in the striatum. The complex interaction between genetic and environmental factors seems to play a role in determining susceptibility to PD and may explain the heterogeneity observed in clinical presentations. The exact etiology is not yet clear, but different possible causes have been identified. Inflammation has been increasingly studied as part of the pathophysiology of neurodegenerative diseases, corroborating the hypothesis that the immune system may be the nexus between environmental and genetic factors, and the abnormal immune function can lead to disease. In this review we report the different aspects of inflammation and immune system in Parkinson's disease, with particular interest in the possible role played by immune dysfunctions in PD, with focus on autoimmunity and processes involving infectious agents as a trigger and alpha-synuclein protein (α-syn).
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Mycobacterium avium ssp. paratuberculosis (Map) is the etiological agent of Paratuberculosis in ruminants. Protein tyrosine phosphatase A (PtpA) and protein kinase G (PknG) are secreted proteins necessary for the survival of the pathogen within macrophages. In this study we analyzed if Map was able to grow within astrocytes and investigated on the presence of antibodies against PtpA and PknG proteins in MS and NMOSD patients by ELISA. Map was unable to proliferate in astrocytes after of 72â¯h post-infection, but we observed a high level of antibodies against both virulence factors, suggesting that these patients have been exposed/infected with Map.
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Anticuerpos Antibacterianos/sangre , Proteínas Bacterianas/sangre , Esclerosis Múltiple/sangre , Mycobacterium avium subsp. paratuberculosis/metabolismo , Neuromielitis Óptica/sangre , Proteínas Serina-Treonina Quinasas/sangre , Proteínas Tirosina Fosfatasas/sangre , Adulto , Astrocitos/metabolismo , Astrocitos/microbiología , Células Cultivadas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/microbiología , Neuromielitis Óptica/microbiologíaRESUMEN
The data article presents the results obtained from fluorescence and synchrotron radiation circular dichroism spectroscopies about the lysozyme-ceftriaxone interaction at neutral and acidic pH values as well as the computational calculations described in the accompanying research article (Ruzza et al., sub) [1].
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Epstein-Barr virus (EBV) is the main environmental agent associated to neuromyelitis optica spectrum disorder (NMOSD). Following to studies reporting an increased prevalence of antibodies against peptides derived from Mycobacterium avium subsp. paratuberculosis (MAP) homologous to EBV and human epitopes (MBP85-98, IRF5424-434) in multiple sclerosis (MS), we investigated whether seroreactivity to these antigens display a NMOSD-specific pattern. The sera of 34 NMOSD patients showed elevated levels of antibodies against MAP and MBP compared to healthy controls (44% vs. 5%, pâ¯<â¯0.0002 and 50% vs. 2%, pâ¯<â¯0.0001, respectively), while, unlike in MS, responsiveness to EBV was similar.
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Anticuerpos Antibacterianos/inmunología , Autoanticuerpos/inmunología , Mycobacterium avium subsp. paratuberculosis/inmunología , Proteína Básica de Mielina/inmunología , Neuromielitis Óptica/inmunología , Adulto , Antígenos Bacterianos/inmunología , Autoantígenos/inmunología , Epítopos/inmunología , Femenino , Humanos , Factores Reguladores del Interferón/inmunología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Lysozyme is a widely distributed enzyme present in a variety of tissue and body fluids. Human and hen egg white lysozyme are used as validated model to study protein folding and stability and to understand protein misfolding and aggregation. We recently found that ceftriaxone, a ß-lactam antibiotic able to overcome the blood-brain barrier, successfully eliminated the cellular toxic effects of misfolded proteins as Glial Fibrillary Acidic Protein (GFAP) and α-synuclein. To further understand the anti-amyloidogenic properties of ceftriaxone, we studied its activity towards lysozyme aggregation with the aim to investigate a possible chaperone-like activity of this molecule. METHODS: Here we present the results obtained from fluorescence and synchrotron radiation circular dichroism spectroscopies and from molecular docking and molecular dynamics about the lysozyme-ceftriaxone interaction at neutral and acidic pH values. RESULTS: We found that ceftriaxone exhibits comparable affinity constants to lysozyme in both experimental pH conditions and that its addition enhanced lysozyme stability reducing its aggregation propensity in acidic conditions. Computational methods allowed the identification of the putative binding site of ceftriaxone, thus rationalizing the spectroscopic results. CONCLUSIONS: Spectroscopy data and molecular dynamics indicated a protective effect of ceftriaxone on pathological aggregation phenomena suggesting a chaperone-like effect of this molecule on protein folding. General significance These results, in addition to our previous studies on α-synuclein and GFAP, confirm the property of ceftriaxone to inhibit the pathological protein aggregation of lysozyme also by a chaperone-like mechanism, extending the potential therapeutic application of this molecule to some forms of human hereditary systemic amyloidosis.
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Ceftriaxona/química , Chaperonas Moleculares , Muramidasa/química , Muramidasa/metabolismo , Multimerización de Proteína , Animales , Sitios de Unión , Ceftriaxona/administración & dosificación , Biología Computacional , Humanos , Concentración de Iones de Hidrógeno , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Unión Proteica , Conformación Proteica , Pliegue de ProteínaRESUMEN
Brain abnormalities in neuromyelitis optica spectrum disorder (NMOSD) are highly heterogeneous and often non-specific. Extensive white matter involvement has been described and frequently manifests with encephalopathy requiring prompt intervention. Rarely, this may represent the only manifestation at onset without concurrent suggestive features of the disease, thus making diagnosis challenging. NMOSD may potentially occur at any age, but it seems that this disorder has distinctive clinical features in the elderly. We describe a case of NMOSD presenting as rapidly progressive leukoencephalopathy with atypical clinical and magnetic resonance imaging (MRI) findings in a 69-year-old woman.
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Leucoencefalopatías/diagnóstico por imagen , Neuromielitis Óptica/diagnóstico por imagen , Neuromielitis Óptica/inmunología , Anciano , Acuaporina 4/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Diagnóstico Diferencial , Progresión de la Enfermedad , Femenino , Humanos , Factores Inmunológicos/uso terapéutico , Leucoencefalopatías/patología , Imagen por Resonancia Magnética , Neuromielitis Óptica/tratamiento farmacológico , Neuromielitis Óptica/patología , Intercambio Plasmático , Rituximab/uso terapéutico , Lóbulo Temporal/diagnóstico por imagen , Lóbulo Temporal/patología , Resultado del Tratamiento , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patologíaAsunto(s)
Enfermedad de Fabry , Corteza Motora , Mapeo Encefálico , Humanos , Imagen por Resonancia Magnética , DescansoRESUMEN
Anti-myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) recently emerged as a potential biomarker in patients with inflammatory demyelinating diseases of the central nervous system. We here compare the clinical and laboratory findings observed in a cohort of MOG-Ab seropositive and seronegative cases and describe IgG subclass analysis results. Consecutive serum samples referred to Verona University Neuropathology Laboratory for aquaporin-4 (AQP4)-Ab and/or MOG-Ab testing were analysed between March 2014 and May 2017. The presence of AQP4-Ab was determined using a cell-based assay. A live cell immunofluorescence assay was used for the detection of MOG-IgG and IgG subclass analysis. Among 454 analysed samples, 29 were excluded due to AQP4-Ab positivity or to the final demonstration of a disorder not compatible with MOG-Ab. We obtained clinical data in 154 out of 425 cases. Of these, 22 subjects resulted MOG-Ab positive. MOG-Ab positive patients were mainly characterised by the involvement of the optic nerve and/or spinal cord. Half of the cases presented relapses and the recovery was usually partial. Brain MRI was heterogeneous while short lesions were the prevalent observation on spinal cord MRI. MOG-Ab titre usually decreased in non-relapsing cases. In all MOG-IgG positive cases, we observed IgG1 antibodies, which were predominant in most subjects. IgG2 (5/22), IgG3 (9/22) and IgG4 (3/22) antibodies were also detectable. We confirm that MOG-Ab-related syndromes have distinct features in the spectrum of demyelinating conditions, and we describe the possible role of the different IgG subclasses in this condition.
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Enfermedades Autoinmunes Desmielinizantes SNC/sangre , Inmunoglobulina G/sangre , Inmunoglobulina G/clasificación , Glicoproteína Mielina-Oligodendrócito/inmunología , Adulto , Encéfalo/diagnóstico por imagen , Estudios de Cohortes , Enfermedades Autoinmunes Desmielinizantes SNC/diagnóstico por imagen , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Italia , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Médula Espinal/diagnóstico por imagen , Adulto JovenRESUMEN
Natalizumab is effective against multiple sclerosis (MS), but is associated with progressive multifocal leukoencephalopathy (PML), fatal disease caused by the JCV polyomavirus. The SF2/ASF (splicing factor2/alternative splicing factor) inhibits JCV in glial cells. We wondered about SF2/ASF modulation in the blood of natalizumab-treated patients and if this could influence JCV reactivation. Therefore, we performed a longitudinal study of MS patients under natalizumab, in comparison to patients under fingolimod and to healthy blood donors. Blood samples were collected at time intervals. The expression of SF2/ASF and the presence and expression of JCV in PBMC were analyzed. A bell-shaped regulation of SF2/ASF was observed in patients treated with natalizumab, increased in the first year of therapy, and reduced in the second one, while slightly changed, if any, in patients under fingolimod. Notably, SF2/ASF was up-regulated, during the first year, only in JCV DNA-positive patients, or with high anti-JCV antibody response; the expression of the JCV T-Ag protein in circulating B cells was inversely related to SF2/ASF protein expression. The SF2/ASF reduction, parallel to JCV activation, during the second year of therapy with natalizumab, but not with fingolimod, may help explain the increased risk of PML after the second year of treatment with natalizumab, but not with fingolimod. We propose that SF2/ASF has a protective role against JCV reactivation in MS patients. This study suggests new markers of disease behavior and, possibly, help in re-evaluations of therapy protocols.
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Interacciones Huésped-Patógeno , Factores Inmunológicos/uso terapéutico , Leucoencefalopatía Multifocal Progresiva/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Natalizumab/uso terapéutico , Factores de Empalme Serina-Arginina/genética , Adulto , Anticuerpos Antivirales/sangre , Relación Dosis-Respuesta a Droga , Femenino , Clorhidrato de Fingolimod/uso terapéutico , Regulación de la Expresión Génica , Humanos , Virus JC/efectos de los fármacos , Virus JC/genética , Virus JC/crecimiento & desarrollo , Leucoencefalopatía Multifocal Progresiva/inmunología , Leucoencefalopatía Multifocal Progresiva/virología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple Recurrente-Remitente/virología , Neuroglía/efectos de los fármacos , Neuroglía/inmunología , Neuroglía/virología , Factores de Empalme Serina-Arginina/inmunología , Transducción de Señal , Activación Viral/efectos de los fármacosRESUMEN
BACKGROUND: Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disease, caused by defects of the alpha-galactosidase A (GLA) gene. AFD can affect the heart, brain, kidney, eye, skin, peripheral nerves, and gastrointestinal tract. Cardiology (hypertrophic cardiomyopathy), neurology (cryptogenic stroke), and nephrology (end-stage renal failure) screening studies suggest the prevalence of GLA variants is 0.62%, with diagnosis confirmation in 0.12%. OBJECTIVES: This study sought to expand screening from these settings to include ophthalmology, dermatology, gastroenterology, internal medicine, pediatrics, and medical genetics to increase diagnostic yield and comprehensively evaluate organ involvement in AFD patients. METHODS: In a 10-year prospective multidisciplinary, multicenter study, we expanded clinical, genetic, and biochemical screening to consecutive patients enrolled from all aforementioned clinical settings. We tested the GLA gene and α-galactosidase A activity in plasma and leukocytes. Inclusion criteria comprised phenotypical traits and absence of male-to-male transmission. Screening was extended to relatives of probands harboring GLA mutations. RESULTS: Of 2,034 probands fulfilling inclusion criteria, 37 (1.8%) were carriers of GLA mutations. Cascade family screening identified 60 affected relatives; clinical data were available for 4 affected obligate carriers. Activity of α-galactosidase A in plasma and leukocytes was diagnostic in male subjects, but not in female subjects. Of the 101 family members harboring mutations, 86 were affected, 10 were young healthy carriers, and 5 refused clinical evaluation. In the 86 patients, involved organs or organ systems included the heart (69%), peripheral nerves (46%), kidney (45%), eye (37%), brain (34%), skin (32%), gastrointestinal tract (31%), and auditory system (19%). Globotriaosylceramide accumulated in organ-specific and non-organ-specific cells in atypical and classic variants, respectively. CONCLUSIONS: Screening probands with clinically suspected AFD significantly increased diagnostic yield. The heart was the organ most commonly involved, independent of the clinical setting in which the patient was first evaluated.