ABSTRACT
Fingolimod is an immunomodulatory sphingosine-1-phosphate (S1P) analogue approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). The identification of biomarkers of clinical responses to fingolimod is a major necessity in MS to identify optimal responders and avoid the risk of disease progression in non-responders. With this aim, we used RNA sequencing to study the transcriptomic changes induced by fingolimod in peripheral blood mononuclear cells of MS-treated patients and their association with clinical response. Samples were obtained from 10 RRMS patients (five responders and five non-responders) at baseline and at 12 months of fingolimod therapy. Fingolimod exerted a vast impact at the transcriptional level, identifying 7155 differentially expressed genes (DEGs) compared to baseline that affected the regulation of numerous signaling pathways. These DEGs were predominantly immune related, including genes associated with S1P metabolism, cytokines, lymphocyte trafficking, master transcription factors of lymphocyte functions and the NF-kB pathway. Responder and non-responder patients exhibited a differential transcriptomic regulation during treatment, with responders presenting a higher number of DEGs (6405) compared to non-responders (2653). The S1P, NF-kB and TCR signaling pathways were differentially modulated in responder and non-responder patients. These transcriptomic differences offer the potential of being exploited as biomarkers of a clinical response to fingolimod.
Subject(s)
Lysophospholipids , Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Sphingosine/analogs & derivatives , Humans , Fingolimod Hydrochloride/pharmacology , Fingolimod Hydrochloride/therapeutic use , Multiple Sclerosis/drug therapy , Multiple Sclerosis/genetics , Immunosuppressive Agents/adverse effects , Leukocytes, Mononuclear , NF-kappa B , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Multiple Sclerosis, Relapsing-Remitting/genetics , Gene Expression Profiling , BiomarkersABSTRACT
Background and objective: Dimethyl fumarate (DMF) is an immunomodulatory drug approved for the therapy of multiple sclerosis (MS). The identification of response biomarkers to DMF is a necessity in the clinical practice. With this aim, we studied the immunophenotypic and transcriptomic changes produced by DMF in peripheral blood mononuclear cells (PBMCs) and its association with clinical response. Material and methods: PBMCs were obtained from 22 RRMS patients at baseline and 12 months of DMF treatment. Lymphocyte and monocyte subsets, and gene expression were assessed by flow cytometry and next-generation RNA sequencing, respectively. Clinical response was evaluated using the composite measure "no evidence of disease activity" NEDA-3 or "evidence of disease activity" EDA-3 at 2 years, classifying patients into responders (n=15) or non-responders (n=7), respectively. Results: In the whole cohort, DMF produced a decrease in effector (TEM) and central (TCM) memory T cells in both the CD4+ and CD8+ compartments, followed by an increase in CD4+ naïve T cells. Responder patients presented a greater decrease in TEM lymphocytes. In addition, responder patients showed an increase in NK cells and were resistant to the decrease in the intermediate monocytes shown by non-responders. Responder patients also presented differences in 3 subpopulations (NK bright, NK dim and CD8 TCM) at baseline and 4 subpopulations (intermediate monocytes, regulatory T cells, CD4 TCM and CD4 TEMRA) at 12 months. DMF induced a mild transcriptional effect, with only 328 differentially expressed genes (DEGs) after 12 months of treatment. The overall effect was a downregulation of pro-inflammatory genes, chemokines, and activators of the NF-kB pathway. At baseline, no DEGs were found between responders and non-responders. During DMF treatment a differential transcriptomic response was observed, with responders presenting a higher number of DEGs (902 genes) compared to non-responders (189 genes). Conclusions: Responder patients to DMF exhibit differences in monocyte and lymphocyte subpopulations and a distinguishable transcriptomic response compared to non-responders that should be further studied for the validation of biomarkers of treatment response to DMF.
Subject(s)
Dimethyl Fumarate , Multiple Sclerosis , Humans , Dimethyl Fumarate/therapeutic use , Immunosuppressive Agents/therapeutic use , Leukocytes, Mononuclear , Killer Cells, Natural , BiomarkersABSTRACT
BACKGROUND: Ischaemic stroke may be a major complication of SARS-CoV-2 infection.Studying and characterising the different aetiological subtypes, clinical characteristics, and functional outcomes may be valuable in guiding patient selection for optimal management and treatment. METHODS: Data were collected retrospectively on consecutive patients with COVID-19 who developed acute focal brain ischaemia (between 1 March and 19 April 2020) at a tertiary university hospital in Madrid (Spain). RESULTS: During the study period, 1594 patients were diagnosed with COVID-19. We found 22 patients with ischaemic stroke (1.38%), 6 of whom did not meet the inclusion criteria. The remaining 16 patients were included in the study (15 cases of ischaemic stroke and one case of transient ischaemic attack).Median baseline National Institutes of Health Stroke Scale score was 9 (interquartile range: 16), and mean (standard deviation) age was 73 years (12.8). Twelve patients (75%) were men. Mean time from COVID-19 symptom onset to stroke onset was 13 days. Large vessel occlusion was identified in 12 patients (75%).We detected elevated levels of D-dimer in 87.5% of patients and C-reactive protein in 81.2%. The main aetiology was atherothrombotic stroke (9 patients, 56.3%), with the predominant subtype being endoluminal thrombus (5 patients, 31.2%), involving the internal carotid artery in 4 cases and the aortic arch in one. The mortality rate in our series was 44% (7 of 16 patients). CONCLUSIONS: In patients with COVID-19, the most frequent stroke aetiology was atherothrombosis, with a high proportion of endoluminal thrombus (31.2% of patients). Our clinical and laboratory data support COVID-19-associated coagulopathy as a relevant pathophysiological mechanism for ischaemic stroke in these patients.
ABSTRACT
BACKGROUND: Sialodochitis fibrinosa is a rare disease which is characterized by recurring episodes of pain and swelling of the salivary glands due to the formation of mucofibrinous plugs. Analytic studies ascertain elevated levels of eosinophils and immunoglobulin E (IgE). Imaging studies such as magnetic resonance imaging (MRI) and sialography reveal dilation of the main salivary duct (duct ectasia). Treatment is initially supportive, consisting of compressive massages, and use of antihistamines and/or corticosteroids. MATERIAL AND METHODS: In the following, 3 cases of sialodochitis fibrinosa are presented which were diagnosed in a third level hospital during the period of 2008 and 2016, as well as a literature review of all cases reported to our knowledge. RESULTS: Of the 41 cases found, including the 3 of this article, 66% were women with an average age of 45 years old. However, 75% of reported cases were of Japanese heritage. Involvement of the parotid glands was more frequent than the submandibular glands. In more than half of all cases treatment with compressive massages, antihistamines and/or corticosteroids was effective. CONCLUSION: Clinicians should consider sialodochitis fibrinosa as a diagnostic possibility when presented with cases of recurring parotid and submandibular gland tumescence.
Subject(s)
Magnetic Resonance Imaging/methods , Submandibular Gland Diseases/diagnosis , Submandibular Gland/diagnostic imaging , Adult , Diagnosis, Differential , Female , Fibrosis/diagnosis , Humans , Middle Aged , Recurrence , SialographyABSTRACT
No disponible
Subject(s)
Humans , Male , Middle Aged , Hearing Loss, Sensorineural/diagnosis , Hemosiderosis/diagnosis , Neurotoxicity Syndromes/diagnosis , Magnetic Resonance SpectroscopyABSTRACT
No disponible
Subject(s)
Adult , Female , Humans , Male , Optic Neuropathy, Ischemic/diagnosis , Optic Neuritis/diagnosis , Magnetic Resonance Spectroscopy , Tomography, X-Ray Computed , Diagnosis, DifferentialABSTRACT
Las lesiones quísticas del triángulo posterior forman una entidad patológica cuyo diagnóstico se realiza en los 2 primeros años de vida. Su presentación en la edad adulta es un hallazgo ocasional y su diagnóstico diferencial incluye el linfangioma quístico, las metástasis linfáticas del cáncer de tiroides y el quiste branquial. Con frecuencia, ante el hallazgo de una tumoración cervical se realiza PAAF previa a la imagen diagnóstica, sin embargo, este procedimiento no siempre es el aconsejable. Hemos revisado los casos de pacientes que acudieron en este último año a nuestro servicio con lesiones en esta localización correlacionando los hallazgos de imagen con los resultados anatomopatológicos. Mostramos los hallazgos de imagen característicos de estas entidades con el fin de realizar un diagnóstico precoz que permita el abordaje y tratamiento adecuado del paciente adulto con una lesión quística en el triángulo cervical posterior (AU)
Cystic lesions of the posterior triangle are a pathologic entity whose diagnosis is made in the first two years of life. Its presentation in adulthood is an incidental finding and the differential diagnosis includes cystic lymphangioma, lymphatic metastasis of thyroid cancer and branchial cyst. Often with the finding of a cervical lump, FNA is made before diagnostic imaging is performed, however, this procedure is not always advisable. We reviewed the cases of patients who came last year to our department with a cystic mass in this location and correlating the imaging findings with pathologic specimen. We show characteristic findings of these lesions in order to make an early diagnosis and thus to get the approach and treatment appropriate of adult patients with a cystic lesion in the posterior cervical triangle (AU)
Subject(s)
Humans , Male , Female , Cysts , Lymphangioma , Head and Neck Neoplasms , Thyroid Neoplasms/pathology , Branchioma , Carcinoma, Papillary , Cysts/pathology , Neck/pathology , Branchioma/pathology , Retrospective Studies , Tomography, X-Ray ComputedABSTRACT
No disponible
Subject(s)
Humans , Male , Aged , Facial Paralysis/etiology , Bone Neoplasms/complications , Bone Neoplasms/secondary , Neoplasm Metastasis/drug therapy , Urinary Bladder Neoplasms/pathology , Temporal Bone/pathology , Tomography, X-Ray ComputedSubject(s)
Hearing Loss, Sensorineural/etiology , Hemosiderosis/complications , Postoperative Complications/etiology , Cervical Vertebrae/surgery , Disease Progression , Hemosiderin/analysis , Hemosiderosis/diagnostic imaging , Humans , Laminectomy , Magnetic Resonance Imaging , Male , Middle Aged , Pia Mater/chemistry , Postoperative Hemorrhage/complications , Subarachnoid Space , Vestibular Nerve/chemistryABSTRACT
Cystic lesions of the posterior triangle are a pathologic entity whose diagnosis is made in the first two years of life. Its presentation in adulthood is an incidental finding and the differential diagnosis includes cystic lymphangioma, lymphatic metastasis of thyroid cancer and branchial cyst. Often with the finding of a cervical lump, FNA is made before diagnostic imaging is performed, however, this procedure is not always advisable. We reviewed the cases of patients who came last year to our department with a cystic mass in this location and correlating the imaging findings with pathologic specimen. We show characteristic findings of these lesions in order to make an early diagnosis and thus to get the approach and treatment appropriate of adult patients with a cystic lesion in the posterior cervical triangle.
