Relevance of Porcine Stroke Models to Bridge the Gap from Pre-Clinical Findings to Clinical Implementation

Altres ajuts: This research is supported by grants from the Fondo de Investigaciones Sanitarias-Instituto de Salud Carlos III (ISCIII) to A.D. that was susceptible to be co-financed by FEDER funds, and a grant from Agència de Gestió d'Ajuts Universitaris i de Recerca to A.D. and to T.G. The group has received funding from "la Caixa Foundation" CI15-00009, from the European Institute of Innovation and Technology (EIT), which receives support from the European Union's Horizon 2020 research and innovation programme, from the Fundación para la Innovación y la Prospectiva en Salud en España (FIPSE) program 3594-18. M.M.-S. is a recipient of a PFIS contract FI19/00174.In the search of animal stroke models providing translational advantages for biomedical research, pigs are large mammals with interesting brain characteristics and wide social acceptance. Compared to rodents, pigs have human-like highly gyrencephalic brains. In addition, increasingly through phylogeny, animals have more sophisticated white matter connectivity; thus, ratios of white-to-gray matter in humans and pigs are higher than in rodents. Swine models provide the opportunity to study the effect of stroke with emphasis on white matter damage and neuroanatomical changes in connectivity, and their pathophysiological correlate. In addition, the subarachnoid space surrounding the swine brain resembles that of humans. This allows the accumulation of blood and clots in subarachnoid hemorrhage models mimicking the clinical condition. The clot accumulation has been reported to mediate pathological mechanisms known to contribute to infarct progression and final damage in stroke patients. Importantly, swine allows trustworthy tracking of brain damage evolution using the same non-invasive multimodal imaging sequences used in the clinical practice. Moreover, several models of comorbidities and pathologies usually found in stroke patients have recently been established in swine. We review here ischemic and hemorrhagic stroke models reported so far in pigs. The advantages and limitations of each model are also discussed

Current Incidence and risk factors of fecal incontinence after acute stroke affecting functionally independent people

Background: Previously published retrospective series show a high prevalence of fecal incontinence (FI) in stroke patients. We aimed to analyze in a prospective series the current incidence of FI in acute stroke in functionally independent patients and its evolution over time and the patient characteristics associated with the appearance of FI in acute stroke. Methods: We included consecutive patients with acute stroke admitted in our stroke unit who fulfilled the following inclusion criteria: a first episode of stroke, aged >18 years, with no previous functional dependency [modified Rankin Scale (mRS) = 2] and without previous known FI. FI was assessed by a multidisciplinary trained team using dedicated questionnaires at 72 ± 24 h (acute phase) and at 90 ± 15 days (chronic phase). Demographic, medical history, clinical and stroke features, mortality, and mRS at 7 days were collected. Results: Three hundred fifty-nine (48.3%) of 749 patients (mean age 65.9 ± 10, 64% male, 84.1% ischemic) fulfilled the inclusion criteria and were prospectively included during a 20-month period. FI was identified in 23 patients (6.4%) at 72 ± 24 h and in 7 (1.9%) at 90 days ± 15 days after stroke onset. FI was more frequent in hemorrhagic strokes (18 vs. 5%, p 0.007) and in more severe strokes [median National Institute of Health Stroke Scale (NIHSS) 18 (14–22) vs. 5 (3–13), p < 0.0001]. No differences were found regarding age, sex, vascular risk factors, or other comorbidities, or affected hemisphere. Patients with NIHSS =12 (AUC 0.81, 95% CI 0.71 to 0.89) had a 17-fold increase for the risk of FI (OR 16.9, IC 95% 4.7–60.1) adjusted for covariates.Peer ReviewedPostprint (published version

Immunophenotype and Transcriptome Profile of Patients With Multiple Sclerosis Treated With Fingolimod: Setting Up a Model for Prediction of Response in a 2-Year Translational Study

BackgroundFingolimod is a functional sphingosine-1-phosphate antagonist approved for the treatment of multiple sclerosis (MS). Fingolimod affects lymphocyte subpopulations and regulates gene expression in the lymphocyte transcriptome. Translational studies are necessary to identify cellular and molecular biomarkers that might be used to predict the clinical response to the drug. In MS patients, we aimed to clarify the differential effects of fingolimod on T, B, and natural killer (NK) cell subsets and to identify differentially expressed genes in responders and non-responders (NRs) to treatment.Materials and methodsSamples were obtained from relapsing–remitting multiple sclerosis patients before and 6 months after starting fingolimod. Forty-eight lymphocyte subpopulations were measured by flow cytometry based on surface and intracellular marker analysis. Transcriptome sequencing by next-generation technologies was used to define the gene expression profiling in lymphocytes at the same time points. NEDA-3 (no evidence of disease activity) and NEDA-4 scores were measured for all patients at 1 and 2 years after beginning fingolimod treatment to investigate an association with cellular and molecular characteristics.ResultsFingolimod affects practically all lymphocyte subpopulations and exerts a strong effect on genetic transcription switching toward an anti-inflammatory and antioxidant response. Fingolimod induces a differential effect in lymphocyte subpopulations after 6 months of treatment in responder and NR patients. Patients who achieved a good response to the drug compared to NR patients exhibited higher percentages of NK bright cells and plasmablasts, higher levels of FOXP3, glucose phosphate isomerase, lower levels of FCRL1, and lower Expanded Disability Status Scale at baseline. The combination of these possible markers enabled us to build a probabilistic linear model to predict the clinical response to fingolimod.ConclusionMS patients responsive to fingolimod exhibit a recognizable distribution of lymphocyte subpopulations and a different pretreatment gene expression signature that might be useful as a biomarker

Responsabilidad social empresarial : decisiones, reflexiones y casos de estudio

Esta obra es resultado del esfuerzo conjunto realizado por miembros de la Asociación Latinoamericana de Casos (ALAC), el Centro Internacional de Casos del Tecnológico de Monterrey (México) y la Universidad del Norte (Colombia). Contiene una selección de trabajos que versan sobre la problemática de la responsabilidad social empresarial en América Latina, la visión de la cultura y el devenir histórico acerca de este tema y una serie de casos que, sin lugar a dudas, se constituyen en un aporte significativo a los procesos de enseñanza-aprendizaje respecto a la ética empresarial y la responsabilidad social

Relevance of Porcine Stroke Models to Bridge the Gap from Pre-Clinical Findings to Clinical Implementation

Altres ajuts: This research is supported by grants from the Fondo de Investigaciones Sanitarias-Instituto de Salud Carlos III (ISCIII) to A.D. that was susceptible to be co-financed by FEDER funds, and a grant from Agència de Gestió d'Ajuts Universitaris i de Recerca to A.D. and to T.G. The group has received funding from "la Caixa Foundation" CI15-00009, from the European Institute of Innovation and Technology (EIT), which receives support from the European Union's Horizon 2020 research and innovation programme, from the Fundación para la Innovación y la Prospectiva en Salud en España (FIPSE) program 3594-18. M.M.-S. is a recipient of a PFIS contract FI19/00174.In the search of animal stroke models providing translational advantages for biomedical research, pigs are large mammals with interesting brain characteristics and wide social acceptance. Compared to rodents, pigs have human-like highly gyrencephalic brains. In addition, increasingly through phylogeny, animals have more sophisticated white matter connectivity; thus, ratios of white-to-gray matter in humans and pigs are higher than in rodents. Swine models provide the opportunity to study the effect of stroke with emphasis on white matter damage and neuroanatomical changes in connectivity, and their pathophysiological correlate. In addition, the subarachnoid space surrounding the swine brain resembles that of humans. This allows the accumulation of blood and clots in subarachnoid hemorrhage models mimicking the clinical condition. The clot accumulation has been reported to mediate pathological mechanisms known to contribute to infarct progression and final damage in stroke patients. Importantly, swine allows trustworthy tracking of brain damage evolution using the same non-invasive multimodal imaging sequences used in the clinical practice. Moreover, several models of comorbidities and pathologies usually found in stroke patients have recently been established in swine. We review here ischemic and hemorrhagic stroke models reported so far in pigs. The advantages and limitations of each model are also discussed

Immunophenotype and Transcriptome Profile of Patients With Multiple Sclerosis Treated With Fingolimod: Setting Up a Model for Prediction of Response in a 2-Year Translational Study

Background: Fingolimod is a functional sphingosine-1-phosphate antagonist approved for the treatment of multiple sclerosis (MS). Fingolimod affects lymphocyte subpopulations and regulates gene expression in the lymphocyte transcriptome. Translational studies are necessary to identify cellular and molecular biomarkers that might be used to predict the clinical response to the drug. In MS patients, we aimed to clarify the differential effects of fingolimod on T, B, and natural killer (NK) cell subsets and to identify differentially expressed genes in responders and non-responders (NRs) to treatment. Materials and methods: Samples were obtained from relapsing-remitting multiple sclerosis patients before and 6 months after starting fingolimod. Forty-eight lymphocyte subpopulations were measured by flow cytometry based on surface and intracellular marker analysis. Transcriptome sequencing by next-generation technologies was used to define the gene expression profiling in lymphocytes at the same time points. NEDA-3 (no evidence of disease activity) and NEDA-4 scores were measured for all patients at 1 and 2 years after beginning fingolimod treatment to investigate an association with cellular and molecular characteristics. Results: Fingolimod affects practically all lymphocyte subpopulations and exerts a strong effect on genetic transcription switching toward an anti-inflammatory and antioxidant response. Fingolimod induces a differential effect in lymphocyte subpopulations after 6 months of treatment in responder and NR patients. Patients who achieved a good response to the drug compared to NR patients exhibited higher percentages of NK bright cells and plasmablasts, higher levels of FOXP3, glucose phosphate isomerase, lower levels of FCRL1, and lower Expanded Disability Status Scale at baseline. The combination of these possible markers enabled us to build a probabilistic linear model to predict the clinical response to fingolimod. Conclusion: MS patients responsive to fingolimod exhibit a recognizable distribution of lymphocyte subpopulations and a different pretreatment gene expression signature that might be useful as a biomarker.This work was mostly supported by grants from Novartis (PI110/13 JGM-INM2014-01) and Fondo de Investigación Sanitaria FIS PI12/02672 and PI15/02099 integrated in the Plan Nacional de I+D+I (2008–2011 and 2013–2016, respectively), supported by the ISCIII—subdirección General de Evaluación and co-financed by the Fondo Europeo de Desarrollo Regional (FEDER). The funding sources had no involvement in the study design, data collection, analysis, interpretation, preparation of the manuscript, and the decision to submit the article for publication.S

Immunophenotype and Transcriptome Profile of Patients With Multiple Sclerosis Treated With Fingolimod: Setting Up a Model for Prediction of Response in a 2-Year Translational Study

International audienc

Data_Sheet_1_Immunophenotype and Transcriptome Profile of Patients With Multiple Sclerosis Treated With Fingolimod: Setting Up a Model for Prediction of Response in a 2-Year Translational Study.PDF

Background<p>Fingolimod is a functional sphingosine-1-phosphate antagonist approved for the treatment of multiple sclerosis (MS). Fingolimod affects lymphocyte subpopulations and regulates gene expression in the lymphocyte transcriptome. Translational studies are necessary to identify cellular and molecular biomarkers that might be used to predict the clinical response to the drug. In MS patients, we aimed to clarify the differential effects of fingolimod on T, B, and natural killer (NK) cell subsets and to identify differentially expressed genes in responders and non-responders (NRs) to treatment.</p>Materials and methods<p>Samples were obtained from relapsing–remitting multiple sclerosis patients before and 6 months after starting fingolimod. Forty-eight lymphocyte subpopulations were measured by flow cytometry based on surface and intracellular marker analysis. Transcriptome sequencing by next-generation technologies was used to define the gene expression profiling in lymphocytes at the same time points. NEDA-3 (no evidence of disease activity) and NEDA-4 scores were measured for all patients at 1 and 2 years after beginning fingolimod treatment to investigate an association with cellular and molecular characteristics.</p>Results<p>Fingolimod affects practically all lymphocyte subpopulations and exerts a strong effect on genetic transcription switching toward an anti-inflammatory and antioxidant response. Fingolimod induces a differential effect in lymphocyte subpopulations after 6 months of treatment in responder and NR patients. Patients who achieved a good response to the drug compared to NR patients exhibited higher percentages of NK bright cells and plasmablasts, higher levels of FOXP3, glucose phosphate isomerase, lower levels of FCRL1, and lower Expanded Disability Status Scale at baseline. The combination of these possible markers enabled us to build a probabilistic linear model to predict the clinical response to fingolimod.</p>Conclusion<p>MS patients responsive to fingolimod exhibit a recognizable distribution of lymphocyte subpopulations and a different pretreatment gene expression signature that might be useful as a biomarker.</p

Stroke etiologies in patients with COVID-19 : the SVIN COVID-19 multinational registry

Coronavirus disease 2019 (COVID-19) is associated with a small but clinically significant risk of stroke, the cause of which is frequently cryptogenic. In a large multinational cohort of consecutive COVID-19 patients with stroke, we evaluated clinical predictors of cryptogenic stroke, short-term functional outcomes and in-hospital mortality among patients according to stroke etiology. We explored clinical characteristics and short-term outcomes of consecutively evaluated patients 18 years of age or older with acute ischemic stroke (AIS) and laboratory-confirmed COVID-19 from 31 hospitals in 4 countries (3/1/20-6/16/20). Of the 14.483 laboratory-confirmed patients with COVID-19, 156 (1.1%) were diagnosed with AIS. Sixty-one (39.4%) were female, 84 (67.2%) white, and 88 (61.5%) were between 60 and 79 years of age. The most frequently reported etiology of AIS was cryptogenic (55/129, 42.6%), which was associated with significantly higher white blood cell count, c-reactive protein, and D-dimer levels than non-cryptogenic AIS patients (p</=0.05 for all comparisons). In a multivariable backward stepwise regression model estimating the odds of in-hospital mortality, cryptogenic stroke mechanism was associated with a fivefold greater odds in-hospital mortality than strokes due to any other mechanism (adjusted OR 5.16, 95%CI 1.41-18.87, p = 0.01). In that model, older age (aOR 2.05 per decade, 95%CI 1.35-3.11, p < 0.01) and higher baseline NIHSS (aOR 1.12, 95%CI 1.02-1.21, p = 0.01) were also independently predictive of mortality. Our findings suggest that cryptogenic stroke among COVID-19 patients carries a significant risk of early mortality. The online version contains supplementary material available at 10.1186/s12883-021-02075-