Myasthenia gravis exacerbation after melatonin administration: case series from a tertiary referral centre

Background: Myasthenia gravis is an autoimmune disease mediated by antibodies against proteins associated with the postsynaptic membrane of the neuromuscular junction. Several drugs may trigger an exacerbation of the disease. Melatonin supplements are widely used for the treatment of insomnia as they are well tolerated with few side effects. The role of melatonin in the immune system and its effects in autoimmune disorders remain uncertain. Case presentation: We identified three patients in our referral centre from 2014 to 2019 who presented a worsening within days or weeks of starting melatonin. Two of them stopped the treatment without clinical improvement in the next week. Increasing dose of corticosteroids did not lead to clinical improvement in the next month and one of the patients was finally administered intravenous immunoglobulins. Conclusion: Melatonin may trigger exacerbations of myasthenia gravis, probably due to an upregulation of the adaptive immune system and an interaction with the corticosteroids and other immunosuppressant treatments. We consider that melatonin should be administered with caution in these patients

Quality of Life in Myasthenia Gravis and Correlation of MG-QOL15 with Other Functional Scales

Health-related quality of life (HRQOL) in myasthenia gravis (MG) is frequently decreased. Further, there are many validated clinical scales and questionnaires to evaluate the clinical status in MG. We aimed to determine if there was an improvement in HRQOL following an intensive treatment for MG, identify which demographic and clinical features influenced patients' HRQOL, and investigate if the questionnaire MG-QOL15 correlated with other evaluation scales. We recruited 45 patients with generalised MG who were starting immunomodulatory treatment with intravenous immunoglobulins and prednisone for the first time. At each visit, we administered several validated scales for MG. The mean MG-QOL15 score improved significantly at 4 and 6 weeks of the study. Additionally, the MG-QOL15 score correlated strong with the Myasthenia Gravis-Activities of Daily Living (MG-ADL) and the Neuro-QOL Fatigue and weakest with the Quantitative Myasthenia Gravis Scoring System (QMG). The QMG score prior to study enrolment was associated with HRQOL. We observed that HRQOL in MG improved after receiving an intensive immunomodulatory treatment and achieving better control of the symptoms. The questionnaire MG-QOL15 correlated positively with other clinical measures. As MG is a fluctuating condition, and some symptoms are difficult to examine, we direct physicians toward the use of scales and questionnaires composed of items perceived by the patient

Intravenous immunoglobulins may prevent prednisone-exacerbation in myasthenia gravis

Corticosteroids may produce a paradoxical worsening of myasthenia gravis (MG) symptoms within the first weeks of treatment. We therefore wanted to assess the hypothesis that a prior infusion of intravenous immunoglobulin (IVIG) may have a protective effect. Our primary objectives were to show that the coadministration of immunoglobulins and glucocorticoids is safe and effective for controlling myasthenic symptoms, and to compare the exacerbation rate with this approach and historical practice without IVIG. We recruited 45 patients with generalized MG who required corticosteroids for the first time and we gave all IVIG before starting the full doses of prednisone. Monitoring was performed with validated scales, questionnaires, and blood tests over a 6-week period. Only 4.4% had severe adverse effects related to IVIG and 86.7% improved clinically. Notably, only 2.2% had a paradoxical symptom exacerbation in the first weeks of starting prednisone, which was statistically lower than the 42% reported in a historical series. We conclude that adjuvant therapy with IVIG when starting prednisone for the first time in patients with generalized MG is safe and effective. Given that the rate of paradoxical worsening was lower than that previously reported, the addition of IVIG may have a protective effect against such exacerbations

Eculizumab as a promising treatment in thymoma-associated myasthenia gravis

Myasthenia gravis is a chronic autoimmune disorder caused by antibodies directed against the neuromuscular junction. Some patients may have an associated thymoma, which confers a worse prognosis. Eculizumab, a monoclonal antibody that inhibits the activation of terminal complement, has recently been approved for the treatment of refractory generalized myasthenia gravis. This is an early case report of thymoma-associated refractory myasthenia gravis successfully treated with eculizumab in a real-world setting

Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy

Hypomyelinating leukodystrophy; Inborn errors of metabolism; PhosphoinositolLeucodistrofia hipomielinizante; Errores innatos del metabolismo; FosfoinositolLeucodistròfia hipomielinizant; Errors innats del metabolisme; FosfoinositolPhosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients’ fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.We thank the CERCA Program/Generalitat de Catalunya for institutional support. This study was supported by grants from the Hesperia Foundation, the Asociación Española contra las Leucodistrofias (ALE-ELA España), the Autonomous Government of Catalonia (SGR 2017SGR1206 and PERIS program URD-Cat SLT002/16/00174) and the Center for Biomedical Research on Rare Diseases (CIBERER) (ACCI19-759 to A.P.). This study was also funded by Fundació La Marató de TV3 (595/C/2020) as well as Instituto de Salud Carlos III (FIS PI20/00758 to C.C.) (co-funded by European Regional Development Fund. ERDF, a way to build Europe). This study was also funded by the Instituto de Salud Carlos III (Rio Hortega, CM18/00145 to V.V.; PFIS, FI18/00141 to L.P.; and Sara Borrell, CD19/00221 to E.V.), co-funded by European Social Fund. ESF investing in your future; the Ministerio de Ciencia e Innovación y Universidades (Juan de la Cierva, FJCI-2016-28811 to E.V.), and the Center for Biomedical Research on Rare Diseases (CIBERER to M.R.). Sequencing and analysis of Patient 5 were performed by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and were funded by the National Human Genome Research Institute, the National Eye Institute, the National Heart, Lung and Blood Institute grants UM1 HG008900 and R01 HG009141 and the Chan Zuckerberg Initiative to the Rare Genomes Project. This work was in part supported by the association ‘Connaître les Syndromes Cérébelleux’ (CSC). This research received funding specifically appointed to the Department of Medical Sciences from the Italian Ministry for Education, University and Research (Ministero dell’istruzione, dell’università e della ricerca-MIUR) under the programme ‘Dipartimenti di Eccellenza 2018-2022’ Project code D15D18000410001. Whole-exome sequencing was performed as part of the Autism Sequencing Consortium and was supported by the NIMH (MH111661). D.R.A. and A.P. are members of the Undiagnosed Disease Network International (UDNI)

A novel mutation in the GFAP gene expands the phenotype of Alexander disease

Background: Alexander disease, an autosomal dominant leukodystrophy, is caused by missense mutations in GFAP. Although mostly diagnosed in children, associated with severe leukoencephalopathy, milder adult forms also exist. Methods: A family affected by adult-onset spastic paraplegia underwent neurological examination and cerebral MRI. Two patients were sequenced by WES. A candidate variant was functionally tested in an astrocytoma cell line. Results: The novel variant in GFAP N-terminal head domain (p.Gly18Val) cosegregated in multiple relatives (LOD score: 2.7). All patients, even those with the mildest forms, showed characteristic signal changes or atrophy in the brainstem and spinal cord MRIs, and abnormal MRS. In vitro, this variant did not cause significant protein aggregation, in contrast to most Alexander disease mutations characterized so far. However, cell area analysis showed larger size, a feature previously described in patients and mouse models. Conclusion: We suggest that this variant causes variable expressivity and an attenuated phenotype of Alexander Disease type II, probably associated with alternative pathogenic mechanisms, i.e. astrocyte enlargement. GFAP analysis should be considered in adult-onset neurologic presentations with pyramidal and bulbar symptoms, in particular when characteristic findings, such as the tadpole sign, are present in MRI. WES is a powerful tool to diagnose atypical cases

Novel intragenic deletion within the FXN gene in a patient with typical phenotype of Friedreich ataxia: may be more prevalent than we think?

Background Friedreich ataxia is the most common inherited ataxia in Europe and is mainly caused by biallelic pathogenic expansions of the GAA trinucleotide repeat in intron 1 of the FXN gene that lead to a decrease in frataxin protein levels. Rarely, affected individuals carry either a large intragenic deletion or whole-gene deletion of FXN on one allele and a full-penetrance expanded GAA repeat on the other allele.Case presentation We report here a patient that presented the typical clinical features of FRDA and genetic analysis of FXN intron 1 led to the assumption that the patient carried the common biallelic expansion. Subsequently, parental sample testing led to the identification of a novel intragenic deletion involving the 5'UTR upstream region and exons 1 and 2 of the FXN gene by MLPA.Conclusions With this case, we want to raise awareness about the potentially higher prevalence of intragenic deletions and underline the essential role of parental sample testing in providing accurate genetic counselling

El covid19 y la responsabilidad social en las empresas en el Ecuador

This study is carried out with the purpose of investigating the elements of components of social business responsibility against Covid-19, to know its impact on good business practices, in a current post-pandemic scenario they condition its immediate future, which is why it is It is essential to offer social commitment practices that allow facing the challenges in relation to its stakeholders, all of whom are powerfully affected by the emergency. The quantitative approach is applied, applying an orderly development that facilitates collecting measurable data; also with a transectional scope, where information is collected for an exclusive time through a structured survey with 12 questions applied to 76 representatives of the considerable companies in the locality. The results obtained show that the coronavirus pandemic caused the companies in Santo Domingo to generate a positive impact on their stakeholders, workers, users and suppliers; that complied with the provisions issued by the National Government, regarding the confinement and payment of wages to workers, in addition to the fact that most had to reduce their operational capacity, likewise several companies implemented remote work for positions that do not need to the physical presence of the worker, for all those who go to the facilities of the companies have established biosecurity measures. It should be noted that the general impact for companies was a 42% reduction in their sales level; in the case of large companies, their capital decreased by 1,093 million dollars.Este estudio se lleva a cabo con el propósito de investigar los elementos de componentes de responsabilidad empresarial social frente al Covid- 19, para conocer su impacto en las buenas prácticas empresariales, en un escenario actual post pandemia condicionan su futuro inmediato, por lo cual es primordial ofrecer prácticas de compromiso social que permitan enfrentar los retos en relación con sus stakeholder, todos ellos son poderosamente damnificados por la emergencia.  Se aplica el enfoque cuantitativo, aplicando un desarrollo ordenado que facilita recoger datos medibles; además con un alcance transeccional, donde se recoge información por una exclusiva vez por medio de una encuesta estructurada con 12 preguntas aplicadas a 76 representantes de las considerables empresas de la localidad.   Los resultados obtenidos muestran que la pandemia por el coronavirus originó que las en las empresas de Santo Domingo generaran un impacto positivo en sus stakeholder, trabajadores, usuarios y proveedores; que acataron las disposiciones emitidas por el Gobierno Nacional, respecto al confinamiento y pago del sueldo a los trabajadores, más allá que la mayor parte tuvo que reducir su capacidad operativa, así mismo varias empresas implementaron el trabajo a distancia para los cargos que no necesitan de la presencia física del trabajador, para todos los que acudan a las instalaciones de las empresas han establecido medidas de bioseguridad. Cabe señalar que el impacto general para las empresas fue una reducción del 42% en su nivel de ventas; en caso de las grandes empresas disminuyeron su capital en dólares 1.093 millones

Research advances in Risaralda. An overview of 8 experiences

I am honored to present to you this remarkable book, a testament to the invaluable research conducted in the fields of Health, Law, Engineering, and Administrative Sciences. Each chapter within these pages represents the culmination of extensive investigations carried out by dedicated scholars affiliated with the Red Universitaria de Risaralda (RUN), a network comprising 15 esteemed higher education institutions. Risaralda has emerged as a thriving hub for higher education, bolstered by its strategic geographical location, high quality of life, rich biodiversity, and competitive development. Today, Pereira ranks third in the index of university cities, with a student enrollment rate exceeding 63%. Close to 50,000 students pursue academic programs within the department. Notably, three institutions have achieved accreditation for their excellence in education, positioning Risaralda among the most competitive regions in terms of accredited academic programs. As we celebrate the 20th anniversary of the Red Universitaria de Risaralda in 2023, it is with great pride that we reflect on its pivotal role in fostering collaboration among public and private higher education institutions. Our mission has been twofold: attracting students to our region and supporting sustainable development and quality of life for our community. The mesa de investigación (research committee) has diligently coordinated the necessary actions to unite our researchers, facilitating an integrated approach to various disciplines and themes associated with the challenges faced in our region.CONTENT Introduction...................................................................................................................5 CHAPTER ONE. Tobacco Use and Social Skills in Children from Two Schools in Pereira, Colombia .......................................................................................................9 Angélica María Blanco Vanegas, Natalia Jeaneth Carmona Valencia and Ángela Liceth Pérez Rendón CHAPTER TWO. Lesbian visibility: between control and family silence.................................................35 Mireya Ospina Botero and Carolina Carmona Castilla CHAPTER THREE. New centralities in the city of Pereira, 1990-2019 .......................................................65 Cesar Augusto Castaño Galvis CHAPTER FOUR. Bibliometric analysis of scientific publications on the effect of roots on slope stability ...........................................................................................................95 Alejandro Alzate Buitrago, Raúl Alberto Gaviria Valencia, César Augusto Peñuela Meneses, Carlos Alberto Ospina Parra CHAPTER FIVE. Sustainability of local agri-food systems in a municipality of the Eje Cafetero, Colombia...............................................................................................131 Jaime Cardona Ocampo, Orlando Ospina Salazar and Julia Arredondo Botero CHAPTER SIX. Organizational strategies aimed at the Emberá Chamí unified indigenous reservation, Inamurcito community located in the municipality of Pueblo Rico, Risaralda............................................................................................................163 Carla Johana Martínez García and Yenny Marcela Vélez Herrera CHAPTER SEVEN. Psychomotor profile of children between 4 and 5 years old in the city of Pereira, Colombia ...................................................................................................199 Jhonatan Gonzalez-Santamaría and Claudia Jimena Lopez-Garcia CHAPTER EIGHT. Analysis of assembly tasks without the use of vision: an opportunity for the design of support technologies in manufacturing environments.....................217 Gustavo Adolfo Peña Marín, Carlos Andrés Quintero Diaztagle and Juan Diego Gallego Góme

Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy

Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath