341 results on '"I. Illa"'
Search Results
52. [Treatment of autoimmune neuromuscular diseases with intravenous immunoglobulins]
- Author
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I, Illa, C, Serrano, and C, Prat
- Subjects
Cytokines ,Humans ,Immunoglobulins, Intravenous ,Neuromuscular Diseases ,Autoantibodies - Published
- 1997
53. Does Campylobacter jejuni infection elicit 'demyelinating' Guillain-Barre syndrome?
- Author
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J. Berciano, I. Illa, S. Kuwabara, and N. Yuki
- Subjects
Neurology (clinical) - Published
- 2005
54. Homozygous myotonic dystrophy: clinical and molecular studies of three unrelated cases
- Author
-
J. Rosell, Loreto Martorell, Montserrat Baiget, J. Benitez, I. Illa, and M.J. Sedano
- Subjects
Genetics ,Adult ,Aged, 80 and over ,Male ,Homozygote ,Late onset ,Biology ,medicine.disease ,Myotonia ,Myotonic dystrophy ,Polymerase Chain Reaction ,Bilateral Cataracts ,Pedigree ,Blotting, Southern ,medicine ,Humans ,Myotonic Dystrophy ,Female ,Allele ,Genetics (clinical) ,Research Article ,Aged - Abstract
We report the clinical and molecular study of three unrelated homozygous myotonic dystrophy patients. In the first family, the homozygous patient shows the classical form of the disease with two DM alleles of very different expansion sizes (1000 and 60 repeats). In the second family, the homozygous patient is mildly affected and carries a minimally expanded allele (64 repeats) and a "normal" allele (38 repeats) that increases in size when transmitted. Such an intergenerational expansion of an allele in this range of repeats has not been reported to date. The third homozygous case has late onset bilateral cataracts as the only symptom. She has two minimally expanded alleles (51 and 120 repeats) that showed different intergenerational enlargement during transmission to the next generation.
- Published
- 1996
55. [Erythroblastopenia during recurrence of a thymoma associated with myasthenia gravis. Apropos of a new case]
- Author
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I, Montserrat, P, Sardà, R, López, I, Illa, R, Bordes, and R, Ayats
- Subjects
Erythroid Precursor Cells ,Thymoma ,Thymus Neoplasms ,Red-Cell Aplasia, Pure ,Combined Modality Therapy ,Autoimmune Diseases ,Immunophenotyping ,Antigens, CD ,T-Lymphocyte Subsets ,Myasthenia Gravis ,Humans ,Female ,Cholinesterase Inhibitors ,Neoplasm Recurrence, Local ,Cells, Cultured ,Aged ,Pyridostigmine Bromide - Abstract
A new case of thymoma, myasthenia gravis and pure red cell aplasia is presented. Pure red cell aplasia came out 10 years after the diagnosis of the two other diseases in one of several relapses of metastatic thymoma with clinical signs of myasthenia. Surgery, chemotherapy and radiotherapy besides pyridostigmine treatment were used in the clinical course of the patient. A phenotypical change of medullary T lymphocytes (CD4 to CD8) was observed at the same time of pure red cell aplasia diagnosis. A dual role of medullary CD2+ T cell lymphocytes, stimulant and suppressive, over erythroid progenitor cells (BFU-E and CFU-E) was suggested by in vitro cultures.
- Published
- 1996
56. [Intravenous immunoglobulins in the treatment of neurologic diseases]
- Author
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I, Illa and C, Serrano
- Subjects
Myasthenia Gravis ,Paraproteinemias ,Polyradiculoneuropathy ,Humans ,Immunoglobulins ,Infusions, Intravenous - Published
- 1996
57. [Anti-gangliosides antibodies in neuromuscular's pathology]
- Author
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I, Illa
- Subjects
Campylobacter jejuni ,Gangliosides ,Immunoglobulin G ,Amyotrophic Lateral Sclerosis ,Polyradiculoneuropathy ,Brain ,Humans ,Antibodies ,Autoantibodies ,Immunoglobulin A - Published
- 1995
58. Common variable immunodeficiency and inclusion body myositis: a distinct myopathy mediated by natural killer cells
- Author
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M C, Dalakas and I, Illa
- Subjects
Adult ,Inclusion Bodies ,Killer Cells, Natural ,Male ,Common Variable Immunodeficiency ,Myositis ,Antigens, CD ,Histocompatibility Antigens Class I ,Humans ,Lymphocyte Count ,Middle Aged ,Intercellular Adhesion Molecule-1 - Abstract
Inclusion body myositis developed in two men, 36 and 48 years old with long-standing common variable immunodeficiency. Immunophenotypic analysis of the endomysial cells showed an increased number of natural killer (NK) cells (defined as CD57+, CD56+, CD3-, CD8-, CD68-) accounting for 8.5 to 9.5% of the total cells, compared with a mean of 1% in sporadic inclusion body myositis. The remaining cells were CD8+, macrophages, and CD4+ T cells. NK cells were positive for intercellular cell adhesion molecule-1 and invaded muscle fibers negative for major histocompatibility complex (MHC) class I. In contrast to ubiquitous endomysial expression of MHC class I antigen in sporadic inclusion body myositis, the MHC class I in common variable immunodeficiency and inclusion body myositis was absent or weakly expressed in only some of the muscle fibers surrounded by CD8+ cells. Enteroviral or retroviral RNA sequences were not amplified. Treatment with intravenous immunoglobulin improved strength in 1 patient whose repeated muscle biopsy specimen showed normal NK cells. We conclude that inclusion body myositis can develop in patients with common variable immunodeficiency. Common variable immunodeficiency with inclusion body myositis is an immune myopathy mediated by NK cells in a non-MHC class I-restricted cytotoxicity, and by CD8+ cells in an MHC class I-restricted process. This is the first description of an inflammatory myopathy in which NK cells participate in the myocytotoxic process.
- Published
- 1995
59. [Sensory polyneuropathy and neural conduction block as an initial manifestation of polyarteritis nodosa]
- Author
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A, Chico, J, de Llobet, R, Corcoy, M, Cuatrecases, M, Dourado, and I, Illa
- Subjects
Male ,Nerve Degeneration ,Neural Conduction ,Humans ,Cerebral Arteries ,Middle Aged ,Cerebral Angiography ,Polyarteritis Nodosa - Abstract
Polyarteritis nodosa (PAN) is a systemic necrotising vasculitis which affects middle calibre arteries and which has a tendency to form aneurysms. It may appear as one of a great variety of clinical forms depending on the vascular territory afflicted. Almost any organ may be involved although the lung is usually unaffected. Neurological manifestations are very frequent in this disease (global incidence being around 80%), especially at the peripheral nervous system level. Multiple mononeuritis is the most usual manifestation classically associated with this type of vasculitis, but it may also appear as distal sensorimotor polyneuropathy, this being its most infrequent form of presentation. The presence of nerve conduction blocks has also been recently described, usually associated with demyelinating processes. However peripheral nerve affectation in vasculitis has its origins in small ischaemic infarcts in the sensorimotor conduction fibres. It may well be that segmentary demyelination and axonal degeneration reflect different levels of ischaemic damage.
- Published
- 1995
60. Cultural Planning and Community Sustainability: The Case of the Cultural Facilities Plan of Catalonia (PECCAT 2010-20)
- Author
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Martínez i Illa, Santi, primary and Rius i Ulldemolins, Joaquim, additional
- Published
- 2011
- Full Text
- View/download PDF
61. Retrovirus-related neuromuscular diseases
- Author
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I. Illa, M. Monzon, and M. C. Dalakas
- Subjects
Pediatrics ,medicine.medical_specialty ,Neuromuscular disease ,biology ,business.industry ,Human immunodeficiency virus (HIV) ,Chronic inflammatory demyelinating polyneuropathy ,biology.organism_classification ,medicine.disease_cause ,medicine.disease ,Inflammatory myopathy ,Retrovirus ,medicine ,Seroconversion ,medicine.symptom ,Myopathy ,business ,Pathological - Abstract
Muscle or peripheral nerve is frequently involved in patients with HIV infection. Neuropathy or myopathy may accompany seroconversion, may represent the first clinical manifestation of an established or undiagnosed HIV infection or may complicate full-blown AIDS1–13 The HIV-related neuromuscular disorders, although rarely life-threatening, are often disabling; hence the need for early diagnosis and initiation of therapy. While pathological studies show that neuromuscular pathology is almost universal in patients dying of AIDS14–17 clinical studies estimate the frequency of symptomatic myopathy at up to 30%18 and that of neuropathy at 35%19. Such clinical under-recognition is probably related to the dysfunction of other organs, commonly affected in this multisystem disease, which overshadows coexistent neuromuscular complications. Because a myopathy or neuropathy may coincide with seroconversion for HIV12,13 or may be the only indication of a chronic, undiagnosed HIV infection, every patient who comes to a neurology clinic with acquired myopathy or neuropathy is now requested to consent to HIV screening.
- Published
- 1994
62. Paricularitats climàtiques del Gran Penedès
- Author
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Miró i Illa, Josep
- Published
- 1993
63. G.P.6.01 Measurements of progression in dysferlin myopathies: A preliminary prospective quantitative study
- Author
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C. Paradas, C. Serrano-Munuera, J. Llauger, M. Martı´nez-Lage, C. Márquez, P. Gallano, N. De Luna, R. Rojas-Garcı´a, E. Gallardo, and I. Illa
- Subjects
Dysferlin ,Pathology ,medicine.medical_specialty ,Neurology ,biology ,business.industry ,Pediatrics, Perinatology and Child Health ,biology.protein ,Medicine ,Neurology (clinical) ,business ,Genetics (clinical) - Published
- 2009
64. Post-polio syndrome: concepts in clinical diagnosis, pathogenesis, and etiology
- Author
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M, Dalakas and I, Illa
- Subjects
Electrophysiology ,Muscular Atrophy ,Spinal Cord ,Risk Factors ,Biopsy ,Muscles ,Amyotrophic Lateral Sclerosis ,Humans ,Neuromuscular Diseases ,Postpoliomyelitis Syndrome ,Syndrome - Published
- 1991
65. [Predictive factors of the response to treatment of myasthenia gravis with prednisone]
- Author
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J, Pradas and I, Illa
- Subjects
Adult ,Male ,Time Factors ,Myasthenia Gravis ,Age Factors ,Humans ,Prednisone ,Female ,Middle Aged ,Prognosis ,Severity of Illness Index - Abstract
The influence of age at onset, sex, duration of disease and severity degree on the response to therapy have been evaluated in 30 patients with myasthenia gravis treated with prednisone. During the evaluation period (3 months as a maximum) the patients were only treated with prednisone. The evaluation of the response was based on the use of quantified tests of clinical fatigability. Among all the evaluated factors, only the age at onset seemed to have a predictive value of the response to prednisone therapy. The patients older than 40 years and particularly those older than 60 years showed a better response than younger patients.
- Published
- 1990
66. Anti-titin antibodies are not associated with a specific thymoma histology
- Author
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Norbert Sommer, H. Kaminski, T. Kirchner, M. Wick, Reinhard Hohlfeld, Raymond Voltz, D. Nagel, I. Illa, F. Schumm, and W. C. Albrich
- Subjects
Pathology ,medicine.medical_specialty ,Letter ,animal structures ,Thymoma ,Blotting, Western ,Muscle Proteins ,Enzyme-Linked Immunosorbent Assay ,Thymus Gland ,Antigen ,Predictive Value of Tests ,Myasthenia Gravis ,medicine ,Humans ,Connectin ,Autoantibodies ,biology ,Thymus Neoplasm ,business.industry ,Autoantibody ,Histology ,Thymus Neoplasms ,musculoskeletal system ,medicine.disease ,Myasthenia gravis ,Psychiatry and Mental health ,embryonic structures ,Immunology ,cardiovascular system ,biology.protein ,Surgery ,Titin ,Neurology (clinical) ,Antibody ,business ,Protein Kinases ,tissues - Abstract
After the first description of antibodies to titin in patients with thymoma associated myasthenia gravis in 1990, this finding was independently confirmed and the main immunogenic region of titin (mgt30) identified.1 This 30 kDa part of titin is now also commercially available as antigen for detecting anti-titin antibodies. Furthermore, in a series of 276 patients, we could confirm the clinical usefulness of measuring anti-titin antibodies for predicting the presence of a thymic epithelial tumour in patients with myasthenia gravis that was significantly better than the …
- Published
- 2003
67. Homozygous myotonic dystrophy: clinical and molecular studies of three unrelated cases
- Author
-
M.J. Sedano, Montserrat Baiget, J. Benitez, I. Illa, J. Rosell, M. Cornet, and Loreto Martorell
- Subjects
Pathology ,medicine.medical_specialty ,Neurology ,business.industry ,Pediatrics, Perinatology and Child Health ,medicine ,Neurology (clinical) ,business ,medicine.disease ,Myotonic dystrophy ,Genetics (clinical) - Published
- 1996
68. Long-term outcomes of adult chronic idiopathic hydrocephalus treated with a ventriculo-peritoneal shunt
- Author
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I. Illán-Gala, J. Pérez-Lucas, A. Martín-Montes, J. Máñez-Miró, J. Arpa, and G. Ruiz-Ares
- Subjects
Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Introduction: Adult chronic idiopathic hydrocephalus (ACIH) is a cause of dementia that can be treated by implanting a ventriculo-peritoneal shunt (VPS). We aim to study clinical and functional outcomes in patients with ACIH corrected with a VPS. Subjects and methods: Observational cohort study of patients diagnosed with probable ACIH (Japan Neurosurgical Society guidelines) and undergoing shunt placement between 2008 and 2013 in a centre of reference for neurosurgery in Spain. Clinical improvement was classified in 4 categories (resolution, partial improvement, equivocal improvement, and no improvement); functional outcome was assessed on the modified Rankin scale (mRS). Results: The study included 29 patients with a mean age of 73.9 years; 62.1% were male and 65.5% had hypertension. Clinical improvement (complete or partial) was observed in 58% after one year and in 48% by the end of the follow-up period (mean follow-up time was 37.8 months). Older age, presence of hypertension, and surgery-related complications were more prevalent in the group responding poorly to treatment. One patient died, 20.7% experienced severe complications, and 69% were dependent (mRS ≥ 3) by the end of the follow-up period. Age at diagnosis was independently associated with poorer clinical response at one year and a higher degree of dependency by the end of follow-up. Conclusion: Symptomatic benefits offered by VPS were partial and transient; treatment was associated with a high complication rate and poor functional outcomes in the long term, especially in the oldest patients. Resumen: Introducción: La hidrocefalia crónica del adulto idiopática (HCAI) es considerada una causa de demencia tratable mediante la implantación de una válvula de derivación ventrículo-peritoneal (VDVP). Nos planteamos estudiar la evolución clínica y funcional de la HCAI tratada con VDVP, así como los factores asociados con una mejor evolución a largo plazo. Sujetos y métodos: Estudio observacional de pacientes con diagnóstico de HCAI probable (según criterios de la Sociedad Japonesa de Neurocirugía) y tratados con VDVP entre 2008 y 2013 en un hospital de tercer nivel español. Se establecieron 4 grupos de respuesta clínica (normalización, mejoría parcial, mejoría dudosa y empeoramiento) y la situación funcional se evaluó mediante la escala de Rankin modificada (ERm). Resultados: Se incluyó a 29 pacientes con una edad media de 73,9 años. El 62,1% eran hombres y el 65,5% presentaban HTA. Se observó una respuesta clínica al menos parcial en el 58 y el 48% al año y al final del seguimiento (seguimiento medio de 37,8 meses), respectivamente. La edad, la frecuencia de HTA y las complicaciones quirúrgicas fueron superiores en el grupo con mala respuesta. Un paciente falleció, el 20,7% presentó complicaciones graves y el 69% era dependiente (ERm ≥ 3) al final del seguimiento. La edad se asoció de manera independiente a peor respuesta clínica al año y una mayor dependencia al final del seguimiento. Conclusión: El beneficio de la VDVP fue parcial y transitorio, con una alta frecuencia de complicaciones y dependencia funcional en el seguimiento a largo plazo, especialmente en los pacientes de mayor edad. Keywords: Normal pressure hydrocephalus, Chronic adult hydrocephalus, Ventriculo-peritoneal shunt, Epidemiology, Treatment, Palabras clave: Hidrocefalia normotensiva, Hidrocefalia crónica del adulto, Derivación ventrículo-peritoneal, Epidemiología, Tratamiento
- Published
- 2017
- Full Text
- View/download PDF
69. Evolución a largo plazo de la hidrocefalia crónica del adulto idiopática tratada con válvula de derivación ventrículo-peritoneal
- Author
-
I. Illán-Gala, J. Pérez-Lucas, A. Martín-Montes, J. Máñez-Miró, J. Arpa, and G. Ruiz-Ares
- Subjects
Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Resumen: Introducción: La hidrocefalia crónica del adulto idiopática (HCAI) es considerada una causa de demencia tratable mediante la implantación de una válvula de derivación ventrículo-peritoneal (VDVP). Nos planteamos estudiar la evolución clínica y funcional de la HCAI tratada con VDVP, así como los factores asociados con una mejor evolución a largo plazo. Sujetos y métodos: Estudio observacional de pacientes con diagnóstico de HCAI probable (según criterios de la Sociedad Japonesa de Neurocirugía) y tratados con VDVP entre 2008 y 2013 en un hospital de tercer nivel español. Se establecieron 4 grupos de respuesta clínica (normalización, mejoría parcial, mejoría dudosa y empeoramiento) y la situación funcional se evaluó mediante la escala de Rankin modificada (ERm). Resultados: Se incluyó a 29 pacientes con una edad media de 73,9 años. El 62,1% eran hombres y el 65,5% presentaban HTA. Se observó una respuesta clínica al menos parcial en el 58 y el 48% al año y al final del seguimiento (seguimiento medio de 37,8 meses), respectivamente. La edad, la frecuencia de HTA y las complicaciones quirúrgicas fueron superiores en el grupo con mala respuesta. Un paciente falleció, el 20,7% presentó complicaciones graves y el 69% era dependiente (ERm ≥ 3) al final del seguimiento. La edad se asoció de manera independiente a peor respuesta clínica al año y una mayor dependencia al final del seguimiento. Conclusión: El beneficio de la VDVP fue parcial y transitorio, con una alta frecuencia de complicaciones y dependencia funcional en el seguimiento a largo plazo, especialmente en los pacientes de mayor edad. Abstract: Introduction: Adult chronic idiopathic hydrocephalus (ACIH) is a cause of dementia that can be treated by implanting a ventriculo-peritoneal shunt (VPS). We aim to study clinical and functional outcomes in patients with ACIH corrected with a VPS. Subjects and methods: Observational cohort study of patients diagnosed with probable ACIH (Japan Neurosurgical Society guidelines) and undergoing shunt placement between 2008 and 2013 in a centre of reference for neurosurgery in Spain. Clinical improvement was classified in 4 categories (resolution, partial improvement, equivocal improvement, and no improvement); functional outcome was assessed on the modified Rankin scale (mRS). Results: The study included 29 patients with a mean age of 73.9 years; 62.1% were male and 65.5% had hypertension. Clinical improvement (complete or partial) was observed in 58% after one year and in 48% by the end of the follow-up period (mean follow-up time was 37.8 months). Older age, presence of hypertension, and surgery-related complications were more prevalent in the group responding poorly to treatment. One patient died, 20.7% experienced severe complications, and 69% were dependent (mRS ≥ 3) by the end of the follow-up period. Age at diagnosis was independently associated with poorer clinical response at one year and a higher degree of dependency by the end of follow-up. Conclusion: Symptomatic benefits offered by VPS were partial and transient; treatment was associated with a high complication rate and poor functional outcomes in the long term, especially in the oldest patients. Palabras clave: Hidrocefalia normotensiva, Hidrocefalia crónica del adulto, Derivación ventrículo-peritoneal, Epidemiología, Tratamiento, Keywords: Normal pressure hydrocephalus, Ventriculo-peritoneal shunt, Epidemiology, Treatment, Chronic adult hydrocephalus
- Published
- 2017
- Full Text
- View/download PDF
70. Chronic intestinal pseudoobstruction and ophthalmoplegia in a patient with mitochondrial myopathy
- Author
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J Coll, A M Garcia-Puges, R Blesa, I Illa, A Bayes, Jordi Bruix, R Cervera, and Universitat de Barcelona
- Subjects
Adult ,Paràlisi ,Intestinal pseudo-obstruction ,Pathology ,medicine.medical_specialty ,Abnormal mitochondria ,Eye disease ,Atrophy ,Muscular Diseases ,Mitochondrial myopathy ,medicine ,Humans ,Paralysis ,Myopathy ,Eye diseases ,Ophthalmoplegia ,Muscle biopsy ,medicine.diagnostic_test ,business.industry ,Intestinal Pseudo-Obstruction ,Gastroenterology ,medicine.disease ,Mitochondria, Muscle ,Chronic intestinal pseudoobstruction ,Intestinal obstruction ,Chronic Disease ,Obstrucció intestinal ,Female ,medicine.symptom ,business ,Oftalmopaties ,Research Article - Abstract
A 38 year old woman having chronic intestinal pseudoobstruction associated with mitochondrial myopathy is reported. The clinical and radiographic features suggested the diagnosis of chronic intestinal pseudoobstruction. Muscular atrophy and ophthalmoplegia led to muscle biopsy, which disclosed accumulation of normal and abnormal mitochondria ('ragged red fibres'), characteristic of mitochondrial myopathy.
- Published
- 1988
71. Myelopathy of unknown etiology A clinical follow-up and MRI study of 57 cases
- Author
-
I. Illa, Joan Martí-Fàbregas, J. M. Martínez, and A. Escartín
- Subjects
Adult ,Male ,medicine.medical_specialty ,Multiple Sclerosis ,Spinal Cord Diseases ,Asymptomatic ,Diagnosis, Differential ,Spinal Osteophytosis ,Myelopathy ,medicine ,Humans ,medicine.diagnostic_test ,business.industry ,Multiple sclerosis ,Magnetic resonance imaging ,General Medicine ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Surgery ,Neurology ,Etiology ,Female ,Neurology (clinical) ,Radiology ,Differential diagnosis ,medicine.symptom ,Paraplegia ,business ,Follow-Up Studies - Abstract
After a careful differential diagnosis of 264 consecutive cases of spinal cord syndrome seen over a period of 10 years, no diagnosis was reached in 72 patients. Of these cases, known as myelopathy of unknown etiology (MUE), 57 were followed-up for a mean of 2.33 years, 50 being chronic cases and 7 acute cases. Diagnosis was reached in 29 (58%) of the 50 chronic cases, the remaining 21 (42%) still being of unknown etiology. The most frequent diagnosis was either definite or probable multiple sclerosis (MS). Magnetic resonance imaging (MRI) was of great value in detecting asymptomatic brain lesions. We conclude that after a long clinical follow-up and the use of MRI we were able to diagnose more than half the previously MUE patients.
- Published
- 1989
72. [Mesencephalic haemorrhages: a CT scan study of 3 cases (author's transl)]
- Author
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C, Roig, A, Carvajal, I, Illa, A, Escartin, J M, Grau, and L, Barraquer
- Subjects
Male ,Hematoma ,Absorptiometry, Photon ,Mesencephalon ,Hypertension ,Humans ,Female ,Middle Aged ,Prognosis ,Tomography, X-Ray Computed ,Cerebral Hemorrhage - Published
- 1982
73. [Acute muscular weakness secondary to the ingestion of clopamide]
- Author
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J, Dalmau Obrador, M, Marco Igual, J, Pradas Orozco, and I, Illa Sendra
- Subjects
Male ,Muscular Diseases ,Acute Disease ,Hypertension ,Humans ,Hypokalemia ,Clopamide ,Aged - Published
- 1984
74. Thalamic hemorrhage. A study of 23 patients with diagnosis by computed tomography
- Author
-
L Barraquer-Bordas, J Ruscalleda, J L Marti-Vilalta, A Escartin, and I Illa
- Subjects
Adult ,Male ,medicine.medical_specialty ,Eye Diseases ,Eye Movements ,Computed tomography ,Speech Disorders ,Thalamic Diseases ,X ray computed ,Medicine ,Humans ,In patient ,Aged ,Cerebral Hemorrhage ,Advanced and Specialized Nursing ,medicine.diagnostic_test ,business.industry ,Pupil ,Middle Aged ,Prognosis ,Agnosia ,Thalamic hemorrhage ,Female ,Neurology (clinical) ,Radiology ,Tomography ,Cardiology and Cardiovascular Medicine ,business ,Tomography, X-Ray Computed ,Dominant hemisphere - Abstract
A series of 23 patients with thalamic hemorrhage with computed tomography confirmation is reported. Nine of these died, all had hematomas larger than 3.3 cm. The value of the syndrome of downward and convergent ocular deviation is stressed, and its possible mechanisms are analyzed. The characteristics and mechanisms of the pupillary abnormalities are reported, as well as the speech abnormalities observed in patients with lesions of the dominant hemisphere. Prognostic conclusions are drawn.
- Published
- 1981
75. vCloud Driver per a OpenNebula
- Author
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Colominas i Illa, Arnau, Consorci de Serveis Universitaris de Catalunya, Cerdà Alabern, Llorenç, and Guijarro i Olivares, Jordi
- Subjects
driver ,OpenNebula ,Computació en núvol ,controlador ,Computació distribuïda ,Computational grids (Computer systems) ,virtualization ,vCloud Director ,núvol ,VMware ,FIB ,virtualització ,Informàtica [Àrees temàtiques de la UPC] ,CSUC ,Cloud computing ,cloud - Abstract
Aquest document és un Projecte Final de Grau en l'especialitat de Tecnologies de la Informació realitzat a la Facultat d' Informàtica de Barcelona. Tracta sobre la creació d'un controlador per a connectar OpenNebula i vCloud Director. The document is a Final Project of Degree in the specialty of Information Technologies conducted at the Facultat d'Informàtica de Barcelona. The main objective of this work is to develop a driver to connect OpenNebula and vCloud Director.
76. QUINST: A Metamodeling Tool
- Author
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Burgués i Illa, Xavier, Franch, Xavier, and Ribó i Balust, Josep M. (Josep Maria)
77. A MOF-Compliant Approach to Software Quality Modeling
- Author
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Burgués i Illa, Xavier, Franch, Xavier, and Ribó i Balust, Josep M. (Josep Maria)
78. More on numb cheek syndrome (Roger's sign)
- Author
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J. Pradas, I. Illa, and J. Kuliseosky
- Subjects
medicine.anatomical_structure ,business.industry ,medicine ,NUMB ,Neurology (clinical) ,Anatomy ,Cheek ,business ,Sign (mathematics) - Published
- 1987
79. Quantitative multiplex immunohistochemistry reveals inter-patient lymphovascular and immune heterogeneity in primary cutaneous melanoma.
- Author
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Femel J, Hill C, Illa Bochaca I, Booth JL, Asnaashari TG, Steele MM, Moshiri AS, Do H, Zhong J, Osman I, Leachman SA, Tsujikawa T, White KP, Chang YH, and Lund AW
- Subjects
- Humans, Retrospective Studies, Immunohistochemistry, Tumor Microenvironment, Melanoma, Skin Neoplasms, Lymphatic Vessels pathology
- Abstract
Introduction: Quantitative, multiplexed imaging is revealing complex spatial relationships between phenotypically diverse tumor infiltrating leukocyte populations and their prognostic implications. The underlying mechanisms and tissue structures that determine leukocyte distribution within and around tumor nests, however, remain poorly understood. While presumed players in metastatic dissemination, new preclinical data demonstrates that blood and lymphatic vessels (lymphovasculature) also dictate leukocyte trafficking within tumor microenvironments and thereby impact anti-tumor immunity. Here we interrogate these relationships in primary human cutaneous melanoma., Methods: We established a quantitative, multiplexed imaging platform to simultaneously detect immune infiltrates and tumor-associated vessels in formalin-fixed paraffin embedded patient samples. We performed a discovery, retrospective analysis of 28 treatment-naïve, primary cutaneous melanomas., Results: Here we find that the lymphvasculature and immune infiltrate is heterogenous across patients in treatment naïve, primary melanoma. We categorized five lymphovascular subtypes that differ by functionality and morphology and mapped their localization in and around primary tumors. Interestingly, the localization of specific vessel subtypes, but not overall vessel density, significantly associated with the presence of lymphoid aggregates, regional progression, and intratumoral T cell infiltrates., Discussion: We describe a quantitative platform to enable simultaneous lymphovascular and immune infiltrate analysis and map their spatial relationships in primary melanoma. Our data indicate that tumor-associated vessels exist in different states and that their localization may determine potential for metastasis or immune infiltration. This platform will support future efforts to map tumor-associated lymphovascular evolution across stage, assess its prognostic value, and stratify patients for adjuvant therapy., Competing Interests: AL reports consulting services for AGS Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Femel, Hill, Illa Bochaca, Booth, Asnaashari, Steele, Moshiri, Do, Zhong, Osman, Leachman, Tsujikawa, White, Chang and Lund.)
- Published
- 2024
- Full Text
- View/download PDF
80. Kinase Insert Domain Receptor Q472H Pathogenic Germline Variant Impacts Melanoma Tumor Growth and Patient Treatment Outcomes.
- Author
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Ibrahim M, Illa-Bochaca I, Fa'ak F, Monson KR, Ferguson R, Lyu C, Vega-Saenz de Miera E, Johannet P, Chou M, Mastroianni J, Darvishian F, Kirchhoff T, Zhong J, Krogsgaard M, and Osman I
- Abstract
Background: We previously reported a higher incidence of a pathogenic germline variant in the kinase insert domain receptor (KDR) in melanoma patients compared to the general population. Here, we dissect the impact of this genotype on melanoma tumor growth kinetics, tumor phenotype, and response to treatment with immune checkpoint inhibitors (ICIs) or targeted therapy., Methods: The KDR genotype was determined and the associations between the KDR Q472H variant (KDR-Var), angiogenesis, tumor immunophenotype, and response to MAPK inhibition or ICI treatment were examined. Melanoma B16 cell lines were transfected with KDR-Var or KDR wild type (KDR-WT), and the differences in tumor kinetics were evaluated. We also examined the impact of KDR-Var on the response of melanoma cells to a combination of VEGFR inhibition with MAPKi., Results: We identified the KDR-Var genotype in 81/489 (37%) patients, and it was associated with a more angiogenic ( p = 0.003) and immune-suppressive tumor phenotype. KDR-Var was also associated with decreased PFS to MAPKi ( p = 0.022) and a trend with worse PFS to anti-PD1 therapy ( p = 0.06). KDR-Var B16 murine models had increased average tumor volume ( p = 0.0027) and decreased CD45 tumor-infiltrating lymphocytes ( p = 0.0282). The anti-VEGFR treatment Lenvatinib reduced the tumor size of KDR-Var murine tumors ( p = 0.0159), and KDR-Var cells showed synergistic cytotoxicity to the combination of dabrafenib and lenvatinib., Conclusions: Our data demonstrate a role of germline KDR-Var in modulating melanoma behavior, including response to treatment. Our data also suggest that anti-angiogenic therapy might be beneficial in patients harboring this genotype, which needs to be tested in clinical trials., Competing Interests: The authors declare no potential competing interests.
- Published
- 2023
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81. Effect of monovalency on anti-contactin-1 IgG4.
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Taieb G, Jentzer A, Vegezzi E, Lleixà C, Illa I, Querol L, and Devaux JJ
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- Nerve Growth Factors, Contactin 1, Cell Adhesion Molecules, Autoantibodies, Immunoglobulin G, Antibodies, Bispecific
- Abstract
Introduction: Autoimmune nodopathies (AN) have been diagnosed in a subset of patients fulfilling criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who display no or poor response to intravenous immunoglobulins. Biomarkers of AN are autoantibodies, mainly IgG4, directed against the ternary paranodal complex composed by neurofascin-155, contactin-1 (CNTN1), and Contactin-associated-protein-1 (CASPR1) or against the nodal isoforms of neurofascin. IgG4 can undergo a Fab-arm exchange (FAE) which results in functionally monovalent antibody. This phenomenon differentially affects the pathogenicity of IgG4 depending on the target of autoantibodies. Here, we have evaluated this issue by examining the impact of valency on anti-CNTN1 IgG4 which induces paranodal destruction through a function blocking activity., Methods: Sera were obtained from 20 patients with AN associated with anti-CNTN1 antibodies. The proportion of monospecific/bispecific anti-CNTN1 antibodies was estimated in each patient by ELISA by examining the ability of serum antibodies to cross-link untagged CNTN1 with biotinylated CNTN1. To determine the impact of monovalency, anti-CNTN1 IgG4 were enzymatically digested into monovalent Fab and tested in vitro on cell aggregation assay. Also, intraneural injections were performed to determine whether monovalent Fab and native IgG4 may penetrate paranode, and antibody infiltration was monitored 1- and 3-days post injection., Results and Discussion: We found that the percentage of monospecific antibodies were lower than 5% in 14 out of 20 patients (70%), suggesting that IgG4 have undergone extensive FAE in situ . The levels of monospecific antibodies correlated with the titers of anti-CNTN1 antibodies. However, no correlation was found with clinical severity, and patients with low or high percentage of monospecific antibodies similarly showed a severe phenotype. Native anti-CNTN1 IgG4 were shown to inhibit the interaction between cells expressing CNTN1/CASPR1 and cells expressing neurofascin-155 using an in vitro aggregation assay. Similarly, monovalent Fab significantly inhibited the interaction between CNTN1/CASPR1 and neurofascin-155. Intraneural injections of Fab and native anti-CNTN1 IgG4 indicated that both mono- and bivalent anti-CNTN1 IgG4 potently penetrated the paranodal regions and completely invaded this region by day 3. Altogether, these data indicate anti-CNTN1 IgG4 are mostly bispecific in patients, and that functionally monovalent anti-CNTN1 antibodies have the pathogenic potency to alter paranode., Competing Interests: LQ received research grants from Instituto de Salud Carlos III – Ministry of Economy and Innovation Spain, Fundació La Marató, GBS-CIDP Foundation International, Novartis Pharma Spain, Roche, UCB and Grifols. LQ received speaker or expert testimony honoraria from CSL Behring, Novartis, Sanofi-Genzyme, Merck, Annexon, Biogen, Janssen, ArgenX, UCB, LFB, Octapharma and Roche. LQ serves at Clinical Trial Steering Committee for Sanofi Genzyme and Roche, and is Principal Investigator for UCB’s CIDP01 trial. JD received a research grant from CSL Behring. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Taieb, Jentzer, Vegezzi, Lleixà, Illa, Querol and Devaux.)
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- 2023
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82. Genomic and Transcriptomic Analyses of NF1-Mutant Melanoma Identify Potential Targeted Approach for Treatment.
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Jour G, Illa-Bochaca I, Ibrahim M, Donnelly D, Zhu K, Miera EV, Vasudevaraja V, Mezzano V, Ramswami S, Yeh YH, Winskill C, Betensky RA, Mehnert J, and Osman I
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- Humans, Neurofibromin 1 genetics, Genomics, Gene Expression Profiling, Protein Kinase Inhibitors pharmacology, Mutation, Transcriptome, Melanoma genetics
- Abstract
There is currently no targeted therapy to treat NF1-mutant melanomas. In this study, we compared the genomic and transcriptomic signatures of NF1-mutant and NF1 wild-type melanoma to reveal potential treatment targets for this subset of patients. Genomic alterations were verified using qPCR, and differentially expressed genes were independently validated using The Cancer Genome Atlas data and immunohistochemistry. Digital spatial profiling with multiplex immunohistochemistry and immunofluorescence were used to validate the signatures. The efficacy of combinational regimens driven by these signatures was tested through in vitro assays using low-passage cell lines. Pathogenic NF1 mutations were identified in 27% of cases. NF1-mutant melanoma expressed higher proliferative markers MK167 and CDC20 than NF1 wild-type (P = 0.008), which was independently validated both in The Cancer Genome Atlas dataset (P = 0.01, P = 0.03) and with immunohistochemistry (P = 0.013, P = 0.036), respectively. Digital spatial profiling analysis showed upregulation of LY6E within the tumor cells (false discovery rate < 0.01, log2 fold change > 1), confirmed with multiplex immunofluorescence showing colocalization of LY6E in melanoma cells. The combination of MAPK/extracellular signal‒regulated kinase kinase and CDC20 coinhibition induced both cytotoxic and cytostatic effects, decreasing CDC20 expression in multiple NF1-mutant cell lines. In conclusion, NF1-mutant melanoma is associated with a distinct genomic and transcriptomic profile. Our data support investigating CDC20 inhibition with MAPK pathway inhibitors as a targeted regimen in this melanoma subtype., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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83. Reduced Number of Thymoma CTLA4-Positive Cells Is Associated With a Higher Probability of Developing Myasthenia Gravis.
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Álvarez-Velasco R, Dols-Icardo O, El Bounasri S, López-Vilaró L, Trujillo JC, Reyes-Leiva D, Suárez-Calvet X, Cortés-Vicente E, Illa I, and Gallardo E
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- Humans, CTLA-4 Antigen genetics, Retrospective Studies, Forkhead Transcription Factors genetics, Probability, Thymoma, Thymus Neoplasms complications, Myasthenia Gravis
- Abstract
Background and Objectives: Myasthenia gravis (MG) is an autoimmune disease associated with comorbid thymoma in 10%-15% of cases. Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) expressed by T cells downregulates T-cell-mediated immune response. Polymorphisms in the CTLA4 gene have been associated with the development of MG. In this context, we aimed to determine whether CTLA4 expression in the thymoma differs between patients with and without MG and whether CTLA4 gene polymorphisms are associated with these differences., Methods: This is a retrospective study of all patients, with and without MG, surgically treated at our institution for thymoma between January 2010 and December 2020. Ten samples were obtained from normal thymuses as controls. The number of CTLA4-positive cells in paraffin-embedded thymoma samples was determined by immunohistochemistry. The presence of follicular-center and regulatory T-cell lymphocytes was determined by immunohistochemistry (B-cell lymphoma [BCL]-6 expression) and double immunofluorescence-based staining of CD4-FOXP3, respectively. We evaluated the association between thymic expression of CTLA4 and the development of MG. We also determined the association between CTLA4 expression and various clinical and prognostic characteristics of MG. We sequenced the CTLA4 gene and evaluated possible associations between CTLA4 polymorphisms and thymic CTLA4 expression. Finally, we assessed the potential association between these polymorphisms and the risk of MG., Results: Forty-one patients with thymoma were included. Of them, 23 had comorbid MG (56.1%). On average, patients with MG had fewer CTLA4-positive cells in the thymoma than non-MG patients: 69.3 cells/mm
2 (95% CIs: 39.6-99.1) vs 674.4 (276.0-1,024.0) cells/mm2 ; p = 0.001 and vs controls (200.74 [57.9-343.6] cells/mm2 ; p = 0.02). No between-group differences (MG vs non-MG) were observed in the number of cells positive for BCL6 or CD4-FOXP3. CTLA4 expression was not associated with differences in MG outcome or treatment refractoriness. Two polymorphisms were detected in the CTLA4 gene, rs231770 (n = 30 patients) and rs231775 (n = 17). MG was present in a similar proportion of patients for all genotypes. However, a nonsignificant trend toward a lower CTLA4-positive cell count was observed among carriers of the rs231775 polymorphism vs noncarriers: 77.9 cells/mm2 (95% CI: -51.5 to 207.5) vs 343.3 cells/mm2 (95% CI: 126.2-560.4)., Discussion: Reduced CTLA4 expression in thymoma may predispose to a higher risk of developing MG., (© 2023 American Academy of Neurology.)- Published
- 2023
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84. Enrichment of serum IgG4 in MuSK myasthenia gravis patients.
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Vergoossen DLE, Ruiter AM, Keene KR, Niks EH, Tannemaat MR, Strijbos E, Lipka AF, van der Zijde ECJ, van Tol MJD, Bakker JA, Wevers BA, Westerberg E, Borges LS, Tong OC, Richman DP, Illa I, Punga AR, Evoli A, van der Maarel SM, Verschuuren JJ, and Huijbers MG
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- Humans, Autoantibodies, Immunoglobulin G, Myasthenia Gravis
- Abstract
Muscle-specific kinase (MuSK) myasthenia gravis (MG) is a neuromuscular autoimmune disease belonging to a growing group of IgG4 autoimmune diseases (IgG4-AIDs), in which the majority of pathogenic autoantibodies are of the IgG4 subclass. The more prevalent form of MG with acetylcholine receptor (AChR) antibodies is caused by IgG1-3 autoantibodies. A dominant role for IgG4 in autoimmune disease is intriguing due to its anti-inflammatory characteristics. It is unclear why MuSK autoantibodies are predominantly IgG4. We hypothesized that MuSK MG patients have a general predisposition to generate IgG4 responses, therefore resulting in high levels of circulating IgG4. To investigate this, we quantified serum Ig isotypes and IgG subclasses using nephelometric and turbidimetric assays in MuSK MG and AChR MG patients not under influence of immunosuppressive treatment. Absolute serum IgG1 was increased in both MuSK and AChR MG patients compared to healthy donors. In addition, only MuSK MG patients on average had significantly increased and enriched serum IgG4. Although more MuSK MG patients had elevated serum IgG4, for most the IgG4 serum levels fell within the normal range. Correlation analyses suggest MuSK-specific antibodies do not solely explain the variation in IgG4 levels. In conclusion, although serum IgG4 levels are slightly increased, the levels do not support ubiquitous IgG4 responses in MuSK MG patients as the underlying cause of dominant IgG4 MuSK antibodies., Competing Interests: Declaration of Competing Interest OT, LB and DR receive research support from NIH and Cabaletta Biopharma. JV, SM, MH are co-inventors on MuSK-related patents. LUMC and JV, SM and MH receive royalties from these patents. LUMC receives royalties on a MuSK ELISA. JV is consultant for Argenx, Alexion, NMD Pharma. ARP is consultant for Argenx. MH receives financial support from the LUMC (OIO 2017, Gisela Their Fellowship 2021), Top Sector Life Sciences & Health to Samenwerkende Gezondheidsfondsen (LSHM18055-SGF and LSHM19130), Prinses Beatrix Spierfonds (W.OR-19.13). The remaining authors declare no interests. The LUMC is part of the European Reference Network for Rare Neuromuscular Diseases [ERN EURO-NMD] and the Netherlands Neuromuscular Center., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2022
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85. IgG4 Valency Modulates the Pathogenicity of Anti-Neurofascin-155 IgG4 in Autoimmune Nodopathy.
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Jentzer A, Attal A, Roué C, Raymond J, Lleixà C, Illa I, Querol L, Taieb G, and Devaux J
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- Animals, Autoantibodies, Cell Adhesion Molecules, Immunoglobulin G, Nerve Growth Factors, Virulence, Polyradiculoneuropathy, Chronic Inflammatory Demyelinating
- Abstract
Background and Objectives: IgG4 autoantibodies to neurofascin-155 (Nfasc155) are associated with a subgroup of patients with chronic inflammatory demyelinating polyneuropathy (CIDP), currently named autoimmune nodopathy. We previously demonstrated that those antibodies alter conduction along myelinated axons by inducing Nfasc155 depletion and paranode destruction. In blood, IgG4 have the potency to exchange their moiety with other unrelated IgG4 through a process called Fab-arm exchange (FAE). This process results in functionally monovalent antibodies and may affect the pathogenicity of autoantibodies. Here, we examined this issue and whether FAE is beneficial or detrimental for Nfasc155 autoimmune nodopathy., Methods: The bivalency and monospecificity of anti-Nfasc155 were examined by sandwich ELISA in 10 reactive patients, 10 unreactive CIDP patients, and 10 healthy controls. FAE was induced in vitro using reduced glutathione and unreactive IgG4, and the ratio of the κ:λ light chain was monitored. To determine the pathogenic potential of bivalent anti-Nfasc155 IgG4, autoantibodies derived from patients were enzymatically cleaved into monovalent Fab and bivalent F(ab')
2 or swapped with unreactive IgG4 and then were injected in neonatal animals., Results: Monospecific bivalent IgG4 against Nfasc155 were detected in the serum of all reactive patients, indicating that a fraction of IgG4 have not undergone FAE in situ. These IgG4 were, nonetheless, capable of engaging into FAE with unreactive IgG4 in vitro, and this decreased the levels of monospecific antibodies and modulated the ratio of the κ:λ light chain. When injected in animals, monovalent anti-Nfasc155 Fab did not alter the formation of paranodes; by contrast, both native anti-Nfasc155 IgG4 and F(ab')2 fragments strongly impaired paranode formation. The promotion of FAE with unreactive IgG4 also strongly diminished the pathogenic potential of anti-Nfasc155 IgG4 in animals and decreased IgG4 clustering on Schwann cells., Discussion: Our findings demonstrate that monospecific and bivalent anti-Nfasc155 IgG4 are detected in patients and that those autoantibodies are the pathogenic ones. The transformation of anti-Nfasc155 IgG4 into monovalent Fab or functionally monovalent IgG4 through FAE strongly decreases paranodal alterations. Bivalency thus appears crucial for Nfasc155 clustering and paranode destruction., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)- Published
- 2022
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86. Rituximab in myasthenia gravis: efficacy, associated infections and risk of induced hypogammaglobulinemia.
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Caballero-Ávila M, Álvarez-Velasco R, Moga E, Rojas-Garcia R, Turon-Sans J, Querol L, Olivé M, Reyes-Leiva D, Illa I, Gallardo E, and Cortés-Vicente E
- Subjects
- Humans, Immunoglobulin G therapeutic use, Immunologic Factors adverse effects, Receptors, Cholinergic, Retrospective Studies, Rituximab adverse effects, Agammaglobulinemia chemically induced, Agammaglobulinemia drug therapy, Myasthenia Gravis
- Abstract
The aim of this study is to evaluate the long-term efficacy, safety, and impact on immunoglobulin G (IgG) levels of rituximab in patients with myasthenia gravis (MG). A retrospective, observational study of drug-refractory MG patients treated with rituximab was done. The MG Foundation of America postintervention status (MGFA-PIS) was used to evaluate clinical response. Serum IgG levels were determined at baseline and post-treatment. Hypogammaglobulinemia was defined as IgG<7g/L. Thirty patients were included, 12 with anti-MuSK and 18 with anti-AChR antibodies. Mean (SD) follow-up was 85.5 (48) months. All 12 MuSK+ patients but only six (33%) AChR+ patients achieved minimal manifestations or remission (p<0.01). Nine severe infections were observed in five patients (17%). One patient was diagnosed with progressive multifocal leukoencephalopathy. At baseline, two patients (2/24; 8%) had hypogammaglobulinemia. During follow-up, hypogammaglobulinemia was observed in 60% (3/5) of patients who developed an infection and in 33% (7/21) who did not. Two of these patients died of infection-related complications. This study supports the effectiveness of rituximab in patients with MG, especially those with anti-MuSK antibodies. Severe infections may appear after rituximab treatment and hypogammaglobulinemia might play a role on it. A standard protocol would be needed to closely monitor IgG levels in MG patients treated with rituximab., (Copyright © 2022 Elsevier B.V. All rights reserved.)
- Published
- 2022
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87. BNIP3 Is Involved in Muscle Fiber Atrophy in Late-Onset Pompe Disease Patients.
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Carrasco-Rozas A, Fernández-Simón E, Suárez-Calvet X, Piñol-Jurado P, Alonso-Pérez J, de Luna N, Schoser B, Meinke P, Domínguez-González C, Hernández-Laín A, Paradas C, Rivas E, Illa I, Olivé M, Gallardo E, and Díaz-Manera J
- Subjects
- Atrophy pathology, Humans, Membrane Proteins genetics, Muscle Fibers, Skeletal metabolism, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases metabolism, Glycogen Storage Disease Type II genetics, Glycogen Storage Disease Type II pathology
- Abstract
Late-onset Pompe disease (LOPD) is a rare genetic disorder produced by mutations in the GAA gene and is characterized by progressive muscle weakness. LOPD muscle biopsies show accumulation of glycogen along with the autophagic vacuoles associated with atrophic muscle fibers. The expression of molecules related to muscle fiber atrophy in muscle biopsies of LOPD patients was studied using immunofluorescence and real-time PCR. BCL2 and adenovirus E1B 19-kDa interacting protein 3 (BNIP3), a well-known atrogene, was identified as a potential mediator of muscle fiber atrophy in LOPD muscle biopsies. Vacuolated fibers in LOPD patient muscle biopsies were smaller than nonvacuolated fibers and expressed BNIP3. The current data suggested that BNIP3 expression is regulated by inhibition of the AKT-mammalian target of rapamycin pathway, leading to phosphorylation of Unc-51 like autophagy activating kinase 1 (ULK1) at Ser317 by AMP-activated protein kinase. Myoblasts and myotubes obtained from LOPD patients and age-matched controls were studied to confirm these results using different molecular techniques. Myotubes derived from LOPD patients were likewise smaller and expressed BNIP3. Conclusively, transfection of BNIP3 into control myotubes led to myotube atrophy. These findings suggest a cascade that starts with the inhibition of the AKT-mammalian target of rapamycin pathway and activation of BNIP3 expression, leading to progressive muscle fiber atrophy. These results open the door to potential new treatments targeting BNIP3 to reduce its deleterious effects on muscle fiber atrophy in Pompe disease., (Copyright © 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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88. Immune Response and Safety of SARS-CoV-2 mRNA-1273 Vaccine in Patients With Myasthenia Gravis.
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Reyes-Leiva D, López-Contreras J, Moga E, Pla-Juncà F, Lynton-Pons E, Rojas-Garcia R, Turon-Sans J, Querol L, Olive M, Álvarez-Velasco R, Caballero-Ávila M, Carbayo Á, Vesperinas-Castro A, Domingo P, Illa I, Gallardo E, and Cortés-Vicente E
- Subjects
- Antibodies, Viral blood, Humans, Immunity, Cellular, Immunity, Humoral, Longitudinal Studies, Prospective Studies, SARS-CoV-2, T-Lymphocytes immunology, 2019-nCoV Vaccine mRNA-1273 adverse effects, 2019-nCoV Vaccine mRNA-1273 immunology, COVID-19 prevention & control, Myasthenia Gravis complications
- Abstract
Background and Objectives: Evidence regarding the safety and efficacy of messenger RNA (mRNA) vaccines in patients with myasthenia gravis (MG) after immunosuppressive therapies is scarce. Our aim is to determine whether the mRNA-1273 vaccine is safe and able to induce humoral and cellular responses in patients with MG., Methods: We performed an observational, longitudinal, prospective study including 100 patients with MG of a referral center for MG in our country, conducted from April 2021 to November 2021 during the vaccination campaign. The mRNA-1273 vaccine was scheduled for all participants. Blood samples were collected before vaccination and 3 months after a second dose. Clinical changes in MG were measured using the MG activities of daily life score at baseline and 1 week after the first and second doses. A surveillance of all symptoms of coronavirus disease 2019 (COVID-19) was conducted throughout the study. Humoral and cellular immune responses after vaccination were assessed using a spike-antibody ELISA and interferon gamma release assay in plasma. The primary outcomes were clinically significant changes in MG symptoms after vaccination, adverse events (AEs), and seroconversion and T-cell immune response rates., Results: Ninety-nine patients completed the full vaccination schedule, and 98 had 2 blood samples taken. A statistically significant worsening of symptoms was identified after the first and second doses of the mRNA-1273 vaccine, but this was not clinically relevant. Mild AEs occurred in 14 patients after the first dose and in 21 patients after the second dose. Eighty-seven patients developed a humoral response and 72 patients showed a T-cell response after vaccination. A combined therapy with prednisone and other immunosuppressive drugs correlated with a lower seroconversion ratio (OR = 5.97, 95% CI 1.46-24.09, p = 0.015) and a lower T-cell response ratio (OR = 2.83, 95% CI 1.13-7.13, p = 0.024)., Discussion: Our findings indicate that the mRNA vaccination against COVID-19 is safe in patients with MG and show no negative impact on the disease course. Patients achieved high humoral and cellular immune response levels., Classification of Evidence: This study provides Class IV evidence that patients with MG receiving the mRNA-1273 vaccine did not show clinical worsening after vaccination and that most of the patients achieved high cellular or immune response levels., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
- Published
- 2022
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89. Predicting Outcome in Guillain-Barré Syndrome: International Validation of the Modified Erasmus GBS Outcome Score.
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Doets AY, Lingsma HF, Walgaard C, Islam B, Papri N, Davidson A, Yamagishi Y, Kusunoki S, Dimachkie MM, Waheed W, Kolb N, Islam Z, Mohammad QD, Harbo T, Sindrup SH, Chavada G, Willison HJ, Casasnovas C, Bateman K, Miller JAL, van den Berg B, Verboon C, Roodbol J, Leonhard SE, Benedetti L, Kuwabara S, Van den Bergh P, Monges S, Marfia GA, Shahrizaila N, Galassi G, Péréon Y, Bürmann J, Kuitwaard K, Kleyweg RP, Marchesoni C, Sedano Tous MJ, Querol L, Illa I, Wang Y, Nobile-Orazio E, Rinaldi S, Schenone A, Pardo J, Vermeij FH, Lehmann HC, Granit V, Cavaletti G, Gutiérrez-Gutiérrez G, Barroso FA, Visser LH, Katzberg HD, Dardiotis E, Attarian S, van der Kooi AJ, Eftimov F, Wirtz PW, Samijn JPA, Gilhuis HJ, Hadden RDM, Holt JKL, Sheikh KA, Karafiath S, Vytopil M, Antonini G, Feasby TE, Faber CG, Gijsbers CJ, Busby M, Roberts RC, Silvestri NJ, Fazio R, van Dijk GW, Garssen MPJ, Straathof CSM, Gorson KC, and Jacobs BC
- Subjects
- Child, Cohort Studies, Humans, Outcome Assessment, Health Care, Prognosis, Prospective Studies, Guillain-Barre Syndrome diagnosis, Guillain-Barre Syndrome therapy
- Abstract
Background and Objectives: The clinical course and outcome of the Guillain-Barré syndrome (GBS) are diverse and vary among regions. The modified Erasmus GBS Outcome Score (mEGOS), developed with data from Dutch patients, is a clinical model that predicts the risk of walking inability in patients with GBS. The study objective was to validate the mEGOS in the International GBS Outcome Study (IGOS) cohort and to improve its performance and region specificity., Methods: We used prospective data from the first 1,500 patients included in IGOS, aged ≥6 years and unable to walk independently. We evaluated whether the mEGOS at entry and week 1 could predict the inability to walk unaided at 4 and 26 weeks in the full cohort and in regional subgroups, using 2 measures for model performance: (1) discrimination: area under the receiver operating characteristic curve (AUC) and (2) calibration: observed vs predicted probability of being unable to walk independently. To improve the model predictions, we recalibrated the model containing the overall mEGOS score, without changing the individual predictive factors. Finally, we assessed the predictive ability of the individual factors., Results: For validation of mEGOS at entry, 809 patients were eligible (Europe/North America [n = 677], Asia [n = 76], other [n = 56]), and 671 for validation of mEGOS at week 1 (Europe/North America [n = 563], Asia [n = 65], other [n = 43]). AUC values were >0.7 in all regional subgroups. In the Europe/North America subgroup, observed outcomes were worse than predicted; in Asia, observed outcomes were better than predicted. Recalibration improved model accuracy and enabled the development of a region-specific version for Europe/North America (mEGOS-Eu/NA). Similar to the original mEGOS, severe limb weakness and higher age were the predominant predictors of poor outcome in the IGOS cohort., Discussion: mEGOS is a validated tool to predict the inability to walk unaided at 4 and 26 weeks in patients with GBS, also in countries outside the Netherlands. We developed a region-specific version of mEGOS for patients from Europe/North America., Classification of Evidence: This study provides Class II evidence that the mEGOS accurately predicts the inability to walk unaided at 4 and 26 weeks in patients with GBS., Trial Registration Information: NCT01582763., (© 2021 American Academy of Neurology.)
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- 2022
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90. Drug-refractory myasthenia gravis: Clinical characteristics, treatments, and outcome.
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Cortés-Vicente E, Álvarez-Velasco R, Pla-Junca F, Rojas-Garcia R, Paradas C, Sevilla T, Casasnovas C, Gómez-Caravaca MT, Pardo J, Ramos-Fransi A, Pelayo-Negro AL, Gutiérrez-Gutiérrez G, Turon-Sans J, López de Munain A, Guerrero-Sola A, Jericó I, Martín MA, Mendoza MD, Morís G, Vélez-Gómez B, Garcia-Sobrino T, Pascual-Goñi E, Reyes-Leiva D, Illa I, and Gallardo E
- Subjects
- Adult, Aged, Cross-Sectional Studies, Female, Follow-Up Studies, Humans, Male, Middle Aged, Outcome Assessment, Health Care, Retrospective Studies, Spain, Immunologic Factors pharmacology, Myasthenia Gravis diagnosis, Myasthenia Gravis drug therapy, Myasthenia Gravis immunology, Registries
- Abstract
Objective: To describe the clinical characteristics and outcomes in patients with refractory myasthenia gravis (MG) and to determine the effectiveness and side effects of the drugs used for their treatment., Methods: This observational retrospective cross-sectional multicenter study was based on data from the Spanish MG Registry (NMD-ES). Patients were considered refractory when their MG Foundation of America post-interventional status (MGFA-PIS) was unchanged or worse after corticosteroids and two or more other immunosuppressive agents. Clinical and immunologic characteristics of drug-refractory patients, efficiency and toxicity of drugs used, and outcome (MGFA-PIS) at end of follow-up were studied., Results: We included 990 patients from 15 hospitals. Eighty-four patients (68 of 842 anti-acetylcholine receptor [AChR], 5 of 26 anti-muscle-specific tyrosine kinase [MusK], 10 of 120 seronegative, and 1 of 2 double-seropositive patients) were drug refractory. Drug-refractory patients were more frequently women (p < 0.0001), younger at onset (p < 0.0001), and anti-MuSK positive (p = 0.037). Moreover, they more frequently presented a generalized form of the disease, bulbar symptoms, and life-threatening events (p < 0.0001; p = 0.018; and p = 0.002, respectively) than non-drug-refractory patients. Mean follow-up was 9.8 years (SD 4.5). Twenty-four (50%) refractory patients had side effects to one or more of the drugs. At the end of follow-up, 42.9% of drug-refractory patients (42.6% of anti-AChR, 100% of anti-MuSK, and 10% of seronegative patients) and 79.8% of non-drug-refractory patients (p < 0.0001) achieved remission or had minimal manifestations. Eighty percent of drug-refractory-seronegative patients did not respond to any drug tested., Interpretation: In this study, 8.5% of MG patients were drug-refractory. New more specific drugs are needed to treat drug-refractory MG patients., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
- Published
- 2022
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91. Clinical and Laboratory Features in Anti-NF155 Autoimmune Nodopathy.
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Martín-Aguilar L, Lleixà C, Pascual-Goñi E, Caballero-Ávila M, Martínez-Martínez L, Díaz-Manera J, Rojas-García R, Cortés-Vicente E, Turon-Sans J, de Luna N, Suárez-Calvet X, Gallardo E, Rajabally Y, Scotton S, Jacobs BC, Baars A, Cortese A, Vegezzi E, Höftberger R, Zimprich F, Roesler C, Nobile-Orazio E, Liberatore G, Hiew FL, Martínez-Piñeiro A, Carvajal A, Piñar-Morales R, Usón-Martín M, Albertí O, López-Pérez MÁ, Márquez F, Pardo-Fernández J, Muñoz-Delgado L, Cabrera-Serrano M, Ortiz N, Bartolomé M, Duman Ö, Bril V, Segura-Chávez D, Pitarokoili K, Steen C, Illa I, and Querol L
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Retrospective Studies, Young Adult, Autoantibodies blood, Autoimmune Diseases of the Nervous System blood, Autoimmune Diseases of the Nervous System drug therapy, Autoimmune Diseases of the Nervous System immunology, Autoimmune Diseases of the Nervous System physiopathology, Cell Adhesion Molecules immunology, Immunologic Factors pharmacology, Nerve Growth Factors immunology, Ranvier's Nodes immunology, Rituximab pharmacology
- Abstract
Background and Objectives: To study the clinical and laboratory features of antineurofascin-155 (NF155)-positive autoimmune nodopathy (AN)., Methods: Patients with anti-NF155 antibodies detected on routine immunologic testing were included. Clinical characteristics, treatment response, and functional scales (modified Rankin Scale [mRS] and Inflammatory Rasch-built Overall Disability Scale [I-RODS]) were retrospectively collected at baseline and at the follow-up. Autoantibody and neurofilament light (NfL) chain levels were analyzed at baseline and at the follow-up., Results: Forty NF155+ patients with AN were included. Mean age at onset was 42.4 years. Patients presented with a progressive (75%), sensory motor (87.5%), and symmetric distal-predominant weakness in upper (97.2%) and lower extremities (94.5%), with tremor and ataxia (75%). Patients received a median of 3 (2-4) different treatments in 46 months of median follow-up. Response to IV immunoglobulin (86.8%) or steroids (72.2%) was poor in most patients, whereas 77.3% responded to rituximab. HLA-DRB1*15 was detected in 91.3% of patients. IgG4 anti-NF155 antibodies were predominant in all patients; anti-NF155 titers correlated with mRS within the same patient ( r = 0.41, p = 0.004). Serum NfL (sNfL) levels were higher in anti-NF155+ AN than in healthy controls (36.47 vs 7.56 pg/mL, p < 0.001) and correlated with anti-NF155 titers ( r = 0.43, p = 0.001), with I-RODS at baseline ( r = -0.88, p < 0.001) and with maximum I-RODS achieved ( r = -0.58, p = 0.01). Anti-NF155 titers and sNfL levels decreased in all rituximab-treated patients., Discussion: Anti-NF155 AN presents a distinct clinical profile and good response to rituximab. Autoantibody titers and sNfL are useful to monitor disease status in these patients. The use of untagged-NF155 plasmids minimizes the detection of false anti-NF155+ cases., Classification of Evidence: This study provides Class IV evidence that anti-NF155 antibodies associate with a specific phenotype and response to rituximab., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2021
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92. Autoantibody screening in Guillain-Barré syndrome.
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Lleixà C, Martín-Aguilar L, Pascual-Goñi E, Franco T, Caballero M, de Luna N, Gallardo E, Suárez-Calvet X, Martínez-Martínez L, Diaz-Manera J, Rojas-García R, Cortés-Vicente E, Turón J, Casasnovas C, Homedes C, Gutiérrez-Gutiérrez G, Jimeno-Montero MC, Berciano J, Sedano-Tous MJ, García-Sobrino T, Pardo-Fernández J, Márquez-Infante C, Rojas-Marcos I, Jericó-Pascual I, Martínez-Hernández E, Morís de la Tassa G, Domínguez-González C, Juárez C, Illa I, and Querol L
- Subjects
- Aged, Animals, Cell Line, Tumor, Cohort Studies, Female, Ganglia, Spinal metabolism, Ganglia, Spinal pathology, Guillain-Barre Syndrome epidemiology, Humans, Macaca, Male, Mass Screening methods, Middle Aged, Prospective Studies, Rats, Spain epidemiology, Autoantibodies blood, Guillain-Barre Syndrome blood, Guillain-Barre Syndrome diagnosis
- Abstract
Background: Guillain-Barré syndrome (GBS) is an acute inflammatory neuropathy with a heterogeneous presentation. Although some evidences support the role of autoantibodies in its pathogenesis, the target antigens remain unknown in a substantial proportion of GBS patients. The objective of this study is to screen for autoantibodies targeting peripheral nerve components in Guillain-Barré syndrome., Methods: Autoantibody screening was performed in serum samples from all GBS patients included in the International GBS Outcome study by 11 different Spanish centres. The screening included testing for anti-ganglioside antibodies, anti-nodo/paranodal antibodies, immunocytochemistry on neuroblastoma-derived human motor neurons and murine dorsal root ganglia (DRG) neurons, and immunohistochemistry on monkey peripheral nerve sections. We analysed the staining patterns of patients and controls. The prognostic value of anti-ganglioside antibodies was also analysed., Results: None of the GBS patients (n = 100) reacted against the nodo/paranodal proteins tested, and 61 (61%) were positive for, at least, one anti-ganglioside antibody. GBS sera reacted strongly against DRG neurons more frequently than controls both with IgG (6% vs 0%; p = 0.03) and IgM (11% vs 2.2%; p = 0.02) immunodetection. No differences were observed in the proportion of patients reacting against neuroblastoma-derived human motor neurons. Reactivity against monkey nerve tissue was frequently detected both in patients and controls, but specific patterns were only detected in GBS patients: IgG from 13 (13%) patients reacted strongly against Schwann cells. Finally, we confirmed that IgG anti-GM1 antibodies are associated with poorer outcomes independently of other known prognostic factors., Conclusion: Our study confirms that (1) GBS patients display a heterogeneous repertoire of autoantibodies targeting nerve cells and structures; (2) gangliosides are the most frequent antigens in GBS patients and have a prognostic value; (3) further antigen-discovery experiments may elucidate other potential antigens in GBS., (© 2021. The Author(s).)
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- 2021
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93. Comment to "Autoantibodies to cortactin and agrin in sera of patients with myasthenia gravis".
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Cortés-Vicente E, Alvárez-Velasco R, Illa I, and Gallardo E
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- Autoantibodies, Cortactin, Humans, Receptors, Cholinergic, Agrin, Myasthenia Gravis
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- 2021
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94. Isolation of human fibroadipogenic progenitors and satellite cells from frozen muscle biopsies.
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Suárez-Calvet X, Fernández-Simón E, Piñol-Jurado P, Alonso-Pérez J, Carrasco-Rozas A, Lleixà C, López-Fernández S, Pons G, Soria L, Bigot A, Mouly V, Illa I, Gallardo E, Jaiswal JK, and Díaz-Manera J
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- Adolescent, Adult, Aged, Cell Differentiation, Female, Healthy Volunteers, Humans, Male, Middle Aged, Multipotent Stem Cells cytology, Multipotent Stem Cells pathology, Muscular Dystrophy, Duchenne pathology, Young Adult, Biopsy, Cell Separation, Cryopreservation, Muscle, Skeletal cytology, Muscle, Skeletal pathology, Satellite Cells, Skeletal Muscle cytology, Satellite Cells, Skeletal Muscle pathology
- Abstract
Skeletal muscle contains multiple cell types that work together to maintain tissue homeostasis. Among these, satellite cells (SC) and fibroadipogenic progenitors cells (FAPs) are the two main stem cell pools. Studies of these cells using animal models have shown the importance of interactions between these cells in repair of healthy muscle, and degeneration of dystrophic muscle. Due to the unavailability of fresh patient muscle biopsies, similar analysis of interactions between human FAPs and SCs is limited especially among the muscular dystrophy patients. To address this issue here we describe a method that allows the use of frozen human skeletal muscle biopsies to simultaneously isolate and grow SCs and FAPs from healthy or dystrophic patients. We show that while the purified SCs differentiate into mature myotubes, purified FAPs can differentiate into adipocytes or fibroblasts demonstrating their multipotency. We find that these FAPs can be immortalized and the immortalized FAPs (iFAPs) retain their multipotency. These approaches open the door for carrying out personalized analysis of patient FAPs and interactions with the SCs that lead to muscle loss., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
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- 2021
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95. Late onset Sandhoff disease presenting with lower motor neuron disease and stuttering.
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Alonso-Pérez J, Casasús A, Gimenez-Muñoz Á, Duff J, Rojas-Garcia R, Illa I, Straub V, Töpf A, and Díaz-Manera J
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- Adult, Female, Hexosaminidase A, Humans, Male, Middle Aged, Mutation, Phenotype, Motor Neuron Disease complications, Sandhoff Disease diagnosis, Stuttering complications
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Defects in the HEXB gene which encodes the β-subunit of β-hexosaminidase A and B enzymes, cause a GM2 gangliosidosis, also known as Sandhoff disease, which is a rare lysosomal storage disorder. The most common form of the disease lead to quickly progressing mental and motor decline in infancy; however there are other less severe forms with later onset that can also involve lower motor neurons. The diagnosis of this disease is based on low serum β-hexosaminidases A and B levels and confirmed using genetic test. We report two siblings with compound heterozygous HEXB mutations whose phenotype was extremely mild consisting in stuttering in both cases associated to mild proximal weakness in one of the cases, broadening the clinical spectrum of late onset Sandhoff disease., Competing Interests: Declaration of Competing Interest All authors report no competing interests., (Copyright © 2021 Elsevier B.V. All rights reserved.)
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- 2021
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96. Platelet Derived Growth Factor-AA Correlates With Muscle Function Tests and Quantitative Muscle Magnetic Resonance in Dystrophinopathies.
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Alonso-Jiménez A, Fernández-Simón E, Natera-de Benito D, Ortez C, García C, Montiel E, Belmonte I, Pedrosa I, Segovia S, Piñol-Jurado P, Carrasco-Rozas A, Suárez-Calvet X, Jimenez-Mallebrera C, Nascimento A, Llauger J, Nuñez-Peralta C, Montesinos P, Alonso-Pérez J, Gallardo E, Illa I, and Díaz-Manera J
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Introduction: Duchenne (DMD) and Becker (BMD) muscular dystrophy are X-linked muscular disorders produced by mutations in the DMD gene which encodes the protein dystrophin. Both diseases are characterized by progressive involvement of skeletal, cardiac, and respiratory muscles. As new treatment strategies become available, reliable biomarkers and outcome measures that can monitor disease progression are needed for clinical trials. Methods: We collected clinical and functional data and blood samples from 19 DMD patients, 13 BMD patients, and 66 healthy controls (8 pediatric and 58 adult controls), and blood samples from 15 patients with dysferlinopathy (DYSF) and studied the serum concentration of 4 growth factors involved in the process of muscle fibrosis. We correlated the serum concentration of these growth factors with several muscle function tests, spirometry results and fat fraction identified by quantitative Dixon muscle MRI. Results: We found significant differences in the serum concentration of Platelet Derived Growth Factor-AA (PDGF-AA) between DMD patients and pediatric controls, in Connective Tissue Growth Factor (CTGF) between BMD patients and adult controls, and in and Transforming Growth Factor- β1 (TGF-β1) between BMD and DYSF patients. PDGF-AA showed a good correlation with several muscle function tests for both DMD and BMD patients and with thigh fat fraction in BMD patients. Moreover, PDGF-AA levels were increased in muscle biopsies of patients with DMD and BMD as was demonstrated by immunohistochemistry and Real-Time PCR studies. Conclusion: Our study suggests that PDGF-AA should be further investigated in a larger cohort of DMD and BMD patients because it might be a good biomarker candidate to monitor the progression of these diseases., Competing Interests: PM is employed by the company Philips Healthcare Iberia. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Alonso-Jiménez, Fernández-Simón, Natera-de Benito, Ortez, García, Montiel, Belmonte, Pedrosa, Segovia, Piñol-Jurado, Carrasco-Rozas, Suárez-Calvet, Jimenez-Mallebrera, Nascimento, Llauger, Nuñez-Peralta, Montesinos, Alonso-Pérez, Gallardo, Illa and Díaz-Manera.)
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- 2021
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97. Clinical characteristics and outcomes of thymoma-associated myasthenia gravis.
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Álvarez-Velasco R, Gutiérrez-Gutiérrez G, Trujillo JC, Martínez E, Segovia S, Arribas-Velasco M, Fernández G, Paradas C, Vélez-Gómez B, Casasnovas C, Nedkova V, Guerrero-Sola A, Ramos-Fransi A, Martínez-Piñeiro A, Pardo J, Sevilla T, Gómez-Caravaca MT, López de Munain A, Jericó I, Pelayo-Negro AL, Martín MA, Morgado Y, Mendoza MD, Pérez-Pérez H, Rojas-García R, Turon-Sans J, Querol L, Gallardo E, Illa I, and Cortés-Vicente E
- Subjects
- Humans, Neoplasm Recurrence, Local, Retrospective Studies, Thymectomy, Myasthenia Gravis complications, Myasthenia Gravis epidemiology, Thymoma complications, Thymoma epidemiology, Thymus Neoplasms complications, Thymus Neoplasms epidemiology
- Abstract
Background and Purpose: Prognosis of myasthenia gravis (MG) in patients with thymoma is not well established. Moreover, it is not clear whether thymoma recurrence or unresectable lesions entail a worse prognosis of MG., Methods: This multicenter study was based on data from a Spanish neurologist-driven MG registry. All patients were aged >18 years at onset and had anti-acetylcholine receptor antibodies. We compared the clinical data of thymomatous and nonthymomatous patients. Prognosis of patients with recurrent or nonresectable thymomas was assessed., Results: We included 964 patients from 15 hospitals; 148 (15.4%) had thymoma-associated MG. Median follow-up time was 4.6 years. At onset, thymoma-associated MG patients were younger (52.0 vs. 60.4 years, p < 0.001), had more generalized symptoms (odds ratio [OR]: 3.02, 95% confidence interval [CI]: 1.95-4.68, p < 0.001) and more severe clinical forms according to the Myasthenia Gravis Foundation of America (MGFA) scale (OR: 1.6, 95% CI: 1.15-2.21, p = 0.005). Disease severity based on MGFA postintervention status (MGFA-PIS) was higher in thymomatous patients at 1 year, 5 years, and the end of follow-up. Treatment refractoriness and mortality were also higher (OR: 2.28, 95% CI: 1.43-3.63, p = 0.001; hazard ratio: 2.46, 95% CI: 1.47-4.14, p = 0.001). Myasthenic symptoms worsened in 13 of 27 patients with recurrences, but differences in long-term severity were not significant. Fifteen thymomatous patients had nonresectable thymomas with worse MGFA-PIS and higher mortality at the end of follow-up., Conclusions: Thymoma-associated MG patients had more severe myasthenic symptoms and worse prognosis. Thymoma recurrence was frequently associated with transient worsening of MG, but long-term prognosis did not differ from nonrecurrent thymoma. Patients with nonresectable thymoma tended to present severe forms of MG., (© 2021 European Academy of Neurology.)
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- 2021
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98. Antibodies to the Caspr1/contactin-1 complex in chronic inflammatory demyelinating polyradiculoneuropathy.
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Pascual-Goñi E, Fehmi J, Lleixà C, Martín-Aguilar L, Devaux J, Höftberger R, Delmont E, Doppler K, Sommer C, Radunovic A, Carvajal A, Smyth S, Williams L, Mazanec R, Potočková V, Hinds N, Cassereau J, Viala K, Lefilliatre M, Nicolas G, Foley P, Leypoldt F, Keddie S, Lunn MP, Zimprich F, Nunkoo VS, Löscher WN, Martínez-Martínez L, Díaz-Manera J, Rojas-Garcia R, Illa I, Rinaldi S, and Querol L
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Autoantibodies immunology, Autoantigens immunology, Cell Adhesion Molecules, Neuronal immunology, Contactin 1 immunology, Polyradiculoneuropathy, Chronic Inflammatory Demyelinating immunology
- Abstract
Previous studies have described the clinical, serological and pathological features of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and antibodies directed against the paranodal proteins neurofascin-155, contactin-1 (CNTN1), contactin-associated protein-1 (Caspr1), or nodal forms of neurofascin. Such antibodies are useful for diagnosis and potentially treatment selection. However, antibodies targeting Caspr1 only or the Caspr1/CNTN1 complex have been reported in few patients with CIDP. Moreover, it is unclear if these patients belong to the same pathophysiological subgroup. Using cell-based assays in routine clinical testing, we identified sera from patients with CIDP showing strong membrane reactivity when both CNTN1 and Caspr1 were co-transfected (but not when CNTN1 was transfected alone). Fifteen patients (10 male; aged between 40 and 75) with antibodies targeting Caspr1/CNTN1 co-transfected cells were enrolled for characterization. The prevalence of anti-Caspr1/CNTN1 antibodies was 1.9% (1/52) in the Sant Pau CIDP cohort, and 4.3% (1/23) in a German cohort of acute-onset CIDP. All patients fulfilled European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite diagnostic criteria for CIDP. Seven (47%) were initially diagnosed with Guillain-Barré syndrome due to an acute-subacute onset. Six (40%) patients had cranial nerve involvement, eight (53%) reported neuropathic pain and 12 (80%) ataxia. Axonal involvement and acute denervation were frequent in electrophysiological studies. Complete response to intravenous immunoglobulin was not observed, while most (90%) responded well to rituximab. Enzyme-linked immunosorbent assay (ELISA) and teased nerve fibre immunohistochemistry confirmed reactivity against the paranodal Caspr1/CNTN1 complex. Weaker reactivity against Caspr1 transfected alone was also detected in 10/15 (67%). Sera from 13 of these patients were available for testing by ELISA. All 13 samples reacted against Caspr1 by ELISA and this reactivity was enhanced when CNTN1 was added to the Caspr1 ELISA. IgG subclasses were also investigated by ELISA. IgG4 was the predominant subclass in 10 patients, while IgG3 was predominant in other three patients. In conclusion, patients with antibodies to the Caspr1/CNTN1 complex display similar serological and clinical features and constitute a single subgroup within the CIDP syndrome. These antibodies likely target Caspr1 primarily and are detected with Caspr1-only ELISA, but reactivity is optimal when CNTN1 is added to Caspr1 in cell-based assays and ELISA., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2021
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99. Inflammation Mediates the Development of Aggressive Breast Cancer Following Radiotherapy.
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Ma L, Gonzalez-Junca A, Zheng Y, Ouyang H, Illa-Bochaca I, Horst KC, Krings G, Wang Y, Fernandez-Garcia I, Chou W, and Barcellos-Hoff MH
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- Animals, Apoptosis, Breast Neoplasms pathology, Cell Proliferation, Female, Humans, Inflammation pathology, Inflammatory Breast Neoplasms etiology, Mice, Mice, Inbred BALB C, Mice, Nude, Prognosis, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Breast Neoplasms radiotherapy, Inflammation complications, Inflammatory Breast Neoplasms pathology, Macrophages immunology, Radiotherapy adverse effects, Tumor Microenvironment
- Abstract
Purpose: Women treated with radiotherapy before 30 years of age have increased risk of developing breast cancer at an early age. Here, we sought to investigate mechanisms by which radiation promotes aggressive cancer., Experimental Design: The tumor microenvironment (TME) of breast cancers arising in women treated with radiotherapy for Hodgkin lymphoma was compared with that of sporadic breast cancers. To investigate radiation effects on carcinogenesis, we analyzed tumors arising from Trp53 -null mammary transplants after irradiation of the target epithelium or host using immunocompetent and incompetent mice, some of which were treated with aspirin., Results: Compared with age-matched specimens of sporadic breast cancer, radiation-preceded breast cancers (RP-BC) were characterized by TME rich in TGFβ, cyclooxygenase 2, and myeloid cells, indicative of greater immunosuppression, even when matched for triple-negative status. The mechanism by which radiation impacts TME construction was investigated in carcinomas arising in mice bearing Trp53 -null mammary transplants. Immunosuppressive TMEs (iTME) were recapitulated in mice irradiated before transplantation, which implicated systemic immune effects. In nu/nu mice lacking adaptive immunity irradiated before Trp53 -null mammary transplantation, cancers also established an iTME, which pointed to a critical role for myeloid cells. Consistent with this, irradiated mammary glands contained more macrophages and human cells cocultured with polarized macrophages underwent dysplastic morphogenesis mediated by IFNγ. Treating mice with low-dose aspirin for 6 months postirradiation prevented establishment of an iTME and resulted in less aggressive tumors., Conclusions: These data show that radiation acts via nonmutational mechanisms to promote markedly immunosuppressive features of aggressive, RP-BCs., (©2021 American Association for Cancer Research.)
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- 2021
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100. Optimization of an automated tumor-infiltrating lymphocyte algorithm for improved prognostication in primary melanoma.
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Chou M, Illa-Bochaca I, Minxi B, Darvishian F, Johannet P, Moran U, Shapiro RL, Berman RS, Osman I, Jour G, and Zhong H
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- Adult, Aged, Automation, Laboratory, Biopsy, Databases, Factual, Disease Progression, Female, Humans, Lymphocyte Count, Male, Melanoma mortality, Melanoma pathology, Melanoma therapy, Middle Aged, Neoplasm Recurrence, Local, Neoplasm Staging, Predictive Value of Tests, Progression-Free Survival, Reproducibility of Results, Retrospective Studies, Risk Assessment, Risk Factors, Skin Neoplasms mortality, Skin Neoplasms pathology, Skin Neoplasms therapy, Tumor Microenvironment immunology, Diagnosis, Computer-Assisted, Image Interpretation, Computer-Assisted, Lymphocytes, Tumor-Infiltrating immunology, Machine Learning, Melanoma immunology, Microscopy, Skin Neoplasms immunology
- Abstract
Tumor-infiltrating lymphocytes (TIL) have potential prognostic value in melanoma and have been considered for inclusion in the American Joint Committee on Cancer (AJCC) staging criteria. However, interobserver discordance continues to prevent the adoption of TIL into clinical practice. Computational image analysis offers a solution to this obstacle, representing a methodological approach for reproducibly counting TIL. We sought to evaluate the ability of a TIL-quantifying machine learning algorithm to predict survival in primary melanoma. Digitized hematoxylin and eosin (H&E) slides from prospectively enrolled patients in the NYU melanoma database were scored for % TIL using machine learning and manually graded by pathologists using Clark's model. We evaluated the association of % TIL with recurrence-free survival (RFS) and overall survival (OS) using Cox proportional hazards modeling and concordance indices. Discordance between algorithmic and manual TIL quantification was assessed with McNemar's test and visually by an attending dermatopathologist. In total, 453 primary melanoma patients were scored using machine learning. Automated % TIL scoring significantly differentiated survival using an estimated cutoff of 16.6% TIL (log-rank P < 0.001 for RFS; P = 0.002 for OS). % TIL was associated with significantly longer RFS (adjusted HR = 0.92 [0.84-1.00] per 10% increase in % TIL) and OS (adjusted HR = 0.90 [0.83-0.99] per 10% increase in % TIL). In comparison, a subset of the cohort (n = 240) was graded for TIL by melanoma pathologists. However, TIL did not associate with RFS between groups (P > 0.05) when categorized as brisk, nonbrisk, or absent. A standardized and automated % TIL scoring algorithm can improve the prognostic impact of TIL. Incorporation of quantitative TIL scoring into the AJCC staging criteria should be considered.
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- 2021
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