[Argentinean consensus guidelines on the use of monoclonal antibodies in patients with migraine]. / Consenso sobre el uso de anticuerpos monoclonales en la migraña en Argentina.

INTRODUCTION: Migraine is a very prevalent disorder that is estimated to affect about 15% of adult subjects. Recently, the efficacy and safety of monoclonal antibodies that act on the calcitonin gene-related peptide pathway (MA-CGRP) has been evaluated in migraine. Several groups around the world have developed consensus guidelines about the use of monoclonal antibodies, however, in some regions is difficult to extrapolate the recommendations. AIM: To provide recommendations for the use of MA-CGRP in migraine in Argentina. DEVELOPMENT: A group of neurology experts from Argentina, by using the online surveys methodology as well as face to face meetings developed the intended consensus for the use of MA-CGRP in migraine in Argentina. Recommendations were established based on published evidence and the expert opinion. Recommendations focused on how, when, treatment duration and patients follow up. CONCLUSION: The recommendations of this consensus guidelines attempt to optimize the use of MA-CGRP in migraine in Argentina.

TITLE: Consenso sobre el uso de anticuerpos monoclonales en la migraña en Argentina.Introducción. La migraña es un trastorno muy prevalente que se estima que afecta a alrededor del 15% de los sujetos adultos. Durante los últimos años, se ha evaluado la eficacia y la seguridad de los anticuerpos monoclonales que actúan sobre la vía del péptido relacionado con el gen de la calcitonina (AM-PRGC) en la migraña. Diversos grupos de trabajo internacionales han intentado clarificar y normatizar el uso de estos medicamentos en la migraña. Sin embargo, en muchas ocasiones se extrapolan datos de otras regiones que no contemplan la realidad de cada lugar o son difíciles de implementar. Objetivo. Proveer recomendaciones sobre el uso de AM-PRGC en pacientes con migraña en Argentina. Desarrollo. Un grupo de expertos de Argentina conformado por neurólogos, mediante metodología de ronda de encuestas en la distancia y reuniones presenciales, llevó adelante la elaboración del consenso pretendido para el uso de AM-PRGC en pacientes con migraña en Argentina. Se establecieron las recomendaciones basadas en la evidencia publicada y en el criterio de los expertos que participaron. Las recomendaciones se enfocaron en el momento de usar los AM-PRGC en la migraña tanto crónica como episódica, la duración, los cuidados y el entorno para hacerlo. Conclusión. Las recomendaciones establecidas en el presente consenso permitirán optimizar el manejo de los AM-PRGC en pacientes con migraña en Argentina.

Free IL-18 and IL-33 cytokines in chronic spontaneous urticaria.

Overproduction of IL-18 has been described in chronic urticaria. To evaluate free IL-18 and IL-33 in chronic spontaneous urticaria (CSU). IL-18, its inhibitor IL-18BP, IL-33 and its soluble receptor ST2 (sST2) were measured (ELISA) in the sera of 73 CSU patients. Free IL-18 was calculated (law of mass action). Autologous serum skin test (ASST) was performed in all patients. Total IL-18, IL-18BP and free IL-18 serum levels were significantly higher in CSU than in controls. IL-18 and IL-18BP increased significantly in both ASST-positive and negative subgroups. Free IL-18 resulted significantly higher in the ASST-negative, but not in the ASST-positive subgroup. No differences in IL-33/sST2 levels were detected between CSU and controls. Increased levels of free IL-18 and IL-18BP, but not IL-33, was detected in CSU. Whether IL-18 up-regulation is a consequence of inflammation or one of the causes of the pathology needs to be addressed.

Intron retention regulates the expression of pectin methyl esterase inhibitor (Pmei) genes during wheat growth and development.

Pectin is an important component of the plant cell wall and its remodelling occurs during normal plant growth or following stress responses. Pectin is secreted into the cell wall in a highly methyl-esterified form and subsequently de-methyl-esterified by pectin methyl esterase (PME), whose activity is controlled by the pectin methyl esterase inhibitor protein (PMEI). Cereal cell wall contains a low amount of pectin; nonetheless the level and pattern of pectin methyl esterification play a primary role during development or pathogen infection. Since few data are available on the role of PMEI in plant development and defence of cereal species, we isolated and characterised three Pmei genes (Tdpmei2.1, Tdpmei2.2 and Tdpmei3) and their encoded products in wheat. Sequence comparisons showed a low level of intra- and inter-specific sequence conservation of PMEIs. Tdpmei2.1 and Tdpmei2.2 share 94% identity at protein level, but only 20% identity with the product of Tdpmei3. All three Tdpmei genes code for functional inhibitors of plant PMEs and do not inhibit microbial PMEs or a plant invertase. RT-PCR analyses demonstrated, for the first time to our knowledge, that Pmei genes are regulated by intron retention. Processed and unprocessed transcripts of Tdpmei2.1 and Tdpmei2.2 accumulated in several organs, but anthers contained only mature transcripts. Tdpmei3 lacks introns and its transcript accumulated mainly in stem internodes. These findings suggest that products encoded by these Tdpmei genes control organ- or tissue-specific activity of specific PME isoforms in wheat.

Paradoxical vocal cord dysfunction: clinical experience and personal considerations.

Paradoxical vocal cord dysfunction is a nosographic entity that remains to be fully elucidated as far as concerns criteria required for diagnosis and underlying aetiopathogenesis. The disorder manifests with repeated episodes of acute dyspnoea associated with a series of symptoms that may include hoarseness, globus, chest pain and "shortness of breath". A retrospective analysis of cases with acute dyspnoea referred to our Department between June 2004 and June 2005 revealed 3 patients with paradoxical vocal cord dysfunction. In 2 of these 3 cases, concomitant psychiatric morbidity was observed and the third also presented gastro-oesophageal reflux. In one patient, the episodes of dyspnoea were triggered by inspiration of irritating substances. Diagnosis of the condition requires a high level of suspicion, which is confirmed by a laryngoscopic investigation that demonstrates hyperadduction of the true vocal cords and a reduction of at least 50% in the breathing space. From a therapeutic point of view, patients with paradoxical vocal cord dysfunction require, in our opinion, a multidisciplinary approach; in fact, only a team comprising otorhinolaryngologists, phoniatricians, pulmonologists, neurologists, allergologists, psychotherapists and speech therapists is capable of defining the appropriate treatment according to the clinical and psychological characteristics of each individual patient. Our results with speech therapy, focused on respiratory and speech retraining, are reported.

Inflammatory mediators and eosinophilia in atopic and non-atopic patients with nasal polyposis.

Nasal polyps are characterized by eosinophilic infiltration and presence of inflammatory mediators, such as total IgE, eosinophil cationic protein (ECP) and cytokines. The role of atopy in nasal polyp pathogenesis is still unclear. Therefore, we evaluated serum IgE levels, nasal mucus concentrations of ECP and cytokines and the number of infiltrating eosinophils in nasal tissue of polyps from atopic and non-atopic patients. Samples were obtained from a randomized population of 31 patients with nasal polyposis having endonasal sinus surgery and of 13 control subjects undergone corrective surgery of the nasal septum. On the basis of medical history of allergy, positive skin-prick tests and total IgE levels, patients with polyposis were divided in atopic (n = 13) and non-atopic (n = 18) patients. We determined levels of IgE in blood, ECP and cytokines (IL-4, IL-6, IL-8, IFN-gamma and IL-2) in nasal mucus, and number of infiltrating eosinophils in nasal tissue. The concentrations of total IgE, ECP, IL-4 and IL-8 and eosinophilia were significantly higher in all patients with nasal polyps compared with controls. Inside, all patients with nasal polyposis showed lower levels of IL-6, IFN-gamma and IL-2 compared with controls. The atopic patients showed significant differences when compared with non-atopic patients for the higher concentrations of total IgE (698.80+/-322.24 vs. 279.63+/-234.11; P < 0.0001) and IL-8 (1437.2 pg/ml+/-1250.7 vs. 605.5 pg/ml+/-481.1; P < 0.015). These findings suggest that inflammation still remains the major factor in the etiology of nasal polyposis and show different levels of inflammatory mediators into atopic and non-atopic patients.

Anti-Sm and anti-RNP antibodies.

Among anti-nuclear antibodies, anti-Sm and anti-RNP antibodies are of the utmost importance in clinical practice. Anti-Sm antibodies are directed against 7 proteins (B/B', D1, D2, D3, E, F, G) that constitute the common core of U1, U2, U4 and U5 small nuclear ribonucleoprotein (snRNP) particles; B/B', D1 and D3 are more frequently targeted. Anti-RNP antibodies react with proteins (70 Kd, A, C) that are associated with U1 RNA and form U1snRNP. Anti-Sm and anti-RNP antibodies are directed towards both discontinuous and linear epitopes which are either contained in the protein sequence or are post-translationally modified. The assays to detect anti-Sm and anti-RNP antibodies are counterimmunoelectrophoresis (CIE), immunoblot, and ELISA, based on purified or recombinant proteins or synthetic peptides. Anti-Sm antibodies are detectable in a percentage of SLE patients comprised between 5 and 30%; they are more prevalent in blacks and because of their high specificity for SLE have been included in the serological criteria for diagnosing the disease.Anti-RNP are detectable in 25-47% of SLE patients; high titers of anti-RNP antibodies are diagnostic of mixed connective tissue disorder (MCTD). The measurement of anti-Sm and anti-RNP antibodies is more important in the diagnosis of SLE than in the follow-up of patients. However, anti-RNP antibodies are more prevalent in patients with Raynaud's phenomenon and are associated with milder renal involvement. On the contrary, anti-Sm antibodies are associated with the severity and the activity of renal involvement. The specificity of anti-Sm antibodies, together with epidemiological data, suggest that Epstein-Barr virus infection has the potential to induce anti-Sm antibodies by molecular mimicry.Anti-nuclear antibodies, a hallmark of the systemic autoimmune diseases, include several populations of antibodies with different specificities. Among them, anti-Sm and anti-RNP antibodies are of the utmost importance in clinical practice; in research, the study of the mechanisms inducing their production has opened up new perspectives and helped to elucidate the pathogenesis of autoimmune disorders.

Distribution of 3-nitrotyrosine in the nasal polyps of atopic patients.

OBJECTIVE: To investigate whether formation of nitrotyrosine in the nasal polyps of atopic patients occurs. STUDY DESIGN: A nonrandomized, retrospective, controlled qualitative and quantitative study. METHODS: Nasal polyp tissue samples were acquired from 12 atopic patients. Control fragments of nasal mucosa were taken from 10 patients undergoing corrective surgery of the nasal septum. For routine histologic examinations, hematoxylin-eosin staining was used. Low-magnification microscopy was designed to yield pathologic characteristics and high magnification to quantify the number of eosinophils in the subepithelial connective tissue. Presence of nitrotyrosine was assessed by immunohistochemical method. RESULTS: Hematoxylin-eosin staining revealed presence of numerous eosinophils in the epithelium and in the subepithelial connective tissue. All polyps were characterized by epithelial damage. Nitrotyrosine was present in the eosinophils, in the ciliated cell, and in cells of the damaged epithelium. Goblet cells, glands, and vessels were found to be negative. No significant differences concerning the localization of nitrotyrosine were recognized among the examined nasal polyps. CONCLUSIONS: Nitrotyrosine immunohistochemical staining in nasal-polyp tissues suggested the existence of progressive epithelium injury caused by peroxynitrite. Consequences of peroxynitrite formation in eosinophils remain to be precisely established. The lack of nitrotyrosine in glands and blood vessels indicated that peroxynitrite does not have a significant role in the vascular and glandular dysfunction of nasal polyps.

Cytokine secretion in nasal mucus of normal subjects and patients with allergic rhinitis.

Allergic rhinitis is regulated by the local production and release of several cytokines. The levels of Th2 cytokines IL-4, IL-6, IL-10 and the Th1 cytokine IFN-gamma were studied in nasal mucus from 30 subjects with allergic rhinitis and 45 non-atopic healthy controls. In this study a sampling technique for collecting nasal mucus, well tolerated by the subjects and with a minimal stimulation of the mucosa, was performed. The cytokine concentrations in nasal mucus samples were detected and quantitated by a new paramagnetic particle-based immunofluorescent assay system more sensitive than the conventional ELISA techniques. The new technique showed reliable values of the measured parameters. The nasal mucus from allergic patients contained significantly higher concentrations of IL-4 (25.5 +/- 3.6 pg/ml; P < 0.001) and IL-10 (1300 +/- 190 pg/ml; P < 0.05) compared to the nasal mucus from control subjects (15.2 +/- 2.3 and 532 +/- 28 pg/ml, respectively, for IL-4 and IL-10). No significant modification in IFN-gamma levels of allergic patients was found when compared to control group (respectively, 19.9 +/- 3.3 vs. 25.7 +/- 5.1 pg/ml; P > 0.05). Moreover, the allergic patients showed lower levels of IL-6 concentrations in the nasal mucus compared to control subjects (64.8 +/- 9.1 vs. 129.0 +/- 18.1 pg/ml; P = 0.0099). These data can be interpreted by the hypothesis that in response to environmental allergens there is a preferential Th2 polarity by activated CD4+ T cells and that the cytokines IL-6 and IL-10 have, respectively, an important anti-inflammatory and counterregulatory action in the pathogenesis of allergic rhinitis.

Immunological alterations in adult obsessive-compulsive disorder.

BACKGROUND: Some recent findings suggest the involvement of autoimmune mechanisms in childhood onset of obsessive-compulsive disorder (OCD), on the basis of a parallel drawn with Sydenham's chorea, a manifestation of rheumatic fever. A monoclonal antibody called D8/D17 characterizing a B-lymphocyte antigen, present in almost all patients with rheumatic fever, has been found also in children affected by OCD, Tourette syndrome, and chronic tics to a greater degree than in healthy control subjects. The few observations of disturbances of some immunologic parameters in adult OCD patients, prompted the authors to investigate and compare subsets of peripheral immunological cells for differences in adult patients with OCD and healthy control subjects. METHODS: Twenty patients suffering from OCD, with no comorbidity for other psychiatric disorders, were compared with a similar group of healthy control subjects. The immune subsets were measured by flow cytometry. RESULTS: The CD8+ lymphocytes were significantly increased and CD4+ lymphocytes significantly decreased in OCD patients, while the other cells did not differ between the two groups. No correlation was found between immunologic and clinical parameters. CONCLUSIONS: These data indicate that patients with adult OCD showed increased CD8+, i.e., suppressor T lymphocytes, and decreased CD4+, which identify helper T lymphocytes, as compared with a similar group of healthy control subjects. The findings appear peculiar to patients with OCD and are suggestive of an immunologic imbalance, which might be related to the stress deriving from the frustrating situation determined by the disorder itself.

Ritmo circadiano y accidente cerebrovascular / Stroke and circadian rhythm

La variación diaria en la aparición de Accidente Cerebro Vascular (ACV) fue examinada en 255 pacientes. Estos incluyeron 173 isquemias y 82 hemorragias intraparenquimatosas (HI). Los pacientes fueron ordenados en despiertos y dormidos, y distribuidos en 4 períodos de 6 horas cada uno. La frecuencia de aparición de ACV isquémico fue significativa (p<0,001) para el período de 08 a 14 horas (46,6%); para las HI también fue significativa (p<0,001) para el mismo período (46,3%). Se analizaron otras variables: edad, sexo y tipo de lesión relacionándolas con el estado del paciente (despierto-dormido) y con el momento (día-noche) en que ocurrió el ACV. El análisis de los pacientes con ACV isquémico y hemorrágico con manifestación al despertar mostró una frecuencia significativa (p<0,001) para las isquemias (81,3%) que para las HI (18,7%)

Ritmo circadiano y accidente cerebrovascular / Stroke and circadian rhythm

La variación diaria en la aparición de Accidente Cerebro Vascular (ACV) fue examinada en 255 pacientes. Estos incluyeron 173 isquemias y 82 hemorragias intraparenquimatosas (HI). Los pacientes fueron ordenados en despiertos y dormidos, y distribuidos en 4 períodos de 6 horas cada uno. La frecuencia de aparición de ACV isquémico fue significativa (p<0,001) para el período de 08 a 14 horas (46,6%); para las HI también fue significativa (p<0,001) para el mismo período (46,3%). Se analizaron otras variables: edad, sexo y tipo de lesión relacionándolas con el estado del paciente (despierto-dormido) y con el momento (día-noche) en que ocurrió el ACV. El análisis de los pacientes con ACV isquémico y hemorrágico con manifestación al despertar mostró una frecuencia significativa (p<0,001) para las isquemias (81,3%) que para las HI (18,7%)

Development of parkinsonism after transient ischemic attacks.

In order to correlate the influence of cerebrovascular disorders with the appearance of parkinsonism, 115 patients aged between 32 and 84 years (mean = 65) with transient ischemic attacks were followed up for one year. They were treated with platelet antiaggregant drugs. None of them received neuroleptics, calcium antagonists or other drugs known to induce parkinsonism. During the study, 8 patients (mean = 75 years) developed parkinsonism, bilateral in all but one, who remarkably enough was the only case responding to L-dopa treatment. On comparing recorded with expected incidence, our series showed significantly greater values. Our findings suggest that cerebrovascular disorders are factors contributing to parkinsonism in the elderly.

Development of parkinsonism after transient ischemic attacks.

In order to correlate the influence of cerebrovascular disorders with the appearance of parkinsonism, 115 patients aged between 32 and 84 years (mean = 65) with transient ischemic attacks were followed up for one year. They were treated with platelet antiaggregant drugs. None of them received neuroleptics, calcium antagonists or other drugs known to induce parkinsonism. During the study, 8 patients (mean = 75 years) developed parkinsonism, bilateral in all but one, who remarkably enough was the only case responding to L-dopa treatment. On comparing recorded with expected incidence, our series showed significantly greater values. Our findings suggest that cerebrovascular disorders are factors contributing to parkinsonism in the elderly.

Development of parkinsonism after transient ischemic attacks

Para tratar de correlacionar la influencia de los trastornos cerebrovasculares en el desarrollo de cuadros parkinsonianos, 115 pacientes con ataques isquémicos transitorios cuyas edades oscilan entre 32 y 84 años fueron evaluados durante un año. Los pacientes recibieron tratamiento con antiagregantes plaquetarios. En ningún caso fueron tratados con neurolépticos, antagonistas del calcio y otras drogas que pudieran causar parkinsonismo. Durante el estudio, 8 pacientes desarrollaron un cuadro parkinsoniano que fue bilateral en 7 de ellos. El único caso asimétrico fue también el único que respondió al tratamiento con L dopa. Al comparar la incidencia registrada con la esperada observamos un valor significativamente mayor en nuestra serie. Estos hallazgos sugieren que los trastornos cerebrovasculares son factores que contribuyen en el desarrollo del parkinsonismo en el anciano (AU)

Development of parkinsonism after transient ischemic attacks

Para tratar de correlacionar la influencia de los trastornos cerebrovasculares en el desarrollo de cuadros parkinsonianos, 115 pacientes con ataques isquémicos transitorios cuyas edades oscilan entre 32 y 84 años fueron evaluados durante un año. Los pacientes recibieron tratamiento con antiagregantes plaquetarios. En ningún caso fueron tratados con neurolépticos, antagonistas del calcio y otras drogas que pudieran causar parkinsonismo. Durante el estudio, 8 pacientes desarrollaron un cuadro parkinsoniano que fue bilateral en 7 de ellos. El único caso asimétrico fue también el único que respondió al tratamiento con L dopa. Al comparar la incidencia registrada con la esperada observamos un valor significativamente mayor en nuestra serie. Estos hallazgos sugieren que los trastornos cerebrovasculares son factores que contribuyen en el desarrollo del parkinsonismo en el anciano