Guideline on the use of onabotulinumtoxinA in chronic migraine. a consensus statement from the European Headache Federation

OnabotulinumtoxinA is being increasingly used in the management of chronic migraine (CM). Treatment with onabotulinumtoxinA poses challenges compared with traditional therapy with orally administered preventatives. The European Headache Federation identified an expert group that was asked to develop the present guideline to provide recommendations for the use of onabotulinumtoxinA in CM. The expert group recommend onabotulinumtoxinA as an effective and well-tolerated treatment of CM. Patients should preferably have tried two to three other migraine prophylactics before start of onabotulinumtoxinA. Patients with medication overuse should be withdrawn from the overused medication before initiation of onabotulinumtoxinA if feasible, if not onabotulinumtoxinA can be initiated from the start or before withdrawal. OnabotulinumtoxinA should be administered according to the PREEMPT injection protocol, i.e. injecting 155 U-195 U to 31-39 sites every 12-weeks. We recommend that patients are defined as non-responders, if they have less than 30% reduction in headache days per month during treatment with onabotulinumtoxinA. However other factors such as headache intensity, disability and patient preferences should also be considered when evaluating response. Treatment should be stopped, if the patient does not respond to the first two to three treatment cycles. Response to continued treatment with onabotulinumtoxinA should be evaluated by comparing the 4 weeks before with the 4 weeks after each treatment cycle. It is recommended that treatment is stopped in patients with a reduction to less than 10 headache days per month for 3 months and that patients are re-evaluated 4-5 months after stopping onabotulinumtoxinA to make sure that the patient has not returned to CM. Questions regarding efficacy and tolerability of onabotulinumtoxinA could be answered on the basis of scientific evidence. The other recommendations were mainly based on expert opinion. Future research on the treatment of CM with onabotulinumtoxinA may further improve the management of this highly disabling disorder

Uncontrolled asthma: assessing quality of life and productivity of children and their caregivers using a cross-sectional Internet-based survey

<p>Abstract</p> <p>Background</p> <p>Results of a national survey of asthmatic children that evaluated management goals established in 2004 by the National Asthma Education and Prevention Program (NAEPP) indicated that asthma symptom control fell short on nearly every goal.</p> <p>Methods</p> <p>An Internet-based survey was administered to adult caregivers of children aged 6-12 years with moderate to severe asthma. Asthma was categorized as uncontrolled when the caregiver reported pre-specified criteria for daytime symptoms, nighttime awakening, activity limitation, or rescue medication based on the NAEPP guidelines. Children's health-related quality of life (HRQOL) and caregivers' quality of life (QOL) were assessed using the Child Health Questionnaire Parent Form 28 (CHQ-PF28) and caregiver's work productivity using a modified Work Productivity and Activity Impairment Questionnaire. Children with uncontrolled vs. controlled asthma were compared.</p> <p>Results</p> <p>360 caregivers of children with uncontrolled asthma and 113 of children with controlled asthma completed the survey. Children with uncontrolled asthma had significantly lower CHQ-PF28 physical (mean 38.1 vs 49.8, uncontrolled vs controlled, respectively) and psychosocial (48.2 vs 53.8) summary measure scores. They were more likely to miss school (5.5 vs 2.2 days), arrive late or leave early (26.7 vs 7.1%), miss school-related activities (40.6 vs 6.2%), use a rescue inhaler at school (64.2 vs 31.0%), and visit the health office or school nurse (22.5 vs 8.8%). Caregivers of children with uncontrolled asthma reported significantly greater work and activity impairment and lower QOL for emotional, time-related and family activities.</p> <p>Conclusions</p> <p>Poorly controlled asthma symptoms impair HRQOL of children, QOL of their caregivers, and productivity of both. Proper treatment and management to improve symptom control may reduce humanistic and economic burdens on asthmatic children and their caregivers.</p

European Headache Federation (EHF) consensus on the definition of effective treatment of a migraine attack and of triptan failure

Attack; Migraine; TriptanAtaque; Migraña; TriptánAtac; Migranya; TriptanBackground Triptans are migraine-specific acute treatments. A well-accepted definition of triptan failure is needed in clinical practice and for research. The primary aim of the present Consensus was to provide a definition of triptan failure. To develop this definition, we deemed necessary to develop as first a consensus definition of effective treatment of an acute migraine attack and of triptan-responder. Main body The Consensus process included a preliminary literature review, a Delphi round and a subsequent open discussion. According to the Consensus Panel, effective treatment of a migraine attack is to be defined on patient well-being featured by a) improvement of headache, b) relief of non-pain symptoms and c) absence of adverse events. An attack is considered effectively treated if patient’s well-being, as defined above, is restored within 2 hours and for at least 24 hours. An individual with migraine is considered as triptan-responder when the given triptan leads to effective acute attack treatment in at least three out of four migraine attacks. On the other hand, an individual with migraine is considered triptan non-responder in the presence of failure of a single triptan (not matching the definition of triptan-responder). The Consensus Panel defined an individual with migraine as triptan-resistant in the presence of failure of at least 2 triptans; triptan refractory, in the presence of failure to at least 3 triptans, including subcutaneous formulation; triptan ineligibile in the presence of an acknowledged contraindication to triptan use, as specified in the summary of product characteristics. Conclusions The novel definitions can be useful in clinical practice for the assessment of acute attack treatments patients with migraine. They may be helpful in identifying people not responding to triptans and in need for novel acute migraine treatments. The definitions will also be of help in standardizing research on migraine acute care.This work is supported by a grant from the European Headache Federation to cover publication fees

Epigenetic modifications as key regulators of Waldenstrom's Macroglobulinemia biology

Waldenstrom's Macroglobulinemia is a low-grade B-cell lymphoma characterized by the presence of lymphoplasmacytic cells in the bone marrow and a monoclonal immunoglobulin M in the circulation. Recent evidences support the hypothesis that epigenetic modifications lead to Waldesntrom cell proliferation and therefore play a crucial role in the pathogenesis of this disease. Indeed, while cytogenetic and gene expression analysis have demonstrated minimal changes; microRNA aberrations and modification in the histone acetylation status of primary Waldenstrom Macroglobulinemia tumor cells have been described. These findings provide a better understanding of the underlying molecular changes that lead to the initiation and progression of this disease

Burden and attitude to resistant and refractory migraine: a survey from the European Headache Federation with the endorsement of the European Migraine & Headache Alliance

Cura de migranya; Migranya refractària; Migranya resistentMigraine care; Refractory migraine; Resistant migraineCuidado de la migraña; Migraña refractaria; Migraña resistenteBackground New treatments are currently offering new opportunities and challenges in clinical management and research in the migraine field. There is the need of homogenous criteria to identify candidates for treatment escalation as well as of reliable criteria to identify refractoriness to treatment. To overcome those issues, the European Headache Federation (EHF) issued a Consensus document to propose criteria to approach difficult-to-treat migraine patients in a standardized way. The Consensus proposed well-defined criteria for resistant migraine (i.e., patients who do not respond to some treatment but who have residual therapeutic opportunities) and refractory migraine (i.e., patients who still have debilitating migraine despite maximal treatment efforts). The aim of this study was to better understand the perceived impact of resistant and refractory migraine and the attitude of physicians involved in migraine care toward those conditions. Methods We conducted a web-questionnaire-based cross-sectional international study involving physicians with interest in headache care. Results There were 277 questionnaires available for analysis. A relevant proportion of participants reported that patients with resistant and refractory migraine were frequently seen in their clinical practice (49.5% for resistant and 28.9% for refractory migraine); percentages were higher when considering only those working in specialized headache centers (75% and 46% respectively). However, many physicians reported low or moderate confidence in managing resistant (8.1% and 43.3%, respectively) and refractory (20.7% and 48.4%, respectively) migraine patients; confidence in treating resistant and refractory migraine patients was different according to the level of care and to the number of patients visited per week. Patients with resistant and refractory migraine were infrequently referred to more specialized centers (12% and 19%, respectively); also in this case, figures were different according to the level of care. Conclusions This report highlights the clinical relevance of difficult-to-treat migraine and the presence of unmet needs in this field. There is the need of more evidence regarding the management of those patients and clear guidance referring to the organization of care and available opportunities.Publication fees for this publication were covered by the European Headache Federation

Sob o signo da invisibilidade: Os trabalhadores rurais na produção familiar de pêssego no extremo sul do Brasil

O processo de institucionalização da agricultura familiar representa um ponto de inflexão na história agrária brasileira. Estado e sociedade civil reconhecem a vocação de uma categoria social que é central para o abastecimento alimentar nacional. Não obstante, pouca atenção é dada ao papel da agricultura familiar na geração de emprego e renda no meio rural. Nos estados meridionais do Brasil a produção de pêssegos é uma das atividades que emprega muitos trabalhadores avulsos em determinadas etapas do ciclo produtivo. Do ponto de vista teórico, tal realidade serve para romper com o mito de que a unidade familiar de produção se basta a si mesma ou de que são essencialmente as médias e grandes explorações que empregam a mão de obra rural. Este artigo explora estas e outras questões a partir de trabalho de campo baseado em metodologia qualitativa com ênfase em entrevistas realizadas com diversos atores mediante uso de roteiro semiestruturado. Este estudo demonstra a essencialidade do trabalho contratado, mas também a invisibilidade e a clandestinidade das relações contraídas entre agricultores familiares e empregados safristas.The institutionalization process of family farming represents a turning point in Brazilian agrarian history. State and civil society recognize the vocation of a social category that is central to the national food supply. Nevertheless, little attention is paid to the role of family farming in generating employment and income in rural areas. In the southern states of Brazil, the production of peaches is one of the activities that employs many independent workers at certain stages of the production cycle. From the theoretical point of view, this reality serves to break with the myth that the family unit of production is sufficient for itself or that it is essentially the medium and large farms that employ rural labor. This article explores these and other issues based on fieldwork based on qualitative methodology with an emphasis on interviews with several actors using a semi-structured script. This study demonstrates the essentiality of the contracted work, but also the invisibility and clandestine nature of the relationships between family farmers and seasonal workers

Novel Tumor Suppressor Function of Glucocorticoid-Induced TNF Receptor GITR in Multiple Myeloma

Glucocorticoid-induced TNF receptor (GITR) plays a crucial role in modulating immune response and inflammation, however the role of GITR in human cancers is poorly understood. In this study, we demonstrated that GITR is inactivated during tumor progression in Multiple Myeloma (MM) through promoter CpG island methylation, mediating gene silencing in primary MM plasma cells and MM cell lines. Restoration of GITR expression in GITR deficient MM cells led to inhibition of MM proliferation in vitro and in vivo and induction of apoptosis. These findings were supported by the presence of induction of p21 and PUMA, two direct downstream targets of p53, together with modulation of NF-κB in GITR-overexpressing MM cells. Moreover, the unbalanced expression of GITR in clonal plasma cells correlated with MM disease progression, poor prognosis and survival. These findings provide novel insights into the pivotal role of GITR in MM pathogenesis and disease progression

C1013G/CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma

C1013G/CXCR4 actúa como una mutación activadora en la WM que conduce a un mayor creci-miento tumoral y como un inductor de resistencia a los medicamentos. BMS936564/MDX1338, un nuevo moAb anti-CXCR4, se dirige con éxito a las células WM, ya sean mutadas en C1013G/CXCR4 o de tipo salvaje. El receptor de quimiocinas C-X-C tipo 4 (CXCR4) desempeña un papel crucial en la modulación del tráfico celular de células madre hematopoyéticas y células B clonales. Se examinaron 418 pacientes con trastornos linfoproliferativos de células B y se describió la presencia de verrugas C1013G/CXCR4, hipogammaglobulinemia, infecciones y mutaciones asociadas a mielocatexis en el 28,2 % (37/131) de los pacientes con linfoma linfoplasmocítico (macroglobulinemia de Walden-ström [WM]), ausente o presente en solo el 7 % de otros linfomas de células B. La caracterización funcional in vivo demuestra su papel activador en las células WM, como lo demuestra la im-portante proliferación tumoral y la diseminación a los órganos extramedulares, lo que conduce a la progresión de la enfermedad y a la disminución de la supervivencia. El uso de un anticuerpo monoclonal anti-CXCR4 condujo a una reducción significativa del tumor en un modelo de WM C1013G/CXCR4, mientras que se observó resistencia a los fármacos en las células WM mutadas expuestas a la tirosina quinasa de Bruton, a la diana de rapamicina en mamíferos y a los inhibi-dores de la fosfatidilinositol 3-quinasa, pero no a los inhibidores del proteasoma. Estos hallazgos demuestran que C1013G/CXCR4 es una mutación activadora en la WM y respaldan su papel como regulador crítico de la patogénesis molecular de la WM y como una importante diana terapéutica. El Dr. Garcia-Sanz fue co-investigador senior en esta publicación que se hizo en colaboración con el Dana Farber Cancer Center de Boston y la Escuela de medicina de la Universidad de Harvard. La serie de casos que se analizó para detectar la mutación en MYD88 y CXCR4 tiene su origen en el Hospital Universitario de Salamanca, cuyo aportación deriva de la actividad asistencial e investigadora de Dr. García Sanz y el trabajo experimental de la licenciada Jiménez, y la super-visión del Dr. San Miguel. El resto de autores participó en el desarrollo de los estudios experi-mentales bajo la dirección ddl Dr. Roccaro y la supervisión de Irene Ghobrial.[EN]The C-X-C chemokine receptor type 4 (CXCR4) plays a crucial role in modulating cell trafficking in hematopoietic stem cells and clonal B cells. We screened 418 patients with B-cell lymphoproliferative disorders and described the presence of the C1013G/CXCR4 warts, hypogammaglobulinemia, infections, and myelokathexis–associated mutation in 28.2% (37/131) of patients with lymphoplasmacytic lymphoma (Waldenström macroglobulinemia [WM]), being either absent or present in only 7% of other B-cell lymphomas. In vivo functional characterization demonstrates its activating role in WM cells, as demonstrated by significant tumor proliferation and dissemination to extramedullary organs, leading to disease progression and decreased survival. The use of a monoclonal antibody anti-CXCR4 led to significant tumor reduction in a C1013G/CXCR4 WM model, whereas drug resistance was observed in mutated WM cells exposed to Bruton's tyrosine kinase, mammalian target of rapamycin, and phosphatidylinositol 3-kinase inhibitors, but not proteasome inhibitors. These findings demonstrate that C1013G/CXCR4 is an activating mutation in WM and support its role as a critical regulator of WM molecular pathogenesis and as an important therapeutic target.Dana Farber Cancer Center de Boston Hospital Universitario de SalamancaHospital Universitario de Salamanc

PROTEINOGRAMA SÉRICO DE BOVINOS INFECTADOS NATURALMENTE COM LEUCOSE ENZOÓTICA BOVINA

A Leucose Enzoótica Bovina (LEB) é uma enfermidade infecto-contagiosa, distribuída em todos os estados brasileiros, sendo frequente na bovinocultura leiteira, estando associada a grandes perdas econômicas. A prevalência da enfermidade cresce à medida que a idade dos animais aumenta. A transmissão se dá principalmente via horizontal, podendo ser transmitida por meio do tatuador, mochador, palpação retal, utilização de luvas obstétricas contaminadas com sangue, coleta de sangue de vários animais com a mesma agulha, entre outros fatores. A utilização do teste Elisa e o de imunodifusão de gel em ágar (IDGA) é amplamente utilizado para o diagnóstico da doença supracitada, no entanto, o uso de eletroforese em gel contendo dodecil sulfato de sódio (SDS- PAGE), vem ganhando seu espaço. A técnica citada permite identificar inúmeras frações proteicas até quatro vezes mais do que os métodos convencionais. Dessa maneira, este trabalho visa comparar os níveis de IgG e ceruloplasmina do soro sanguíneo de animais testados positivos com o de animais testados negativos para Leucose Enzoótica Bovina realizando o proteinograma sérico através da técnica de Eletroforese em gel de poliacrimilamida (SDS-PAGE). Objetivou-se nesse estudo realizar o fracionamento das proteínas do soro sanguíneo de bovinos infectados naturalmente pelo vírus da Leucose. Foram utilizados os soros sanguíneos de 37 animais de diferentes propriedades do oeste do estado de Santa Catarina, sendo eles 24 positivos e 13 negativos pelo teste de IDGA. As amostras foram cedidas pelo Laboratório de Patologia Veterinária do Instituto Federal Catarinense Campus Concórdia. A separação das frações proteicas foi realizada utilizando a técnica de eletroforese em gel de poliacrilamida contendo dodecil sulfato de sódio (SDS – PAGE). Através de conjuntos de reagentes comerciais da marca LABTEST com leitura em analisador bioquímico semi-automático ROBONIK, em comprimento de onda adequado foi possível mensurar a proteína sérica total, na qual os animais positivos apresentaram média de 7,612 g/dl (± 0,873). Já as amostras negativas apresentaram média de 6,792 g/dl (± 1,312). As frações proteicas detectadas no gel de poliacrilamida foram: IgA, apresentando média de 0,685 g/dl (± 0,324) para os positivos e os negativos 0,786 g/dl (± 0,396); ceruloplasmina com média de 2,289 g/dl (± 0,961) para os positivos e para os negativos 0,885 g/dl (± 0,327); Albumina média de 2,616 g/dl (± 0,254) para os positivos e 3,183 g/dl (± 0,384) para os negativos; IgG – Cadeia pesada com média 0,793 g/dl (± 0,228) para os positivos e 1,082 g/dl (± 0, 403) para os negativos; e IgG – Cadeia leve para os positivos média de 0,699 g/dl (± 0,214) e para negativos 0,734 g/dl (± 0,180). Dentre as proteínas identificadas foi possível verificar que a ceruloplasmina apresentou aumento significativo nos animais positivos para LEB, e que apesar de não possuir alterações significativas, os valores de IgG pesada e IgG leve apresentaram-se reduzidos nos animais positivos. Suporte financeiro IFC campus Concórdia – Edital nº 19/202

INQUÉRITO EPIDEMIOLÓGICO SOBRE A LEUCOSE ENZOÓTICA BOVINA NO SUL DO BRASIL

A Leucose Enzoótica Bovina (LEB) é uma enfermidade infectocontagiosa, de distribuição mundial, que acomete principalmente bovinos leiteiros e está associada a grandes perdas econômicas. O objetivo deste trabalho é analisar o grau de conhecimento e informação, que os produtores possuem sobre essa enfermidade. Para isto, um questionário foi elaborado, sendo as perguntas direcionadas para questões epidemiológicas das propriedades, bem como conhecimento direto sobre a doença. Foram feitas entrevistas presenciais, além da disponibilização do questionário via Google Forms®. Até o momento foram registradas 36 respostas, de 14 municípios diferentes do Sul do Brasil. Os proprietários têm experiência na criação de bovinos há 21,8 ± 14,3 anos. A maioria dos participantes da pesquisa não é formado, nem estudante de Medicina Veterinária (58,3%), já 25% são estudantes das primeiras fases, seguidos de estudantes das fases finais do curso (11,1%) e profissionais formados (5,6%). Nesse cenário, 55,6% afirmam já ter ouvido falar da enfermidade, inferem ainda não haver casos em sua propriedade (p&lt;0,05). A idade média dos rebanhos é de 4,3 ± 1,9 anos. Das raças criadas a Holandesa prevaleceu, sendo criada em 50% das propriedades, em segundo lugar a Jersey com 47,2% de frequência e em terceiro a raça Angus com 16,6%. No que tange os fatores epidemiológicos, 61,1% afirmam utilizar agulhas descartáveis em seu rebanho. Sendo que na pergunta subsequente 50% afirmou utilizar uma agulha por medicamento por animal, 23,1% utiliza uma por medicamentos para vários animais, 19,2% faz uso de uma agulha para vários medicamentos para um animal e 7,7% usa uma agulha para vários medicamentos para vários animais. A maioria dos bezerros são nascidos e criados na propriedade (80,6%), enquanto que 33,3% são comprados de outras propriedade e 2,8% são nascidos na propriedade e criados fora dela. Em todas as respostas os participantes afirmam que a colostragem é feita com colostro da vaca recém-parida. Em relação ao controle de moscas, 61,1% das respostas inferem que o controle é feito em algumas épocas do ano quando necessário, já 33,3% fazem durante todo o ano. O controle de insetos em sua maior parte é feito nos animais e no ambiente. Para a palpação retal e inseminação artificial 63,9% utiliza uma luva para cada vaca, 16,7% afirma usar a mesa luva para mais que três vacas, 11,1% não realizam palpação e nem inseminação artificial. Quanto ao atendimento veterinário, 50% afirmam que recebem acompanhamento periódico por profissional da área, já 47,2% apenas em casos de urgência ou emergência. Entre os procedimentos cirúrgicos mais mencionados pelos participantes estão a castração (orquiectomia), correção de deslocamento de abomaso, cesariana e descorna cirúrgica. A partir dos dados parciais infere-se que há pontos favoráveis ao controle da doença, por exemplo, o conhecimento da enfermidade, baixa idade média dos rebanhos e utilização individual de agulhas e luvas de palpação transretal. Nesse contexto a pesquisa seguirá em andamento, de acordo com o Edital 88/2021, responsável pelo suporte financeiro