Rootstock mediates transcriptional regulation of citrulline metabolism in grafted watermelon / Mediação do porta-enxerto na regulação transcricional do metabolismo da citrulina na melancia enxertada

Abstract Citrulline is a non-essential amino acid, involved in key biological functions in plants and humans. Rootstocks have a major impact on citrulline accumulation in grafted watermelon. Information regarding rootstock induced changes in citrulline metabolism is elusive. To understand the regulatory mechanism, parallel changes in the expression profiles of citrulline metabolic genes and citrulline content of watermelon were monitored during the development of self-rooted watermelon and watermelon grafted onto pumpkin, wild and bottle gourd rootstocks. Results demonstrated that rootstocks regulated the expression profiles in different ways to influence the citrulline content. GAT, NAGPR, ASS3 ASS2 and Asl2 showed the negative correlation with citrulline content in pumpkin grafted watermelon. Pumpkin rootstock promoted the citrulline content by high down-regulation and synergistic effect of ASS2, ASS3, ASL1 and ASl2 genes. In wild grafted watermelon, citrulline was accumulated as a result of down regulation of GAT, NAGS and ASL2 genes, which showed an inverse correlation with citrulline. In gourd grafted watermelon, changes in citrulline content were observed to be linked with lower expressions of GAT, NAGK, ASS2, ASS3, ASL1 and ARG which were negatively correlated with citrulline content. Our study will provide the basis to understand the molecular mechanism of citrulline accumulation in various rootstocks.

Resumo A citrulina é um aminoácido não essencial, envolvida em importantes funções biológicas de plantas e seres humanos. Os porta-enxertos têm um grande impacto no acúmulo de citrulina na melancia enxertada. Informações sobre alterações induzidas por porta-enxertos no metabolismo da citrulina ainda não foram descritas. Para entender o mecanismo regulatório, foram monitoradas mudanças paralelas nos perfis de expressão dos genes metabólicos de citrulina e no teor de citrulina da melancia durante o desenvolvimento da melancia e da melancia enxertada em porta-enxertos de abóbora, silvestre e cabaça. Os resultados demonstraram que o porta-enxerto regulou os perfis de expressão de diferentes maneiras para influenciar no conteúdo de citrulina. GAT, NAGPR, ASS3, ASS2 e ASL2 apresentaram correlação negativa com o teor de citrulina em melancia enxertada de abóbora. O porta-enxerto de abóbora promoveu o conteúdo de citrulina por meio de baixa regulação e efeito sinérgico de duas famílias de genes ASS e ASL. Na melancia enxertada, a acumulação de citrulina resultou na regulação negativa de GAT, NAGS e ASL2, que mostraram uma correlação inversa com a citrulina. Na melancia enxertada, observou-se que as alterações no conteúdo de citrulina foram associadas a menores expressões de GAT, NAGK, ASS2, ASS3, ASL1 e ARG, que foram negativamente correlacionadas com o conteúdo de citrulina. Esses resultados fornecem a base para identificar o mecanismo molecular do acúmulo de citrulina em vários porta-enxertos.

Inter-Individual Responses to Citrulline Malate Oral Supplementation on Post-Exercise Hypotension in Hypertensives: A 24-Hour Analysis / Respostas Interindividuais à Suplementação Oral de Citrulina Malato na Hipotensão Pós-Exercício em Hipertensos: Uma Análise de 24 Horas

Abstract Background: Studies have persuasively demonstrated that citrulline has a key role in the arginine-nitric oxide system, increasing nitric oxide bioavailability, an important mediator of peripheral vasodilation. Objective: To analyze the inter-individual post-exercise hypotension responsiveness following acute citrulline supplementation in hypertensives. Methods: Forty hypertensives were randomly assigned to one of the four experimental groups (control-placebo, control-citrulline, exercise-placebo, and exercise-citrulline). They ingested placebo or citrulline malate [CM] (6 grams). During the exercise session, individuals performed 40 minutes of walking/running on a treadmill at 60-70% of HR reserve. For the control session, the individuals remained seated at rest for 40 minutes. Office blood pressure (BP) was taken every 10 minutes until completing 60 minutes after the experimental session. The ambulatory BP device was programmed to take the readings every 20 minutes (awake time) and every 30 minutes (sleep time) over the course of 24 hours of monitoring. Statistical significance was defined as p < 0.05. Results: Unlike the other experimental groups, there were no "non-responders" in the exercise/citrulline (EC) for "awake" (systolic and diastolic BP) and "24 hours" (diastolic BP). The effect sizes were more consistent in the EC for systolic and diastolic ambulatorial BP response. The effects were "large" (> 0.8) for "awake", "asleep", and "24 hours" only in the EC for diastolic BP. Conclusion: CM supplementation can increase the post-exercise hypotensive effects in hypertensives. In addition, the prevalence of non-responders is lower when associated with aerobic exercise and CM supplementation.

Resumo Fundamento: Estudos demonstraram de maneira persuasiva que a citrulina tem um papel fundamental no sistema arginina-óxido nítrico, aumentando a biodisponibilidade do óxido nítrico, um importante mediador da vasodilatação periférica. Objetivo: Analisar a responsividade interindividual da hipotensão pós-exercício após suplementação aguda com citrulina em hipertensos. Métodos: Quarenta hipertensos foram aleatoriamente designados para um dos quatro grupos experimentais (controle-placebo, controle-citrulina, exercício-placebo e exercício-citrulina). Eles ingeriram placebo ou citrulina malato [CM] (6 gramas). Durante a sessão de exercício, os indivíduos realizaram 40 minutos de caminhada/corrida em esteira a 60-70% da FC de reserva. Para a sessão de controle, os indivíduos permaneceram sentados em repouso por 40 minutos. A medida da pressão arterial (PA) no consultório foi realizada a cada 10 minutos até completar 60 minutos após a sessão experimental. O dispositivo ambulatorial de PA foi programado para fazer as leituras a cada 20 minutos (tempo de vigília) e a cada 30 minutos (tempo de sono) ao longo de 24 horas de monitoramento. A significância estatística foi definida como p < 0,05. Resultados: Diferentemente de outros grupos experimentais, não houve "não respondedores" no exercício/citrulina (EC) para "acordado" (PA sistólica e diastólica) e "24 horas" (PA diastólica). Os tamanhos de efeito foram mais consistentes no EC para a resposta sistólica e diastólica da PA ambulatorial. Os efeitos foram "grandes" (> 0,8) para "acordado", "dormindo", e para "24 horas" apenas no EC para a PA diastólica. Conclusão: A suplementação com CM pode aumentar os efeitos hipotensivos pós-exercício em hipertensos. Além disso, a prevalência de "não respondedores" é menor quando associada ao exercício aeróbico e à suplementação com CM.

Biomarkers for intestinal failure in short bowel syndrome: A new era in GI rehabilitation? / Biomarcadores para la insuficiencia intestinal en síndrome de intestino corto: ¿Una nueva era en la rehabilitación gastrointestinal?

Damage control and gastrointestinal surgery have come a long way from the first reported case of an enterocutaneous fistula to advances in Intestinal transplant and vacuum assisted therapy. Everything we have known in between such as intestinal resections, enteral/parenteral nutrition, delayed abdominal wall closure and intestinal reconstruction have all lead to an exponential increase in our knowledge of gastrointestinal surgery. One area that still remains a significant challenge and clinical dilemma to the general surgeon is intestinal failure in short bowel syndrome. Not only does the anatomical complexity of short bowel syndrome offer difficulties in the definite reconstruction, but also the accompanying intestinal failure increases patient morbidity and mortality. There are no current algorithms or systematic approaches to these daunting clinical scenarios and although surgery has come a long way, there is still room for determining optimal approaches. Therefore, it is critical to keep researching new ways to treat these patients. A relatively new horizon in managing intestinal failure in short bowel syndrome is the use of biomarkers. Here we present a short review on the possible future treatment. The aim of this paper is to provide a pathway for future research into the treatment of this complex area of general surgery

La cirugía gastrointestinal y de control de daños ha tenido un recorrido amplio desde el primer caso reportado de fístula entero-cutánea, hasta llegar al uso de presión subatmosférica para el cierre asistido y el trasplante intestinal. Todos los avances propuestos en el intermedio, como las resecciones intestinales, los planes de nutrición entérica y parenteral, el cierre postergado de la pared abdominal y la reconstrucción intestinal, han llevado a un aumento exponencial del conocimiento de la cirugía gastrointestinal. A pesar de esto, hay un área que permanece como un reto significativo y un dilema clínico para el cirujano general: la falla intestinal en el síndrome de intestino corto. En esta, su complejidad anatómica presenta dificultades a la hora de su reconstrucción, y su alteración funcional aumenta la morbimortalidad del paciente. Así como sucede en la mayoría de las fallas específicas de órganos, esta se caracteriza por cambios en los marcadores séricos que ya han sido bien descritos en la literatura médica. En la falla cardiaca hay elevación del péptido natriurético auricular; en la falla renal, elevación de la creatinina sérica; en la falla hepática, elevación de las transaminasas, y así sucesivamente. Estos marcadores no solo indican la gravedad de la situación, sino que se relacionan con la suficiencia del órgano en cuanto a su función y su mejoría con la rehabilitación. Ahora, ¿cuáles son los marcadores del sistema gastrointestinal? Recientemente, la seriedad de la falla intestinal y su solución han sido objeto de la observación clínica y sintomática con el fin de determinar la orientación de la rehabilitación intestinal y el momento ideal para el inicio de la vía oral. En los últimos años han surgido biomarcadores pertinentes al estudio del sistema digestivo. En esta revisión se discuten los aspectos relacionados con el presente y el futuro de los marcadores serológicos intestinales en el síndrome de intestino corto

Acute citrulline oral supplementation induces greater post-exercise hypotension response in hypertensive than normotensive individuals / Suplementação oral aguda de citrulina induz maior resposta hipotensiva pós-exercício em indivíduos hipertensos do que normotensos

ABSTRACT Objective To investigate whether acute citrulline supplementation might influence post-exercise hypotension in normotensive and hypertensive individuals. Methods Following a randomized double-blind design, twenty normotensive (28±7 years, 74±17kg, 1.7±0.09m) and 20 hypertensive individuals (55±12 years, 76±15kg, 1.59±0.09m) were randomly assigned to one of the four experimental groups (Normotensive-Placebo; Normotensive-Citrulline; Hypertensive-Placebo; Hypertensive-Citrulline). The placebo groups ingested 6g of corn starch and the citrulline groups ingested 6g of citrulline dissolved in water. The participants performed 40 minutes of walking/running on a treadmill at 60-70% heart rate reserve. Blood pressure was measured immediately after a 60-min exercise session using an oscillometric device and 24-h ambulatory monitoring. Results The post-exercise hypotension was more pronounced in hypertensives and the Hypertensive-Citrulline group showed a consistent systolic blood pressure reduction during the laboratorial phase, which can be seen by looking at the mean of 60 minutes (-15.01mmHg vs -3.14mmHg [P=0.005]; -4.16mmHg [P=0.009]; -6.30mmHg [P=0.033] in comparison with the Normotensive-Placebo, Normotensive-Citrulline, and Hypertensive-Placebo groups, respectively). During ambulatory blood pressure monitoring, the Hypertensive-Citrulline group showed a significant reduction in systolic blood pressure (-21.05mmHg) in the awake period compared with the Normotensive-Citrulline group (-3.17mmHg [P=0.010]). Conclusion Acute citrulline oral supplementation can induce greater post-exercise hypotension response in hypertensive than normotensive individuals.

RESUMO Objetivo Investigar se a suplementação aguda de citrulina pode influenciar a hipotensão pós-exercício em indivíduos normotensos e hipertensos. Métodos Seguindo delineamento duplo-cego randomizado, vinte indivíduos normotensos (28±7 anos, 74±17kg, 1,7±0,09m) e 20 hipertensos (55±12 anos, 76±15kg, 1,59±0,09m) foram randomizados e distribuídos em um dos quatro grupos experimentais (Normotenso-Placebo; Normotenso-Citrulina; Hipertenso-Placebo; Hipertenso--Citrulina). Os grupos placebo ingeriram 6g de amido de milho e os grupos citrulina 6g de citrulina, dissolvidos em água. Os participantes realizaram 40 minutos de caminhada/corrida em esteira a uma intensidade entre 60-70% da frequência cardíaca de reserva. A pressão arterial foi aferida imediatamente após a sessão de exercício por 60 minutos usando um equipamento oscilométrico, e durante 24 horas por monitorização ambulatorial. Resultados A hipotensão pós-exercício foi mais pronunciada nos hipertensos e o grupo Hipertenso-Citrulina mostrou uma redução consistente da pressão arterial sistólica durante a fase laboratorial, o que pode ser visto pela média de 60 minutos (-5,01mmHg vs -3,14mmHg [P=0,005]; -4,16mmHg [P=0,009]; -6,30mmHg [P=0,033] em comparação com o Normotenso-Placebo, Normotenso-Citrulina e Hipertenso-Placebo, respectivamente). Durante a monitorização ambulatorial da pressão arterial, o Hipertenso-Citrulina demonstrou uma redução significativa na pressão arterial sistólica (-21,05mmHg) durante a vigília em comparação com o Normotenso-Citrulina (-3,17mmHg [P=0,010]). Conclusão A suplementação oral aguda de citrulina induz maior resposta hipotensiva pós-exercício em indivíduos hipertensos do que normotensos.

Effect of S-methyl-l-thiocitrulline dihydrochloride on rat micturition reflex

ABSTRACT Objective: To evaluate the effect of neuronal nitric oxide synthase on the striated urethral sphincter and the urinary bladder. Materials and Methods: A coaxial catheter was implanted in the proximal urethra and another one in the bladder of female rats, which were anesthetized with subcutaneous injection of urethane. The urethral pressure with saline continuous infusion and bladder isovolumetric pressure were simultaneously recorded. Two groups of rats were formed. In group I, an intrathecal catheter was implanted on the day of the experiment at the L6-S1 level of the spinal cord; in group II, an intracerebroventricular cannula was placed 5-6 days before the experiment. Results: It was verified that the group treated with S-methyl-L-thio-citrulline, via intrathecal pathway, showed complete or partial inhibition of the urethral sphincter relaxation and total inhibition of the micturition reflexes. The urethral sphincter and the detrusor functions were recovered after L-Arginine administration. When S-methyl-L-thio-citrulline was administered via intracerebroventricular injection, there was a significant increase of urethral sphincter tonus while preserving the sphincter relaxation and the detrusor contractions, at similar levels as before the use of the drugs. Nevertheless there was normalization of the urethral tonus when L-Arginine was applied. Conclusions: The results indicate that, in female rats anaesthetized with urethane, the nNOS inhibitor administrated through the intrathecal route inhibits urethral sphincter relaxation, while intracerebroventricular injection increases the sphincter tonus, without changing bladder function. These changes were reverted by L-Arginine administration. These findings suggest that the urethral sphincter and detrusor muscle function is modulated by nitric oxide.

Análisis de impacto presupuestal de los anticuerpos antipéptidos cíclicos citrulinados (anti-CCP) para el diagnóstico de artritis reumatoide en pacientes mayores de 16 años en Colombia / Budget impact analysis of citrullinated cyclic antipeptide antibodies (anti-CCP) for the diagnosis of rheumatoid arthritis in patients older than 16 years in Colombia

Tecnologías evaluadas: Nueva: anticuerpos antipéptidos cíclicos citrulinados; Actual: Factor reumatoide. Población: Pacientes mayores de 16 años con artritis reumatoide en Colombia. Perspectiva: La perspectiva del presente AIP corresponde al tercero pagador, que en este caso es el Sistema General de Seguridad Social en Salud (SGSSS) en Colombia. Horizonte temporal: El horizonte temporal de este AIP en el caso base corresponde a un año. Adicionalmente se reportan las estimaciones del impacto presupuestal para los años 2 y 3, bajo el supuesto de la inclusión en el POS en el año 1. Costos incluidos: Costos de las tecnologías analizadas. Fuente de costos: Los precios de cada tecnología considerada fueron\r\nconsultados en el manual tarifario ISS 2001 y ajustados con un +25%, +30% y +48%. Los precios de las consultas médicas fueron consultados en el manual tarifario ISS 2001 y ajustados con un +30%. Escenarios: \r\nEn tanto el escenario 1 como el escenario 2 se asume que la adopción de las nuevas tecnologías resultará en que su participación de mercado equilibraría debido a la preferencia de los clínicos de utilizar la combinación de tanto la tecnología actual con la tecnología nueva. Resultados: Se necesitaría una inversión de $11.136.331.800,00 para el año 1, $12.624.171.516,00 para el año 2 y 14.436.417.841,56 para el año 3 para la inclusión de la prueba anti-CCP en el POS para pacientes con artritis reumatoide mayores de 16 años en Colombia, bajo el presupuesto que la adopción de la nueva tecnología llevaría a un cambio en la participación del mercado.(AU)

Prueba de anticuerpos anti-péptido citrulinado cíclico para el diagnóstico de la artritis reumatoide / Cyclic citrullinated antibody test anti-peptide for the diagnosis of rheumatoid arthritis

Código SCPC (Sociedad Colombiana de Patología Clínica): 51820. Código CUPS (Codificación Única de Procedimientos en Salud): 906442. Sección: Inmunología. Nivel de complejidad: Alto. Metodología: Inmunoensayo quimioluminiscente de macropartículas (CMIA). Sinónimos: Anti-CCP, anti-citrulina.DefiniciónLa prueba de anticuerpos anti-péptido citrulinado cíclico es una prueba de laboratorio que detecta y mide de forma semi-cuantitativa los niveles en sangre (suero o plasma) de auto-anticuerpos de clase IgG específicos para el péptido citrulinado cíclico mediante una prueba de inmunoensayo quimioluminiscente de macropartículas (CMIA), como ayuda diagnóstica de la artritis reumatoide.Esta prueba representa uno de los parámetros, que en conjunto con otra información clínica relevante, constituyen los criterios en el proceso diagnóstico de esta enfermedad.Espectro clínico de aplicaciónLa artritis reumatoide es una enfermedad común, sistémica, autoinmune que afecta aproximadamente el 1% de la población mundial. Está caracterizada por inflamación crónica de la sinovia que conlleva a la destrucción de la articulación, discapacidad y reducción en la calidad de vida [1]. Los sueros de personas que sufren esta enfermedad, incluso antes de la aparición de los síntomas, tienen gran variedad de auto-anticuerpos como el factor reumatoideo y los anticuerpos anti-péptido citrulinado cíclico [2].

Utilidad diagnóstica del anticuerpo antipéptidocíclico citrulinado como prueba diagnóstica enpacientes con artritis reumatoide / Diagnostic utility of antibody to cyclic citrullinated peptide as a diagnostic test for rheumatoid arthritis patients

Introducción: La artritis reumatoide es una enfermedad autoinmune sistémica, inflamatoria y crónica. En el diagnóstico confirmatorio la presencia del anticuerpo contra el péptido cíclico citrulinado parece tener mejor especificidad que el factor reumatoide. Objetivo: Evaluar las características operativas de los anticuerpos contra el péptido cíclico citrulinado y factor reumatoide en pacientes con artritis reumatoide. Métodos: Estudio retrospectivo convencional de pruebas diagnósticas, en 68 pacientes con artritis reumatoide, y 68 con patologías ortopédicas. El diagnóstico de la artritis se hizo a través de los criterios del Colegio Americano de Reumatología. La determinación del anticuerpo contra el péptido cíclico citrulinado se realizó por electroquimioluminiscencia y factor reumatoide por inmunoturbidimetría. Para el análisis de datos se usó el software R. A través de tabulaciones cruzadas se determinaron las características operacionales del método. Se construyó la gráfica de Receiver Operating Curve. Resultados: La sensibilidad, especificidad, valor predictivo positivo y negativo del anticuerpo contra el péptido cíclico citrulinado fueron 81%, 92%, 90% y 82%, respectivamente. Para el factor reumatoide los resultados fueron similares, excepto en la especificidad (90%). Con cualquiera de las dos pruebas positivas la sensibilidad alcanza 89% y la especificidad 86%, con razón de verosimilitud positiva de 6,35. La positividad simultánea de ambas pruebas disminuye la sensibilidad a 67% y la especificidad aumenta 100% con razón de verosimilitud negativa de 0,33. Conclusión: Por la sensibilidad y especificidad del anticuerpo contra el péptido cíclico citrulinado es considerado como una prueba útil para el diagnóstico temprano. El uso combinado de las dos pruebas aumenta significativamente la sensibilidad, especificidad y razón de verosimilitud positiva.

Introduction: Rheumatoid arthritis is a systemic autoimmune, inflammatory and chronic disease. In the confirmatory diagnosis, the presence of anti-cyclic citrullinated peptide antibody seems to have better specificity than rheumatoid factor. Objective: To evaluate the operating characteristics of anti cyclic citrullinated peptide antibody and rheumatoid factor in patients with rheumatoid arthritis. Methods: Retrospective conventional diagnostic test study in 68 patients with rheumatoid arthritis and 68 with orthopedic conditions.The diagnostic was made using the American College of Rheumatology criteria. Serum levels of antibody to cyclic citrullinated peptide were determined by electrochemiluminescence and rheumatoid factor by inmunoturbidimetry. Data analysis was used software R. Through cross tabulations, operational characteristics of the method where determined. Receiver Operating Curve grahp was constructed. Results: The sensitivity, specificity, positive and negative predictive value of antibody to cyclic citrullinated peptide were 81%, 92%, 90% and 82% respectively. Similar results for rheumatoid factor except in specificity (90%). With either of the two positive tests the sensitivity reached 89 and specificity 86% and the positive likelihood ratio for these data was 6.3. The simultaneous positivity of both tests decreases the sensitivity to 67% and specificity increases to 100%, and negative likelihood ratio of 0.33. Conclusion: For the sensitivity and specificity of the antibody against cyclic citrullinated peptide test is considered useful for early diagnosis. The combined use of both tests significantly increases the sensitivity, specificity and positive likelihood ratio.

Anticuerpo anticitrulina y manifestaciones extra articulares en artritis reumatoidea / Anticitrulin antibody and the extra-articular manifestations in rheumatoid arthritis

Los pacientes con artritis reumatidea (AR) pueden desarrollar manifestaciones extra articulares (MExA), relacionadas a su morbi-mortalidad. Los anticuerpos anti-péptidos citrulinados cíclicos (ACCP) son específicos para la AR y estan relacionados con el daño articular; y podrían tener rol patogénico en las MExA. Nuestro objetivo fue determinar la relación entre los anticuerpos ACCP y MExA en pacientes con AR. Se incluyeron 74 pacientes con diagnóstico de AR (ACR 1987) mayores de 18 años, de más de 6 meses de evolución, con MExA, y un control apareado por sexo y edad sin MExA por cada paciente. Las variables demográficas, clínicas y de laboratorio se compararon con test t, chi cuadrado o Mann-Whitney. Se realizó análisis multivariado; p ≤ 0.05. Los pacientes con MExA presentaron mayor título de anticuerpo ACCP (116 vs. 34, p < 0.01) y de factor reumatoideo (FR) (108 vs. 34.5, p < 0.01). En el análisis multivariado hubo asociación entre la presencia de MExA y tabaquismo activo (p = 0.02, OR: 3.78, IC 95%: 1.17-12.2), FR positivo (p = 0.04, OR: 3.23, IC95%: 1.04-11.8) y anticuerpo ACCP positivo (p = 0.04, OR: 3.23, IC 95%: 1.04-10). Presentaron mayor título de anticuerpo ACCP que los controles los pacientes con xerostomía (109 vs. 34, p = 0.04), xeroftalmia (150 vs. 34, p < 0.01), nódulos sub-cutáneos (NSC) (141 vs. 34, p < 0.01) y fibrosis pulmonar (158 vs. 34, p = 0.04). En conclusión, el anticuerpo ACCP positivo, el FR positivo y el tabaquismo activo fueron factores de riesgo independientes para el desarrollo de MExA.

A large proportion of rheumatoid arthritis (RA) patients develop extra-articular manifestations (EAM), which are associated with morbidity and early mortality. Anti cyclic citrullinated peptide (ACCP) antibody has proven to be highly specific for the diagnosis of RA, associated with severe joint damage and may have some role in the pathogenesis of EAM. The aim of this study was to determine the relationship between ACCP antibody and the presence of EAM in RA patients. Seventy four RA patients (ACR 1987) with EAM, > 18 years, more than 6 months duration were included, and an EAM free control, matched by sex and age, for each patient. Demographic, clinical and laboratory variables were compared using t-test, chi-square or Mann-Whitney test. Multivariate analysis was performed: p ≤ 0.05. Patients with EAM presented a greater value of ACCP antibody (116 vs. 34, p < 0.01) and rheumatoid factor (108 vs. 34.5, p < 0.01). Independent association with current smoking habit (p = 0.02, OR = 3.78, 95%: 1.17-12.2), RF positive (p = 0.04, OR 3.23, CI 95%: 1.04 to 11.8) and ACCP antibody positive (p = 0.04, OR 3.23, 95% CI: 1.04-10) was found. The patients with xerostomia (109 vs. 34, p = 0.04), xerophthalmia (150 vs. 34, p < 0.01), subcutaneous nodules (141 vs. 34, p < 0.01) and pulmonary fibrosis (158 vs. 34, p = 0.04) had a higher degree of the ACCP antibody, than controls. In conclusion, ACCP antibody positive, RF positive and smoking were independent risk factors for the development of MEXA.

Autoanticorpos na artrite reumatoide inicial: coorte Brasília - resultados de uma análise seriada de três anos / Autoantibodies in early rheumatoid arthritis: Brasília cohort - results of a three-year serial analysis

O valor diagnóstico e prognóstico da análise seriada dos anticorpos como fator reumatoide (FR), anticorpos antipeptídeos citrulinados cíclicos (anti-CCP) e antivimentina citrulinada (anti-Sa) não está definido nos pacientes com artrite reumatoide inicial (ERA). OBJETIVOS: Avaliar de forma prospectiva a presença de FR, anti-CCP e anti-Sa em pacientes com ERA. PACIENTES E MÉTODOS: Quarenta pacientes da coorte Brasília de ERA (menos de 12 meses) foram avaliados e monitorados durante três anos. Os dados clínicos e demográficos foram registrados, além dos resultados (ELISA) para FR (IgM, IgG e IgA), anti-CCP (CCP2, CCP3 e CCP3.1) e anti-Sa na avaliação inicial e aos 3, 6, 12, 18, 24 e 36 meses de acompanhamento. Comparações pelos testes t de Student e t pareado. RESULTADOS: A idade média foi de 45 anos, 90% dos pacientes do gênero feminino. No momento do diagnóstico, FR foi observado em 50% dos casos (FR IgA 42%, FR IgG 30% e FR IgM 50%), anti-CCP em 52,5% (não houve diferença entre CCP2, CCP3 e CCP3.1) e anti-Sa em 10%. Após três anos, não houve diferença na prevalência de FR e anti-CCP, mas a de anti-Sa aumentou para 17,5% (P = 0,001). CONCLUSÃO: A análise repetida do FR e anti-CCP, incluindo aqui diferentes isotipos, durante três anos de acompanhamento, não mostrou mudanças significativas. A terceira geração do anti-CCP não aumentou o valor diagnóstico dos testes de segunda geração.

The diagnostic and prognostic value of the serial measurement of antibodies, such as rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), and anti-citrullinated vimentin (anti-Sa) antibodies, has not been defined in early rheumatoid arthritis (ERA). OBJECTIVES: To prospectively assess the presence of RF, anti-CCP, and anti-Sa in ERA patients. PATIENTS AND METHODS: Forty ERA (less than 12 months) patients of the Brasília cohort were evaluated and followed up for three years. Both clinical and demographic data were recorded, in addition to the results (ELISA) of RF (IgM, IgG, and IgA), anti-CCP (CCP2, CCP3, and CCP3.1), and anti-Sa at the baseline assessment and after 3, 6, 12, 18, 24 and 36 months of follow-up. The results were compared by use of Student t test and paired t test. RESULTS: The patients' mean age was 45 years, and 90% of them were female. At the time of diagnosis, RF was identified in 50% of the patients (RF IgA, 42%; RF IgG, 30%; and RF IgM, 50%), anti-CCP in 52.5% (no difference between CCP2, CCP3, and CCP3.1), and anti-Sa in 10%. After three years, no difference was observed in RF and anti-CCP prevalence, but anti-Sa increased to 17.5% (P = 0.001). CONCLUSION: Repeated RF and anti-CCP measurement, including different isotypes, during three years of follow-up showed no significant changes. The third generation of anti-CCP assays did not increase the diagnostic value of the second-generation assays.

Utilización de la citrulina plasmática como marcador de la función intestinal: aplicaciones en trasplante de intestino y otras enfermedades digestivas / Plasma citrulline levels as marker of intestinal function: applications in intestinal transplantation and digestive diseases

El intestino delgado es responsable, no sólo de la digestión y la absorción de los nutrientes, sino también del metabolismo de varios aminoácidos, entre ellos, la glutamina, principal precursor de la citrulina plasmática.El metabolismo único de la citrulina ha atraído interés científico en la aplicación clínica como marcador de la función intestinal en algunas enfermedades y en procedimientos quirúrgicos como el trasplante de intestino delgado y en resecciones intestinales extensas, que desencadenan el síndrome de intestino corto. Se han propuesto diversos marcadores para la valoración de la función intestinal pero, ante la baja sensibilidad y especificidad, además de la difícil aplicación clínica, la citrulina viene mostrándose como una herramienta no invasiva de la valoración de la masa y funcionalidad de los enterocitos. El objetivo de esta revisión es describir la importancia de la citrulina en las principales enfermedades y procedimientos quirúrgicos del intestino delgado, destacando su metabolismo, aplicaciones en el trasplante de intestino y perspectivas de su aplicación clínica en otras enfermedades digestivas.

Marcadores de estrés oxidativo en aterogénesis inducida por hiperfibrinogenemia / Oxidative stress markers in atherogenesis induced by hyperfibrinogenemia

INTRODUCTION: We studied plasmatic TNF-alpha, nitric oxide (NO) and citrulline behaviors and probable morphological mitochondrial alterations in aortic smooth muscle cells, in rats with atherogenesis induced by hyperfibrinogenemia in: A) control, B) multiple injured for 30 days and C) multiple injured for 60 days. MATERIAL AND METHODS: Hyperfibrinogenemia induction: adrenaline injection (0,1 mg/rat/day). TNF-alpha (pg/dL) was determined by Elisa and NO (microM) and citrulline (mM) by spectrophotometry. Morphological mitochondrial alterations were studied by electronic microscopy. Variables were analized: ANOVA, r coefficient and chi2 test. RESULTS: We observed a significant increment of TNF-alpha in multiple injured for 30 days (B) (50.05 +/- 2.29) as well as in multiple injured for 60 days (C) (74.99 +/- 2.82) related to control (A) (33.01 +/- 1.49) (p<0.001 in both groups). Citrulline presented a significant increased in (B) (5.56 +/- 0.20) and (C) (6.84 +/- 0.13) when compared to (A) (4.41 +/- 0.23) (p<0.001 in both situations). Mean while NO biodisponibility diminished significantly in (B) (8.97 +/- 0.70) and in (C) (5.32 +/- 0.68) when compared to (A) (21.65 +/- 1.74) (p<0.001 in both situations). CONCLUSIONS: Hyperfibrinogenemia could modify the NO physiopathological pathway and produced morphological mitochondrial alterations in aortic smooth muscle cells, probably producing ischemic lesions in the vascular wall and altering the vasodilatation response.

Artritis reumatoídea precoz / Early rheumatoid arthritis

Early rheumatoid arthritis, defined as being diagnosed between 6 months and 2 years of the onset of symptoms, is a picture that has gained great importance in recent times because its detection involves possibility of early aggressive treatment from the beginning, avoiding evolution to a chronic and disabling poli symptomtics. It is characterized by pain and stiffness polyarticular symmetrical what can be correlated with physical examination in the presence of arthritis and synovitis. In its management and diagnosis are keys specific examinations as rheumatoid factor and antibodies anti peptide cyclical citrulline, when both are positive allow confirm the diagnosis by 100% along with confer prognostic value, like the x-ray study of hands or feet to confirm the presence of erosions joints. The treatment includes drugs that influence the management of symptomatic patients and the early introduction of disease-modifying drugs, which gets a better prognosis in the medium and long term.

La artritis reumatoídea precoz, definida como aquella que se diagnostica entre 6 meses y 2 años del inicio de los síntomas, es un cuadro que ha adquirido gran importancia en el último tiempo debido a que su detección implica posibilidad de tratamiento agresivo precoz desde el inicio, evitando la evolución a una enfermedad crónica polisintomática e incapacitante. Se caracteriza por dolor poliarticular simétrico y rigidez lo que puede correlacionarse en el examen físico con presencia de artritis y sinovitis. En su manejo y diagnóstico son claves los exámenes específicos como el factor reumatoídeo y anticuerpos antipéptido cíclico citrulinado, que cuando ambos son positivos permiten confirmar el diagnóstico en un 100% junto con conferir valor pronóstico, al igual que el estudio radio lógico de manos o pies para confirmar la presencia de erosiones articulares. El tratamiento, incluye drogas que influyen en el manejo sintomático del paciente y la introducción precoz de fármacos modificadores de la enfermedad, con lo que se obtiene un mejor pronóstico en el mediano y largo plazo.

Valor crítico da citrulina para as complicações do enxerto no transplante de intestino / Critical value of citrulline for complications of intestinal transplant graft

OBJETIVO: Analisar, numa ampla amostra, o valor crítico da citrulina que confirma a presença das principais complicações do enxerto: rejeição e infecção. MÉTODOS: Foram coletadas 2135 amostras de citrulina sérica, na forma de gota de sangue seca, de 57 doentes submetidos a transplante de intestino/multivisceral no Jackson Memorial Hospital na Universidade de Miami, de março de 2004 a abril de 2006. Todas as amostras são do pós-operatório três meses em diante, passada a conhecida curva de elevação da citrulina após a recuperação das lesões causadas pela isquemia e reperfusão do pós-transplante. RESULTADOS: Utilizando um valor limite menor que 13 µmoles/L, a sensibilidade da citrulina foi de 96,4 por cento para detectar rejeicão celular aguda (RCA) moderada ou grave. A especificidade para as complicações mais freqüentes, rejeição e infecção foi de 54 por cento-74 por cento nas crianças e 83 por cento-88 por cento nos adultos, e o valor preditivo negativo (VPN) foi > 99 por cento. CONCLUSÃO: A citrulina pode ser utilizada como método não-invasivo para avaliar a evolução do enxerto intestinal após três meses do TI. Os episódios de RCA moderado e grave podem ser afastados quando o valor da citrulina for maior que 13 µmoles/L devido ao alto valor preditivo negativo.

OBJECITIVE: A biochemical marker for detection of acute cellular rejection following small intestine transplantation has been sought. Citrulline, a non- protein amino acid synthesized mainly by functioning enterocytes, has been proposed. Trial sensitivity has been reportedly high but with low specificity. Thus, the goal was to determine, in a sufficiently large analysis, the significant value of citrulline level in the post-transplant setting, which would correlate with complications such as rejection and infection. METHODS: Since March, 2004 2,135 dried blood spot (DBS) citrulline samples were obtained from 57 small intestine transplant recipients three months or more after post-transplant, i.e., once the expected period of recovery in the citrulline levels had occurred. RESULTS: Using a <13 vs. > 13 µmoles/L cut off point, sensitivity of DBS citrulline for the detection of moderate or severe ACR was extremely high (96.4 percent). Furthermore, specificity estimates (given the absence of ACR and these particular infections), while controlling for time-to-DBS sample were reasonably high (54 percent-74 percent in children and 83 percent-88 percent in adults), and the negative predictive value (NPV) was >99 percent. CONCLUSION: Citrulline is a non-invasive marker to evaluate problems of the intestinal graft after three months post-transplant. Due to the high NPV, a moderate or severe ACR can be ruled out, based exclusively on knowledge of a high value for DBS citrulline.

Anticorpos antiproteínas citrulinadas e a artrite reumatóide / Auto-antibodies to citrullinated proteins and rheumatoid arthritis

Pacientes com artrite reumatóide (AR) possuem uma variedade de auto-anticorpos no soro e no líquido sinovial. Entre esses auto-anticorpos, destacam-se aqueles direcionados a proteínas citrulinadas, que são específicos para AR, aparecem precocemente durante a evolução da enfermidade e são bastante úteis para auxiliar no diag-nóstico da doença. Entre os antígenos citrulinados reconhecidos por auto-anticorpos na AR, encontram-se a profilagrina, a filagrina e a vimentina. Células e tecidos ricos nessas proteínas serviram de substrato para os primeiros ensaios laboratoriais para detecção dessa classe de auto-anticorpos. A descoberta de que os epitopos reconhecidos por esses auto-anticorpos eram peptídeos contendo citrulina permitiu o desenvolvimento de uma plataforma baseada em ELISA. O formato de ELISA possibilitou maior padronização e reprodutibilidade dos ensaios, resultando em ampla aceitação mundial como os auto-anticorpos mais específicos e precoces para o diagnóstico da AR. Há controvérsia quanto à capacidade dos anticorpos contra proteínas citrulinadas predizerem a gravidade da doença. O papel dos antígenos citrulinados na fisiopatologia da artrite reumatóide é sugerido pela forte especificidade desses auto-anticorpos para a doença, pelo achado de proteínas citrulinadas na sinóvia inflamada, pela produção intra-articular desses auto-anticorpos e pela extrema afinidade de peptídeos citrulinados por moléculas de HLA-DRB1 que contêm o epitopo compartilhado. Esses achados acenam com a possibilidade de novas e fascinantes descobertas rumo à melhor compreensão da fisiopatologia da AR.

Rheumatoid arthritis (RA) patients have a variety of auto-antibodies in the serum and synovial fluid. Among these auto-antibodies, those directed against citrullinated proteins are distinguished because that are specific for RA, appear early during the evolution of the disease and they are important to assist in the diagnosis of the illness. Examples of citrullinated antigens recognized by autoantibodies in rheumatoid arthritis are profillagrin, fillagrin and vimentin. Cells and tissues rich in those proteins have been used as substrate for the first laboratory assays for the detection of this class of autoantibodies. The discovery that the epitopes recognized by these autoantibodies are citrullin-bearing peptides permited the development of ELISA assays. The ELISA format allows better standardization and higher reproducibility for the tests, resulting in worldwide acceptance of these autoantibodies as the most specific and early serologic markers for the diagnosis of rheumatoid arthritis. There is controversy regarding the ability of these autoantibodies in predicting disease evolution. The role of antibodies to citrullinated peptides in the pathophysiology of rheumatoid arthritis is supported by their extreme specificity for the disease, by the finding of citrullinated proteins in inflamed synovia, by the intraarticular production of these autoantibodies and by the extreme affinity of citrullinated peptides for HLA-DRB1 molecules bearing the shared epitope. These findings forecast the possibility of novel and exciting discoveries towards a better understanding of the pathophysiology of rheumatoid arthritis.

Anticuerpos anti-péptido citrulinado cíclico / Cyclic citrullinated peptide antibodies

The determination of anti-cyclic citrullinated peptide antibodies (anti-CCP) is an extremely useful laboratory test in the differential diagnosis of patients in which Rheumatoid Arthritis (RA) is suspected. Citrullination is an unspecific protein modification associated to inflammation. The production of antibodies directed against citrullinated antigens in the synovial membrane is, on the contrary, specific for RA, for which important associations between these and the pathogen of the disease have been described. This review focuses on the different characteristics that make this test routinely asked for in clinical practice: high specificity; high positive predictive value in undifferentiated arthritis; early manifestation, development prior to clinical disease, and its association with a more aggressive course of the disease.

Anticuerpos anti-péptido citrulinado cíclico en artritis reumatoide, artritis psoriática y otras enfermedades / Anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis and psoriatic arthritis

The anti-cyclic citrullinated peptide (Anti-CCP) antibodies are actually the markers of highly specific recognize for rheumatoid arthritis (RA). Its presence in RA has been associated with higher disease clinical activity characterize by greater loss of function and development of erosive illness with important radiological damage. Furthermore, its production is an early process in RA development and because that, their presence is predictive for disease development. But in spite of the fact its high specificity, in the last years they also has been detected in other arthropathies diseases like psoriatic arthritis (PsA). Even if the prevalence of Anti-CCP in PsA reach values greater than expected for a disease different of AR, doesn`t reach statistical value, but its presence in this illness, like in AR, could might considerer a marker of disease severity, with development of aggressive clinic characteristics, polyarticular predominance, erosion presence and associated with shared epitope allele. The existing information don´t allow defining if this patience will develop more aggressive illness or existing concomitance of two joint diseases. More detail studies are necessary to defined that.

La arginina en su contexto metabólico y fisiológico / Arginine on its metabolic and physiological context

La L-arginina es uno de los aminoácidos más versátiles desde el punto de vista metabólico y fisiológico. Entre sus funciones conocidas se incluyen: sustrato de la biosíntesis de proteínas y de péptidos bioactivos, participación en la detoxificación de amonio, liberación de hormonas, y biosíntesis de poliaminas y creatina. Las funciones de la arginina se han visto recientemente incrementadas con el descubrimiento de su papel como sustrato precursor del óxido nítrico, un efector multifuncional implicado en la vasodilatación, neurotransmisión, y con actividad antimicrobiana y antitumoral. Desde el punto de vista nutricional, la arginina es un aminoácido "condicionalmente esencial" para los mamíferos. Sus requerimientos se cubren gracias al aporte dietético y la síntesis endógena, siendo ésta última en el hombre, al parecer, suficiente para cubrir las necesidades fisiológicas habituales pero insuficiente en períodos o condiciones de elevada demanda del aminoácido. Tal situación sugiere un potencial uso terapéutico para la arginina que está comenzando a ser analizado. Esta revisión pretende resumir los conocimientos actuales sobre la síntesis de arginina y sus principales destinos metabólicos