Guiding value of dynamic monitoring citrulline for early enteral nutrition in patients with severe gastrointestinal injury / 中华危重病急救医学

OBJECTIVE@#To investigate whether dynamic monitoring of citrulline (Cit) has guiding value for early enteral nutrition (EN) in patients with severe gastrointestinal injury.@*METHODS@#A observational study was conducted. A total of 76 patients with severe gastrointestinal injury admitted to different intensive care units of Suzhou Hospital Affiliated to Nanjing Medical University from February 2021 to June 2022 were enrolled. Early EN was performed in 24-48 hours after admission as recommended by the guidelines. Those who did not terminate EN after 7 days were enrolled in the early EN success group, and those who terminated EN within 7 days due to persistent feeding intolerance or deterioration of general condition were enrolled in the early EN failure group. There was no intervention during the treatment. Serum Cit levels were measured by mass spectrometry at admission, before EN starting and EN 24 hours, respectively, and the changes in Cit within EN 24 hours (ΔCit) were calculated (ΔCit = EN 24-hour Cit-Cit before EN starting). Receiver operator characteristic curve (ROC curve) was plotted to investigate the predictive value of ΔCit for early EN failure, and the optimal predictive value was calculated. Multivariate unconditional Logistic regression was used to analyze the independent risk factors for early EN failure and death at 28 days.@*RESULTS@#Seventy-six patients were enrolled in the final analysis, of which 40 succeeded in early EN and 36 failed. There were significant differences in age, main diagnosis, acute physiology and chronic health evaluation II (APACHE II) score at admission, blood lactic acid (Lac) before EN initiation and ΔCit between the two groups. Multivariate Logistic regression analysis showed that age [odds ratio (OR) = 0.929, 95% confidence interval (95%CI) was 0.874-0.988, P = 0.018], ΔCit (OR = 2.026, 95%CI was 1.322-3.114, P = 0.001) and increased feeding rate within 48 hours (OR = 13.719, 95%CI was 1.795-104.851, P = 0.012) were independent risk factors for early EN failure in patients with severe gastrointestinal injury. ROC curve analysis showed that ΔCit had a good predictive value for early EN failure in patients with severe gastrointestinal injury [area under the ROC curve (AUC) = 0.787, 95%CI was 0.686-0.887, P < 0.001], and the optimal predictive value of ΔCit was 0.74 μmol/L (sensitivity was 65.0%, specificity was 75.0%). Combined with the optimal predictive value of ΔCit, "overfeeding" was defined as ΔCit < 0.74 μmol/L and increased feeding within 48 hours. Multivariate Logistic regression analysis showed that age (OR = 0.825, 95%CI was 0.732-0.930, P = 0.002), APACHE II score (OR = 0.696, 95%CI was 0.518-0.936, P = 0.017) and early EN failure (OR = 181.803, 95%CI was 3.916-8 439.606, P = 0.008) were independent risk factors for 28-day death in patients with severe gastrointestinal injury. The new variable "overfeeding" was also associated with an increased risk of death at 28 days (OR = 27.816, 95%CI was 1.023-755.996, P = 0.048).@*CONCLUSIONS@#Dynamic monitoring of Cit has guiding value for early EN in patients with severe gastrointestinal injury.

Neonate-onset ornithine transcarbamylase deficiency / 中国当代儿科杂志

The male neonate in this case study was admitted to the hospital at 15 hours of age due to respiratory distress for 15 hours and poor response for 3 hours after resuscitation from asphyxia. The neonate was highly unresponsive, with central respiratory failure and seizures. Serum ammonia was elevated (>1 000 μmol/L). Blood tandem mass spectrometry revealed a significant decrease in citrulline. Rapid familial whole genome sequencing revealed OTC gene mutations inherited from the mother. Continuous hemodialysis filtration and other treatments were given. Neurological assessment was performed by cranial magnetic resonance imaging and electroencephalogram. The neonate was diagnosed with ornithine transcarbamylase deficiency combined with brain injury. He died at 6 days of age after withdrawing care. This article focuses on the differential diagnosis of neonatal hyperammonemia and introduces the multidisciplinary management of inborn error of metabolism.

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.

Strong inflammation is essential for expression of articular cartilage-specific citrullinated antigens / 南方医科大学学报

OBJECTIVE@#To investigate the expression of citrullinated epitopes in articular cartilage protein and whether its expression is sufficient to induce anti-citrullinated protein antibody (ACPA) response in mice.@*METHODS@#The experimental group was treated with different concentrations of lipopolysaccharide (LPS), heat-inactivated bacteria ( and ) or specific monoclonal antibody against type Ⅱ collagen to induce citrullination of articular cartilage protein, with PBS as the control. Immunohistochemistry with the monoclonal antibody ACC4 (IgG1) that specifically binds to the citrullinated epitope of cartilage protein was performed for detecting the expression of citrullinated protein, with ACC1 (IgG2a) as a positive control antibody and L243 (IgG2a) and Hy2.15 (IgG1) as the negative isotype control. In the in vivo experiment, SD rats were subjected to injection of different doses of LPS in the right knee (with PBS as the controls in the left knee), and 3 days later frozen sections were prepared for immunohistochemical detection of the expression of citrullinated protein. Models of collagen-induced arthritis (CIA) established in different mouse strains were observed for incidence and severity of CIA. Serum samples collected from these models and the sera from rheumatoid arthritis patients were examined for anti-citrullinated protein antibody, and immunohistochemistry was performed to detect the expression of citrullinated protein in the cartilage of the mouse.@*RESULTS@#The citrullinated CII epitope-specific antibody ACC4 did not bind to articular cartilage tissues with different treatments as compared with the positive control antibody ACC1. The ACC4 antibody and the antibodies from patients with rheumatoid arthritis with high titers of anti-citrullinated protein antibody were capable of binding to the synovial tissue around the articular cartilage of the CIA. Luminex analysis showed that the anti-citrullinated protein antibody was lowly expressed in mouse serum, but the anti-type Ⅱ collagen triple helix structure peptide antibody exhibited strong reactivity.@*CONCLUSIONS@#Mild acute inflammatory response is not enough to cause citrullination of articular cartilage protein, and the expression of specific epitope requires a high-intensity inflammatory response. Inflammatory articular cartilage protein can express citrullinated epitopes in type Ⅱ collagen-induced arthritis in mice, but the expression of citrullinated epitopes is not sufficient to induce an immune response to anti-citrullinated antibodies. Stronger stimulation signals are required to induce an immune response for producing anti-citrullinated protein antibodies.

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.

Short Bowel Syndrome as the Leading Cause of Intestinal Failure in Early Life: Some Insights into the Management / 대한소아소화기영양학회지

Intestinal failure (IF) is the critical reduction of the gut mass or its function below the minimum needed to absorb nutrients and fluids required for adequate growth in children. Severe IF requires parenteral nutrition (PN). Pediatric IF is most commonly due to congenital or neonatal intestinal diseases or malformations divided into 3 groups: 1) reduced intestinal length and consequently reduced absorptive surface, such as in short bowel syndrome (SBS) or extensive aganglionosis; 2) abnormal development of the intestinal mucosa such as congenital diseases of enterocyte development; 3) extensive motility dysfunction such as chronic intestinal pseudo-obstruction syndromes. The leading cause of IF in childhood is the SBS. In clinical practice the degree of IF may be indirectly measured by the level of PN required for normal or catch up growth. Other indicators such as serum citrulline have not proven to be highly reliable prognostic factors in children. The last decades have allowed the development of highly sophisticated nutrient solutions consisting of optimal combinations of macronutrients and micronutrients as well as guidelines, promoting PN as a safe and efficient feeding technique. However, IF that requires long-term PN may be associated with various complications including infections, growth failure, metabolic disorders, and bone disease. IF Associated Liver Disease may be a limiting factor. However, changes in the global management of IF pediatric patients, especially since the setup of intestinal rehabilitation centres did change the prognosis thus limiting “nutritional failure” which is considered as a major indication for intestinal transplantation (ITx) or combined liver-ITx.

Clinical features of children with lysinuric protein intolerance and SLC7A7 gene mutation: an analysis of 3 cases / 中国当代儿科杂志

Lysinuric protein intolerance (LPI) is an autosomal recessive disorder caused by SLC7A7 gene mutation and often involves severe lesions in multiple systems. Lung involvement is frequently seen in children with LPI and such children tend to have a poor prognosis. This article summarizes the clinical manifestations and gene mutation characteristics of three children diagnosed with LPI by SLC7A7 gene analysis. All three children had the manifestations of aversion to protein-rich food after weaning, delayed development, anemia, hepatosplenomegaly, and osteoporosis, as well as an increase in orotic acid in urine. In addition, interstitial pneumonia and diffuse pulmonary interstitial lesions were observed in two children. SLC7A7 gene detection showed three pathogenic mutations in these children, namely c.1387delG(p.V463CfsX56), c.1215G>A(p.W405X) and homozygous c.625+1G>A. After a definite diagnosis was made, all three children were given a low-protein diet and oral administration of citrulline [100 mg/(kg.d)], iron protein succinylate [4 mg/(kg.d)], calcium and zinc gluconates oral solution (10 mL/day) and vitamin D (400 IU/day). In addition, patient 3 was given prednisone acetate (5 mg/day). The children had varying degrees of improvement in symptoms and signs. It is hard to distinguish LPI from urea cycle disorder due to the features of amino acid and organic acid metabolism in LPI, and SLC7A7 gene analysis is the basis for a definite diagnosis of LPI.

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.

Homo-Genius: Homocitrulline Can Be a Better Target than Citrulline as a Biomarker for Rheumatoid Arthritis?

No abstract available.

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)

Screening of citrullinated proteins in ten tumor cell lines / 中华肿瘤杂志

<p><b>OBJECTIVE</b>The conversion of arginine into citrulline, termed citrullination, has important consequences for the structure and function of proteins. The present study aimed to identify novel citrullinated proteins in 10 tumor cell lines by 2-D Western blotting (2-D WB).</p><p><b>METHODS</b>Two identical two-dimensional electrophoresis (2-DE) gels were prepared using extracts from ten cultured human tumor cell lines: ECA(esophageal cancer cells), HEPG2 (hepatocellular carcinoma cells), SKOV3 (ovarian cancer cells), MCF-7 (breast cancer cells), H292 (lung mucoepidermoid carcinoma cells), HeLa (cervical cancer cells), Lovo (colon cancer cells), OS-RC (renal cell carcinoma cells), PANC-1 (pancreatic cancer cells), and SGC (gastric cancer cells). The expression profiles on one 2-DE gels were trans-blotted to PVDF membranes, and the blots were then probed with an anti-citrulline antibody. By comparing the 2-DE profile with the parallel 2-D WB profile at a global level, protein spots with immuno-signals were collected from the second 2-DE gel and identified using mass spectrometry. Immunoprecipitation was used to verify the expression and citrullination of the targeted proteins in the tumor cell lines.</p><p><b>RESULTS</b>2-D WB and mass spectrometry identified citrullinated ENO1 (α-enolase), HSP60 (heat shock protein 60), KRT8 (keratin 8), TUBB (tubulin beta), TCRβ (T cell receptor β chain), VIME (vimentin) and PDI in these cell lines. Immunoprecipitation analyses verified the expression and citrullination of ENO1, HSP60, KRT8, and TUBB in the total protein lysates of the tumor cell lines.</p><p><b>CONCLUSION</b>The citrullination of proteins ENO1, HSP60, KRT8, and TUBB suggests a new mechanism in the tumorigenic process.</p>

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.

Value of four serum markers in the diagnosis of rheumatoid arthritis / 南方医科大学学报

<p><b>OBJECTIVE</b>To systematically evaluate the values of 4 serum markers in the diagnosis of rheumatoid arthritis (RA).</p><p><b>METHODS</b>Serum samples were obtained from 278 RA patients and 510 control subjects and the levels of rheumatoid factor (RF), anticyclic citrullinated peptide antibody (CCP), antikeratin antibody (AKA), and glucose-6-phosphate isomerase (GPI) were detected using immune turbidimetry, ELISA, indirect immunofluorescence, and ELISA, respectively. The values of these 4 serum markers and their combinations in RA diagnosis were systemically assessed.</p><p><b>RESULTS</b>In RA diagnosis using one serum marker, two markers, and three or four markers, RF, RF+CCP, RF+CCP+GPI, respectively, had the highest sensitivity; CCP, CCP+AKA, and RF+CCP+AKA+GPI, respectively, had the highest specificity; CCP, CCP+GPI, and RF+CCP+AKA+GPI, respectively, had the highest positive predictive value; GPI, RF+CCP, and RF+CCP+GPI, respectively, had the highest negative predictive value; CCP, CCP+GPI, and RF+CCP+AKA+GPI, respectively, had the highest positive likely ratio; GPI, RF+CCP, and RF+CCP+GPI, respectively, had the lowest negative likely ratio.</p><p><b>CONCLUSION</b>CCP, RF+CCP, and RF+CCP+GPI are the most ideal for RA diagnosis using one, two, and three or more markers, respectively. CCP is the essential marker for RA diagnosis, and a combined detection of the serum makers can significantly improve the diagnostic accuracy.</p>

Clinical effect of stem cell transplantation via hepatic artery in the treatment of type II hyperammonemia: a report on 6 cases / 中国当代儿科杂志

This study aimed to investigate the clinical effect of transplantation of CD133⁺ peripheral blood stem cells or umbilical cord mesenchymal stem cells via the hepatic artery in children with type II hyperammonemia and its possible action mechanism. Umbilical cord mesenchymal stem cells were obtained by collecting cord blood (100-150 mL) from healthy fetuses and separating stem cell suspension (5 mL) from the cord blood by hydroxyethyl starch sedimentation. CD133⁺ peripheral blood stem cells were obtained by mobilizing peripheral blood from the fathers of sick children using recombinant human granulocyte colony-stimulating factor for 5 days, collecting mononuclear cells (120 mL), and separating out CD133⁺ cells by sorting. With catheterization and percutaneous puncture, the obtained stem cells were slowly injected into the liver of sick children via the hepatic artery. The changes in clinical symptoms and laboratory indices such as blood ammonia, liver function, and arginine and citrulline concentrations were observed. After stem cell transplantation via the hepatic artery, the 6 children showed significantly decreased blood ammonia levels, and their blood ammonia levels slowly increased 1 to 2 weeks later, but remained below 100 μmol/L, and changes in glutamic-pyruvic transaminase levels were similar to blood ammonia. Plasma citrulline and arginine concentrations increased significantly after transplantation and the increase in citrulline level exceeded the increase in arginine level. An 8 months follow-up visit for one typical patient showed that the weight and height increased after transplantation and sleep was improved without night crying. The child could actively gaze at interesting objects instead of responding indifferently and started to say simple words. With regard to fine motor skills, the child could pinch things with the thumb and middle finger instead of displaying a lack of hand-eye coordination and progress was also made in gross motor skills. Gesell test showed that the child made progress for an average of 3.82 months in all areas. It was concluded that after stem cell transplantation, children with type II hyperammonemia have decreased blood ammonia levels, stable and improved liver function and steadily increased plasma citrulline and arginine concentrations. They display a progressive trend in such aspects as movement, language and environmental adaptability. It is hypothesized that stem cell transplantation via the hepatic artery partially or totally activates, or provides supplementary ornithine carbamoyl transferase, so that plasma citrulline and arginine concentrations increase and urea cycle disorder can be corrected to some extent.