The reversal of epigenetic silencing of the EBV genome is regulated by viral bZIP protein.

EBV (Epstein-Barr virus) alternates between latency and lytic replication. During latency, the viral genome is largely silenced by host-driven methylation of CpG motifs and in the switch to the lytic cycle this epigenetic silencing is overturned. A key event is the activation of the viral protein Zta with three ZREs (Zta-response elements) from the BRLF1 promoter (referred to as Rp). Two of these ZREs contain CpG motifs and are methylated in the latent genome. Biochemical analyses and molecular modelling of Zta bound to methylated RpZRE3 indicate the precise contacts made between a serine and a cysteine residue of Zta with methyl cytosines. A single point mutant of Zta, C189S, is defective in binding to the methylated ZREs both in vitro and in vivo. This was used to probe the functional relevance of the interaction. ZtaC189S was not able to activate Rp in a B-cell line, demonstrating the relevance of the interaction with methylated ZREs. This demonstrates that Zta plays a role in overturning the epigenetic control of viral latency.

Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein-Barr virus lytic switch protein.

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with various malignancies, including Burkitt's lymphoma and nasopharyngeal carcinoma. Like all herpesviruses, the EBV life cycle alternates between latency and lytic replication. During latency, the viral genome is largely silenced by host-driven methylation of CpG motifs and, in the switch to the lytic cycle, this epigenetic silencing is overturned. A key event is the activation of the viral BRLF1 gene by the immediate-early protein Zta. Zta is a bZIP transcription factor that preferentially binds to specific response elements (ZREs) in the BRLF1 promoter (Rp) when these elements are methylated. Zta's ability to trigger lytic cycle activation is severely compromised when a cysteine residue in its bZIP domain is mutated to serine (C189S), but the molecular basis for this effect is unknown. Here we show that the C189S mutant is defective for activating Rp in a Burkitt's lymphoma cell line. The mutant is compromised both in vitro and in vivo for binding two methylated ZREs in Rp (ZRE2 and ZRE3), although the effect is striking only for ZRE3. Molecular modeling of Zta bound to methylated ZRE3, together with biochemical data, indicate that C189 directly contacts one of the two methyl cytosines within a specific CpG motif. The motif's second methyl cytosine (on the complementary DNA strand) is predicted to contact S186, a residue known to regulate methyl-ZRE recognition. Our results suggest that C189 regulates the enhanced interaction of Zta with methylated DNA in overturning the epigenetic control of viral latency. As C189 is conserved in many bZIP proteins, the selectivity of Zta for methylated DNA may be a paradigm for a more general phenomenon.

Cecostomía percutanea en pediatría / Percutaneous cecostomy in cChildren

Propósito: Reportar nuestra experiencia con la Cecostomía Percutánea en el manejo de pacientes pediátricos con incontinencia fecal. Pacientes Método: Entre marzo 2002 y agosto 2005, se efectuaron 20 cecostomías percútáneas. La edad promedio fue de 8.9 años. Las causas de incontinencia fueron: malformación anorectal en 18 casos, mielomeningocele en 1 caso y constipación crónica en el restante. Todos los procedimientos se realizaron bajo anestesia general y control radioscópico. En todos los casos se utilicó un catéter Dawson Mueller de 8.5 F, que se reemplazó luego de 45 días, por un botón ad-hoc (trapdoor catheter). Resultados: Todos los procedimientos fueron satisfactorios. No se registraron complicaciones mayores. Conclusión: La Cecostomia Pecutánea es un procedimiento seguro y efizaz para el manejo de pacientes con incontinencia fecal de cualquier origen. El objetivo de este procedimiento es permitir el lavado anterógrado de todo el colon. Con ello se evita la necesidad de repetidos enemas evacuantes, lo que contribuye significtivamente a la mejor calidad de vida de estos pacientes.

Evolución de niños post-trasplante hepático luego del primer año de sobrevida / Evolution of children one year post liver transplant

Orthotopic liver transplantation is the only definitive mode of therapy for children with end-stage liver disease. However, it remains challenging because of the necessity to prevent long-term complications. The aim of this study was to analyze the evolution of transplanted patients with more than one year of follow up. Between November 1992 and November 2001, 238 patients underwent 264 liver transplantations. A total of 143 patients with more than one year of follow up were included. The median age of patients +/- SD was 5.41 years +/- 5.26 (r: 0.58-21.7 years). All children received primary immunosuppression with cyclosporine. The indications for liver replacement were: fulminant hepatic failure (n: 50), biliary atresia (n: 38), cirrhosis (n: 37), chronic cholestasis (n: 13) and miscellaneous (n: 5). The indications for liver re-transplantation were: biliary cirrhosis (n: 7), hepatic artery thrombosis (n: 4) and chronic rejection (n: 3). Reduced-size liver allografts were used in 73/157 liver transplants, 14 of them were from living-related donors and 11 were split-livers. Patient and graft survival rates were 93% and 86% respectively. Death risk was statistically higher in retransplanted and reduced-size grafted patients. Growth retardation and low bone density were recovered before the first 3 years post-transplant. The incidence of lymphoproliferative disease was 7.69%. De novo hepatitis B was diagnosed in 7 patients (4.8%). Social risk did not affect the outcome of our population. The prevention, detection and early treatment of complications in the long-term follow up contributed to improve the outcome.

Evolución de niños post-trasplante hepático luego del primer año de sobrevida / Evolution of children one year post liver transplant

Orthotopic liver transplantation is the only definitive mode of therapy for children with end-stage liver disease. However, it remains challenging because of the necessity to prevent long-term complications. The aim of this study was to analyze the evolution of transplanted patients with more than one year of follow up. Between November 1992 and November 2001, 238 patients underwent 264 liver transplantations. A total of 143 patients with more than one year of follow up were included. The median age of patients +/- SD was 5.41 years +/- 5.26 (r: 0.58-21.7 years). All children received primary immunosuppression with cyclosporine. The indications for liver replacement were: fulminant hepatic failure (n: 50), biliary atresia (n: 38), cirrhosis (n: 37), chronic cholestasis (n: 13) and miscellaneous (n: 5). The indications for liver re-transplantation were: biliary cirrhosis (n: 7), hepatic artery thrombosis (n: 4) and chronic rejection (n: 3). Reduced-size liver allografts were used in 73/157 liver transplants, 14 of them were from living-related donors and 11 were split-livers. Patient and graft survival rates were 93% and 86% respectively. Death risk was statistically higher in retransplanted and reduced-size grafted patients. Growth retardation and low bone density were recovered before the first 3 years post-transplant. The incidence of lymphoproliferative disease was 7.69%. De novo hepatitis B was diagnosed in 7 patients (4.8%). Social risk did not affect the outcome of our population. The prevention, detection and early treatment of complications in the long-term follow up contributed to improve the outcome.(AU)

[Laparoscopic Kasai's operation. Technical details and preliminary results of a promising technique]. / Operación de Kasai laparoscópica. Detalles técnicos y resultados iniciales de una técnica promisoria.

OBJECTIVE: The purpose of this study is to describe the technical details of laparoscopic porto-enterostomy and comment the identical results using this technique in patients with biliary atresia. METHODS. We analyzed the results of the first three patients with biliary atresia who underwent a laparoscopic surgical approach. RESULTS: There were no complications during surgery or in the postoperative period. The average surgical time was 220 minutes (150-270 minutes). The three patients began oral feedings 12 hours after the procedure and achieved bowel movement after 24 hours. All of them showed signs of adequate bile flow, such as pigmented stools, and disappearance of jaundice. The cosmetic results were excellent. CONCLUSIONS: The Kasai porto-enterostomy may be performed by laparoscopy without complications. The initial results were encouraging and the patients recovered promptly after this procedure. The surgical time was significantly diminished, thus in the third case it was similar or less than the required with open surgery. The laparoscopic portoenterostomy is a promising technique and its real role will be known after more number of cases.

Trasplante hepático. Seguimiento a largo plazo / Liver transplantation. Long term follow up

El trasplante hepático (TH) constituye la única alternativa terapéutica para numerosas enfermedades hepáticas avanzadas. Los adelantos en la técnica quirúrgica y en la inmunosupresión desarrollados en los últimos años permitieron mejorar la sobrevida. En la evolución a largo plazo de los pacientes trasplantados pueden presentarse complicaciones de diversa severidad. Objetivo: analizar la evolución a largo plazo de los pacientes trasplantados con un seguimiento mayor de 1 año post-TH. Material y Métodos: Durante el período 11/92-11/01 se realizaron 264 TH en 238 pacientes. De estos pacientes 143 (157 TH) fueron seguidos más allá de un año post-TH. La mediana de edad (m.a más menos DS) fue de 5,41 años más menos 5,26 (r:0.58 - 21.7 años); 76 pertenecían al sexo femenino. Catorce (9.79 por ciento) recibieron un re-TH. Fueron excluidos los pacientes que no habían cumplido todavía un años post- TH o los que fallecieron antes de ese lapso de seguimiento. Las indicaciones de TH fueron: falla hepática fulminante (FHF) (n:50); atresia de vías biliares (AVB) (n:38); cirrosis (n: 37); colestasis crónica (n: 13) y otras (n: 5). Las indicaciones de Re-TH fueron: cirrosis biliar (n: 7); trombosis de la arteria hepática (n: 4) y rechazo crónico (n: 3). En 73/157 TH se utilizaron injertos reducidos: 14 donantes vivos relacionados (DVR) y 11 biparticiones hepáticas. Se sometieron a análisis estadístico variables potenciales de morbimortalidad. Resultados: La sobrevida global fue: pacientes 93 por ciento: injerto: 86 por ciento. El re-TH y el injerto reducido fueron las variables de mayor significación para aumento del riesgo de muerte en nuestra población. El déficit de talla y masa ósea se recuperó anes de los 3 años post-TH. La incidencia del síndrome linfoproliferativo (SLP) fue del 7.69 por ciento, su diagnóstico y tratamiento temprano permitió una evolución favorable en la mayoria de los casos.

Pseudoquiste pancreático en niños: rol del drenaje percutáneo / Pancreatic pseudocyst in children: role of the percutaneous drainage

El pseudoquiste de páncreas(PQP)es una enfermedad infrecuente en pediatría.Revisamos los resultados de la terapéutica mínimamente invasiva mediante la colocación de un drenaje al exterior.Se analizaron las historias clínicas de 16 pacientes ingresados a nuestro hospital con diagnótico de PQP entre enero de 1989y enero de 1999.El rango de edades fue entre 2 y 13 años(media 6.9).14 eran varones y 2 mujeres,La etiología fue:traumatismo abdominal en 11,secuela de pancreatitis aguda en 3 e ideopática en 2.Tres pacientes fueron operados antes de instituir como terapeúticael drenaje al exterior.En 5 se realizó drenaje percutáneo guiado con ultrasonografía,uno en punción evacuadora y en los 7 restantes la conducta fue expectante debido a una evolución con tendencia a la desaparición del PQP.En 4 niños que recibieron tratamiento percutáneo guiado con ultrasonografía,uno en punción evacuadora y en los 7 restantes la conducta fue expectante debido a una evolución con tendencia a la desaparición del PQP.En 4 niños que recibieron tratamiento percutáneo se registró la curación de PQP,el otro debió ser drenado por segunda vez,por la remoción accidental precoz del catéter.Si bien tanto nuestras series como las consultadas muestran un 50 a 75 por ciento de casos de resolución espontánea,el drenaje percutáneo es un buena alternativa en aquellos pacientes con PQP que no resuelven espontáneamente

Pseudoquiste pancreático en niños: rol del drenaje percutáneo / Pancreatic pseudocyst in children: role of the percutaneous drainage

El pseudoquiste de páncreas(PQP)es una enfermedad infrecuente en pediatría.Revisamos los resultados de la terapéutica mínimamente invasiva mediante la colocación de un drenaje al exterior.Se analizaron las historias clínicas de 16 pacientes ingresados a nuestro hospital con diagnótico de PQP entre enero de 1989y enero de 1999.El rango de edades fue entre 2 y 13 años(media 6.9).14 eran varones y 2 mujeres,La etiología fue:traumatismo abdominal en 11,secuela de pancreatitis aguda en 3 e ideopática en 2.Tres pacientes fueron operados antes de instituir como terapeúticael drenaje al exterior.En 5 se realizó drenaje percutáneo guiado con ultrasonografía,uno en punción evacuadora y en los 7 restantes la conducta fue expectante debido a una evolución con tendencia a la desaparición del PQP.En 4 niños que recibieron tratamiento percutáneo guiado con ultrasonografía,uno en punción evacuadora y en los 7 restantes la conducta fue expectante debido a una evolución con tendencia a la desaparición del PQP.En 4 niños que recibieron tratamiento percutáneo se registró la curación de PQP,el otro debió ser drenado por segunda vez,por la remoción accidental precoz del catéter.Si bien tanto nuestras series como las consultadas muestran un 50 a 75 por ciento de casos de resolución espontánea,el drenaje percutáneo es un buena alternativa en aquellos pacientes con PQP que no resuelven espontáneamente

Neuroblastoma IVs con hepatomegalia masiva / Stage IV-S neuroblastoma with massive hepatomegaly

El neuroblatoma IVs es en general un tumor de buen pronóstico.Existe un grupo de pacientes(10-25 por ciento)con esta enfermedad que tienen mal pronóstico debido a que progresan a un estadio IV a que asocian a hepatomegalia masiva.Presentamos la táctica quirúrgica seguida en un niño con neuroblatoma IVs asociado a hepatomegalia masiva

Neuroblastoma IVs con hepatomegalia masiva / Stage IV-S neuroblastoma with massive hepatomegaly

El neuroblatoma IVs es en general un tumor de buen pronóstico.Existe un grupo de pacientes(10-25 por ciento)con esta enfermedad que tienen mal pronóstico debido a que progresan a un estadio IV a que asocian a hepatomegalia masiva.Presentamos la táctica quirúrgica seguida en un niño con neuroblatoma IVs asociado a hepatomegalia masiva

Development of a pediatric liver transplantation program in Argentina.

This article describes the preliminary experimental steps and clinical implementation of a purely pediatric liver transplantation (LT) program in a large public children's hospital in Buenos Aires, Argentina, a city with well over 10 million inhabitants and a referral population of over 30 million. Between 1993 and 1997, 84 LTs were performed in 81 patients, of which one-fourth weighed below 10 kg. The main indications were biliary atresia (n = 25, 30%) and fulminant liver failure (n = 23, 27%), followed by autoimmune cirrhosis (n = 14, 16%) and other liver diseases. Shortage of organs due to local conditions led to the use of liver-reduction techniques in 48 cases (57%), split liver in 2, and living-related donor (LRD) in 2. Retransplantation was necessary in 3 instances. Seventy-eight percent of the recipients survived for more than 1 year and 71% were alive after 4 years. The authors comment on the need for adaptation to local conditioning factors when developing a pediatric LT program in any country in which demographics and economic, medical, and sociological environments have a decisive influence on organ procurement, the actual performance of the operation, and the lifelong postoperative medication. In Buenos Aires, where the hospital setting is well-developed, the indications are in part determined by the high incidence of hepatitis A. Organ shortages in our area led to liberal use of liver reduction, split-liver, and LRD techniques. The overall results of the first years of such a program were largely satisfactory.

[Histologic factors as elements of prognostic value in biliary atresia]. / Factores histológicos como elemento de valor pronóstico en atresia de vías biliares.

Biliary atresia (BA) is one of the biliary tree anomaly more frequent. Occurs in about 0.8 to 1/10.000 live births. BA is defined as a progressive biliary tree. The prognosis depends on the age of the diagnosis and precocity surgery. We present the results of a retrospective analysis of 71 RA carried out at the Garrahan Hospital from 1987 to 1993. 47 were female and 24 were male. Age ranged from 45 to 120 days of life. This study involved a consecutive series of 58 patients with histopathologic study of Porta-hepatis (PH) and liver biopsy obtained during the Kasai. The purpose of this study was to determine the value of histological factors as type of PH and hepatocytic giant cell transformation (GCT). 82.8% had favorable type of PH and the CCT was mild in 84.5%. 72.4% had bad outcome and was independent of the type of PH. Neither of them were statistically significant with survive and evolution. In our service neither PH non CGT were predictors of a bad outcome. There were good outcome in 27.5%, died 37.9% and 10.3% undergo liver transplantation. The precocity in a diagnosis and surgical procedure before two months of age are the most important factors in correlation with survival. Others immunomorphologic factors must be studied in BA that explained the etiopathogenic process. Orthotopic liver transplantation is the successful therapy in children with BA.

Factores histológicos como elemento de valor pronóstico en atresia de vias biliares / Histologic factors as an element of prognosis value in biliary atresia

Biliary atresia (BA) is one of the biliary tree anomaly more frecuent. Occurs in about 0,8 to 1/10.000 live births. BA is defined as a progressive biliary tree. The prognosis depends ond the age of the diagnosis and precocity surgery. We present the resuls of a retrospective analysis of 71 RA carried out at the Garrahan Hospital from 1987 to 1993. 47 were female and 24 were male. Age ranged from 45 to 120 days of life. This study involved a consecutive series of 58 patients with histopathologic study of Porta-hepatis (PH) and liver biopsy obteined during the Kasai. The purpose of this study was to determine the value of histological factors as type of PH and hepatocitic giant cell transformation (GCT). 82.8 per cent had favorable type of PH and the CCT was mild in 84,5 per cent. 72,4 per cent had bad outcome and was independent of the type of PH. Neither of them were statiscaly significant with survive and evolution. In our serice neither PH non CGT were predicators of a bad outcome. There were good outcome in 27.5 per cent, died 37,9 per cent and 10.3 per cent undergo liver transplantation. The precocity in a diagnosis and surgical procedure before two months of age are the most important factors in correlation with survival. Others immunomorphologic factors must be estudied in BA that explained the ethiopatogenic process. Orthotopic liver transplantation is the succesful therapy in childrens with BA.

Factores histológicos como elemento de valor pronóstico en atresia de vias biliares / Histologic factors as an element of prognosis value in biliary atresia

Biliary atresia (BA) is one of the biliary tree anomaly more frecuent. Occurs in about 0,8 to 1/10.000 live births. BA is defined as a progressive biliary tree. The prognosis depends ond the age of the diagnosis and precocity surgery. We present the resuls of a retrospective analysis of 71 RA carried out at the Garrahan Hospital from 1987 to 1993. 47 were female and 24 were male. Age ranged from 45 to 120 days of life. This study involved a consecutive series of 58 patients with histopathologic study of Porta-hepatis (PH) and liver biopsy obteined during the Kasai. The purpose of this study was to determine the value of histological factors as type of PH and hepatocitic giant cell transformation (GCT). 82.8 per cent had favorable type of PH and the CCT was mild in 84,5 per cent. 72,4 per cent had bad outcome and was independent of the type of PH. Neither of them were statiscaly significant with survive and evolution. In our serice neither PH non CGT were predicators of a bad outcome. There were good outcome in 27.5 per cent, died 37,9 per cent and 10.3 per cent undergo liver transplantation. The precocity in a diagnosis and surgical procedure before two months of age are the most important factors in correlation with survival. Others immunomorphologic factors must be estudied in BA that explained the ethiopatogenic process. Orthotopic liver transplantation is the succesful therapy in childrens with BA. (AU)