Evaluación del proceso de atención urológica de pacientes pediátricos con mielomeningocele / Evaluation of the urological care process of pediatric patients with myelomeningocele

Introducción: El mielomeningocele (MMC) es una de las malformaciones congénitas más severas compatible con la vida. El 90% de los pacientes presenta vejiga neurogénica que debe ser evaluada y tratada precozmente. Objetivos: Describir la evaluación y tratamiento nefrourológico recibido por pacientes con MMC hasta el momento de la primera consulta en el Hospital Garrahan (periodo pre-ingreso). Describir la evaluación realizada y el tratamiento urológico implementado a partir del ingreso al hospital Garrahan (periodo post-ingreso). Evaluar la prevalencia de Enfermedad Renal Crónica (ERC). Población y Métodos: Se realizó un estudio con diseño clínico analítico, retrospectivo, longitudinal sobre pacientes con MMC de 1 mes a 18 años derivados al Hospital Garrahan para atención ambulatoria en los años 2011 y 2012. Resultados: Se incluyeron115 pacientes. Al momento de la derivación al hospital ("pre-ingreso") 7% de los pacientes habían logrado completar evaluación nefrourológica, (ecografía vesicorenal, urodinamia, Cistouretrografía, Centellograma renal y Creatininemia). Tratamiento: 33% vaciaban vejiga por CIL o vesicostomía y 21% recibían Oxibutinina. A partir del ingreso al seguimiento en el Garrahan 83% lograron completar la evaluación, y en función del resultado de la misma se indicó CIL en 87% y Oxibutinina en el 66% de los pacientes. La prevalencia de ERC al ingreso fue de 43%; la mayoría en estadio I. Conclusiones: La mayoría de los pacientes con MMC fueron derivados al hospital de tercer nivel con evaluaciones urológicas incompletas y sin el tratamiento adecuado de la vejiga neurogénica. El inicio del seguimiento interdisciplinario en un hospital de alta complejidad facilitó la realización de las evaluaciones necesarias y la implementación del tratamiento adecuado (AU)

Introduction: Myelomeningocele (MMC) is one of the most severe congenital malformations compatible with life. Of all the patients, 90% presents with a neurogenic bladder requiring early evaluation and treatment. Objectives: To describe the uronephrological evaluation and treatment received by patients with MMC up to the first consultation at Garrahan Hospital (pre-follow-up period). To describe the urological evaluation and treatment implemented from referral to Garrahan Hospital (follow-up period). To evaluate the prevalence of chronic kidney disease (CKD). Population and Methods: A retrospective, longitudinal study with a clinical, analytical design was conducted in patients with MMC between 1 months and 18 years of age referred to Garrahan Hospital for outpatient care in 2011 and 2012. Results: 115 patients were included. At the time of referral to the hospital ("pre-follow-up") 7% of the patients had undergone complete uronephrological evaluation (kidney-bladder ultrasonography, urodynamic studies, cystourethrography, renal scintigraphy, and creatininemia levels). Treatment: 33% emptied their bladder by CIC or vesicostomy and 21% received oxybutynin. From follow-up initiation at Garrahan Hospital, 83% underwent complete evaluation, and based on the results CIC was indicated in 87% and oxybutynin in 66% of the patients. On admission, prevalence of CKD was 43%; with stage I in the majority of the patients. Conclusions: The majority of the patients with MMC were referred to a third-level hospital with incomplete urological studies and without adequate treatment of the neurogenic bladder. Initiation of interdisciplinary follow-up at a tertiary hospital allowed for the necessary studies and implementation of adequate treatment (AU)

Heminefrectomía en pacientes con doble sistema renal. Experiencia en el Hospital Garrahan / Heminephrectomy in patients with a duplex kidney. Experience at the Garrahan Hospital

La heminefrectomía puede constituir el tratamiento definitivo en el 85% de los pacientes con diagnóstico de doble sistema con uno de los mismos no funcionante. Actualmente el abordaje laparoscópico es de elección tanto por sus resultados estéticos como evolución postoperatoria. Materiales y métodos: se efectuó una revisión y análisis retrospectivo de todos los pacientes operados de heminefrectomía desde el año 2000 a 2014. Resultados: 44 pacientes fueron operados de forma convencional durante el período 2000-2010 y 30 de forma laparoscópica transperitoneal durante el período 2010-2014. La media de duración del procedimiento fue menor para el grupo convencional (89,6 vs 128 min, p = 0,000) mientras que la media de estadía hospitalaria fue menor para el grupo laparoscópico (4,2 vs 5,1, p = 0,19). La tasa de reoperación fue mayor en el grupo convencional (20,4% vs 6,7%, p = 0,18) y la principal causa fue por la presencia un muñón ureteral sintomático. En los controles por centellograma DMSA (en 19 pacientes del segundo grupo) no se objetivó la pérdida de función de la unidad remanente en ningún individuo. Conclusiones: La heminefrectomía es un procedimiento seguro con baja tasa de complicaciones cuya tendencia actual es realizar la cirugía de forma laparoscópica obteniendo resultados similares y menor tasa de complicaciones que en la forma convencional (AU)

Heminephrectomy may be the definitive treatment in 85% of patients diagnosed with a duplex kidney system of which one is not working. Currently, a laparoscopic approach is the treatment of choice because of both esthetic results and postoperative outcome. Material and methods: A retrospective analysis of all patients who underwent heminephrectomy between 2000 and 2014 was conducted. Results: 44 patients underwent conventional surgery in the period 2000-2010 and 30 underwent transperitoneal laparoscopy in the period 2010-2014. Mean duration of the procedure was less in the conventional group (89.6 vs 128 min, p = 0.000), while the mean hospital stay was less in the laparoscopic group (4.2 vs 5.1, p = 0.19). Reoperation rate was higher in the conventional group (20.4% vs 6.7%, p = 0.18) and the main cause was presence of a symptomatic ureteral stump. On DMSA whole body scan controls (in 19 patients in the second group) no loss of function of the remaining unit was observed in any of the patients. Conclusions: Heminephrectomy is a safe procedure with a low complication rate and a current trend to be performed using laparoscopy with similar results and a lower complication rate than in conventional surgery (AU)

Rol de onabotulinumtoxin A en el tratamiento de niños con vejiga neurogénica / The rol of Onabotulinumtoxin A in the treatment of children with a neurogenic bladder

Introducción: Onabotulinumtoxina es una alternativa terapéutica de segunda línea en pacientes sin respuesta a los anticolinérgicos. Objetivo: Evaluar los efectos de repetidas inyecciones de onabotulinumtoxina en vejigas neurogénicas refractarias al tratamiento clásico. Pacientes y métodos: Se evaluaron 82 pacientes menores de 18 años con vejiga neurogénica, en su mayoría por disrafia espinal. Todos fueron refractarios a oxibutinina oral. Si luego del tercer mes de la primer inyección en el detrusor se constataba mejoría clínica y/o urodinámica; se reinyectaban entre los 9 y 12 meses, nuevamente. De lo contrario, se indicaba cistoplastia de aumento. En algunos casos se utilizaron otros procedimientos endoscópicos - quirúrgicos accesorios. Resultados: Se reinyectaron con Onabotulinumtoxina, dos, tres, cuatro y cinco veces: 20 casos, 7, 4 y un caso, respectivamente. En el 51% promedio se logró continencia urinaria total (score cero-seco). En la primera y segunda inyección hubo incremento significativo en la media de capacidad cistométrica: de 254 a 331 ml (p: 0.007) y de 257 a 367 ml (p: 0.014); respectivamente. En algunos casos, luego de la primer inyección mejoró significativamente la compliance: de 6,9 a 11,4 ml/cmH2O (p: 0.05). La media de presión del detrusor al final del llenado disminuyó en promedio de 37 a 34,4 cmH2O. La sobreactividad del detrusor (n:22) se atenuó en el 54,4% luego de la primer inyección. No se registraron efectos adversos mayores con las reinyecciones. En 15 pacientes refractarios a OnabotulinumtoxinA se realizó ampliación vesical. Conclusión: Luego del tratamiento con onabotulinumtoxina, la continencia urinaria alcanzada fue del 50% promedio. La capacidad cistometrica se incrementó significativamente con las dos primeras inyecciones; aunque no se acompañó paralelamente de un importante descenso de presiones endovesicales. El uso de onabotulinumtoxina ha logrado suprimir o retrasar la clásica indicación de cistoplastia de aumento en niños refractarios a los anticolinérgicos (AU)

Introduction: OnabotulinumtoxinA is a second-line alternative therapy for patients who do not respond to anticholinergics. Aim: To evaluate the impact of repeated injections of OnabotulinumtoxinA in neurogenic bladders refractory to conventional treatment. Patients and methods: 82 patients younger than 18 years with a neurogenic bladder, in the majority due to spinal dysraphism, were evaluated. All were refractory to oral oxybutynin. If in the third month after the first injection in the detrusor clinical and/or urodynamic improvement was observed, between 9 and 12 months later a second injection was given. If not, augmentation cystoplasty was indicated. In some cases other endoscopic/surgical procedures were used. Results: Twenty, seven, four, and one case were reinjected with OnabotulinumtoxinA, two, three, four, and five times, respectively. In a mean of 51% of the patients total urinary continence was achieved (score zero - completely dry). On the first and second injection a significant increase of the maximum cystometric capacity was observed: from 254 to 331 ml (p: 0.007) and from 257 to 367 ml (p: 0.014), respectively. In some cases, after the first injection compliance improved significantly: from 6.9 to 11.4 ml/cmH2O (p: 0.05). Mean end filling detrusor pressure diminished from 37 to 34.4 cmH2O. Detrusor overactivity (n: 22) attenuated in 54.4% after the first injection. No major adverse effects were recorded after the reinjections. In 15 patients that were refractory to OnabotulinumtoxinA augmentation cystoplasty was performed. Conclusion: After OnabotulinumtoxinA treatment, 50% urinary continence was achieved. Cystometric capacity increased significantly after the first two injections; however, it was not associated with an important decrease of intravesical pressure. The use of OnabotulinumtoxinA may avoid or delay the classical indication of augmentation cystoplasty in anticholinergicrefractory children (AU)

Sobrevida de pacientes e injerto en niños con trasplante renal: experiencia del Hospital Garrahan en dos períodos / Patient and graft survival in children with a kidney transplant: The experience at Garrahan Hospital over two periods

En adultos y niños con trasplante renal (TxR) la sobrevida de paciente e injerto ha mejorado. En Argentina no existen datos de sobrevida en niños con TxR en diferentes décadas. El objeto de este trabajo fue valorar en niños con TxR sobrevida de paciente e injerto y analizar causas de muerte, perdida de injerto y factores de riesgo de pérdida. Dado que desde el año 2001 se unificaron prácticas de diagnóstico y tratamiento, se compararon dos periodos: 1988-2000 y 2001-2015. Se incluyeron 773 niños. A 1, 3, 5, 7 y 10 años, En TxR de DV (n=327), la sobrevida del paciente fue de 99%, 99%, 98%, 95%, 95% vs 100% y 96%, 96%, 96% y 96% (p=0.74); la del injerto de 97%, 91%, 85%, 78% y 67% vs 95%, 88%, 85%, 81% y 76% (p=0.81). En TxR de DC (n=446) la sobrevida de paciente fue de 97%, 93%, 90%, 89% y 87% en el 1er. periodo vs. 100%, 99% y 98% 98% y 98% en el 2do (p<0.001); la del injerto de 83%, 75%, 68%, 64% y 52% vs. 95%, 87%, 83%, 76% y 61% respectivamente (p<0. 001). El Rechazo Crónico fue la 1er causa de perdida (61% vs 62%); la 2da la muerte del paciente con injerto funcionante. La sepsis bacteriana fue la 1era causa de muerte (56% vs 67%). Ningún niño falleció por neoplasia entre el 2001 y 2015. En DV, fueron predictores de perdida de injerto: DGF (HR: 4.8; p<0.001), edad al TxR > 12 años (HR: 2.7; p=0.002) y RA tardío (HR: 2.1; p=0.009). En DC la necesidad de diálisis en la 1er semana post TxR (DGF): (HR: 4.4; p<0.001), el rechazo agudo (RA) tardío (HR: 3.7; p<0.001), GSFS como causa de IRC (HR: 2.5; p=0.01), y RA temprano (HR: 2.2; p=0.02). Conclusión: En el 2do periodo la sobrevida de paciente e injerto los TxR con DC mejoro, y en los TxR con DV no tuvo cambios. El rechazo crónico continúa siendo la 1era causa de perdida. Ningún paciente tuvo neoplasia (AU)

Patient and graft survival in kidney transplantation (KTx) has improved. In Argentina there are no data comparing transplant outcomes in children over different eras. The aim of this study was to evaluate patient and graft survival in children with KTx and to analyze cause of death, graft loss, and risk factors of graft loss. As diagnostic and treatment practices were unified in 2001, two periods were compared: 1988-2000 and 2001-2015. Overall, 773 children were included. Survival at 1, 3, 5, 7, and 10 years after a living-related donor (LRD) KTx was 99%, 99%, 98%, 95%, 95% vs 100% y 96%, 96%, 96% and 96% (p=0.74); graft survival was 97%, 91%, 85%, 78% y 67% vs 95%, 88%, 85%, 81%, and 76% (p=0.81). Patient survival after deceased donor (DD) KTx (n=446) was 97%, 93%, 90%, 89%, and 87% in the 1st period vs. 100%, 99% y 98% 98%, and 98% in the 2nd (p<0.001); graft survival was 83%, 75%, 68%, 64%, and 52% vs. 95%, 87%, 83%, 76%, and 61%, respectively (p<0. 001). Chronic rejection was the first cause of graft loss (61% vs 62%); the second was death of the patient with a functioning graft. Bacterial sepsis was the first cause of death (56% vs 67%). None of the patients died because of malignancies between 2001 and 2015. Among LRD transplants predicting factors of graft loss were: DGF (HR: 4.8; p<0.001), age at KTx >12 years (HR: 2.7; p=0.002), and late acute rejection (AR) (HR: 2.1; p=0.009). Among DD need for dialysis in the first week post-KTx (DGF): (HR: 4.4; p<0.001), late AR (HR: 3.7; p<0.001), FSGS-related CFR (HR: 2.5; p=0.01), and early AR (HR: 2.2; p=0.02). Conclusion: In the second period patient and graft survival after DD improved, while that of KTx with LRD remained unchanged. Chronic rejection continues being the first cause of graft loss. None of the patients developed malignancies.

Heritability analysis of IgG4 antibodies in autoimmune thyroid disease.

A study of IgG4 autoantibody levels in juvenile thyroid disease patients showed evidence of heritability using the ROMP screening method. These levels increased with time despite the fact that total IgG antibody decreased with time. Evidence of heritability was demonstrated only in patients with high titers of autoantibodies to both thyroglobulin (Tg) and thyroperoxidase (TPO) unlike family members who may show high titers of one or the other and be asymptomatic at the time of sampling. Since high and low IgG4 levels give different heritability plots, these findings may represent a more severe fibrotic form of thyroiditis with a distinct genetic background. Hence a simple predictive approach is offered by this screening tool for the disease in patients and family members which may be helpful in the future to identify IgG4-related thyroiditis early in the course of disease without the requirement for biopsy.

Augmentation cystoplasty in children without preoperative mechanical bowel preparation.

OBJECTIVE: To retrospectively assess early postoperative complications in augmentation cystoplasty without preoperative mechanical bowel preparation (MBP). MATERIAL AND METHODS: Between May 1987 and May 2006, 162 cystoplasties were performed in 158 children. The segments used were: sigmoid colon (81.5%), ileum (13%), and ileocecum (5.5%). The mean age was 8.65 years (range 2.1-22.7 years). No preoperative MBP of any kind was used in any of the patients and all of them received antibiotics preoperatively and postoperatively. RESULTS: No intraoperative complications related to the procedure were reported. The mean hospital stay was 9.48 days (range 4-30 days). The mean time to intake of oral fluids was 94.77 h (range 48-288 h). Postoperative complications occurred in 9.87%: urinary fistula was the most common (2.4%); only 3 patients presented wound infection (1.85%); 5 patients required reoperative surgery (hemoperitoneum, patch necrosis and 3 cases of urinary peritonitis); 1 patient presented an intra-abdominal abscess that resolved with antibiotic treatment. CONCLUSIONS: Preoperative MBP can be omitted in children that require augmentation cystoplasty without an increased risk of infectious or anastomotic complications. Further prospective, randomized clinical trials should be carried out in order to validate our findings in the pediatric population.

Invariant NKT Cell Lines Derived from the NOD·H2 Mouse Enhance Autoimmune Thyroiditis.

To study the role of invariant Natural Killer T cell ( iNKT) cells in autoimmune thyroiditis, we derived two iNKT cell lines from the spleens of NOD· H2(h4) mice, a strain that develops spontaneous autoimmune thyroiditis exacerbated by excess dietary iodine. The two lines were CD1d-restricted and expressed CD4(+), DX5(+), and the Vα4Jα281 gene segment, of the T-cell receptor α locus. Upon stimulation with α-galactosyl-ceramide (α-GalCer), both lines rapidly produced IL-2, IL-4, IFN-γ, IL-10, and TNF-α. Strikingly, a similar cytokine response was also induced by thyroglobulin, one of the most abundant protein in the thyroid gland and a major autoantigen in human autoimmune thyroiditis. Transfer of the iNKT cell lines to syngeneic hosts enhanced autoimmune thyroiditis. Intraperitoneal injections of α-GalCer in iodine primed mice also induced thyroid disease. This paper reports for the first time that iNKT cells respond to thyroglobulin and enhance autoimmune thyroiditis in iodine fed NOD·H2(h4) mice.

Renal autotransplantation for the treatment of renovascular hypertension in the pediatric population.

PURPOSE: To evaluate the effectiveness of renal autotransplantation (RA) for the treatment of renovascular hypertension (RVH) in a selected group of children in whom medical care, a percutaneous transluminal angioplasty or vascular reconstruction failed or was technically impossible, in addition to the short-term and long-term morbidity. MATERIALS AND METHODS: A retrospective case review of 13 pediatric patients with severe or complicated RVH who underwent RA between May 1993 and August 2008 was conducted. We defined blood pressure (BP) response as follows: Cured: normal BP values with no need of antihypertensive medication (AM); Improved: normal BP values with AM requirements; Failed: abnormal BP values despite treatment with AM. RESULTS: 16 RA were performed in 7 female and 6 male patients. Bilateral RA were performed in 2 females and in 1 male. The average age at consultation for hypertension was 8.5 years (range 4-12 years) and the time of transplantation was 9.12 years (range 6-13 years). Etiological diagnoses were: Takayasu disease (n = 5); renal artery fibrodysplasia (n = 3); mid-aortic syndrome (n = 3) and neurofibromatosis type I (n = 2). Results after RA were: Cured: 61.5%; Improved: 38.5%. No patient presented therapeutic failure during follow up time (median = 53.4 months). Only 1 case presented a postoperative complication. CONCLUSIONS: RA is a procedure with no mortality and low morbidity rates that renders very satisfactory therapeutic results in the pediatric population.

Toxina botulínica-A en el tratamiento de niños con vejiga neurogénica / Botulínic toxin type a in the treatment of children with neurogenic bladder

Introducción. La toxina botulínica A (ToxBA) es una alternativa en niños refractarios a anticolinérgicos. Objetivo. Evaluar los efectos “iniciales” de ToxBA en vejigas neurogénicas .Pacientes y métodos. Se estudiaron 12 pacientes. Las etiologíasfueron: 9 mielomeningocele; 1 médula anclada; 1 astrocitoma medulary 1 sarcoma Ewing. La evaluación pretratamiento incluyó: cartilla-score de incontinencia, ecografía renovesical, cistouretrografía y urodinamia. Se inyectaron 300 UI de ToxBA en detrusor. Se reevaluaron al1, 3 y 6 meses. Si se constataba mejoría se reinyectaban. De lo contrario, se indicaba cirugía. Resultados. Luego de la inyección inicial, 50% de los pacientes alcanzaron la continencia y 20% permanecieron con mínimas fugas. La media de la capacidad vesical máxima se incrementó de 264 ± 117 mla 324 ± 170 ml (P=0,322). La media de la presión del detrusor disminuyó de 46 ± 17 cm H2O a 42 ± 14 cm H2O (P=0,596). La media de la complacencia se incremento de 7,6 ± 5,9 ml/cm H2O a 10,4 ± 6,4 ml/cmH2O (P=0,290). Las contracciones miccionales reflejas desaparecieron (..) (AU)

Introduction. Botulinum toxin A (BoNTA) is an alternative in children with neurogenic bladder refractory to anticholinergics. Objective. To evaluate the initial effects of BoNTA in neurogenic bladders .Patients and Methods. 12 patients (9 myelomeningoceles,1tetheredcord, 1 medullary astrocytoma, 1 Ewing’s sarcoma) were studied. The pretreatment evaluation included: voiding diary, incontinence score, renovesicalultra sound, cystourethrography and urodynamic parameters. Patients received 300 UI of BoNTA via detrusor injections. They were re-evaluated at months 1, 3 and 6. After the third control, if improvement was confirmed, patients were injected again. Otherwise, surgery was indicated. Results. After the initial injection, 50% of patients achieved complete continence and 20% remained with minimal leaks. The mean maximum bladder capacity increased from 264 ± 117 ml to 324 ± 170 ml(P=0.322). The mean detrusor pressure decreased from 46 ± 17 cm H2Oto 42 ± 14 cm H2O (P=0.596). The mean bladder compliance increased (..) (AU)

Autoantibody heritability in thyroiditis: IgG subclass contributions.

Using a simple screening technique called regression of offspring on mid-parent (ROMP) to examine the role of IgG subclasses in affected and unaffected siblings of children and adolescents with autoimmune thyroid disease and their parents, both total-restricted and subclass-restricted autoantibodies to thyroglobulin (Tg) were assayed quantitatively for each of the IgG subclasses. There was a significant correlation of anti-Tg titer of probands with parental titers in thyrotoxicosis (TT), (R(2) = 0.569, p = 0.001), but not in chronic lymphocytic thyroiditis. The most striking correlation was in TT patients of African-American ancestry, (R(2) = 0.9863, p = 0.0007). Additional insight is provided by examining the contributions of the IgG subclasses individually, particularly those whose concentrations appear not to have direct influence on the total IgG titers. Thus, using small numbers of patients, and assaying the IgG subclass distributions, as well as any other immunoglobulin isotypes that are significantly altered in autoantibody assays, ROMP can be performed rapidly to ascertain which quantifiable parameters may be usefully extended to predict disease onset and progression.

[Botulinic toxin type A in the treatment of children with neurogenic bladder]. / Toxina botulínica-A en el tratamiento de niños con vejiga neurogénica.

UNLABELLED: INTRODUCTION. Botulinum toxin A (BoNTA) is an alternative in children with neurogenic bladder refractory to anticholinergics. OBJECTIVE. To evaluate the initial effects of BoNTA in neurogenic bladders. PATIENTS AND METHODS 12 patients (9 myelomeningoceles, 1 tethered cord, 1 medullary astrocytoma, 1 Ewing's sarcoma) were studied. The pretreatment evaluation included: voiding diary, incontinence score, renovesical ultrasound, cystourethrography and urodynamic parameters. Patients received 300 UI of BoNTA via detrusor injections. They were re-evaluated at months 1, 3 and 6. After the third control, if improvement was confirmed, patients were injected again. Otherwise, surgery was indicated. RESULTS: After the initial injection, 50% of patients achieved complete continence and 20% remained with minimal leaks. The mean maximum bladder capacity increased from 264 +/- 117 ml to 324 +/- 170 ml (P = 0.322). The mean detrusor pressure decreased from 46 +/- 17 cm H2O to 42 +/- 14 cm H2O (P=0.596). The mean bladder compliance increased from 7.6 +/- 5.9 ml/cm H2O to 10.4 +/- 6.4 ml/cm H2O (P = 0.290). The reflex voiding contractions disappeared in 2 patients; 8 presented trabeculae. Ten patients were reinjected and two underwent surgery. CONCLUSION: 70% urinary continence was achieved after the initial injection. No significant urodynamic changes were observed. A longer follow-up with subsequent injections is needed.

Report from the EPAA workshop: in vitro ADME in safety testing used by EPAA industry sectors.

There are now numerous in vitro and in silico ADME alternatives to in vivo assays but how do different industries incorporate them into their decision tree approaches for risk assessment, bearing in mind that the chemicals tested are intended for widely varying purposes? The extent of the use of animal tests is mainly driven by regulations or by the lack of a suitable in vitro model. Therefore, what considerations are needed for alternative models and how can they be improved so that they can be used as part of the risk assessment process? To address these issues, the European Partnership for Alternative Approaches to Animal Testing (EPAA) working group on prioritization, promotion and implementation of the 3Rs research held a workshop in November, 2008 in Duesseldorf, Germany. Participants included different industry sectors such as pharmaceuticals, cosmetics, industrial- and agro-chemicals. This report describes the outcome of the discussions and recommendations (a) to reduce the number of animals used for determining the ADME properties of chemicals and (b) for considerations and actions regarding in vitro and in silico assays. These included: standardisation and promotion of in vitro assays so that they may become accepted by regulators; increased availability of industry in vivo kinetic data for a central database to increase the power of in silico predictions; expansion of the applicability domains of in vitro and in silico tools (which are not necessarily more applicable or even exclusive to one particular sector) and continued collaborations between regulators, academia and industry. A recommended immediate course of action was to establish an expert panel of users, developers and regulators to define the testing scope of models for different chemical classes. It was agreed by all participants that improvement and harmonization of alternative approaches is needed for all sectors and this will most effectively be achieved by stakeholders from different sectors sharing data.

Autoimmune thyroiditis research at Johns Hopkins University.

Autoimmune thyroiditis is an organ-specific autoimmune disorder characterized by infiltration of the thyroid gland by lymphocytic inflammatory cells, often followed by hypothyroidism due to destruction and replacement of the follicular tissue. Dr. Noel Rose and members of his laboratory at Johns Hopkins University have continued to study autoimmunity using autoimmune thyroiditis as a model. Autoimmune thyroiditis is multifactorial, with both genetic and environmental factors involved. We have studied familial association of thyroid antibodies in juveniles with either autoimmune thyroiditis or Graves' disease. Epitope analysis of thyroglobulin autoantibodies showed that autoantibodies from unrelated patients with disease had greater similarity of epitope binding than members of their own family. Subclass analysis of thyroglobulin autoantibodies indicated that IgG2 was dominant in autoimmune thyroiditis. Much of our work focused around iodine as an environmental trigger of autoimmune thyroiditis. We showed that iodination of the human thyroglobulin molecule alters its immunoreactivity. We explored the role of excess iodine ingestion in exacerbating thyroiditis using the NOD.H2h4 mouse as a model. We found multiple effects of excess iodine, including changing the immunogenicity of the thyroglobulin molecule and the upregulation of ICAM-1 and ROS in the thyrocyte itself. These observations may help to delineate the mechanisms by which iodine exacerbates thyroiditis and to explain differences in the host response of genetically susceptible individuals compared to those who are resistant to disease.

NOD2 mutations and anti-Saccharomyces cerevisiae antibodies are risk factors for Crohn's disease in African Americans.

OBJECTIVES: NOD2 mutations and anti-Saccharomyces cerevisiae antibodies (ASCAs) are established risk factors of Crohn's disease (CD) in whites but have not been assessed in African-American (AA) adults with CD. METHODS: AAs with CD and controls were recruited by the Mid-Atlantic African-American IBD Study as part of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) IBD Genetics Consortium. Genotyping for the three common CD NOD2 mutations (Leu1007fsinsC, G908R/2722g>c, and R702W/2104c>t) and ASCA enzyme-linked immunosorbent assays were performed in 183 AA CD patients and in 143 controls. Logistic regression was used to calculate adjusted odds ratios (ORs) for the association between ASCA and disease phenotype. RESULTS: ASCA sensitivity and specificity values were 70.5 and 70.4%, respectively. On univariate analysis, ASCA was significantly associated with younger age at diagnosis, ileal involvement, and complicated (stricturing/penetrating) behavior. On multivariate analysis, ASCA titer (per 25 Units) was associated with ileal involvement (OR 1.18, 95% confidence interval (CI): 1.04-1.34), complicated behavior (OR 1.13, 95% CI: 1.01-1.28), and surgery (hazard ratio: 1.11, 95% CI: 1.02-1.21). Cigarette smoking and CD family history were also significantly associated with surgery. NOD2 carriers (all heterozygotes) were more common among CD cases than controls (8.2 vs. 2.1%; OR 4.17%, 95% CI: 1.18-14.69). The NOD2 mutation population attributable risk was 6.2%. CONCLUSIONS: In comparison with whites, ASCA in AAs has a similar sensitivity but a lower specificity for CD. ASCA is associated with ileal involvement, complicated behavior, and surgery in AAs with CD. NOD2 is a risk gene for AA CD, although mutation frequency and population attributable risk are much lower than in whites.

Environmental triggers of autoimmune thyroiditis.

Autoimmune thyroiditis is among the most prevalent of all the autoimmunities. Autoimmune thyroiditis is multifactorial with contributions from genetic and environmental factors. Much information has been published about the genetic predisposition to autoimmune thyroiditis both in experimental animals and humans. There is, in contrast, very little data on environmental agents that can serve as the trigger for autoimmunity in a genetically predisposed host. The best-established environmental factor is excess dietary iodine. Increased iodine consumption is strongly implicated as a trigger for thyroiditis, but only in genetically susceptible individuals. However, excess iodine is not the only environmental agent implicated as a trigger leading to autoimmune thyroiditis. There are a wide variety of other synthetic chemicals that affect the thyroid gland or have the ability to promote immune dysfunction in the host. These chemicals are released into the environment by design, such as in pesticides, or as a by-product of industry. Candidate pollutants include polyaromatic hydrocarbons, polybrominated biphenols, and polychlorinated biphenols, among others. Infections are also reputed to trigger autoimmunity and may act alone or in concert with environmental chemicals. We have utilized a unique animal model, the NOD.H2(h4) mouse to explore the influence of iodine and other environmental factors on autoimmune thyroiditis.

Sex differences in a murine model of Sjögren's syndrome.

Sex differences in a NOD.H2(h4) murine model of Sjögren's syndrome were analyzed. Compared to males, female NOD.H2(h4) mice have increased severity of sialoadenitis and have a significantly increased percentage of CD4(+) T cells in salivary gland infiltrates. CD4(+) T cells in female infiltrates produce more Th2 and Th17 cytokines than in males, while males have greater Th1 responses. Females also have enhanced B cell responses, with higher levels of SSA and SSB serum antibodies, and B cell activation factor F (BAFF). Thus, sex has a strong impact on the severity of murine Sjögren's syndrome by affecting the immune mechanisms driving the autoimmune inflammation.

Evaluación del transplante renal en pacientes con tracto urinario anormal / Evaluation of kidney trnasplantation in patients with urinary tract abnormalities

Objetivo: Determinar si los procedimientos quirúrgicos del tracto urinario inferior, previos y complementarios al trasplante renal en pacientes que llegaron a la insuficiencia renal por causa urológica, afectan la evolución del mismo en cuanto a complicaciones y sobrevida del injerto. Material y método: Entre diciembre de 1988 y noviembre de 2007 se realizaron 156 trasplantes renales en 150 pacientes de 11 años edad promedio (94 varones y 56 niñas) con insuficiencia renal crónica terminal (IRCT) de causa urológia. El promedio de seguimiento fue 67 meses. Los pacientes se clasificaron en tres grupos: grupo A (n:66): Los que no requirieron procedimientos quirúrgicos en tracto urinario bajo; grupo B (n:46): Los que necesitaron de procedimientos quírúrgicos en tracto urinario bajo y conservaron adecuada función vesical y grupo C (n:38): Los que necesitaron procedimientos quirúrgicos en vía urinaria baja por inadecuada función vesical. Resultados: la sobrevida del implante, al año, fue del 93.38 por ciento para el grupo A; 95,45 por ciento para el B y 93 por ciento para el C. A los cindo años del trasplante renal las sobrevidas respectivas para los mismos grupos fueron: 82.45 por ciento, 79.85 por ciento y 85.58 por ciento (p: 0.9 no significativo). Complicaciones: Estenosis ureterovesicales: 2 en el grupo A (3.0 por ciento), 3 en el grupo B (6,3 por ciento) y 1 en el grupo C (2,5 por ciento). Reflujo vesicoureteral: 1 paciente del grupo A (1,5 por ciento); 1 del grupo B (2 por ciento) y en 10 del grupo C (25 por ciento). La necrosis del uréter distal ocurrió en dos casos en el grupo A (3.0 por ciento), en dos del grupo B (4.2 por ciento y en uno del grupo C (2,5 por ciento). Infección tracto urinario bajo (ITUB): 9 por ciento, 7,5 por ciento y 27,8 por ciento en el grupo A, B y C respectivamene. Infección tracto urinario alto (ITUA): 12 por ciento, 25 por ciento y 42,5 por ciento en los grupo A, B y C, respectivamente.

Evaluación del transplante renal en pacientes con tracto urinario anormal / Evaluation of kidney trnasplantation in patients with urinary ract abnormalities

Objetivo: Determinar si los procedimientos quirúrgicos del tracto urinario inferior, previos y complementarios al trasplante renal en pacientes que llegaron a la insuficiencia renal por causa urológica, afectan la evolución del mismo en cuanto a complicaciones y sobrevida del injerto. Material y método: Entre diciembre de 1988 y noviembre de 2007 se realizaron 156 trasplantes renales en 150 pacientes de 11 años edad promedio (94 varones y 56 niñas) con insuficiencia renal crónica terminal (IRCT) de causa urológia. El promedio de seguimiento fue 67 meses. Los pacientes se clasificaron en tres grupos: grupo A (n:66): Los que no requirieron procedimientos quirúrgicos en tracto urinario bajo; grupo B (n:46): Los que necesitaron de procedimientos quírúrgicos en tracto urinario bajo y conservaron adecuada función vesical y grupo C (n:38): Los que necesitaron procedimientos quirúrgicos en vía urinaria baja por inadecuada función vesical. Resultados: la sobrevida del implante, al año, fue del 93.38 por ciento para el grupo A; 95,45 por ciento para el B y 93 por ciento para el C. A los cindo años del trasplante renal las sobrevidas respectivas para los mismos grupos fueron: 82.45 por ciento, 79.85 por ciento y 85.58 por ciento (p: 0.9 no significativo). Complicaciones: Estenosis ureterovesicales: 2 en el grupo A (3.0 por ciento), 3 en el grupo B (6,3 por ciento) y 1 en el grupo C (2,5 por ciento). Reflujo vesicoureteral: 1 paciente del grupo A (1,5 por ciento); 1 del grupo B (2 por ciento) y en 10 del grupo C (25 por ciento). La necrosis del uréter distal ocurrió en dos casos en el grupo A (3.0 por ciento), en dos del grupo B (4.2 por ciento y en uno del grupo C (2,5 por ciento). Infección tracto urinario bajo (ITUB): 9 por ciento, 7,5 por ciento y 27,8 por ciento en el grupo A, B y C respectivamene. Infección tracto urinario alto (ITUA): 12 por ciento, 25 por ciento y 42,5 por ciento en los grupo A, B y C, respectivamente. (AU)

Identification of novel serological biomarkers for inflammatory bowel disease using Escherichia coli proteome chip.

Specific antimicrobial antibodies present in the sera of patients with inflammatory bowel disease (IBD) have been proven to be valuable serological biomarkers for diagnosis/prognosis of the disease. Herein we describe the use of a whole Escherichia coli proteome microarray as a novel high throughput proteomics approach to screen and identify new serological biomarkers for IBD. Each protein array, which contains 4,256 E. coli K12 proteins, was screened using individual serum from healthy controls (n = 39) and clinically well characterized patients with IBD (66 Crohn disease (CD) and 29 ulcerative colitis (UC)). Proteins that could be recognized by serum antibodies were visualized and quantified using Cy3-labeled goat anti-human antibodies. Surprisingly significance analysis of microarrays identified a total of 417 E. coli proteins that were differentially recognized by serum antibodies between healthy controls and CD or UC. Among those, 169 proteins were identified as highly immunogenic in healthy controls, 186 proteins were identified as highly immunogenic in CD, and only 19 were identified as highly immunogenic in UC. Using a supervised learning algorithm (k-top scoring pairs), we identified two sets of serum antibodies that were novel biomarkers for specifically distinguishing CD from healthy controls (accuracy, 86 +/- 4%; p < 0.01) and CD from UC (accuracy, 80 +/- 2%; p < 0.01), respectively. The Set 1 antibodies recognized three pairs of E. coli proteins: Era versus YbaN, YhgN versus FocA, and GabT versus YcdG, and the Set 2 antibodies recognized YidX versus FrvX. The specificity and sensitivity of Set 1 antibodies were 81 +/- 5 and 89 +/- 3%, respectively, whereas those of Set 2 antibodies were 84 +/- 1 and 70 +/- 6%, respectively. Serum antibodies identified for distinguishing healthy controls versus UC were only marginal because their accuracy, specificity, and sensitivity were 66 +/- 5, 69 +/- 5, and 61 +/- 7%, respectively (p < 0.04). Taken together, we identified novel sets of serological biomarkers for diagnosis of CD versus healthy control and CD versus UC.