Sirolimus to treat chronic and steroid-resistant allograft rejection-related fibrosis in pediatric liver transplantation.

This study aimed to report our experience with the use of sirolimus in pediatric liver transplant patients with chronic rejection or steroid-resistant rejection with hepatic fibrosis, focusing on their histological evolution. All pediatric liver transplant recipients who received off-label treatment with sirolimus for chronic ductopenic rejection or cortico-resistant rejection between July 2003 and July 2022 were included in the study. All nine patients included in the study showed improvement in liver enzymes and cholestasis parameters as soon as 1-month after postsirolimus introduction. A decrease in fibrosis stage was observed in 7/9 (77.7%) patients at 36 months. All but one patient experienced an improvement in the Rejection Activity Index and ductopenia at 12 months. A single patient had to discontinue sirolimus treatment owing to nephrotic proteinuria. In conclusion, sirolimus may be a safe and effective treatment for chronic and steroid-resistant rejection and may improve allograft rejection-related fibrosis and ductal damage.

Brunn-Minkowski Inequality for θ-Convolution Bodies via Ball's Bodies.

We consider the problem of finding the best function φn:[0,1]→R such that for any pair of convex bodies K,L∈Rn the following Brunn-Minkowski type inequality holds |K+θL|1n≥φn(θ)(|K|1n+|L|1n),where K+θL is the θ-convolution body of K and L. We prove a sharp inclusion of the family of Ball's bodies of an α-concave function in its super-level sets in order to provide the best possible function in the range 34n≤θ≤1, characterizing the equality cases.

Development and validation of a new simplified diagnostic scoring system for pediatric autoimmune hepatitis.

BACKGROUND: Children with autoimmune hepatitis (AIH) often exhibit particular features. Accordingly, seven pediatric-specific criteria have been proposed. AIM: To develop a prediction model based on them, transform it into a scoring system and study its accuracy. METHODS: A cohort of children under study for liver disease was consecutively selected. AIH diagnosis was based on classical criteria. Already proposed pediatric criteria were recorded. The best possible regression model was selected, and the beta coefficient of each criterion was translated into a whole number (points). Total scores were obtained following the points system and the best cut-off was calculated. Subsequently, accuracy of the diagnostic score was studied in the validation set. RESULTS: Among 212 included patients, 100 had AIH. The score included 5 criteria: autoantibodies (0-2 points), hypergammaglobulinemia, exclusion of viral hepatitis, exclusion of Wilson's disease (1 point each) and liver histology (3 points). In addition, a normal cholangiogram is mandatory. The validation set was formed of 70 patients (24 with AIH). In this subsample, a score of ≥6 renders a sensitivity/specificity of 95.8%/100%. The area under the receiver operating characteristic curve was 97.1%. CONCLUSION: Pediatric-specific criteria for the diagnosis of AIH can be reliably used as a scoring system.

Accuracy of the 2008 Simplified Criteria for the Diagnosis of Autoimmune Hepatitis in Children.

PURPOSE: Classical criteria for diagnosis of autoimmune hepatitis (AIH) are intended as research tool and are difficult to apply at patient's bedside. We aimed to study the accuracy of simplified criteria and the concordance with the expert diagnosis based on the original criteria. METHODS: A cohort of children under study for liver disorder was selected through consecutive sampling to obtain the prevalence of AIH within the group of differential diagnoses. AIH was defined, based on classical criteria, through committee review of medical reports. Validity indicators of the simplified criteria were obtained in an intention to diagnose approach. Optimal cut-off and the area under the receiver operating characteristic (ROC) curve were calculated. RESULTS: Out of 212 cases reviewed, 47.2% were AIH. For the optimal cut-off (6 points), the simplified criteria showed a sensitivity of 72.0% and a specificity of 96.4%, with a 94.7% positive and a 79.4% negative predictive value. The area under the ROC curve was 94.3%. There was a good agreement in the pre-treatment concordance between the classical and the simplified criteria (kappa index, 0.775). CONCLUSION: Simplified criteria provide a moderate sensitivity for the diagnosis of AIH, but may help in indicating treatment in cases under suspicion with 6 or more points.

Waiting list outcome of Peld/Meld exceptions: A single-center experience in Argentina.

As PELD/MELD-based allocation policy was adopted in Argentina in 2005, a system of exception points has been in place in order to award increased waitlist priority to those patients whose severity of illness is not captured by the PELD/MELD score. We aimed to investigate the WL outcome of patients with granted PELD/MELD exceptions. A retrospective cohort study was conducted in children under 18 years old. WL outcomes were evaluated using univariable analysis. From 07/2005 to 01/2014, 408 children were listed for LT. There were 304 classified by calculated PELD/MELD. During this time, 85 (30%) PELD/MELD exceptions were granted. In this cohort, 89.4% (76 of 85) were transplanted and 7.1% (6 of 85) died while on the WL. The remaining 3 pts (3.5%) were removed from the WL due to other causes. We compared the impact of PELD/MELD exceptions in those 85 patients to outcomes in 87 non-exception patients with PELD/MELD ≥19 points. Patients with the exception had significantly better access to WL and lower WL mortality. Our data suggest that children listed by PELD/MELD exceptions had an advantage compared to children with CLD with equivalent PELD/MELD listing priorities.

DNA methylation is not involved in specific down-regulation of HSD3B2, NR4A1 and RARB genes in androgen-secreting cells of human adrenal cortex.

We hypothesized that DNA methylation is involved in human adrenal functional zonation. mRNAs expression and methylation pattern of RARB, NR4A1 and HSD3B2 genes in human adrenal tissues (HAT) and in pediatric virilizing adrenocortical tumors (VAT) were analyzed. For analysis of the results samples were divided into 3 age groups according to FeZ involution, pre and post-adrenarche ages. In all HAT, similar RARB mRNA was found including microdissected zona reticularis (ZR) and zona fasciculata, but HSD3B2 and NR4A1 mRNAs were lower in ZR (p < 0.05). NR4A1 and RARB promoters remained unmethylated in HAT and VAT. No adrenal zone-specific differences in NR4A1 methylation were observed. In summary, RARB was not associated with ZR-specific downregulation of HSD3B2 in postnatal human adrenocotical zonation. DNA methylation would not be involved in NR4A1 adrenocortical cell-type specific downregulation. Lack of CpG islands in HSD3B2 suggested that HSD3B2 ZR-specific downregulation would not be directly mediated by DNA methylation.

Síndrome de Alagille asociado a atresia intestinal / Alagille syndrome associated with intestinal atresia

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Cellulitis multifocal recurrent en una nena de 7 anys / No disponible

No disponible

The simultaneous high expression of Vα24, IFN-γ and FoxP3 characterizes the liver of children with type I autoimmune hepatitis.

The immunopathogenesis of type I autoimmune hepatitis (AIH-I) might involve the deregulation of different cellular processes. Here, we investigated the liver expression of selected cytokines and genes of regulatory cell populations in children both at diagnosis and during biochemical remission following immunosuppressive treatment (AIH-Ir). We found a higher Vα24, IFN-γ, FoxP3, IL-27p28, IL-12p40 and IL-21 expression at diagnosis as well as a positive correlation between IL-21 and transaminase levels. Interestingly, only IFN-γ and FoxP3 were decreased in AIH-Ir. An "AIH-I phenotype" (high Vα24, IFN-γ and FoxP3 expression at diagnosis) was observed in only 5 out of 22 AIH-Ir patients but not in controls. These results indicate a local deregulation of the innate and adaptive immune responses with an increased transcriptional activity of immunoregulatory cells at diagnosis. In addition, IL-21 is highlighted as a mediator of liver injury. AIH-Ir is characterized by a partial reversal of the deregulated response.

Identification and developmental changes of aromatase and estrogen receptor expression in prepubertal and pubertal human adrenal tissues.

CONTEXT: The mechanisms of postnatal adrenal zonation remain unclear. OBJECTIVE: To provide a clue for a possible role of estrogens in adrenarche, we studied the expression of estrogen receptor (ER)alpha, ERbeta, G protein-coupled receptor (GPR)30, and cP450aromatase (cP450arom) in human adrenal tissue. DESIGN: Human adrenal tissue was collected from three postnatal age groups (Grs): Gr 1, younger than 3 months (n = 12), fetal zone involution; Gr 2, 3 months to 6 yr (n = 17), pre-adrenarche; and Gr 3, older than 6-20 yr (n = 12), post-adrenarche period. RESULTS: ERbeta mRNA in Grs 1 and 3 was higher than in Gr 2 (P < 0.05). By immunohistochemistry and laser capture microdissection followed by RT-PCR, ERbeta was expressed in zona reticularis and fetal zone, GPR30 in zona glomerulosa (ZG) and adrenal medulla, while ERalpha mRNA and protein were undetectable. cP450arom mRNA in Gr 3 was higher than in Grs 1 and 2 (P < 0.05), and localized to ZG and adrenal medulla by laser capture microdissection. cP450arom Immunoreactivity was observed in adrenal medulla in the three Grs and in subcapsular ZG of Gr 3. Double-immunofluorescence studies revealed that cP450arom and chromogranin A only colocalize in adrenal medulla of subjects younger than 18 months. In these samples, exon 1.b-derived transcript was 3.5-fold higher, while exon 1.a-, 1.c-, and 1.d-derived transcripts were 3.3-, 1.9-, and 1.7-fold lower, respectively, than in subjects older than 6 yr. CONCLUSIONS: Our results suggest that estrogens produced locally in adrenal medulla would play a role in zona reticularis functional differentiation through ERbeta. The cP450arom and GPR30 expression in subcapsular ZG, colocalizing with a high-cell proliferation index, previously reported, suggests a local GPR30-dependent estrogen action in proliferation and migration of progenitor adrenal cells.

Simultaneous expression of Th1 cytokines and IL-4 confers severe characteristics to type I autoimmune hepatitis in children.

To investigate the immunopathogenic mechanisms of type I autoimmune hepatitis in children, we analyzed by quantitative or semiquantitative reverse transcription-polymerase chain reaction the expression of cytokines interferon (IFN)-gamma, interleukin (IL)-12p40, IL-18, IL-4, IL-10, and IL-12R beta 2. In addition, liver and peripheral blood was collected to investigate the expression of the natural killer T (NKT) cell marker V alpha 24. The presence of NKT cells in hepatic lesions were also identified by immunohistochemistry. The analysis was performed on liver biopsies from 25 children with type I autoimmune hepatitis. As disease controls, we included six children with hepatitis C virus-related chronic hepatitis and nine control livers. The expression of IFN-gamma and IL-12p40 was not detected in controls but was clearly upregulated in pathologic biopsies. In addition, these samples showed an increased expression of IL-18 (p = 0.0003), IL-4 (p = 0.0055), and IL-12R beta 2 (p = 0.007). Western blot analysis confirmed the expression of IL-12p40 and IL-18. However, for IL-18, we detected only the immature biologically inactive polypeptide. The V alpha 24 transcripts were found increased in the liver (p = 0.0007) where V alpha 24(+) cells were also localized, but decreased in peripheral blood mononuclear cells (p = 0.041). In addition to a type I immune response, NKT cells might play a substantial role in the pathogenesis of type I autoimmune hepatitis in children.