Longitudinal osmotic and neurometabolic changes in young rats with chronic cholestatic liver disease.

Type C hepatic encephalopathy (type C HE) is increasingly suspected in children with chronic liver disease (CLD), and believed to underlie long-term neurocognitive difficulties. The molecular underpinnings of type C HE in both adults and children are incompletely understood. In the present study we combined the experimental advantages of in vivo high field <sup>1</sup> H magnetic resonance spectroscopy with immunohistochemistry to follow longitudinally over 8 weeks the neurometabolic changes in the hippocampus of animals having undergone bile duct ligation as pups. Rats who develop CLD early in life displayed pronounced neurometabolic changes in the hippocampus characterized by a progressive increase in glutamine concentration which correlated with plasma ammonia levels and a rapid decrease in brain myo-inositol. Other neurometabolic findings included a decrease in other organic osmolytes (taurine, choline-containing compounds and creatine), ascorbate and glutamate. At the cellular level, we observed an increase in glial fibrillary acidic protein (GFAP) and aquaporin 4 (AQP4) expression in the hippocampus at 4 weeks post bile duct ligation (BDL), together with astrocytic morphological alterations. These findings differ from observations in the brain of adult rats following BDL, and are in keeping with the commonly accepted theory of age-dependent vulnerability

Prenatal magnetic resonance imaging of complex female genitourinary system abnormalities, what the fetal medicine specialist needs to know.

Complex female genitourinary system anomalies include a wide spectrum of uncommon pathologies, caused from the abnormal separation of the urorectal septum and the urogenital sinus in early embryonic life. The resulting fusion of the distal urinary, genital and intestinal tracts increases the risk of death in utero and alters the normal organ functionality and the quality of life in survivors. An accurate prenatal identification of these pathologies depends mainly on prior suspicion at ultrasound screening, but also requires a solid knowledge of embryology and familiarity with the different patterns of malformation. Prenatal MRI provides an excellent anatomic evaluation of the fetal anatomy that may improve the diagnosis in complex cases with inconclusive echographic findings. The additional information can help both families and medical teams to better evaluate the severity of the pathology and the postnatal prognosis and therefore to better orientate the management during pregnancy, at delivery and after birth. This review article describes the embryological basis and the clinical findings of the most relevant pathologies included in the spectrum. It also describes the imaging signs on prenatal MRI studies in a series of confirmed cases and proposes a diagnostic algorithm based on imaging findings for guiding prenatal diagnosis

A National Long-Term Study of Neuroendocrine Tumors of the Appendix in Children: Are We Too Aggressive?

Pediatric neuroendocrine tumors (NETs) of the appendix are mostly detected incidentally after appendectomy for acute appendicitis. NET management is a matter of controversy. In this national, multicenter study, we aimed to establish guidelines based on our results and the literature. Medical records of children (0-16 years) with NET of the appendix, treated in Switzerland (1991-2012), were reviewed. Forty cases (28 girls) were analyzed. Median age at diagnosis was 12.7 years (interquartile range [IQR]: 4.0). Tumor size was 0.1-24 mm (median: 0.6, IQR: 0.6). Four patients (10%) underwent additional surgery because of either tumor size > 15 mm (1/4), extension to the mesoappendix (1/4), or incomplete resection (2/4). Three patients with a tumor of ≥ 20 mm had no additional surgery. No patient had lymph node metastases. All patients were in complete remission at the last follow-up (median: 3.0 years, IQR: 10.9). We conclude from this study and from an extensive review of the literature that two criteria may point to the need for additional surgery, i.e., the possibility of regional lymph node involvement: tumor size > 20 mm and incomplete surgical resection margins. Childhood NET of the appendix has an excellent prognosis

Fetal Anthropometric Features: A Postmortem Study of Fetuses After the Termination of Pregnancy for Psychosocial Reasons Between 12 and 20 Gestational Weeks.

Reference ranges in fetal postmortem anthropometric data derive from heterogeneous studies and rely on data obtained after intrauterine fetal death and abortion, which may introduce bias in the reported fetal growth parameters. We report anthropometric findings in fetuses with the least variation due to cause of death or developmental anomalies. We analyzed fetuses after the termination of pregnancy for psychosocial reasons. The external measurements, X-ray dimensions, and body and organ weights were recorded as well as the placenta weight. A thorough and standardized postmortem analysis allowed the design of 2 different groups. Group 1 was composed of fetuses (1) born to mothers with no relevant obstetrical history, (2) no X-ray anomaly, (3) no abnormal autopsy findings, and (4) unremarkable placenta histology. An anomaly in any of these 4 entities moved the fetuses to Group 2. For reference ranges and graph construction, a well-designed statistical methodology was applied. A total of 335 fetuses were analyzed during an 11-year period. Group 1 comprised 232 fetuses aged 12 to 20 gestational weeks, whereas 103 fetuses were considered in Group 2. Comparison between the 2 groups showed almost no differences. Only the Group 1 results were submitted to statistical analysis, and reference ranges and graphs were constructed. To the best of our knowledge, we provide in this study the first anthropometric references established from almost normal fetuses, albeit for a limited fetal timeframe

Peripheral donor specific antibodies are associated with histology and cellular subtypes in protocol liver biopsies of pediatric recipients.

The cellular infiltrate in protocol liver biopsies (PB) following pediatric liver transplantation remains mostly uncharacterized, yet there is increasing concern about the role of inflammation and fibrosis in long-term liver allografts. We aimed to define cell types in PB and to analyze their relationship with donor specific antibodies and histological phenotype. PB were performed at least 1 year after transplantation. We identified 4 phenotypes: normal, fibrosis, inflammation, inflammation with fibrosis. Cell types were counted after immunostaining for CD3, CD4, CD8, CD68, CD20, MUM1 and FoxP3. Forty-four (44) patients underwent 1 PB between 2000 and 2015. Eleven percent (5/44) of PB displayed normal histology, 13.6% (6/44) fibrosis, 34.1% (15/44) inflammation and 40.9% (18/44) inflammation and fibrosis. The main cell types in the portal tracts and lobules were CD3+ and CD68+ cells. Frequency of de novo DSA was 63% (27/44). The presence of CD8+ cells in the lobules was associated with fibrosis. Inflammation and fibrosis in PB were associated with the presence of circulating de novo DSA, number of de novo DSA, and C1q binding activity when compared to other phenotypes. T cells (CD3+) and macrophages (CD68+) were the most prevalent cell-types in PB. In the presence of inflammation, portal tracts were enriched in CD3+, CD20+ but displayed fewer CD68+. This coincided with the presence and number of de novo DSA. How these cellular and humoral actors interact is unclear, but peripheral DSA may be a marker of immune cellular activity in the seemingly quiescent allograft

Preformed and de novo DSA are associated with T-cell-mediated rejection in pediatric liver transplant recipients requiring clinically indicated liver biopsy.

Despite growing interest about the impact of donor-specific HLA antibodies (DSA) in LT limited data are available for pediatric recipients. Our aim was to perform a retrospective single-center chart review of children (0-16 years) having undergone LT between January 1, 2005 and December 31, 2017, to characterize DSA, to identify factors associated with the development of de novo DSA, and to analyze potential associations with the diagnosis of TCMR. Information on patient- and donor-characteristics and LB reports were analyzed retrospectively. Serum obtained before LT and at LB was analyzed for presence of recipient HLA antibody using Luminex <sup>®</sup> technology. MFI > 1000 was considered positive. In 63 pediatric LT recipients with a median follow-up of 72 months, the overall prevalence of de novo DSA was 60.3%. Most were directed against class II antigens (33/38, 86.8%). Preformed DSA were present in 30% of patients. Twenty-eight (28/63) patients (44.4%) presented at least one episode of TCMR, mostly (12/28, 43%) moderate (Banff 6-7). De novo DSA were significantly more frequent in patients with TCMR than in patients without (75% vs 48.6%, P = .03), and patients with preformed and de novo DSA had a significantly higher rate of TCMR than patients without any DSA (66.7% vs 20%, P = .02). Neither preformed DSA nor de novo DSA were associated with frequency or severity of TCMR. Recipients with lower weight at LT developed de novo DSA more frequently (P = .04). De novo DSA were highly prevalent in pediatric LT recipients. Although associated with the development of TCMR, they did not appear to impact the frequency or severity of TCMR or graft survival. Instead, de novo DSA may suggest a state of insufficient IS

Evaluating intimal hyperplasia under clinical conditions.

Open arterial revascularization using venous segments is frequently associated with the development of intimal hyperplasia (IH), leading to severe restenosis and graft failure. The lack of treatment to prevent this pathology is a major problem. Therefore, we generated a new porcine model, which closely mimics the clinical development of human IH, to test the therapeutic potential of candidate drugs. A patch of jugular vein was sutured to the right common carotid artery of pigs, to expose the vein to haemodynamic conditions of the arterial bed. Four weeks after surgery, the operated vessels which received no further treatment (the control group) were compared with (i) contralateral, non-operated vessels (the healthy group); (ii) vessels of pigs that received a perivascular application of a drug-free microparticle gel (the placebo group) and (iii) vessels of pigs that perioperatively received the same gel loaded with 10-mg atorvastatin (the atorvastatin group). When compared with non-operated vessels, all operated segments displayed a sizable IH which was thicker in the venous patch than in the host artery. These alterations were associated with a thickening of the intima layer of both vessels in the absence of inflammation. The intima/media ratio has been significantly increased by 2000-fold in the vein patches. Perivascular application of atorvastatin did not prevent IH formation. However, the drug increased the adventitial neovascularization in the operated vessels. The novel porcine model allows for monitoring IH formation under haemodynamic conditions which mimic clinical situations. It should facilitate the screening of innovative treatments to prevent restenosis