Direct and Indirect Effects of Fibroblast Growth Factor (FGF) 15 and FGF19 on Liver Fibrosis Development.

Farnesoid X receptor (FXR) induces fibroblast growth factor 15 (FGF15; human ortholog FGF19) in the gut to potently inhibit bile acid (BA) synthesis in the liver. FXR activation in hepatic stellate cells (HSCs) reduces liver fibrosis (LF). Fgf15-/- mice develop attenuated LF, but the underlying mechanisms for this protection are unclear. We hypothesized that FGF15/19 functions as a profibrotic mediator or mitogen to HSCs and increased BAs in Fgf15-/- mice leads to enhanced FXR activation in HSCs, subsequently reducing fibrogenesis. In this study, complimentary in vivo and in vitro approaches were used: (1) CCl4 -induced LF model in wild type (WT), Fgf15-/- , and Fgf15 transgenic (TG) mice with BA levels modulated by feeding cholestyramine- or cholic acid-containing diets; (2) analysis of primary HSCs isolated from WT and Fgf15-/- mice; and (3) treatment of a human HSC line, LX-2, with FXR activators and/or recombinant FGF19 protein. The results showed that Fgf15-/- mice had lower basal collagen expression, which was increased by BA sequestration. CCl4 induced fibrosis with similar severity in all genotypes; however, cholestyramine increased fibrosis severity only in Fgf15-/- mice. HSCs from Fgf15-/- mice showed increased FXR activity and reduced expression of profibrotic mediators. In LX-2 cells, FXR activation increased peroxisome proliferator-activated receptor gamma activity and reduced proliferation. FGF19 activated both signal transducer and activator of transcription 3 and c-Jun N-terminal kinase pathways and reduced nuclear factor kappa-light-chain-enhancer of activated B cells signaling without increasing fibrogenic gene expression or cell proliferation. Conclusion: FGF15/19 does not act as a direct profibrotic mediator or mitogen to HSCs in our models, and the protection against fibrosis by FGF15 deficiency may be mediated through increased BA activation of FXR in HSCs.

Enhanced alcoholic liver disease in mice with intestine-specific farnesoid X receptor deficiency.

Alcoholic fatty liver disease (AFLD) is one of the major causes of liver morbidity and mortality worldwide. We have previously shown that whole-body, but not hepatocyte-specific, deficiency of farnesoid X receptor (FXR) in mice worsens AFLD, suggesting that extrahepatic FXR deficiency is critical for AFLD development. Intestinal FXR is critical in suppressing hepatic bile acid (BA) synthesis by inducing fibroblast growth factor 15 (FGF15) in mice and FGF19 in humans. We hypothesized that intestinal FXR is critical for reducing AFLD development in mice. To test this hypothesis, we compared the AFLD severity in wild type (WT) and intestine-specific Fxr knockout (FXRInt-/-) mice following treatment with control or ethanol-containing diet. We found that FXRInt-/- mice were more susceptible to ethanol-induced liver steatosis and inflammation, compared with WT mice. Ethanol treatment altered the expression of hepatic genes involved in lipid and BA homeostasis, and ethanol detoxification. Gut FXR deficiency increased intestinal permeability, likely due to reduced mucosal integrity, as revealed by decreased secretion of Mucin 2 protein and lower levels of E-cadherin protein. In summary, intestinal FXR may protect AFLD development by maintaining gut integrity.

Fibroblast Growth Factor 15-Dependent and Bile Acid-Independent Promotion of Liver Regeneration in Mice.

The role of intestine-derived factors in promoting liver regeneration after partial hepatectomy (PHx) are not entirely known, but bile acids (BAs) and fibroblast growth factor 15 (Fgf15) that is highly expressed in the mouse ileum could promote hepatocyte proliferation. Fgf15 strongly suppresses the synthesis of BAs, and emerging evidence indicates that Fgf15 is important for liver regeneration. The mechanisms by which Fgf15 promotes liver regeneration are unclear, but Fgf15 may do so indirectly by reducing BA levels and/or directly by promoting cell proliferation. However, it remains undetermined whether these two mechanisms are independent or integrated. In this study, we aimed to clarify these relationships by generating Fgf15 Tet-Off, transgenic mice (Fgf15 Tg) that had very low BA levels as a result from overexpressed Fgf15-mediated suppression of BA synthesis. Compared with wild-type mice, the Fgf15 Tg mice showed increased hepatocyte proliferation even without surgery, and a further induction of the genes in cell-cycle progression after PHx. Moreover, overexpression of Fgf15 by adeno-associated virus (AAV)-Fgf15 transduction or treatment with the recombinant Fgf15 protein led to increased cell proliferation in vivo. Furthermore, Fgf15 Tg mice exhibited an earlier and greater activation of mitogen-activated protein kinase, signal transducer and activator of transcription 3, and NF-κB signaling pathways in the priming stage, and a disruption of the hippo signaling pathway in the termination stage of liver regeneration. Conclusion: Direct in vivo evidence demonstrates that Fgf15 is critical in stimulating the phases of priming and termination of liver regeneration that are critical for cell survival and liver-size determination, independent of BA levels. (Hepatology 2018; 00:000-000).

The impact of postnatal antibiotics on the preterm intestinal microbiome.

BACKGROUND: Development of the intestinal microbiome in preterm infants has significant impact on infant health. Our objective was to determine if duration of antibiotics within the first 10 and 30 d after birth affects the intestinal microbiome. METHODS: Subjects were 24 0/7-31 6/7 wk of gestational age who received ≥ 50% breast milk and a total of ≥ 100 ml/kg of feeds by 10 d. Rectal (fecal) swabs were collected at 10 and 30 d and analyzed by 16S rRNA pyrosequencing. At both time points, we examined the rectal microbiome from infants who received only 2 d of antibiotics and those who received at least 7 d of antibiotics. RESULTS: In the 29 infants enrolled in our study, we found a decrease in diversity index from 10 d samples in those who received more antibiotics. Such difference in diversity and richness was not as pronounced in 30 d samples. Firmicutes and Bacteroidetes were most abundant in the 10 d samples. While these two phyla remained dominant in 30 d samples, there was an increase in Proteobacteria and Actinobacteria. CONCLUSION: Despite antibiotic therapy, neonates continued to acquire bacteria in the gastrointestinal tract. The process of bacterial acquisition is perturbed with the use of antibiotics.

Opportunity for Reduction of Intensive Care Unit Resource Utilization in Pediatric Blunt Liver and Spleen Injuries: A National Trauma Data Bank Analysis.

INTRODUCTION: Guidelines for blunt liver and spleen injury (BLSI) by the Arizona-Texas-Oklahoma-Memphis-Arkansas Consortium (ATOMAC) emphasize hemodynamic stability over injury grade when considering non-operative management (NOM). In this study, we examined rates of intensive care unit (ICU) admission for children with isolated low-risk BLSI among US hospitals. METHODS: The National Trauma Data Bank (NTDB) was queried for patients ages 1-15 admitted between 2017 and 2019 with BLSI. Patients with penetrating injuries and/or concomitant non-abdominal injuries with AIS score ≥3 were excluded. Isolated BLSI was considered low-risk if the patient had normal admission vitals and did not require operative intervention. Primary outcomes measured were ICU admission, ICU length of stay (LOS), and overall LOS. RESULTS: 5777 patients ages 15 and under presented with isolated BLSI during the study period. 2031/5777 (35.2%) were considered low-risk. Low-risk patients had lower rates of ICU admission compared to high-risk patients (30.9% vs. 41.6%, p < 0.001) and had shorter ICU LOS (median 2 days vs. 2, p < 0.001) and shorter overall LOS (median 41 h vs. 54, p < 0.001). Pediatric verified and non-pediatric verified trauma centers had similar rates of ICU admission (36.8% vs. 38.9%, p = 0.11). CONCLUSION: Further work is needed to capture opportunities for reduction in ICU utilization in isolated BLSI. LEVEL OF EVIDENCE: III.

Effects of intestine-specific deletion of FGF15 on the development of fatty liver disease with vertical sleeve gastrectomy.

BACKGROUND: Vertical sleeve gastrectomy (SGx) is a type of bariatric surgery to treat morbid obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular mechanisms of SGx to improve MASLD are unclear, but increased bile acids (BAs) and FGF19 (mouse FGF15) were observed. FGF15/19 is expressed in the ileum in response to BAs and is critical in not only suppressing BA synthesis in the liver but also promoting energy expenditure. We hypothesized the reduction of obesity and resolution of MASLD by SGx may be mediated by FGF15/19. METHODS: First, we conducted hepatic gene expression analysis in obese patients undergoing SGx, with the results showing increased expression of FGF19 in obese patients' livers. Next, we used wild-type and intestine-specific Fgf15 knockout mice (Fgf15ile-/-) to determine the effects of FGF15 deficiency on improving the metabolic effects. RESULTS: SGx improved metabolic endpoints in both genotypes, evidenced by decreased obesity, improved glucose tolerance, and reduced MASLD progression. However, Fgf15ile-/- mice showed better improvement compared to wild-type mice after SGx, suggesting that other mediators than FGF15 are also responsible for the beneficial effects of FGF15 deficiency. Further gene expression analysis in brown adipose tissue suggests increased thermogenesis. CONCLUSIONS: FGF15 deficiency, the larger BA pool and higher levels of secondary BAs may increase energy expenditure in extrahepatic tissues, which may be responsible for improved metabolic functions following SGx.

Outcome differences between gastroschisis repair methods.

BACKGROUND: Gastroschisis is a congenital abdominal wall defect that is repaired with either a primary closure or staged closure. The outcome of these infants may differ because of different closure techniques. In addition to the usual markers of parenteral nutrition (PN) use and length of stay (LOS) as outcome measures, we examined the duration of postoperative acidosis and positive fluid balance as markers for postoperative stress associated with these two techniques. METHODS: A retrospective review of newborns with gastroschisis was conducted at a free-standing children's hospital from 2002 to 2008. The demographic data, gestational age, birth weight, operative reports, days on PN, LOS, duration of postoperative acidosis and fluid balances were reviewed. Data were analyzed using the Fisher's exact test or unpaired t test. RESULTS: Thirty-two infants with gastroschisis were identified. One was excluded from analysis due to incomplete follow-up. The patients were classified as either primary closure (n = 8) or staged repair (n = 23). There was one death in our series. Patients who underwent primary closure had significantly older gestational age and higher birth weight. Primary closure is associated with significantly less duration of postoperative metabolic acidosis and fewer days with positive fluid balance. Patients who had primary repair also had less parenteral nutrition use and shorter length of hospitalization, though not statistically significant. Gastroschisis with associated intestinal atresia was more likely to be repaired with staged closures. CONCLUSIONS: There are physiologic advantages to primary repair of gastroschisis that can lead to better outcome, but the indications for the choices of closure technique remain unclear. Primary closure should be used when possible.

Pediatric COVID-19 and Appendicitis: A Gut Reaction to SARS-CoV-2?

BACKGROUND: We describe the temporal pattern of COVID-19 admissions to a tertiary care children's hospital in central New Jersey during the SARS-CoV-2 surge, covering the time period from March 29 to July 26, 2020. METHODS: Medical charts were reviewed for the date of admission, past medical history, and demographic variables, presenting signs and symptoms, admitting laboratory values, diagnostic imaging, diagnosis, treatment modalities, and outcomes including length of stay and disease severity. RESULTS: Patients with symptomatic SARS-CoV-2 infection tended to present with pneumonia early during the study period, which coincided with the early surge in New Jersey cases. Approximately 2 weeks after the peak in reported SARS-CoV-2 cases in New Jersey, we began to see fewer pneumonia cases and an increase in admissions for Multi-Inflammatory Syndrome in Children and cases of acute appendicitis in association with a diagnosis of SARS-CoV-2 infection. CONCLUSIONS: We present a novel association of acute appendicitis in children infected with SARS-CoV-2 and postulate that it may represent a postinfectious hyperinflammatory complication of SARS-CoV-2 infection occurring 2 weeks after the early manifestation of acute pneumonia disease in children.

A Giant Childhood Mesenteric Lipoblastoma With Extensive Maturation.

Abdominal lipoblastomas are uncommon soft tissue tumors in children and rarely arise from the mesentery. Due to intraabdominal location and slow growth, these masses can go unnoticed for long periods of time and often found on surgical exploration. We present a case of a 12-year-old male with years of abdominal distension accompanied by new onset early satiety that was found to have an intra-abdominal mass. He underwent an exploratory laparotomy revealing a large 33 x 27 x 15 cm rubbery mesenteric mass displacing the entire intra-abdominal contents, connected by a single vascular pedicle and encasing a loop of small intestine. The mass was resected and the patient did well without signs of recurrence. Histology confirmed the presence of mature adipocytes but on further cytogenetic analysis, a translocation between chromosomes 2 and 8 at the 12q arm was detected, which is often associated with lipoblastomas. This case represents the one of the largest mesenteric lipoblastomas that matured extensively to lipoma-like histology at the time of surgical resection.

Initial experience with laparoscopic Chait Trapdoor cecostomy catheter placement for the management of fecal incontinence in children: outcomes and lessons learned.

BACKGROUND: Antegrade enemas administered through a percutaneously placed Chait Trapdoor cecostomy catheter have resulted in a marked improvement in compliance and outcome of patients with fecal incontinence. The percutaneous technique, however, is a two-step procedure that is not performed under direct vision. This report presents the results and lessons learned from our experience with the laparoscopic approach to placement of Chait cecostomy catheters. METHODS: Retrospective review of patients who underwent laparoscopic placement of Chait cecostomy catheters from 1999 to 2008. Data collected included patient demographics, primary diagnosis, hospital stay, complications, follow-up duration and outcome. RESULTS: Seventeen patients, mean age 11.8 + or - 4.2 years (range 5-17), underwent laparoscopic Chait cecostomy catheter placement over a period of 8 years. Median follow-up was 46 + or - 21 months (range 4-67). The primary diagnosis was spina bifida in 82% of patients. There was one intraoperative complication, which consisted of tangential needle placement into the cecum, and required conversion to an open procedure. Mean hospital stay was 3.8 + or - 1.5 days (range 2-7). Emergency department visits related to Chait catheter complications were mainly due to catheter dislodgement and breakage. Long-term complications included accidental dislodgement of the catheter in seven patients (41%), mechanical failure of the catheter (breaks/leaks) in six patients (35%), hypertrophic granulation tissue in six patients (35%), wound infections at the catheter site in three patients (18%), complications related to the use of fasteners in two patients (12%) and ventirculoperitoneal (VP) shunt infection in two patients (11.8%). CONCLUSION: The laparoscopic approach to Chait cecostomy catheter placement is a simple and effective procedure. The rate of long term complications such as catheter dislodgement and mechanical failure, which are responsible for the majority of unplanned ED visits, may be decreased by routine yearly catheter exchanges. VP shunt infections are the most serious complications in this patient population consisting mostly of patients with spina bifida.

Children after motor vehicle crashes: Restraint utilization and injury severity.

BACKGROUND: Although injury patterns after motor vehicle crashes (MVCs) are well documented, association between adequate restraint and injury severity is unclear. We aimed to determine if improper restraint affects injury rates and severity. METHODS: A retrospective chart review of 477 children hospitalized in Pediatric Trauma Center after MVC was performed. Injuries in various age groups (0-7, 8-12, 13-16, 17-18 years) with different restraint quality measures (proper [PR] and improper/unrestrained [IUR]) as well as injury severity score (ISS: mild [1-9], moderate [10-15], severe [16-25], and profound [>25]) were evaluated and compared. Chi-square and Wilcoxon rank-sum tests were used for statistics. RESULTS: In all age groups head/neck injuries were most common (55-63%), while abdominal and pelvic injuries were least likely except group 8-12 years where abdominal injuries ranked third (17.1%). Overall, 64.5% had PR and 35.5% IUR. Interestingly, that greatest proportion of IUR was in the youngest age group (0-7). It decreased with aging and children aged 17-18 years were significantly less likely to be IUR compared to those 0-7 years (OR[odds ratio] = 0.58; 95%CI[confidence interval] 0.35-0.94). We did not find significant differences in rates of various injuries between PR and IUR. However, ISS severity in IUR was significantly greater than in PR (median with interquartile range 6(2-14) and 5(1-9), respectively; P = 0.001). As a result, IUR compared to PR were less likely to have mild ISS (OR = 0.6, 95%CI 0.39-0.90) but more likely to have profound ISS (OR = 3.3, 95%CI 1.48-7.43). CONCLUSION: Restraint quality has significant impact on injury severity in children after MVC. LEVEL OF EVIDENCE: Level III.

FXR deficiency alters bile acid pool composition and exacerbates chronic alcohol induced liver injury.

Recent studies have investigated the roles of FXR deficiency in the pathogenesis of alcoholic liver disease (ALD). However, the underlying molecular mechanisms remain unclear. In this study, FXR knockout (FXR-/-) and wild-type (WT) mice were subjected to chronic-plus-binge alcohol feeding to study the effect of FXR deficiency on ALD development. The degree of liver injury was greater in FXR-/- mice compared to WT mice. Ethanol feeding enhanced hepatic steatosis in FXR-/- mice, accompanied by decreased mRNA levels of Pparα and Srebp-1c. The expression of Lcn2 was increased by ethanol treatment, despite unchanged expression of pro-inflammatory cytokines Tnfα, Il6 and Il-1ß. Furthermore, ethanol treatment altered bile acid (BA) homeostasis to a greater extent in FXR-/- mice, as well as serum and hepatic BA pool composition. The mRNA levels of hepatic Cyp7a1 and Shp, as well as intestinal Fgf15, were decreased in WT mice with ethanol feeding, which were further reduced in FXR-/- mice. Levels of both primary and secondary BAs were markedly elevated in FXR-/- mice, which were further increased after ethanol treatment. Moreover, hepatic MAPK signaling pathways were disturbed presumably by increased hepatic BA levels. In summary, FXR deficiency increased hepatic steatosis and altered BA pool composition, contributing to worsened liver toxicity.

FXR deletion in hepatocytes does not affect the severity of alcoholic liver disease in mice.

Emerging evidence has shown that FXR activation ameliorates the development of alcoholic liver diseases (ALD) while whole-body deficiency of FXR in mice leads to more severe ALD. However, it's unknown whether the enhanced susceptibility to ALD development in FXR-/- mice is due to deficiency of hepatic FXR or increased toxicity secondary to increased bile acid (BA) levels. Hepatocyte-specific FXR knockout mice (FXRhep-/-) present similar BA levels compared to wild-type mice, and are therefore a useful model to study a direct role of hepatic FXR in ALD development. FXRhep-/- mice were subject to an ALD model with chronic plus binge drinking of alcohol to determine the effects of hepatic FXR deficiency on ALD development. The FXRhep-/- mice showed an altered expression of genes involved in BA and lipid homeostasis with alcohol treatment. Despite a slightly increased trend in hepatic lipid deposition and collagen accumulation in FXRhep-/- mice, there were no significant differences in the severity of steatosis, inflammation, or fibrosis between WT and FXRhep-/- mice. Therefore, these findings indicate that FXR deficiency in hepatocytes might only play a minor role in ALD development. Deficiency of FXR in other non-hepatic tissues and/or increased BA levels resultant from whole-body FXR deficiency might be responsible for more severe ALD development.

Current management of hernias and hydroceles.

The repair of inguinal hernia and hydrocele is one of the most common operations in a pediatric surgery practice. This work reviews current concepts in the management of the inguinal hernia and hydrocele. The authors describe current concepts of anesthetic management of children undergoing repair of inguinal hernia. The authors also discuss current management of the contralateral hernia, hernias in premature infants, and the management of an incarcerated hernia. In addition, the authors discuss the role of laparoscopy in the surgical treatment of an inguinal hernia and its application for investigation of the contralateral inguinal canal.

The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease is growing in prevalence worldwide. It is marked by the presence of macrosteatosis on liver histology but is often clinically asymptomatic. However, it can progress into nonalcoholic steatohepatitis which is a more severe form of liver disease characterized by inflammation and fibrosis. Further progression leads to cirrhosis, which predisposes patients to hepatocellular carcinoma or liver failure. The mechanism by which simple steatosis progresses to steatohepatitis is not entirely clear. However, multiple pathways have been proposed. A common link amongst many of these pathways is disruption of the homeostasis of bile acids. Other than aiding in the absorption of lipids and lipid-soluble vitamins, bile acids act as ligands. For example, they bind to farnesoid X receptor, which is critically involved in many of the pathways responsible for maintaining bile acid, glucose, and lipid homeostasis. Alterations to these pathways can lead to dysregulation of energy balance and increased inflammation and fibrosis. Repeated insults over time may be the key to development of steatohepatitis. For this reason, current drug therapies target aspects of these pathways to try to reduce and halt inflammation and fibrosis. This review will focus on the role of bile acids in these various pathways and how changes in these pathways may result in steatohepatitis. While there is no approved pharmaceutical treatment for either hepatic steatosis or steatohepatitis, this review will also touch upon the multitude of potential therapies.

Impact of prematurity and nutrition on the developing gut microbiome and preterm infant growth.

BACKGROUND: Identification of factors that influence the neonatal gut microbiome is urgently needed to guide clinical practices that support growth of healthy preterm infants. Here, we examined the influence of nutrition and common practices on the gut microbiota and growth in a cohort of preterm infants. RESULTS: With weekly gut microbiota samples spanning postmenstrual age (PMA) 24 to 46 weeks, we developed two models to test associations between the microbiota, nutrition and growth: a categorical model with three successive microbiota phases (P1, P2, and P3) and a model with two periods (early and late PMA) defined by microbiota composition and PMA, respectively. The more significant associations with phase led us to use a phase-based framework for the majority of our analyses. Phase transitions were characterized by rapid shifts in the microbiota, with transition out of P1 occurring nearly simultaneously with the change from meconium to normal stool. The rate of phase progression was positively associated with gestational age at birth, and delayed transition to a P3 microbiota was associated with growth failure. We found distinct bacterial metabolic functions in P1-3 and significant associations between nutrition, microbiota phase, and infant growth. CONCLUSION: The phase-dependent impact of nutrition on infant growth along with phase-specific metabolic functions suggests a pioneering potential for improving growth outcomes by tailoring nutrient intake to microbiota phase.

ROHHADNET syndrome presenting as major behavioral changes in a 5-year-old obese girl.

Behavioral issues are a frequent problem in the pediatric population. Often, these are evaluated and considered to be psychiatric in origin. We report on a pediatric patient who presented with severe behavioral disturbance and developed organic symptoms including hypoventilation and dysautonomia and who was ultimately diagnosed with ROHHADNET syndrome, a syndrome of rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation associated with a neuroendocrine tumor. Autopsy findings revealed novel findings of the syndrome, including hypothalamic encephalitis.

Transluminal migration of ingested foreign body without peritonitis.

The authors present 2 cases of transluminal migration of an ingested foreign body into the peritoneal cavity without causing peritonitis. Clinical and radiologic features and surgical approach are described, focusing on the absence of an acute abdomen in transluminal migration and the use of laparoscopy in achieving extraction of the foreign object.

An alternative to open incision and drainage for community-acquired soft tissue abscesses in children.

BACKGROUND: The continually rising incidence of soft tissue abscesses in children has prompted us to seek an alternative to the traditional open incision and drainage (I&D) that would minimize the pain associated with packing during dressing changes and eliminate the need for home nursing care. STUDY DESIGN: A retrospective review of all patients with soft tissue abscesses from November 2007 to June 2008 was conducted after institutional review board approval. Patients who were treated with open I&D were compared to those treated with placement of subcutaneous drains through the abscess cavities. Both groups received equivalent antibiotic treatment, and all patients were followed in outpatient clinics until infection resolved. The demographics, presenting temperature, culture results, and outcomes were compared between these 2 groups. RESULTS: A total of 219 patients were identified; 134 of them underwent open I&D, whereas 85 were treated with subcutaneous drains. The demographics, anatomical location of the abscesses, and bacteriology were comparable between the 2 groups. There were equal number of patients in each group who presented with fever initially. Of those treated with open I&D, 4 had metachronous recurring abscesses within the same anatomical region and 1 patient required an additional procedure because of incomplete drainage. There were no recurrences or incomplete drainages in the subcutaneous drain group. The cosmetic appearance of the healed wound from subcutaneous drain placement during the immediate follow-up period is better than that of an open I&D. CONCLUSIONS: Placement of a subcutaneous drain for community-acquired soft tissue abscesses in children is a safe and equally effective alternative to the traditional I&D.