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Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder affecting respiratory control and autonomic nervous system function caused by variants in the paired-like homeobox 2B (

OBJECTIVES To advance our understanding of monogenic forms of intrahepatic cholestasis. METHODS Analyses included participants with pathogenic biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 11 (ABCB11) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 (ATP8B1) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 4 (ABCB4) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data. RESULTS Ninety-eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations [severe] and 10 with p.E297G or p.D482G [mild]), or MDR3 (n = 19, including four monoallelic) deficiency were analyzed. Thirty-five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported. CONCLUSIONS In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype-phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.

Few data exist on bisphenol A (BPA) or triclosan (TCS) residue levels in foods consumed by adults in everyday settings. In a further analysis of study data, the objectives were to determine BPA and TCS residue concentrations in duplicate-single solid food items consumed by adults and to estimate dietary exposure and intake doses per food item. A convenience sample of 50 adults was recruited in North Carolina (2009–2011). Participants completed 24 h food diaries and collected 24 h duplicate-diet solid food samples consumed on days 1 and 2 during sampling weeks 1, 2, and 6. A total of 188 of the collected 776 duplicate-diet solid food samples contained a single, solid food item. BPA and TCS residue levels were quantified in the 188 food items using GC–MS. BPA and TCS were detected in 37% and 58% of these food items, respectively. BPA concentrations were highest in a cheese and tomato sandwich (104 ng/g), whereas the highest TCS concentrations were in a burrito (22.1 ng/g). These chemicals co-occurred in 20% of the samples (maximum = 54.7 ng/g). Maximum dietary intake doses were 429 ng/kg/day for BPA in a vegetable soup with tortilla sample and 72.0 ng/kg/day for TCS in a burrito sample.

Paragangliomas are rare neuroendocrine tumors where hypoxia-inducible factor plays a critical role in tumorigenesis. It has been suggested that patients with congenital heart disease, in particular, may have cellular environment and relative hypoxia favorable to the development of these neuroendocrine tumors. Here, we present a case of an 11-year-old child with hypoplastic left heart syndrome previously palliated with Fontan procedure, diagnosed with paraganglioma on surveillance imaging. We present the clinical course, intervention, and outcome as well as review the possible contributory mechanisms. As we continue to improve long-term survival for single ventricle patients, awareness of these tumors during surveillance may be warranted as timely intervention may lead to cure.

Pyrethroid insecticides are widely used to control insects in both agricultural and residential settings worldwide. Few data are available on the temporal variability of pyrethroid metabolites in the urine of non-occupationally exposed adults. In this work, we describe the study design and sampling methodology for the Pilot Study to Estimate Human Exposures to Pyrethroids using an Exposure Reconstruction Approach (Ex-R study). Two major objectives were to quantify the concentrations of several pyrethroid metabolites in bedtime, first morning void (FMV), and 24-h urine samples as concentration (wet weight), specific-gravity (SG) corrected, creatinine (CR) corrected, and excretion rate values for 50 Ex-R adults over a six-week monitoring period and to determine if these correction approaches for urine dilution reduced the variability of the biomarker levels. The Ex-R study was conducted at the United States Environmental Protection Agency's Human Studies Facility in Chapel Hill, North Carolina USA and at participants' homes within a 40-mile radius of this facility. Recruitment of participants and field activities occurred between October 2009 and May 2011. Participants, ages 19-50 years old, provided daily food, activity, and pesticide-use diaries and collected their own urine samples (bedtime, FMV, and 24-h) during weeks 1, 2, and 6 of a six-week monitoring period. A total of 2503 urine samples were collected from the study participants. These samples were analyzed for the pyrethroid metabolites 3-phenoxybenzoic acid (3-PBA), cis/trans-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane carboxylic acid (cis/trans-DCCA), and 2-methyl-3-phenylbenzoic acid (MPA) using high performance liquid chromatography/tandem mass spectrometry. Only 3-PBA was frequently detected (>50%) in the adult urine samples. Median urinary 3-PBA levels were 0.88 ng/mL, 0.96 ng/mL-SG, 1.04 ng/mg, and 1.04 ng/min for concentration, SG-corrected, CR-corrected, and excretion rate values, respectively, across all urine samples. The results showed that median urinary 3-PBA concentrations were consistently the lowest in FMV samples (0.77 ng/mL, 0.68 ng/mL-SG, 0.68 ng/mg, and 0.58 ng/min) and the highest in 24-h samples (0.92 ng/mL, 1.06 ng/mL-SG, 1.18 ng/mg, and 1.19 ng/min) across all four methods. Intraclass correlation coefficient (ICC) estimates for 3-PBA indicated poor reproducibility (

To evaluate the efficacy of nontransplant surgery for pediatric cholestasis, 58 clinically diagnosed children, including 20 with Alagille syndrome (ALGS), 16 with familial intrahepatic cholestasis-1 (FIC1), 18 with bile salt export pump (BSEP) disease, and 4 others with low γ-glutamyl transpeptidase disease (levels100 U/L), were identified across 14 Childhood Liver Disease Research Network (ChiLDReN) centers. Data were collected retrospectively from individuals who collectively had 39 partial external biliary diversions (PEBDs), 11 ileal exclusions (IEs), and seven gallbladder-to-colon (GBC) diversions. Serum total bilirubin decreased after PEBD in FIC1 (8.1 ± 4.0 vs. 2.9 ± 4.1 mg/dL, preoperatively vs. 12-24 months postoperatively, respectively; P = 0.02), but not in ALGS or BSEP. Total serum cholesterol decreased after PEBD in ALGS patients (695 ± 465 vs. 457 ± 319 mg/dL, preoperatively vs. 12-24 months postoperatively, respectively; P = 0.0001). Alanine aminotransferase levels increased in ALGS after PEBD (182 ± 70 vs. 260 ± 73 IU/L, preoperatively vs. 24 months; P = 0.03), but not in FIC1 or BSEP. ALGS, FIC1, and BSEP patients experienced less severely scored pruritus after PEBD (ALGS, 100% vs. 9% severe; FIC1, 64% vs. 10%; BSEP, 50% vs. 20%, preoperatively vs.24 months postoperatively, respectively; P0.001). ALGS patients experienced a trend toward greater freedom from xanthomata after PEBD. There was a trend toward decreased pruritus in FIC1 after IE and GBC. Vitamin K supplementation increased in ALGS after PEBD (33% vs. 77%; P = 0.03). Overall, there were 15 major complications after surgery. Twelve patients (3 ALGS, 3 FIC1, and 6 BSEP) subsequently underwent liver transplantation.This was a multicenter analysis of nontransplant surgical approaches to intrahepatic cholestasis. Approaches vary, are well tolerated, and generally, although not uniformly, result in improvement of pruritus and cholestasis. (Hepatology 2017;65:1645-1654).

Enteritis caused by Clostridium difficile toxin (Tx) is a nosocomial disease of increasing clinical concern, but the local mediators of C. difficile TxA inflammation are unknown. The potent vasodilator calcitonin gene-related peptide mediates neurogenic inflammation via the calcitonin receptor-like receptor (CLR). Here we examined the ileum-specific effects of reducing CLR on TxA ileitis by local preinjection of double-stranded RNAs. Treatment with CLR dsRNA for 7 d decreased CLR immunoreactivity, whereas treatment with non-CLR dsRNA did not. Subsequent injection of TxA in the same location increased CLR in rats treated with non-CLR dsRNA but not in rats treated with CLR dsRNA, documenting that local injection of dsRNA is effective in preventing the increase in CLR immunoreactivity in response to local TxA. After non-CLR dsRNA pretreatment, TxA induced robust intestinal secretion, myeloperoxidase activity, and histopathologic indications of inflammation including epithelial damage, congestion, neutrophil infiltration, loss of mucin from goblet cells, and increase in mast cell numbers. After CLR dsRNA pretreatment, TxA-induced changes in intestinal secretion and histopathologic inflammation were improved, including normal mucin staining and fewer resident mast cells. Loss of CLR prevented TxA-mediated activation of NF-κB and concomitant increases in pERK1/2 and TNF-α mRNA. Locally produced CLR plays a proinflammatory role in TxA ileitis via MAPK signaling and TNF-α. The results reported here strongly suggest that a local injection of dsRNA targeting CLR could be an effective local therapeutic approach at the inflammation site in the treatment of a growing, clinically relevant hospital-acquired disease, C. difficile infection.

Iatrogenic esophageal perforation in infants is an uncommon though recognized complication resulting from the insertion of a transesophageal echocardiogram (TEE) probe into the oropharynx. Infants requiring TEE are almost universally affected by underlying cardiac disease; thus, minimizing unnecessary interventions is the goal. We reviewed our institution's experience with esophageal perforation resulting from TEE probes in order to define effective management strategies. After IRB approval, we conducted a 12-year retrospective review of our institution's experience with esophageal perforation in infants resulting from TEE probes. During our study period, 3322 infants had a TEE probe placed. Four infants (age range 2–120 days) sustained an esophageal perforation from a TEE probe, indicating that the incidence at our institution is 0.12%. Evaluation with contrast esophagram or direct laryngoscopy confirmed the presence of perforation in all cases. Management consisted of broad-spectrum antibiotics and nothing per os. One patient developed a pseudodiverticulum, which regressed spontaneously. There were no other complications resulting from perforation. Transesophageal echocardiogram probe insertion in infants with cardiac anomalies can lead to esophageal perforation. These patients can be managed non-operatively with broad-spectrum antibiotics and nothing per os. Oral feeding may resume once the perforation is healed on esophagram.

Respiratory distress syndrome (RDS) is a major cause of neonatal morbidity and mortality due to insufficient surfactant production in the lungs (1–3). The disease primarily affects premature infants and is the seventh leading cause of death in infants under 1 year of age (1,2). Excreted surfactant aggregates to form a monolayer complex that reduces alveolar surface tension and facilitates alveolar inflation (4). Insufficient surfactant at birth results in collapse of the fetal alveoli and RDS. Surfactant is composed predominantly of phosphatidylcholine (lecithin) (70%) with lesser amounts of other phospholipids, including phosphatidylglycerol, phosphatidylethanolamine, and phosphatidylinositol (5). Measurement of the lecithin-to-sphingomyelin (LS) ratio in amniotic fluid samples is traditionally considered to be the gold standard for fetal lung maturity testing, but the assay is time-consuming and technically challenging to perform. Consequently, many hospitals now measure the surfactant-to-albumin (SA) ratio, which is a faster and simpler test, although there is not good concordance between the two measurements (6). These traditional methods of evaluating fetal lung maturity have a number of disadvantages. Analysis of amniotic fluid requires amniocentesis, with the associated risks of this invasive procedure including infection and miscarriage (7,8). The tests are also associated with a high rate of false-positive results in fetuses with intermediate lung maturity, even when several different measurements are incorporated into a more comprehensive assessment (9–11). In these cases the laboratory tests can indicate fetal lung maturity yet the fetus may still develop RDS (12). Choline, a major component of surfactant, can be easily detected and quantified by 1H MR spectroscopy ex vivo. Case reports of 1H MRS of amniotic fluid pockets in utero have generated interest in pursuing this technique for the potential noninvasive evaluation of fetal lung maturity in vivo (13–15). However, in vivo studies are lower in spectroscopic resolution and sensitivity, and are expensive and technically challenging to perform (16). Accordingly, a systematic study of amniotic fluid samples ex vivo would be useful to establish metabolic markers of fetal lung maturity (such as choline) and provide proof of concept to justify pursuing in vivo protocol development. High-resolution magic angle spinning (HR-MAS) spectroscopy is an ex vivo MRS technique that can be applied to intact tissues, cells, and biofluids. Although HR-MAS spectroscopy is normally used to improve spectral resolution, in the case of amniotic fluid, which contains mostly water, the small sample volume relative to the coil size allows for much better water suppression than a conventional liquids probe. Because reproducibility of measurements is an important fundamental parameter that needs to be established in such studies, the reproducibility of the MRS quantification technique first needs to be evaluated. Thus, the purpose of this study was to determine the intra- and interobserver reproducibility of metabolite concentration measurements (including choline concentration) detectable by 1H HR-MAS spectroscopy using a semiautomated software program for peak fitting.

Polybrominated diphenyl ethers (PBDEs) are used as flame retardants in furniture foam, electronics, and other home furnishings. A field study was conducted that enrolled 139 households from California, which has had more stringent flame retardant requirements than other countries and areas. The study collected passive air, floor and indoor window surface wipes, and dust samples (investigator collected using an HVS3 and vacuum cleaner) in each home. PentaBDE and BDE209 were detected in the majority of the dust samples and many floor wipe samples, but the detection in air and window wipe samples was relatively low. Concentrations of each PBDE congener in different indoor environmental media were moderately correlated, with correlation coefficients ranging between 0.42 and 0.68. Correlation coefficients with blood levels were up to 0.65 and varied between environmental media and age group. Both investigator-collected dust and floor wipes were correlated with serum levels for a wide range of congeners. These two sample types also had a relatively high fraction of samples with adequate mass for reliable quantification. In 42 homes, PBDE levels measured in the same environmental media in the same home 1year apart were statistically correlated (correlation coefficients: 0.57-0.90), with the exception of BDE209 which was not well correlated longitudinally.

Background Polybrominated diphenyl ethers (PBDEs) are used as flame retardants in many household items. Given concerns over their potential adverse health effects, we identified predictors and evaluated temporal changes of PBDE serum concentrations. Methods PBDE serum concentrations were measured in young children (2-8 years old; N = 67), parents of young children (

Background: Patients who have successfully undergone gender reassignment surgery seek further aesthetic refinements to suit their new gender role. Objective: The study evaluated secondary aesthetic procedures, laryngeal surgery, and adjuvant hormone therapy in 22 male-to-female gender reassignment change patients. Methods: Thirty-two aesthetic procedures performed in 22 patients were evaluated for operation type, surgical technique, complications, and satisfaction rates. Aesthetic procedures included rhytidectomy, platysmaplasty, rhinoplasty, brow lift, blepharoplasty, cheek or chin surgery, and body contouring. Results: A wide range of secondary aesthetic procedures was successfully performed with only 1 minor complication and 1 major psychological depressive episode. Conclusions: Secondary surgery in gender reassignment patients extends the frontier of aesthetic surgery and provides lessons that can be extrapolated to facial and body con-tour aesthetic surgery in the general patient population.

Urocortins (UCNs) and their receptors are potent immunoregulators in the gastrointestinal (GI) tract, where they can exert both pro- and anti-inflammatory effects. We examined the contribution of Ucn1 and its receptors to the pathogenesis, progression, and resolution of colitis. Trinitrobenzene sulfonic acid was used to induce colitis in rats. Ucn1 mRNA and immunoreactivity (IR) were ubiquitously expressed throughout the GI tract under basal conditions. During colitis, Ucn1 mRNA levels fell below basal levels on day 1 then increased again by day 6, in association with an increase in the number of Ucn1-IR inflammatory cells. Ucn1-IR cells were also numerous in proliferating granulation tissue. In contrast to Ucn1 expression, average phosphorylated ERK1/2 (pERK1/2) expression rose above controls levels on day 1 and was very low on day 6 of colitis. Knockdown of corticotropin-releasing factor 2 (CRF2) but not CRF1 by RNA interference during colitis significantly decreased the macroscopic lateral spread of ulceration compared with uninjected controls or animals with CRF1 knockdown. After knockdown of CRF2, but not of CRF1 during colitis, edema resolution assessed microscopically was slowed, and myeloperoxidase activity remained elevated even at day 6. Ucn1 and TNF-α mRNA peaked earlier, whereas pERK1/2 activation was attenuated after CRF2 knockdown. Thus we conclude that local CRF2 and pERK1/2 activation is pivotal for macroscopic spread of colitis and resolution of edema. Elimination of CRF2, but not CRF1, results in uncoordinated immune and pERK1/2 signaling responses.

The lipocalins are secreted proteins that bind small organic molecules. Scn-Ngal (also known as neutrophil gelatinase associated lipocalin, siderocalin, lipocalin 2) sequesters bacterial iron chelators, called siderophores, and consequently blocks bacterial growth. However, Scn-Ngal is also prominently expressed in aseptic diseases, implying that it binds additional ligands and serves additional functions. Using chemical screens, crystallography and fluorescence methods, we report that Scn-Ngal binds iron together with a small metabolic product called catechol. The formation of the complex blocked the reactivity of iron and permitted its transport once introduced into circulation in vivo. Scn-Ngal then recycled its iron in endosomes by a pH-sensitive mechanism. As catechols derive from bacterial and mammalian metabolism of dietary compounds, the Scn-Ngal-catechol-Fe(III) complex represents an unforeseen microbial-host interaction, which mimics Scn-Ngal-siderophore interactions but instead traffics iron in aseptic tissues. These results identify an endogenous siderophore, which may link the disparate roles of Scn-Ngal in different diseases.

It is becoming increasingly evident that the urocortins (Ucns) and their receptors are involved in the initiation and development of inflammation in the gastrointestinal (GI) tract. There has not been a systematic study of the basal expression of Ucns or their receptors in the GI tract. Here, we examined basal expression of Ucn 2 and its high-affinity receptor, CRF-R2 in the rat GI tract. Ucn 2 mRNA was expressed throughout the small and large intestine. Surprisingly, CRF-R2 mRNA expression was detected in only a subset of GI regions that expressed Ucn 2. Immunohistochemical study showed that both Ucn 2 immuno-reactivity (Ucn 2-IR) and CRF-R2-IR were consistently seen in the neurons of the myenteric plexus and the nerve fibers innervating the circular muscle. By and large, Ucn 2-IR was detected in all layers, including the mucosal and the submucosal layers throughout the GI regions. In contrast, CRF-R2-IR was very low or undetectable in the mucosal layers of all regions examined. The role of Ucn 2 and CRF-R2 was then examined in a rat model of chemically-induced colitis. In the early phase of colitis, Ucn 2 mRNA levels peaked, whereas, in striking contrast, CRF-R2 mRNA expression decreased approximately 2.5-fold below control levels. At the peptide level, Ucn 2-IR was specifically induced in a large population of immune cells that infiltrated the lamina propria and submucosa of the distal colon, whereas CRFR2-IR was detected in only a small fraction of infiltrated immune cells. CRF-R2-IR was dramatically reduced in the neurons of the myenteric plexus. Thus, we show, for the first time, that in the acute phase of inflammation, Ucn 2 levels are increased whereas expression levels of its only identified receptor, CRF-R2, are decreased. This suggests that Ucn 2 exerts its effects only in part via CRF-R2.

Calcitonin gene-related peptide (CGRP) mediates neurogenic inflammation and modulates intestinal motility. The CGRP receptor is a heterodimer of calcitonin receptor-like receptor (CLR) and receptor-associated modifying protein 1. We used RNA interference to elucidate the specific role of CLR in colonic motility and inflammation. Intramural injection of double-stranded RNA (dsRNA) against CLR (dsCLR) into the colonic wall at two sites caused the spatial and temporal downregulation of CLR in the colon within 1 day of dsRNA injection. Knockdown of CLR persisted for 7-9 days, and the effect of knockdown spread to approximately 2 cm proximal and distal to the injection sites, whereas control dsRNA injection did not affect CLR expression. Measurement of isometric contractions of isolated colonic muscle segments revealed that in control dsRNA-injected rats, CGRP abrogated contractions entirely and decreased resting muscular tone, whereas in dsCLR-injected rats, CGRP decreased muscle tone but slow-wave contractions of varying amplitude persisted. In trinitrobenzene sulfonic acid-induced colitis, rats with knockdown of CLR displayed a significantly greater degree of edema and necrosis than saline- or control dsRNA-injected rats. Levels of the proinflammatory cytokines TNF-alpha and IL-6 were markedly upregulated by trinitrobenzene sulfonic acid treatment. TNF-alpha mRNA levels were further increased in CLR knockdown rats, whereas levels of IL-6 were unaltered. Thus this study demonstrates that CLR is a functional receptor for CGRP.

G A A b st ra ct s proximal colon by day 7, had no effect on mucosa from mid-colon, and caused a timedependent decrease (47% by day 7) in mucosa from distal colon. In muscle, there was a time-dependent decrease (35% by day 7) in NT-3 in proximal colon but a time-dependent increase in muscle from mid-colon (105%) and distal colon (43%) by day 7. In conclusion, NGF, BDNF, and NT-3 are expressed in distinct region-and tissue-specific patterns in naive rats. Colonic inflammation results in differential changes in these patterns which are neurotrophin-specific.