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Centrifugal contactors (CCs) are a technology candidate for the development of advanced reprocessing flowsheets. While they offer many advantages, such as process intensification, there are still uncertainties regarding their industrial deployment. The presence of particles in the process streams in particular may present a challenge to both performance and operability. Preliminary studies have been undertaken to evaluate the accumulation of particles in the contactors and the effect upon the extraction behaviour of nitric acid. Aluminium oxide (Al2O3) particles were suspended in the aqueous feed solution during the operation of a three-stage, 40 mm diameter CC cascade. The presence of insoluble solid particles in the aqueous feed, up to 7 g/L, were not observed to affect phase separation and entrainment under the experimental conditions investigated. The particles were centrifuged out of solution and accumulated as a thin cake/bed in the rotors of each stage. This work also illustrates that particles do entrain through the cascade. The predominant effect on the rate of accumulation was particle concentration in the aqueous feed solution, and increasing solids loading was observed to have an impact upon the extraction of nitric acid across the cascade. [ABSTRACT FROM AUTHOR]

This work reports the effect of scaling up annular centrifugal contactors (ACCs) upon the residence time distribution and the efficiency of extraction of uranium. The experiments were carried out in a multi-scale ACC platform of three ACCs with rotor diameters of 12, 25, and 40 mm. To enable direct comparison across all three scales of ACC, the residence time distributions were acquired by injecting dye into the solvent phase at a constant relative volume related to the ACC liquid holdup. Across all scales and flowrates, there was little difference in residence time distribution (<6 residence volumes), except for the smallest 12 mm rotor diameter ACC with a high solvent/aqueous feed ratio, which required 12 residence volumes, potentially due to internal circulation in the annulus. At low flowrates, the stage efficiency in all cases was >95%, and it improved further in larger rotor diameter ACCs. [ABSTRACT FROM AUTHOR]

This review focuses on consolidating solvent extraction performed in the process intensification equipment known as Centrifugal Contactors (CCs), implemented in Spent Nuclear Fuel (SNF) reprocessing and radioactive waste processing. Recovery of valuable actinides is important from sustainability perspectives as it is a source of metals of technological interest from SNF, specifically the recovery of fissile and fertile material, and can also be employed in the processing of Waste Electrical and Electronic Equipment (WEEE). Solvent extraction (also referred to as liquid–liquid extraction, or aqueous separation), is employed in the separation of f-block elements and fission products in SNF. The sequential isolation using different flowsheets has been performed on a range of scales using CCs. However, solids, either present in the feed solution or formed in situ, are always cited as a concern for the operability of CCs, and their extraction efficiencies. This review quantifies the unexpected solid arisings and accumulation during operation in the presence and absence of highly radioactive isotopes from bench to plant scale. The review concludes with techniques implemented for the removal of solids from CCs. [ABSTRACT FROM AUTHOR]

The chemistry of iodine in spent nuclear fuel (SNF) solutions is extremely complex and numerous species have been identified. These include iodine (I 2), iodide (I−), iodate (IO 3 −), triiodide (I 3 −) and insoluble colloidal compounds with the fission products silver and palladium (AgI and PdI 2). The experimental parameters that control the removal of iodine from SNF solutions are poorly understood. Experiments were performed at two temperatures representative of dissolver conditions. It was found that iodine, added as iodide, was rapidly removed from solution; within 30 s over 70% and 90% of the initially added amount was removed at 60 and 80 °C, respectively. [Display omitted] • Iodineis efficiently removed from simulated SNF dissolver solutions containing the fission products silver and palladium. • Increasing the temperature of the solution from 60 °C to 80 °C increased the initial amount of iodine removal from 70% to 90%. • Iodine removal from dissolver solutions is efficient with over 95% being removed at the conclusion of the experiment. [ABSTRACT FROM AUTHOR]

Annular centrifugal contactors (ACCs) are process intensification equipment for liquid-liquid extraction (also known as solvent extraction) that use centrifugal force that 200x greater than traditional gravity settling (Baker et al., 2022a). The size and throughput of ACCs have been denoted by their increasing rotor diameter (RD), from 10 mm up to 1330 mm. In this work a multiscale ACC platform has been commissioned, (consisting of 10, 25, 40 mm RD ACCs), to collect the physical liquid-holdup and mass transfer across several sizes to inform future computation modelling flowsheets of liquid-liquid extraction (LLE). Experimental studies have been performed with nitric acid with tributyl phosphate in odourless kerosene (TBP/OK) relevant to the development of advanced PUREX processes for recovery of actinides from spent fuel. Hydrodynamic trials determined the minimum Relative Centrifugal Force (RCF) required to separate extreme solvent/aqueous (S/A) feed ratios and total throughputs across the three sizes of ACC. The novel 'stepped stop' method has provided understanding of the actual liquid holdups within the two distinctly different regions (mixing annulus and separating rotor) ACC during operation to provide accurate residence times. These values were subsequently used to calculate the mass transfer and stage efficiency of aqueous nitric acid with tributyl phosphate in odourless kerosene. The smallest contactor was determined to be distinct and likely under-predicting performance of larger contactors. Ultimately the geometry and the aspect ratio supersedes using rotor diameter for defining scale-up of annular centrifugal contactors. [Display omitted] • How to construct a multi-scale platform. • Determination of the minimum Relative Centrifugal Force required to separate extreme solvent/aqueous (S/A) feed ratios across three sizes of ACC. • A novel "stepped stop" method providing the actual liquid holdups within the two distinct mixing annulus and separating rotor ACC zones. • Mass transfer and stage efficiency of aqueous nitric acid across three sizes of ACC. • Geometries and aspect ratios of different rotor diameters and lengths as parameters for defining the scale-up of annular centrifugal contactors. [ABSTRACT FROM AUTHOR]

Implementing statistical training into undergraduate or postgraduate chemistry courses can provide high-impact learning experiences for students. However, the opportunity to reinforce this training with a combined laboratory practical can significantly enhance learning outcomes by providing a practical bolstering of the concepts. This paper outlines a flow chemistry laboratory practical for integrating design of experiments optimisation techniques into an organic chemistry laboratory session in which students construct a simple flow reactor and perform a structured series of experiments followed by computational processing and analysis of the results. [ABSTRACT FROM AUTHOR]

A packed‐bed reactor with oxone has been employed for selective oxidations of sulfur compounds. Various sulfides containing different functional groups are efficiently oxidized to the corresponding sulfoxides without formation of sulfones or other side products. [ABSTRACT FROM AUTHOR]

Infants with cholestatic liver disease are at risk of various nutritional deficiencies. They require regular review with appropriate interventions to prevent complications and ensure optimum possible status if liver transplantation becomes necessary. We propose evidence based and internationally agreed guidelines for their care with recommendations for therapeutic strategies and for service organization. [ABSTRACT FROM AUTHOR]

This paper uses Alistair Mant's colourful systems metaphor of the frog and the bicycle to explore the current changes in the NHS. Considering the implications of these system changes from this organisational health perspective, a possible leadership strategy is considered to navigate through the challenging transitional period. [ABSTRACT FROM AUTHOR]

SummaryBackgroundBiliary atresia is an obliterative cholangiopathy of infancy that is fatal if untreated. Surgical treatment, the Kasai portoenterostomy, may restore bile flow and clear jaundice, and, if successful, achieve a 10-year survival of 90% with a native liver. The outcome of a 2-year cohort of children with biliary atresia in the UK and Ireland was assessed to find the current frequency, the factors influencing outcome, and the medium-term need for liver transplantation.MethodsCases diagnosed between March, 1993, and February, 1995, were notified by paediatricians to the British Paediatric Surveillance Unit via a monthly reporting system. Confirmed cases were followed up by postal questionnaires to notifying paediatricians.Findings93 cases were confirmed, a frequency of 1/16700 livebirths. Primary surgery was done in 91 children in 15 surgical centres with an early success rate for clearing jaundice of 55% overall. Centres were grouped according to caseload; group A had more than 5 cases/year and group B fewer than 5 cases/year. Early success was higher in group-A centres, odds ratio 2.02 (95% CI 0.86-4.73), but this did not reach statistical significance. Of 41 children in whom surgery was unsuccessful in clearing jaundice 9 (22%) died and 30 (73%) underwent liver transplantation. Survival without liver transplantation and overall survival were both significantly greater in group-A centres, rate ratios 0.48 (95% CI 0.27-0.86) and 0.32 (0.11-0.94). Actuarial 5-year survival without transplantation was 61.3% in group-A centres and 13.7% in group-B centres. Actuarial 5-year overall survival was 91.2% in group A and 75% in group B. Once centre size was taken into account, no other factor, including age at surgery, was predictive of survival without transplantation or overall survival.InterpretationThe outcome of children with biliary atresia is related to the caseload of the surgical centre where they have their primary surgery. Children with biliary atres... [ABSTRACT FROM AUTHOR]

Background Pediatric gastrointestinal motility disorders present significant challenges for diagnosis and management, emphasizing the need for appropriate training in Pediatric Neurogastroenterology and Motility (PNGM). The aim of this survey, part of a comprehensive survey on training in pediatric gastroenterology, hepatology and nutrition, was to evaluate training related to PNGM across European training centers. Method Standardized questionnaires were collected from training centers through the National Societies Network of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), from June 2016 to December 2019 Results In total, 100 training centers from 19 countries participated in the survey. Dedicated PNGM clinics were available in 22 centers; pH-monitoring in 60; pH/impedance in 66; standard manometry in 37; and high-resolution manometry in 33. If all motility studies were performed partially or fully by the trainees, the median (range) annual numbers/per trainee were as follows: pH-monitoring 30 (1-500); pH/impedance 17 (1-131); standard manometries 10 (1-150); and high-resolution manometries 8 (1-75). The motility assessment was performed by pediatric gastroenterologists (43 centers); adult gastroenterologists (10 centers); pediatric surgeons (5 centers); and both pediatric gastroenterologists and pediatric surgeons (9 centers). Annual numbers =10 for pH-monitoring, pH/impedance, standard manometries and high-resolution manometries were reported by 7 (12%), 15 (23%), 11 (30%) and 14 (42%) centers, respectively Conclusions Significant differences exist in PNGM-related infrastructure, staff and procedural volumes at training centers across Europe. ESPGHAN and the National Societies should take initiatives to ensure the acquisition of competence in PNGM-related knowledge and skills, and develop strategies for assessment and accreditation. [ABSTRACT FROM AUTHOR]

Background This survey evaluated the effects of the recognition of pediatric gastroenterology, hepatology and nutrition (PGHN) on European PGHN training centers. Method Standardized questionnaires were collected from training centers via the presidents/representatives of the National Societies Network of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition, from June 2016 to December 2019 Results A total of 100 training centers from 19 countries participated in the survey: 55 from 12 countries where PGHN is formally recognized (Group 1) and 45 from 7 countries where it is not (Group 2). Training centers in Group 2 were less likely to have an integrated endoscopy suite, a written training curriculum and a training lead (P=0.059, P<0.001 and P=0.012, respectively). Trainees in Group 2 were less likely to be exposed to an adequate number of diagnostic endoscopies, while no differences were found in relation to liver biopsies. Half of the training centers in both Groups do not have dedicated beds for PGHN patients, while in 64% and 58%, respectively, trainees do not participate in on-call programs for PGHN emergencies. Research training is mandatory in 26% of the centers. The duration of training, as well as the assessment and accreditation policies, vary between countries Conclusions This study has revealed significant discrepancies and gaps in infrastructure and training programs, training leadership, and assessment of training and certification across European training centers in PGHN. Strategies to support the recognition of PGHN and to standardize and improve training conditions should be developed and implemented. [ABSTRACT FROM AUTHOR]

Background: Severe HPS increases morbidity and mortality after LT in children. We reviewed the combined experience of LT for HPS in children from two LT centers in Europe and Asia. Methods: All children with "proven" HPS as per ERS Task Force criteria (detailed in manuscript) who underwent LT were categorized into M (PaO2 ≥80 mmHg), Mo (PaO2 = 60–79 mmHg), S (50–59 mmHg), and VS (PaO2 <50 mmHg) HPS, based on room air PaO2. Results: Twenty‐four children with HPS underwent 25 LT (one re‐transplantation) at a median age of 8 years (IQR, 5–12), after a median duration of 8 (4–12) months following HPS diagnosis. Mechanical ventilation was required for a median of 3 (1.5–27) days after LT. Ten children had "S" post‐operative hypoxemia, requiring iNO for a median of 5 (6–27) days. "VS" category patients had significantly prolonged invasive ventilation (median 35 vs. 3 and 1.5 days; p =.008), ICU stay (median 39 vs. 8 and 8 days; p =.007), and hospital stay (64 vs. 26.5 and 23 days; p <.001) when compared to "S" and "M/Mo" groups, respectively. The need for pre‐transplant home oxygen therapy was the only factor predicting need for re‐intubation. Patient and graft survival at 32 (17–98) months were 100% and 95.8%. All children ultimately had complete resolution of HPS. Conclusions: VS HPS is associated with longer duration of mechanical ventilation and hospital stay, which emphasizes the need for early LT in these children. [ABSTRACT FROM AUTHOR]

Disrupted binding of the transcription factor Sp1 to the mutated promoter region of the mannosyl transferase–encoding gene PIGM: causes inherited glycosylphosphatidylinositol (GPI) deficiency characterized by splanchnic vein thrombosis and epilepsy. We show that this results in histone hypoacetylation at the promoter of PIGM:. The histone deacetylase inhibitor butyrate increases PIGM: transcription and surface GPI expression in vitro as well as in vivo through enhanced histone acetylation in an Sp1-dependent manner. More important, the drug caused complete cessation of intractable seizures in a child with inherited GPI deficiency. [ABSTRACT FROM AUTHOR]

Background: Alagille syndrome is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical, sodium-dependent, bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in Alagille syndrome.Methods: ICONIC was a placebo-controlled, randomised withdrawal period (RWD), phase 2b study with open-label extension in children (aged 1-18 years) with Alagille syndrome (NCT02160782). Eligible participants had more than three times the normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 μg/kg once per day, participants were randomly assigned (1:1) to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat until week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 μg/kg twice per day. The primary endpoint was the mean sBA change during the RWD in participants with at least 50% sBA reduction by week 18. Cholestastic pruritus was assessed using observer-rated, patient-rated, and clinician-rated 0-4 scales. The safety population was defined as all participants who had received at least one dose of maralixibat. This trial was registered with ClinicalTrials.gov, NCT02160782, and is closed to recruitment.Findings: Between Oct 28, 2014, and Aug 14, 2015, 31 participants (mean age 5·4 years [SD 4·25]) were enrolled and 28 analysed at week 48. Of the 29 participants who entered the randomised drug withdrawal period, ten (34%) were female and 19 (66%) were male. In the RWD, participants switched to placebo had significant increases in sBA (94 μmol/L, 95% CI 23 to 164) and pruritus (1·7 points, 95% CI 1·2 to 2·2), whereas participants who continued maralixibat maintained treatment effect. This study met the primary endpoint (least square mean difference -117 μmol/L, 95% CI -232 to -2). From baseline to week 48, sBA (-96 μmol/L, -162 to -31) and pruritus (-1·6 pts, -2·1 to -1·1) improved. In participants who continued to week 204 (n=15) all improvements were maintained. Maralixibat was generally safe and well tolerated throughout. The most frequent adverse events were gastrointestinal related. Most adverse events were self-limiting in nature and mild-to-moderate in severity.Interpretation: In children with Alagille syndrome, maralixibat is, to our knowledge, the first agent to show durable and clinically meaningful improvements in cholestasis. Maralixibat might represent a new treatment paradigm for chronic cholestasis in Alagille syndrome.Funding: Mirum Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Eighteen children aged between 7 and 16 years who had undergone a liver transplantation were interviewed using the Child Post-Traumatic Stress Reaction Index (CPTS-RI) to discover if they had post-traumatic stress symptoms. A case control design was used to define which factors were important for the development of post-traumatic stress. Results of a one-way analysis of variance (ANOVA), with post-traumatic stress symptom intensity as measured on the CPTS-RI as the dependant variable, revealed a significant difference between the liver transplantation group compared with children who had a chronic life-threatening illness or had undergone a routine surgical operation. A post hoc (Tukey's HSD test) statistical analysis was performed and significance at the .05 level was found between the liver transplantation group and both the chronic illness group and the routine surgical operation group. Our results indicate that the acute life-threat involved in the liver transplantation contributed to the development of post-traumatic stress. It was thought that dissociation may be important in preventing the resolution of the trauma. Additional investigations are needed with larger numbers in a longitudinal study beginning before the transplant to determine the course of the PTSD symptoms and the appropriate timing of interventions to reduce the harmful effects of these symptoms. [ABSTRACT FROM AUTHOR]

This final report of the Lancet Commission into liver disease in the UK stresses the continuing increase in burden of liver disease from excess alcohol consumption and obesity, with high levels of hospital admissions which are worsening in deprived areas. Only with comprehensive food and alcohol strategies based on fiscal and regulatory measures (including a minimum unit price for alcohol, the alcohol duty escalator, and an extension of the sugar levy on food content) can the disease burden be curtailed. Following introduction of minimum unit pricing in Scotland, alcohol sales fell by 3%, with the greatest effect on heavy drinkers of low-cost alcohol products. We also discuss the major contribution of obesity and alcohol to the ten most common cancers as well as measures outlined by the departing Chief Medical Officer to combat rising levels of obesity-the highest of any country in the west. Mortality of severely ill patients with liver disease in district general hospitals is unacceptably high, indicating the need to develop a masterplan for improving hospital care. We propose a plan based around specialist hospital centres that are linked to district general hospitals by operational delivery networks. This plan has received strong backing from the British Association for Study of the Liver and British Society of Gastroenterology, but is held up at NHS England. The value of so-called day-case care bundles to reduce high hospital readmission rates with greater care in the community is described, along with examples of locally derived schemes for the early detection of disease and, in particular, schemes to allow general practitioners to refer patients directly for elastography assessment. New funding arrangements for general practitioners will be required if these proposals are to be taken up more widely around the country. Understanding of the harm to health from lifestyle causes among the general population is low, with a poor knowledge of alcohol consumption and dietary guidelines. The Lancet Commission has serious doubts about whether the initiatives described in the Prevention Green Paper, with the onus placed on the individual based on the use of information technology and the latest in behavioural science, will be effective. We call for greater coordination between official and non-official bodies that have highlighted the unacceptable disease burden from liver disease in England in order to present a single, strong voice to the higher echelons of government. [ABSTRACT FROM AUTHOR]

We present the synthesis of metal nanowires in a multiplexed device configuration using single‐walled carbon nanotubes (SWNTs) as nanoscale vector templates. The SWNT templates control the dimensionality of the wires, allowing precise control of their size, shape, and orientation; moreover, a solution‐processable approach enables their linear deposition between specific electrode pairs in electronic devices. Electrical characterization demonstrated the successful fabrication of metal nanowire electronic devices, while multiscale characterization of the different fabrication steps revealed details of the structure and charge transfer between the material encapsulated and the carbon nanotube. Overall the strategy presented allows facile, low‐cost, and direct synthesis of multiplexed metal nanowire devices for nanoelectronic applications. [ABSTRACT FROM AUTHOR]

We present the synthesis of metal nanowires in a multiplexed device configuration using single‐walled carbon nanotubes (SWNTs) as nanoscale vector templates. The SWNT templates control the dimensionality of the wires, allowing precise control of their size, shape, and orientation; moreover, a solution‐processable approach enables their linear deposition between specific electrode pairs in electronic devices. Electrical characterization demonstrated the successful fabrication of metal nanowire electronic devices, while multiscale characterization of the different fabrication steps revealed details of the structure and charge transfer between the material encapsulated and the carbon nanotube. Overall the strategy presented allows facile, low‐cost, and direct synthesis of multiplexed metal nanowire devices for nanoelectronic applications. [ABSTRACT FROM AUTHOR]

This report contains new and follow-up metric data relating to the eight main recommendations of the Lancet Standing Commission on Liver Disease in the UK, which aim to reduce the unacceptable harmful consequences of excess alcohol consumption, obesity, and viral hepatitis. For alcohol, we provide data on alcohol dependence, damage to families, and the documented increase in alcohol consumption since removal of the above-inflation alcohol duty escalator. Alcoholic liver disease will shortly overtake ischaemic heart disease with regard to years of working life lost. The rising prevalence of overweight and obesity, affecting more than 60% of adults in the UK, is leading to an increasing liver disease burden. Favourable responses by industry to the UK Government's soft drinks industry levy have been seen, but the government cannot continue to ignore the number of adults being affected by diabetes, hypertension, and liver disease. New direct-acting antiviral drugs for the treatment of chronic hepatitis C virus infection have reduced mortality and the number of patients requiring liver transplantation, but more screening campaigns are needed for identification of infected people in high-risk migrant communities, prisons, and addiction centres. Provision of care continues to be worst in regions with the greatest socioeconomic deprivation, and deficiencies exist in training programmes in hepatology for specialist registrars. Firm guidance is needed for primary care on the use of liver blood tests in detection of early disease and the need for specialist referral. This report also brings together all the evidence on costs to the National Health Service and wider society, in addition to the loss of tax revenue, with alcohol misuse in England and Wales costing £21 billion a year (possibly up to £52 billion) and obesity costing £27 billion a year (treasury estimates are as high as £46 billion). Voluntary restraints by the food and drinks industry have had little effect on disease burden, and concerted regulatory and fiscal action by the UK Government is essential if the scale of the medical problem, with an estimated 63 000 preventable deaths over the next 5 years, is to be addressed. [ABSTRACT FROM AUTHOR]

Primary hyperoxaluria type 1 (PH1) is an inherited metabolic disease that culminates in ESRF. Pre-emptive liver transplantation (pLTx) treats the metabolic defect and avoids the need for kidney transplantation (KTx). An institutional experience of pediatric PH1 LTx is reported and compared to the literature. Between 2004 and 2015, eight children underwent p LTx for PH1. Three underwent pLTx with a median GFR of 40 (30-46) mL/min/1.73 m2 and five underwent sequential combined liver-kidney transplantation (cLKTx); all were on RRT at the time of cLKTx. In one case of pLTx, KTx was required eight and a half yr later. pLTx was performed in older (median 8 vs. 2 yr) and larger children (median 27 vs. 7.75 kg) that had a milder PH1 phenotype. In pediatric PH1, pLTx, ideally, should be performed before renal and extrarenal systemic oxalosis complications have occurred, and pLTx can be used 'early' or 'late.' Early is when renal function is preserved with the aim to avoid renal replacement. However, in late ( GFR < 30 mL/min/1.73 m2), the aim is to stabilize renal function and delay the need for KTx. Ultimately, transplant strategy depends on PH1 phenotype, disease stage, child size, and organ availability. [ABSTRACT FROM AUTHOR]

Background & Aims Liver disease in Alagille syndrome is highly variable. Many of the patients presenting with severe cholestasis early in life improve spontaneously; 10-20%, however, have progressive disease. It is currently not possible to predict long-term hepatic outcomes in Alagille syndrome. This international, multicentre study was aimed at identifying early life predictors of liver disease outcome. Methods Retrospective clinical, laboratory and radiographic data from a cohort of 144 Alagille syndrome patients, whose long-term hepatic outcomes had been determined a priori based on previously published criteria, were collected. Results Sixty-seven patients had mild and 77 had severe hepatic outcome. Univariate analysis demonstrated that cholestasis and fibrosis on biopsy, as well as the presence of xanthomata were significantly different between the groups ( P < 0.05 for all). Mixed model analysis revealed that total serum bilirubin and serum cholesterol were also associated with outcome ( P = 0.001 and P = 0.002, respectively). Graphical representation of the data revealed a change in total bilirubin levels between 12 and 24 months of age in the mild group. Recursive partitioning identified a threshold for total bilirubin of 3.8 mg/dl (65 mmol/L) in that age-frame that differentiated between outcomes. A multivariable logistic regression model was developed using fibrosis, xanthomata and the total bilirubin cut-off of 3.8 mg/dl (65 mmol/L), which generated an area under the ROC curve of 0.792. Conclusions The long-term hepatic outcomes of patients with Alagille syndrome can be predicted based on serum total bilirubin between the ages of 12-24 months combined with fibrosis on liver biopsy and the presence of xanthomata on physical examination. [ABSTRACT FROM AUTHOR]

Data is presented on the colour and spectral reflectances of stool samples from healthy young infants (mean age 6 days). The range of spectral reflectances is well described by a pigment mixture model with three components-a pale component corresponding to partially digested milk fats, a yellow component corresponding to bilirubin breakdown products, and a dark component corresponding to meconium and bilirubin. Most stools were tan, beige or olive but white, grey and light grey were also observed. © 2014 Wiley Periodicals, Inc. Col Res Appl, 40, 585-591, 2015 [ABSTRACT FROM AUTHOR]

The study of biliary disease has been constrained by a lack of primary human cholangiocytes. Here we present an efficient, serum-free protocol for directed differentiation of human induced pluripotent stem cells into cholangiocyte-like cells (CLCs). CLCs show functional characteristics of cholangiocytes, including bile acids transfer, alkaline phosphatase activity, γ-glutamyl-transpeptidase activity and physiological responses to secretin, somatostatin and vascular endothelial growth factor. We use CLCs to model in vitro key features of Alagille syndrome, polycystic liver disease and cystic fibrosis (CF)-associated cholangiopathy. Furthermore, we use CLCs generated from healthy individuals and patients with polycystic liver disease to reproduce the effects of the drugs verapamil and octreotide, and we show that the experimental CF drug VX809 rescues the disease phenotype of CF cholangiopathy in vitro. Our differentiation protocol will facilitate the study of biological mechanisms controlling biliary development, as well as disease modeling and drug screening. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the clinical utility gene card for Alagille syndrome (ALGS). Two genes analyzed by the authors are highlighted which include the JoggedI gene (JAGI) and the Notch2 gene (NOTCH2). The incidence as well as the prevalence of the disease at birth are investigated. The diagnostic features of ALGS are emphasized which include cholestatic liver disease, cardiac disease and skeletal abnormalities.

CD46 is a complement regulator with important roles related to the immune response. CD46 functions as a pathogen receptor and is a potent costimulator for the induction of interferon-? (IFN-?)-secreting effector T helper type 1 (TH1) cells and their subsequent switch into interleukin 10 (IL-10)-producing regulatory T cells. Here we identified the Notch family member Jagged1 as a physiological ligand for CD46. Furthermore, we found that CD46 regulated the expression of Notch receptors and ligands during T cell activation and that disturbance of the CD46-Notch crosstalk impeded induction of IFN-? and switching to IL-10. Notably, CD4+ T cells from CD46-deficient patients and patients with hypomorphic mutations in the gene encoding Jagged1 (Alagille syndrome) failed to mount appropriate TH1 responses in vitro and in vivo, which suggested that CD46-Jagged1 crosstalk is responsible for the recurrent infections in subpopulations of these patients. [ABSTRACT FROM AUTHOR]

Attachment to the plasma membrane by linkage to a glycosylphosphatidylinositol (GPI) anchor is a mode of protein expression highly conserved from protozoa to mammals. As a clinical entity, deficiency of GPI has been recognized as paroxysmal nocturnal hemoglobinuria, an acquired clonal disorder associated with somatic mutations of the X-linked PIGA gene in hematopoietic cells. We have identified a novel disease characterized by a propensity to venous thrombosis and seizures in which deficiency of GPI is inherited in an autosomal recessive manner. In two unrelated kindreds, a point mutation (c → g) at position −270 from the start codon of PIGM, a mannosyltransferase-encoding gene, disrupts binding of the transcription factor Sp1 to its cognate promoter motif. This mutation substantially reduces transcription of PIGM and blocks mannosylation of GPI, leading to partial but severe deficiency of GPI. These findings indicate that biosynthesis of GPI is essential to maintain homeostasis of blood coagulation and neurological function. [ABSTRACT FROM AUTHOR]

OBJECTIVE Complications of childhood cirrhosis include abnormal growth and malnutrition, associated with abnormalities in circulating IGFs and IGFBPs. Controlled studies suggest that intensive enteral feeding enhances nutritional status. The aim was to ascertain whether nasogastric feeding improves nutritional status in clinical practice and to assess the effect of feeding on serum IGF-I and IGFBPs. PATIENTS Thirty-three children (median age 0.6 years) with biliary atresia and failure to thrive who were treated with nasogastric feeding. MEASUREMENTS Height, weight and triceps skin fold thickness were measured prior to feeding and regularly for 1 year or until feeding was stopped. Serum IGF-I and IGFBPs were measured by immunoassay at the same intervals. RESULTS The median duration of feeding was 3.7 months. Twenty-two stopped feeding after liver transplantation, while 10 stopped electively and 1 boy died. Before feeding, the children were losing weight and height centile. Triceps skin fold thickness, weight and height sd scores improved with feeding. Baseline serum IGF-I and IGFBP-3 were low, while IGFBP-1 and IGFBP-2 were raised. IGF-I and IGFBP-1 did not change with feeding. IGFBP-2 fell and reached a nadir by 3 months, while IGFBP-3 rose temporarily for 4–6 weeks. CONCLUSIONS Nasogastric feeding improves body composition in paediatric liver disease but circulating IGF-I and IGFBPs remain abnormal and do not play a major role in mediating these changes. This does not exclude a paracrine or autocrine effect of IGF-I. [ABSTRACT FROM AUTHOR]

The progressive familial intrahepatic cholestases (PFIC) are a group of inherited disorders with severe cholestatic liver disease from early infancy. A subgroup characterized by normal serum cholesterol and γ-glutamyltranspeptidase (γGT) levels is genetically heterogeneous with loci on chromosomes 2q (PFIC2) and 18q. The phenotype of the PFIC2-linked group is consistent with defective bile acid transport at the hepatocyte canalicular membrane. The PFIC2 gene has now been identified by mutations in a positional candidate, BSEP, which encodes a liver-specific ATP-binding cassette (ABC) transporter, sister of p-glycoprotein (SPGP). The product of the orthologous rat gene has been shown to be an effective bile acid transporter in vitro. These data provide evidence that SPGP is the human bile salt export pump (BSEP). [ABSTRACT FROM AUTHOR]

OBJECTIVELeptin, the product of the ob gene, is a postulated feedback regulator of adiposity with appetite suppressant and catabolic effects. Catabolic states are associated with decreased body fat mass as a result of both nutritional and metabolic perturbation. Low serum leptin has been described previously in a number of catabolic states. It has been unclear whether the observed changes in leptin are a cause or consequence of changes in adiposity. Paediatric end-stage liver disease (ESLD) is characterized by decreased body fat mass and poor linear growth. Successful treatment by orthotopic liver transplantation (OLT) is accompanied by increase in fat mass. We investigated the hypothesis that serum leptin would be low in paediatric ESLD and that increase in body fat mass post-OLT would result in increased serum leptin. DESIGNSerum leptin and insulin were measured by radioimmunoassay in children with ESLD before and after successful OLT and in age-matched controls. PATIENTSTwenty-four children with ESLD attending the outpatient department of King's College Hospital, London and 10 age-matched controls. MEASUREMENTSAnthropometric measurements were performed according to standard techniques and standard deviation (SDS) derived from population standards. Serum leptin and insulin were measured by radioimmunoassay. RESULTSSerum leptin pre-OLT, leptin (4.06 μg/l, [3.45, 5.68] median, with 25th and 75th interquartile ranges) was significantly lower than controls (6.62 μg/l, [4.33, 8.05], P = 0.02). Following OLT, serum leptin fell to levels which were significantly lower than pre-OLT values (3.32 μg/l, [2.30, 3.99], P = 0.01). There was no significant difference between boys and girls either pre-OLT (boys; 3.64 μg/l, [2.45, 5.57], girls; 4.14 μg/l, [3.18, 5.65]) or post-OLT (boys; 3.32 μg/l, [2.93, 3.62], girls; 3.69 μg/l, [2.23, 4.63]. Neither the age at OLT nor the age at the time of blood sampling was correlated with serum leptin... [ABSTRACT FROM AUTHOR]

Patients with Crigler-Najjar Type 1 (CN-1) disorder have an unconjugated hyperbilirubinaemia due to the complete absence in activity of uridinediphosphate glucuronosyltransferase, a bilirubin-conjugating enzyme. In pregnant women with CN-1, the foetus is at high risk of being adversely affected by the bilirubin, as unconjugated bilirubin can cross the placenta and is potentially neurotoxic. We report the long-term outcomes of two infants born to women with CN-1. These infants had exchange transfusions soon after birth and have normal neurodevelopmental outcomes at 18 months and four years of age, respectively. We propose that this intervention might have improved the neurological outcome of these infants. [ABSTRACT FROM AUTHOR]