Biliary atresia (BA) is a fibroinflammatory disease of the intrahepatic and extrahepatic biliary tree. Surgical hepatic portoenterostomy (HPE) may restore bile drainage, but progression of the ...intrahepatic disease results in complications of portal hypertension and advanced cirrhosis in most children. Recognizing that further progress in the field is unlikely without a better understanding of the underlying cause(s) and pathogenesis of the disease, the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored a research workshop focused on innovative and promising approaches and on identifying future areas of research. Investigators discussed recent advances using gestational ultrasound and results of newborn BA screening with serum direct (conjugated) bilirubin that support a prenatal onset of biliary injury. Experimental and human studies implicate the toxic properties of environmental toxins (e.g., biliatresone) and of viruses (e.g., cytomegalovirus) to the biliary system. Among host factors, sequence variants in genes related to biliary development and ciliopathies, a notable lack of a cholangiocyte glycocalyx and of submucosal collagen bundles in the neonatal extrahepatic bile ducts, and an innate proinflammatory bias of the neonatal immune system contribute to an increased susceptibility to damage and obstruction following epithelial injury. These advances form the foundation for a future research agenda focused on identifying the environmental and host factor(s) that cause BA, the potential use of population screening, studies of the mechanisms of prominent fibrosis in young infants, determinations of clinical surrogates of disease progression, and the design of clinical trials that target subgroups of patients with initial drainage following HPE. (Hepatology 2018; 00:000‐000).
Biliary atresia (BA) is a progressive, fibro‐obliterative disorder of the intrahepatic and extrahepatic bile ducts in infancy. The majority of affected children will eventually develop end‐stage ...liver disease and require liver transplantation (LT). Indications for LT in BA include failed Kasai portoenterostomy, significant and recalcitrant malnutrition, recurrent cholangitis, and the progressive manifestations of portal hypertension. Extrahepatic complications of this disease, such as hepatopulmonary syndrome and portopulmonary hypertension, are also indications for LT. Optimal pretransplant management of these potentially life‐threatening complications and maximizing nutrition and growth require the expertise of a multidisciplinary team with experience caring for BA. The timing of transplant for BA requires careful consideration of the potential risk of transplant versus the survival benefit at any given stage of disease. Children with BA often experience long wait times for transplant unless exception points are granted to reflect severity of disease. Family preparedness for this arduous process is therefore critical. Liver Transplantation 23:96–109 2017 AASLD.
Prolonged parenteral nutrition (PN) can lead to PN associated cholestasis (PNAC). Intestinally derived lipopolysaccharides and infused PN phytosterols lead to activation of NFκB, a key factor in ...PNAC. Our objective was to determine if inhibition of HNF4α could interfere with NFκB to alleviate murine PNAC. We showed that HNF4α antagonist BI6015 (20 mg/kg/day) in DSS-PN (oral DSS x4d followed by Total PN x14d) mice prevented the increased AST, ALT, bilirubin and bile acids and reversed mRNA suppression of hepatocyte Abcg5/8, Abcb11, FXR, SHP and MRP2 that were present during PNAC. Further, NFκB phosphorylation in hepatocytes and its binding to LRH-1 and BSEP promoters in liver, which are upregulated in DSS-PN mice, were inhibited by BI6015 treatment. BI6015 also prevented the upregulation in liver macrophages of Adgre1 (F4/80) and Itgam (CD11B) that occurs in DSS-PN mice, with concomitant induction of anti-inflammatory genes (Klf2, Klf4, Clec7a1, Retnla). In conclusion, HNF4α antagonism attenuates PNAC by suppressing NFκB activation and signaling while inducing hepatocyte FXR and LRH-1 and their downstream bile and sterol transporters. These data identify HNF4α antagonism as a potential therapeutic target for prevention and treatment of PNAC.
Context. Direct sampling of neutral interstellar (NIS) atoms by the Interstellar Boundary Explorer (IBEX) can potentially provide a complementary method for studying element abundances in the Local ...Interstellar Cloud (LIC) and processes in the heliosphere interface. Aims. We set the stage for abundance-aimed in-depth analysis of measurements of NIS He, Ne, and O by IBEX and determine systematic differences between abundances derived from various calculation methods and their uncertainties. Methods. Using a model of ionization rates of the NIS species in the heliosphere, based on independent measurements of the solar wind and solar EUV radiation, we developed a time-dependent method of calculating the survival probabilities of NIS atoms from the termination shock (TS) of the solar wind to IBEX. With them, we calculated densities of these species along the Earth’s orbit and simulated the fluxes of NIS species as observed by IBEX. We studied pairwise ratios of survival probabilities, densities, and fluxes of NIS species at IBEX to calculate correction factors for inferring the abundances at TS. Results. The analytic method of calculating the survival probabilities gives acceptable results only for He and Ne during low solar activity. For the remaining portions of the solar cycle, and at all times for O, a fully time-dependent model should be used. Electron-impact ionization is surprisingly important for NIS O. Interpreting the IBEX observations using the time-dependent model yields the LIC Ne/O abundance of 0.16 ± 40%. The uncertainty is mostly due to uncertainties in the ionization rates and in the NIS gas flow vector. Conclusions. The Ne/He, O/He, and Ne/O ratios for survival probabilities, local densities, and fluxes scaled to TS systematically differ and thus an analysis based only on survival probabilities or densities is not recommended, except the Ne/O abundance for observations at low solar activity.
NASA's Interstellar Boundary Explorer (IBEX) mission has operated in space for a full solar activity cycle (Solar Cycle 24), and IBEX observations have exposed the global three-dimensional structure ...of the heliosphere and its interaction with the very local interstellar medium for the first time. Here, we extend the prior IBEX observations of energetic neutral atoms (ENAs) by adding a comprehensive analysis of four additional years (2016 through 2019). We document several improvements and rerelease the entire 11 yr, IBEX-Hi data set. The new observations track the continuing expansion of the outer heliosphere's response to the large solar wind pressure increase in late 2014. We find that the intensification of ENAs from the heliosheath continued to expand progressively over time to directions farther from the initial, closest direction to the heliospheric boundaries, ∼20° south of the upwind direction. This expansion extended beyond the south pole in 2018 and the north pole in 2019, demonstrating that the termination shock and heliopause are closer in the south. The heliotail has not yet responded, indicating that the boundaries are significantly farther away in the downwind direction. Finally, the slow solar wind (∼1 keV) ENAs just started to intensify from the closest regions of the IBEX Ribbon. This is about two and a half years after the initial response from heliosheath ENAs and about four and a half years after the increase in solar wind output, both clearly implicating a "secondary ENA" source in the draped interstellar magnetic field, just beyond the heliopause.
Summary Biliary Atresia and other cholestatic childhood diseases are rare conditions affecting the function and/or anatomy along the canalicular-bile duct continuum, characterised by onset of ...persistent cholestatic jaundice during the neonatal period. Biliary atresia (BA) is the most common among these, but still has an incidence of only 1 in 10–19,000 in Europe and North America. Other diseases such as the genetic conditions, Alagille syndrome (ALGS) and Progressive Familial Intrahepatic Cholestasis (PFIC), are less common. Choledochal malformations are amenable to surgical correction and require a high index of suspicion. The low incidence of such diseases hinder patient-based studies that include large cohorts, while the limited numbers of animal models of disease that recapitulate the spectrum of disease phenotypes hinders both basic research and the development of new treatments. Despite their individual rarity, collectively BA and other cholestatic childhood diseases are the commonest indications for liver transplantation during childhood. Here, we review the recent advances in basic research and clinical progress in these diseases, as well as the research needs. For the various diseases, we formulate current key questions and controversies and identify top priorities to guide future research.
Elucidating genetic causes of cholestasis has proved to be important in understanding the physiology and pathophysiology of the liver. Here we show that protein-truncating mutations in the tight ...junction protein 2 gene (TJP2) cause failure of protein localization and disruption of tight-junction structure, leading to severe cholestatic liver disease. These findings contrast with those in the embryonic-lethal knockout mouse, highlighting differences in redundancy in junctional complexes between organs and species.
ABSTRACT We analyzed observations of interstellar neutral helium (ISN He) obtained from the Interstellar Boundary Explorer (IBEX) satellite during its first six years of operation. We used a refined ...version of the ISN He simulation model, presented in the companion paper by Sokó et al. (2015b), along with a sophisticated data correlation and uncertainty system and parameter fitting method, described in the companion paper by Swaczyna et al. We analyzed the entire data set together and the yearly subsets, and found the temperature and velocity vector of ISN He in front of the heliosphere. As seen in the previous studies, the allowable parameters are highly correlated and form a four-dimensional tube in the parameter space. The inflow longitudes obtained from the yearly data subsets show a spread of ∼6°, with the other parameters varying accordingly along the parameter tube, and the minimum χ2 value is larger than expected. We found, however, that the Mach number of the ISN He flow shows very little scatter and is thus very tightly constrained. It is in excellent agreement with the original analysis of ISN He observations from IBEX and recent reanalyses of observations from Ulysses. We identify a possible inaccuracy in the Warm Breeze parameters as the likely cause of the scatter in the ISN He parameters obtained from the yearly subsets, and we suppose that another component may exist in the signal or a process that is not accounted for in the current physical model of ISN He in front of the heliosphere. From our analysis, the inflow velocity vector, temperature, and Mach number of the flow are equal to λISNHe = 255 8 0 5, βISNHe = 5 16 0 10, TISNHe = 7440 260 K, vISNHe = 25.8 0.4 km s−1, and MISNHe = 5.079 0.028, with uncertainties strongly correlated along the parameter tube.
ABSTRACT Following the high-precision determination of the velocity vector and temperature of the pristine interstellar neutral (ISN) He via a coordinated analysis summarized by McComas et al., we ...analyzed the Interstellar Boundary Explorer (IBEX) observations of neutral He left out from this analysis. These observations were collected during the ISN observation seasons 2010-2014 and cover the region in the Earth's orbit where the Warm Breeze (WB) persists. We used the same simulation model and a parameter fitting method very similar to that used for the analysis of ISN He. We approximated the parent population of the WB in front of the heliosphere with a homogeneous Maxwell-Boltzmann distribution function and found a temperature of ∼9500 K, an inflow speed of 11.3 km s−1, and an inflow longitude and latitude in the J2000 ecliptic coordinates 251 6, 12 0. The abundance of the WB relative to ISN He is 5.7% and the Mach number is 1.97. The newly determined inflow direction of the WB, the inflow directions of ISN H and ISN He, and the direction to the center of the IBEX Ribbon are almost perfectly co-planar, and this plane coincides within relatively narrow statistical uncertainties with the plane fitted only to the inflow directions of ISN He, ISN H, and the WB. This co-planarity lends support to the hypothesis that the WB is the secondary population of ISN He and that the center of the Ribbon coincides with the direction of the local interstellar magnetic field (ISMF). The common plane for the direction of the inflow of ISN gas, ISN H, the WB, and the local ISMF is given by the normal direction: ecliptic longitude 349 7 0 6 and latitude 35 7 0.6 in the J2000 coordinates, with a correlation coefficient of 0.85.
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