Long-term liver transplant outcomes for progressive familial intrahepatic cholestasis type 1: The Pittsburgh experience.

BACKGROUND: Progressive familial intrahepatic cholestasis type 1 (PFIC1) arises from biallelic variants in the ATP8B1 gene that annul FIC1 activity, resulting in progressive liver disease. Liver transplant (LT) is indicated in refractory disease; however, post-LT complications including worsening diarrhea and steatohepatitis progressing to fibrosis with graft loss have been reported. We aim to describe long-term outcomes of PFIC1 LT recipients at our center, focusing on the histological changes of the allografts. METHODS: We assessed 7 PFIC1 patients post-LT at the Children's Hospital of Pittsburgh (CHP). All pre-transplant, explant, and sequential post-transplant pathology samples were reviewed. Continuous data are presented as the mean ± SD. We compared the pre- and post-transplant height and weight z-scores using Wilcoxon signed-rank test. RESULTS: Seven (29% male) patients with PFIC1 received a LT (n = 6) or had post-LT care (n = 1) at CHP. Six had confirmed or suspected identical genetic. At a mean follow-up of 10.9 years, both patient survival and graft survival were 100%. Diarrhea persisted (n = 3) or newly developed (n = 4) in all patients after LT contributing to ongoing growth failure, with mean z-scores -2.63 (weight) and -2.98 (height) at follow-up. Histologically, allograft steatosis was common but was not accompanied by significant inflammation, ballooning, or fibrosis. CONCLUSION: We show that extrahepatic disease persists and near-universal allograft steatosis occurs. However, at a mean follow-up period of over 10 years, no patients developed steatohepatitis or significant fibrosis, and both patient survival and graft survival are excellent.

Video sleds effectively survey epibenthic communities at dredged material disposal sites.

This research assessed the effectiveness of benthic video sleds for monitoring the impacts of dredged material disposal on epifauna at shallow and deep water disposal sites near the mouth of the Columbia River, USA. Video sleds collected visual transects at the two disposal sites and comparable reference areas during 2014 and 2015 within a Before-After, Control-Impact (BACI) experimental design. These flat, soft-bottom habitats are populated by demersal fish and benthic invertebrates, including the economically important Dungeness crab (Cancer magister). At the shallow site, results from multivariate Similarity Profile Analysis (SIMPROF) and univariate ANOVA tests on prominent species did not detect any significant differences between disposal and reference communities. At the deep site, the multivariate and univariate analyses detected differences in communities and abundances between years, rather than between disposal and reference locations. At the scale of this research, there was no detectable impact of dredged material disposal on the epifauna communities at these two Pacific Northwest disposal sites. While the species resolution of cryptic or small organisms was found to be limited, the video sled technique had sufficient power to detect potential differences in most epifaunal species densities with a BACI statistical design. We found the video sleds were an effective tool to assess potential impacts of dredged material disposal on epifauna.

Assessing differences in macrofaunal assemblages as a factor of sieve mesh size, distance between samples, and time of sampling.

With increasing cascading effects of climate change on the marine environment, as well as pollution and anthropogenic utilization of the seafloor, there is increasing interest in tracking changes to benthic communities. Macrofaunal surveys are traditionally conducted as part of pre-incident environmental assessment studies and post-incident monitoring studies when there is a potential impact to the seafloor. These surveys usually characterize the structure and/or spatiotemporal distribution of macrofaunal assemblages collected with sediment cores; however, many different sampling protocols have been used. An assessment of the comparability of past and current survey methods was in need to facilitate future surveys and comparisons. This was the aim of the present study, conducted off the Oregon coast in waters 25-35 m deep. Our results show that the use of a sieve with a 1.0-mm mesh size gives results for community structure comparable to results obtained from a 0.5-mm mesh size, which allows reliable comparisons of recent and past spatiotemporal surveys of macroinfauna. In addition to our primary objective of comparing methods, we also found interacting effects of seasons and depths of collection. Seasonal differences (summer and fall) were seen in infaunal assemblages in the wave-induced sediment motion zone but not deeper. Thus, studies where wave-induced sediment motion can structure the benthic communities, especially during the winter months, should consider this effect when making temporal comparisons. In addition, some macrofauna taxa-like polychaetes and amphipods show high interannual variabilities, so spatiotemporal studies should make sure to cover several years before drawing any conclusions.

Seasonal variability in energetic value of Crangon alaskensis and effects of marine heatwaves in the Northeast Pacific Ocean.

Research cruises were conducted to sample the invertebrate community along the shelf off the central coast of Oregon from 2010 to 2018. A large marine heatwave (MHW) hit the northeast Pacific in fall 2014 and persisted locally through 2015. Here, we assessed the caloric content changes of Crangon alaskensis (a common sandy shrimp) before, during, and after the 2014-2015 MHW. We found significant reductions in the caloric density of shelf populations of C. alaskensis during summer 2015. Oceanographic indices like the Biologically Effective Upwelling Transport Index (BEUTI) and the Pacific Decadal Oscillation (PDO) had greater predictive power for caloric density and biomass than in situ conditions, although bottom temperature and dissolved oxygen were also significantly correlated with caloric density. Caloric density of C. alaskensis was highest in 2018, indicating favorable conditions after the intense MHW of 2014-2015 allowed the caloric density to rebound.

Leptin enhances the potency of circulating angiogenic cells via src kinase and integrin (alpha)vbeta5: implications for angiogenesis in human obesity.

OBJECTIVE: To investigate the capacity of the adipokine leptin to promote angiogenesis by modulating the function of circulating angiogenic cells (CACs). METHODS AND RESULTS: In vitro, leptin specifically promoted CAC adhesion to tubular endothelial structures and migration along outgrowing sprouts of endothelial cells. In vivo, stimulation of CACs with leptin increased their capacity to promote new vessel formation in the chorioallantoic membrane of chicken embryos and to improve neovascularization of ischemic murine hind limbs. These effects required the phosphorylation of alphavbeta5 integrins, which depended on the interaction of leptin with its receptor ObR, and on Janus kinase (JAK) 2- and phospholipase C (PLC) gamma-mediated activation of Src kinase. Protein tyrosine phosphatase 1B, a negative regulator of leptin signaling, was overexpressed in CACs from obese, hyperleptinemic individuals, and this was associated with insensitivity of CACs to the angiogenic effects of leptin. Weight loss (by 30+/-15 kg) normalized protein tyrosine phosphatase 1B expression in CACs and restored their responsiveness to leptin. A similar dose-dependent response was found after incubation of CACs from obese subjects with a protein tyrosine phosphatase 1B inhibitor ex vivo. CONCLUSIONS: Our results point to the ObR-Src kinase-alphavbeta5 cross talk as a distinct novel component of the network of specific interactions between integrins and cytokine receptors in angiogenesis.

Pharmacological management of portal hypertension and its complications in children: lessons from adults and opportunities for the future.

INTRODUCTION: Portal hypertension (PHT) and its complications in children are thought to be distinct from adult PHT in several areas, including the underlying bio-physiology of a child in which PHT develops, but also because of the pediatric-specific etiologies that drive disease progression. And yet pharmacologic approaches to PHT in children are mainly based on adult data, modified for pediatric practice. This reality has been driven by a lack of data specific to children. AREAS COVERED: The authors discuss current therapeutic approaches to PHT in children, including management of acute gastrointestinal variceal bleed, pharmacotherapy in prophylaxis, and established and emerging therapies to combat systemic co-morbidities that result from PHT. The few areas where pediatric-specific data exist are highlighted and the many gaps in knowledge that remain unresolved are underscored. EXPERT OPINION: Despite decades of experience, optimal management of pediatric PHT remains undefined. In large part, this can be directly linked to a lack of basic understanding related to the unique pathophysiology and natural history that defines PHT in children. As a result, meaningful research into the utility and effectiveness of pharmacotherapy in children with PHT remains in its infancy. Large, multi-center, prospective studies will be needed to begin to establish an infrastructure on which a pediatric-specific research agenda can be built.

Expanding etiology of progressive familial intrahepatic cholestasis.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) refers to a disparate group of autosomal recessive disorders that are linked by the inability to appropriately form and excrete bile from hepatocytes, resulting in a hepatocellular form of cholestasis. While the diagnosis of such disorders had historically been based on pattern recognition of unremitting cholestasis without other identified molecular or anatomic cause, recent scientific advancements have uncovered multiple specific responsible proteins. The variety of identified defects has resulted in an ever-broadening phenotypic spectrum, ranging from traditional benign recurrent jaundice to progressive cholestasis and end-stage liver disease. AIM: To review current data on defects in bile acid homeostasis, explore the expanding knowledge base of genetic based diseases in this field, and report disease characteristics and management. METHODS: We conducted a systemic review according to PRISMA guidelines. We performed a Medline/PubMed search in February-March 2019 for relevant articles relating to the understanding, diagnosis, and management of bile acid homeostasis with a focus on the family of diseases collectively known as PFIC. English only articles were accessed in full. The manual search included references of retrieved articles. We extracted data on disease characteristics, associations with other diseases, and treatment. Data was summarized and presented in text, figure, and table format. RESULTS: Genetic-based liver disease resulting in the inability to properly form and secrete bile constitute an important cause of morbidity and mortality in children and increasingly in adults. A growing number of PFIC have been described based on an expanded understanding of biliary transport mechanism defects and the development of a common phenotype. CONCLUSION: We present a summary of current advances made in a number of areas relevant to both the classically described FIC1 (ATP8B1), BSEP (ABCB11), and MDR3 (ABCB4) transporter deficiencies, as well as more recently described gene mutations -- TJP2 (TJP2), FXR (NR1H4), MYO5B (MYO5B), and others which expand the etiology and understanding of PFIC-related cholestatic diseases and bile transport.

Assessment of spatial patterns in benthic macrofauna of the U.S. west coast continental shelf.

AIM: We assessed whether currently described marine biogeographic boundaries apply to shelf macrofauna and which environmental drivers were most associated with species differences among regions. LOCATION: Pacific coast of North America from the Strait of Juan de Fuca in Washington to the California-Mexico border. METHODS: Van Veen grab samples were collected from soft sediment 28-138 m deep and sieved using 1 mm mesh. Spatial patterns of species richness, diversity, and abundance were examined in relation to latitude and environmental parameters (temperature, salinity, dissolved oxygen, sediment % fines, and total organic carbon). Analyses of latitudinal distribution patterns of individual species were combined with multivariate analyses of community composition to determine biogeographic and habitat boundaries for mid-depth continental shelf macrofauna. RESULTS: Species richness, diversity, and abundance significantly decreased with increasing latitude, primarily between 32 and 40° N. There were positive associations of richness, diversity (H'), and abundance with upwelling index, sediment % fines, and TOC (<2%). Temperature and DO also were significant for richness and H' but not abundance. Assessment of individual species ranges found major faunal transitions at latitudes 33-34°, 37°, 44°, and 46-47°. Major assemblage differences were found at 34.5°, and 42°. Within each latitudinal region, significantly different macrofauna communities were found in sediment with <5% fines. MAIN CONCLUSIONS: The biogeographic boundaries proposed under the Marine Ecoregions of the World schema are more closely aligned with shelf fauna distributions than those developed using west coast rocky intertidal communities. However, the proposed province boundary at Cape Mendocino is not apparent in the shelf macrofauna, and a transition appears to occur closer to the Oregon-California border. Further, the shelf macrofauna indicate the Channel Islands should be a separate subregion from mainland southern California Bight. Multivariate community analyses minimizing the impact of rare species appeared more useful in determining macrofaunal community biogeographic boundaries than analysis of individual species range endpoints, which are strongly influenced by uncommon species.