Genetic Analysis of Victorin Sensitivity and Identification of a Causal Nucleotide-Binding Site Leucine-Rich Repeat Gene in Phaseolus vulgaris.

Cochliobolus victoria, the causal agent of Victoria blight, is pathogenic due to its production of a toxin called victorin. Victorin sensitivity in oats, barley, Brachypodium spp., and Arabidopsis has been associated with nucleotide-binding site leucine-rich repeat (NLR) genes, a class of genes known for conferring disease resistance. In this work, we investigated the sensitivity of Phaseolus vulgaris to victorin. We found that victorin sensivity in Phaseolus vulgaris is a developmentally regulated, quantitative trait. A single quantitative trait locus (QTL) accounted for 34% of the phenotypic variability in victorin sensitivity among Stampede × Red Hawk (S×R) recombinant inbred lines. We cloned two NLR-encoding genes within this QTL and showed one, Phvul05G031200 (PvLOV), confers victorin-dependent cell death when overexpressed in Nicotiana benthamiana. Protein sequences of PvLOV from victorin-sensitive and the victorin-resistant bean parents differ by two amino acids in the leucine-rich repeat region, but both proteins confer victorin-dependent cell death when overexpressed in N. benthamiana.

Expression of drought tolerance genes in tropical upland rice cultivars (Oryza sativa).

Gene expression related to drought response in the leaf tissues of two Brazilian upland cultivars, the drought-tolerant Douradão and the drought-sensitive Primavera, was analyzed. RNA-seq identified 27,618 transcripts in the Douradão cultivar, with 24,090 (87.2%) homologous to the rice database, and 27,221 transcripts in the Primavera cultivar, with 23,663 (86.9%) homologous to the rice database. Gene-expression analysis between control and water-deficient treatments revealed 493 and 1154 differentially expressed genes in Douradão and Primavera cultivars, respectively. Genes exclusively expressed under drought were identified for Douradão, including two genes of particular interest coding for the protein peroxidase precursor, which is involved in three distinct metabolic pathways. Comparisons between the two drought-exposed cultivars revealed 2314 genes were differentially expressed (978 upregulated, 1336 downregulated in Douradão). Six genes distributed across 4 different transcription factor families (bHLH, MYB, NAC, and WRKY) were identified, all of which were upregulated in Douradão compared to Primavera during drought. Most of the genes identified in Douradão activate metabolic pathways responsible for production of secondary metabolites and genes coding for enzymatically active signaling receptors. Quantitative PCR validation showed that most gene expression was in agreement with computational prediction of these transcripts. The transcripts identified here will define molecular markers for identification of Cis-acting elements to search for allelic variants of these genes through analysis of polymorphic SNPs in GenBank accessions of upland rice, aiming to develop cultivars with the best combination of these alleles, resulting in materials with high yield potential in the event of drought during the reproductive phase.

Co-segregation analysis and mapping of the anthracnose Co-10 and angular leaf spot Phg-ON disease-resistance genes in the common bean cultivar Ouro Negro.

Anthracnose (ANT) and angular leaf spot (ALS) are devastating diseases of common bean (Phaseolus vulgaris L.). Ouro Negro is a highly productive common bean cultivar, which contains the Co-10 and Phg-ON genes for resistance to ANT and ALS, respectively. In this study, we performed a genetic co-segregation analysis of resistance to ANT and ALS using an F2 population from the Rudá × Ouro Negro cross and the F2:3 families from the AND 277 × Ouro Negro cross. Ouro Negro is resistant to races 7 and 73 of the ANT and race 63-39 of the ALS pathogens. Conversely, cultivars AND 277 and Rudá are susceptible to races 7 and 73 of ANT, respectively. Both cultivars are susceptible to race 63-39 of ALS. Co-segregation analysis revealed that Co-10 and Phg-ON were inherited together, conferring resistance to races 7 and 73 of ANT and race 63-39 of ALS. The Co-10 and Phg-ON genes were co-segregated and were tightly linked at a distance of 0.0 cM on chromosome Pv04. The molecular marker g2303 was linked to Co-10 and Phg-ON at a distance of 0.0 cM. Because of their physical linkage in a cis configuration, the Co-10 and Phg-ON resistance alleles are inherited together and can be monitored with great efficiency using g2303. The close linkage between the Co-10 and Phg-ON genes and prior evidence are consistent with the existence of a resistance gene cluster at one end of chromosome Pv04, which also contains the Co-3 locus and ANT resistance quantitative trait loci. These results will be very useful for breeding programs aimed at developing bean cultivars with ANT and ALS resistance using marker-assisted selection.

Cholestatic Jaundice Associated with Carnitine Palmitoyltransferase IA Deficiency.

Liver dysfunction usually accompanies metabolic decompensation in fatty acid oxidation disorders, including carnitine palmitoyltransferase (CPT) Ia deficiency. Typically, the liver is enlarged with raised plasma transaminase activities and steatosis on histological examination. In contrast, cholestatic jaundice is rare, having only been reported in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. We report a 3-year-old boy with CPT Ia deficiency who developed hepatomegaly and cholestatic jaundice following a viral illness. No cause for the jaundice could be found, apart from the fatty acid oxidation disorder. Liver histology showed diffuse, predominately macrovesicular steatosis, hepatocellular and canalicular cholestasis but no bile duct paucity or evidence of large duct obstruction. The liver dysfunction resolved in 4-7 weeks.

Demographic factors shaped diversity in the two gene pools of wild common bean Phaseolus vulgaris L.

Wild common bean (Phaseolus vulgaris L.) is distributed throughout the Americas from Mexico to northern Argentina. Within this range, the species is divided into two gene pools (Andean and Middle American) along a latitudinal gradient. The diversity of 24 wild common bean genotypes from throughout the geographic range of the species was described by using sequence data from 13 loci. An isolation-migration model was evaluated using a coalescent analysis to estimate multiple demographic parameters. Using a Bayesian approach, Andean and Middle American subpopulations with high percentage of parentages were observed. Over all loci, the Middle American gene pool was more diverse than the Andean gene pool (π(sil)=0.0089 vs 0.0068). The two subpopulations were strongly genetically differentiated over all loci (F(st)=0.29). It is estimated that the two current wild gene pools diverged from a common ancestor ∼111 000 years ago. Subsequently, each gene pool underwent a bottleneck immediately after divergence and lasted ∼40 000 years. The Middle American bottleneck population size was ∼46% of the ancestral population size, whereas the Andean was 26%. Continuous asymmetric gene flow was detected between the two gene pools with a larger number of migrants entering Middle American gene pool from the Andean gene pool. These results suggest that because of the complex population structure associated with the ancestral divergence, subsequent bottlenecks in each gene pool, gene pool-specific domestication and intense selection within each gene pool by breeders; association mapping would best be practised within each common bean gene pool.

Infection control and meticillin-resistant Staphylococcus aureus decolonization: the perspective of nursing home staff.

BACKGROUND: Infection control and meticillin-resistant Staphylococcus aureus (MRSA) in nursing homes have started to assume greater importance in practice and policy. AIM: To explore infection control and MRSA decolonization in nursing homes in Northern Ireland from the perspective of nursing home staff. METHODS: Semi-structured interviews with nursing home managers and focus group discussions with nursing home staff were conducted, transcribed verbatim and analysed via the framework method. FINDINGS: Six one-to-one interviews and six focus group discussions (N = 7, 6, 6, 5, 5 and 4 participants, respectively) were conducted. Three overarching themes with inter-related subthemes were identified as influencing infection control and MRSA decolonization in the nursing homes: organizational factors (e.g. time, financial resources, environment, management and culture), external factors [e.g. hospitals, regulation and general practitioners (GPs)], and residents and families. It was reported that when the workload was unmanageable, aspects of infection control were not adhered to and more financial resources were necessary. There was conflict in maintaining an environment that was both 'homely' and clinical, and it was difficult to achieve good infection control practices with confused residents, some families, GPs and members of staff who were resistant to change. Support for MRSA decolonization in nursing homes was tempered by the risk of recolonization, particularly from hospital admissions. CONCLUSIONS: Infection control and MRSA decolonization in the nursing home environment appear to be affected by many factors, some of which may be beyond the direct control of staff.

Consumptive hypothyroidism: a case report and review of the literature.

Hepatic haemangioendothelioma is a rare vascular tumour in infants and may be associated with a unique form of thyroid function abnormalities. Hepatic haemangioendotheliomata is capable of producing an excess of the thyroid hormone inactivating enzyme, type 3 iodothyronine deiodinase. The increased enzyme activity leads to rapid degradation of thyroid hormones, resulting in frank hypothyroidism. We report a case of a three-month-old neonate with multiple hepatic haemangioendotheliomata and associated hypothyroidism. The patient required increasing doses of thyroid hormone.

Linkage mapping of the Phg-1 and Co-1(4) genes for resistance to angular leaf spot and anthracnose in the common bean cultivar AND 277.

The Andean common bean AND 277 has the Co-1(4) and the Phg-1 alleles that confer resistance to 21 and eight races, respectively, of the anthracnose (ANT) and angular leaf spot (ALS) pathogens. Because of its broad resistance spectrum, Co-1(4) is one of the main genes used in ANT resistance breeding. Additionally, Phg-1 is used for resistance to ALS. In this study, we elucidate the inheritance of the resistance of AND 277 to both pathogens using F(2) populations from the AND 277 × Rudá and AND 277 × Ouro Negro crosses and F(2:3) families from the AND 277 × Ouro Negro cross. Rudá and Ouro Negro are susceptible to all of the above races of both pathogens. Co-segregation analysis revealed that a single dominant gene in AND 277 confers resistance to races 65, 73, and 2047 of the ANT and to race 63-23 of the ALS pathogens. Co-1(4) and Phg-1 are tightly linked (0.0 cM) on linkage group Pv01. Through synteny mapping between common bean and soybean we also identified two new molecular markers, CV542014(450) and TGA1.1(570), tagging the Co-1(4) and Phg-1 loci. These markers are linked at 0.7 and 1.3 cM, respectively, from the Co-1(4) /Phg-1 locus in coupling phase. The analysis of allele segregation in the BAT 93/Jalo EEP558 and California Dark Red Kidney/Yolano recombinant populations revealed that CV542014(450) and TGA1.1(570) segregated in the expected 1:1 ratio. Due to the physical linkage in cis configuration, Co-1(4) and Phg-1 are inherited together and can be monitored indirectly with the CV542014(450) and TGA1.1(570) markers. These results illustrate the rapid discovery of new markers through synteny mapping. These markers will reduce the time and costs associated with the pyramiding of these two disease resistance genes.

Metabolic effects of sustained activation of the GLP-1 receptor alone and in combination with background GIP receptor antagonism in high fat-fed mice.

AIM: Enzyme-resistant glucagon-like peptide-1 (GLP-1) receptor agonists and GIP receptor antagonists have been proposed to have therapeutic potential for the treatment of type 2 diabetes. Such benefits are based on actions mediated primarily through stimulation of insulin secretion or alleviation of insulin resistance respectively. This study examined the long-term actions of the stable GLP-1 receptor agonist (D-Ala(8))GLP-1 and the GIP receptor antagonist (Pro(3))GIP alone and in combination in high fat-fed mice. METHODS: Mice on high-fat diet for 155 days were injected once daily with (D-Ala(8))GLP-1 or (Pro(3))GIP (25 nmol/kg body weight) for 24 days. In the following 24-day period, half of the (Pro(3))GIP-treated mice were administered an additional dose of (D-Ala(8))GLP-1 (25 nmol/kg body weight), while the remaining mice continued their original treatment regimes. RESULTS: Daily intraperitoneal injections of (D-Ala(8))GLP-1 or (Pro(3))GIP restored glycaemic control to normal levels and significantly (p < 0.05) improved glucose tolerance compared with high-fat controls by day 24. Food intake and body weights were not affected. On day 48, all treatment groups displayed significantly improved glucose tolerance (p < 0.05) and insulin sensitivity (p < 0.001) compared with high-fat controls on day 48. HDL cholesterol levels were significantly increased in mice treated with (D-Ala(8))GLP-1 alone (p < 0.05) or in combination with (Pro(3))GIP (p < 0.01) compared with normal chow-fed controls. CONCLUSIONS: These results illustrate efficacy of (Pro(3))GIP and (D-Ala(8))GLP-1 for treatment of glucose intolerance and insulin resistance caused by high-fat feeding. Combination therapy appeared to have little benefit over either treatment alone.

Epidemiology of biliary atresia in England and Wales (1999-2006).

OBJECTIVE: To identify the epidemiological characteristics of infants with biliary atresia in England and Wales, since centralisation of its management in 1999. METHODS: The care of infants with biliary atresia (BA) in England and Wales is centralised to only three centres. All infants (treated from January 1999 to December 2006) were identified from a prospective national database; demographic details were ascertained from medical records and compared between two groups based on presumed aetiology (isolated biliary atresia (IBA) and developmental biliary atresia (DBA) (for example, syndromic infants, biliary atresia splenic malformation, cystic biliary atresia)). RESULTS: There were 302 (133 male (44%)) infants with BA that could be divided into IBA (n = 219, 73%) and DBA (n = 76, 25%). The overall incidence was 0.58/10 000 (1 in 17,049) live births with marked regional differences along a north-west/south-east axis varying from 0.38 (north-west England) to 0.78 (south-east England)/10,000 live births (OR 2.05 (95% CI 1.26-3.41); p = 0.002). The commonest month of birth was September with December being the least common, although there was no evidence for significant seasonal variation (p = 0.2). Infants with DBA were more likely to be female (p<0.001), of white background (p = 0.01), first-born (p = 0.04) and to be formula-fed (p = 0.07). Infants of south Asian origin came to surgery at an older age (59 (IQ 45-75) versus 52 (IQ 42-65) days; p = 0.03). CONCLUSIONS: There is a remarkable variation of incidence of biliary atresia within England and Wales, some of which may have been caused by factors related to a different aetiological and racial background.

The reduced left lateral segment in pediatric liver transplantation: an alternative to the monosegment graft.

Tailoring graft size to small paediatric recipients is a challenge. We have developed a reduced left lateral segment as an alternative to monosegment transplantation for small size recipients. Since November 2000, 89 children have been transplanted with 100 deceased donor liver grafts in our unit. Our median patient and graft survival is 89% and 88% respectively. Four of these cases were performed using a new technique of creating a small donor graft by reducing the left lateral segment. The median weight of the reduced liver graft was 264 g (range: 165-390 g). The median blood transfusion requirement was 101 mL/kg body weight (range 69-167 mL/kg). The median values of peak ALT were 1473 IU/L, INR 2.2 and bilirubin 293 micromol/L in the first two wk following surgery. One neonatal recipient died five days after transplantation from a massive intracranial haemorrhage despite satisfactory graft function. Another recipient with excellent graft function died 10 months later from primary pulmonary hypertension and secondary cardiac failure. Hepatic artery thrombosis occurred in one patient with successful revascularization but he was retransplanted three months later for chronic rejection. No biliary or venous outflow complications occurred in this group. This technique of reduced left lateral segment liver transplantation is an alternative to the monosegment graft and allows small recipients to be successfully transplanted with few technical complications related to graft preparation.

(Pro(3))GIP[mPEG]: novel, long-acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity-diabetes (diabesity) therapy.

BACKGROUND AND PURPOSE: Antagonism of the gastric inhibitory polypeptide (GIP) receptor with daily injection of proline-3 gastric inhibitory polypeptide ((Pro(3))GIP) can reverse or prevent many of the metabolic abnormalities associated with diet-induced obesity-diabetes (diabesity). This study has examined the ability of a novel and longer-acting form of (Pro(3))GIP, (Pro(3))GIP mini-polyethylene glycol ((Pro(3))GIP[mPEG]), to counter diet-induced diabesity in mice, using a daily and intermittent dosing regime. EXPERIMENTAL APPROACH: We studied the actions of (Pro(3))GIP[mPEG] at the GIP receptor in vitro and in vivo in both dietary and genetic diabesity. KEY RESULTS: (Pro(3))GIP[mPEG] was completely resistant to degradation by dipeptidyl peptidase IV. (Pro(3))GIP[mPEG] inhibited GIP-induced cAMP and insulin production in vitro. A greater and prolonged antagonism of GIP-induced glucose-lowering action was followed (Pro(3))GIP[mPEG] administration, compared with (Pro(3))GIP. In contrast with (Pro(3))GIP, mice injected once every 3 days for 48 days with (Pro(3))GIP[mPEG] displayed reduced body weight gain and hyperinsulinemia with improved glucose tolerance and insulin secretory responses, compared with high-fat-fed controls. Daily i.p. injection of (Pro(3))GIP, (Pro(3))GIP[mPEG] or (Pro(3))GIP b.i.d. for 21 days also decreased body weight, circulating plasma insulin levels and improved glucose tolerance, compared with high-fat controls. Plasma triglycerides were decreased by (Pro(3))GIP[mPEG] and (Pro(3))GIP b.i.d. treatment groups. The observed changes were accompanied by enhancement of insulin sensitivity in all treatment regimes. (Pro(3))GIP[mPEG] was also effective over 16 days treatment of genetically obese-diabetic ob/ob mice. CONCLUSIONS AND IMPLICATIONS: These data demonstrate the utility of GIP receptor antagonism for the treatment of diabesity and the potential offered by (Pro(3))GIP[mPEG] as a long-acting stable GIP receptor antagonist.

Daily administration of the GIP-R antagonist (Pro3)GIP in streptozotocin-induced diabetes suggests that insulin-dependent mechanisms are critical to anti-obesity-diabetes actions of (Pro3)GIP.

AIM: Glucose-dependent insulinotropic polypeptide-receptor (GIP-R) antagonism using (Pro3)GIP improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure and function in a commonly used model of obesity-diabetes, namely ob/ob mice. The effect of GIP-R antagonism in a streptozotocin (STZ)-induced model of insulin deficiency has not been evaluated. The present study has investigated the effects of daily administration of (Pro(3))GIP to STZ-treated mice. METHODS: Swiss TO mice received once-daily injection of (Pro3)GIP (25 nmol/kg body weight) or saline 4 days prior to and 16 days after injection of STZ, and effects on metabolic parameters and islet architecture were assessed. RESULTS: (Pro3)GIP treatment had no significant effect on hyperphagia or body weight loss. However, hyperglycaemia and glycated haemoglobin were worsened, glucose tolerance further decreased and insulin sensitivity was impaired by (Pro3)GIP. These effects were observed on an STZ-induced background characterized by severe reductions of circulating insulin, beta-cell mass and pancreatic insulin stores. CONCLUSIONS: These data indicate that the beneficial actions of the GIP-R antagonist, (Pro3)GIP, in obesity-diabetes appear to be largely mediated through insulin-dependent mechanisms that merit further investigation.

Successful liver retransplantation for recurrent hepatopulmonary syndrome.

HPS is defined as arterial hypoxemia because of pulmonary vasodilation as a result of cirrhotic or non-cirrhotic portal hypertension. This report describes a teenager with HPS because of primary sclerosing cholangitis/autoimmune hepatitis overlap syndrome requiring OLT. HPS resolved completely within three months of OLT, but recurred again at 12 months post-OLT following liver dysfunction secondary to a biliary stricture. She underwent a second OLT successfully and remains well two yr and three months post-second OLT. Recurrent HPS after OLT may occur because of graft dysfunction and as this novel case illustrates, retransplantation may lead to a successful outcome.

Chemical gastric inhibitory polypeptide receptor antagonism protects against obesity, insulin resistance, glucose intolerance and associated disturbances in mice fed high-fat and cafeteria diets.

AIMS/HYPOTHESIS: Gastric inhibitory polypeptide (GIP) receptor antagonism with (Pro(3))GIP improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure/function in ob/ob mice. This study examined the ability of (Pro(3))GIP to counter the development of obesity, insulin resistance and diabetes in mice fed high-fat and cafeteria diets. MATERIALS AND METHODS: Young Swiss TO mice on standard chow or high-fat, cafeteria or high-carbohydrate diets received daily injections of either saline or (Pro(3))GIP (25 nmol kg(-1)day(-1)) over 16 weeks. Food intake, body weight, and circulating glucose and insulin were measured frequently. At 16 weeks, glucose tolerance, insulin sensitivity, HbA(1c), circulating hormones and plasma lipids were assessed. Adipose tissue, liver and muscle were excised and weighed, and their histology and triacylglycerol content were further examined. RESULTS: (Pro(3))GIP significantly reduced body weight, enhanced locomotor activity, and improved HbA(1c), glucose tolerance, beta cell responsiveness and insulin sensitivity in mice fed high-fat and cafeteria diets (p < 0.05 to p < 0.01). Similarly, (Pro(3))GIP significantly reduced plasma corticosterone and triacylglycerols (p < 0.05 to p < 0.001), while glucagon, resistin and adiponectin were unchanged. (Pro(3))GIP decreased adipose tissue mass (p < 0.01) and the triacylglycerol content of liver, muscle and adipose tissue (p < 0.01 to p < 0.001). Adipocyte size and liver morphology were partially normalised. (Pro(3))GIP did not significantly affect any of these parameters in mice fed a high-carbohydrate diet. CONCLUSIONS/INTERPRETATION: (Pro(3))GIP protects against obesity, insulin resistance, glucose intolerance and associated disturbances in mice fed high-fat and cafeteria diets. This highlights chemical GIP receptor antagonism as a new possibility for the treatment of obesity and associated metabolic disturbances.

Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro3)GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice.

AIMS/HYPOTHESIS: Ablation of gastric inhibitory polypeptide (GIP) receptor action is reported to protect against obesity and associated metabolic abnormalities. The aim of this study was to use prediabetic ob/ob mice to examine whether 60 days of chemical GIP receptor ablation with (Pro(3))GIP is able to counter the development of genetic obesity-related diabetes. MATERIALS AND METHODS: Young (5-7 weeks) ob/ob mice received once daily i.p. injections of either saline vehicle or (Pro(3))GIP (25 nmol kg(-1) day(-1)) over a 60 day period. Food intake, body weight and circulating glucose and insulin were measured at frequent intervals. At 60 days, glucose tolerance, response to native GIP, postprandial responses, insulin sensitivity, HbA(1c), circulating hormones and plasma lipids were assessed. RESULTS: Body weight and food intake in (Pro(3))GIP-treated mice did not differ from ob/ob controls. GIP receptor blockade significantly improved non-fasting glucose (p < 0.001), HbA(1c) (p < 0.05), glucose tolerance (p < 0.001), meal tolerance (p < 0.001) and insulin sensitivity (p < 0.05). Remarkably, (Pro(3))GIP treatment prevented the age-related development of diabetes, as none of these parameters differed significantly between treated ob/ob mice and normal age-matched lean controls. Circulating levels of glucagon, corticosterone, adiponectin and total cholesterol were unchanged by (Pro(3))GIP, while levels of triacylglycerol, LDL-cholesterol and resistin were decreased (p < 0.05) compared with those in control ob/ob mice. Plasma and pancreatic insulin concentrations were generally lower after (Pro(3))GIP treatment than in control ob/ob mice (p < 0.01), but plasma insulin levels remained substantially raised (p < 0.001) compared with those observed in lean controls. CONCLUSIONS/INTERPRETATION: These data indicate that sustained GIP receptor antagonism provides an effective means of preventing the development of many of the metabolic abnormalities of obesity-driven diabetes.

Successful recovery of aplastic anemia following orthotopic liver transplantation for non-A-E acute liver failure.

This report describes a teenager who developed aplastic anemia (AA) because of non-A-E acute liver failure (ALF) requiring orthotopic liver transplantation (OLT). His AA did not recover spontaneously and he required treatment with ATG 9 months post-OLT. Bone marrow recovery occurred 4 months after immunotherapy and coincided with further intensification of immunusuppression required to treat early chronic rejection of the liver graft. Three years post-OLT he remains well with good bone marrow and liver function. Intensification of immunosuppression can lead to successful resolution of AA associated with non-A-E ALF.

Liver transplantation for a hilar inflammatory myofibroblastic tumor.

A 7-yr-old boy presented with obstructive jaundice secondary to an inflammatory myofibroblastic tumor centered on the hepatic hilum and extending into the liver. The tumor was further complicated by portal vein phlebitis and occlusion. Attempted resection of the tumor with portal vein reconstruction and bilioenteric drainage was unsuccessful and he required urgent orthotopic liver transplantation. In contrast to more peripheral inflammatory myofibroblastic tumors in the liver, hilar lesions are locally aggressive, causing occlusive portal phlebitis and biliary obstruction. Successful management may include the need for liver transplantation.