Patient and graft survival after liver transplantation for hereditary hemochromatosis: Implications for pathogenesis

The clinical outcome of patients who have undergone liver transplantation for hereditary hemochromatosis (HH) or who have received iron-loaded donor grafts is unclear. We reviewed 3,600 adult primary orthotopic liver transplants and assessed the outcomes in 22 patients with HH. We also evaluated graft function and iron mobilization in 12 recipients of iron-loaded donor grafts. All 22 subjects who received liver transplants for HH were male; 13 had other risk factors for liver disease. HH patients had comparatively poor outcomes following transplantation: survival at 1, 3, and 5 years posttransplantation were 72%, 62%, and 55%, respectively. Recurrent hepatocellular cancer was the most common cause of death. There was no convincing evidence of reaccumulation of iron in the grafted liver in HH; however, 1 subject demonstrated increased serum ferritin concentration and grade 2 hepatic siderosis. Liver iron stores were slow to mobilize in 7 of the 12 recipients of iron-loaded grafts. These recipients had appropriate early graft function, but 2 patients with heavy iron loading and increased hepatic iron developed hepatic fibrosis. In conclusion. (1) HH is an uncommon indication for liver transplantation, and the majority of patients requiring transplantation had other risk factors for chronic liver disease; (2) reaccumulation of liver iron in HH patients is very unusual, but increased iron stores may be slow to mobilize in normal recipients of iron-loaded grafts, potentially compromising late graft function; (3) post-liver transplant survival is reduced in HH, and affected patients require careful clinical evaluation of perioperative and postoperative risk factors. Our data suggest that iron excess in HH does not wholly depend on intestinal iron absorption but is also influenced by liver factors that moderate iron metabolism.

Estimates of sex- and age-class-specific survival probabilities for a southern Great Barrier Reef green sea turtle population

Sex- and age-class-specific survival probabilities of a southern Great Barrier Reef green sea turtle population were estimated using a capture - mark - recapture (CMR) study and a Cormack - Jolly - Seber (CJS) modelling approach. The CMR history profiles for 954 individual turtles tagged over a 9-year period ( 1984 - 1992) were classified into three age classes ( adult, subadult, juvenile) based on somatic growth and reproductive traits. Reduced-parameter CJS models, accounting for constant survival and time-specific recapture, fitted best for all age classes. There were no significant sex-specific differences in either survival or recapture probabilities for any age class. Mean annual adult survival was estimated at 0.9482 (95% CI: 0.92 - 0.98) and was significantly higher than survival for either subadults or juveniles. Mean annual subadult survival was 0.8474 ( 95% CI: 0.79 - 0.91), which was not significantly different from mean annual juvenile survival estimated at 0.8804 ( 95% CI: 0.84 - 0.93). The time-specific adult recapture probabilities were a function of sampling effort but this was not the case for either juveniles or subadults. The sampling effort effect was accounted for explicitly in the estimation of adult survival and recapture probabilities. These are the first comprehensive sex- and age-class-specific survival and recapture probability estimates for a green sea turtle population derived from a long-term CMR program.

Embryonic mortality in buffaloes synchronized and mated by AI during the seasonal decline in reproductive function

The aim was to determine the factors that contribute to embryonic mortality in buffaloes mated by AI during a period of increasing day length which corresponds to a natural decline in reproductive activity. Italian Mediterranean buffalo cows (n = 243) showing regular estrous cycles were synchronized using the Ovsynch-TAI program and mated by AI at 16 and 40 h after the second injection of GnRH. Blood samples were collected on Days 10 and 20 after the first AI and assayed for progesterone (P-4). Pregnancy diagnosis was undertaken on Days 26 and 40 after the first AI using rectal ultrasonography. Buffaloes with a conceptus on Day 26 but not on Day 40 were judged to have undergone embryonic mortality and for these animals uterine fluid was recovered by flushing and analysed for common infectious agents. Estrus synchronization was achieved in 86% of buffaloes and the pregnancy rate on Day 40 was 34%. Embryonic mortality between Days 26 and 40 occurred in 45% of buffaloes and was associated with the presence of significant infectious agents in only 10 buffaloes (8%). Concentrations of P-4 on Day 10 after AI were higher (P < 0.05) in buffaloes that established a pregnancy than in buffaloes that showed embryonic mortality that was not associated with infectious agents. Similarly, on Day 20 after AI P-4 concentrations were higher (P < 0.01) in pregnant buffaloes compared with non-pregnant buffaloes and buffaloes that had embryonic mortality. It is concluded that a reduced capacity for P-4 secretion can explain around 50% of embryonic mortalities in buffaloes synchronised and mated by AI during a period of low reproductive activity and that other as yet unidentified factors also have a significant effect on embryonic survival. (c) 2004 Elsevier Inc. All rights reserved.

The Runx1 transcription factor controls CSF-1-dependent and -independent growth and survival of macrophages

Gene translocations that repress the function of the Runx1 transcription factor play a critical role in the development of myeloid leukemia. In this report, we demonstrate that Runx1 precisely regulates c-fms (CSF-1 receptor) gene expression. Runx1 controlled expression by binding to multiple sites within the mouse c-fms gene, allowing interaction between promoter and downstream enhancer elements. The runx1 and c-fms genes showed an identical pattern of expression in mature macrophages. Runx1 expression was repressed in CSF-1 stimulated, proliferating bone marrow-derived macrophages (BMM) and significantly increased in quiescent, CSF-1 starved cells. The RAW264.7 and Mono-Mac-6, macrophage-like cell lines expressed low levels of Runx1 and both showed growth arrest and cell death with ectopic expression of Runx1. The EM-3 cell line, which represents an early myeloid progenitor cell line, showed growth arrest with Runx1 expression in the absence of any detectable changes in cell differentiation. These findings suggest that Runx1 regulates growth and survival of myeloid cells and provide a novel insight into the role of Runx family gene translocations in leukemogenesis.

HOXA1 is required for E-cadherin-dependent anchorage-independent survival of human mammary carcinoma cells

Forced expression of HOXA1 is sufficient to stimulate oncogenic transformation of immortalized human mammary epithelial cells and subsequent tumor formation. We report here that the expression and transcriptional activity of HOXA1 are increased in mammary carcinoma cells at full confluence. This confluence-dependent expression of HOXA1 was abrogated by incubation of cells with EGTA to produce loss of intercellular contact and rescued by extracellular addition of Ca2+. Increased HOXA1 expression at full confluence was prevented by an E-cadherin function-blocking antibody and attachment of non-confluent cells to a substrate by homophilic ligation of E-cadherin increased HOXA1 expression. E-cadherin-directed signaling increased HOXA1 expression through Rac1. Increased HOXA1 expression consequent to E-cadherin-activated signaling decreased apoptotic cell death and was required for E-cadherin-dependent anchorage-independent proliferation of human mammary carcinoma cells. HOXA1 is therefore a downstream effector of E-cadherin-directed signaling required for anchorage-independent proliferation of mammary carcinoma cells.