UK experience of liver transplantation for erythropoietic protoporphyria

Erythropoietic protoporphyria (EPP) is characterised by excess production of free protoporphyrin from the bone marrow, most commonly due to deficiency of the enzyme ferrochelatase. Excess protoporphyrin gives rise to the cutaneous photosensitivity characteristic of the disease, and in a minority of patients leads to end-stage liver disease necessitating liver transplantation (LT). There is limited information regarding the timing, impact and long-term outcome of LT in such patients, thus we aimed to identify the indications and outcomes of all transplants performed for EPP in the UK using data from the UK Transplant Registry. Between 1987 and 2009, five patients underwent LT for EPP liver disease. Median follow-up was 60 months, and there were two deaths at 44 and 95 months from causes unrelated to liver disease. The remaining recipients are alive at 22.4 years, 61 months and 55 months after transplant. A high rate of postoperative biliary stricturing requiring multiple biliary interventions was observed. Recurrent EPP-liver disease occurred in 4/5 (80%) of patients but graft failure has not been observed. Given the role of biliary obstruction in inducing EPP-mediated liver damage, we suggest that consideration should be given for construction of a Roux loop at the time of transplant. Thus we demonstrate that although EPP liver transplant recipients have a good long-term survival, comparable to patients undergoing LT for other indications, biliary complications and disease recurrence are almost universal, and bone marrow transplantation should be considered where possible

Conceptualizing pathways linking women's empowerment and prematurity in developing countries.

BackgroundGlobally, prematurity is the leading cause of death in children under the age of 5. Many efforts have focused on clinical approaches to improve the survival of premature babies. There is a need, however, to explore psychosocial, sociocultural, economic, and other factors as potential mechanisms to reduce the burden of prematurity. Women's empowerment may be a catalyst for moving the needle in this direction. The goal of this paper is to examine links between women's empowerment and prematurity in developing settings. We propose a conceptual model that shows pathways by which women's empowerment can affect prematurity and review and summarize the literature supporting the relationships we posit. We also suggest future directions for research on women's empowerment and prematurity.MethodsThe key words we used for empowerment in the search were "empowerment," "women's status," "autonomy," and "decision-making," and for prematurity we used "preterm," "premature," and "prematurity." We did not use date, language, and regional restrictions. The search was done in PubMed, Population Information Online (POPLINE), and Web of Science. We selected intervening factors-factors that could potentially mediate the relationship between empowerment and prematurity-based on reviews of the risk factors and interventions to address prematurity and the determinants of those factors.ResultsThere is limited evidence supporting a direct link between women's empowerment and prematurity. However, there is evidence linking several dimensions of empowerment to factors known to be associated with prematurity and outcomes for premature babies. Our review of the literature shows that women's empowerment may reduce prematurity by (1) preventing early marriage and promoting family planning, which will delay age at first pregnancy and increase interpregnancy intervals; (2) improving women's nutritional status; (3) reducing domestic violence and other stressors to improve psychological health; and (4) improving access to and receipt of recommended health services during pregnancy and delivery to help prevent prematurity and improve survival of premature babies.ConclusionsWomen's empowerment is an important distal factor that affects prematurity through several intervening factors. Improving women's empowerment will help prevent prematurity and improve survival of preterm babies. Research to empirically show the links between women's empowerment and prematurity is however needed

Inter-examiner reliability of the diagnosis of cervical pillar hyperplasia (CPH) and the correlation between CPH and spinal degenerative joint disease (DJD)

BACKGROUND: Cervical pillar hyperplasia (CPH) is a recently described phenomenon of unknown aetiology. Its clinical importance is poorly understood at the present time; therefore, the objective of this study was to determine (1) the inter-examiner reliability of detecting CPH and (2) if there is a clinically important correlation (r > 0.4) between the number of cervical spine levels showing signs of degenerative joint disease (DJD) and CPH. METHODS: The sample consisted of 320 radiographs of human male and female subjects who ranged from 40 to 79 years of age. The inter-examiner reliability of assessing the presence/absence of pillar hyperplasia was evaluated on 50 neutral lateral radiographs by two examiners using line drawings and it was quantified using the kappa coefficient of concordance. To determine the presence/absence of hyperplastic pillars as well as the presence/absence of DJD at each intervertebral disc and zygapophysial joint, 320 AP open mouth, AP lower cervical and neutral lateral radiographs were then examined. The unpaired t-test at the 5% level of significance was performed to test for a statistically significant difference between the number of levels affected by DJD in patients with and without hyperplasia. The Spearman's rho at the 5% level of significance was performed to quantify the correlation between DJD and age. RESULTS: The inter-examiner reliability of detecting cervical pillar hyperplasia was moderate with a kappa coefficient of 0.51. The unpaired t-test indicated that there was no statistically significant difference (p > 0.05) between the presence/absence of cervical pillar hyperplasia and the number of levels affected by DJD in an age-matched population, regardless of whether all elements were considered together, or the discs and facets were analyzed separately. A Spearman correlation rank of 0.67 (p < 0.05) suggested a moderately strong correlation between the number of elements (i.e. discs/facets) affected, and the age of the individual. CONCLUSION: Cervical pillar hyperplasia is a reasonable concept that requires further research. Its evaluation is easy to learn and acceptably reliable. Previous research has suggested that CPH may affect the cervical lordosis, and therefore, alter biomechanics which may result in premature DJD. This current study, however, indicates that, globally, CPH does not appear to be related to the development of DJD

Association between Variations in Cell Cycle Genes and Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a devastating and progressive lung disease. Its aetiology is thought to involve damage to the epithelium and abnormal repair. Alveolar epithelial cells near areas of remodelling show an increased expression of proapoptotic molecules. Therefore, we investigated the role of genes involved in cell cycle control in IPF. Genotypes for five single nucleotide polymorphisms (SNPs) in the tumour protein 53 (TP53) gene and four SNPs in cyclin-dependent kinase inhibitor 1A (CDKN1A), the gene encoding p21, were determined in 77 IPF patients and 353 controls. In peripheral blood mononuclear cells (PBMC) from 16 healthy controls mRNA expression of TP53 and CDKN1A was determined

Determinants of intra-household food allocation between adults in South Asia - a systematic review.

BACKGROUND: Nutrition interventions, often delivered at the household level, could increase their efficiency by channelling resources towards pregnant or lactating women, instead of leaving resources to be disproportionately allocated to traditionally favoured men. However, understanding of how to design targeted nutrition programs is limited by a lack of understanding of the factors affecting the intra-household allocation of food. METHODS: We systematically reviewed literature on the factors affecting the allocation of food to adults in South Asian households (in Afghanistan, Bangladesh, Bhutan, India, Islamic Republic of Iran, Maldives, Nepal, Pakistan, Sri Lanka) and developed a framework of food allocation determinants. Two reviewers independently searched and filtered results from PubMed, Web of Knowledge and Scopus databases by using pre-defined search terms and hand-searching the references from selected papers. Determinants were extracted, categorised into a framework, and narratively described. We used adapted Downs and Black and Critical Appraisal Skills Programme checklists to assess the quality of evidence. RESULTS: Out of 6928 retrieved studies we found 60 relevant results. Recent, high quality evidence was limited and mainly from Bangladesh, India and Nepal. There were no results from Iran, Afghanistan, Maldives, or Bhutan. At the intra-household level, food allocation was determined by relative differences in household members' income, bargaining power, food behaviours, social status, tastes and preferences, and interpersonal relationships. Household-level determinants included wealth, food security, occupation, land ownership, household size, religion / ethnicity / caste, education, and nutrition knowledge. In general, the highest inequity occurred in households experiencing severe or unexpected food insecurity, and also in better-off, high caste households, whereas poorer, low caste but not severely food insecure households were more equitable. Food allocation also varied regionally and seasonally. CONCLUSION: Program benefits may be differentially distributed within households of different socioeconomic status, and targeting of nutrition programs might be improved by influencing determinants that are amenable to change, such as food security, women's employment, or nutrition knowledge. Longitudinal studies in different settings could unravel causal effects. Conclusions are not generalizable to the whole South Asian region, and research is needed in many countries

The FunGenES Database: A Genomics Resource for Mouse Embryonic Stem Cell Differentiation

Embryonic stem (ES) cells have high self-renewal capacity and the potential to differentiate into a large variety of cell types. To investigate gene networks operating in pluripotent ES cells and their derivatives, the “Functional Genomics in Embryonic Stem Cells” consortium (FunGenES) has analyzed the transcriptome of mouse ES cells in eleven diverse settings representing sixty-seven experimental conditions. To better illustrate gene expression profiles in mouse ES cells, we have organized the results in an interactive database with a number of features and tools. Specifically, we have generated clusters of transcripts that behave the same way under the entire spectrum of the sixty-seven experimental conditions; we have assembled genes in groups according to their time of expression during successive days of ES cell differentiation; we have included expression profiles of specific gene classes such as transcription regulatory factors and Expressed Sequence Tags; transcripts have been arranged in “Expression Waves” and juxtaposed to genes with opposite or complementary expression patterns; we have designed search engines to display the expression profile of any transcript during ES cell differentiation; gene expression data have been organized in animated graphs of KEGG signaling and metabolic pathways; and finally, we have incorporated advanced functional annotations for individual genes or gene clusters of interest and links to microarray and genomic resources. The FunGenES database provides a comprehensive resource for studies into the biology of ES cells

Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice

<p>Abstract</p> <p>Background</p> <p>Type 2 diabetes (T2D) is the most common form of diabetes in humans and is closely associated with dyslipidemia and obesity that magnifies the mortality and morbidity related to T2D. The genetic contribution to human T2D and related metabolic disorders is evident, and mostly follows polygenic inheritance. The TALLYHO/JngJ (TH) mice are a polygenic model for T2D characterized by obesity, hyperinsulinemia, impaired glucose uptake and tolerance, hyperlipidemia, and hyperglycemia.</p> <p>Results</p> <p>In order to determine the genetic factors that contribute to these T2D related characteristics in TH mice, we interbred TH mice with C57BL/6J (B6) mice. The parental, F1, and F2 mice were phenotyped at 8, 12, 16, 20, and 24 weeks of age for 4-hour fasting plasma triglyceride, cholesterol, insulin, and glucose levels and body, fat pad and carcass weights. The F2 mice were genotyped genome-wide and used for quantitative trait locus (QTL) mapping. We also applied a genetical genomic approach using a subset of the F2 mice to seek candidate genes underlying the QTLs. Major QTLs were detected on chromosomes (Chrs) 1, 11, 4, and 8 for hypertriglyceridemia, 1 and 3 for hypercholesterolemia, 4 for hyperglycemia, 11 and 1 for body weight, 1 for fat pad weight, and 11 and 14 for carcass weight. Most alleles, except for Chr 3 and 14 QTLs, increased phenotypic values when contributed by the TH strain. Fourteen pairs of interacting loci were detected, none of which overlapped the major QTLs. The QTL interval linked to hypercholesterolemia and hypertriglyceridemia on distal Chr 1 contains <it>Apoa2 </it>gene. Sequencing analysis revealed polymorphisms of <it>Apoa2 </it>in TH mice, suggesting <it>Apoa2 </it>as the candidate gene for the hyperlipidemia QTL. Gene expression analysis added novel information and aided in selection of candidates underlying the QTLs.</p> <p>Conclusions</p> <p>We identified several genetic loci that affect the quantitative variations of plasma lipid and glucose levels and obesity traits in a TH × B6 intercross. Polymorphisms in <it>Apoa2 </it>gene are suggested to be responsible for the Chr 1 QTL linked to hypercholesterolemia and hypertriglyceridemia. Further, genetical genomic analysis led to potential candidate genes for the QTLs.</p

Genetic architecture of gene expression in ovine skeletal muscle

In livestock populations the genetic contribution to muscling is intensively monitored in the progeny of industry sires and used as a tool in selective breeding programs. The genes and pathways conferring this genetic merit are largely undefined. Genetic variation within a population has potential, amongst other mechanisms, to alter gene expression via cis- or trans-acting mechanisms in a manner that impacts the functional activities of specific pathways that contribute to muscling traits. By integrating sire-based genetic merit information for a muscling trait with progeny-based gene expression data we directly tested the hypothesis that there is genetic structure in the gene expression program in ovine skeletal muscle. Results The genetic performance of six sires for a well defined muscling trait, longissimus lumborum muscle depth, was measured using extensive progeny testing and expressed as an Estimated Breeding Value by comparison with contemporary sires. Microarray gene expression data were obtained for longissimus lumborum samples taken from forty progeny of the six sires (4-8 progeny/sire). Initial unsupervised hierarchical clustering analysis revealed strong genetic architecture to the gene expression data, which also discriminated the sire-based Estimated Breeding Value for the trait. An integrated systems biology approach was then used to identify the major functional pathways contributing to the genetics of enhanced muscling by using both Estimated Breeding Value weighted gene co-expression network analysis and a differential gene co-expression network analysis. The modules of genes revealed by these analyses were enriched for a number of functional terms summarised as muscle sarcomere organisation and development, protein catabolism (proteosome), RNA processing, mitochondrial function and transcriptional regulation. Conclusions This study has revealed strong genetic structure in the gene expression program within ovine longissimus lumborum muscle. The balance between muscle protein synthesis, at the levels of both transcription and translation control, and protein catabolism mediated by regulated proteolysis is likely to be the primary determinant of the genetic merit for the muscling trait in this sheep population. There is also evidence that high genetic merit for muscling is associated with a fibre type shift toward fast glycolytic fibres. This study provides insight into mechanisms, presumably subject to strong artificial selection, that underpin enhanced muscling in sheep populations