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

Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium

The transcytosis of antigens across the gut epithelium by microfold cells (M cells) is important for the induction of efficient immune responses to some mucosal antigens in Peyer’s patches. Recently, substantial progress has been made in our understanding of the factors that influence the development and function of M cells. This review highlights these important advances, with particular emphasis on: the host genes which control the functional maturation of M cells; how this knowledge has led to the rapid advance in our understanding of M-cell biology in the steady-state and during aging; molecules expressed on M cells which appear to be used as “immunosurveillance” receptors to sample pathogenic microorganisms in the gut; how certain pathogens appear to exploit M cells to infect the host; and finally how this knowledge has been used to specifically target antigens to M cells to attempt to improve the efficacy of mucosal vaccines

Interfacial charge-transfer doping of metal halide perovskites for high performance photovoltaics

We demonstrate a method for controlled p-doping of the halide perovskite surface using molecular dopants, resulting in reduced non-radiative recombination losses and improved device performance

Global Assessment of Extinction Risk to Populations of Sockeye Salmon Oncorhynchus nerka

BACKGROUND: Concern about the decline of wild salmon has attracted the attention of the International Union for the Conservation of Nature (IUCN). The IUCN applies quantitative criteria to assess risk of extinction and publishes its results on the Red List of Threatened Species. However, the focus is on the species level and thus may fail to show the risk to populations. The IUCN has adapted their criteria to apply to populations but there exist few examples of this type of assessment. We assessed the status of sockeye salmon Oncorhynchus nerka as a model for application of the IUCN population-level assessments and to provide the first global assessment of the status of an anadromous Pacific salmon. METHODS/PRINCIPAL FINDINGS: We found from demographic data that the sockeye salmon species is not presently at risk of extinction. We identified 98 independent populations with varying levels of risk within the species' range. Of these, 5 (5%) are already extinct. We analyzed the risk for 62 out of 93 extant populations (67%) and found that 17 of these (27%) are at risk of extinction. The greatest number and concentration of extinct and threatened populations is in the southern part of the North American range, primarily due to overfishing, freshwater habitat loss, dams, hatcheries, and changing ocean conditions. CONCLUSIONS/SIGNIFICANCE: Although sockeye salmon are not at risk at the species-level, about one-third of the populations that we analyzed are at risk or already extinct. Without an understanding of risk to biodiversity at the level of populations, the biodiversity loss in salmon would be greatly underrepresented on the Red List. We urge government, conservation organizations, scientists and the public to recognize this limitation of the Red List. We also urge recognition that about one-third of sockeye salmon global population diversity is at risk of extinction or already extinct

Surface pretreatment for prolonged survival of cemented tibial prosthesis components: full- vs. surface-cementation technique

BACKGROUND: One of few persisting problems of cemented total knee arthroplasty (TKA) is aseptic loosening of tibial component due to degradation of the interface between bone cement and metallic tibial shaft component, particularly for surface cemented tibial components. Surface cementation technique has important clinical meaning in case of revision and for avoidance of stress shielding. Degradation of the interface between bone cement and bone may be a secondary effect due to excessive crack formation in bone cement starting at the opposite metallic surface. METHODS: This study was done to prove crack formation in the bone cement near the metallic surface when this is not coated. We propose a newly developed coating process by PVD layering with SiO(x )to avoid that crack formation in the bone cement. A biomechanical model for vibration fatigue test was done to simulate the physiological and biomechanical conditions of the human knee joint and to prove excessive crack formation. RESULTS: It was found that coated tibial components showed a highly significant reduction of cement cracking near the interface metal/bone cement (p < 0.01) and a significant reduction of gap formation in the interface metal-to-bone cement (p < 0.05). CONCLUSION: Coating dramatically reduces hydrolytic- and stress-related crack formation at the prosthesis interface metal/bone cement. This leads to a more homogenous load transfer into the cement mantle which should reduce the frequency of loosening in the interfaces metal/bone cement/bone. With surface coating of the tibial component it should become possible that surface cemented TKAs reveal similar loosening rates as TKAs both surface and stem cemented. This would be an important clinical advantage since it is believed that surface cementing reduces metaphyseal bone loss in case of revision and stress shielding for better bone health

Comprehensive evaluation of matrix factorization methods for the analysis of DNA microarray gene expression data

<p>Abstract</p> <p>Background</p> <p>Clustering-based methods on gene-expression analysis have been shown to be useful in biomedical applications such as cancer subtype discovery. Among them, Matrix factorization (MF) is advantageous for clustering gene expression patterns from DNA microarray experiments, as it efficiently reduces the dimension of gene expression data. Although several MF methods have been proposed for clustering gene expression patterns, a systematic evaluation has not been reported yet.</p> <p>Results</p> <p>Here we evaluated the clustering performance of orthogonal and non-orthogonal MFs by a total of nine measurements for performance in four gene expression datasets and one well-known dataset for clustering. Specifically, we employed a non-orthogonal MF algorithm, BSNMF (Bi-directional Sparse Non-negative Matrix Factorization), that applies bi-directional sparseness constraints superimposed on non-negative constraints, comprising a few dominantly co-expressed genes and samples together. Non-orthogonal MFs tended to show better clustering-quality and prediction-accuracy indices than orthogonal MFs as well as a traditional method, K-means. Moreover, BSNMF showed improved performance in these measurements. Non-orthogonal MFs including BSNMF showed also good performance in the functional enrichment test using Gene Ontology terms and biological pathways.</p> <p>Conclusions</p> <p>In conclusion, the clustering performance of orthogonal and non-orthogonal MFs was appropriately evaluated for clustering microarray data by comprehensive measurements. This study showed that non-orthogonal MFs have better performance than orthogonal MFs and <it>K</it>-means for clustering microarray data.</p

Cyanogenesis of Wild Lima Bean (Phaseolus lunatus L.) Is an Efficient Direct Defence in Nature

In natural systems plants face a plethora of antagonists and thus have evolved multiple defence strategies. Lima bean (Phaseolus lunatus L.) is a model plant for studies of inducible indirect anti-herbivore defences including the production of volatile organic compounds (VOCs) and extrafloral nectar (EFN). In contrast, studies on direct chemical defence mechanisms as crucial components of lima beans' defence syndrome under natural conditions are nonexistent. In this study, we focus on the cyanogenic potential (HCNp; concentration of cyanogenic glycosides) as a crucial parameter determining lima beans' cyanogenesis, i.e. the release of toxic hydrogen cyanide from preformed precursors. Quantitative variability of cyanogenesis in a natural population of wild lima bean in Mexico was significantly correlated with missing leaf area. Since existing correlations do not by necessity mean causal associations, the function of cyanogenesis as efficient plant defence was subsequently analysed in feeding trials. We used natural chrysomelid herbivores and clonal lima beans with known cyanogenic features produced from field-grown mother plants. We show that in addition to extensively investigated indirect defences, cyanogenesis has to be considered as an important direct defensive trait affecting lima beans' overall defence in nature. Our results indicate the general importance of analysing ‘multiple defence syndromes’ rather than single defence mechanisms in future functional analyses of plant defences

Erythropoietic protoporphyria

Erythropoietic protoporphyria (EPP) is an inherited disorder of the haem metabolic pathway characterised by accumulation of protoporphyrin in blood, erythrocytes and tissues, and cutaneous manifestations of photosensitivity. EPP has been reported worldwide, with prevalence between 1:75,000 and 1:200,000. It usually manifests in early infancy upon the first sun exposures. EPP is characterised by cutaneous manifestations of acute painful photosensitivity with erythema and oedema, sometimes with petechiae, together with stinging and burning sensations upon exposure to sunlight, without blisters. These episodes have a variable severity depending on the exposure duration and may result in chronic permanent lesions on exposed skin. As protoporphyrin is a lipophilic molecule that is excreted by the liver, EPP patients are at risk of cholelithiasis with obstructive episodes, and chronic liver disease that might evolve to rapid acute liver failure. In most patients, EPP results from a partial deficiency of the last enzyme of the haem biosynthetic pathway, ferrochelatase, EC 4.99.1.1/FECH (encoded by the FECH gene). EPP appears to be inherited as an autosomal dominant disease, the clinical expression of which is modulated by the presence of the hypomorphic FECH IVS3-48C allele trans, but recessive inheritance with two mutated FECH alleles has also been described. In about 2% of patients, overt disease was recently shown to be caused by gain-of-function mutations in the erythroid-specific aminolevulinic acid synthase 2 (ALAS2/ALAS, EC 2.3.1.27) gene and named X-linked dominant protoporphyria. Diagnosis is established by finding increased levels of protoporphyrin in plasma and red blood cells, and detection of a plasma fluorescence peak at 634 nm. Investigations for hepatic involvement, ferrochelatase activity level, genetic analysis (FECH mutations, presence of the hypomorphic FECH IVS3-48C allele trans and ALAS2 mutations) and family studies are advisable. Differential diagnosis includes phototoxic drug reactions, hydroa vacciniforme, solar urticaria, contact dermatitis, angio-oedema and, in some cases, other types of porphyria. Management includes avoidance of exposure to light, reduction of protoporphyrin levels and prevention of progression of possible liver disease to liver failure. As the major risk in EPP patients is liver disease, a regular follow-up of hepatic involvement is essential. Sequential hepatic and bone marrow transplantation should be considered as a suitable treatment for most severe cases of EPP with hepatic involvement. EPP is a lifelong disorder whose prognosis depends on the evolution of the hepatic disease. However, photosensitivity may have a significant impact on quality of life of EPP patients