Combined effect of regulatory polymorphisms on transcription of UGT1A1 as a cause of Gilbert syndrome

<p>Abstract</p> <p>Background</p> <p>Gilbert syndrome is caused by defects in bilirubin UDP-glucuronosyltransferase (UGT1A1). The most common variation believed to be involved is A(TA)7TAA. Although several polymorphisms have been found to link with A(TA)7TAA, the combined effect of regulatory polymorphisms in the development of Gilbert syndrome remains unclear.</p> <p>Methods</p> <p>In an analysis of 15 patients and 60 normal subjects, we detected 14 polymorphisms and nine haplotypes in the regulatory region. We classified the 4-kbp regulatory region of the patients into: the TATA box including A(TA)7TAA; a phenobarbital responsive enhancer module including c.-3275T>G; and a region including other ten linked polymorphisms. The effect on transcription of these polymorphisms was studied.</p> <p>Results</p> <p>All haplotypes with A(TA)7TAA had c.-3275T>G and additional polymorphisms. In an <it>in-vitro </it>expression study of the 4-kbp regulatory region, A(TA)7TAA alone did not significantly reduce transcription. In contrast, c.-3275T>G reduced transcription to 69% of that of wild type, and the linked polymorphisms reduced transcription to 88% of wild type. Transcription of the typical regulatory region of the patients was 56% of wild type. Co-expression of constitutive androstane receptor (CAR) increased the transcription of wild type by a factor of 4.3. Each polymorphism by itself did not reduce transcription to the level of the patients, however, even in the presence of CAR.</p> <p>Conclusions</p> <p>These results imply that co-operation of A(TA)7TAA, c.-3275T>G and the linked polymorphisms is necessary in causing Gilbert syndrome.</p

Haematopoietic stem cell transplantation for severe autoimmune diseases in children : a review of current literature, registry activity and future directions on behalf of the autoimmune diseases and paediatric diseases working parties of the European Society for Blood and Marrow Transplantation

Although modern clinical management strategies have improved the outcome of paediatric patients with severe autoimmune and inflammatory diseases over recent decades, a proportion will experience ongoing or recurrent/relapsing disease activity despite multiple therapies often leading to irreversible organ damage, and compromised quality of life, growth/development and long-term survival. Autologous and allogeneic haematopoietic stem cell transplantation (HSCT) have been used successfully to induce disease control and often apparent cure of severe treatment-refractory autoimmune diseases (ADs) in children. However, transplant-related outcomes are disease-dependent and long-term outcome data are limited in respect to efficacy and safety. Moreover, balancing risks of HSCT against AD prognosis with continually evolving non-transplant options is challenging. This review appraises published literature on HSCT strategies and outcomes in individual paediatric ADs. We also provide a summary of the European Society for Blood and Marrow Transplantation (EBMT) Registry, where 343 HSCT procedures (176 autologous and 167 allogeneic) have been reported in 326 children (<18 years) for a range of AD indications. HSCT is a promising treatment modality, with potential long-term disease control or cure, but therapy-related morbidity and mortality need to be reduced. Further research is warranted to establish the position of HSCT in paediatric ADs via registries and prospective clinical studies to support evidence-based interspeciality guidelines and recommendations

The overwintering of Antarctic krill, Euphausia superba, from an ecophysiological perspective

A major aim of this review is to determine which physiological functions are adopted by adults and larvae to survive the winter season with low food supply and their relative importance. A second aim is to clarify the extent to which seasonal variation in larval and adult krill physiology is mediated by environmental factors with a strong seasonality, such as food supply or day light. Experimental studies on adult krill have demonstrated that speciWc physiological adaptations during autumn and winter, such as reduced metabolic rates and feeding activity, are not caused simply by the scarcity of food, as was previously assumed. These adaptations appear to be inXuenced by the local light regime. The physiological functions that larval krill adopt during winter (reduced metabolism, delayed development, lipid utilisation, and variable growth rates) are, in contrast to the adults, under direct control by the available food supply. During winter, the adults often seem to have little association with sea ice (at least until early spring). The larvae, however, feed within sea ice but mainly on the grazers of the ice algal community rather than on the algae themselves. In this respect, a miss-match in timing of the occurrence of the last phytoplankton blooms in autumn and the start of the sea ice formation, as has been increasingly observed in the west Antarctic Peninsula (WAP) region, will impact larval krill development during winter in terms of food supply and consequently the krill stock in this region