Mouse genomic variation and its effect on phenotypes and gene regulation.

We report genome sequences of 17 inbred strains of laboratory mice and identify almost ten times more variants than previously known. We use these genomes to explore the phylogenetic history of the laboratory mouse and to examine the functional consequences of allele-specific variation on transcript abundance, revealing that at least 12% of transcripts show a significant tissue-specific expression bias. By identifying candidate functional variants at 718 quantitative trait loci we show that the molecular nature of functional variants and their position relative to genes vary according to the effect size of the locus. These sequences provide a starting point for a new era in the functional analysis of a key model organism.

Improvements to services at the European Nucleotide Archive.

The European Nucleotide Archive (ENA; http://www.ebi.ac.uk/ena) is Europe's primary nucleotide sequence archival resource, safeguarding open nucleotide data access, engaging in worldwide collaborative data exchange and integrating with the scientific publication process. ENA has made significant contributions to the collaborative nucleotide archival arena as an active proponent of extending the traditional collaboration to cover capillary and next-generation sequencing information. We have continued to co-develop data and metadata representation formats with our collaborators for both data exchange and public data dissemination. In addition to the DDBJ/EMBL/GenBank feature table format, we share metadata formats for capillary and next-generation sequencing traces and are using and contributing to the NCBI SRA Toolkit for the long-term storage of the next-generation sequence traces. During the course of 2009, ENA has significantly improved sequence submission, search and access functionalities provided at EMBL-EBI. In this article, we briefly describe the content and scope of our archive and introduce major improvements to our services.

Ensembl's 10th year.

Ensembl (http://www.ensembl.org) integrates genomic information for a comprehensive set of chordate genomes with a particular focus on resources for human, mouse, rat, zebrafish and other high-value sequenced genomes. We provide complete gene annotations for all supported species in addition to specific resources that target genome variation, function and evolution. Ensembl data is accessible in a variety of formats including via our genome browser, API and BioMart. This year marks the tenth anniversary of Ensembl and in that time the project has grown with advances in genome technology. As of release 56 (September 2009), Ensembl supports 51 species including marmoset, pig, zebra finch, lizard, gorilla and wallaby, which were added in the past year. Major additions and improvements to Ensembl since our previous report include the incorporation of the human GRCh37 assembly, enhanced visualisation and data-mining options for the Ensembl regulatory features and continued development of our software infrastructure.

Locus-specific induction of gene expression from heterochromatin loci during cellular senescence.

Senescence is a fate-determined state, accompanied by reorganization of heterochromatin. Although lineage-appropriate genes can be temporarily repressed through facultative heterochromatin, stable silencing of lineage-inappropriate genes often involves the constitutive heterochromatic mark, histone H3 lysine 9 trimethylation (H3K9me3). The fate of these heterochromatic genes during senescence is unclear. In the present study, we show that a small number of lineage-inappropriate genes, exemplified by the LCE2 skin genes, are derepressed during senescence from H3K9me3 regions in fibroblasts. DNA FISH experiments reveal that these gene loci, which are condensed at the nuclear periphery in proliferative cells, are decompacted during senescence. Decompaction of the locus is not sufficient for LCE2 expression, which requires p53 and C/EBPß signaling. NLRP3, which is predominantly expressed in macrophages from an open topologically associated domain (TAD), is also derepressed in senescent fibroblasts due to the local disruption of the H3K9me3-rich TAD that contains it. NLRP3 has been implicated in the amplification of inflammatory cytokine signaling in senescence and aging, highlighting the functional relevance of gene induction from 'permissive' H3K9me3 regions in senescent cells.

Review: Trunnionosis leading to modular femoral head dissociation.

Component dissociation secondary to trunnionosis is rare, and its causes are multifactorial. It is a major complication of total hip replacement, in most cases requiring revision arthroplasty. In this paper, we present a case of taper/head modular interface dissociation in a metal-on-metal total hip replacement. We review the literature of both trunnionosis, as well as a systematic review of modular dissociation of the femoral component in total hip arthroplasty, identifying commonalities with our own case.

Systematic Review and Meta-Analysis of the Impact of Bariatric Surgery on Lower Urinary Tract Symptoms in Males.

BACKGROUND: Obesity is a chronic disease with multisystem morbidity. There are multiple studies reporting the effect of bariatric surgery on cardiovascular and metabolic disease, but few examine its impact on lower urinary tract symptoms. This article aims to perform a systematic review with meta-analysis, to determine the effects of bariatric surgery on lower urinary tract symptoms in male patients. METHODS: Medline, Embase, conference proceedings, and reference lists were searched for studies reporting the quantitative measurement of lower urinary tract symptoms score pre- and postweight loss surgery. The primary outcome was International Prostate Symptom Score (IPSS) before and after bariatric surgery. Secondary outcomes were changed in body mass index (BMI) and total body weight (TBW). Weighted mean differences (MD) were calculated for continuous outcomes. RESULTS: Seven studies were included in the analysis of 334 patients undergoing bariatric surgery. Mean study follow-up was between 3 and 36 months. IPSS score ranged from 3-12.7 preoperatively and 1.9-6.9 postoperatively. There was a statistically significant improvement in the IPSS score following bariatric surgery (MD 2.82, 95% CI 0.96 to 4.69, p=0.003). Bariatric surgery also resulted in statistically significant reduction of BMI and TBW. CONCLUSION: Bariatric surgery produces a significant improvement on lower urinary tract symptoms in men with obesity. This may be due to improvement of insulin sensitivity, testosterone levels or lipid profile associated with weight loss.

Regional Variation in Unmet Need for Metabolic Surgery in England: a Retrospective, Multicohort Analysis.

Metabolic surgery provision is severely limited despite extensive supportive trial evidence. This study estimated the eligible population and the unmet need for metabolic surgery within English regions. Health Survey for England, National Diabetes Audit and population estimates were used to estimate the metabolic surgery eligible population by English region. Hospital Episode Statistics data was examined for metabolic surgery procedure volume by region (2013-2019). Regression analysis examined factors associated with metabolic surgery eligibility. 7.3% of the English population is potentially eligible for metabolic surgery; equivalent to 3.21 million people. Only 0.20% of the eligible English population receive metabolic surgery per year (regional variation 0.08-0.41%). The metabolic surgery eligible population was more likely to be female, older, have fewer educational qualifications and live in more deprived areas.

Neuron type-specific increase in lamin B1 contributes to nuclear dysfunction in Huntington's disease.

Lamins are crucial proteins for nuclear functionality. Here, we provide new evidence showing that increased lamin B1 levels contribute to the pathophysiology of Huntington's disease (HD), a CAG repeat-associated neurodegenerative disorder. Through fluorescence-activated nuclear suspension imaging, we show that nucleus from striatal medium-sized spiny and CA1 hippocampal neurons display increased lamin B1 levels, in correlation with altered nuclear morphology and nucleocytoplasmic transport disruption. Moreover, ChIP-sequencing analysis shows an alteration of lamin-associated chromatin domains in hippocampal nuclei, accompanied by changes in chromatin accessibility and transcriptional dysregulation. Supporting lamin B1 alterations as a causal role in mutant huntingtin-mediated neurodegeneration, pharmacological normalization of lamin B1 levels in the hippocampus of the R6/1 mouse model of HD by betulinic acid administration restored nuclear homeostasis and prevented motor and cognitive dysfunction. Collectively, our work points increased lamin B1 levels as a new pathogenic mechanism in HD and provides a novel target for its intervention.

A Meta-analysis of the Impact of Bariatric Surgery on Back Pain.

BACKGROUND: The functional aspects of obesity are increasingly recognised as a significant clinical and public health concern. Whilst there is substantial evidence for the beneficial impact of bariatric surgery on metabolic and cardiovascular disease, there is less understanding of the quantitative effect of bariatric surgery on back pain. The aim of this meta-analysis was to assess the impact of bariatric surgery on back pain in reported studies. METHODS: Medline, Embase, conference proceedings and reference lists were searched for studies assessing quantitative back pain scores both before and after bariatric surgery. The primary outcome was visual analogue score for back pain pre- and post-bariatric surgery. Secondary outcomes were change in BMI, SF-36 quality of life scores and Oswestry Disability Index (ODI) scores. Weighted mean differences (MD) were calculated for continuous outcomes. RESULTS: Seven studies were included in the analysis of 246 patients undergoing bariatric surgery. Mean study follow-up was between 3 and 24 months. There was a statistically significant reduction in visual analogue score for back pain following bariatric surgery (MD - 3.01; 95% CI - 4.19 to - 1.89; p < 0.001). Bariatric surgery also resulted in statistically significant improvements in BMI, SF-36 score and ODI score. CONCLUSIONS: Bariatric surgery produces significant and quantifiable reductions in back pain. This may be commuted through reductions in axial load or improved quality of life, but further studies will improve understanding and aid preoperative counselling.

Transcription-dependent cohesin repositioning rewires chromatin loops in cellular senescence.

Senescence is a state of stable proliferative arrest, generally accompanied by the senescence-associated secretory phenotype, which modulates tissue homeostasis. Enhancer-promoter interactions, facilitated by chromatin loops, play a key role in gene regulation but their relevance in senescence remains elusive. Here, we use Hi-C to show that oncogenic RAS-induced senescence in human diploid fibroblasts is accompanied by extensive enhancer-promoter rewiring, which is closely connected with dynamic cohesin binding to the genome. We find de novo cohesin peaks often at the 3' end of a subset of active genes. RAS-induced de novo cohesin peaks are transcription-dependent and enriched for senescence-associated genes, exemplified by IL1B, where de novo cohesin binding is involved in new loop formation. Similar IL1B induction with de novo cohesin appearance and new loop formation are observed in terminally differentiated macrophages, but not TNFα-treated cells. These results suggest that RAS-induced senescence represents a cell fate determination-like process characterised by a unique gene expression profile and 3D genome folding signature, mediated in part through cohesin redistribution on chromatin.

Simultaneous bilateral total hip arthroplasty dislocation with unilateral foot drop following closed reduction.

Dislocation following primary and revision arthroplasty is a well-recognised complication with an estimated incidence rate of 0.2-10%. We present a rare case of simultaneous bilateral total hip replacement dislocation, complicated by unilateral foot drop following closed reduction, with no improvement in neurological function at 6-month follow-up.

Automated generation of heuristics for biological sequence comparison.

BACKGROUND: Exhaustive methods of sequence alignment are accurate but slow, whereas heuristic approaches run quickly, but their complexity makes them more difficult to implement. We introduce bounded sparse dynamic programming (BSDP) to allow rapid approximation to exhaustive alignment. This is used within a framework whereby the alignment algorithms are described in terms of their underlying model, to allow automated development of efficient heuristic implementations which may be applied to a general set of sequence comparison problems. RESULTS: The speed and accuracy of this approach compares favourably with existing methods. Examples of its use in the context of genome annotation are given. CONCLUSIONS: This system allows rapid implementation of heuristics approximating to many complex alignment models, and has been incorporated into the freely available sequence alignment program, exonerate.

Laparoscopic adjustable gastric banding prior to renal transplantation.

End-stage renal failure is most commonly caused by the obesity-related diseases, diabetes mellitus and essential hypertension, and is best treated with renal transplantation. Obesity may contribute to poor patient and graft survival, and is an exclusion criterion in some renal transplant programs. Diet and exercise programs have not proven to be effective for weight loss before transplantation, and bariatric surgery in any form has not been used in this setting before. We report three morbidly obese patients who underwent laparoscopic adjustable gastric banding to meet the criteria for renal transplantation and subsequently were successfully transplanted.

Poor weight loss despite biliopancreatic diversion and subsequent revision to a 30-cm common channel after initial laparoscopic adjustable gastric banding: an analysis of 8 cases.

BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) fails in 5% of patients due to band-related complications or patient intolerance. A subset of patients subsequently managed with biliopancreatic diversion (BPD) have failed to achieve a percentage of excess weight loss (%EWL) > 50% or a body mass index (BMI) < 35 kg/m(2) even after a further procedure shortening the common channel to 30 cm. METHOD: A computerized obesity database was used to identify the study group and collect preoperative and outcome data. Patient outcomes were analyzed in 2 groups: LAGB removed either because of a failure to lose weight (FTLW) or because of a band-related complication (eg, recurrent gastric prolapse, gastric erosion, intractable dysphagia). RESULTS: A total of 2300 patients underwent LAGB between 1996 and 2003. LAGB failed in 95 (4%) of these patients, 79 of whom had subsequent BPD. Of these 79 patients, 8 (10%) failed to lose further weight and had their common channel shortened to 30 cm. Six patients were identified who, despite this revision surgery, still had a BMI > 35 kg/m(2) or %EWL < 50 and are considered failures. Two further patients failed to lose any weight after revision for what they saw as an unsatisfactory outcome. There was minimal evidence of malabsorption in these 8 patients, and 4 had slow intestinal transit down the alimentary limb of the BPD. CONCLUSION: The reasons for the failure of malabsorption and restrictive surgery in these patients appear to be physiological, not psychological. Uncontrolled hunger, particularly in the patients with FTLW, and an abnormally slow metabolism are likely to be important.

Combining laparoscopic adjustable gastric banding and biliopancreatic diversion after failed bariatric surgery.

BACKGROUND: A percentage of all types of bariatric surgery will fail. Our experience with failed biliopancreatic diversion (BPD) as a primary operation or revision operation for failed laparoscopic adjustable gastric banding (LAGB) convinced us that uncontrolled hunger is often the underlying cause. To control hunger after failed bariatric surgery,a novel approach combining LAGB with BPD-duodenal switch (DS) has been tried. METHODS: Patients who had failed to lose weight after BPD or LAGB were considered in 2 groups. Group 1: patients who had failed LAGB underwent laparoscopic BPD-DS without sleeve gastrectomy, with the LAGB left in-situ. Group 2: patients who had failed primary (subgroup 2a) or revision (subgroup 2b) BPD had a LAGB placed with no other revision of their surgery. RESULTS: 11 patients have undergone this form of revision surgery with little morbidity. Mean age at the original operation was 45 years, mean (range) BMI was 45.3 (38-62) kg/m(2). After the reoperation, at 3 months (9 patients) mean BMI was 30 kg/m(2) and at 6 months (4 patients) mean BMI was 27 kg/m(2). CONCLUSION: In this small study, combination surgery was safe and effective for failed BPD or LAGB. LAGB failure may be best managed with DS malabsorption without gastric resection.

Bowel-associated dermatosis-arthritis syndrome after biliopancreatic diversion.

The bowel-associated dermatosis-arthritis syndrome (BADAS), originally called the bowel bypass syndrome, and described after jejuno-ileal bypass, has subsequently been reported in association with inflammatory bowel disease and after gastric resection. BADAS has not been reported after biliopancreatic diversion (BPD). This case report describes a 47-year-old female who presented with recurrent skin rashes and arthralgia after a BPD, consistent with a clinical diagnosis of BADAS which was confirmed by skin biopsy. To date, she has been managed with cyclical courses of antibiotics without reversal of her surgery. This syndrome may be under-diagnosed and is a condition with which bariatric surgeons should be familiar.

Serum fat-soluble vitamin deficiency and abnormal calcium metabolism after malabsorptive bariatric surgery.

Weight loss after biliopancreatic diversion or duodenal switch is due to decreased calorie absorption secondary to fat malabsorption. Fat malabsorption may also cause essential fat-soluble vitamin deficiencies, which may have severe clinical consequences and alter calcium metabolism. Serum vitamins A, D, E, and K, zinc, parathyroid hormone, corrected calcium, and alkaline phosphatase levels were measured in a cohort of patients who had previously undergone biliopancreatic diversion. Two bariatric surgery units were involved in the study: New York University School of Medicine (New York, NY), and the Wesley Medical Center (Brisbane, Australia). A total of 170 patients completed the study. The incidence of vitamin A deficiency was 69%, vitamin K deficiency 68%, and vitamin D deficiency 63% by the fourth year after surgery. The incidence of vitamin E and zinc deficiency did not increase with time after surgery. The incidence of hypocalcemia increased from 15% to 48% over the study period with a corresponding increase in serum parathyroid hormone values in 69% of patients in the fourth postoperative year. There is a progressive increase in the incidence and severity of hypovitaminemia A, D, and K with time after biliopancreatic diversion and duodenal switch. Calcium metabolism is affected with an increasing incidence of secondary hyperparathyrodisim and evidence of increased bone resorption in 3% of patients. Long-term nutritional monitoring is necessary after malabsorptive operations for morbid obesity.

An overview of Ensembl.

Ensembl (http://www.ensembl.org/) is a bioinformatics project to organize biological information around the sequences of large genomes. It is a comprehensive source of stable automatic annotation of individual genomes, and of the synteny and orthology relationships between them. It is also a framework for integration of any biological data that can be mapped onto features derived from the genomic sequence. Ensembl is available as an interactive Web site, a set of flat files, and as a complete, portable open source software system for handling genomes. All data are provided without restriction, and code is freely available. Ensembl's aims are to continue to "widen" this biological integration to include other model organisms relevant to understanding human biology as they become available; to "deepen" this integration to provide an ever more seamless linkage between equivalent components in different species; and to provide further classification of functional elements in the genome that have been previously elusive.