Hodson L.,Churchill Hospital |
Fielding B.A.,Churchill Hospital |
Fielding B.A.,University of Surrey
Progress in Lipid Research | Year: 2013
Different lipid fractions in humans have characteristic fatty acid profiles and these are maintained partly through diet and to a lesser extent through endogenous synthesis. The enzyme stearoyl-CoA desaturase (SCD; EC 18.104.22.168) is the rate-limiting enzyme in the synthesis of monounsaturated fatty acids such as palmitoleic acid (16:1 n-7) and oleic acid (18:1 n-9). These are the two most abundant monounsaturated fatty acids in human plasma lipids, membranes and adipose tissue. Although in quantitative terms, the endogenous synthesis of fatty acids in humans is not great in most circumstances, it is becoming increasingly evident that SCD plays important structural and metabolic roles. In addition, 16:1 n-7 has been purported to act as a beneficial 'lipokine' in an animal model. Research in humans has relied on indirect measurements of SCD1 activity and therefore, much of our understanding has come from work on animal models. However, results have been somewhat counterintuitive and confusing, so the purpose of this review is to try to summarise our current understanding of this fascinating enzyme.© 2012 Elsevier Ltd. All rights reserved.
Visscher P.M.,University of Queensland |
Brown M.A.,University of Queensland |
McCarthy M.I.,University of Oxford |
McCarthy M.I.,Churchill Hospital |
Yang J.,Queensland Institute of Medical Research
American Journal of Human Genetics | Year: 2012
The past five years have seen many scientific and biological discoveries made through the experimental design of genome-wide association studies (GWASs). These studies were aimed at detecting variants at genomic loci that are associated with complex traits in the population and, in particular, at detecting associations between common single-nucleotide polymorphisms (SNPs) and common diseases such as heart disease, diabetes, auto-immune diseases, and psychiatric disorders. We start by giving a number of quotes from scientists and journalists about perceived problems with GWASs. We will then briefly give the history of GWASs and focus on the discoveries made through this experimental design, what those discoveries tell us and do not tell us about the genetics and biology of complex traits, and what immediate utility has come out of these studies. Rather than giving an exhaustive review of all reported findings for all diseases and other complex traits, we focus on the results for auto-immune diseases and metabolic diseases. We return to the perceived failure or disappointment about GWASs in the concluding section. © 2012 The American Society of Human Genetics.
Hirt R.P.,Northumbria University |
Sherrard J.,Churchill Hospital
Current Opinion in Infectious Diseases | Year: 2015
Purpose of review: To integrate a selection of the most recent data on Trichomonas vaginalis origins, molecular cell biology and T. vaginalis interactions with the urogenital tract microbiota with trichomoniasis symptoms and clinical management. Recent findings: Transcriptomics and proteomics datasets are accumulating, facilitating the identification and prioritization of key target genes to study T. vaginalis pathobiology. Proteins involved in host sensing and cytoskeletal plasticity during T. vaginalis amoeboid transformation were identified. T. vaginalis was shown to secrete exosomes and a macrophage migration inhibitory factor-like protein that both influence host-parasite interactions. T. vaginalis co-infections with Mycoplasma species and viruses were shown to modulate the inflammatory responses, whereas T. vaginalis interactions with various Lactobacillus species inhibit parasite interactions with human cells. T. vaginalis infections were also shown to be associated with bacterial vaginosis. A broader range of health sequelae is also becoming apparent. Diagnostics for both women and men based on the molecular approaches are being refined, in particular for men. Summary: New developments in the molecular and cellular basis of T. vaginalis pathobiology combined with data on the urogenital tract microbiota and immunology have enriched our knowledge on human-microbe interactions that will contribute to increasing our capacity to prevent and treat T. vaginalis and other sexually transmitted infections. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Ashcroft F.M.,University of Oxford |
Rorsman P.,University of Oxford |
Rorsman P.,Churchill Hospital
Cell | Year: 2012
Diabetes is a major global problem. During the past decade, the genetic basis of various monogenic forms of the disease, and their underlying molecular mechanisms, have been elucidated. Many genes that increase type 2 diabetes (T2DM) risk have also been identified, but how they do so remains enigmatic. Nevertheless, defective insulin secretion emerges as the main culprit in both monogenic and polygenic diabetes, with environmental and lifestyle factors, via obesity, accounting for the current dramatic increase in T2DM. There also have been significant advances in therapy, particularly for some monogenic disorders. We review here what ails the β cell and how its function may be restored. © 2012 Elsevier Inc.
Church D.N.,Churchill Hospital |
Talbot D.C.,Churchill Hospital
Current Oncology Reports | Year: 2012
Survivin is a 16.5 kDa protein that functions to inhibit apoptosis, promote proliferation, and enhance invasion. Absent in most adult tissues, survivin is selectively upregulated in many human tumors, where its overexpression correlates with poor outcome and treatment resistance. Consequently, survivin is a promising target for cancer therapy. Preclinical data demonstrate that survivin inhibition reduces cell proliferation, increases apoptosis, and sensitises cells to cytotoxic agents and radiotherapy. The pharmacological surviving inhibitors LY2181308 and YM155 have demonstrated acceptable toxicity and evidence of therapeutic efficacy as single agents in early-phase clinical trials. Current efforts seek to define the optimum use of survivin inhibitors in combination with cytotoxic therapies, where it is hoped that preclinical evidence of treatment synergy will translate into improved therapeutic efficacy. Results from these ongoing studies are keenly awaited. © 2012 Springer Science+Business Media, LLC.
Karavitaki N.,Churchill Hospital
Journal of Endocrinological Investigation | Year: 2014
Craniopharyngiomas are rare epithelial tumours arising along the path of the craniopharyngeal duct. Their pathogenesis remains uncertain and they can present with a variety of manifestations attributed to pressure effects to surrounding structures. The optimal management of craniopharyngiomas remains challenging mainly due to their sharp, irregular borders and their tendency to adhere to vital neurovascular structures making surgical manipulations potentially hazardous to vital brain areas. Non-aggressive surgery followed by radiotherapy is currently the most widely used option possibly achieving the most optimal long-term outcome. Other treatment modalities including intracystic irradiation, intracystic instillation of antineoplasmatic agents and stereotactic radiotherapy are also available in our armamentarium. The long-term morbidities related with the craniopharyngiomas and their treatment remain significant, with hypothalamic damage playing the protagonist role and requiring further studies to identify measures that will improve the prognosis of the patients. © Italian Society of Endocrinology (SIE) 2014.
Venning V.A.,Churchill Hospital
Dermatologic Clinics | Year: 2011
Linear IgA disease is one of the rarer subepidermal blistering diseases. Linear IgA disease is a chronic, acquired, autoimmune blistering disease that is characterized by subepidermal blistering and linear deposition of IgA basement membrane antibodies. The disease affects both children and adults and, although there are some differences in their clinical presentations, there is considerable overlap with shared immunopathology and immunogenetics. © 2011 Elsevier Inc.
Tzivanakis A.,Churchill Hospital
Diseases of the colon and rectum | Year: 2012
Ileocecal resection is the most commonly performed operation in patients with Crohn's disease. Anastomotic-associated complications, with their associated morbidity, are the most feared risks of surgery. This study aimed to assess the influence of a variety of putative risk factors in a homogenous group of patients undergoing first or subsequent surgery for Crohn's disease to quantify the cumulative risk for anastomotic-associated complications. All patients undergoing ileocecal or ileocolic resections for Crohn's disease from 2000 to 2010 were studied with the use of a prospective database. Demographics, operative details, possible risk factors, and anastomotic-associated complications were recorded. Patients having strictureplasties, multiple resections, or subtotal colonic resections were excluded from analysis. Statistical analysis was by univariate analysis (Mann-Whitney U test) and binary logistic regression. An anastomotic-associated complication was defined as a proven anastomotic leak, postoperative fistulation, or intra-abdominal abscess formation. Two hundred seven patients (109 female) with a median age of 35 years (range, 13-75 years) were identified. One hundred seventy-three underwent primary anastomosis, 94 as an emergency procedure. Fifty-three had laparoscopic (5 converted) procedures. Nineteen of 173 anastomotic complication events (11%) were recorded. Steroid usage (OR 2.67, 95% CI 1.0-7.2) and the presence of preoperative abscess formation (OR 3.4, 95% CI 1.2-9.8) were identified as independent predictors of anastomotic-associated complications. In the absence of both steroids and intra-abdominal abscess, the risk of anastomotic complications was 6%, which increased to 14% if either risk factor was present. When both risk factors were present, complication rates reached 40%. Steroid usage and preoperative abscess were associated with higher rates of anastomotic complications following ileocolic resection for Cohn's disease. When both risk factors are present, it is best to avoid primary anastomosis.
Turney B.W.,Churchill Hospital
Journal of Endourology | Year: 2014
Background and Purpose: Obtaining renal access is one of the most important and complex steps in learning percutaneous nephrolithotomy (PCNL). Ideally, this skill should be practiced outside the operating room. There is a need for anatomically accurate and cheap models for simulated training. The objective was to develop a cost-effective, anatomically accurate, nonbiologic training model for simulated PCNL access under fluoroscopic guidance. Methods: Collecting systems from routine computed tomography urograms were extracted and reformatted using specialized software. These images were printed in a water-soluble plastic on a three-dimensional (3D) printer to create biomodels. These models were embedded in silicone and then the models were dissolved in water to leave a hollow collecting system within a silicone model. These PCNL models were filled with contrast medium and sealed. A layer of dense foam acted as a spacer to replicate the tissues between skin and kidney. Results: 3D printed models of human collecting systems are a useful adjunct in planning PCNL access. The PCNL access training model is relatively low cost and reproduces the anatomy of the renal collecting system faithfully. A range of models reflecting the variety and complexity of human collecting systems can be reproduced. The fluoroscopic triangulation process needed to target the calix of choice can be practiced successfully in this model. Conclusions: This silicone PCNL training model accurately replicates the anatomic architecture and orientation of the human renal collecting system. It provides a safe, clean, and effective model for training in accurate fluoroscopy-guided PCNL access. © 2014, Mary Ann Liebert, Inc.
Harrison P.,Churchill Hospital
Platelets | Year: 2012
Although there are many new and effective anti-P2Y12 drugs available, clopidogrel in its original or generic forms will probably remain the most widely used and cheaper option. As clopidogrel is a pro-drug, there is marked heterogeneity in drug responsiveness between individuals and lack of responsiveness is associated with poorer clinical outcomes. Various platelet function and genetic tests are now available for potentially measuring whether clopidogrel effectively inhibits platelet function. Monitoring of P2Y12 inhibition and/or identification of loss of function cytochrome P-450 genotypes could, therefore, offer the potential of tailoring therapy by identifying poor responders to clopidogrel and optimizing the levels of platelet inhibition using, for example, alternative drugs such as prasugrel or ticagrelor. The question remains whether any of these tests have prognostic utility with a defined therapeutic window to reliably identify hypo or hyper-responsive patients who may have an increased risk of thrombosis or bleeding, respectively? Once such patients are identified, can the tests then be subsequently used to demonstrate a change or improvement in platelet reactivity by using alternative therapies and equate this with improved clinical outcome? In this review, we describe an overview of the current platelet and genetic tests available and discuss whether these tests will ever become used routinely. © 2012 Informa UK Ltd.