2016 RD&E publications

Permanent URI for this collection

A summary list of all RD&E research outputs published or issued in 2016.


Recent Submissions

Now showing 1 - 5 of 412
  • Item
    PIVOT: Patient information videos on operations trial. A single blinded randomised controlled study
    (Wiley, 2016-06-16) Zimmermann, E; Gordon, E; Homan, E; Heddon, S; Powell, R; Taylor, M
  • Item
    Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study.
    (BioMed Central, 2016-06-01) Iacovazzo, D.; Caswell, R.; Bunce, B.; Jose, S.; Yuan, B.; Hernández-Ramírez, L. C.; Kapur, S.; Caimari, F.; Evanson, J.; Ferraù, F.; Dang, M. N.; Gabrovska, P.; Larkin, S. J.; Ansorge, O.; Rodd, C.; Vance, M. L.; Ramírez-Renteria, C.; Mercado, M.; Goldstone, A. P.; Buchfelder, M.; Burren, C. P.; Gurlek, A.; Dutta, P.; Choong, C. S.; Cheetham, T.; Trivellin, G.; Stratakis, C. A.; Lopes, M-B; Grossman, A. B.; Trouillas, J.; Lupski, J. R.; Ellard, Sian; Sampson, J. R.; Roncaroli, F.; Korbonits, M.
    Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly.We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants.We identified 12 patients (10 females and 2 males; 7.8 %) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases.In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing.
  • Item
    GCK gene mutations are a common cause of childhood-onset MODY (maturity-onset diabetes of the young) in Turkey.
    (Wiley, 2016-09) Haliloglu, B.; Hysenaj, G.; Atay, Z.; Guran, T.; Abalı, S.; Turan, S.; Bereket, A.; Ellard, Sian
    Inactivating heterozygous mutations in the GCK gene are a common cause of MODY and result in mild fasting hyperglycaemia, which does not require treatment. We aimed to identify the frequency, clinical and molecular features of GCK mutations in a Turkish paediatric cohort.
  • Item
    Targeting surface voids to counter membrane disorders in lipointoxication-related diseases.
    (The Company of Biologists, 2016-06-15) Ferru-Clément, R.; Spanova, M.; Dhayal, S.; Morgan, Noel; Hélye, R.; Becq, F.; Hirose, H.; Antonny, B.; Vamparys, L.; Fuchs, P. F. J.; Ferreira, T.
    Saturated fatty acids (SFA), which are abundant in the so-called western diet, have been shown to efficiently incorporate within membrane phospholipids and therefore impact on organelle integrity and function in many cell types. In the present study, we have developed a yeast-based two-step assay and a virtual screening strategy to identify new drugs able to counter SFA-mediated lipointoxication. The compounds identified here were effective in relieving lipointoxication in mammalian β-cells, one of the main targets of SFA toxicity in humans. In vitro reconstitutions and molecular dynamics simulations on bilayers revealed that these molecules, albeit according to different mechanisms, can generate voids at the membrane surface. The resulting surface defects correlate with the recruitment of loose lipid packing or void-sensing proteins required for vesicular budding, a central cellular process that is precluded under SFA accumulation. Taken together, the results presented here point at modulation of surface voids as a central parameter to consider in order to counter the impacts of SFA on cell function.
  • Item
    Microstructure and mechanics of human resistance arteries.
    (American Physiological Society, 2016-12-01) Bell, J S; Adio, A O; Pitt, A; Hayman, L; Thorn, C E; Shore, Angela; Whatmore, J. L.; Winlove, C. P.
    Vascular diseases such as diabetes and hypertension cause changes to the vasculature that can lead to vessel stiffening and the loss of vasoactivity. The microstructural bases of these changes are not presently fully understood. We present a new methodology for stain-free visualization, at a microscopic scale, of the morphology of the main passive components of the walls of unfixed resistance arteries and their response to changes in transmural pressure. Human resistance arteries were dissected from subcutaneous fat biopsies, mounted on a perfusion myograph, and imaged at varying transmural pressures using a multimodal nonlinear microscope. High-resolution three-dimensional images of elastic fibers, collagen, and cell nuclei were constructed. The honeycomb structure of the elastic fibers comprising the internal elastic layer became visible at a transmural pressure of 30 mmHg. The adventitia, comprising wavy collagen fibers punctuated by straight elastic fibers, thinned under pressure as the collagen network straightened and pulled taut. Quantitative measurements of fiber orientation were made as a function of pressure. A multilayer analytical model was used to calculate the stiffness and stress in each layer. The adventitia was calculated to be up to 10 times as stiff as the media and experienced up to 8 times the stress, depending on lumen diameter. This work reveals that pressure-induced reorganization of fibrous proteins gives rise to very high local strain fields and highlights the unique mechanical roles of both fibrous networks. It thereby provides a basis for understanding the micromechanical significance of structural changes that occur with age and disease.