Colonic perforation following mild abdominal trauma in a patient with Crohn's disease: a case report

Colonic perforation following mild abdominal trauma in patients with Crohn's disease is a rare occurrence. We present a case of a 21 year old Crohn's sufferer, who presented to the emergency department with signs of shock and peritonitis following minor abdominal trauma. A computed tomography (CT) scan revealed ascending colonic perforation and he underwent a subsequent right hemicolectomy. This is the first UK report of a patient with inflammatory bowel disease suffering colonic perforation following minimal trauma

Truthmakers and modality

This paper attempts to locate, within an actualist ontology, truthmakers for modal truths: truths of the form or . In section 1 I motivate the demand for substantial truthmakers for modal truths. In section 2 I criticise Armstrong’s account of truthmakers for modal truths. In section 3 I examine essentialism and defend an account of what makes essentialist attributions true, but I argue that this does not solve the problem of modal truth in general. In section 4 I discuss, and dismiss, a theistic account of the source of modal truth proposed by Alexander Pruss. In section 5 I offer a means of (dis)solving the problem

Opportunities and Challenges for the development of 'Core Outcome Sets' in Neuro-Oncology

Core Outcome Sets (COS) define minimum outcomes to be measured and reported in clinical effectiveness trials for a particular health condition/health area. Despite recognition as critical to clinical research design for other health areas, none have been developed for neuro-oncology. COS development projects should carefully consider: scope (how the COS should be used), stakeholders involved in development (including patients as both research partners and participants), and consensus methodologies used (typically a Delphi survey and consensus meeting), as well as dissemination plans. Developing COS for neuro-oncology is potentially challenging due to extensive tumor subclassification (including molecular stratification), different symptoms related to anatomical tumor location, and variation in treatment options. Development of a COS specific to tumor subtype, in a specific location, for a particular intervention may be too narrow and would be unlikely to be used. Equally, a COS that is applicable across a wider area of neuro-oncology may be too broad and therefore lack specificity. This review describes why and how a COS may be developed, and discusses challenges for their development, specific to neuro-oncology. The COS under development are briefly described, including: adult glioma, incidental/untreated meningioma, meningioma requiring intervention, and adverse events from surgical intervention for pediatric brain tumors. Keywords: clinical trial; core outcome set; effectiveness; glioma; meningioma

Using automated imaging to interrogate gonadotrophin-releasing hormone receptor trafficking and function

Gonadotrophin-releasing hormone (GnRH) acts via seven transmembrane receptors on gonadotrophs to stimulate gonadotrophin synthesis and secretion, and thereby mediates central control of reproduction. Type I mammalian GnRHR are unique, in that they lack C-terminal tails. This is thought to underlie their resistance to rapid homologous desensitisation as well as their slow rate of internalisation and inability to provoke G-protein-independent (arrestin-mediated) signalling. More recently it has been discovered that the vast majority of human GnRHR are actually intracellular, in spite of the fact that they are activated at the cell surface by a membrane impermeant peptide hormone. This apparently reflects inefficient exit from the endoplasmic reticulum and again, the absence of the C-tail likely contributes to their intracellular localisation. This review is intended to cover some of these novel aspects of GnRHR biology, focusing on ways that we have used automated fluorescence microscopy (high content imaging) to explore GnRHR localisation and trafficking as well as spatial and temporal aspects of GnRH signalling via the Ca(2+)/calmodulin/calcineurin/NFAT and Raf/MEK/ERK pathways

Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer.

Protein homeostasis (proteostasis) is a potential mechanism that contributes to cancer cell survival and drug resistance. Constitutively active androgen receptor (AR) variants confer anti-androgen resistance in advanced prostate cancer. However, the role of proteostasis involved in next generation anti-androgen resistance and the mechanisms of AR variant regulation are poorly defined. Here we show that the ubiquitin-proteasome-system (UPS) is suppressed in enzalutamide/abiraterone resistant prostate cancer. AR/AR-V7 proteostasis requires the interaction of E3 ubiquitin ligase STUB1 and HSP70 complex. STUB1 disassociates AR/AR-V7 from HSP70, leading to AR/AR-V7 ubiquitination and degradation. Inhibition of HSP70 significantly inhibits prostate tumor growth and improves enzalutamide/abiraterone treatments through AR/AR-V7 suppression. Clinically, HSP70 expression is upregulated and correlated with AR/AR-V7 levels in high Gleason score prostate tumors. Our results reveal a novel mechanism of anti-androgen resistance via UPS alteration which could be targeted through inhibition of HSP70 to reduce AR-V7 expression and overcome resistance to AR-targeted therapies

Terrane correlation between Antarctica, Mozambique and Sri Lanka; comparisons of geochronology, lithology, structure and metamorphism and possible implications for the geology of southern Africa and Antarctica

Analysis of new lithological, structural, metamorphic and geochronological data from extensive mapping in Mozambique permits recognition of two distinct crustal blocks separated by the Lurio Belt shear zone. Extrapolation of the Mozambique data to adjacent areas in Sri Lanka and Dronning Maud Land, Antarctica permits the recognition of similar crustal blocks and allows the interpretation that the various blocks in Mozambique, Sri Lanka and Antarctica were once part of a mega-nappe, forming part of northern Gondwana, which was thrust-faulted c. 600 km over southern Gondwana during amalgamation of Gondwana at c. 590-550 Ma. The data suggest a deeper level of erosion in southern Africa compared with Antarctica. It is possible that this thrust domain extends, through the Zambezi Belt or Valley, as far west as the Damara Orogen in Namibia with the Naukluft nappes in Namibia, the Makuti Group, the Masoso Suite in the Rushinga area and the Urungwe klippen in northern Zimbabwe, fitting the mega-nappe pattern. Erosional products of the mountain belt are now represented by 700-400 Ma age detrital zircons present in the various sandstone formations of the Transantarctic Mountains, their correlatives in Australia, as well as the Urfjell Group (western Dronning Maud Land) and probably the Natal Group in South Africa

Identification and characterization of a spontaneous ovarian carcinoma in Lewis rats

<p>Abstract</p> <p>Background</p> <p>Ovarian carcinoma is the fourth most common cause of death from cancer in women. Limited progress has been made toward improving the survival rate of patients with this disease in part because of the lack of a good animal model. We present here a model of spontaneous ovarian carcinoma arising in a normal Lewis rat.</p> <p>Methods</p> <p>A spontaneously occurring tumor of the left ovary was found in a normal Lewis rat during necropsy, which was sectioned for histological examination and placed into single cell suspension. Tumor cells were passaged <it>in vivo </it>by intraperitoneal injection into immunocompetent Lewis rats, and <it>in vitro </it>culture resulted in generation of a cell line. Tumor cells were examined by flow cytometry for expression of estrogen receptor α, progesterone receptor, androgen receptor, her-2/neu, epithelial cell adhesion molecule, and CA125. β-catenin expression and cellular localization was assessed by immunocytochemistry. RNA was harvested for gene expression profiling and studying the expression of cytokines.</p> <p>Results</p> <p>The tumor, designated FNAR, could be serially transplanted into Lewis rats and propagated as a cell line <it>in vitro</it>, maintaining the properties of the original tumor. The FNAR cells displayed striking morphologic similarities to human ovarian carcinoma, resembling the endometrioid carcinoma subtype of surface epithelial neoplasms. The cells expressed estrogen receptor α, progesterone receptor, androgen receptor, her-2/neu, epithelial cell adhesion molecule, CA125, and nuclear β-catenin. A gene expression profile showed upregulation of a number of genes that are also upregulated in human ovarian carcinoma.</p> <p>Conclusion</p> <p>This reliable model of ovarian carcinoma should be helpful in better understanding the biology of the disease as well as the development of novel treatment strategies.</p

Constraining Disk Parameters of Be Stars using Narrowband H-alpha Interferometry with the NPOI

Interferometric observations of two well-known Be stars, gamma Cas and phi Per, were collected and analyzed to determine the spatial characteristics of their circumstellar regions. The observations were obtained using the Navy Prototype Optical Interferometer equipped with custom-made narrowband filters. The filters isolate the H-alpha emission line from the nearby continuum radiation, which results in an increased contrast between the interferometric signature due to the H-alpha-emitting circumstellar region and the central star. Because the narrowband filters do not significantly attenuate the continuum radiation at wavelengths 50 nm or more away from the line, the interferometric signal in the H-alpha channel is calibrated with respect to the continuum channels. The observations used in this study represent the highest spatial resolution measurements of the H-alpha-emitting regions of Be stars obtained to date. These observations allow us to demonstrate for the first time that the intensity distribution in the circumstellar region of a Be star cannot be represented by uniform disk or ring-like structures, whereas a Gaussian intensity distribution appears to be fully consistent with our observations.Comment: 23 pages, 14 figures, accepted for publication in A