Involution of the mouse mammary gland is associated with an immune cascade and an acute-phase response, involving LBP, CD14 and STAT3

INTRODUCTION: Involution of the mammary gland is a complex process of controlled apoptosis and tissue remodelling. The aim of the project was to identify genes that are specifically involved in this process. METHODS: We used Affymetrix oligonucleotide microarrays to perform a detailed transcript analysis on the mechanism of controlled involution after withdrawal of the pups at day seven of lactation. Some of the results were confirmed by semi-quantitative reverse transcriptase polymerase chain reaction, Western blotting or immunohistochemistry. RESULTS: We identified 145 genes that were specifically upregulated during the first 4 days of involution; of these, 49 encoded immunoglobulin genes. A further 12 genes, including those encoding the signal transducer and activator of transcription 3 (STAT3), the lipopolysaccharide receptor (CD14) and lipopolysaccharide-binding protein (LBP), were involved in the acute-phase response, demonstrating that the expression of acute-phase response genes can occur in the mammary gland itself and not only in the liver. Expression of LBP and CD14 was upregulated, at both the RNA and protein level, immediately after pup withdrawal; CD14 was strongly expressed in the luminal epithelial cells. Other genes identified suggested neutrophil activation early in involution, followed by macrophage activation late in the process. Immunohistochemistry and histological staining confirmed the infiltration of the involuting mammary tissue with neutrophils, plasma cells, macrophages and eosinophils. CONCLUSION: Oligonucleotide microarrays are a useful tool for identifying genes that are involved in the complex developmental process of mammary gland involution. The genes identified are consistent with an immune cascade, with an early acute-phase response that occurs in the mammary gland itself and resembles a wound healing process

A Glasgow tipple-transjugular intrahepatic portosystemic shunt insertion prior to Whipple resection

Abdominal surgery performed in patients with significant liver disease and portal hypertension is associated with high mortality rates, with even poorer outcomes associated with complex pancreaticobiliary operations. We report on a patient requiring portal decompression via transjugular intrahepatic portosystemic shunt (TIPS) prior to a pancreaticoduodenectomy. The 49-year-old patient presented with pain, jaundice and weight loss. At ERCP an edematous ampulla was biopsied, revealing high-grade dysplasia within a distal bile duct adenoma. Liver biopsy was performed to investigate portal hypertension, confirming congenital hepatic fibrosis (CHF). A TIPS was performed to enable a pancreaticoduodenectomy. Prophylactic TIPS can be performed for preoperative portal decompression for patients requiring pancreatic resection. A potentially curative resection was performed when abdominal surgery was initially thought impossible. Notably, CHF has been associated with the development of cholangiocarcinoma in only four previous instances, with this case being only the second reported distal bile duct cholangiocarcinoma

Nonorientable spacetime tunneling

Misner space is generalized to have the nonorientable topology of a Klein bottle, and it is shown that in a classical spacetime with multiply connected space slices having such a topology, closed timelike curves are formed. Different regions on the Klein bottle surface can be distinguished which are separated by apparent horizons fixed at particular values of the two angular variables that eneter the metric. Around the throat of this tunnel (which we denote a Klein bottlehole), the position of these horizons dictates an ordinary and exotic matter distribution such that, in addition to the known diverging lensing action of wormholes, a converging lensing action is also present at the mouths. Associated with this matter distribution, the accelerating version of this Klein bottlehole shows four distinct chronology horizons, each with its own nonchronal region. A calculation of the quantum vacuum fluctuations performed by using the regularized two-point Hadamard function shows that each chronology horizon nests a set of polarized hypersurfaces where the renormalized momentum-energy tensor diverges. This quantum instability can be prevented if we take the accelerating Klein bottlehole to be a generalization of a modified Misner space in which the period of the closed spatial direction is time-dependent. In this case, the nonchronal regions and closed timelike curves cannot exceed a minimum size of the order the Planck scale.Comment: 11 pages, RevTex, Accepted in Phys. Rev.

Fluctuations as probe of the QCD phase transition and freeze-out in heavy ion collisions at LHC and RHIC

We discuss the relevance of higher order moments of net baryon number fluctuations for the analysis of freeze-out and critical conditions in heavy ion collisions at LHC and RHIC. Using properties of O(4) scaling functions, we discuss the generic structure of these higher moments at vanishing baryon chemical potential and apply chiral model calculations to explore their properties at non-zero baryon chemical potential. We show that the ratios of the sixth to second and eighth to second order moments of the net baryon number fluctuations change rapidly in the transition region of the QCD phase diagram. Already at vanishing baryon chemical potential they deviate considerably from the predictions of the hadron resonance gas model which reproduce the second to fourth order moments of the net proton number fluctuations at RHIC. We point out that the sixth order moments of baryon number and electric charge fluctuations remain negative at the chiral transition temperature. Thus, they offer the possibility to probe the proximity of the thermal freeze-out to the crossover line.Comment: 24 pages, 12 EPS files, revised version, to appear in EPJ

Classical and Quantum Strings in compactified pp-waves and Godel type Universes

We consider Neveu-Schwarz pp-waves with spacetime supersymmetry. Upon compactification of a spacelike direction, these backgrounds develop Closed Null Curves (CNCs) and Closed Timelike Curves (CTCs), and are U-dual to supersymmetric Godel type universes. We study classical and quantum strings in this background, with emphasis on the strings winding around the compact direction. We consider two types of strings: long strings stabilized by NS flux and rotating strings which are stabilized against collapse by angular momentum. Some of the latter strings wrap around CNCs and CTCs, and are thus a potential source of pathology. We analyze the partition function, and in particular discuss the effects of these string states. Although our results are not conclusive, the partition function seems to be dramatically altered due to the presence of CNCs and CTCs. We discuss some interpretations of our results, including a possible sign of unitary violation.Comment: 42 pages, LaTeX, 2 figure

Remote detection of past habitability at Mars-analogue hydrothermal alteration terrains using an ExoMars Panoramic Camera emulator

JKH is funded by a Birkbeck University of London Graduate Teaching Assistantship. CRC is funded by a Royal Society of Edinburgh Personal Research Fellowship co-funded by Marie Curie Actions. The Aberystwyth research leading to these results has been funded by the UK Space Agency, ExoMars Panoramic Camera (PanCam) Grant Nos. ST/G003114/1, ST/I002758/1, STL001454/1, and the UK Space Agency CREST2 PanCam-2020 research Grant No. ST/L00500X/1. Additional Aberystwyth funding has come from The European Community’s Seventh Framework Programme (FP7/2007-2013), Grant Agreement Nos. 21881 PRoVisG, 241523 PRoViScout, and Grant Agreement No. 312377 PRoViDE. PMG is funded by a UK Space Agency Aurora Fellowship (grants ST/J005215/1 and ST/L00254X/1).A major scientific goal of the European Space Agency’s ExoMars 2018 rover is to identify evidence of life within the martian rock record. Key to this objective is the remote detection of geological substrates that are indicative of past habitable environments, which will rely on visual (stereo wide-angle, and high resolution images) and multispectral (440–1000 nm) data produced by the Panoramic Camera (PanCam) instrument. We deployed a PanCam emulator at four hydrothermal sites in the Námafjall volcanic region of Iceland, a Mars-analogue hydrothermal alteration terrain. At these sites, sustained acidic–neutral aqueous interaction with basaltic substrates (crystalline and sedimentary) has produced phyllosilicate, ferric oxide, and sulfate-rich alteration soils, and secondary mineral deposits including gypsum veins and zeolite amygdales. PanCam emulator datasets from these sites were complemented with (i) NERC Airborne Research and Survey Facility aerial hyperspectral images of the study area; (ii) in situ reflectance spectroscopy (400–1000 nm) of PanCam spectral targets; (iii) laboratory X-ray Diffraction, and (iv) laboratory VNIR (350–2500 nm) spectroscopy of target samples to identify their bulk mineralogy and spectral properties. The mineral assemblages and palaeoenvironments characterised here are analogous to neutral–acidic alteration terrains on Mars, such as at Mawrth Vallis and Gusev Crater. Combined multispectral and High Resolution Camera datasets were found to be effective at capturing features of astrobiological importance, such as secondary gypsum and zeolite mineral veins, and phyllosilicate-rich substrates. Our field observations with the PanCam emulator also uncovered stray light problems which are most significant in the NIR wavelengths and investigations are being undertaken to ensure that the flight model PanCam cameras are not similarly affected.Publisher PDFPeer reviewe

Prioritising research areas for antibiotic stewardship programmes in hospitals: a behavioural perspective consensus paper

SCOPE: Antibiotic stewardship programmes (ASPs) are necessary in hospitals to improve the judicious use of antibiotics. While ASPs require complex change of key behaviours on individual, team, organisation and policy levels, evidence from the behavioural sciences is underutilised in antibiotic stewardship studies across the world, including high-income countries (HICs). A consensus procedure was performed to propose research priority areas for optimising effective implementation of ASPs in hospital settings, using a behavioural perspective. METHODS: A workgroup for behavioural approaches to ASPs was convened in response to the fourth call for leading expert network proposals by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR). Eighteen clinical and academic specialists in antibiotic stewardship, implementation science and behaviour change from four high-income countries with publicly-funded health care systems (that is Canada, Germany, Norway and the UK), met face-to-face to agree on broad research priority areas using a structured consensus method. QUESTION ADDRESSED AND RECOMMENDATIONS: The consensus process on the 10 identified research priority areas resulted in recommendations that need urgent scientific interest and funding to optimise effective implementation of antibiotic stewardship programmes for hospital inpatients in HICs with publicly-funded health care systems. We suggest and detail, behavioural science evidence-guided research efforts in the following areas: 1) Comprehensively identifying barriers and facilitators to implementing antibiotic stewardship programmes and clinical recommendations intended to optimise antibiotic prescribing; 2) Identifying actors ('who') and actions ('what needs to be done') of antibiotic stewardship programmes and clinical teams; 3) Synthesising available evidence to support future research and planning for antibiotic stewardship programmes; 4) Specifying the activities in current antibiotic stewardship programmes with the purpose of defining a 'control group' for comparison with new initiatives; 5) Defining a balanced set of outcomes and measures to evaluate the effects of interventions focused on reducing unnecessary exposure to antibiotics; 6) Conducting robust evaluations of antibiotic stewardship programmes with built-in process evaluations and fidelity assessments; 7) Defining and designing antibiotic stewardship programmes; 8) Establishing the evidence base for impact of antibiotic stewardship programmes on resistance; 9) Investigating the role and impact of government and policy contexts on antibiotic stewardship programmes; and 10) Understanding what matters to patients in antibiotic stewardship programmes in hospitals. Assessment, revisions and updates of our priority-setting exercise should be considered, at intervals of 2 years. To propose research priority areas in low- and medium income countries (LIMCs), the methodology reported here could be applied

Development and validation of the satisfaction with treatment for pain questionnaire (STPQ) among patients with sickle cell disease

A brief measure of patient satisfaction with treatment for pain is needed to help improve the treatment of painful episodes caused by sickle cell disease (SCD), especially during and after the transition from paediatric to adult care. Focus groups of 28 adolescent and adult patients were consulted about the content, clarity and relevance of 30 potential items, resulting in an 18-item version. This was validated by analysing questionnaire responses from 120 patients aged 12-53 years. Confirmatory factor analysis and item analysis indicated five subscales with high internal reliability: ‘Communication and Involvement’ (6 items, α=0.87); ‘Respect and Dignity’ (3 items, α=0.82); ‘Pain Control’ (3 items, α=0.91); ‘Staff Attitudes and Behaviour’ (4 items, α=0.88); and ‘Overall Satisfaction’ (2 items, α=0.85); plus a Total Satisfaction score (18 items, α=0.96). High negative correlations with the Picker Patient Experience Questionnaire, a measure of problem experiences, indicated good convergent validity. Lower satisfaction scores among patients aged over 18 years, those admitted via the emergency department, those treated by non-specialist hospital staff, and those reporting more breakthrough pain indicated good concurrent validity. The questionnaire provides a convenient brief measure that can be used to inform and evaluate improvements in healthcare for adolescent and adult patients with SCD, and could potentially be adapted for other painful conditions.Bart’s Charity Strategic Research Grant (Reference Number 1704); non-restricted financial grants from Kyowa Kirin and Mundipharma; University of Derby Undergraduate Research Scholarship awards; University of Derby REF reinvestment programme