Population-based Research in South Wales: The MRC Pneumoconiosis Research Unit and the MRC Epidemiology Unit

©The Trustee of the Wellcome Trust, London, 2002. First published by the Wellcome Trust Centre for the History of Medicine at UCL, 2002. All volumes are freely available online at: www.history.qmul.ac.uk/research/modbiomed/wellcome_witnesses/Annotated and edited A4 transcript of a Witness Seminar held on 23 March 1999, with extracts from a Witness Seminar on the MRC Pneumoconious Unit held on 9 November 1994. Introduction by Professor George Davey Smith.Annotated and edited A4 transcript of a Witness Seminar held on 23 March 1999, with extracts from a Witness Seminar on the MRC Pneumoconious Unit held on 9 November 1994. Introduction by Professor George Davey Smith.Annotated and edited A4 transcript of a Witness Seminar held on 23 March 1999, with extracts from a Witness Seminar on the MRC Pneumoconious Unit held on 9 November 1994. Introduction by Professor George Davey Smith.Annotated and edited A4 transcript of a Witness Seminar held on 23 March 1999, with extracts from a Witness Seminar on the MRC Pneumoconious Unit held on 9 November 1994. Introduction by Professor George Davey Smith.Annotated and edited A4 transcript of a Witness Seminar held on 23 March 1999, with extracts from a Witness Seminar on the MRC Pneumoconious Unit held on 9 November 1994. Introduction by Professor George Davey Smith.Annotated and edited A4 transcript of a Witness Seminar held on 23 March 1999, with extracts from a Witness Seminar on the MRC Pneumoconious Unit held on 9 November 1994. Introduction by Professor George Davey Smith.Population-based research in south Wales was initially to investigate occupational lung disease in miners. Archie Cochrane, the renowned epidemiologist, and his clinical and environmental studies group at the Pneumoconiosis Research Unit at Llandough Hospital, Cardiff, conducted respiratory and blood pressure surveys of workers in the Welsh valleys. In 1960 the epidemiological studies were separated from pneumoconiosis research and detailed studies began in the new Epidemiological Research Unit (South Wales) in Cardiff on glaucoma, dust diseases in flax, asbestos, steel and slate workers, with later work on iron deficiency anaemia, environmental lead, migraine, asthma, and two high-profile trials showing improved survival following a heart attack with regular use of aspirin and with consumption of a diet rich in oily fish. Statisticians and field workers made important contributions to both randomized controlled trials and observational studies at the unit over five decades. Selections from archived interviews with former members of both units appear as well as a section on the impact on data analysis from steadily increasing computational capacity. Contributors include: the late Dr David Bainton, Sir Christopher Booth, Dr Michael Burr, the late Dr Jeffrey Chapman, Professor Sir Richard Doll (Chair), Dr Peter Elwood, the late Dr Joan Faulkner, Dr Philip D’Arcy Hart, Dr Julian Tudor Hart, Mr Nick Henderson, the late Dr Sheila Howarth, Mrs Janie Hughes, Dr Philip Hugh-Jones, Mrs Marion Jones, Professor Stewart Kilpatrick, the late Dr Bill Miall, Dr Shaun Murphy, Dr Andy Ness, Professor John Pemberton, Professor George Davey Smith, Dr Selwyn St Leger, Dr Stephen Stansfeld, Professor David Strachan, Mr Peter Sweetnam, Dr Hugh Thomas, Mrs Mary Thomas, Dr David Tyrrell, Professor Owen Wade, Professor Estlin Waters, Dr Jean Weddell, Mrs Sheila Wright and Dr John Yarnell. Ness A R, Reynolds L A, Tansey E M. (eds) (2002) Population-based Research in South Wales: The MRC Pneumoconiosis Research Unit and the MRC Epidemiology Unit, Wellcome Witnesses to Twentieth Century Medicine, vol. 13. London: The Wellcome Trust Centre for the History of Medicine at UCL.The Wellcome Trust Centre for the History of Medicine at UCL is funded by the Wellcome Trust, which is a registered charity, no. 210183

High Energy Cosmic Rays From Supernovae

Cosmic rays are charged relativistic particles that reach the Earth with extremely high energies, providing striking evidence of the existence of effective accelerators in the Universe. Below an energy around $\sim 10^{17}$ eV cosmic rays are believed to be produced in the Milky Way while above that energy their origin is probably extragalactic. In the early '30s supernovae were already identified as possible sources for the Galactic component of cosmic rays. After the '70s this idea has gained more and more credibility thanks to the the development of the diffusive shock acceleration theory, which provides a robust theoretical framework for particle energization in astrophysical environments. Afterwards, mostly in recent years, much observational evidence has been gathered in support of this framework, converting a speculative idea in a real paradigm. In this Chapter the basic pillars of this paradigm will be illustrated. This includes the acceleration mechanism, the non linear effects produced by accelerated particles onto the shock dynamics needed to reach the highest energies, the escape process from the sources and the transportation of cosmic rays through the Galaxy. The theoretical picture will be corroborated by discussing several observations which support the idea that supernova remnants are effective cosmic ray factories.Comment: Final draft of a chapter in "Handbook of Supernovae" edited by Athem W. Alsabti and Paul Murdi

Validity-Guided Synthesis of Reactive Systems from Assume-Guarantee Contracts

Automated synthesis of reactive systems from specifications has been a topic of research for decades. Recently, a variety of approaches have been proposed to extend synthesis of reactive systems from proposi- tional specifications towards specifications over rich theories. We propose a novel, completely automated approach to program synthesis which reduces the problem to deciding the validity of a set of forall-exists formulas. In spirit of IC3 / PDR, our problem space is recursively refined by blocking out regions of unsafe states, aiming to discover a fixpoint that describes safe reactions. If such a fixpoint is found, we construct a witness that is directly translated into an implementation. We implemented the algorithm on top of the JKind model checker, and exercised it against contracts written using the Lustre specification language. Experimental results show how the new algorithm outperforms JKinds already existing synthesis procedure based on k-induction and addresses soundness issues in the k-inductive approach with respect to unrealizable results.Comment: 18 pages, 5 figures, 2 table

Effects of senescence on the tumour microenvironment and response to therapy

Cellular senescence is a state of durable cell arrest that has been identified both in vitro and in vivo. It is associated with profound changes in gene expression and a specific secretory profile that includes pro-inflammatory cytokines, growth factors and matrix-remodelling enzymes, referred to as the senescence-associated secretory phenotype (SASP). In cancer, senescence can have anti- or pro-tumour effects. On one hand, it can inhibit tumour progression in a cell autonomous manner. On the other hand, senescence can also promote tumour initiation, progression, metastatic dissemination and resistance to therapy in a paracrine manner. Therefore, despite efforts to target senescence as a potential strategy to inhibit tumour growth, senescent cancer and microenvironmental cells can eventually lead to uncontrolled proliferation and aggressive tumour phenotypes. This can happen either through overcoming senescence growth arrest or through SASP-mediated effects in adjacent tumour cells. This review will discuss how senescence affects the tumour microenvironment, including extracellular matrix remodelling, the immune system and the vascular compartment, to promote tumourigenesis, metastasis and resistance to DNA-damaging therapies. It will also discuss current approaches used in the field to target senescence: senolytics, improving the immune clearance of senescent cells and targeting the SASP

Water dispersible microbicidal cellulose acetate phthalate film

BACKGROUND: Cellulose acetate phthalate (CAP) has been used for several decades in the pharmaceutical industry for enteric film coating of oral tablets and capsules. Micronized CAP, available commercially as "Aquateric" and containing additional ingredients required for micronization, used for tablet coating from water dispersions, was shown to adsorb and inactivate the human immunodeficiency virus (HIV-1), herpesviruses (HSV) and other sexually transmitted disease (STD) pathogens. Earlier studies indicate that a gel formulation of micronized CAP has a potential as a topical microbicide for prevention of STDs including the acquired immunodeficiency syndrome (AIDS). The objective of endeavors described here was to develop a water dispersible CAP film amenable to inexpensive industrial mass production. METHODS: CAP and hydroxypropyl cellulose (HPC) were dissolved in different organic solvent mixtures, poured into dishes, and the solvents evaporated. Graded quantities of a resulting selected film were mixed for 5 min at 37°C with HIV-1, HSV and other STD pathogens, respectively. Residual infectivity of the treated viruses and bacteria was determined. RESULTS: The prerequisites for producing CAP films which are soft, flexible and dispersible in water, resulting in smooth gels, are combining CAP with HPC (other cellulose derivatives are unsuitable), and casting from organic solvent mixtures containing ≈50 to ≈65% ethanol (EtOH). The films are ≈100 µ thick and have a textured surface with alternating protrusions and depressions revealed by scanning electron microscopy. The films, before complete conversion into a gel, rapidly inactivated HIV-1 and HSV and reduced the infectivity of non-viral STD pathogens >1,000-fold. CONCLUSIONS: Soft pliable CAP-HPC composite films can be generated by casting from organic solvent mixtures containing EtOH. The films rapidly reduce the infectivity of several STD pathogens, including HIV-1. They are converted into gels and thus do not have to be removed following application and use. In addition to their potential as topical microbicides, the films have promise for mucosal delivery of pharmaceuticals other than CAP

Monitoring the vascular response and resistance to sunitinib in renal cell carcinoma in vivo with susceptibility contrast MRI

Antiangiogenic therapy is efficacious in metastatic renal cell carcinoma (mRCC). However, the ability of antiangiogenic drugs to delay tumor progression and extend survival is limited, due to either innate or acquired drug resistance. Furthermore, there are currently no validated biomarkers that predict which mRCC patients will benefit from antiangiogenic therapy. Here, we exploit susceptibility contrast MRI (SC-MRI) using intravascular ultrasmall superparamagnetic iron oxide particles to quantify and evaluate tumor fractional blood volume (fBV) as a noninvasive imaging biomarker of response to the antiangiogenic drug sunitinib. We also interrogate the vascular phenotype of RCC xenografts exhibiting acquired resistance to sunitinib. SC-MRI of 786-0 xenografts prior to and 2 weeks after daily treatment with 40 mg/kg sunitinib revealed a 71% (P < 0.01) reduction in fBV in the absence of any change in tumor volume. This response was associated with significantly lower microvessel density (P < 0.01) and lower uptake of the perfusion marker Hoechst 33342 (P < 0.05). The average pretreatment tumor fBV was negatively correlated (R2 = 0.92, P < 0.0001) with sunitinib-induced changes in tumor fBV across the cohort. SC-MRI also revealed suppressed fBV in tumors that acquired resistance to sunitinib. In conclusion, SC-MRI enabled monitoring of the antiangiogenic response of 786-0 RCC xenografts to sunitinib, which revealed that pretreatment tumor fBV was found to be a predictive biomarker of subsequent reduction in tumor blood volume in response to sunitinib, and acquired resistance to sunitinib was not associated with a parallel increase in tumor blood volume

Prognostic potential of body composition indices in detecting risk of musculoskeletal injury in army officer cadet profiles.

OBJECTIVES: High values in most of the body composition indices have been related to musculoskeletal injuries, but limited data exists on the accuracy of these diagnoses when detecting musculoskeletal injuries in military populations. METHODS: The suitability of body fat percentage, body mass index, fat mass index and fat free mass index to identify injury risk was examined in a group of army officer recruits. All body composition diagnoses were measured in 268 male army officer recruits prior to the commencement of basic combat training. Musculoskeletal injury was identified using codes from the International Classification of Diseases. The area under the curve, in the receiver operating characteristic curve, was used to quantify the overall ability to discriminate between those who were injured and those who were not. RESULTS: The statistics indicated that all indices, apart from body mass index, had a significant possibility to detect musculoskeletal injury potential (p 22, for fat mass index >6.5 and for fat free mass index <16.5. CONCLUSION: Body mass index values can not similarly detect the possibility of occurrence of musculoskeletal injuries in army officer recruits, just as other body composition diagnoses related to fat mass or/and free fat mass. However, the cut off-points related to the overall diagnostic performance of each body composition index should be used with caution and in accordance with the aims of each experimental setting

Cosmic ray diffusion near the Bohm limit in the Cassiopeia A supernova remnant

Supernova remnants (SNRs) are believed to be the primary location of the acceleration of Galactic cosmic rays, via diffusive shock (Fermi) acceleration. Despite considerable theoretical work the precise details are still unknown, in part because of the difficulty in directly observing nucleons that are accelerated to TeV energies in, and affect the structure of, the SNR shocks. However, for the last ten years, X-ray observatories ASCA, and more recently Chandra, XMM-Newton, and Suzaku have made it possible to image the synchrotron emission at keV energies produced by cosmic-ray electrons accelerated in the SNR shocks. In this article, we describe a spatially-resolved spectroscopic analysis of Chandra observations of the Galactic SNR Cassiopeia A to map the cutoff frequencies of electrons accelerated in the forward shock. We set upper limits on the electron diffusion coefficient and find locations where particles appear to be accelerated nearly as fast as theoretically possible (the Bohm limit).Comment: 18 pages, 5 figures. Accepted for publication in Nature Physics (DOI below), final version available week of August 28, 2006 at http://www.nature.com/nphy