Migraine: Diagnosis, treatment and understanding c1960-2010

seminar transcriptThere are around eight million migraine sufferers in the UK today. This Witness Seminar looked at the last 50 years of research into the diagnosis and treatment of the condition and the changing attitudes of the medical profession towards this debilitating disorder. Chaired by Dr Mark Weatherall, the participants, some of whom were also migraine sufferers, included neurologists and pharmacologists, representatives from patient organizations such as Migraine Action and the Migraine Trust, and GPs and headache nurses. The discussion covered the vascular and neuronal theories of migraine, the early treatment with ergotamine, analgesics and antiemetics, and investigations into the importance of 5-HT. It then moved on to examine the scientific research behind the development of the triptans during the 1980s and impact of their introduction in the early 1990s. More recent treatments, such as the use of Botox (botulinum toxin), were also considered. Other topics included the development of headache classification and diagnostic criteria for migraine; the support for migraine sufferers such as headache clinics, specialist headache nurses, and charities; and the reason why, despite the number of sufferers and its high socio-economic cost, there is often little interest in migraine and research attracts limited fundin

The Recent History of Seasonal Affective Disorder (SAD)

Seminar TranscriptPsychiatric diagnosis is controversial and is regarded by some principally as a means of reinforcing the vested interests of medical professionals and pharmaceutical companies. On the other hand, the phenomena that are described in clinical psychiatric practice are real and clearly extend across time and between cultures. ‘In every culture there is some notion of emotional or psychological difference. Not all cultures identify these differences in the same way, nor do they use identical terms. Equally, however no culture is indifferent to those who are sad, frightened or unintelligible in their conduct.’ 1 The description and diagnosis of Seasonal Affective Disorder (SAD) or ‘winter depression’ is a comparatively recent development which provides an unrivalled opportunity to explore the construction of a psychopathological entity through the relevant peer-reviewed publications, as well as the professional and public reaction to these scientific discoveries. This Witness Seminar provides a riveting insight into the thinking of some key protagonists, both the scientists who developed the diagnosis of SAD as well as those for whom this new clinical entity resonated so clearly with their own experiences. What is the point of diagnosis? Ideally a diagnosis should point to a particular disease process, though even in general medicine this is often not the case. However, in a pragmatic sense the value of diagnosis is that it enables a group of people manifesting particular clinical phenomena to be identified as sharing a common prognosis and response to treatment – in the case of SAD a therapeutic response to artificial bright light. Indeed with SAD, it may be that increasing knowledge about the circadian effects of bright light stimulated a search for medical conditions in which it might be effective, that is, in some sense the availability of a treatment led to the identification of the condition. How truly recent is the identification of SAD as a diagnostic entity? In fact, seasonal variation in mood disorder has long been recognized and Rosenthal and colleagues (1984) quote the eminent nineteenth-century psychiatrist, Emil Kraepelin, as commenting in his standard textbook: ‘Repeatedly I saw in these cases moodiness set in in autumn and pass over in spring ... corresponding in a certain sense to the emotional changes which come over even healthy individuals at the changes of the seaso

Drugs Affecting 5-HT Systems

Seminar transcriptIt was in the very early hours of a February morning in 1977 that I first looked down the microscope and saw yellow fluorescence, characteristic of 5-hydroxytryptamine (5-HT) in frozen sections of Octopus brain. After struggling for two years with the capricious fluorescence histochemical technique to locate catecholamines and 5-HT, I finally had a successful result, and the PhD that had seemed a remote possibility for many months finally began to look feasible. Given the enormously important topic of this volume – the discovery and development of drugs affecting 5-HT systems – this small excursion into Octopus neurochemistry might seem irrelevant. However, cephalopod molluscs have played important roles in the history of 5-HT. More than 30000 pairs of posterior salivary glands of Octopus vulgaris were used by Vittorio Erspamer, for the first extraction and identification of enteramine, which was later shown to be identical to serotonin discovered by John Gaddum, and chemically characterized as 5-hydroxytryptamine. Other molluscs have provided some of the most sensitive bioassays for 5-HT, as Gaddum and Paasonen described in 1955, and several participants in this Witness Seminar recollected either using such bioassays or investigating invertebrate pharmacology at the beginning of their careers. Many reflected, however, that invertebrate receptors seemed to be very different from those found in mammals; they had, as David Wallis put it, ‘a parallel pharmacology’. One Witness, Merton Sandler, remembered attending a lecture by Vittorio Erspamer in London in the early 1950s, and being intrigued enough to start work on the degradative enzyme monoamine oxidase, a field which became highly significant for the development of a whole class of therapeutic drugs: the monoamine oxidase inhibitor

History of the Avon Longitudinal Study of Parents and Children , c.1980-2000

Annotated and edited transcript of a Witness Seminar held on 24 May 2011. Introduction by Professor David Gordon, World Federation for Medical Education.Annotated and edited transcript of a Witness Seminar held on 24 May 2011. Introduction by Professor David Gordon, World Federation for Medical Education.Annotated and edited transcript of a Witness Seminar held on 24 May 2011. Introduction by Professor David Gordon, World Federation for Medical Education.Annotated and edited transcript of a Witness Seminar held on 24 May 2011. Introduction by Professor David Gordon, World Federation for Medical Education.The Avon Longitudinal Survey of Parents and Children (ALSPAC) arose from a proposal in the mid-1980s to design a cohort study in Europe which concentrated on the health of children. The UK-side of this was developed in the former county of Avon and the study has followed more than 14000 children, due between April 1991 and December 1992, from their mothers' pregnancies onwards. A vast amount of data has been collected on health, lifestyle, and environment as well as biological samples of urine, blood and DNA. This has been used to establish genetic and environmental determinants of development and health. With an introduction by Professor David Gordon, this volume addresses the origin and development of ALSPAC, the problems of funding such a major study, the variety of methodologies employed, and the ethical questions associated with the project. Contributors include several of the major scientists involved with ALSPAC including Professor Jean Golding, Scientific and Executive Director of the study until December 2005, as well as clinical scientists, epidemiologists, members of the ethics committee, field workers and study parents.https://qmro.qmul.ac.uk/xmlui/handle/123456789/272

History of the National Survey of Sexual Attitudes and Lifestyles

Annotated and edited transcript of a Witness Seminar held on 14 December 2009. Introduction by Professor Clive Seale, QMUL. First published by Queen Mary, University of London, 2011. ©The Trustee of the Wellcome Trust, London, 2011. All volumes are freely available online at www.history.qmul.ac.uk/research/modbiomed/Annotated and edited transcript of a Witness Seminar held on 14 December 2009. Introduction by Professor Clive Seale, QMULAnnotated and edited transcript of a Witness Seminar held on 14 December 2009. Introduction by Professor Clive Seale, QMULAnnotated and edited transcript of a Witness Seminar held on 14 December 2009. Introduction by Professor Clive Seale, QMULAnnotated and edited transcript of a Witness Seminar held on 14 December 2009. Introduction by Professor Clive Seale, QMULAnnotated and edited transcript of a Witness Seminar held on 14 December 2009. Introduction by Professor Clive Seale, QMULAnnotated and edited transcript of a Witness Seminar held on 14 December 2009. Introduction by Professor Clive Seale, QMULA National Survey of Sexual Attitudes and Lifestyles (NATSAL) was proposed in the mid-1980s. This was to provide data to help predict and prevent the transmission and spread of HIV, in response to the critical need for information on the AIDS epidemic. Set up by biomedical and social scientists, NATSAL-1 was carried out in 1990, and the results used for AIDS projections and the national HIV and sexual health strategy. Subsequent surveys (NATSAL-2 and -3) have followed in 2000 and 2010 extending the objectives to include other sexually transmitted infections such as Chlamydia and Human Papillomavirus. Introduced by Professor Clive Seale, this volume focusses primarily on NATSAL-1 and addresses the background to the survey, the methodology, the results, and the funding: its initial support by the Department of Health, the dramatic withdrawal of government funds and subsequent funding by the Wellcome Trust. Contributors include many of the key people involved in setting up the survey, experts in public and sexual health, individuals from the Wellcome Trust, interviewers, and the Sunday Times journalist who, in September 1989, reported Margaret Thatcher’s veto of Government support.The History of Modern Biomedicine Research Group is funded by the Wellcome Trust, which is a registered charity, no. 210183

Dating the Cryptococcus gattii Dispersal to the North American Pacific Northwest.

The emergence of Cryptococcus gattii, previously regarded as a predominantly tropical pathogen, in the temperate climate of the North American Pacific Northwest (PNW) in 1999 prompted several questions. The most prevalent among these was the timing of the introduction of this pathogen to this novel environment. Here, we infer tip-dated timing estimates for the three clonal C. gattii populations observed in the PNW, VGIIa, VGIIb, and VGIIc, based on whole-genome sequencing of 134 C. gattii isolates and using Bayesian evolutionary analysis by sampling trees (BEAST). We estimated the nucleotide substitution rate for each lineage (1.59 × 10-8, 1.59 × 10-8, and 2.70 × 10-8, respectively) to be an order of magnitude higher than common neutral fungal mutation rates (2.0 × 10-9), indicating a microevolutionary rate (e.g., successive clonal generations in a laboratory) in comparison to a species' slower, macroevolutionary rate (e.g., when using fossil records). The clonal nature of the PNW C. gattii emergence over a narrow number of years would therefore possibly explain our higher mutation rates. Our results suggest that the mean time to most recent common ancestor for all three sublineages occurred within the last 60 to 100 years. While the cause of C. gattii dispersal to the PNW is still unclear, our research estimates that the arrival is neither ancient nor very recent (i.e., <25 years ago), making a strong case for an anthropogenic introduction. IMPORTANCE The recent emergence of the pathogenic fungus Cryptococcus gattii in the Pacific Northwest (PNW) resulted in numerous investigations into the epidemiological and enzootic impacts, as well as multiple genomic explorations of the three primary molecular subtypes of the fungus that were discovered. These studies lead to the general conclusion that the subtypes identified likely emerged out of Brazil. Here, we conducted genomic dating analyses to determine the ages of the various lineages seen in the PNW and propose hypothetical causes for the dispersal events. Bayesian evolutionary analysis strongly suggests that these independent fungal populations in the PNW are all 60 to 100 years old, providing a timing that is subsequent to the opening of the Panama Canal, which allowed for more direct shipping between Brazil and the western North American coastline, a possible driving event for these fungal translocation events

Transcriptomic and Exometabolomic Profiling Reveals Antagonistic and Defensive Modes of Clonostachys rosea Action Against Fusarium graminearum

The mycoparasite Clonostachys rosea ACM941 is under development as a biocontrol organism against Fusarium graminearum, the causative agent of Fusarium head blight in cereals. To identify molecular factors associated with this interaction, the transcriptomic and exometabolomic profiles of C. rosea and F. graminearum GZ3639 were compared during coculture. Prior to physical contact, the antagonistic activity of C. rosea correlated with a response heavily dominated by upregulation of polyketide synthase gene clusters, consistent with the detected accumulation of corresponding secondary metabolite products. Similarly, prior to contact, trichothecene gene clusters were upregulated in F. graminearum, while those responsible for fusarielin and fusarin biosynthesis were downregulated, correlating with an accumulation of trichothecene products in the interaction zone over time. A concomitant increase in 15-acetyl deoxynivalenol-3-glucoside in the interaction zone was also detected, with C. rosea established as the source of this detoxified mycotoxin. After hyphal contact, C. rosea was found to predominantly transcribe genes encoding cell wall–degradation enzymes, major facilitator superfamily sugar transporters, anion:cation symporters, as well as alternative carbon source utilization pathways, together indicative of a transition to necrotropism at this stage. F. graminearum notably activated the transcription of phosphate starvation pathway signature genes at this time. Overall, a number of signature molecular mechanisms likely contributing to antagonistic activity by C. rosea against F. graminearum, as well as its mycotoxin tolerance, are identified in this report, yielding several new testable hypotheses toward understanding the basis of C. rosea as a biocontrol agent for continued agronomic development and application

Provinciality and the Art World: The Midland Group 1961- 1977

This paper takes as its focus the Midland Group Gallery in order to first, make a case for the consideration of the geographies of art galleries. Second, highlight the importance of galleries in the context of cultural geographies of the sixties. Third, discuss the role of provinciality in the operation of art worlds. In so doing it explicates one set of geographies surrounding the gallery – those of the local, regional and international networks that connected to produce art works and art space. It reveals how the interactions between places and practices outside of metropolitan and regional hierarchies provides a more nuanced insight into how art worlds operated during the sixties, a period of growing internationalism of art, and how contested definitions of the provincial played an integral role in this. The paper charts the operations of the Midland Group Gallery and the spaces that it occupied to demonstrate how it was representative of a post-war discourse of provincialism and a corresponding re-evaluation of regional cultural activity

Metabolomic Analysis of Campylobacter jejuni by Direct-Injection Electrospray Ionization Mass Spectrometry

Direct-injection mass spectrometry (DIMS) is a means of rapidly obtaining metabolomic phenotype data in both prokaryotes and eukaryotes. Given our generally poor understanding of Campylobacter metabolism, the high-throughput and relatively simple sample preparation of DIMS has made this an attractive technique for metabolism-related studies and hypothesis generation, especially when attempting to analyze metabolic mutants with no clear phenotype. Here we describe a metabolomic fingerprinting approach with sampling and extraction methodologies optimized for direct-injection electrospray ionization mass spectrometry (ESI-MS), which we have used as a means of comparing wild-type and isogenic mutant strains of C. jejuni with various metabolic blocks