Henry Wellcome Research Articles

Neuroanatomical correlates of HPA axis biomarkers among children at elevated risk for schizophrenia

Background: The hypothalamic-pituitary-adrenal (HPA) axis disturbances observed in psychosis might feasibly contribute to some of the structural brain abnormalities associated with the disorder (i.e., via the potentially toxic effects of elevated glucocorticoid levels on the brain). However, the association between brain structure and cortisol has rarely been investigated. The current study examined relationships between salivary cortisol and regional brain volumes among at-risk children aged 11-14 years, who present multiple antecedents of schizophrenia (ASz=30) or a family history of illness (FHx=22), and typically-developing children (TD=32). Methods: Volumes of specific brain regions known to express glucocorticoid receptors were extracted from structural brain images using FreeSurfer. Diurnal cortisol levels and the cortisol awakening response (CAR) were determined from multiple salivary cortisol samples obtained throughout the day. Results: In the FHx group only, higher diurnal cortisol was correlated with smaller right amygdala and white matter hypointensity volumes (r=-0.51 and -0.62, respectively, p<0.05). In post-hoc analyses, a higher CAR was associated with smaller bilateral cerebellum, bilateral hippocampus, right ventral diencephalon, and total subcortical grey matter volumes among FHx children with a first-degree relative with schizophrenia. In FHx children with an affected second-degree relative, increased diurnal cortisol levels were associated with smaller left hippocampal and white matter hypointensity volumes. Conclusions: Our findings are consistent with the few previous studies examining cortisol and brain structure among adults with established psychosis. These associations may not necessarily reflect a direct effect of cortisol on the developing brain; indeed, abnormal neurodevelopment affecting these brain regions may contribute to HPA-axis dysregulation. Funding: This work was supported by a Sir Henry Wellcome Postdoctoral Fellowship (107395/Z/15/Z) and a Waterloo Foundation Child Development Fund grant (164/1719)

Benjamin A. Elman, Antiquarianism, Language, and Medical Philology: From Early Modern to Modern Sino-Japanese Medical Discourses, Leiden: Brill (Sir Henry Wellcome Asian Series; 12), 2015, viii+232 pp.

Benjamin A. Elman, Antiquarianism, Language, and Medical Philology: From Early Modern to Modern Sino-Japanese Medical Discourses, Leiden: Brill (Sir Henry Wellcome Asian Series; 12), 2015, viii+232 pp.

ASSYRIOLOGY AT THE MARGINS, THE CASE OF WILLIAM ST. CHAD BOSCAWEN (1855–1913)

This study presents the career of late-nineteenth-century Assyriologist William St. Chad Boscawen (1855–1913) as a case study in recovering contributions to knowledge-making by low-status, marginal actors. Boscawen took Assyriological knowledge and expertise, gained at the British Museum, into a new disciplinary setting: a private museum of history of medicine, owned by pharmaceuticals entrepreneur Henry Wellcome (1853–1936). Yet his relocation was only partially successful, and his contributions to knowledge were transient. I employ a sociological framework to explore how social factors, as much as academic ones, influenced Boscawen's career trajectory. In doing so, I argue that studying marginal figures offers a richer understanding of past Assyriological practices and the wider research community in which the most prominent figures operated.

Sir Henry Solomon Wellcome and Dr Andrew Balfour: an enterprise on the Nile and the early foundation of public health and medical research in the Sudan (1899-1935).

In Sudan, modern medical practice and medical research began soon after the creation of Anglo-Egyptian Sudan at the turn of the 20th century. The benevolent involvement of Sir Henry Solomon Wellcome, and the ingenious feat of his protégé Sir Andrew Balfour, was crucial to the strong foundation of that establishment. Sir Henry Wellcome provided the financial sponsorship plus influential, logistical and moral support. Dr Balfour put great energy into making the enterprise one of the most amazing medical achievements in colonial medicine. Improvement in the public health of the capital Khartoum was emulated by other doctors working in this vast country. Research was not restricted to tropical medicine; it also encompassed agricultural and chemical research. This helped with the establishment of the first modern medical school in the country in 1924 and resulted in the medical service in Sudan being described as one of the best in the world. Many British doctors flocked to Sudan to make a fortune and to set a path for their career back in Britain.

Corrigendum to “Annexin-A1 protein and its relationship to cortisol in human saliva” [Psychoneuroendocrinology 38 (5) (2013) 722–727

a Endocrine Signalling Group, Royal Veterinary College, Royal College Street, London NW1 0TU, UK Centre for Biochemical Pharmacology, The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK Department of Chemistry, University of Basilicata, Potenza, Italy d School of Life Sciences, University of Westminster, London W1W 6UW, UK Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol BS1 3NY, UK

The Journal of Physiology Annual Report 2013–14:Another year of progress

We have just completed another busy and fruitful year for The Journal of Physiology as we continue our mission to promote excellence in the communication of physiology to the world. The Journal is without international boundaries, and below is a summary of where we have recently been, and where we plan to go in 2014–15. We value the support of our readers and those who publish their outstanding findings with us. At the beginning of 2013, The Journal of Physiology Consulting Editor Carol Robinson FRS was made a Dame Commander of the Most Excellent Order of the British Empire (DBE) for Services to Science and Industry. She is widely recognised for her ground-breaking research in mass spectrometry and as a role model for women scientists. In the 2014 New Year Honours list, Peter Ratcliffe FRS, another of The Journal's esteemed Consulting Editors, was awarded a knighthood for his services to clinical medicine. Sir Peter is Head of the Nuffield Department of Clinical Medicine based at the Henry Wellcome Building for Molecular Physiology in Oxford. His laboratory works on understanding the mechanisms by which cells sense and signal hypoxia. In 2013 we published a paper based on the Annual Review Prize Lecture which Peter delivered at Physiology 2012 (the annual meeting of The Physiological Society), Edinburgh, UK, 4 July 2012. Oxygen sensing and hypoxia signalling pathways in animals: the implications of physiology for cancer Ratcliffe PJ (2013) J Physiol 591, 2027–2042 http://jp.physoc.org/content/591/8/2027.full Sadly in 2013 we said goodbye to one of the legends in the field of physiology who had his Nobel Prize winning work in The Journal. David H. Hubel FRS passed away in October after a long and distinguished career in visual neuroscience. Physiology lost one of its giants. The Journal of Physiology lost one of its heroes. David H. Hubel – A man of vision J Physiol 592, issue 1. http://jp.physoc.org/content/592/1.toc

Jebel Moya (Sudan): new dates from a mortuary complex at the southern Meroitic frontier

This paper proposes a new chronology for the burial complex at Jebel Moya, south-central Sudan. It reassesses the body of evidence from Sir Henry Wellcome's original 1911–1914 excavations in order to place the site within a firm chronological framework by: (a) applying an attribute-based approach to discern discrete pottery assemblages; and (b) applying initial OSL dates to facilitate the reliable dating of this site for the first time. Jebel Moya is re-interpreted as a burial complex situated on the southern periphery of the late Meroitic state, and its potential to serve as a chronological and cultural reference point for future studies in south-central and southern Sudan is outlined.

Correction: Genetics of Callous-Unemotional Behavior in Children

The published Financial Disclosure is missing funding information. The following is the correct funding information: We gratefully acknowledge the ongoing contribution of the parents and children in the Twins Early Development Study (TEDS). TEDS is supported by a program grant [G0901245; and previously G0500079] from the U.K. Medical Research Council (MRC), with additional support from the US National Institutes of Health [{type:entrez-nucleotide,attrs:{text:HD044454,term_id:300614086}}HD044454; {type:entrez-nucleotide,attrs:{text:HD046167,term_id:300615601}}HD046167 {type:entrez-nucleotide,attrs:{text:HD059215,term_id:300429756}}HD059215]. Genome-wide genotyping was made possible by grants from the Wellcome Trust Case Control Consortium 2 project [085475/B/08/Z; 085475/Z/08/Z]. RP is supported by a Medical Research Council Research Professorship award [G19/2] and a European Advanced Investigator award [295366]; O.S.P.D. is supported by a Sir Henry Wellcome Fellowship from the Wellcome Trust [WT088984]; C.M.A.H. is supported by a research fellowship from the British Academy. We also thank the Wellcome Trust Case Consortium 2 team for their help with genotyping and quality control of our data.

Roy Lee Moodie (1880–1934) and the beginnings of palaeopathology

Roy Lee Moodie was a geologist whose interest in ancient disease was stimulated by his finding of pathological change in some of the fossils that he studied, including many from the Rancho La Brea site in California. He occupied teaching positions in Chicago, Dallas and Santa Monica and in 1928 began an acquaintance and a correspondence with Henry Wellcome who was then in the United States and appearing before the Senate Committee on Foreign Affairs. Moodie persuaded Wellcome to sponsor his palaeopathological work and the following year he was appointed palaeopathologist to the Wellcome Historical Medical Museum (WHMM) at a salary of six thousand dollars a year, the first person to hold such a title and the first and only occupant of the title at the WHMM or its successor organisations. He published extensively from 1915 until his death in 1934, including his great compendium Paleopathology; an Introduction to the Study of Ancient Evidences of Disease, and the collected papers of Sir Marc Armand Ruffer. He is perhaps best remembered or, at least, most widely quoted for attributing the beginnings of palaeopathology to a publication of Esper in 1774 although the passage in which he did so contained two major errors that have been perpetuated in the literature ever since, the authorship of the publication and the diagnosis of the lesion that he supposed began the study of disease in antiquity.

Professor William Bynum: Academic Pioneer, Role Model and Dear Friend

Professor William Bynum: Academic Pioneer, Role Model and Dear Friend

119 Effect of Ketoconazole Coadministration On Lenvatinib (E7080) Exposure in Healthy Volunteers

B. Carbain, R. Bayliss, K. Boxall, C. Coxon, H. Lebraud, C. Matheson, D. Turner, L. Zhen-Wang, R.J. Griffin. Newcastle Cancer Centre Northern Institute for Cancer Research, University of Newcastle, Newcastle-upon-Tyne, United Kingdom; Department of Biochemistry Henry Wellcome Building, University of Leicester, Leicester, United Kingdom; The Institute of Cancer Research, Cancer Research UK Cancer Therapeutics Unit, Sutton, United Kingdom

118 2-arylamino-6-ethynylpurines as Potent Irreversible Inhibitors of the Mitotic Kinase Nek2

B. Carbain, R. Bayliss, K. Boxall, C. Coxon, H. Lebraud, C. Matheson, D. Turner, L. Zhen-Wang, R.J. Griffin. Newcastle Cancer Centre Northern Institute for Cancer Research, University of Newcastle, Newcastle-upon-Tyne, United Kingdom; Department of Biochemistry Henry Wellcome Building, University of Leicester, Leicester, United Kingdom; The Institute of Cancer Research, Cancer Research UK Cancer Therapeutics Unit, Sutton, United Kingdom

Wellcome Trust: A Long-Term Perspective

The Wellcome Trust was established in 1936 following the death of Sir Henry Wellcome, a pharmaceutical pioneer, progressive industrialist, philanthropist, and archaeologist. Sir Henry left the entire share capital of his pharmaceutical company, theWellcome Foundation, to establish the Trust. From 1966 to 1986, the Wellcome Foundation expanded dramatically, and in 1986, the Wellcome Foundation was floated on the stockmarket asWellcomeplc, eventually becoming part of GlaxoSmithKline. Over the next 15 years all shares in Wellcome plc were sold, and the proceeds were used to form an investment fund—now standing at almost $23.15 billion (£14.98 billion)—creating the independent charitable foundation that the Wellcome Trust is today. The Trust’s broadly definedmission allows it to respond flexibly to medical needs and scientific opportunities. The Trust offers a wide variety of funding schemes, including Investigator Awards, fellowships, and Strategic Awards, and it also supports several major initiatives. Its independence and long-term perspective enable the Trust not only to tackle immediate priorities but to support research that will benefit future generations.

Prestin links extrinsic tuning to neural excitation in the mammalian cochlea

Summary The sensory hair cells of amniote hearing organs are usually distributed in tonotopic array from low to high frequencies and are very sensitively and sharply tuned to acoustic stimulation. Frequency tuning and tonotopicity of non-mammalian auditory hair cells is due largely to intrinsic properties of the hair cells [1], but frequency tuning and tonotopic organisation of the mammalian cochlea has an extrinsic basis in the basilar membrane (BM); a spiralling ribbon of collagen-rich extracellular matrix that decreases in stiffness from the high-frequency base of the cochlea to the low-frequency apex [2,3]. Sensitive frequency tuning is due to amplification, which specifically boosts low-level input to the mechanosensitive hair cells at their tonotopic location to overcome viscous damping [1–3]. In non-mammalian hearing organs, at least, amplification is attributed to calcium-mediated hair bundle motion [1]. In the mammalian cochlea, amplification is the remit of the sensory-motor outer hair cells (OHCs), located within the organ of Corti to exercise maximum mechanical effect on the motion of the BM and transmit cochlear responses to the adjacent sensory inner hair cells (IHCs) and, consequently, to the auditory nerve [1–3] (Figure 1A). OHCs behave like piezoelectric actuators, developing forces along their long axis in response to changes in membrane potential [2]. These forces are due to voltage-dependent conformational changes in the motor molecule prestin, which is densely distributed in the OHC lateral membranes [2].

An anti-hypertensive role for the GPR182 orphan receptor in the rostral ventrolateral medulla of hypertensive rats?

s / Autonomic Neuroscience: Basic and Clinical 163 (2011) 1–133 76 P.092 An anti-hypertensive role for the GPR182 orphan receptor in the rostral ventrolateral medulla of hypertensive rats? S. Milosavljevic (University of Bristol, Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, United Kingdom), N. Japundzic-Zigon (University of Belgrade, Institue of Pharmacology, Clinical Pharmacology and Toxicology, School of Medicine, Serbia), J.F.R. Paton (University of Bristol — Physiology & Pharmacology, United Kingdom), D. Murphy (University of Bristol, Henry Wellcome L.I.N.E, United Kingdom) Affymetrix microarray studies have suggested that the expression of the gene encoding the orphan G protein-coupled receptor GPR182 is up-regulated in the rostral ventrolateral medulla (RVLM) of adult spontaneously hypertensive (SHR) rats in comparison with matched normotensive Wistar control rats. We thus hypothesized that RVLM GPR182 may have a role in the aetiology of high blood pressure in the SHR. To test this hypothesis, we suppressed the expression of GPR182 in the RVLM using Adenoviral vectors expressing specific short hairpin RNAs (shRNAs). Animals were first implanted with radiotelemetry transmitters for chronic MAP and HR registration. Following recovery, rats (SHR, n=6; WKY, n=5) were subjected to bilateral microinjections of Adenoviral vectors (2x10E9 pfu/ml) into the RVLM. In SHRs, both systolic blood pressure (SBP) and diastolic blood pressure (DBP) increased (40±9 mm Hg (p<0.01) and 37±7 mm Hg (p<0.01), respectively) five days after GPR182 knockdown. Heart rate (HR) increased by 69±16 bpm (p<0.01). Similarly, an increase in both SBP and DBP of WKY rats reached a peak five days after the adenoviral vectors administration (29±12 mm Hg (p<0.001) and 22±7 mm Hg (p<0.01), respectively). HR did not exhibit significant changes. A virus expressing enhanced green fluorescent protein had no effect on blood pressure in either strain. These results suggest that GPR182 has a protective, anti-hypertensive role in regulation of blood pressure. GPR182 up-regulation in the SHR maybe a futile attempt by the autonomic nervous system to compensate for the harmful increase in blood pressure.

The Curious and the Glorious

<p>This paper examines the narrative of British history and culture on display at the Wellcome Historical Medical Museum in London from 1913-1932. The Museum was founded by Henry Wellcome (1853-1936), an American pharmaceuticals magnate and naturalized British citizen. This paper focuses on the British scientific relics and healing amulets displayed at the Museum. By way of comparison, it explores the vision of British Empire that was portrayed in the advertising literature produced by Wellcome's firm, Burroughs Wellcome and Company. It also investigates Wellcome's relationship with the British folklorist, Edward Lovett (1852-1933).</p><p>My collection of curiosities, Indian [Native American] relics etc. tally admirably with the house, and so everybody seems rather fascinated with the effect, and in fact I rather like it myself. Some call it ‘Aesthetic’, some say ‘Heathenish’, some ‘Bohemian’, ‘Ideal’, ‘Artistic’, etc. … All in it is very cheerful …</p><p>[Wellcome's] gray eyes glow under his bushy grey eyebrows as he talks of [his childhood], and of the tomahawks, arrows and stone hammers he still treasures to show his British friends. He chuckles: "They sometimes think the people must have been ALL barbarians!"</p>

Commentary: Disengaging the infant mind: Genetic dissociation of attention and cognitive skills in infants - reflections on Leppänen et al. (2011)

Commentary: Disengaging the infant mind: Genetic dissociation of attention and cognitive skills in infants - reflections on Leppänen et al. (2011)

Wellcome's world: a biography of a collection

An Infinity of Things: How Sir Henry Wellcome Collected the World . Frances Larson. Oxford University Press; 2009. If you have a passion, one that leads you to collect hockey cards or porcelain figurines, ask yourself this: Were it not for limitations of space in which to put your things, time in

Peter Williams, The Story of the Wellcome Trust: Unlocking Sir Henry’s Legacy to Medical Research (Hindringham: J.J.G. Publishing, 2010), pp. xvi + 118, £16.95, hardback, ISBN: 978-1-899163-92-2.

Peter Williams, The Story of the Wellcome Trust: Unlocking Sir Henry’s Legacy to Medical Research (Hindringham: J.J.G. Publishing, 2010), pp. xvi + 118, £16.95, hardback, ISBN: 978-1-899163-92-2. - Volume 55 Issue 1

Websites of note

Websites of note