PHYSIOLOGY NEWS

autumn 2007 | number 68

In this issue Picking the ‘best’ political party for science Unexpected hazards of cold and heat Facing the media with animal research Photos by Nick Boros-Toby and Ivor Williams A full report and more images of LifeSciences2007 will appear in the next issue of Physiology News. PHYSIOLOGY NEWS Editorial 3 Meetings The Society’s dog. ‘Rudolf Physiological sciences meet up in Bratislava Chris Fry 4 Magnus gave me to Charles Physiology in Galicia Nataliya Fedirko, Alexej Verkhratsky 5 Sherrington, who gave me to Why did the amino acid cross the placenta? Jane Cleal 7 Henry Dale, who gave me to The Physiological Society in October Living History 1942’ Researching unexpected hazards of cold and heat William Keatinge 9

Published quarterly by The Physiological Society A week in the life of ... David Bunton, Chief Operating Officer at Biopta Ltd 12 Contributions and queries Letter from ... Senior Publications Executive The United Arab Emirates Michelle McLean, Chris Howarth 13 Linda Rimmer The Physiological Society Publications Office Features P O Box 502, Cambridge CB1 0AL, UK What happens to the central respiratory rhythm during breath-holding Michael Parkes 16 Tel: +44 (0)1223 400180 Molecular water pumps – or how water can move uphill Fax: +44 (0)1223 246858 across epithelia Thomas Zeuthen 18 Email: [email protected] Web site: http://www.physoc.org Exercise is a good habit for bowel health Ozgur Kasimay, Berrak Yegen 21

Magazine Editorial Board Central CO2 chemoreception: how can it be done without Editor the perfect receptors? Chun Jiang, Junda Su, Asheebo Rojas 23 Austin Elliott Inspiratory muscle training as an ergogenic aid: credible at University of Manchester, Manchester, UK last? Alison McConnell 26 Members Patricia de Winter Limitation to exercise performance at altitude – where is University College London, London, UK peripheral muscle fatigue important? Markus Amann 28 Sarah Hall Circulating ATP and ADP: important regulators of blood flow Cardiff University, Cardiff, UK and platelet reactivity during exercise Gennady Yegutkin, José González-Alonso 31 Munir Hussain University of Liverpooll, Liverpool, UK Muscular dystrophy and the brain Stewart Head, John Morley 34 John Lee Letters to the Editor 36 Rotherham General Hospital, Rotherham, UK Animal Research Thelma Lovick Facing the media with animal research Sarah Bailey, University of Birmingham, Birmingham, UK Thelma Lovick 37 Bill Winlow The dawn of glasnost for research using animals? Selina Chameleon Communications International, London/ Pearson 38 University of Liverpool, Liverpool, UK Biosciences Federation 39

Foreign Correspondents Prize Lectures John Hanrahan The Physiological Society’s G L Brown Prize Lectures McGill University, Montreal, Canada Peter Taylor, Alexander Zholos, Madeleine Ennis 40 John Morley Workshops University of Western Sydney, NSW, Australia Molecular Techniques Workshops 1996–2007: an integrated approach to teaching molecular biology to physiologists © 2007 The Physiological Society Patrick Harrison, Stanley White, Rod Dimaline 41 ISSN 1476-7996 Education The Physiological Society is registered in England as Teaching physiology – challenges, successes and rewards a company limited by guarantee: No 323575. Judy Harris, Richard Helyer 42 Registered office: PO Box 11319, London WC1X 8WQ Teachers turn students for the day Jayne Hastings 43 Registered Charity: No 211585. From the archives 45 The Society’s journals Printed by The Lavenham Press Ltd The Journal of Physiology 46 Experimental Physiology 46 Memorable Members Edward Conway Roderick Kernan 48 Noticeboard 49 Parliamentary and Scientific Committee 50 Society News 52 Unbelievable! 54 Book reviews 55 PHYSIOLOGY NEWS

Action points Guidelines for contributors In this issue Grants These guidelines are intended to assist For full information on Members ’ authors in writing their contributions Welcome to the Autumn 2007 and Affiliates’ Travel Grants, and to reduce the subsequent editing Physiology News. Network Interaction Grants, Non- process. The Editorial Board of Society Symposia Grants, Physiology News tries to ensure that all Recent ministerial changes and Vacation Studentship Scheme, articles are written in a journalistic style departmental restructurings in so that they will have an immediate Departmental Seminar Scheme, interest value for a wide readership and the UK have ‘moved’ govern- Centres of Excellence and Junior will be readable and comprehensible to mental responsibility for science Fellowships visit: non-experts. In particular, scientific and science policy. It is therefore http://www.physoc.org/grants articles should give a good overview of a appropriate that this issue sees field rather than focus entirely on the our first editorial from outside Membership applications authors’ own research. The Society, as Hilary Leevers Applications for Physiological from CASE discusses the attitude Format of articles of the UK political parties to Society membership are accepted The main message or question posed should throughout the year; applications be introduced in the first paragraph. The science. There are some positives, are reviewed by the Membership background for the topic should then be although the demise of the House Committee on a monthly basis established, leading up to the final of Commons Select Committee and a decision is normally made conclusion. on Science and Technology is a within 15 working days of each worrying development, as Length of articles testified by open letters from the deadline. For full details please This will be determined by the subject matter visit: and agreed with the Senior Publications scientific community in the press http://www.physoc.org/membership Executive. pleading for its retention, e.g. http://education.guardian.co.uk/ Submission of articles higher/news/story/0,,2130978,00.html Change of address Authors should submit articles as a Word Members should inform the document attached to an email. Illustrations This issue also sees our first diary Administration Office of any should be sent as separate attachments (see from the private sector (p. 12), changes of address, telephone, below) and not embedded in the text. and a look at the improving fax or email address. Changes can Illustrations and authors’ photographs climate for animal research be emailed to: [email protected] Authors are encouraged to submit diagrams, (p. 37–39). We also have all our drawings, photographs or other artwork with regular features. their articles or to suggest appropriate illustrations. A photograph of the author(s) Physiology News should also accompany submissions, if Exercise features large in the Deadlines possible. Illustrations and photographs may News and Views articles (four in be colour or black and white, prints, my count), as well as appearing in Letters and articles and all other transparencies or tif/jpeg files with a Teachers turn students for the day contributions for inclusion in the minimum resolution of 300 dpi. Electronic (p. 43), in From the archives Winter 2007 issue, No. 69, should colour figures should be saved in CMYK (p. 45), and in the book reviews reach the Publications Office mode. (p. 55). Given the increasing ([email protected]) by 12 References concern about obesity in the UK’s October 2007. Short news items Authors are requested to keep the number of population, including children, are encouraged, and can usually references to a minimum – preferably no and in our pets too if you believe be included as late copy if space more than two or three. Please cite all recent news reports, perhaps this permits. references in the style of The Journal of Physiology (see Instructions to Authors at will prompt more sedentary Suggestions for articles http://www.physoc.org). physiologists (including me!) to Suggestions for future articles are get exercising. welcome. Please contact either the Senior Publications Executive The Society permits the single copying of Austin Elliott individual articles for private study or Editor or a member of the Editorial research. For copying or reproduction for any Board of Physiology News (see other purpose, written permission must be contents page for details). sought from The Physiological Society ([email protected]).

Physiology News Online Opinions expressed in articles and letters Physiology News is now available submitted by, or commissioned from, Members, Affiliates or outside bodies are not on The Society’s web site: necessarily those of The Physiological A week in the life of ... http://www.physoc.org. Society. David Bunton (p. 12) EDITORIAL PN 3

teachers, three quarters of schools are research of the kind that is getting Picking the ‘best’ political cancelling practical classes, and squeezed out by the increasing party for science universities lose money on every science bureaucracy and central control student they take. associated with most Government The recent reorganisation of Government funding. Taylor has proposed an ministries gives some indication of what Ian Pearson, the new science minister has Innovative Projects Agency (IPA) with a the new Prime Minister thinks of science. said: ‘I express a personal oath that budget of £1 billion a year to ‘create a He has spent most of the last 10 years science will run through, and be at the bridge that links the ideas of today to the telling us that science and technology are heart of, the new Department’s policies. industries and products of tomorrow’. crucial to the country’s future, but [You] will not find us lacking in making Crucially, the IPA is intended to be despite expectant rumours to the sure that science is regarded as being of tolerant of risk. ‘Put simply,’ says Ian contrary, he baulked at the idea of the utmost importance.’ These are fine Taylor, ‘the Research Councils support creating a Department of State with the words, and everyone in the science research; the IPA would procure word ‘science’ in its title. community will hope they are fulfilled. development’. The organisation will be Hopefully, Pearson will not let other free from intrusive intervention from The structure that Gordon Brown did ministers raid the science budget of £98 Ministers and civil servants, and the create – a Department for Innovation, million, as his predecessor did in taskforce has recognised that it will need Universities and Skills – gives a very clear February, with a rather casual attitude to a special arrangement with the National picture of his view of why science is the so-called ‘ring fence’ that is meant Audit Office, which has a risk-averse important. He wants the people of to protect it. attitude that can be harmful to research. Britain to develop science and engineering skills in order to engage in Until about 2005, the Conservative Party Not surprisingly, it’s harder to define a the innovation that will drive the spent years ignoring the existence of specific science agenda from the third economy. Science is a utilitarian science policy, let alone engaging with party Liberal Democrats, but a number of endeavour that can be utilised to the science community. But in the last their key players are driving important enhance social, cultural, environmental couple of years, all of that has changed. agendas. Phil Willis, who took the Chair and especially economic wellbeing. Shadow Chancellor George Osborne has of the House of Commons Science & used his platform to criticise the lack of Technology Committee after the last Nobody can disagree about the academic freedom inherent in some of election, has made great efforts to economic utility of science. Every aspect Gordon Brown’s policies. But his plans emphasise that the more he learns about of the economy is based on technology for a ‘flatter’ tax regime, while plausible science policy, the more clearly he in one way or another, and the UK will and attractive in principle could harm understands how everything is certainly become a much poorer country science unless they were implemented interrelated. We need far more if we do not put our research to good with safeguards to protect the benefits coordination of scientific policies than use. But a good deal of Labour’s effort currently delivered by the tax credits has been the case under all Governments over the past few years has seemed to available for research and development, for the past 20 years. His colleague Evan work from the assumption that by especially those that support smaller Harris has been a great friend to the forcing the research community into companies. scientific community – especially doing research with predicted ‘economic physiology researchers – as an outspoken impact,’ they can create a prosperous The Opposition education team has defender of animal research, while in the high-technology sector. In fact, the started getting to grips with the big House of Lords, Margaret Sharp has been universities have changed out of all issues – like the dramatic shortage of relentless in holding the Government to recognition over the last decade and a qualified teachers and the need to fund account on its Higher Education policy. half, and it seems that almost every really interesting research. Boris In a recent debate, she posed hard young researcher wants to spin out a Johnson’s work at Higher Education and questions about how we can adequately company or license his or her technology. David Willetts’ interest across the range fund research across a diverse university More effort should now be going into of educational issues have started to system, making sure that the high flying creating the economic conditions in develop some interesting thinking about institutions can complete on a global which industry is willing and able to pull science. Mr Willetts will be giving CaSE’s stage without condemning the students those technologies through. Annual Distinguished Lecture on 17 in other universities to courses that do October and setting out some more not involve proper honours-level But the one thing you cannot take away detail (details from Susan O’Dwyer on research projects. from the Labour Party is the dramatic 020 7670 4995). Iain Duncan Smith’s increase in the total finance available for review of social breakdown has also If you had to pick a political Party that research, so that we can now discuss identified the need to address poor was ‘best’ for science, it would not what to do with the money rather than educational achievement in some necessarily be easy. But in all of the complaining because there isn’t any. communities, especially in hard subjects major groups these days, there is at least like science. an understanding that science policy Tony Blair promised ‘education, cannot be ignored in the way that it used education and education’ and Gordon Importantly, David Cameron’s overall to be. That is a great opportunity for the Brown wants the UK to be ‘the most review of his Party’s policies includes a science community, and we should make educated nation in the world’ but their taskforce under former Science Minister sure we use it. policies so far have failed to tackle the Ian Taylor that is looking into all aspects country’s real educational problems, of science and technology. Most Hilary Leevers certainly in science. A million children interestingly, the group has recognised Acting Director, Campaign for Science & are taught physics by unqualified the need to fund genuinely novel Engineering, London, UK

Physiology News | No. 68 | Autumn 2007 | www.physoc.org 4 PN BRATISLAVA, SLOVAKIA

Physiological sciences meet up in Bratislava

This September sees three physiological societies (the Slovak Society, FEPS and our own Society) joining up to host a meeting in Bratislava, the capital of Slovakia. The idea for such a joint venture originated after a FEPS committee meeting in 2003 that saw the after the formal establishment of the by FEPS and our Society given by inclusion of several physiological Slovak Academy of Sciences in 1953. Torben Clausen and Ian McGrath, as societies from Eastern European There remains also a close link with well as an IUPS lecture given by Ole countries into the wider fold of the Czech society, exemplified by the Petersen. Preceding this is a European physiology. There was, annual Physiological Days meeting. European Young Physiologists day and still is, clearly a desire for An example of how Slovak science that allows the new generation of physiologists in many such countries has impacted on public health comes physiologists to choose the agenda to become more involved from the Institute of Experimental and provide pointers for the future. internationally. However, a number Endocrinology, of which our host of factors, not least the cost of travel, Vladimir Strbak is currently Director. Outside the meeting, Bratislava is a limited for many the ability to Goitre was endemic in Slovakia and charming place with an old city participate freely. It was thought one of the first projects of the dominated by the Danube, and that a general physiological Institute after its foundation in 1951 overlooked by a castle that offers societies’ meeting in central Europe was to find its cause and implement fantastic views of the city. You can would faciliate better exchange a programme of iodine prophylaxis travel along the Danube by boat to among scientists throughout Europe by salt iodination, one which Vienna or even to Budapest if you and so the motivation for this achieved resounding success. want a longer excursion, walk into meeting was born. Austria or Hungary themselves along The meeting will host 15 widely the Danube – they are only a few Bratislava was an excellent choice for differing symposia on the mornings kilometres away! - or go many reasons: it is centrally located of each day, and will incorporate free immediately to the north to the with good connections; it is relatively communications from submitted origins of the Carpathian mountains, inexpensive, at least compared to abstracts. The afternoon sessions from where they arc round central most of western Europe, and Slovak will be devoted to other oral and Europe for 1500 km back to the physiology has a long and poster sessions. There are also three Danube in Romania. For those honourable tradition, in particular prestigious lectures, two organised interested in the less obvious sights, to the south of the river is a truly gigantic panelák, the huge and uniform blocks of flats erected by Communist governments as a monument to collectivism and a desire for affordable housing, connected to the old town by a striking bridge.

Whatever your reason for attending, all the organisers welcome you to Bratislava and trust you will find the meeting valuable and fun.

Chris Fry

Physiology News | No. 68 | Autumn 2007 | www.physoc.org INTERNATIONAL WORKSHOP PN 5

Physiology in Galicia Alexej Verkhratsky sets the scene for The Society’s International Workshop

This year The Physiological Society will explore the depths of Western Ukraine. The workshop on Molecular physiology of membrane transport and cell excitability (organised by Alexei Verkhratsky, Oleg Krishtal, Andrey Sibirny and Volodymir Lushchak) will take place in the Carpathian Mountains, in the small resort of Yaremche. Various aspects of molecular physiology of membrane transport will be presented by invited lecturers (see box below), and 40 students will be given the opportunity to present both oral and poster Clockwise from above: Yaremche; the presentations. This meeting continues monastery in the Karpathian mountains; the very successful series of Society the mountain river. workshops, which have run throughout Europe, from Seville to kings and declared wars under Prague, Bucharest, Krakow and Kiev to consensus principles: every nobleman St Petersburg. Incidentally, the very – and these nobleman or 'shlyachta' first Society workshop was organised numbered around 500,000 – had a in Ukraine in Kiev in 2000, and more liberum veto [the forbidding voice], and than 500 students and 100 invited by casting the veto every gentleman lecturers have participated in the could block any and all decision(s). workshops since then. Amazingly, this system worked for many generations and, in the 16th and Western Ukraine has a long and 17th century Polish-Lithuanian turbulent history. It was the only Commonwealth, to a large extent Kievan Rus Princedom which shaped the history of Eastern Europe. withstood the Tatar invasion in the 13th At the beginning of the17th century, century, remaining independent as Polish-Ukrainian troops occupied Halych-Volyn Principality well into the Moscow and remained until 1618. 14th century. Then it gradually fell under Polish control, and in 1569 Yet the country was internally unstable became a part of the Polish-Lithuanian- and plagued with both nationalistic Ukrainian Commonwealth (or 'Rech and religious differences. These Pospolitaya'). This was a most unusual resulted in the 1648 Great Civil War in The Treaty of Versailles in 1919 European political system, based on a which millions of Ukrainians and Poles dismantled Austro-Hungary, and democracy of gentry, which elected perished, thus eventually ruining the Galicia became part of the recreated Commonwealth. This period of decline Poland until 1939, when, under the was heroically interrupted in 1683, framework of the Molotov-Ribbentrop Invited speakers when the Polish-Ukrainian army, led by Nazi-Soviet pact, it was invaded by Jan Sobiessky, routed the Turks under Alexandr Chvatal (Prague , Czech Republic) Soviet troops. During World War II the the walls of Vienna, saving the South- Graham McGeown (Belfast, UK) Ukraine was a major battleground of Jerzi Duszynski (Warsaw, Poland) East of Europe from devastation. The the Eastern Front, seeing vicious th Francis Edwards (London, UK) 18 century witnessed the further fighting and savage guerilla war. Great Leshek Kachmarek (Warsaw, Poland) decay of the Polish-Lithuanian tragedies befell the region, with the Oleg Krishtal (Kiev, Ukraine) Commonwealth, until finally between death and displacement of a large Volodymyr Lushchak (Ivano-Frankovsk, 1772 and 1795 all its lands were proportion of its inhabitants, including Ukraine) partitioned between Russia, Austria the systematic murder of much of Erwin Neher (Göttingen, Germany) and Prussia; Galicia was delivered into Ukraine’s Jewish population. The total Alan North (Manchester, UK) the hands of the Austrian emperor and WWII civilian death roll in the Ukraine Ole Petersen (Liverpool, UK) remained a part of the Austro- has been estimated at 5–8 million. Bert Sakmann (Heidelberg, Germany) Andras Spät (Budapest, Hungary) Hungarian Empire until the end of Galicia was successively occupied by World War I. Soviet, German and again in 1944 by

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Soviet forces, with this final occupation physiologists Jakub Kostzhevski, forcibly re-incorporating Western Tomash Sadej and Gustav Piottovski. At Ukraine into the Soviet Union. The present the Department of Physiology modern history of the Ukraine began is mainly concentrating on the on 24 August 1991, when investigations of electrophysiology and Independence was declared following calcium signalling in various types of the collapse of Soviet communism. secretory cells.

Galicia has long-lasting academic The 2007 Society workshop will be traditions. The first academic hosted by two Galician institutions, the institution was established in 1586 as Institute of Cell Biology (ICB) based in a form of the 'Brotherhood School', Lviv and the Department of which taught languages, mathematics, Biochemistry at Precarpathian astronomy, philosophy and rhetoric. University. The ICB, under the The first university (which initially was directorship of Andrey Sibirny, was almost entirely dedicated to theology established in 2000 as a research and philosophy and was controlled by institute of the Ukrainian Academy of Jesuits) was opened in Lviv on 20 Sciences. The Institute has four January 1661. In the 18th century chairs research departments and two in mathematics, physics and laboratories, which employs ~100 astronomy were established. This staff, working in various aspects of cell Jesuit university was closed in 1773, and molecular biology, microbiology, after the dismantling of the Jesuit biochemistry, genetics and order. immunology and biotechnology.

In 1784, however, EmperorJoseph II The Department of Biochemistry, decreed the creation of a new headed by Volodymyr Lushchack, was University of Lviv, which was officially created in 2002 in the new opened on 16 November 1784. The Precarpathian National University, University comprised four faculties named after the Ukrainian writer (philosophy, law, medicine and Vassyl Stefanyk, granted university theology) and the appointment status in 1993. The Department has six procedure (at least on paper) was academics, nine technicians and 10 decreed to be open and based on merit PhD students, focusing on the – the nationality and religion of investigation of free radical prospective candidates being metabolism in bacteria, yeast and fish. irrelevant. The workshop will be held in the Physiology was taught in Lviv from recreation complex ('Karpaty'), which 1895, when Adolf Beck (1863–1942) is located in the picturesque resort city accepted a chair in animal physiology. of Yaremche about 60 km from Ivano- Beck was a remarkable neurophysiol- Frankivsk at an altitude of 650 m above ogist, and remains the most famous sea level. The city of Yaremche was physiologist to work in Lviv. His founded at the end of 18th century. The research was mainly dedicated to city’s nickname is ‘Pearl of the electroencephalography. He was one Carpathians’, which reflects its unique of the first to discover the spontaneous beauty. Yaremche is surrounded by cerebral potential oscillations (these wooded, picturesque mountains. The observations were published in 1890 in Prut River flows through the area and Centerblatt für Physiologie). Incidentally, falls through a scenic gorge that is the same spontaneous electrical visited by many tourists. activity was observed by Richard Caton in Liverpool in 1875. Adolf Beck also Nataliya Fedirko described the localization of sensory University of Lviv, Ukraine modalities on the cerebral cortex by Alexej Verkhratsky electrical or sensory stimulation and by University of Manchester, UK recording electrical activities with clay electrodes and a string galvanometer. From top: Central square, Ivano- Using these techniques Beck also Frankivsk; old Town Hall, Ivano- discovered a potential decrease in Frankivsk; main building of the sensory stimulation. Further advances University of Lviv; wooden Ukrainian in physiology in Lviv University were church in the Carpathian mountains; also closely connected with the Polish Volodymyr Lushchak in his laboratory.

Physiology News | No. 68 | Autumn 2007 | www.physoc.org EDINBURGH FOCUSED MEETING PN 7

Why did the amino acid cross the placenta? … to get to the other side Jane Cleal (pictured right) presents the work which won her the Blue Riband Prize at the recent Society Focused Meeting in Edinburgh

I am a postdoctoral research fellow building blocks of proteins, amino working with Rohan Lewis and Mark acids are required as metabolic Hanson at the Institute of precursors for multiple essential Developmental Sciences at the biosynthetic pathways and for fetal University of Southampton. After energy metabolism. Impaired amino completing a PhD in 2005 which acid transport is associated with studied the long term physiological intrauterine growth restriction effects of altered fetal and infant (Jansson et al. 2006) and nutrient supply using in vivo whole understanding the processes systems physiology, I worked for a involved in placental amino acid year on a commercially funded transport is crucial. project developing a new fetal ECG monitor before taking up my current Transport of amino acids from the position last year. mother to the fetus involves amino acid uptake by the maternal facing The placenta is a fascinating organ microvillous membrane (MVM) and which acts as an interface between efflux across the fetal facing basal the mother and the fetus. One of the membrane (BM) of the placental major roles of the placenta is to syncytiotrophoblast. The two main supply the fetus with nutrients. If the types of amino acid transporter placenta cannot do this the fetus will involved in amino acid transport are become growth restricted and is Na+ dependent transporters and Jane Cleal and her New Forest pony, more likely to become ill or die after amino acid exchangers (Fig. 1). The Farrier’s Brown Bear, winning the British Riding Clubs’ National Cross Country birth. Furthermore, fetuses who do mechanisms of transport protein Championships in 2006. not grow properly in utero are at mediated amino acid uptake by cells greater risk of chronic disease in are well understood and their the BM of the placental adult life (Gluckman & Hanson, function in the placenta has been syncytiotrophoblast, and this 2004). I am particularly interested in extensively studied. In contrast, process is still not well understood, the transport of amino acids across much less attention has been given particularly as the Na+ dependent the placenta. As well as forming the to the release of amino acids from transporters that are so important for amino acid uptake are not thought to mediate efflux and so cannot contribute directly to amino acid efflux from the BM. The current focus of my work is therefore to establish the mechanisms of amino acid transport across the BM of the placenta into the fetal circulation.

I have been using a novel adaptation of the isolated perfused human placental cotyledon technique developed in our laboratory. This allows us to study the transport of amino acids out of the placenta and into the fetal circulation in intact placental tissue. Knowing that amino acid exchangers are obligate exchangers, whereby they cannot Figure 1. Amino acid (aa) transport across the placental syncytiotrophoblast. Na+ operate unless they transport one dependent transporters (#) mediate influx but not efflux of amino acids. Transport by exchange (*) can only occur when there are amino acids present on both sides of the amino acid from within the placenta cell membrane. We have demonstrated that amino acid efflux acros the BM occurs by in exchange for one fetal amino acid mechanisms other than exchangers; however, the transporters that mediate this have on the fetal side of the BM (Fig. 1), not yet been identified. has allowed us to study their activity

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amino acids to be transported out of the placenta and into the fetus, and characterizing these transport systems is now the focus of my work. Once these systems have been properly characterized I plan to investigate their role in the pathogenesis of intrauterine growth retardation.

Acknowledgements This work was supported by The Henry Smith Charity.

Jane Cleal Institute of Developmental Sciences, Southampton General Hospital, Southampton, UK Figure 2. Serine, leucine and glycine release into the fetal circulation following fetal amino acid boli: data (mean ± SEM) is presented as AUC. * P < 0.05 the AUC is References different from glutamate (Cleal et al. 2007). Cleal JK, Brownhill P, Godfrey KM, Jackson JM, Jackson AA, Sibley CP, Hanson MA & Lewis RM (2007). Modification of fetal plasma amino on the BM by altering the However, transport by exchange is acid composition by placental amino acid concentrations of amino acids in the not sufficient to meet fetal amino exchangers in vitro. J Physiol fetal circulation. Adding specific acid requirements as one amino acid 10.1113/jphysiol.2007.130690. amino acids that are substrates of is swapped for another meaning that Gluckman PD & Hanson MA (2004). Living specific exchangers to the fetal the number of amino acids in the with the past: evolution, development, and circulation will activate that fetal circulation does not increase. patterns of disease. Science 305, 1733-1736. exchanger and allow us to observe its There must therefore be other activity. In this way we are transporters on the BM that mediate Jansson N, Pettersson J, Haafiz A, Ericsson A, Palmberg I, Tranberg M, Ganapathy V, Powell characterizing the activity of amino amino acid efflux. My studies have TL & Jansson T (2006). Down-regulation of acid exchange on the BM of placental indeed identified that there is efflux placental transport of amino acids precedes syncytiotrophoblast. So far we have of leucine, but not serine or glycine the development of intrauterine growth established the fetal amino acids from the placenta to the fetus by restriction in rats fed a low protein diet. J Physiol 576, 935-946. that stimulate exchange for serine, means other than exchange (Fig. 3). leucine and glycine within the This suggests that there are placenta (Fig. 2). mechanisms that allow specific In brief Animals in research: make up your own mind The Society has produced a new DVD in parternship with the Coalition for Medical Progress, GlaxoSmithKline and the Biomedical Research Education Trust. The DVD was distributed to all UK schools in May 2007. To request a copy please contact Liz Bell ([email protected]).

Facing the media with animal research/The dawn of glasnost for research using animals? Sarah Bailey, Thelma Lovick and Selina Pearson think the climate is changing – see their articles starting on p. 37.

The Royal College of Nursing Figure 3. Fetal uptake of serine, leucine and glycine in the absence of fetal amino acids conference and events programme for for exchange. Data (mean ± SEM) as a percentage of substrate perfused into the 2007/2008 now available at maternal circulation. * P < 0.01, different to creatinine (a marker of paracellular www.rcn.org.uk. diffusion): below line (----) = diffusion; above line = active transport (Cleal et al. 2007).

Physiology News | No. 68 | Autumn 2007 | www.physoc.org LIVING HISTORY PN 9

Researching unexpected hazards of cold and heat Cold and heat are large environmental causes of death. The nature of the hazards they present often differs greatly from general assumptions. Here William Keatinge (pictured below) describes research that showed this. Much of the research was made possible by the traditional independence of British universities and the flexibility of their research funding, and he makes a plea to restore it

As a young doctor, I found myself although a thick layer of fat under drafted into the Navy for 2 years. the skin greatly reduced body heat Hodgkin, Huxley and Katz’s loss in moderately cold water, even breakthroughs on nerve conduction very fat people cooled rapidly in had left me fired up to find how the water colder than about 10 OC. brain worked. The Navy was not Experiments on isolated blood interested in how the brain worked, vessels explained that. The vessels but it had lost around 30,000 people became paralysed by cold. Skin from cold immersion in World War 2, blood vessels normally shut down in and it did need to know how to the cold, to stop blood from carrying reduce deaths from cold. It sent me body heat to the skin, but at these to McCance’s department at extreme low temperatures they Cambridge to investigate that. could no longer do so. As they Responses to cold and heat were relaxed at temperatures below 10 OC, never at the heart of British and blood flow returned to the skin, physiology but the problems they water. That caused many people, even fat people cooled rapidly. caused, and shortage of people particularly children, to drown trying investigating them, repeatedly called to swim short distances from This presented a challenge. If some me back from other topics. overturned boats to shore. way could be found to make blood Buoyancy aids could prevent that. vessels resistant to cold paralysis, fat Experiments with Malcolm Evans and Skin froze at 0.53OC, and could freeze people would be able to work in cold Peter Cannon at Cambridge, and in seawater, which stays liquid down water for extended periods without later with many people at Julius to -1.9 OC. Ordinary non-waterproof heating or special protection. That Comroe’s Cardiovascular Research clothing kept skin temperature could be valuable for divers carrying Institute in San Francisco and Sir several degrees above water out urgent rescue or salvage work. George Pickering’s Department of temperature. In water cold enough Medicine at Oxford, answered many to cause progressive body cooling, Experiments in Oxford on isolated questions on immersion deaths with or without clothing, exercise arteries showed that cold blocked (Keatinge, 1969). Reflex gasping for usually increased people’s heat loss their electrical response to breath, and high viscosity of water more than heat production. All that noradrenaline, the neurohormone near freezing point, often prevented provided obvious practical advice for that makes them contract in life. even good swimmers from shipwreck victims. Their smooth muscle cells were only swimming many yards in very cold The most intriguing finding was that a few microns wide and surrounded by tough connective tissue. This made microelectrode records difficult, but an Icelander in Oxford called Johann Axelsson was recording electrical activity of intestinal smooth muscle by a sucrose gap method. Unexpectedly, after some modification, this did work on smooth muscle of arteries, and showed that noradrenaline induced action potentials in the muscle, which in turn triggered contraction. Temperatures below 10OC blocked the electrical response, but artificial electrical stimulation could still cause contraction. Actomyosin in the cells could clearly contract at low Figure 1. Lynne Cox swimming to Russia and Inuit walrus skin boat temperature, and only the initial

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action of noradrenaline on the cell down to 35 OC, the upper limit of membrane failed. hypothermia. Using low reading thermometers, we showed that Systematic recordings of electrical hypothermia was extremely rare activity in arteries opened a whole among people admitted to London new field. Jeffrey Graham, one of my hospitals. Experiments on former students at Oxford, joined me volunteers showed that mild when I moved to the London exposure to cold caused changes in Hospital Medical College. We the blood that would promote recorded patterns of electrical clotting (Keatinge et al. 1984). activity that contract inner muscle of When blood vessels in the skin shut arteries to reduce leak of blood after down to preserve body heat, salt and injury, and unusual discharges that water were excreted. This prevented drove its rhythmical contractions the displaced blood from during anoxia. We also recorded overloading central organs of the localised discharges in outer muscle body, but left the blood more that amplified its response to nerves. concentrated and more prone to clot. The practical message was that Progress on cold paralysis resumed heart attacks and strokes in winter many years later, when Johann were due to these adjustments to Axelsson, then dean of the medical mild cold stress, not to severe cold school in Iceland, told me that overwhelming the body’s defences. Gudlaugur Fridthorssen had made a Elderly people needed to be fully remarkable swim after his fishing warm. boat overturned in water at 5.2 OC. Gudlaugur’s companions Until then, getting support for these disappeared within a few minutes, Figure 2. Yakut in traditional outdoor research projects often needed but he was able to swim for 5 hours winter clothing persistence, but if they were to shore, 3 miles away. An important and well planned, immersion in our tank in London someone would finally free essential showed that he could indeed our tank in London showed that she funds or overcome obstacles. The stabilise his body temperature in could maintain low skin blood flow Medical Research Council was now water at that temperature, with little and stabilise body temperature in so pressed for cash that any hostility O clothing. His skin blood flow and water at 5 C. Colder water causes from a committee member could heat loss stayed low, allowing his other problems, but down to 5 OC prevent them funding a project. It considerable fat layer to keep him cold adapted people with enough fat even refused for a time to consider warm. Blood vessels in his skin could maintain body temperature research outside limited areas that stayed contracted, probably because without protection (Fig. 1). they had already designated for his work on the fishing boat had priority. That cut out the most adapted them to cold. Reports that 100,000 elderly people innovative projects. chill to death in their homes every In 1998 an experienced American winter caused huge media and public I was now dean of a faculty of basic cold water swimmer called Lynne concern. We had shown that medical science formed at Queen Cox ‘phoned me to say that she was insidious hypothermia was Mary and Westfield College from the going to try to swim from an responsible for unexplained errors departments of The London and American to a Russian island in the being made by North Sea divers, and Bart’s, but support from a first rate Bering Straits. Two weeks later she the MRC asked if I would investigate team left me time to continue set out from Little Diomede Island, deaths from hypothermia in elderly research. We now needed a Europe- and I monitored her temperature by people. I did not think hypothermia wide survey to assess factors radiotelemetry from an Inuit walrus was causing the winter deaths, but affecting winter mortality. There skin boat. A little over 2 hours later said I would be happy to investigate was little chance of MRC finance for she landed on the Russian island to what was causing them. Death that, but my luck was in, and the be greeted by a welcome party sent certificates showed coronary and European Union’s Biomed 1 by Gorbachov. The swim led to cerebral thrombosis as the cause of programme provided funds. The opening of that frontier for visitors most winter deaths, with respiratory survey showed that people in from both sides, in a striking easing disease causing most of the rest, but countries with the severest winters of the Cold War. It also showed that it was argued that hypothermia was took so much care to keep warm Lynne could maintain safe body really responsible. That was that they had little winter mortality. temperature for 2 hours in water at plausible, as ordinary clinical thermo- Protection from outdoor cold stress 7 OC. A fully monitored immersion in meters only recorded temperatures was as important as warm housing.

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A Wellcome grant let us find that Keatinge WR, Coleshaw SRK, Cotter F, Mattock platelet and red cell counts, blood viscosity people in the world’s coldest city, M, Murphy M & Chelliah R (1984). Increases in and plasma cholesterol level during heat platelet and red cell counts, blood viscosity, stress, and mortality from coronary and Yakutsk, wore massive fur clothing and arterial pressure during mild surface cerebral thromboses. Am J Med 81, 795–800. and remarkably had no excess cooling: factors in mortality from coronary mortality in winter (Fig. 2). and cerebral thrombosis in winter. Br Med J 289, 1405–1408. Keatinge WR & Donaldson GC (2006). Heat acclimatization and sunshine cause false Excess winter deaths had now fallen Keatinge WR, Coleshaw SRK, Easton JC, Cotter indications of mortality due to ozone. to around 20,000 a year, and global F, Mattock MB & Chelliah R (1986). Increased Environmental Research 100, 387-393. warming shifted interest to heat. Coronary and cerebral thromboses cause many of the British deaths in Left-handed or right- In the Hebrew text the word heat waves, We had found that heat restrained? interpreted as left-handed in the like cold stress caused increased King James version was not one word concentration of the blood, in this Pat Merton (1920–2000), well but three: ‘yter yad yemino’ which known for his pioneering work on case because people lose salt as well literally translates as ‘with his right muscle spindles and muscle fatigue, as water in sweat (Keatinge et al. hand tied’. was much influenced by Adrian’s 1986) . Once a meal replaces the salt lectures when he was a medical The Hebrew meaning is clear, and they feel thirsty and drink water, but student in Cambridge during World until then their blood remains further explicitly described in The War II. Even 40 years after First Book of Chronicles 12:2, a clarity concentrated. Gavin Donaldson and graduation, he kept referring to his retained in the King James version of I analysed mortality trends that undergraduate lecture notes in this passage: showed people were generally supervisions and lectures. If you adjusting to hotter summers, but were taught physiology by Pat, the ‘… and could use both the right hand occasional unprecedented heat following episode may help correct a and the left in hurling stones and waves caused many deaths. Advice little misconception. shooting arrows out of a bow, even of on managing heat stress was Saul’s brethren of Benjamin.’ important when a severe heat wave One day, in the mid 1980s, Pat asked was forecast. Air pollution by ozone me to check on the statistics about In Hebrew it is immediately clear that the 700 chosen men from the caused some asthma and other ill left-handedness in biblical times, by tribe of Benjamin had been trained health, but claims that it caused up reference to the original Hebrew to be ambidextrous, and that the to half of the deaths in heat waves text. The reason was that he was following Adrian’s notes stating that training involved restraining their faded when allowance was made for right hands. Pat was satisfied that sunshine, which heats people as well the proportion of left-handed people had increased substantially from there was no basis for statistical as generating ozone, and for wind about 3% in biblical times to about comparison of the proportion of left- which cools people as well as th 8–15% currently. After repeating this handed people in the 20 century blowing away ozone (Keatinge & conclusion in his lectures a number with that in biblical times. Donaldson, 2006. of times he wished to reconsider the I believe that this part of the course, original evidence. I remember and associated interpretations, did I was lucky. The new commercial asking him what made him doubt it, not surface again in his lectures. style of management and loss of job but all I got was a grunt and a wink security in British universities came interpreted by me at the time as his too late to affect me. It now way of implying that there is nothing Virgilio L Lew profoundly limits their traditional to explain about doubting, even if Department of Physiology, freedom to teach and research it’s Adrian’s sacred word ... Development and Neuroscience, without fear or favour. Without that University of Cambridge, UK freedom, little of my and my Adrian’s statistics were based on The colleagues’ work would have been Book of Judges 20:15 and 20:16. In New Fellows possible, and restoration of some of the King James Bible, which Adrian Congratulations to Physiological that freedom is the universities ’ used, 20:15 reads: Society Members Peter Barnes main need today. ‘ And the children of Benjamin were (Professor of Thoracic Medicine at numbered at that time out of the cities the National Heart and Lung William R Keatinge twenty and six thousand men that Institute and Head of Respiratory Queen Mary, University of London drew sword’, Medicine at Imperial College London) and William Harris (Head and in 20:16 we learn that: References of the Department of Physiology, Keatinge WR (1969). Survival in cold water. The ‘ Among all these people there were Development and Neuroscience at physiology and treatment of immersion seven hundred chosen men left - the University of Cambridge) on hypothermia and of drowning. Blackwell handed; every one could sling stones at their election as Fellows of the Scientific Publications, Oxford. an hair breadth, and not miss.’ Royal Society.

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A week in the life of ... David Bunton, Chief groups. In our experience the use of human tissue generally fits into an Operating Officer at Biopta Ltd industrial R&D programme in one of two areas: discovery biology or safety David Bunton is co-founder and pharmacology. This means we get Operations Director at Biopta Ltd, a requests to participate in an extremely contract research organisation that wide range of projects with some very carries out in vitro pharmacology specific tissue requirements. After that research for the pharmaceutical and it’s into the lab to assist with the biotechnology industries. He has a dissection of some lung tissue and I physiology degree from the University then have time for a quick sales of Glasgow and a PhD in vascular meeting before heading home. biology from Glasgow Caledonian University and then spent 8 years as a Thursday Lecturer in Physiology at Glasgow Figure 1. Claire Stevenson draws the Catch the early flight to London which Caledonian’s Department of Biological short straw and dissects some human means a 4 a.m. rise; however, this is and Biomedical Sciences where he co- tissue in the small hours. only 45 minutes earlier than normal founded Biopta with Chris Hillier in because my 1 year old daughter has 2002. David and Chris identified an sheets and cash flows thoroughly taken to rising at 4.45am. Despite tip- emerging market for human tissue- reinforce physiology as a great choice toeing around the house I still manage based research services and began to of career. Back in the lab it’s a day for to wake her so we all have an early develop their first instrument, the report writing and data analysis rather start. Karen, our CRO Manager, and I PM-1, which quickly became an than lab work; we’ve discovered that attend the UK Bio Entrepreneurial opportunity to fully commercialise the when working with the NHS the Awards at Lancaster House. Apparently research by the creation of a spin-out number of operations that generate the event has been moved here company. Since its inception Biopta residual human tissue increases because a VVIP (which turns out to be has received numerous awards for exponentially during the week, with Prince Charles) wanted to use the innovation including a Scottish peak deliveries of tissue at 5 p.m. on a previous venue; however, the new Executive SMART award, a John Logie Friday. setting is impressive and the event is a Baird Award and a Nexxus Award for good opportunity to meet some the innovative development of PM-1, a clients face to face. Karen does a great new system for the study of pressure Tuesday 90 second pitch about Biopta and flow in isolated blood vessels. In addition to providing contract (interesting approach for next Phys Biopta has also received approximately research services for drug safety and Soc?) but unfortunately we don’t win £1 million in private investment and efficacy, we also develop new lab our category. Infuriatingly the judges has grown to a successful GLP- instruments and today we visit a later inform us that we might have compliant test facility that focuses on company in Dundee that can won had we been entered in the the use of fresh human tissue for drug potentially manufacture our new in ‘ enabling biotechnology’ category efficacy and safety studies. Biopta now vitro pharmacology instrument. Derek, rather than ‘drug discovery’ by our employs 14 people at its laboratory at Biopta’s product design engineer, development agency, but we resist the the University of Glasgow. Here, David accompanies me to ask the technical temptation to ever mention this. Bunton (pictured right) describes a questions and interpret the engineers ’ typical week at Biopta. own language (again reinforcing physiology as a good choice of career). Friday Monday I’m impressed by their ability to My time spent away from the office has Our working week starts with a group rapidly understand the relevance of meant that a number of proposals meeting to plan our contract research physiology and pharmacology need to be sent out urgently. Each activities, a task which is easier said instruments to drug research and project tends to be quite different so than done because of the irregular development. After the journey back I proposals often turn into a miniature pattern by which human tissues start to prepare my reports for the grant application, often preceded by a become available. As 90% of the work monthly Board meeting, an important rapid review of the relevant literature we do is on fresh human tissue, we task as the reports are circulated to all (who said cramming for exams was a need to be pretty flexible in our work the investors and our Board meetings futile exercise). Although we don’t get patterns and thankfully have a team of can at times resemble an episode of to spend too long on any one project people who don’t mind working the The Apprentice (but no one has been the plus side is that we all develop a odd night-shift (Fig. 1)! After that it’s a fired as yet), so the documents need to real breadth of knowledge by trip to meet the bank manager to be thought out well in advance. becoming involved in various drug discuss the latest management development programmes. At accounts and financial forecasts. Our Wednesday weekends we take turns being ‘on bank has been quite supportive of a Back in the office today to work on a call’ for any human tissue that business like ours which is very European Framework 7 application becomes available, which different from most of their customers. with other SMEs (small and medium- unsurprisingly creates mixed feelings A couple of hours navigating balance sized enterprises) and academic as this weekend it’s my turn!

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Letter from the United Arab Emirates Biomedical science research: from humble beginnings to an integral part of the undergraduate medical curriculum at the Faculty of Medicine and Health Sciences, United Arab Emirates University

Evidence-based medicine (EBM) How do we develop skills such as involves integrating the appropriate critical analysis and review, an current best clinical evidence with academic approach to medicine and clinical expertise, to make decisions research methodologies in our about individual patients (Sackett et students? Activities such as research, al. 1996). ‘ B est available clinical scheduled early in an undergraduate evidence ’ refers to studies that medical student’s studies would involve the basic sciences of certainly be one way. At the FMHS, medicine as well as those that relate, community medicine projects, in inter alia, to the safety and efficacy of which students investigate health therapeutic regimes, diagnostic tests and well-being issues relating to UAE and surgical interventions. The GP communities, were introduced into Notebook defines EBM as ‘a discipline Year 6 for the first cohort of senior The Faculty of Medicine and Health that formalises the long-practiced clerks in 1992 and have remained an Sciences (FMHS), one of nine principle of basing clinical practice on integral component of the clerkship. colleges in the United Arab Emirates scientific evidence ’. The ability to As the research profile of the new University (UAEU), is located in the seek information, often from faculty developed, formal ‘ Garden City’ of Al Ain, which forms research, and to evaluate its merits undergraduate research became part part of the Abu Dhabi Emirate. The and applicability therefore becomes of the second year programme Faculty accepted its first cohort of an important requirement of today’s (Medical Sciences Course) in 2001. medical students in 1986. The medical practitioner. Such skills, Initially, presumably because of their medical curriculum is a 6 year along with being able to work as a supervision experience of clerkship programme, comprising a 2 year member of a team, plan one’s projects, many of the research topics medical sciences course, a 2 year learning, manage one’s time, were offered by Community organ systems course, which is generates hypotheses and design Medicine faculty. Today, only a few followed by a 2 year clinical sciences experiments have been reported to years later, things are very different. course. Students then complete a 1 be core skills for engendering life- Much of the supervision is overseen year internship. Currently, the FMHS long learning in medical students by biomedical scientists in the accepts only Emirati nationals and (Whittle & Murdoch-Eaton, 2001). traditional pre-clinical disciplines of typically has an annual intake of around 30-35 female and 15-20 male students. One of the benefits of a relatively small annual intake of students is that we are able to offer a variety of educational activities which would be difficult in larger faculties. Research is becoming an increasingly important aspect for career development and we pride ourselves in offering our students several opportunities for curricular and extra-curricular research. This article, written by Chris Howarth (who joined the Department of Physiology in 1998 from Leeds University), who oversees most of the undergraduate research and Michelle McLean (who joined the Department of Medical Education in 2006 from the University of KwaZulu-Natal, South Africa), Table 1. Types of second year research projects and the disciplines of the supervisors. discusses the development of Projects were introduced into the curriculum in the 2001/2002 academic year. undergraduate research in the FMHS. *Refers to discipline; **mixed, e.g. clinical/laboratory.

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another country and another culture. Supervisors may, from time to time, present their students’ work abroad, with due acknowledgement.

Some of our student research has appeared in peer-reviewed journals. As publications are a measure of scholarship, this will undoubtedly strengthen FMHS students’ applications for residencies in North America, where many choose to specialise.

At the FMHS, although biomedical Mohammed and Abdulla Al Kuwaiti working in Chris Howarth’s laboratory in the science research started from Faculty of Medicine and Health Sciences, one of nine colleges in the United Arab humble beginnings in 2001, it has Emirates University. developed into an integral component of the undergraduate anatomy, physiology, biochemistry Students’ Research Conference medical curriculum, largely due to and medical microbiology (Table 1). rotates each year around the Gulf the enthusiasm and commitment of Projects are generally laboratory- states of Oman, the UAE, Saudi the medical science faculty. It has based, with many involving rat and Arabia, Bahrain and Kuwait. Some been recognised by external review mouse models or tissue culture to students choose to attend committees as a valuable study diseases such as diabetes and international conferences. Last year, component of the curriculum that Parkinson’s. a student who spent his summer at a warrants continuation. Under the UK research laboratory won a prize mentorship of the physiologists, A recent audit of the first few years at the Young European Scientists’ anatomists, biochemists and of undergraduate research has Symposium in Portugal. In March microbiologists, we believe that our revealed that medical scientists are 2007, a group of 12 students young students, by being introduced also largely responsible for the attended the Leiden Medical to biomedical research early in their supervision of the summer vacation Students’ Conference, where one studies, develop a number of skills research, introduced soon after poster entitled Teratogenic that will ultimately assist them with mainstream research projects (Table mechanisms of craniofacial their medical practice. In fact, this 2). Over the past year or two, malformations in mouse embryos was year, a second year project has increasing numbers of first year awarded second prize. These sought to glean students’ students are now starting their experiences give our students an perceptions of the benefit of research project in the summer insight into life as a student in research on skills development and before they begin their second year of medical studies. This allows them 4-6 weeks of additional research time, leading to the collection of more meaningful data.

Each year, for 2-3 FMHS students who excel in research, a joint initiative of the FMHS and the British Council sponsors a visit to a research laboratory at a UK university (e.g. Leeds, Manchester, Glasgow, Bristol). The value of such an experience for a young medical student cannot be underestimated.

Opportunities exist for our students to present their research at public fora, locally and abroad. Apart from annual faculty and university events to showcase their research, the Gulf Table 2. Extra-curricular faculty-based projects and the disciplines of supervisors Co-operation Council (GCC) Medical (2003-2006).

Physiology News | No. 68 | Autumn 2007 | www.physoc.org LETTER FROM ... PN 15 on future studies and medical practice. Although the data are in the process of being analyzed, the indications are that students view their research experience as contributing to their development as medical practitioners.

We also believe that engaging junior students in the rigors of biomedical research provides firm foundations in the basic medical sciences that they require for their clinical years. Hopefully, this early experience will stimulate a research interest in some students, serving as a springboard for a career in clinical research, Shaikha Al-Muhairi working in David Eisner’s laboratory at the University of particularly into ‘endangered’ Manchester. disciplines (Solomon et al. 2002; Halpain et al. 2005) – ‘career pipelining’, in the words of Halpain – from humble beginnings to an integral part of the medical Rhyne RL (2000). A scholarly research and his colleagues (2005). requirement for medical students: the curriculum, thanks to the ultimate problem-based learning experience. The FMHS may be in the fortunate commitment of a handful of Acad Med 75, 523–524. position of having small student biomedical scientists. We believe that by providing numerous Sackett DL, Rosenberg WMC, Gray JAM, Hayes numbers, allowing each learner to RB & Richardson WS (1996). Evidence based actively participate in one or more of opportunities for research for our medicine: what it is and what it isn’t. Br Med J the research projects of faculty students within and beyond the 312, 71–72. members. Large student numbers in curriculum we are contributing to a more critical and informed cadre of Schor NF, Troen P, Kanter SL & Leving AS many UK and USA universities may (2005). The scholarly project initiative: not permit the same level of medical graduates. introducing scholarship in medicine through a involvement. Notwithstanding, the longitudinal, mentored curriculum programme. Acad Med 80, 824–831. move in the UK of a ‘core Michelle McLean curriculum’ with special study Chris Howarth Solomon SS, Tom SC, Pichert J, Wasserman D modules is encouraging (Murdoch- Medical Education and Physiology, & Powers AC (2002). Impact of medical Eaton et al. 2004). If research is student research in the development of Faculty of Medicine and Health physician-scientists. J Invest Med 51, 149–156. offered as one of the special study Sciences, United Arab Emirates modules, interested students will University Whittle S & Murdoch-Eaton DG (2001). have an opportunity to participate. Development of lifelong learning and self- North American institutions too are evaluation skills through special study References modules. Med Educ 35, 1073–1074. beginning to appreciate the value of Dewey M (2003). Students’ evaluation of research in medical studies and research during medical studies: medical many curricula now include research dissertation in Friedrich MJ (2003). A novel (Rhyne, 2000; Schor et al. 2005; programme seeks to take clinical scientists off Society for Endocrinology prize Solomon et al. 2002). Some German the endangered species list. JAMA 290, 1019–1020. Congratulations to Harry Leitch, an universities recognised the need for undergraduate medical student in the research in medical studies many GP Notebook Department of Physiology, years ago, and a research (http://www.gpnotebook.co.uk/simplepage.cf Development and Neuroscience at the dissertation has been a requirement m?ID=812318776). University of Cambridge, who won for a medical degree for some time. first prize from the Society for Halpain MC, Jeste DV, Trinidad GI, Wetherell JL Endocrinology for an essay on the role This intensive research has & Lebowitz BD (2005). Intensive short-term of kisspeptins in the reproductive axis. research training for undergraduate, graduate, contributed significantly to the The title of his winning entry is productivity and scholarship of the and medical students: early experience with a new national-level approach to geriatric Re-engaging undergraduates with institutions, with many students mental health. Acad Psychiatry 29, 1. endocrinology – another role for appearing as first authors on peer- kisspeptin? For more details see reviewed publications (Dewey, Murdoch-Eaton DG, Ellershaw J, Garden A, http://www.endocrinology.org/news/. 2003). Newble D, Perry M, Robinson L, Smith J, Stark Harry’s thoughts on what it was like P & Whittle S (2004). Student-selected doing a summer project were components in the undergraduate medical published in Physiology News (67, 41). So, biomedical research for curriculum: a multi-institutional consensus on undergraduate students at the FMHS purpose. Med Teacher 26, 33–38.

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What happens to the central respiratory rhythm during breath-holding? Michael Parkes considers some of the implications of the continuation of the central respiratory rhythm during breath-holding

Humans have virtually no voluntary from the phrenic nerve. (Conversely, control of their heart beating, but do animal training has so far failed to have considerable voluntary control elicit breath-holding experiments of breathing. For example, they can longer than about 5 seconds.) In easily synchronise breathing to a humans, the activity of the central metronome over the range of 5–30 respiratory rhythm is normally beats per minute. There has always inferred from respiratory motor been a tacit presumption that output such as inspiratory pressure, humans stop their respiratory airflow or chest movement. rhythm during breath-holding. Obviously, such respiratory motor Recent evidence shows, however, output stops during breath-holding, that this is not the case. but this doesn’t necessarily establish that the central respiratory rhythm It is not yet possible to measure the has stopped. central respiratory rhythm directly in humans. Recordings cannot yet be In a classic study in 1963, Emilio made from brainstem neurones with Agostoni had three subjects swallow respiratory-related discharge, nor a catheter, enabling measurement of

A Figure 1. A, Appearance of rhythmic diaphragm EMG activity towards the end of breath-holding. Oesophageal pressure (upper trace) and diaphragm EMG activity (lower trace) in one 22 year old subject during breath-holding at resting lung volume in air. Used with the permission of Agostoni (1963) and the American Physiological Society. The start and end of the breath-hold are indicated by circled arrows. B, Sinus arrhythmia in 1A, from the start of breath-holding. Using a copy of the original record from 1A, kindly provided by Emilio Agostoni, I B have measured the time of each R wave (to within 20 ms) in each ECG artefact to calculate instantaneous heart period as described in Cooper et al. (2004) and measured the time and size of each of the 12 oesophageal pressure waves. The start and end of the breath-hold are indicated by arrows. C, Some of the sinus arrhythmia in 1A is respiratory. I have sampled the instantaneous heart period and pressure waves from 1B every 2.5% of time between the start of each C pressure wave and the next. I then averaged both over the 11 oesophageal pressure wave intervals during the breath-hold as described in Cooper et al. (2004). This shows that some of the sinus arrhythmia is respiratory, i.e. some sinus arrhythmia shows a similar relationship to rhythmic diaphragm activity (heart period decreases during inspiration) to that seen during eupnea (see Fig. 1C in Cooper et al.[2004]). Figs. 1B & 1C are reproduced with permission from Blackwell Publishing.

Physiology News | No. 68 | Autumn 2007 | www.physoc.org FEATURES PN 17 oesophageal pressure and electromyogram activity (emg). He showed (Fig. 1A) that rhythmic emg bursts appeared towards the end of the breath-hold. Since each burst was accompanied by a wave of negative pressure, the emg activity was believed to be recorded across the oesophagus from the diaphragm. Subsequent studies by William Whitelaw showed that the amplitude and frequency of these negative pressure waves increased towards the end of the breath-hold.

Since PCO2 rises linearly throughout breath-holding, these waves possess the CO2 sensitivity characteristic of the central respiratory rhythm. These studies show that the central respiratory rhythm reappears before the breakpoint of breath-holding. They do not, however, establish whether the central respiratory rhythm suddenly reappears, or whether it had not stopped but was simply too difficult to detect at the Figure 2. Sinus arrhythmia in the subject with the longest breath-hold (6.7 min) in start of breathing. normocapnia with preoxygenation at maximum inflation (Cooper et al. 2003), used with the permission of the American Physiological Society. (a) Eupnea immediately We have developed another preceding breath-holding. (b) Distribution of the 13 breath intervals in (a) within the approach to reveal the presence of 30 bins describing frequency (0.03 –0.5Hz). The dotted line indicates his eupneic the central respiratory rhythm, by frequency range (bins 7–10). (c-h) Instantaneous heart period and its power using respiratory sinus arrhythmia. 0.03–0.5Hz density spectra in eupnea (c-d), the first 2 (e-f) and last 2 (g-h) minutes The factors contributing to sinus of breath-holds from normocapnia (6 minutes). The horizontal scale in (b), (d) & (f) arrhythmia are complex. Animal indicates each of the 32 bins describing 0-0.5Hz. studies show that these include effects of the central respiratory during hyperventilation by addition In some ways, breath-holding is an rhythm and of pulmonary inflation of CO2 to the inspirate. In humans, ideal way to reveal whether the and its mechanical sequelae hypocapnia augments the potency of central respiratory rhythm continues (including complex interactions with the pulmonary stretch reflex but to cause respiratory sinus the baroreflex and atrial stretch). attenuates the central respiratory arrhythmia, because rhythmic No study has established the precise rhythm, so it is an ideal condition to pulmonary inflation and its contribution each makes to total reveal the predominant contribution mechanical sequelae are absent. respiratory sinus arrhythmia. to respiratory sinus arrhythmia. We There has been much debate about induced hypocapnia (24 mmHg) by a whether respiratory sinus arrhythmia

We therefore established first that surreptitious removal of CO2 from does continue during breath- the central respiratory rhythm does the inspirate, which was imper- holding. The Handbook of Physiology make a substantial contribution to ceptible to subjects. We showed that seems to suggests that it does not, sinus arrhythmia in unanaesthetised during hypocapnia the rhythmic yet it is clearly evident in some early humans (Cooper et al. 2004). We did changes in pulmonary inflation were studies (e.g. Valentinuzzi & Geddes, this by devising a regime of unchanged but the respiratory 1974). Much of the debate arises mechanical hyperventilation, where motor output disappeared i.e., the because of the difficulties in using the central respiratory rhythm central respiratory rhythm was relatively short breath-holds (20– remained demonstrable in greatly attenuated. The fact that 45 s). If some subjects happen to normocapnia from respiratory motor there was also a large reduction in breathe naturally at relatively low output (diaphragm emg activity sinus arrhythmia establishes that the frequencies (e.g. < 6 breaths per recorded from the chest surface and central respiratory rhythm makes the minute), there would be so few from the shape of the inflation predominant contribution to respiratory cycles that respiratory pressure waveform). We maintained respiratory sinus arrhythmia in sinus arrhythmia may well be normocapnia (PetCO2 of 41 mmHg) humans. difficult to identify.

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We avoided these difficulties Second, many previous studies Molecular water (Cooper et al. 2003) by prolonging (particularly in cardiovascular breath-hold duration to a mean of 4 control), have used breath-holding pumps – or how water minutes with preoxygenation. to study mechanisms in the (Preoxygenation has the additional presumed absence of the central can move uphill across advantage of preventing the respiratory rhythm. This epithelia chemoreflex stimulation of heart presumption is no longer valid. All How are water and glucose rate that normally occurs during that is absent is rhythmic pulmonary absorbed by the small intestine breath-holding.) Fig. 2(e) shows that inflation. Similarly, it is no longer sinus arrhythmia does continue from correct to presume either that end- after a meal? In this situation the the start of breath-holding. This expiratory breath-holds stop the glucose concentration is high and sinus arrhythmia is also CO2 central respiratory rhythm in its the water concentration low in sensitive. The spectral power density expiratory phase, or that end- the lumen and water has to be measurements indicate that sinus inspiratory breath-holds stop it in the transported uphill, into the body, arrhythmia moves to higher inspiratory phase. Indeed, for breath- against osmotic pressure frequencies as pCO2 increases hold research, the lung volume itself differences of up to five throughout the breath-hold and that may be the only important feature, atmospheres. The transport there is less sinus arrhythmia in not the means by which it is mechanisms responsible are achieved. breath-holds from hypocapnia. molecular and can be stimulated In 2006 I was able to perform a Finally, the mechanism of breath- to balance the severe similar analysis on some of Emilio holding is not voluntary cessation of dehydrations experienced in, for Agostoni’s 1963 data when he kindly the central respiratory rhythm but is example, cholera lent me some of his original records. voluntary suppression of the From enlargements I was able to expression of this rhythm. The latest In order to live on land we must closely measure sinus arrhythmia from the techniques of brain imaging might control and maintain our internal ECG artefacts and its relationship to be useful in identifying the location(s) of this suppression. aqueous milieu. Each day the small the oesophageal emg and pressure intestine receives a total of about 10 l waves (Parkes, 2006). Fig. 1B shows, of water which originates from in this 1963 data too, that sinus Michael J Parkes glandular secretions plus what is being arrhythmia persists from the start of School of Sport & Exercise Science, ingested. This water and its contents of breath-holding. Furthermore, Fig. 1C University of Birmingham, UK sugars, amino acids, salts etc. have to shows that it coincides with the be absorbed during its passage rhythmic emg and negative pressure References through the intestine. This is done waves when they appear. In the Agostoni E (1963). Diaphragm activity during efficiently – only 0.1 l (1%) is lost to absence of direct measures of the breath holding: factors related to its onset. J the outside. Clearly, diseases which central respiratory rhythm in Appl Physiol 18, 30–36. upset this balance lead to fatal dehydrations. In the kidney the humans, the persistence of CO2- Cooper HE, Clutton-Brock TH, & Parkes MJ sensitive sinus arrhythmia (2004). The contribution of the respiratory situation is even more dramatic. Each throughout breath-holding provides rhythm to sinus arrhythmia in normal day, 180 l of plasma (four times our the best evidence that the central unanesthetized subjects during mechanical total body water!) is being filtered in hyperventilation with positive pressure. Am J the nephrons. Fortunately, most of this respiratory rhythm does continue Physioly 286, H402–H411. water is reabsorbed and only about 2 l from the start of breath-holding. Cooper HE, Parkes MJ, & Clutton-Brock TH lost in the urine. At present, there is no This has a number of important (2003). CO2-dependent components of sinus adequate explanation of how water is implications for our understanding arrhythmia from the start of breath-holding in absorbed in the intestine and the Man. Am J Physiol 285, H841–H848. of basic human physiology. kidney. Most models presume the existence of an intraepithelial First, humans clearly have less Parkes MJ (2006). Breath-holding and its hyperosmolar compartment, such as in voluntary control of their central breakpoint. Exp Physiol 91, 1–15. the lateral intercellular spaces. Despite respiratory rhythm than was Valentinuzzi ME & Geddes LA (1974). The numerous investigations no such previously supposed. It would be far central component of the respiratory heart- hyperosmolarities have been found too dangerous to be able to stop the rate response. Cardiovascular Research Center yet. heart beating voluntarily. It now Bulletin 12, 87–103. appears that humans also lack this Whitelaw WA, McBride B, Amar J, & Corbet K Uphill water transport in the small level of control over their other vital (1981). Respiratory neuromuscular output intestine rhythm. This, in turn, has interesting during breath holding. J Appl Physiol 50, A major stumbling block for epithelial implications for our understanding 435–443. models has been to explain uphill of ‘apnea’ and ‘central apnea’ and Whitelaw WA, McBride B, & Ford GT (1987). water transport, i.e. transport against their clinical diagnosis and Effect of lung volume on breath holding. J Appl an osmotic gradient. This problem is treatment. Physiol 2, 1962–1969. illustrated most clearly in the small

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intestine just after a meal consisting of Figure 1 (left). Early days of studying sugars. water transport in Xenopus oocytes. Thomas Zeuthen is monitoring (crudely) In order to be absorbed, sugars are the volume changes of an SGLT1- cleaved by local enzymes into expressing Xenopus oocyte in the monosaccharides such as glucose. In laboratory of E M Wright, UCLA in 1995. the process, the concentration of At present the resolution of the glucose becomes much higher and the measurements is equivalent to an increase in oocyte diameter of 100Å concentration of water much lower in which is close to the thickness of a lipid the lumen than in the blood plasma bilayer (photo by D D F Loo). (Fig. 2, upper panel). Thus glucose could, in principle, be transported The idea of molecular water pumps conventional unstirred layer effects can passively or downhill into the blood originated from measurements in the be excluded due to the relatively high plasma. Water, in contrast, has to choroid plexus epithelium where it was rates of diffusion inside the oocytes. move actively or uphill in order to be found that transport by the K+/Cl- How could the structural features and absorbed. It has been established for cotransporter (KCC) was strictly conformational changes in co- more than a century that the small coupled to transport of water transporters give rise to cotransport intestine is able to absorb significant (Zeuthen, 1991). Today, the idea is of water? One model is an extension amounts of water from a hyperosmolar pursued by expression of co- of the mobile barrier model first solution. Indeed, the human small transporters in frog eggs (Xenopus suggested by Mitchell (1990) and intestine can absorb water from laevis oocytes), a technique that allows explained in Fig. 3. On this model a luminal solutions that contain up to for the detection of minute water shift between closed conformations 250 mM of glucose in addition to the fluxes (Fig. 1). So far, we have found and conformations open to the outside electrolytes (Pappenheimer, 1998) coupling between substrates and or the inside of the membrane gives equivalent to uphill transport of water water in all Na+-coupled cotransporters rise to a coupling between the against an osmotic pressure difference of the symport type. Artefacts such as transport of water and substrates. of about five atmospheres. This ability is not unique for the small intestine. Even the very water-permeable epithelium of the kidney proximal tubule transports water uphill, although to a lesser degree. Key questions are therefore: • why is water not lost into the intestinal lumen but instead transported into the plasma? • what is energizing the water transport? • how is the water transport linked to the glucose transport?

Molecular water pumps To answer these questions, we have suggested that cotransporters function as molecular water pumps. In the human Na+/glucose cotransporter (hSGLT1), for example, a wide range of experiments has shown that 250 water molecules follow the transport of 2 Na+ ions and 1 glucose molecule in a strict stoichiometrical relationship; in the rabbit SGLT1 360 water molecules (Loo et al. 2002). As a result, these Figure 2. A molecular model of water and glucose transport in the small intestine cotransporters can utilize the energy just after a meal. Upper panel: after a meal the glucose concentrations (red squares) contained in the Na+ gradient for the are high and water concentrations (blue circles) low in the lumen compared to uphill transport of water. The tightness plasma, yet both substances are absorbed. Lower panel: the transport of water is of the coupling between ions and coupled to the Na+ and glucose transport in the luminal SGLT1 and to K+ and Cl- in the water is emphasized by the fact that it abluminal KCC. The energy for the uphill transport is derived from the Na+/K+ATPase. works both ways: a gradient in water There is possibly a small water flux coupled to the efflux of glucose in the GLUT2 in chemical potential can drive an uphill the abluminal membrane. GLUT2 is present both in the luminal and the abluminal flux of ions in the same stoichio- membrane during a meal. Between meals, GLUT2 is absent from the luminal metrical ratio as above. membrane.

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water each day. The underlying molecular mechanism is the insertion of a Cl- channel in the luminal membrane. Fortunately, the situation can be countered by the stimulation of the absorptive mechanism outlined in Fig. 2. The two molecular mechanisms, the secretory and the absorptive, are, so to speak, matching each other while the infection is treated. The absorptive component is maximized by ORT: The patient drinks a solution containing 75 mM of NaCl, 75 mM of glucose, and water. This stimulates the uptake of water by the SGLT1 to a degree that compensates for the amount secreted; the uptake of 120 gram of NaCl and Figure 3. SGLT1 as a molecular water pump. It is assumed that the cotransport of 200 gram of glucose would be linked Na+ ions (yellow +), glucose (red) and water (blue) takes place through a series of to the uptake of 4 to 5 l of water. ORT conformational changes (1-6). First, a Na+ ion binds and water enters the protein is estimated to save more than half the from the lumen to form an aqueous cavity (state 1 and 2). This allows the glucose to children suffering from severe bind (state 3). The protein changes from an outside-open to an inside-open diarrhoea. conformation (state 4). The glucose (state 5), and the Na+ ion and water (state 6) are expelled from the SGLT1 into the cytoplasm. As a result Na+, glucose and water are In conclusion, the molecular model of cotransported across the membrane. For clarity, only one Na+ ion is shown. epithelial water transport gives a Interestingly, Mitchell did allude to a rather tight to water (Zeuthen et al. rational background for the link between water movements and 2007). Glucose finally leaves the cell understanding and treatment of life conformational changes: 'If, as seems and enters the plasma via the threatening dehydrations. likely, the mobile barrier mechanism ubiquitous, abluminal GLUT2. Acknowledgements involves the opening and closing of a The water absorption requires energy. The author wishes to thank Nanna cleft on either side of a substrate- The influx of water takes place via the MacAulay, Emil Zeuthen, Svend binding domain, one might expect SGLT1 and is energized by the coupling Christoffersen and Magnus Bundgaard considerable hydrodynamic action as to the influx of Na+, which, in turn, for their help with this manuscript. aqueous medium was sucked in and derives its energy from the squirted out by the crevices.' Each step + + Na /K ATPase. The final step of water Thomas Zeuthen in the cycle suggested in Fig. 3 is well transport, from the cell into the established for aqueous enzymes. plasma, is energized by a coupling to Nordic Centre for Water Imbalance Hexokinase, for example, looses and the downhill efflux of K+ and Cl- by the Related Disorders, The Panum Institute, University of Copenhagen, takes up 300 water molecules in the K+/Cl- cotransporter (KCC), which is process of phosphorylating a glucose found abluminally in most epithelia. Denmark molecule. A clear picture of how the Again, the energy is provided indirectly conformational changes are linked to References by the Na+/K+ATPase. In addition, there water transport must await structural Kellett GL (2001). The facilitated component is preliminary evidence for a coupling determination at the atomic level for of intestinal glucose absorbtion. J Physiol 531, between glucose and water transport each of the conformations shown in 585-595. in the GLUT2 working in the efflux Fig. 3. So far, it is encouraging that a direction (Zeuthen et al. 2007). The Loo DDF, Wright EM & Zeuthen T (2002). wide aqueous cavity has been found in model in Fig. 2 shows only the Water Pumps. J Physiol 542, 53-60. the substrate binding conformation of molecular water pumps; in a given a variety of cotransporters. Mitchell P (1990). Osmochemistry of solute epithelium there are, of course, plenty translocation. Res Microbiol 141, 286-289. of other transporters. The kidney Molecular mechanism of water and proximal tubules, for example, are Pappenheimer JR (1998). Scaling of glucose transport across epithelia richly provided with water channels dimensions of small intestines in non- How could molecular water pumps (aquaporins) taking advantage of the ruminant eutherian mammals and its significance for absorptive mechanisms. Comp explain the uphill transport of water downhill gradient for water absorption Biochem Physiol 121, 45-58. and the downhill transport of glucose across this epithelium in vivo. just after a meal (Fig. 2)? Glucose Zeuthen T (1991). Secondary active transport absorption into the cell takes place via Cholera and oral rehydration of water across ventricular cell membrane of two transporters, the SGLT1 and the therapy (ORT) choroid plexus epithelium of necturus maculosus. J Physiol 444, 153-173. luminal glucose monoport GLUT2. Cholera toxins give rise to major Interestingly, this GLUT2 is only active secretions of fluid into the intestinal Zeuthen T, Zeuthen E & MacAulay N (2007). in connection with a meal (Kellett, lumen. The patients experience severe Water transport by GLUT2 expressed in 2001). In this location the GLUT2 is diarrhoea and may loose 3 l or more of Xenopus laevis oocytes. J Physiol 579, 345-361.

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Exercise is a good habit for bowel health

against reflux, as gas retention during rest decreases with dietary fibers and physical exercise. In particular, regular exercise at low intensity may reduce the risk of gastrointestinal disorders such as gastrointestinal hemorrhage, Ozgur Kasimay (left) and Berrak Yegen inflammatory bowel disease, cholelithiasis, diverticular disease or A substantial body of evidence constipation. verifies the benefits of regular physical activity on physiological and Lack of physical activity is closely psychological well-being. Mild and related to the development of colon moderate physical activity is cancer. There is strong evidence that associated with a lower incidence of regular exercise not only reduces the mortality from any cause, especially risk of developing colon cancer by up from heart disease. Physical activity to 50%, but it also lowers the risk of is beneficial to health because it death from colon cancer. A cohort reduces the risk of cardiovascular study of Swedish men demonstrated and endocrine diseases, improves that leisure-time physical activity bone and muscle conditioning and was inversely associated with lessens anxiety and depression (Bi & colorectal cancer risk (Larsson et al. Triadafilopoulos, 2003). It also 2006). Similarly, a Danish cohort diminishes high blood pressure, study that aimed to assess the metabolic disorders such as diabetes association between leisure-time mellitus, colon and rectal cancers, physical activity and incidence of estrogen-dependent cancers of the cancer in the general population of ovary, breast, and endometrium adult men and women, showed a (Woods, 1998), osteoporosis and significant inverse relationship mental depression; moreover, it can between vigorous physical activity improve the quality of life. and cancer of the ovary for physically active women, while vigorous The impact of exercise on the activity was associated with a non- gastrointestinal system can be either significant lower risk of colon cancer beneficial or harmful for the in men (Schnohr et al. 2005). These gastrointestinal tract (Bi & results support a role of physical Triadafilopoulos, 2003), depending activity in reducing the risk of colon, partly on training intensity. The rectal and ovarian cancer. occurrence of gastrointestinal symptoms such as heartburn, Ulcerative colitis is an idiopathic nausea, vomiting, abdominal inflammatory bowel disease (IBD) cramps, diarrhea and gastrointestinal with diffuse, recurrent inflammation bleeding is common during vigorous of the colon and rectum, which is sports, causing the athlete to limit predominantly characterized by performance by reducing exercise cycles of acute inflammation, intensity or duration (Peters et al. ulceration and bleeding of the Figure 1. The protective effect of 2001). On the other hand, regular colonic mucosa. There is a long exercise on oxidative injury of the colon, exercise at a low intensity may have history of observations suggesting as indicated with a depression of protective effects on the that psychological stress contributes neutrophil infiltration to the colon (MPO, gastrointestinal tract. Mild physical to the course of IBD (Maunder, 2005) myleoperoxidase activity – top panel) , an inhibition of lipid peroxidation (MDA, activity reduces abdominal and that chronic stress increases the malondialdehyde – middle panel) and an distension by increasing intestinal severity of intestinal inflammation elevation in tissue antioxidant level gas clearance and transit of (Gulpinar et al. 2004). Considering (GSH, glutathione – bottom panel). **p intraluminal gas (Villoria et al. 2006). the improvements in psychological < 0.01 and ***p < 0.001, compared to The combination of diet and exercise outcomes (i.e., depression, anxiety, control rats, +p < 0.05 and +++p < 0.001, therapy is effective in protection mood states) reached by habitual compared to non-runner colitis group.

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Figure 2 (left). The anxiolytic effect of exercise on rats with colitis. Colitis increases the freezing time, indicating increased anxiety level. *p < 0.05, compared with corresponding non- runner rats, +p < 0.05 , compared with non-runner control group.

Figure 3 (below). The protective effect of exercise on colonic injury as assessed macroscopically. *p < 0.05 and **p < 0.01, compared with control rats, +p < 0.05, compared with non-runner colitis group. exercise (Byrne & Byrne, 1993), a Since increased physical activity being and quality of life were number of studies has investigated prevented colonic glutathione improved (Loudon et al. 1999). the preventive effect of physical depletion, it appears that exercise Among the possible explanations for activity on IBD. Sonnenberg (1990) supports the maintenance of psychological outcomes are the showed that sedentary and antioxidant capacity in protecting direct effects of neurotransmitters physically less demanding the colonic tissue against oxidative (e.g., serotonin) in the brain that occupations were associated with a stress (Fig. 1, bottom panel). function to elevate mood (McDonald higher risk of inflammatory bowel Exercise-induced increases in aerobic & Hodgdon, 1991). We recently disease than were physically more fitness were shown to have beneficial demonstrated that regular exercise demanding occupations. Further- short-term and long-term effects on attenuates the anxiety of stressed more, the results of a case control psychological outcomes (DiLorenzo animals. However, in accordance study comparing incidence rates of et al. 1999). Similarly, physical with previous studies demonstrating IBD showed a reduced risk for activity was postulated to reduce that psychological stress might physically active patients with disease activity and perceived stress amplify intestinal inflammation Crohn’s disease or ulcerative colitis. in IBD patients, while general well- (Collins, 2001), severity of colitis was However, in another study active Crohn’s disease patients had a high risk (Klein et al. 1998). Suggested underlying mechanisms in this preventive effect were the stress- reducing effects of physical activity and changes in local neuro-immuno- endocrine effects (Loudon et al. 1999). In accordance with these studies, we demonstrated that physical activity attenuates the severity of the colonic inflammation by a neutrophil-dependent mechanism (Fig. 1, top panel), by attenuating the oxidative tissue damage, by reducing lipid peroxidation (Fig. 1, middle panel) and by enhancing the antioxidative enzyme activity on the oxidative injury of the colon (Kasimay et al. 2006). Our results also support the fact that depletion of colonic glutathione is one of the major factors permitting lipid peroxidation and subsequent colonic damage.

Physiology News | No. 68 | Autumn 2007 | www.physoc.org FEATURES PN 23 enhanced as the level of anxiety was Klein I, Reif S, Farbstein H, Halak A & Gilat T Central CO2 exaggerated. On the other hand, the (1998). Pre-illness non dietary factors and habits in inflammatory bowel disease. Ital J degree of anxiety was reduced Gastroenterol Hepato 30, 247–251. chemoreception: how (Fig. 2) in regularly exercised rats that had significant attenuation of Larsson SC, Rutegard J, Bergkvist L, Wolk A can it be done without colonic inflammation (Fig. 3). (2006). Physical activity, obesity, and risk of colon and rectal cancer in a cohort of Swedish the perfect receptors? men. Eur J Cancer 42, 2590–2597. Exercise should be considered as a Central CO2 chemoreception is a non-pharmacological intervention in Loudon CP, Corroll V, Butcher J, Rawsthorne P vital sensory function believed to controlling the course of & Bernstein CN (1999). The effects of physical be carried out by specific CO2 inflammatory bowel diseases, exercise on patients with Crohn's disease. Am J Gastroenterol 94, 697–703. chemoreceptors. Recent studies specifically during stressful suggest that brainstem neuronal conditions that would trigger the Maunder RG (2005). Evidence that stress exacerbation of the symptoms. In contributes to inflammatory bowel disease: networks may be able to achieve Evaluation, synthesis, and future directions. order to benefit from physical high CO2 sensitivity and a wide Inflamm Bowel Dis 11, 600–608. activity, including the health of the sensing spectrum by common gut, people should perform McDonald DG & Hodgdon JA (1991). pH-sensitive ion channels and moderate exercise at moderate Psychological effects of aerobic fitness training: synaptic interactions intensity for 30 minutes/day at least Research and therapy. Springer-Verlag, New York. 3 days/week. Regular exercise may Only a handful of sensory functions not only help us attain a longer life, Peters HP, De Vries WR, Vanberge- remain without cellular identity. but also more years living Henegouwen GP, Akkermans LM (2001). Central CO2 chemoreception is one of independently with a better quality Potential benefits and hazards of physical them. Since it was first described activity and exercise on the gastrointestinal almost a half century ago, of life. tract. Gut 48, 435–439. tremendous efforts have been Ozgur Kasimay Schnohr P, Gronbaek M, Petersen L, Hein HO & devoted to identify the central CO2 Sorensen TI (2005). Physical activity in leisure- Berrak Ç Yegen chemoreceptors (CCRs). We now time and risk of cancer: 14-year follow-up of know their likely locations in certain 28,000 Danish men and women. Scand J Public Department of Physiology, Marmara brainstem nuclei in which several University School of Medicine, Health 33, 244–249. types of CO2-chemosensitive neurons Istanbul, Turkey Sonnenberg A (1990). Occupational have been observed. We even know distribution of inflammatory bowel disease some potential cellular and molecular References among German employees. Gut 31, mechanisms for CO2 sensing. Bi L & Triadafilopoulos G (2003). Exercise and 1037–1040. gastrointestinal function and disease: An However, the identity of the CCRs evidence-based review of risks and benefits. Villoria A, Serra J, Azpiroz F, Malagelada JR remains uncertain. As a result, several Clin Gastroenterol Hepatol 1, 345–355. (2006). Physical activity and intestinal gas phenomena observed in central CO clearance in patients with bloating. Am J 2 Byrne A & Byrne DG (1993). The effects of Gastroenterol 101, 2552–2557. chemoreception are rather controversial. exercise on depression, anxiety and other Woods JA (1998). Exercise and resistance to mood states: A review. J Psychosom Res 37, neoplasia. Can J Physiol Pharmacol 76, 565–574. 581–588. The ideal CCR cells would be highly sensitive to CO , project to Collins SM (2001). Stress and the 2 gastrointestinal tract-IV. Modulation of respiratory-modulated neurons, and intestinal inflammation by stress: Basic dictate systemic CO2 responses. mechanisms and the clinical relevance. Am J However, experimental evidence Physiol 280, G315–318. supporting the existence of such DiLorenzo TM, Bargman EP, Stucky-Ropp R, typical sensory cells is lacking. In

Brassington GS, Frensch PA & LaFontaine T contrast, neurons with various CO2 (1999). Long-term effects of aerobic exercise chemosensitivity are found in many on psychological outcomes. Prev Med 28, 75–85. parts of the medulla and pons, although their functional significance Gulpinar MA, Ozbeyli D, Arbak S & Yegen BC is still not fully understood (2004). Anti-inflammatory effect of acute (Richerson, 2004). stress on experimental colitis is mediated by cholecystokinin-B receptors. Life Sci 75, The search for molecular CO2/pH 77–91. sensors has led to a number of Kasimay O, Guzel E, Gemici A, Abdyli A, candidate molecules in the past Sulovari A, Ercan F, Yegen BC (2006). Colitis- decade (Jiang et al. 2005). Studies induced oxidative damage of the colon and involving transgenic mice, however, skeletal muscle is ameliorated by regular indicate that CO chemoreception exercise in rats: The anxiolytic role of exercise. 2 Exp Physiol 91, 897–906. appears normal in animals lacking

Physiology News | No. 68 | Autumn 2007 | www.physoc.org 24 PN FEATURES one or other of these putative sensing molecules, such as 5-HT2a receptor, TASK-1 channel and P2x receptor is disrupted (Linden et al. 2006; Popa et al. 2005; Rong et al. 2003). This raises the question as to how the results from previous physiological studies on these sensing molecules can be explained.

Perhaps the most paradoxical phenomenon in central CO2 chemoreception is how the high CO2 sensitivity and a wide sensing Figure 1. The pH-effect relationship (e.g. on an ionic current) is described with the h spectrum are achieved. The Hill equation: Y = Imax / (Imax + (pKa / X) ), where Y is the effect on amplitude, Imax the respiratory neuronal networks are maximum effect, pKa the pH value at 50% activation, X the pH levels, and h the Hill highly sensitive to CO2 over a wide coefficient. Blue curve: pKa = 7.0, h = 1. Red curve: pKa = 7.0, h = 4.0. The grey sensing range (pCO 20–90 mm Hg), shaded area is the pH spectrum covered by the blue cure, and the yellow is the pH 2 spectrum for the red cure. Both are calculated as a 30% change in Y. allowing a 20–30% change in systemic ventilation with a minute steepness of its pH titration curve. Therefore, the sensor molecule that is increase (by 1–2 mm Hg) in pCO2 The steeper the curve (corresponding supreme in both sensitivity and (Feldman et al. 2003). The high to a high ‘h’ value in the Hill spectrum does not seem to exist. sensitivity and wide sensing spectrum equation), the narrower the pH- cannot be produced by a single pH sensing range. Thus, a highly pH- How does the respiratory neuronal sensing molecule. sensitive molecule tends to work in a network resolve the high sensitivity rather narrow pH range. On the other versus wide spectrum paradox? To As shown in Fig. 1, the pH sensitivity hand, the sensitivity becomes low if it address this, it is necessary to have a of a molecule is determined by the senses pH in a broad range. preparation that allows observation, as well as manipulation, of the cell- intrinsic membrane properties and neuronal interactions in their networks. For the latter simultaneous recordings from multiple neurons are essential. Thus, we have made primary neuronal cultures in a multi- electrode array (MEA) dish. Still in its infancy, the preparation has several weaknesses such as the loss of anatomical identity and the reduction in network components. Despite these problems, it is a useful preparation for the studies of both intrinsic membrane properties and synaptic interactions as well as simultaneous and repetitive recordings from multiple neurons.

Using the MEA technique, we studied the paradox of high sensitivity versus broad spectrum. We have found that Figure 2. CO chemosensitivity of cultured brainstem neurons studied in multi- 2 cultured brainstem neurons retain electrode arrays (MEA). A, A single unit was recorded from one channel of an MEA their high CO chemosensitivity in a dish. The unit was stimulated reversibly with an exposure to 10% CO . B , Thirteen 2 2 1 broad sensing range in the MEA dish units were recorded in another MEA dish. The firing rate (FR) of these units was (Fig. 2). Blockade of inward rectifier modulated by CO2 in a concentration-dependent manner. A linear response in the FR K+ (Kir) channels disrupts neuronal was seen in PCO 20–80 torr. Note that each thin coloured line indicates a unit, and 2 sensitivity to moderate hypercapnia the average of all units is shown as the thick blue line with large solid circles (means ± s.e.). The FR response can be described with a linear equation as shown with the and hypocapnia, whereas inhibition of TASK channels abrogates the straight black line, and the C slope value is 0.011. B2, The response was reproducible as seen with repetitive exposure in a 24-hr interval with the C value 0.011. C, An MEA neuronal response to more severe dish viewed in different magnifications. hypercapnia. These are consistent

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Of course, these observations need to be verified in other preparations, as they were made in an in vitro preparation of reduced neuronal networks. It is the reduced network preparation however that allows us to make a leap from individual cells to neuronal networks. We believe that with the emphasis on both individual

neurons in several brainstem CO2 Figure 3. Schematic of CO2 sensing in two neurons. Both cells express CO2/pH sensitive ion channels. These sensing molecules work in parallel and cover different chemosensitive nuclei and the neuronal networks, better pH ranges allowing the cell to depolarize with an increase in ambient pCO2 at various levels (parallel process). The cell on the left projects to the other with an excitatory preparations can be developed, which synapse. Since both cells are CO2 chemosensitive, the response of the post-synaptic will surely lead to an improved cell is enhanced with these cells in a serial network (serial process). Note that for understanding of central CO2 simplification other sensing molecules are not included. Abbreviations: Kir, inward chemoreception. rectifier K+ channels; TASK, two-pore domain K+ channels. Chun Jiang, Junda Su, with the pH sensitivities of the connections, some neurons increase heteromeric Kir4.1-Kir5.1 and the their firing rate by 20–30% with a rise Asheebo Rojas

TASK-1 channels, both of which are in1 mm Hg PCO2, suggesting that an Department of Biology, Georgia expressed in the brainstem, amplification mechanism by pre- and State University, Atlanta, Georgia, suggesting that the broad PCO2 post-synaptic neurons exists, which USA spectrum can be covered by multiple we termed the ‘serial process’ sensors (Su et al. 2007). Since these (Fig. 3). References molecules work in parallel for the Feldman JL, Mitchell GS & Nattie EE (2003). With the demonstration of the detection of PCO2 levels in the same Breathing: rhythmicity, plasticity, cells, we termed this sensing the parallel and serial processes of CO2 chemosensitivity. Annu Rev Neurosci 26, ‘ parallel process’ (Fig. 3). chemosensitivity, we may find 239–266. explanations for other controversial Jiang C, Rojas A, Wang R & Wang X (2005). phenomena: Although the parallel arrangement of CO2 central chemosensitivity: why are there so multiple sensors helps neurons to many sensing molecules? Respir Physiol • why are the optimal CCRs hard to Neurobiol 145, 115–126. preserve the CO2 sensitivity of each find? The systemic CO response + 2 sensor, these K channels do not can be fulfilled by neurons in Linden AM, Aller MI, Leppa E, Vekovischeva O, appear to be sensitive enough to Aitta-Aho T, Veale EL, Mathie A, Rosenberg P, several CO2-chemosensitive nuclei transduce a change of 1–2 mm Hg Wisden W & Korpi ER (2006). The in vivo and their synaptic connections with contributions of TASK-1-containing channels PCO2 into a 20–30% change in cellular respiratory neurons through signal to the actions of inhalation anesthetics, the activity. We have calculated the amplification, but may not be alpha(2) adrenergic sedative dexmede- possible effect of the pH-sensitive Kir accomplished by individual cells tomidine, and cannabinoid agonists. J Pharmacol Exp Ther 317, 615–626. channels on membrane potentials, without the signal amplification; and found that at best they can Popa D, Lena C, Fabre V, Prenat C, Gingrich J, produce a depolarization of ~1.5mV / • why are there so many CO2- Escourrou P, Hamon M & Adrien J (2005). 1 mm Hg PCO2. Clearly, the high CO2 chemosensitive neurons? The signal Contribution of 5-HT2 receptor subtypes to sensitivity may not be produced by amplification may involve a large sleep-wakefulness and respiratory control, the primary sensory neurons alone. number of interneurons, motor and functional adaptations in knock-out mice lacking 5-HT receptors. J Neurosci 25 , Therefore, we included neuronal 2A neurons and peripheral sensory 11231–11238. network properties in our studies. We neurons as well if they are CO2- Richerson GB (2004). Serotonergic neurons as have found that CO2 chemosensitivity chemosensitive; carbon dioxide sensors that maintain pH is greatly reduced when neurons are homeostasis. Nat Rev Neurosci 5, 449–461. isolated from their networks, • why does knockout of a likely CO2 suggesting that the CO2 chemo- sensing molecule impose very few Rong W, Gourine AV, Cockayne DA, Xiang Z, sensitivity relies on not only the cell- adverse consequences to the Ford AP, Spyer KM & Burnstock G (2003). intrinsic sensing mechanism, but also system? The overlap in the Pivotal role of nucleotide P2X2 receptor subunit of the ATP-gated ion channel on neuronal interactions through spectrum of the sensing molecules mediating ventilatory responses to hypoxia. J synaptic transmission. Indeed, our may allow them to compensate for Neurosci 23, 11315–11321. results show that several major the functional defect of each other, Su J, Yang L, Zhang X, Rojas A, Shi Y & Jiang C excitatory neurotransmitters critical a likely evolutional strategy for the (2007). High CO2 chemosensitivity versus for respiratory control are involved in reservation of certain vital wide sensing spectrum: a paradoxical problem chemosensing synaptic transmission functions such as control of and its solutions in cultured brainstem (Su et al. 2007). With intact network respiration. neurons. J Physiol 578, 831–841.

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Inspiratory muscle training as an ergogenic aid: credible at last? Recent evidence points to an important role for respiratory muscle work in limiting exercise tolerance. Alison McConnell (below) proposes that it is time to start thinking differently about the role of inspiratory muscle training in alleviating this limitation

For most of the 20th century, exercise the 6 minute time trial (from an ~11% physiologists viewed the respiratory deficit in strength to ~3%), despite the system as one that was the exception fact that the athletes had completed to the rule of symorphosis (structural the time trial more quickly. design is matched to functional demand). After all, at sea level, oxygen In a subsequent study on well-trained transport is not limited by the diffusion male cyclists, the rigour of the research of oxygen, and human beings appear design was improved by using a to have considerable breathing double-blind placebo-controlled reserve, even at maximal exercise. design, and by quantifying both the What, then, might be the point of IMT and the whole-body training training the respiratory pump (Romer et al. 2002). The latter was to RMT as an ergogenic aid, i.e. as a muscles? The past decade has ensure that any changes in exercise performance-enhancing intervention witnessed a considerable advancement performance could not be ascribed to in athletes. An important aspect of in our understanding of the limitations changes in the athletes’ whole-body research on the ergogenic properties imposed by respiratory muscle work, training. The performance outcome of interventions is to establish as well as providing insights into the measures in this study were a 20 km outcome measures that are not only mechanisms by which specific training and a 40 km cycling time trial, which reliable, but also have the external of the respiratory pump elicits were simulated under laboratory validity to make them relevant to improvements in exercise tolerance. conditions. After the 6 week period of athletic performance. In this context, IMT, the 20 km and 40 km time trial time trials (performance against the Research on respiratory muscle performances improved by 3.8% and clock) provide both validity and, in the training (RMT) has its origins in the 4.6% above placebo, respectively. The right hands, reliability. The 1970s, when early studies sought to study also demonstrated attenuation disadvantage of time trials is that the demonstrate that the respiratory of both respiratory and whole-body effect size of a performance change is muscles were responsive to specific effort sensations, and a reduction in generally very small (< 5%), which training. Later research sought to exercise-induced inspiratory muscle means that participants must have evaluate the potential benefits of such fatigue. Thus, in both oarswomen and excellent pacing skills and be training with respect to exercise male cyclists, IMT induced a range of accustomed to reproducing truly tolerance in both healthy people and physiological and perceptual changes maximal time trial performances. patients with respiratory disease. Up that were consistent and repeatable. until the late 1990s, the literature on RMT in healthy young adults was The first study to examine the Neither the rowing nor the cycling contradictory to say the least influence of RMT on time trial study demonstrated any change in (McConnell & Romer, 2004b). Poor performance used rowing as the maximal oxygen uptake (VO max) research design and inappropriate exercise modality, and chose well- 2 outcome measures had created a very trained oarswomen as participants after IMT, which is consistent with ‘mixed bag’ of data that only served (Volianitis et al. 2001). The advantage observations of other investigators to confirm the perceived wisdom that of using well-trained athletes is that (see McConnell & Romer, 2004b). breathing does not limit exercise the reliability of their time trials is very Some exercise physiologists tolerance. The picture was equally high. A single-blind placebo-controlled interpreted this finding as a weakness murky with respect to research on design was implemented, and of the studies; after all, how could patients with lung disease, but performance was assessed using two training the respiratory pump increase interpretation of this body of research rowing ergometer time trials in the exercise performance without was also hampered by a lack of laboratory. The 11 week period of increasing maximal oxygen uptake? Of rigorously conducted studies (see pressure threshold inspiratory muscle course, a change in VO2max would McConnell & Romer, 2004a). A turning training (IMT) increased the distance have completely contradicted our point in research on RMT came during covered during a 6 minute all-out understanding of the factors that limit the late 1990s, when more reliable effort by 1.9% above placebo, and the oxygen transport, since the methods of training became more time taken to cover 5,000 m improved participants were not diffusion limited. widely used (specifically pressure by 2.2%. In addition, there were For a time it was thought that the threshold training) and a more accompanying reductions in blood answer may lie in a change in the rigorous approach to research design lactate concentration and breathing lactate threshold, which is the other was adopted. effort during a separate ergometer trial key mechanism by which exercise incorporating a series of fixed work performance improvements are My own group has had a particular rates. Finally, IMT also reduced normally achieved following whole- interest in the potential application of inspiratory muscle fatigue induced by body training. However, in a carefully

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conducted study we later showed that inspiratory muscle training did not improve the lactate threshold (McConnell & Sharpe, 2005).

These observations led to the conclusion that the mechanism underlying the apparent ergogenic effect of IMT must lie outside our conventional view of training-induced improvements in performance, i.e. it was not due to improvements in

VO2max and/or the lactate threshold. During this same period of the 1990s, Jerry Dempsey’s group at the University of Wisconsin was undertaking some outstanding and elegant research into the influence of Figure 1. Comparison of the fatigue profile of the plantar flexors. respiratory muscle work upon exercise Note: MVCTI = maximal voluntary contraction force with superimposed twitch; Tlim = tolerance. A review of this research was time limit of plantar flexion (time to decrease below 50% of baseline MVCTI); PF = published in Physiology News (65, plantar flexion; IMF = inspiratory muscle fatigue; 50 mmHg and 140 mmHg = 25–27) and will not be rehearsed again mechanical blood flow occlusion with cuff inflation to 50 mmHg and 140 mmHg; here – suffice to say Jerry Dempsey and IMFrest = 30 min rest after IMF; IMFpre = IMF at 60% of pre-IMT inspiratory muscle his colleagues have now provided very strength; IMFpost = IMF at 60% of post-IMT inspiratory muscle strength. convincing evidence for the existence of an inspiratory muscle metaboreflex Furthermore, if IMT modulated the was increased to take account of the that can result in a blood flow ‘steal’ reflex, then the fatigue profile of the training-induced improvement in from the locomotor muscles. Could limb should also be modulated after strength, the rate of plantar flexion inspiratory muscle training be exerting IMT. To validate our limb fatigue model fatigue was once again accelerated. its ergogenic effect by delaying or (plantar flexion), we first assessed its These data support the notion that the attenuating this reflex? sensitivity to mechanical restriction of inspiratory muscle metaboreflex blood flow. In addition, we confirmed operates at exercise intensities where Hitherto, studies of the inspiratory the ability of a fatiguing inspiratory there is cardiac output reserve. muscle metaboreflex had been muscle-loading protocol (IMF) to Furthermore, they suggest that IMT confined to models that studied activate the inspiratory muscle changes the threshold of inspiratory vascular responses to the metaboreflex metaboreflex. Following this, a muscle work required to elicit the in either the resting limb, or during number of manipulations of the pre- vasomotor response to activation of whole body cycling at maximal plantar flexion conditions were this metaboreflex. Thus, the most exercise. Thus, there was evidence that implemented: (1) a bout of IMF important determinant of the fatiguing inspiratory muscle work was immediately prior to the plantar functional repercussions of inspiratory capable of inducing vasoconstriction in flexion, and (2) an identical bout of IMF muscle work appears to be the relative the resting limb, and under conditions followed by a 30-minute period of rest intensity of that inspiratory muscle where cardiac output was maximal. (to allow the metaboreflex to work. However, it was unclear whether the dissipate) before plantar flexion. After metaboreflex could override the a 4 week period of IMT, condition (1) In summary, RMT research has been functional hyperaemia of exercise was repeated. In addition, we hampered by the results of some poor under conditions where there was implemented a final condition in which studies that have generated cardiac output reserve. Furthermore, the intensity of the inspiratory muscle contradictory data. In addition, there even if the metaboreflex did operate loading was increased to account for has been a natural scepticism about an under such conditions, it was far from the training-induced improvement in intervention that appeared to fly in the clear whether IMT could modulate its inspiratory muscle strength. face of exercise physiologists’ operation. understanding of the role of the When plantar flexion was preceded respiratory pump in oxygen transport. In our most recent study we have immediately by IMF, the rate of plantar However, respiratory muscle work has examined these questions using an flexor fatigue was accelerated (Fig. 1). far wider repercussions than were isolated human lower leg model When a 30 minute period of rest was previously appreciated, and it is now (McConnell & Lomax, 2006). Our basic given between the IMF and plantar known that these muscles contribute premise was that if the inspiratory flexion, the fatigue profile was not to both the metabolic demand and muscle metaboreflex induced a significantly different to control. sensory experience of exercise. Recent functionally meaningful reduction in Similarly, after IMT, the same bout of studies suggest that IMT generates limb vascular conductance, then the IMF failed to induce any change in the improvements in exercise tolerance resulting impairment of limb blood rate of plantar flexion fatigue. In through two main mechanisms, which flow should accelerate limb fatigue. contrast, when the intensity of the IMF are probably also interlinked:

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(1) attenuation of effort sensations Limitation to exercise performance at altitude – (exercise feels easier after IMT) and (2) attenuation of the inspiratory muscle where is peripheral muscle fatigue important? metaboreflex leading to a preservation You might think the answer is ‘where it hurts’, but there is of limb blood flow during exercise. much more to it. Markus Amann explains The role of RMT in enhancing exercise performance in athletes, as well as We have previously proposed that on strong correlative data, we think exercise tolerance in patients with neural afferent feedback associated that sensory afferent feedback, dyspnoea, increased work of with peripheral locomotor muscle originating in the fatiguing breathing, and/or circulatory fatigue exerts an inhibitory influence locomotor muscle, back to the CNS is limitations (e.g. chronic obstructive on the central motor drive resulting a key determinant of the conscious pulmonary disease, chronic heart in a centrally mediated limitation of (and/or subconscious) regulation of failure) has been made considerably exercise. This regulatory mechanism central motor drive (i.e. exercise more credible by newly acquired appears to be valid from sea level up performance). We believe in a strong insights into the wider consequences to moderate altitudes (Amann et al. link between ‘peripheral’ (i.e. of exercise-induced inspiratory muscle 2006a; Romer et al. 2007). More biochemical changes within the work. recently we have shown that the muscle) and ‘central’ fatigue Acknowledgements magnitude of this inhibitory (reductions in CNS motor drive to The author acknowledges a beneficial peripheral feedback limiting central the working muscle) (Amann et al. interest in the POWERbreathe® motor drive is significantly less at 2006a). Furthermore, we think that inspiratory muscle trainer in the form exhaustion in severe hypoxia, the magnitude of this inhibitory of a royalty share on license income to although exercise performance is neural feedback is proportional to the University of Birmingham. She also limited even more (Amann et al. the magnitude of peripheral provides consultancy services to Gaiam 2007). These observations suggest locomotor muscle fatigue, which in Ltd. that, beyond moderate altitudes, turn is highly sensitive to arterial O2 other sources of inhibition of central Alison K McConnell content (CaO2) (Amann et al. 2006b), motor drive start to outweigh the and consequently acts as a dose- Centre for Sports Medicine & Human limiting effects of peripheral muscle dependent trigger of central fatigue. Performance, Brunel University, fatigue and its associated inhibitory In lay terms: the lower the O2 Uxbridge, UK feedback (Fig. 1). transport to the working legs during References exercise the faster your locomotor McConnell AK & Lomax M (2006). The However, before going into further muscle fatigue, the greater the influence of inspiratory muscle work history details of our newly proposed fatigue inhibitory feedback to the CNS, the and specific inspiratory muscle training upon theorem, we will take a few steps human limb muscle fatigue. J Physiol 577, less the magnitude of central motor 445–457. back to recapitulate and reflect on command and the greater the some of our earlier findings. Based limitation to exercise performance. McConnell AK & Romer LM (2004a). Dyspnoea in health and obstructive pulmonary disease: the role of respiratory muscle function and training. Sports Med 34, 117–132.

McConnell AK & Romer LM (2004b). Respiratory muscle training in healthy humans: resolving the controversy. Int J Sports Med 25, 284–293.

McConnell AK & Sharpe GR (2005). The effect of inspiratory muscle training upon maximum lactate steady-state and blood lactate concentration. Eur J Appl Physiol 94, 277–284.

Romer LM & Dempsey JA (2006). Legs pay out for the cost of breathing! Physiology News 65, 25–27.

Romer LM, McConnell AK & Jones DA (2002). Effects of inspiratory muscle training on time- trial performance in trained cyclists. J Sports Sci 20, 547–562. Members of the John Rankin Laboratory of Pulmonary Medicine: Markus Amann (far Volianitis S, McConnell AK, Koutedakis Y, right), Jerry Dempsey (middle) and our Medical Director Marlowe Eldridge (second McNaughton L, Backx K & Jones DA (2001). Inspiratory muscle training improves rowing from left). Also two friends on a short visit, lab alumnus Lee Romer (Brunel performance. Med Sci Sports Exerc 33, University, UK, far left) who assisted with the study and UW Program Specialist 803–809. Margaret Rankin, youngest daughter of our laboratory’s founder.

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The purpose of such a regulatory feedback mechanism is presumably to protect the muscle from an ‘ excessive’ development of peripheral fatigue beyond a critical threshold or ‘sensory tolerance limit’ (Gandevia, 2001). Based on a series of experiments during which we altered the inspiratory O2 fraction

(FIO2) to simulate various altitudes, we demonstrated that this regulatory mechanism is crucial in hyperoxia and up to a level of acute hypoxia equivalent to an altitude of approximately 4,000 m (Amann et al 2006a; Romer et al. 2007). After these initial studies, the following questions arose naturally: what happens if the mountaineer continues to climb beyond this altitude? Is the exercise-induced magnitude of peripheral locomotor Figure 1. Haemoglobin saturations (SpO2) and associated estimated altitudes muscle fatigue and/or the rate of subdivided in three zones. The yellow zone indicates the range at which peripheral development of fatigue of these locomotor muscle fatigue and associated neural feedback is thought to be the main muscles still as important a determinant of the reduction in central motor drive. The blue zone indicates the regulated variable at extreme altitude at which CNS hypoxia presumably dominates the development of central altitudes? Or does the priority fatigue. The ‘grey area’ illustrates the range of arterial oxygenation at which the change and other organ systems, like switch from a predominant effect of peripheral fatigue to a predominant effect of the brain, take over the hierarchy of CNS hypoxia might occur. The background picture was taken by the author at the regulated variables due to the lakefront of the Fairmont Chateau Lake Louise Hotel (Alberta, Canada) during the 2007 Hypoxia meeting. increased threat associated with severe systemic hypoxemia induced those ‘re-oxygenation’ experiments procedure, reached task failure in by exercise beyond moderate be tied together – is there a link? Is each condition, arterial hypoxemia altitudes? there a fluctuating impact on the was rapidly removed by

development of central fatigue? How surreptitiously switching to an FIO2 of Previous reports in the literature is the magnitude of the impact of 0.3 (re-oxygenation). A significant have already implied that severe CNS each of these determinants of central prolongation of exercise time to hypoxia may result in inhibitory fatigue regulated? exhaustion was not achieved effects on central motor drive following re-oxygenation at task (Kayser et al. 1994; Calbet et al. We have suggested that the relative failure in normoxia [arterial 2003). These conclusions were effects of centrally versus peripherally hemoglobin saturation (SpO2) of originating impairments of central drawn from the observation that ~94%] and moderate hypoxia (SpO2 after cycling to exhaustion at great motor drive (i.e. limitations in ~82%). However, in severe hypoxia exercise performance) change with altitudes (> 5,000 m) the (SpO2 ~67%), re-oxygenation at task the level of convective O2 transport administration of 100% O2 – thereby failure elicited a significant reversing the arterial desaturation – as affected by acute hypoxia (Amann prolongation (+170 %!) of time to enabled the subjects to continue to et al. 2007). Subjects were instructed exhaustion. exercise. Ultimately, these findings to pedal against a heavy intensity argue against the validity of our fixed workload to task failure in Why this difference with severe proposed regulatory mechanism normoxia, moderate and severe hypoxia? At task failure in normoxia (Amann et al. 2006a) (the hypoxia (FIO2 0.21, 0.15, and 0.10, and moderate hypoxia peripheral development of central fatigue respectively). Clear criteria for task locomotor muscle fatigue – assessed based on peripheral feedback) in failure (drop in pedal cadence below via changes in quadriceps twitch extreme altitudes and indicate the 70% of self-selected target cadence force (∆Qtw) as measured pre- versus existence of fast responding hypoxia- for ≥5 s) and exhaustion (drop in post-exercise in response to sensitive sources of inhibition of pedal cadence below 60% of self- supramaximal femoral nerve central motor drive. Now, how can selected target cadence for ≥5 s) stimulation – has reached the our recently proposed regulatory were established prior to the study. individual critical threshold (∆Qtw mechanism and the indications of When the subjects, unaware of the from pre- to post-exercise of about

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–36%). As expected, this magnitude independent from any inhibitory influencing central motor output, of peripheral fatigue did not change afferent feedback originating in the and therefore exercise performance, further within the additional few periphery. This central inhibitory occurs below a threshold level of seconds of exercise to exhaustion effect of severe hypoxia probably acutely compromised O2 transport. after re-oxygenation following either serves to avoid severe cerebral This level is represented by a range of normoxia or moderate hypoxia. This dysfunction far in advance of 75–68% SaO2, or the corresponding is consistent with the literature reaching the individual critical acute exposure to altitudes of about indicating that re-oxygenation has threshold of peripheral muscle 4100–5100 m. no instant alleviating effect on the fatigue. already induced magnitude of Markus Amann peripheral muscle fatigue. Why is end-exercise peripheral The John Rankin Laboratory of Interestingly, however, at task failure muscle fatigue at exhaustion Pulmonary Medicine, University of in severe hypoxia peripheral muscle (following re-oxygenation at task Wisconsin-Madison Medical School, fatigue was significant but only failure) identical in all three USA about two-thirds of the level of conditions? At sea level and at fatigue measured at task failure in moderate altitude, peripheral normoxia and moderate hypoxia and locomotor muscle fatigue rises all References Amann M, Eldridge MW, Lovering AT, Stickland therefore far below the individual the way to the individual critical MK, Pegelow DF & Dempsey JA (2006a). threshold or sensory tolerance limit. threshold. Exercise is thus, despite Arterial oxygenation influences central motor Following re-oxygenation in severe re-oxygenation at task failure, output and exercise performance via effects hypoxia, subjects continued to terminated via a reduction in central on peripheral locomotor muscle fatigue. J exercise and peripheral fatigue motor output to prevent further Physiol 575, 937–952. continued to develop to the same development of peripheral fatigue Amann M, Romer LM, Pegelow DF, Jacques AJ, level (critical threshold) as observed beyond the individual critical Hess CJ & Dempsey JA (2006b). Effects of at exhaustion in normoxia and threshold. By reversing the arterial arterial oxygen content on peripheral ∆ locomotor muscle fatigue. J Appl Physiol 101, moderate hypoxia ( Qtw about hypoxemia and CNS hypoxia at task 119–127. –36%). failure in severe hypoxia, the constraint to exercise quickly Amann M, Romer LM, Subudhi AW, Pegelow So, what limits endurance exercise in vanishes, exercise can be continued DF & Dempsey JA (2007). Severity of arterial normoxia and moderate hypoxia vs. hypoxaemia affects the relative contributions and the locomotor muscles continue of peripheral muscle fatigue to exercise severe hypoxia and why was there to accumulate fatigue until the performance in healthy humans. J Physiol 581, significantly less locomotor muscle individual critical threshold is 389–403. fatigue at task failure in severe reached. hypoxia? The data indicate that Calbet JA, Boushel R, Radegran G, Sondergaard H, Wagner PD & Saltin B (2003). exercise- and altitude-induced To date we only have correlative data Determinants of maximal oxygen uptake in arterial hypoxemia as experienced at to support the role of peripheral severe acute hypoxia. Am J Physiol Regul Integr sea level and up to moderate muscle fatigue and associated Comp Physiol 284, R291–303. altitudes (~ 4100 m), per se, is not inhibitory feedback on central motor Gandevia SC (2001). Spinal and supraspinal severe enough – by itself – to impose drive. We are currently investigating factors in human muscle fatigue. Physiol Rev an inhibitory influence on central the effects of a direct blockade of 81, 1725–1789. motor drive in healthy humans. The neural feedback originating in the CNS at these altitudes ‘allows’ the Kayser B, Narici M, Binzoni T, Grassi B & exercising and fatiguing locomotor Cerretelli P (1994). Fatigue and exhaustion in development of peripheral muscles on central motor drive and chronic hypobaric hypoxia: influence of locomotor muscle fatigue until the the development of peripheral exercising muscle mass. J Appl Physiol 76, individual critical threshold – or muscle fatigue. 634–640. sensory tolerance limit – is achieved. Romer LM, Haverkamp HC, Amann M, This then in turn curtails central In summary, we believe the current Lovering AT, Pegelow DF & Dempsey JA motor output, presumably via strong data support the concept that the (2007). Effect of acute severe hypoxia on peripheral fatigue and endurance capacity in inhibitory neural feedback to the dominance of CNS hypoxia over CNS. healthy humans. Am J Physiol Regul Integr Comp peripheral muscle fatigue in Physiol 292, R598–606. At severe altitudes (> 5100 m) the roles seem to be reversed. The level Significant increase in impact factors of arterial hypoxemia during exercise The Society is pleased to announce a significant increase in the 2006 impact at these extreme altitudes imposes a factors for both its journals. The Journal of Physiology has increased its impact severe threat to brain function itself, factor to 4.407 (4.272 in 2005), with an increase in ranking from 10/75 to 9/76 in possibly operating via interference the ISI’s physiology category. The impact factor for Experimental Physiology has with cerebral neurotransmitter increased to 2.339 (2.054 in 2005), and its ranking from 40/75 to 33/76. turnover. Accordingly, central motor output is constrained largely For more news on The Society’s journals, see p. 46.

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Circulating ATP and ADP: important regulators of blood flow and platelet reactivity during exercise

G-protein-coupled receptors (Bours • ectoenzymatic inactivation; et al. 2006). Extracellular adenosine • nucleoside uptake by the cell. is then either transported into the cell by nucleoside transporters or The concept of a purinergic further inactivated to inosine via signalling system is now widely ecto-adenosine deaminase reaction appreciated, and studies on (Yegutkin et al. 2002). Together, the pathophysiology and therapeutic extracellular nucleotide turnover potential of extracellular purines depends on functional interactions represent a novel and rapidly Gennady Yegutkin (left) and José between distinct processes expanding field (Burnstock, 2006). González-Alonso including: In particular, recent findings provide evidence for important roles of Extracellular ATP and other • transient release of ATP, ADP and circulating nucleotides in the nucleotides (ADP, UTP, UDP) are other agonists; regulation of platelet reactivity, important signalling molecules in • triggering of signaling events via haemostasis and blood flow under the cardiovascular system, where nucleotide- and nucleoside- exercising conditions. Regular they induce diverse vasodilatatory, selective receptors; exercise training is consistently immunomodulatory and prothrombotic responses (Bours et al. 2006; Burnstock, 2006). These effects are mediated through G- protein-coupled P2Y receptors as well as via ligand-gated P2X receptors (Fig.1A), which are ubiquitously expressed on various cell types, including the vascular endothelium and haematopoietic cells. Subsequent to signal transduction, nucleotides need to be rapidly inactivated and vascular endothelial ectoenzymes nucleoside triphosphate diphosphohydrolase (NTPDase; known as ecto-ATPDase, CD39) and ecto-5’-nucleotidase/ CD73 are considered the major regulators of the duration and magnitude of purinergic signalling in the vasculature (Bours et al. 2006). In contrast to traditional paradigms that focus on nucleotide-inactivating mechanisms, it has now become clear that ‘classical’ intracellular enzymes, adenylate kinase and nucleoside diphosphate kinase, are also co-expressed on surfaces of endothelial cells, lymphocytes and other cell types and finely control local nucleotide concentrations via Figure 1. Turnover of extracellular nucleotides and nucleosides. A, Signalling effects backward ATP-regenerating pathway of nucleotides occur through a series of ionotropic ATP-specific P2X receptors and (Fig. 1B) (Yegutkin et al. 2002). The metabotropic P2Y receptors that are classified by their affinities towards ATP, ADP and other putative nucleotide and nucleotide sugar agonists. Adenosine acts at four generated adenosine, in turn, has a own nucleoside-selective receptors. B, Major exchange activities of extracellular non-redundant counteracting role in nucleotides and their conversion into adenosine (Ado) and inosine (Ino). The the attenuation of inflammation and elements of purine-inactivating chain comprise at least three ectoenzymes, mediates cardioprotective, NTPDase/CD39, ecto-5’-nucleotidase/CD73 and adenosine deaminase (ADA), vasodilatory, angiogenic and other whereas an opposite ATP-regenerating pathway is mediated via sequential adenylate responses via interaction with own kinase (AK) and nucleoside diphosphate kinase (NDPK) reactions.

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2007). A salient finding of this work is the demonstration that plasma from exercising humans, but not from resting control samples, up- regulates the expression level of the platelet activation marker P-selectin and that these prothrombotic effects can be attenuated after scavenging nucleotides by exogenous apyrase (Fig. 2). Subsequent reverse-phase high-performance liquid chromatographic analysis directly confirmed a significant increase in plasma ADP during exercise. This work additionally pointed to a role of ADP in platelet function beyond its immediate activity as a primary agonist. Probably, other synergistic factors like adrenaline (epinephrine) or some chemokines are released simultaneously with ADP that, in conjunction with the increased blood flow, would provide the stimuli for platelet activation during exercise.

While preferential activation of the coagulation cascade may predispose exercising subjects to the enhanced risk of intravascular thrombosis Figure 2. Plasma from exercising humans stimulates P-selectin expression on platelet formation, other accompanying surface. Blood was collected from the right atrium of endurance-trained athletes at haemostatic changes such as rest, and during submaximal (sub) and maximal (max) cycling exercise and after 10 activation of fibrinolysis and min of recovery (rec). A, Plasma samples were then co-incubated with platelets from increased blood flow should work to resting volunteers while platelet activation was monitored by flow cytometry with counterbalance it. Blood flow and its anti-P-selectin monoclonal antibody. B, The percentage of P-selectin expression after surrogate oxygen delivery regulation platelet-plasma co-incubation was determined from the above fluorescence are generally thought to result from histograms (*p < 0.05 as compared with resting plasma; n = 8). Plasma from the interplay of neural, myogenic exercising subjects was also pretreated with exogenous apyrase (1 unit/ml) prior to and metabolic signals. A number of addition to platelet suspension (**p < 0.05 as compared with non-treated plasma; n = 4). observations raised the possibility that purinergic signalling can also be associated with a variety of formation of thromboxane-A2 by implicated in the precise regulation favourable alterations in cardio- cyclooxygenase or secretion of ADP of oxygen supply to contracting vascular function, including reduced from dense granules with muscle under exercising and other heart rate and increased maximal subsequent activation of platelet hypoxic and hypercapnic conditions. oxygen uptake, reduced blood ADP-selective P2Y1/P2Y12 receptors. Specifically, in addition to serving as pressure, activation of fibrinolysis In turn, vascular endothelium an efficient oxygen carrier, the red and lower platelet activation. controls platelet reactivity and blood cells act as sensors and However, unfavourable haemostatic prevents thrombus formation via controllers of local blood flow via changes might occur at extreme three pathways, including nitric transient release of ATP in proportion exercise and environmental to the degree of haemoglobin oxide and prostaglandin-I2 synthesis conditions that predispose to and ADP scavenging via NTPDase deoxygenation (González-Alonso et occlusive thrombus formation in activity (Burnstock, 2006). al. 2002; Ellsworth, 2004). The coronary or cerebral vessels, and the released ATP subsequently induces a extremely rare phenomenon of Recently, we have shown that conducted vasodilatatory response sudden cardiac death during intravascular nucleotide turnover is upstream and regulates oxygen exertion. Platelet activation and acutely activated both in endurance- supply to contracting muscles via recruitment, followed by trained and sedentary subjects binding to the endothelial P2Y1/P2Y2 haemostatic plug formation, is during performance of maximal receptors and stimulation of vascular generally initiated either via cycling exercise (Yegutkin et al. endothelium to release nitric oxide

Physiology News | No. 68 | Autumn 2007 | www.physoc.org FEATURES PN 33 and arachidonic acid metabolites concurrent up-regulation of soluble (Ellsworth, 2004; Burnstock, 2006). nucleotide-inactivating activities The fallibility of referees induced by endurance training, may The following extract (see Bynum, Identification of a network of soluble represent an efficient control system 1976) from the 1941 Report of the purine-converting enzymes freely that finely regulates both tissue O2 Editorial Board of The Journal of circulating in the bloodstream adds delivery and platelet reactivity in Physiology illustrates the pitfalls of another level of complexity to healthy subjects. On the other hand, the refereeing process. understanding the regulatory acute disturbances in the pattern of mechanisms of purine homeostasis intravascular nucleotide turnover Curious situations occasionally arise within the vasculature. We have occurring during exhaustive exertion in the interplay between referees ’ shown that two soluble nucleotide- might contribute, in conjunction judgements. One paper was inactivating enzymes, nucleotide with other prothrombotic synergistic considered completely unintelligible pyrophosphatase/ phospho- factors, to the enhanced risk of by the Board and the advice of a diesterase (NPP) and NTPDase, cardiovascular morbidity and referee was sought. After much constitutively circulate in the human mortality, especially in the elderly labour which entailed the rewriting bloodstream, and we have further and sedentary subjects suffering of many paragraphs, the paper was demonstrated that their activities from endothelial dysfunction and returned to the office with the are transiently up-regulated during insufficient release of anti-platelet request that another referee should strenuous exercise by 20–25 and compounds. see it before it was passed to the 80–100%, respectively (Yegutkin et press. So a second opinion was al. 2007). The exercise-mediated Gennady G Yegutkin1 sought, and in his report the second increase revealed in serum NPP 2 referee had the misfortune to select activity may allow the by-passing of José González-Alonso as unintelligible the very paragraphs the generation of a principal platelet- 1MediCity Research Laboratory, to the rewriting of which the first recruiting agent ADP, via direct University of Turku and National referee had devoted so much time conversion of circulating ATP into Public Health Institute, Turku, and labour.

AMP and PPi. Furthermore, Finland 2 Bynum, W F (1976). A short history of The concurrent activation of another Centre for Sports Medicine and Physiological Society 1926–1976. J Physiol soluble nucleotidase NTPDase might Human Performance, Brunel 263, 67. represent a novel and currently University, Uxbridge, UK unappreciated effector system Further fallibilities of contributing, along with vascular References referees endothelial NTPDases, to the Bours MJL, Swennen ELR, Di Virgilio F, termination of acute prothrombotic Cronstein BN & Dagnelie PC (2006). Adenosine An Australian visitor to the (then) effects of ADP under hyperaemic 5'-triphosphate and adenosine as endogenous Institute of Animal Physiology at exercising conditions. signaling molecules in immunity and Babraham told of his experience inflammation. Pharmacology & Therapeutics with an American journal soon Of note is the fact that the 112, 358–404. recombinant soluble form of human after the war. NTPDase/CD39 is currently Burnstock G (2006). Pathophysiology and considered a promising aspirin- therapeutic potential of purinergic signalling. He thought it good training to Pharmacol Rev 58, 58–86. insensitive antithrombotic drug, make his student responsible for which potently inhibits platelet Ellsworth ML (2004). Red blood cell-derived submitting the manuscript to the reactivity under various ATP as a regulator of skeletal muscle journal. When, after several experimental prothrombotic perfusion. Med Sci Sports Exerc 36, 35–41. weeks, no acknowledgement had been received he discovered the conditions. Therefore, data on González-Alonso J, Olsen DB & Saltin B (2002). constitutive presence of soluble Erythrocyte and the regulation of human paper had been sent by surface NTPDase in human blood and its up- skeletal muscle blood flow and oxygen mail (airmail was not necessarily regulation during exhaustive delivery: role of circulating ATP. Circ Res 91, the automatic choice in those far 1046–1055. exercise may open up further off days). A second copy was research for future therapeutic Yegutkin GG, Henttinen T, Samburski SS, rapidly dispatched by air resulting, applications of this major ADP- Spychala J & Jalkanen S (2002). The evidence equally rapidly, in an airmailed inactivating nucleotidase as a for two opposite, ATP-generating and ATP- rejection letter. News that the consuming, extracellular pathways on original manuscript had been ‘ natural antithrombotic enzyme’ for endothelial and lymphoid cells. Biochem J 367, anti-platelet therapy in hypoxia- 121–128. accepted followed a week or so associated and other vascular later. diseases. Yegutkin GG, Samburski SS, Mortensen SP, Jalkanen S & González-Alonso J (2007). Ann Silver In summary, transient exercise- Intravascular ADP and soluble nucleotidases contribute to acute prothrombotic state Cambridge, UK mediated increases in circulating ATP during vigorous exercise in humans. J Physiol and ADP levels, together with 579, 553–564.

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Muscular dystrophy and the brain

Duchenne muscular dystrophy (DMD) of the disease and individual variability is the second most common fatal in the alterations of brain function, genetic disease of human beings. It possibly reflecting the diversity of occurs with an incidence of about one dystrophin gene mutation, the in every 3500 live male births. The cognitive impairment has largely been main characteristic of the disease is a overlooked. The mdx mouse, the most progressive loss of skeletal muscle commonly used animal model of tissue, which eventually leads to the muscular dystrophy, also exhibits a John Morley (left) and Stewart Head. death of the afflicted boy. DMD was range of behavioural and cognitive John has recently been appointed first described in the 17th century by deficits (Anderson et al. 2002). Foreign Correspondent for Physiology the French physician Duchenne de News, along with John Hanrahan (McGill Boulogne, and also in England by the Dystrophin localization studies have University, Canada). British physician Edward Meryon. In identified at least seven isoforms of his first description of the disease, dystrophin, each with its own tissue- skeletal muscle, where dystrophin is Duchenne noted the boys often specific promoter, of which four are distributed uniformly on the inside of showed significant mental found in the CNS (Kunkel et al. 1985). the membrane, in neurons dystrophin impairment. Studies in the latter half of Dystrophin is not uniformly distributed is found in discrete punctate units the 20th century confirmed the mental throughout the CNS, work on the mdx localised at the postsynaptic density. impairment, with DMD boys having an mouse shows that it is found in Intriguingly, punctate clusters of average IQ of 85, and in addition, discrete areas of the brain and dystrophin are not found at all independently of their actual IQs, DMD associated with specific neurons postsynaptic densities, rather they are boys have a poor performance in digit (Górecki & Barnard 1997). Clusters of extensively co-localised with the span, story recall, comprehension, dystrophin are most abundant on the GABAA inhibitory receptor in cerebral serial position memory, reading and soma and proximal dendrites of the cortex, hippocampus and cerebellar mathematical ability (Anderson et al. pyramidal cells in cerebral cortex and Purkinje cells. 2002). In boys, perhaps because of the hippocampus and on cerebellar severity of the skeletal muscle wasting Purkinje cells (Fig. 1A). In contrast to Knuesel and colleagues (1999) elegantly demonstrated that in mdx mice the absence of dystrophin from the postsynaptic clusters does not

eliminate clustering of the GABAA receptors, rather, it reduces both the number and size of clusters at the postsynaptic density of the inhibitory synapses. In our laboratory we used Western blots to show that there is no

Figure 1. A, Distribution of dystrophin. (a and b) Layers III and V of rat neocortex, respectively; (c and d) hippocampus CA3 area; (e and f) cerebellum; immunofluorescence staining with the monoclonal antibody Dys-1. Abbreviations: sp, stratum pyramidale; so, stratum oriens; sl, stratum lucidum; ml, molecular layer; gcl, granule cell layer. Scale bars, 20 µm (a,c,e); 10 µm (b,d,f) (reproduced from Knuesel et al. 1999). B, In each case the large oval is a cartoon representation of a neuron, and the indentation in the oval represents the postsynaptic density. In the top oval, where dystrophin is present, it serves to aggregate the receptors into large clusters in the postsynaptic density. In the lower oval, where dystrophin is absent, there is a reduction in the size of the clusters present at the postsynaptic density and an increase in the number of extra synaptic receptors.

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mechanical role in neurons, however, 2+ its absence may alter [Ca ]i in neurons. As indicated above, in the CNS dystrophin is involved in the

aggregation of large clusters of GABAA receptors at the postsynaptic inhibitory junction. In our laboratory we decided to use cerebellar brain slices from the mdx mouse to investigate the electrophysiological consequences of an absence of dystrophin from the Purkinje cell. The decision to use cerebellar Purkinje cells was an obvious one, primarily because Purkinje cells are the only neuron type in the cerebellum which express dystrophin and secondly because the Purkinje cells are large and easy to identify using infrared microscopy with differential interference contrast. Whole-cell patch clamping showed spontaneous miniature inhibitory post synaptic currents (mIPSCs) are reduced in frequency and amplitude in the dystrophic mice (Fig. 2A), a fairly predictable outcome of the reported reduction in the cluster size of the

GABAA receptors. When we looked at an experimental model of synaptic plasticity, the effect of dystrophins absence was far from predictable. The Purkinje cell/parallel fibre synapse is a well studied model of long term depression (LTD). Using standard LTD induction paradigms we stimulated the parallel fibres in high-frequency Figure 2. A, Miniature inhibitory post synaptic currents in littermate control and mdx bursts, while periodically mimicking Purkinje cells. Distribution of mIPSCs for a (i) littermate control and (ii) mdx mice the climbing fibre input to the Purkinje Purkinje cell. The insert shows a section of the recording showing mIPSCs. The mdx cell by depolarising the cell via a sharp mice has fewer large amplitude mIPSCs compared to littermate control. The bar intracellular microelectode. We graph shows the average frequency and amplitude of mIPSCs from littermate deliberately chose to use the more controls were significantly different from mdx mice (frequency, p = 0.002; amplitude, classical sharp microelectrodes to p = 0.04, two-tailed unpaired t-test). B, Long term depression in cerebellar Purkinje record LTD in the Purkinje cells because cells of control and mdx mice. The break in the graph indicates the period when the we felt that if the absence of long term depression was induced. The horizontal bars above the abscissa illustrate dystrophin altered the Ca2+ the two 10 minute periods during which the EPSP slopes were averaged, and homoeostasis, this effect would be represent the early phase and late phase of long term depression. The bar graph masked if the Purkinje cells were displays the average slope for all control and mdx cells in the early and late phases effectively [Ca2+] clamped by dialysing following induction of long term depression. i them with a whole-cell patch clamp difference between littermate control population of extrasynaptic GABAA electrode. To our surprise we found a and mdx mice in the overall expression receptors than in normal cells (Fig. 1B). marked blunting of the LTD in the α of GABAA receptor 1 subunit, which dystrophic Purkinje cells (Fig2B). Our provides strong support for the What role is dystrophin playing in the finding of altered long-term synaptic suggestion that it is the clustering of central nervous system? In skeletal plasticity in the mouse model of DMD receptors at the synapse that is muscle, it has been generally accepted is supported by work on a dystroglycan affected in DMD, and that dystrophin that dystrophin plays an important protein knockout model of congenital 2+ may aid in trapping ion channels at the role in maintaining normal [Ca ]i and, muscular dystrophy which showed synaptic membrane and to aggregate more controversially, has a mechanical blunting of hippocampal long term them into large clusters for effective function in stabilising the fragile lipid potentiation (LTP) (Moore et al. 2002). synaptic function. As a result, in bilayer against stresses associated with dystrophic Purkinje cells it is likely that skeletal muscle contraction. It seems At first sight the blunting of LTD in the there is a substantially larger unlikely that dystrophin has a similar cerebellum of the dystrophin-deficient

Physiology News | No. 68 | Autumn 2007 | www.physoc.org 36 PN FEATURES/LETTER TO THE EDITOR mdx mice seems somewhat paradox- Whatever the underlying mechanisms, References ical, given LTD involves the excitatory a change in the electrophysiological Anderson JL, Head SI, Rae C & Morley JW (2002). Brain function in Duchenne muscular AMPA receptors and dystrophin is characteristics of GABAA inhibitory dystrophy Brain 125, 4-13. associated with the inhibitory GABAA receptors and the blunting of long receptors. However, when we consider term synaptic plasticity in dystrophin- Górecki DC & Barnard EA (1997). Expression that dystrophin may be playing a role deficient muscular dystrophy will lead of dystrophin complex in the brain. In 2+ Dystrophin gene, protein and cell biology, ed. in [Ca ]i homoeostasis in the neurons, to a disruption in motor control and 2+ motor learning, and may underlie Brown SC & Lucy JA. Cambridge University a pathological alteration of [Ca ]i Press, Cambridge, UK. homoeostasis will alter induction of some of the CNS problems reported in 2+ both in the mdx mice and boys with LTD as [Ca ]i levels are critical in Knuesel I, Mastrocola M, Zuellig RA, setting the thresholds for the DMD. Bornhauser B, Schaub MC, Fritschy JM (1999). induction of both LTD and LTP. We Altered synaptic clustering of GABAA Acknowledgement receptors in mice lacking dystrophin (mdx propose that one mechanism by which mice). Eur J Neurosci 11, 4457-4462. the[Ca2+] homoeostasis could be The work in our laboratory is i supported by the Muscular Dystrophy disrupted in the Purkinje neuron by the Kunkel LM, Monaco AP, Middlesworth W, Ochs Association, USA. absence of dystrophin is if the larger HD & Latt SA (1985). Specific cloning of DNA fragments absent from the DNA of a male population of extrasynaptic GABAA patient with an X chromosome deletion. Proc 2+ 1 receptors alters the influx of Ca . Fig. Stewart I Head Natl Acad Sci 82, 4778-4482. 1B illustrates what happens to the 1,2 John W Morley Moore SA, Saito F, Chen J, Michele DE, Henry GABAA receptors when dystrophin is 1School of Medical Sciences, MD, Messing A, Cohn RD, Ross-Barta SE, absent. We are currently in the process Westra S, Williamson RA, Hoshi T & Campbell of using calcium sensitive dyes to test University of New South Wales and KP (2002). Deletion of brain dystroglycan 2+ 2 the extent to which [Ca ]i levels are School of Medicine, University of recapitulates aspects of congenital muscular disrupted in the mdx Purkinje cells. Western Sydney, NSW, Australia dystrophy. Nature 25, 418(6896):376-377.

Which book shall I read?

Perhaps the most frequently asked looked down upon by their peers. Of Curious case of an author falling question by the first year medical course, there was ample time to read victim to his own writings! students, it continues to puzzle many and understand the books, for in teachers of physiology. It was much those days, the basic sciences were But it is the second peak that yielded a easier to answer this in my student taught for two full years before bumper crop of innumerable days, for there were only three books entering the clinics. publications. In addition to the word recommended! Abbreviated after the physiology in their titles, these books authors, these books- BT, SW and Now, after three decades of teaching, display terms like instant, nutshell, BDS- held sway for over decades in I am still confronted by this question. guaranteed, last choice and panacea. this country. Best & Taylor was the Things have changed a lot. The One book, believe me, calls itself favoured tome of the top students medical council of India in its wisdom 'Pretty Darned Quick' physiology! The who fancied some kind of closeness to has restricted the basic science books are profusely illustrated with all the first author who, as a medical teaching to one year and every colours and shades. The authors' titles student assisted Banting and shared student appears to be in a hurry! I and examinerships held in the past the Nobel Prize. Those who read notice two distinct peaks in the and at present, are printed in bold Samson Wright continued to use it in frequency with which the old question letters. They often carry the clinical years, since many applied is fielded. The first one, at the time of photograph of the author with spouse aspects were presented clearly. My their entry into the medical school, and children and an invariable favourite was the book written by Bell, when the students' enthusiasm about proclamation that 'but for their co- Davidson and Scarborough. Written in their studies is at the maximum. The operation, the writer could not have simple English, I found it a pleasure to second when they perceive that the produced a better book'. (If you wish, read this book. It featured simple exams are fast approaching! (the omit the negative). In their prefaces, diagrams to illustrate many concepts time of perception is variable though, the word exam appears several times of physiology. Moreover it also from weeks to days) A number of to impress the gullible. One such book included Biochemistry obviating the good books are available for the was awarded a platinum disc for need of buying another book. All serious minded. Bound volumes have creating a record, for the number of these books were available in bound gone out of fashion and given rise to sales! So when the perennial question form only and needed patience and paperbacks, pocket editions or is posed to me, I am really at a loss! effort to carry them around. Attempt concise concentrated physiology For an answer, of course. to subdivide and rebind them, was reviews. Some Indian authors have considered a sacrilege! However many also tried their hand. One particularly J Prakasa Rao later generations of medical students well written book with a chapter on Department of Physiology, resorted to such practice. Students yoga appended, ceased publication Kasturba Medical College, seen reading any other book were because the writer turned a mystic. Manipal, India.

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Facing the media with animal research Why are we so backward when it comes to going forward? In the past, a history of attacks and intimidation of Society Members by animal rights groups understandably encouraged a culture of reticence towards speaking out about work on animals. But the climate is changing. Sarah Bailey, a lecturer in the Department of Pharmacy and Pharmacology at the University of Bath (pictured below), recently went public with her work. Thelma Lovick talked to her about her experience of facing the media

Andrew, my Press Officer from the Thelma Lovick (TL) What persuaded University of Bath. We handed out you to go public with your work? the press release and then had a question and answer session with Sarah Bailey (SB) When I worked in the journalists. I was still nervous Bristol I had been involved in various that they would challenge me about events designed to communicate why I was using animals … but they science to schoolchildren and the never did. They just asked me about general public. I really enjoyed it but the science and what it meant. They I’d never really talked about my own that Accutane (Roaccutane in UK), a really wanted to understand as much research. At that stage, I was still popular treatment for severe acne, about it as they could. The use of quite anxious about the animal issue. might cause depression in patients. animals was never an issue. They The active ingredient is 13-cis- were really very good – no TL So what changed your mind? retinoic acid (isotretinoin), a aggressiveness at all. retinoid. That really sparked my SB Well, in 2005 I went to a seminar interest and we decided to carry out TL Did you have any media training on Speaking out on animal research in a scientific study to see whether before you decided to do this or did the media at the Science Media Roaccutane could alter behaviour in you go in cold? Centre in London and I was mice. The outcome was that our persuaded by their arguments that work was the first to show in animals SB No – apart from a few ‘do’s and there is no real personal danger that chronic treatment with don’ts’ from my press officer on the these days. I talked to Fiona Fox from Roaccutane increases depression- train, I went in cold – which was both the Science Media Centre and she related behaviours (O’Reilly et al exciting and terrifying. But I was thought the research I was doing Neuropsychopharmacology 31 used to talking to people who were might strike a chord with the public (2006) 191-127). non-specialists by doing the schools and excite their interest. and general public stuff in Bristol, so TL When did you decide to go public I did have some idea of how to put it TL Tell me a bit more about your with this finding? over. work. SB After meeting Fiona Fox at the TL It all sounds really positive. What SB Well, it all came about as a result Science Media Centre event, she told happened after that – did you get a of an invitation to spend me to get back in touch when the flurry of interest? Thanksgiving with Michelle Lane, a research was about to be published. I friend who was working at the was anxious about going to the SB When I got the train back home University of Texas at Austin. Over media with this work, in part that night after the media briefing, I the holiday period we decided to because it involved animal studies, thought that would be the end of it. visit NASA in Houston and on the but also in case the findings were But I woke up next day to find that long car journey there, of course we taken out of context or exaggerated the story has been published in most started talking about work. I told her by various interest groups for their of the national press – Times, about my work on anxiety and own benefit. Fiona convinced me Telegraph, Guardian and even the depression and she explained about that the best approach was to ‘set Metro! That morning I got phone her work on retinoids, a class of the agenda’ myself by telling the calls to do local and national radio compound that includes vitamin A story directly to invited science interviews, I talked to journalists and its derivatives, in relation to journalists in a media briefing at the from Brussels and Rio de Janiero and cancer. This class of compounds is Science Media Centre. in the evening I went on BBC well known for its role in the News24. It was just a crazy day – but development of the nervous system, TL Scary. good fun! but not much is known about the actions in the adult brain. She asked SB Yes it was rather! I went to the TL What about the longer term? Did me if I had heard about the reports Science Media Centre in London with it all die down?

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SB I have not had any negative scientists’ point of view there is charities. So if we want people to reactions as a result of publicising my nothing to be gained from work on keep on funding research, then we work with animals. One outcome an animal that isn’t in the best need to let them know what we’re that I hadn’t thought about in possible condition, then the public doing with their money. You’ve got advance was that people who had might be prepared to accept the to have a good story, or at least a been on Roaccutane would try to work. But, of course, it is up to the good angle though, one that will contact me. I got lots of e-mails from individual scientist to decide what appeal to the public because after people who said they were so they are comfortable talking about all, journalists are in the business of grateful I was doing this work. to the public. selling newspapers rather than Usually they were, or had been, on promoting science! the drug and had always had these TL Do you think it’s better to go for a feelings that they were getting media briefing rather than a press Further information and advice about depressed or had low mood. After release? ‘going public’ can be obtained from the hearing about our work they felt Science Media Centre vindicated. That was actually quite SB Yes I do. I was lucky having made (http://www.sciencemediacentre.org) and the Research Defence Society rewarding and after that first big day the contact with Fiona Fox already, (http://www.rds-online.org.uk). it didn’t take up too much time. but given the sensitivity around the topic I felt I had more control by TL Your work involved mainly talking directly to the journalists. I The dawn of glasnost behavioural studies on intact mice. think the journalists liked talking to a What about work that involves more real person – to get it from the for research using invasive techniques: lesioned horse’s mouth rather than via an animals? animals, animals with implanted impersonal press release. They really electrodes etc. Do you think the wanted to understand what I had A Research Defence Society public is ready for that? done and what it meant. event held in Birmingham suggested that the activity of SB I know that behavioural work on TL Would you do it again? extreme animal rights groups mice is not invasive and therefore in some respects is easier to talk about SB Definitely! I believe the more may be on the wane than other types of animal work. I scientists feel able to talk about their personally think that, if carefully work with animal research, the more In the past, extremist animal rights explained and described, the public acceptance we’re going to get in the groups wreaked havoc with the lives will not mind the more invasive public arena for the work that we do. and livelihoods of many associated studies. I think that once you have I think we do have a duty to talk with animal research in the UK. With made it clear that animal research is about our research and to a few notable exceptions, such very tightly regulated in this country, communicate that to people. After events lead to an understandable that the welfare of animals is all, our research is publicly funded, reticence amongst those involved in paramount and that from the be it from research councils or experimentation on animals. The belief that anyone who put their head above the parapet made Sudden decline seen in attacks by animal rights extremists themselves a target for the · Far fewer protests at homes of scientists extremists, or might be forced into · Tougher laws and stronger policing seen as factors defending animal experimentation instead of explaining their science, The level of activity by animal rights extremists has reached a new low, has not encouraged a culture of according to police. Apart from in Oxford, where there is still a vigorous openness. However, there are campaign against a new laboratory at the university, attacks at the homes indications that the tide of opinion is of academic scientists who engage in animal research have ceased. turning and that the public accepts the need for animal experimentation "What has been very noticeable is quite a sudden and very marked decline and understands the potential in targeting individual researchers around the country in a personal way," benefits it can bring. said Simon Festing, director of the Research Defence Society, which monitors extremist activity and receives police briefings. "This has really The Research Defence Society (RDS) struck me because it has been a major feature of animal rights extremism is currently running a series of for 30 years since the Animal Liberation Front was founded in 1976. At any regional events to encourage those one time there would be many researchers around the country who were involved in animal research to be being actively targeted and now it has just gone." more open. Their Midlands event, hosted by the University of For the full story, published in the Guardian on 30 June visit: Birmingham in June, was very much http://www.guardian.co.uk/animalrights/story/0,,2115343,00.html an upbeat occasion. During the

Physiology News | No. 68 | Autumn 2007 | www.physoc.org ANIMAL RESEARCH/BIOSCIENCES FEDERATION PN 39 course of an afternoon, talks on receded and those involved in discuss animal research publicly. different aspects of the ‘animal research involving animals should However, it is to be hoped that question’ were given by have no fear of being proactive in younger scientists, who have not representatives from the scientific talking to the public about their experienced extremism first hand, community, the police and the work. It remains to be seen whether will now have the confidence to be media. this message will be translated into a more forthcoming. new openness about animal Simon Festing of the RDS and research. More experienced Selina Pearson Gordon Mills of NETCU (under the researchers who recall when activism University of Birmingham police’s anti-terrorism banner) was rife, may still be reluctant to painted a rosy view of the situation in the UK as it stands at the moment. They acknowledged that the extremists do still inspire fear. Why do I write about this today? However, their terrorising tactics Use of primates for The answer is that the Declaration have led the public to turn away and medical research on Primate Research has been to lend their support to campaigns signed by many of our UK MEPs. such as the Pro-Test movement or You may know that the European Their postbags are filled by letters the People’s Petition set up by the Commission/Parliament is from those who want to see animal Coalition for Medical Research. With currently considering revisions to experiments cease. The BSF, the exception of Oxford, where EU Directive 86/609. This Directive together with other lead protests continue, activity against concerns the protection of organisations, has written to all UK researchers in the UK is now at an all vertebrate animals used for MEPs on this matter and we will go time low. The Government’s experimental and other scientific to Brussels in October to speak standpoint on animal research has purposes. with some of them. However, also changed drastically. Fuelled private letters are also very partly by concerns of economic What you may not know is that a important. Have you ever written damage to the pharmaceutical written declaration on primate to an MP on this or any other industry, legislation has been research has been tabled. matter? Sometimes you should brought in to protect those involved and this is one of those occasions. in animal research. Written declarations are documents that MEPs are invited A private letter from you is more effective than your signature The Open University’s Steven Rose, to sign. If the total signatures get alongside many others in a letter and Sarah Bailey from the University to 393 the declaration is from the BSF. And you can be of Bath, both described their positive ‘ approved’ and lodged in positive and helpful at the same experience of speaking publicly parliament: today there are more time. All MPs like something to do! about their work (see interview with than 300 signatories and five Why not suggest that the Sarah on p. 37). Neil Yates, Director weeks to go. However, Commission should provide more of Biomedical Services at the importantly, if the signatories do funding for research on University of Nottingham described get to 393 it does not mean that alternatives and the three Rs more the successful scheme run in legislation will follow. Nonethe- generally. This additional funding Nottingham whereby members of less, the declaration becomes very might hasten our progress along the University are invited into the useful ammunition and, in this the route to the predictive systems animal facility to see for themselves case, proposes that all primate biology that we need. The what really goes on. For the media, research be stopped within a approach might encourage Alok Jha of the Guardian, explained defined time period. substitution of ‘timelines’ by that journalists are intent solely on ‘milestones’ in the thinking of informing the public about scientific Of course, we would all like to see those UK MEPs who signed the developments. For them, animal the use of primates reduced declaration. research is really a non-issue. substantially and ultimately eliminated. However, we all know If you want to know more, and/or The take home message from this that we remain far from the would like to receive contact event was that there has been no predictive systems biology that details for your MEP, please contact better and safer time than the would allow this to happen. In the Caroline Wallace present to raise the profile of meantime some primate research ([email protected]). research and counteract the is an essential element in our fight propaganda and misrepresentation against some neurological and that has been put out by the anti- other diseases. Richard Dyer vivisection movement. The threat from animal rights activists has now

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The Physiological Society’s G L Brown Prize Lectures Richard Boyd’s 2006/2007 lecture tour took in Dundee and Belfast

Dundee academics from different disciplines. University of Dundee ‘old-boy ’ Richard gave a fantastic lecture Richard Boyd returned to the North which made us laugh and think earlier this year to present his G L deeply about the joys of epithelial Brown Prize Lectures. Richard was at physiology. What was wonderful for one time a lecturer in the former us was his knowledge of the history Department of Physiology at Dundee of the subject and how he brought it and many old friends and colleagues, alive and showed that in some ways including retired Physiological the old work is as important as our Society Members Alan Chipperfield current work. In many ways it was a and Grant Leslie, were amongst the homecoming for Richard as his parents had met while studying enthusiastic audience of staff and G L Brown (1903-1971). Photograph students from our Colleges of Life courtesy of Godfrey Argent Studio medicine at Queen's. Sciences and Medicine. We were all delighted that he had chosen In addition to his lecture, Richard Dundee – a university with a large if Nobel Prize?’ (no vote was taken on gave generously of his time and now somewhat dispersed cadre of this issue, although the debate spent the morning at the Medical biomedical and clinical physiologists continued long into the evening). Biology Centre with members of the – as one of the lecture venues. Cell and Metabolic Signalling The lecture took place in the Sean Broader discussion ranged from the Research Cluster, and then the entire Connery Boardroom (Room 007 to suitability of Bahnhof kiosks as afternoon with members of the us locals) of the College of Life physiological equipment suppliers Respiratory Research Group at the Sciences on our main city campus. (see Boyd & Ward, J Physiol 324, Institute of Clinical Science. He heard (Whilst in name-dropping mode, I 411–428) to the admirable qualities short presentations from PhD and must mention that the new College of Dundee tap water for rearing post-doctoral students about their building has been named after Sir amphibians such as Necturus and work culturing bronchial and nasal James Black, another ex-member of Xenopus. The lecture was followed by epithelial cells from patients with the Department of Physiology). a short reception where speaker and asthma, COPD and cystic fibrosis. audience made (or renewed) He was particularly interested in our After a short introduction on G L acquaintances, then a thoroughly preliminary studies on cystic fibrosis Brown himself, Richard delighted us pleasant Italian meal (all well within epithelial cells. However, he had with historical anecdotes about budget, as Richard asked me to point something pertinent to say to pioneers of epithelial physiology out). Richard stayed in Dundee to everybody and he made them feel so including H H Ussing and Dundee’s visit friends after the lecture and, to special because his questions very own E Waymouth-Reid, quote him verbatim, ‘the Glens of showed how carefully he had been highlighting their seminal insights Angus were simply a reminder of listening to their work. Our last into the mechanisms underlying why the people who stay(ed) in that speaker was a young anaesthetist vectorial transport. Their legacies part of the world (like Waymouth who talked about his planned were then placed into the context of Reid) have a lot going for them!’ work - this research will be much contemporary knowledge and Haste ye back, Richard. improved after Richard's current research into the physiology suggestions. and pathophysiology of Peter Taylor biomembrane transport and Molecular Physiology, Sir James Black His visit to the Department of epithelial functions. He finished by Centre, University of Dundee Physiology was finished by a superb revealing some novel and dinner together with the wonderful unexpected functions of Belfast company of his wife who has research connections with the transporters as sensing and Richard Boyd delivered The University of Ulster. They were signalling molecules which provide Physiological Society's G L Brown planning on touring Northern Ireland information on the external Lecture, Epithelial physiology: facts, for the rest of the weekend and we environment to their home cell. fantasies and fun, at Queen’s hope that they had a lovely time. Questions encompassed a broad University Belfast on 16 February range of scientific (and eventually 2007. The South Lecture Theatre at political) issues including, of course, The Medical Biology Centre was Alexander Zholos, Madeleine ‘ was H H Ussing the greatest 20th packed with undergraduate and Ennis century physiologist not to win a postgraduate students as well as Queen's University Belfast

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Molecular Techniques Workshops 1996–2007: an integrated approach to teaching molecular biology to physiologists

April 2007 marked the end of a 10 year programme of Molecular Techniques Workshops (MTW) sponsored by The Physiological Society and the Wellcome Trust. Since 1996, more than 150 post-graduate students, post-doctoral fellows and the odd professor or two have enrolled in these 10 day residential workshops gaining hands-on expertise in how to extract, amplify, characterise, and modify genetic material, and then learning how to apply this knowledge to problems of physiological interest. The workshops have benefited immensely from the vast range of external Molecular Techniques Workshop organisers 1999–2007 – Stan White (left), Rod seminar speakers who have travelled to Dimaline and Patrick Harrison. Cork and Glasgow to share their insight and expertise on almost every area of (Allen, 1997). The second was the the delivery of theoretical and hands- molecular physiology from in vitro and establishment of an annual residential on training in molecular techniques to in silico characterisation and two-week basic training programme in those with very limited previous modification of individual genes, to in practical and theoretical molecular experience. In the early days, more vivo modification of the genomes of biology techniques for a much smaller than 100 applicants applied for the 16 animals and even patients through the group of research-active physiologists. coveted places on the workshops. use of virus vectors. However, in more recent times, the The first three workshops were number of applicants has dropped Molecular biology and physiology organised by Janet Allen at the suggesting that an increasing number arguably went their separate ways with University of Glasgow (Allen, 1998). of students are gaining theoretical the Nobel Prizes in Medicine and Since 1999, the workshop has been training, and at least some practice, in Physiology for discoveries concerning directed by Patrick Harrison, initially at the techniques from their physiology the 'Molecular structure of nucleic the University of Glasgow and, since BSc and PhD programmes. Moreover, acids and its significance for 2001, at University College Cork. With the substantial increase in physiology information transfer in living material' invaluable assistance from Rod research papers which include in 1962 and the 'ionic mechanisms Dimaline (University of Liverpool) and molecular techniques (often published involved in excitation and inhibition in Stan White (University of Leeds), the in physiology journals) provides further the peripheral and central portions of workshop has evolved to cover a range evidence that molecular biology is now the nerve cell membrane' in 1963. of molecular techniques taught in the a fully integrated part of the discipline Despite the intrinsic relationship context of a physiology research of physiology. between the two disciplines, a project (Harrison, 2004). One key aim majority of physiologists had trained in of the workshop was to encourage a Thus, it would appear that the 10 day the absence of molecular biology long-term adoption of molecular MTW has succeeded in providing an techniques. The Physiological Society techniques by participants. When insight and basic training in a broad made a commitment in the early contacted up to 2 years after their range of molecular techniques for 1990s to close the gap between the attendance at workshops (de Winter, students who could not obtain it disciplines and ignite a wider interest 2004), many participants indicated elsewhere during an era when in the use of molecular techniques by that they had adopted a number of the molecular biology was disconnected physiologists. The first step was the techniques from the workshop into from physiology. Now that the two formation of a Special Interest Group their research. Moreover, attendance subjects are integrated, and a new (SIG) in Molecular Physiology which at the workshop had allowed generation of students is being taught held its first scientific meeting at the participants to 'speak the same physiology by physiologists who have a University of Oxford (Allen, 1995). This language as molecular biologists', sound grasp and research experience was followed by two further teaching facilitating 'sensible discussion of of molecular techniques, the challenge initiatives to train physiologists in collaborative projects with molecular would appear to be to provide more molecular techniques. The first was the biologists' and, in some instances, hands-on specialised training in organisation of one-day teaching made them 'better integrative techniques applicable to their symposia to deliver 'Jargon-free physiologists'. particular research programmes. molecular biology for physiologists' to Whatever the future of such training a relatively large audience at summer So, after 10 workshops, what next? the most profitable use of molecular meetings of The Physiological Society The workshop has always focused on techniques will arise from discussions

Physiology News | No. 68 | Autumn 2007 | www.physoc.org 42 PN WORKSHOPS/EDUCATION and collaborations with other scientists Teaching physiology – challenges, successes using such methods; 'Never clone alone' (Allen & Brickman, 1973). and rewards

1 Teaching Special Interest Group co-convenors Judy Harris and Richard Helyer Patrick T Harrison (pictured below planning a new physiology practical class) report on an Stanley J White2 ‘information-gathering’ workshop held at King’s College London in July for Rod Dimaline3 staff responsible for leading and co-ordinating physiology teaching 1Department of Physiology and This workshop, funded by The BioSciences Institute, University Physiological Society’s Education College Cork, Ireland Committee, enabled representatives 2 Institute of Membrane & Systems from 24 institutions across the UK to Biology, University of Leeds, Leeds, discuss the challenges, successes and LS2 9JT, UK rewards associated with physiology 3Physiological Laboratory, School of teaching. We also discussed how The Biomedical Sciences, University of Society in general, and the Teaching Liverpool, Crown Street, Liverpool SIG in particular, could support L69 3BX, UK. members with a keen, and possibly principal, interest in teaching. undergraduates, but also for a wide References A widespread current challenge in range of vocational degrees such as Allen JM (1995). First meeting of the teaching is preserving physiology as a medicine, dentistry, nursing and Molecular Physiology SIG at Society's Oxford distinct discipline in the eyes of veterinary science. It was agreed that Meeting. Physiology News 20. undergraduates when there are now so this is largely due to the recent Allen JM (1997). Teaching Symposium held at few physiology departments in the UK explosion in molecular physiology University of Sheffield: 'Jargon-free molecular – only one identified physiology combined with a cultural shift in the biology for physiologists'. Physiology News 26. department (Bristol) was represented expectations of staff, many of whom Allen JM (1998). Success for first workshop. at the workshop and even that was no longer expect to teach outside their www.gla.ac.uk:443/newsletter/184/news.htm shortly to merge into a department of research area. #News4. physiology and pharmacology! An Allen W & Brickman M (1973). Sleeper. United on-line questionnaire completed by These challenges have been partially Artists. around half of the participating HEIs resolved in several HEIs by the (Fig. 1) showed that, whereas it is still recruitment of physiology teaching de Winter, P (2004). Long-term feedback from the Molecular Techniques Workshop. possible to graduate with a degree in specialists and there was a lively Physiology News 56, 35. physiology from a number of debate on the need to support and universities, many more students now reward such staff. Prem Kumar Harrison PT (2004). Development of methods for teaching molecular biology to graduate with a generalist degree in (Society Meetings Secretary) physiologists: the molecular techniques biomedical sciences. suggested that The Society could workshop 1999 – 2004. J Physiol 560P, C22. consider offering full membership to Another common experience was the teaching specialists and encourage dwindling number of staff willing and them to attend meetings and The Society's Education Committee is workshops by providing travel grants currently exploring the 'fourth' series of able to teach systems physiology Molecular Techniques Workshops . We despite its fundamental importance, and bursaries. The new Themed envisage that the 10 day all not only for physiology Meetings – at which teaching-related encompassing workshop will be replaced with a number of short workshops offered on a mix-and-match basis in locations around the country. Basic theoretical and practical molecular techniques (e.g. DNA/RNA extraction and analysis) will be included, as in the current workshop. We also plan to introduce workshops and include materials on newer technologies such as Microarrays and SiRNA. It is important that these workshops support the needs of our membership; we will therefore be circulating a questionnaire to find out how you would like these workshops to run, the techniques you'd like covered and, indeed, if you think there is a still a need to run the MTW now that basic molecular biology is integrated into most physiology(-related) degree courses. Figure 1. Numbers of undergraduates who receive physiology teaching on various degree programmes (data obtained from 14 HEIs throughout the UK).

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posters and oral communications will As well as the clear potential for may not normally have access to in be welcomed – are intended to provide Members of The Society to exchange their school/college, but tutors taking a forum for disseminating advances in teaching materials and practices the laboratory sessions did provide teaching as well as research. amongst ourselves, there was also suggestions for, and give the support for future teaching events to opportunity to use, alternative and There was widespread support for an include invited speakers who could more accessible equipment when additional suggestion from the floor address topics such as current changes available. that The Society, possibly with other in the school science curriculum, the learned societies, could work with school/university interface, learning Bodycare® products supply equipment organisations such as HEFCE and the styles, and educational research used in physiology and sport science Higher Education Academy to develop approaches that could be applied to teaching to many educational criteria for scholarly activity that could physiology. establishments in this country and we be used in relation to career were very pleased that they could progression/promotion for teaching The workshop was a very useful and support the event, with Spencer specialists. enjoyable ‘networking’ opportunity Newport joining us for the day. The and threw up several ideas for future event was organised in collaboration The increasing size and diversity of events – we will do our best to with The Physiological Society. student cohorts puts pressure on staff incorporate them into a lively to develop innovative and efficient programme of activities for the After a welcome cuppa on arrival, the methods of teaching and assessment Teaching Special Interest Group! teachers had a brief introduction that engage students without followed by a session on Careers in ‘dumbing down’ the subject. Judy Harris physiology by Rob James. A brief Furthermore, physiology practical Richard Helyer introductory talk then followed to teaching has to take due regard for Department of Physiology and bring the teachers ‘up to speed’ on Health & Safety, disability and animal the physiology behind each of the legislation. Pharmacology, University of Bristol, UK laboratory sessions that they would be taking part in during the day. It must Despite these undoubted challenges, it be noted that the teachers were very was clear that there is a wealth of Teachers turn students well behaved in the classroom and sat expertise, enthusiasm and innovation quietly throughout this part of the in physiology teaching that deserves to for the day ... morning (unlike most of their students be shared, celebrated and debated ... but are they as well behaved I bet), but were eager to get into the more widely within The Society. Some laboratory after another cuppa! good practices depend on local as their own students? Jayne resources and/or infrastructure and Hastings, organiser of the The first lab session, lead by Andi may therefore be difficult to export to latest Physiological Society Drake, allowed teachers to look at other HEIs but many are ‘transferable ’ supported teachers workshop methods to determine metabolic rate activities. reveals all and energy expenditure using expired air analysis as well as various The latter include problem-based and A recent A-level teachers’ workshop procedures for the direct enquiry-based learning; patient-based hosted by the Department of determination of oxygen uptake which case studies; skills development Biomolecular and Sport Sciences at included the Douglas bag method and modules (e.g. maths, physics, Coventry University drew upon the a breath by breath online method. chemistry, writing, research); activities strengths of lecturers who teach Bodycare’s Spencer Newport put a related to the public understanding of physiology on biological, biomedical, couple of the teachers through their science; quizzes/games; field courses; and sport and exercise science degree paces on the cycle ergometer whilst web-based resources; and learning programmes. The workshop was demonstrating Fitmate®, a desktop collaborations with schools, businesses aimed at those teaching physiology to size metabolic system designed by and the community. Within the area A-level Biology, PE or Sport Science COSMED. This system performs fitness of assessment there is much good students by including aspects of assessments and functional evaluation, practice in developing cardiovascular and respiratory including accurate measures of Resting grading/marking schemes, assessing physiology and metabolism common Metabolic Rate (RMR) and oxygen practical skills and developing student to both subject areas. uptake during either sub maximal or peer assessment. The programme was designed to maximal oxygen uptake (VO2max) tests. Another initiative with great potential update the knowledge and practical value for teachers – flagged by Society skills of teachers, provide ideas for After a lovely lunch in the University’s Education and Membership Manager, teaching physiology in their own Riley Lounge, the teachers then went Donna Brown – is the development of classrooms and generally excite on to look at the cardiovascular system a shared resource of web-based interest in the subject area. The lead by Ray Carson. Teachers used the physiology teaching materials in laboratory activities were designed to PowerLab® setup with LabTutor® collaboration with the American be very 'hands-on' and allowed software to look at the Physiological Society. teachers to use equipment which they electrocardiogram (ECG). In this lab

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Please contact Irrum Magre ([email protected]) for more information.

Jayne Hastings Senior Lecturer in Sport and Exercise Science, Coventry University, UK

Physiology for schools and colleges Dates for your diary 9–15 September 2007, BA Festival of Science, York The Physiological Society is organising two events for 6th form students Performance enhancement: the good, the bad and the Olympic gold and The bionic ear show and debate. For details and to register for free tickets: http://www.physoc.org/education

3–5 January 2008, The Association for Science Education Annual Conference Biology in the real world. Taking the theory of science and putting it into the context of our everyday lives. Extend your knowledge, talk to experts: an excellent CPD opportunity for teachers and Top: Teachers get on their bikes to look at how respiratory volumes change with technicians working with 14-19 exercise. Above: Experimenting with methods to determine metabolic rate and age group. Further details will be energy expenditure using expired air analysis. posted on our web site http://www.physoc.org/education the teachers identified the major by those that had built up a sweat in components of the ECG, how they the labs, and a brief talk by Irrum relate to the electrical activity of the Magre, who had joined us for the day Can you help? heart, and the relationships between from The Physiological Society. Irrum The Society is looking to develop the electrical activity of the heart (as spoke to the teachers about The resources to support the teaching recorded in the ECG) and the Society and what it has to offer for of practical physiology within the mechanical activity of the heart (as teachers, including the Schools and A/AS level biology-related judged from the heart sounds). College Associate membership which curriculum (see Physiology News has recently become available to those 67). If you have resources you The final lab class was lead by Sadie who teach physiology. would like to share with us or an Mercer with the aim of demonstrating idea you would like to develop the different volumes that can be The feedback from the teachers who contact Donna Brown measured in lung function testing attended was very positive, both ([email protected]). using spirometers and peak flow verbally and via the evaluation forms meters. This also included looking at completed, even from those teachers The Society has a number of how respiratory volumes change (but that we had put through their paces in educational grants for its not the overall capacity) with exercise the lab! This was very pleasing to hear Members to run practical so meant our teachers were told to after all the hard work that went into physiology workshops for 6th form ‘get on ya bike’ one last time during organising and delivering the day. A the day. big thank you to everyone involved. students. If you would are interested in running a workshop The day ended with some cold We are now planning a student during 2008 please contact Irrum refreshments, welcomed in particular workshop for 21 November 2007. Magre ([email protected]).

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100 years ago in J Physiol A second reason for choosing this Member of The Physiological Society paper is that it is one of only two in 1894 (thanks to The Society’s appearances as an author in J Physiol scrupulous record-keeping, we even The action of caffeine on the of W H R Rivers. know he was elected on 20 January). capacity for muscular work His physiologist period seems to have W H R Rivers and H N Webber. Rivers was a scientist of remarkable begun when he joined the National range, although in his case somewhat Hospital for the Paralysed and August 1907, 36, 33-47. sequentially. Apart from physiologist, Epileptic, meeting London and Why pick this one? Not because it is which might rank somewhere down Cambridge physiological luminaries an easy read. Like many papers of the the list, the count of Rivers’ other such as Michael Foster, Schafer, era, the absence of schematics professions would include physician, Sherrington and Henry Head. Rivers detailing experimental design, of neurologist, psychiatrist, began teaching sensory physiology in summary figures and of statistics psychoanalyst, psychologist, Cambridge in 1893, and was makes for heavy going. Also a touch ethnologist and social anthropologist. appointed in 1897 to a University odd to modern eyes is the inclusion of Rather startlingly, given this, some of lectureship in ‘physiological and unnecessary, but charming detail: Rivers’ biographies describe how he experimental psychology’. Here he ‘ fatigued easily’ and for much of his founded the Cambridge psychology ‘ In the first two intervals [between life ‘rarely worked more than 4 hours laboratory and co-founded the British series of ergograms] light work was a day’! Contemporary academics can Journal of Psychology (1904). In done in connection with tracings only dream of such productivity with 1903–7 Rivers was Head’s co- (cutting them up, pasting them in a such economy of effort. investigator in a celebrated book, etc.); the third interval was experiment in which Head had the passed in light reading and a few Rivers has also achieved posthumous one of the sensory nerves in his arm biscuits were eaten.’ fame in literature and on film. He severed and rejoined. The two spent WW1 as a military psychiatrist investigators then plotted the return However, features we would definitely treating shell-shocked officers, of sensation over the next several recognise lie buried in the paper. including the war poet Siegfried years. Rivers was elected FRS in 1908, Normalizing data to an initial control Sassoon. This relationship features in around the time he largely ceased value is one; but a second, and the Pat Barker’s novel Regeneration physiological work and turned almost paper’s main claim to fame, is its (1991), and the 1998 film of the same entirely to psychological, ethnological early use of a double blind design name in which Jonathan Price and sociological areas. employing a control substance, with portrays Rivers. both experimenter and subject Rivers died in 1924 of acute intestinal unaware of whether the substance Rivers’ physiological interests were obstruction. Many links to material taken was caffeine: mostly concerned with the senses, about him, and some of his writings, and early on he combined an interest can be found in his Wikipedia entry1. ‘ We took the caffeine in the form of in vision with his anthropological and the citrate and the control consisted expedition work. Rivers became a Austin Elliott of a mixture of gentian and citric acid 1 … it was not till the end of the whole http://en.wikipedia.org/wiki/William_Halse_Rivers_Rivers experiment that we acquainted ourselves with the nature of the dose on any given day.’

The doses of caffeine used are modest, roughly equating to peak body water concentrations of 15–30 uM. The authors argue for both central and peripheral fatigue- combatting effects of caffeine, although from a modern standpoint central effects would be assumed likely to dominate. The work also shows marked difference between the two subjects (the authors), who lament their inability to analyse the results statistically. The first reliable approach to small sample statistics actually arrived the following year (1908) in the work of W S Gosset (‘student’ of t-test fame).

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Nathanielsz, Ernst Niggli, Bernd submit an all encompassing article Nilius, Quentin J Pittman and Uwe summarising their work. Proske. Their commitment and The Editorial Board enthusiasm has been much Dimaline R. Attack and defence in The Journal of Physiology recently appreciated by the Officers of The the gastric epithelium - a delicate welcomed three new Editors, Abigail Journal. balance (92.4, July1). Fowden (Cambridge, UK), Mark Harridge S. Plasticity of human Hargreaves (Melbourne, Australia) Impact factor skeletal muscle: gene expression to and Thomas Voets (Leuven, Belgium) The impact factor for 2006 rose to in vivo function (92.5, September2). to its Editorial Board. 4.407 (4.272 in 2005), with a cited half-life of 9.2 years (unchanged Coming soon from 2005). • Garry D. Degenerative medicine and the use of cell based therapies for cardiovascular diseases; • Pack A. Functional genomic strategies in sleep research; • Hay B. Translating fetal nutrition into Impact factor nutrition of the preterm infant. Experimental Physiology's Editorial Abigail Fowden (above, left) is Symposium Reports from Board was delighted to see another Professor of Perinatal Physiology in Experimental Biology 2007 rise in its impact factor to 2.339 the Department of Physiology, Neural-glial-vascular (2.054 In 2005). EP now ranks 33 of Development and Neuroscience at communication in the brain 79 physiology journals (a rise from the University of Cambridge. Her 51/74 in 2003). Over a century ago seminal research interests are in the investigations revealed that brain regulation of fetal development with activity was tightly associated with particular emphasis on the role of an increase in blood flow (Mosso, hormones in these processes and on 1880; Roy & Sherrington, 1890), a the intrauterine programming of phenomenon known today as physiological systems. She teaches functional hyperemia. Since then, reproductive biology to medical, enormous efforts have focused on veterinary and science students and understanding the cellular is a Professorial Fellow of Girton mechanism underlying functional College, Cambridge. hyperemia in the brain. It is now clear that rapid increases in blood Thomas Voets (above, right) is an Translational review articles flow in response to neuronal associate professor in the Division of The July issue of Experimental activation require an exquisite Physiology, Department of Molecular Physiology contains the first in a organization involving multiple cell Cell Biology at the Katholieke series of translational review articles types and signals, a process also Universiteit Leuven, Belgium. During Contributors to this series have been referred to as 'neurovascular his PhD in the laboratory of Bernd identified by the Editorial Board as coupling'. Recent findings have Nilius (also at KU Leuven, Belgium), performing outstanding translational demonstrated the importance of he studied cell volume regulation research in their field and invited to various signals derived from and the gating properties of volume- neuronal and glial sources in regulated anion channels. As a translating the state of neuronal postdoc with Erwin Neher (Max activity to dynamic alterations in the Planck Institute for Biophysical nearby microcirculation. Chemistry, Göttingen, Germany) he The purpose of the Neural-glial- investigated the mechanisms of vascular communication in the brain large dense-core vesicle exocytosis. symposium3 was to provide an Currently, his research focuses on the update on some of the most recent TRP superfamily, with particular findings addressing the nature of the interest in the mechanisms neurovascular response and the underlying the thermosensitivity of potential mechanisms mediating certain TRP channels. such orchestrated phenomenon. The

Nine Editors left the Editorial Board 1http://ep.physoc.org/content/vol92/issue4/#TRANSLATIONAL_REVIEW at the end of June – George 2http://ep.physoc.org/content/vol92/issue5/#TRANSLATIONAL_REVIEW Augustine, Jens Bo Nielsen, Jack L 3http://ep.physoc.org/content/vol92/issue4/#SYMPOSIUM_REPORTS Feldman, Paul L Greenhaff, Peter W 4http://ep.physoc.org/content/vol92/issue5/#SYMPOSIUM_REPORTS

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in health and disease. The articles by Eduardo Artz (Department of Physiology and Molecular Biology, School of Sciences, University of Buenos Aires, Argentina), Wilson Savino (Oswaldo Cruz Institute, Rio de Janeiro, Brazil) and Julio Licinio (Department of Psychiatry, University of Miami)cover different investigative approaches using high- throughout technologies such as molecular induction or repression of gene transcription, genome wide scan, genotyping, microarray expression, proteomics and metabolomics. four reports summarize the topics Neuroimmune interactions addressed by the speakers during the The articles to be published in the These three articles demonstrate symposium. Eric Newman discussed September issue of Experimental without any doubt that neuro- + the involvement of K siphoning, Physiology4 summarize information immunendocrine interactions are metabolites of the arachidonic acid regarding the integration between taking place at central level such as pathway and nitric oxide in the the immune, endocrine and central brain and pituitary gland, and in the signaling mechanisms underlying nervous systems, an interaction peripheral organs such as thymus neurovascular coupling in the retina discovered by Hans Selye in the and lymph nodes. (Metea & Newman, 2007). Jessica 1930s. During the last decade the The knowledge of immuno- Filosa addressed current evidence importance of neuroimmune regulation failed to produce practical supporting a role for K+ signalling regulation has been recognized, and solutions to treating human diseases between astrocytic endfeet and this recognition has stimulated involving autoimmune or chronic vascular smooth muscle cells and research in this area. This interaction inflammatory diseases and cancer. A described the changes in intracellular assures that immune and neuro- 2+ reason for this failure is probably that Ca that occur in both cell types endocrine responses are in harmony the immunoregulatory pathways are during vascular responses in the with other physiological functions, in subject to neuroendocrine brain microcirculation (Filosa & order to maintain homeostasis and regulation. Therefore, it is necessary Blanco, 2007). Dale Pelligrino health. Neuroimmune interactions to study the role of hormones and presented new findings addressing provide host defense against neurotransmitters in the immuno- the importance of purinergic infection, injury, cancer, and also regulatory pathways. Also, it is very mechanisms involving ATP release psychiatric disorders. Neuroimmuno- important to study the participation and hydrolysis, with emphasis on the regulation also contributes to of cytokines in the normal and signaling events underlying the intestinal physiology, secretory pathological functioning of the communication between the glial immune function, conception and neuroendocrine system. These limitans and pial arterioles (Xu and the transfer of immunity to studies promise a better Pelligrino, 2007). Finally, Jeffrey Iliff offsprings. It also affects sleep and understanding of the role of the provided evidence for the expression recovery from diseases. During acute immune/neuroendocrine systems in of a P450 epoxygenase isoform (CYP illness these interactions are health and may lead to elucidate the 2C11) and of soluble epoxide responsible for the profound neuro- fundamental alterations in diseases, hydrolase in extrinsic parasympa- endocrine and metabolic changes which may lie in the neuroimmun- thetic and sensory vasodilatory that play a key role in health endocrine regulation. Only after nerve fibers contacting and recovery. The 'cross-talk' between understanding the interactions proposed a novel role for P450 the neuroendocrine and immune between the immune and eicosanoids in the neurovascular systems is accepted. This crosstalk neuroendocrine systems we can control of the cerebral circulation involves common ligands and develop rational approaches for the (Iliff et al. 2007). receptors being used by both treatment of inflammatory diseases, systems, allowing a physiological cancer and psychiatric disorders. Altogether, these reports add new communication circuitry to play a impetus to this exciting area of relevant role in homeostasis. These Valerie Rettori research and highlight the invited articles provide a review of Coming soon complexity of the neurovascular current investigations regarding this response in the brain. Physiological genomics: bench to crosstalk – in particular, the bedside. Reports form M Dwinnel, G Jessica Filosa neuroimmunendocrine interactions Semenza, N Lee and A Kwitek (92.6).

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Edward Joseph of blood or other fluid to be analysed was placed on one side of the outer Conway compartment and a reagent to 1894–1968 release a volatile component from it on the other; an absorbent was placed in the middle compartment. The following is a summary of an After sealing the dish with a greased address given by Richard Keynes FRS cover, it was gently rocked to mix the (Emeritus Professor of Physiology at reagents, and equilibrium with the the University of Cambridge) to the central measuring compartment was Royal Irish Academy in Dublin on 12 quickly reached. December 1994 to celebrate the centenary of the birth of Edward ‘Conway’s original purpose was the Conway (formerly at the Physiology estimation of blood ammonia which Department, University College was released by the addition of alkali Dublin). to the blood, and absorbed by a standard acid which could then be ‘ Conway was born and went to back-titrated.’ The technique was school in Nenagh, North Tipperary. adapted for estimation of blood It was in that pleasant countryside urea, oxygen capacity, carbon that he acquired his lifelong passion dioxide, glucose and chloride. for fly-fishing and I have noted with interest on looking at the map that it ‘It continued to give valuable service is not far from Foynes and Limerick for many years, until it was displaced and Adare, where on one of my few by more sophisticated and more previous visits to Ireland I had the expensive techniques. If you wanted involuntary, but nevertheless very Edward Conway (above) and a sample of to measure blood bicarbonate at pleasurable experience, in 1944 of the correspondence between Donnan 15,000 ft in the Andes one would getting stuck for a week because of and Conway (Fig. 1, below). still have to use a Conway Unit.’ excessive head winds, when I was analytical and rigorously quantitative supposed to be on my way across the treatment that characterised Returning from Gustav Embden’s Atlantic in one of the old Boeing virtually all his papers’. The first laboratory in Frankfurt, Conway Clipper flying boats. After four phase of the research from 1921 to carried out what was perhaps his wartime years of rationing, the 1937 was concerned with the most important research on the excellence of the food and cellar at localisation of function in the renal application of the double-Donnan the hotel at Adare was memorable, tubule, the important outcome of equilibrium to the distribution of and had the marooned passengers which was his invention of the monovalent ions in isolated frog had Conway to give us his expert ‘ Conway Unit’ and microdiffusion skeletal muscles [Boyle PJ & Conway advice on our choice of whisky we analysis of volatile substances at EJ (1941). Potassium accumulation might have enjoyed ourselves even atmospheric pressure. The unit in muscle and associated changes. J more. consisted of a 3 inch glass or Physiol 100, 1–63]. The work was porcelain dish containing two based on a theory of the Belfast ‘ Conway went on to Blackrock concentric chambers whose circular physical chemist Frederick Donnan College and thence in 1912 to dividing wall was slightly lower than to explain the swelling of gels due to University College. He graduated in the outer boundary wall. The sample fixed charges. At the time Donnan medicine in 1921, but never did any house appointments, nor did he ever practice, joining the staff of the Physiology Department under Professor James O’Connor until 1932 when he became the first holder of the Professorship in Biochemistry and Pharmacology at University College. ’

Keynes dealt firstly with Conway’s earliest research on the structural relations in kidneys from a wide range of terrestrial mammals with ‘ special emphasis on a mathematical

Physiology News | No. 68 | Autumn 2007 | www.physoc.org MEMORABLE MEMBERS/NOTICEBOARD/BEN FUND PN 49 lived in London, and a lively Noticeboard Themed Meeting with a Focused correspondence passed between the Symposium on Determining control of two scientists, a sample of which is PHYSIOLOGICAL SOCIETY the cardiovascular system in health shown in Fig. 1. MEETINGS & INTERNATIONAL and disease: from brain to blood vessel. WORKSHOPS Cambridge, UK Conway’s daughter, Dorothy, kindly 2007 made available to us Donnan’s 14–16 July Manchester, UK letters to Conway in which he Main Annual Meeting. 5–6 September indicated the limitations of his Focused Meeting Cardiac Oxford, UK original theory to which Conway electrophysiology: with a special 9–11 September replied in letters obtained by me celebration of the centenary of the Metabolism and endocrinology from archives at UCL. Here he discovery of the sinoatrial and Themed meeting with a Focused outlined the double Donnan atrioventricular nodes. Symposiun on Orchestration of equilibrium with the virtual exclusion metabolism in health and disease. of sodium from within the fibres Bratislava, Slovakia coupled with fixed intracellular 11–14 September Beijing, China anionic charge. Keynes illustrated his Joint Meeting of The Physiological 20–22 October talk with these letters as well as Society, the Slovakian Physiological Joint International Meeting of the those carried by Nature (4 April 1942, Society and FEPS. Chinese Association for Physiological p. 383). By adding potassium Sciences, the Canadian Physiological chloride to physiological saline Yaremche, Ukraine Society, the Australian Physiological bathing isolated muscles of frog, 19–23 September Society, the American Physiological Conway showed that the International Workshop Molecular Society and The Physiological membranes were permeable to physiology of membrane transport and Society. chloride and that at equilibrium the cell excitability. product of molar concentration of King’s College London, UK these permeable ions within the Bristol, UK December fibres was equal to that of bathing 17–18 December Vascular and smooth muscle fluid. Focused Meeting Renal cortex: physiology Themed Meeting with a physiological basis of glomerular and Focused Symposium on Vascular Richard Keynes also reviewed tubular diseases. responses to mechanical stress: cellular cross-talk and integration. Conway’s work on the evolution of 2008 the ocean, published in the Leeds, UK For full details of Society Meetings Proceedings of the Royal Irish 17–18 March (to be confirmed) and International Workshops visit Academy, illustrating the breadth of Cardiac & Respiratory Physiology http://www.physoc.org/meetings. his interests. The great grandson of Charles Darwin showed how Conway demolished Macallum’s over- simplification of evolution with The Benevolent Fund respect to salinity of oceans and for more information blood. Every year, at The Society’s Main (www.physoc.org/benfund). Meeting, the Benevolent Fund puts Finally, Keynes reviewed Conway’s on a raffle. This year at Glasgow Life The Benevolent Fund exists to help redox pump theory which originally Sciences, £136 was raised with all anyone who is, or has been sought to explain gastric acid proceeds going directly to the Fund. employed in the field of physiology secretion, using as a model acid The winner of the raffle was Alasdair and pharmacology; they don’t have to be Members or former Members secretion by yeast fermenting in the Gibb (University College London). The raffle prize, a case of wine of The Society. The Fund helps by presence of potassium chloride, but worth £100, was kindly donated by providing grants in aid of funeral perhaps unwisely extended to the The Physiological Society. expenses and emergency travel, active transport of other cations. medical costs, childcare The Trustees of the Benevolent Fund arrangements, relocation costs and Sadly, Conway didn’t see its would like to thank everyone who other unexpected bills. If you know relevance to the synthesis of ATP for bought a raffle ticket, as well as all of someone who the Benevolent which Peter Mitchell reaped the those who have contributed, and Fund might be able to help, then benefit, resulting in his Nobel Prize in continue to contribute, to the Fund. please contact the Chair of the Physiology in 1988. If you are interested in donating, Trustees, David A Brown, at please contact Elfa Wilmot at The University College London Roderick P Kernan Physiological Society’s London ([email protected]), or Elfa Dublin, Republic of Ireland office or visit The Society’s web site Wilmot ([email protected])

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Chalmers talked about how conflicts of Conflicts of interest interest can arise in clinical science. Here and science education industry can have a big influence, even down to the level of design of studies Two meetings in the last few months that affect reports sent to agencies in might be of wider interest to our pre-licensing submissions. It is often left Members – one on conflicts of interest to industry to fund relevant studies, and the other on science education. I more public funding is needed to also attended an interesting discussion support research instead of this to avoid on Science and religion in the hope that some of the biases, e.g. under-reporting something would be said about topics of potential side effects of new close to our research hearts such as treatments, and to open up wider embryos/stem cells. Unfortunately, it scientific debate on potentially concentrated on Intelligent Design (ID) problematic issues. The Italian drug versus Darwinism, so I haven’t written regulatory agency has taken this on that one up in detail. However, I was board and now provides funding for interested to note in my discussions with independent clinical evaluations, the UK the proponents of ID (and yes, I was should take heed of this. More terrified, I think I would personally have transparency is generally needed, for found it easier sitting next to animal example the creation of a register of rights activists – at least I know what to clinical trials. say to them), that the ID debates seem welfare or the validity of research) tends somewhat different to the creationist to be unduly influenced by a secondary Wilson noted that the downside of the debates of the 19th Century. I was interest such as financial gain. There was concern that conflicts of interest could be entrepreneurial spirit can be selfishness. surprised to find that they didn’t seem to The danger in the pharmaceutical dispute natural selection or the pervasive in healthcare, bur rarely declared. industry is that in the worst cases the mutability of species (which I would have patient’s interests are not necessarily put felt qualified to argue about) as affecting Smith gave an interesting example of ahead of the shareholder. Cases of bad populations of creatures in the current where funding of projects looking at practice that have been uncovered cast biosphere, but were unprepared to whether contraceptive pills led to an doubt on a purely market-led approach. believe that complex biological systems increased risk of clotting, seemed to have He highlighted the rise of the could have evolved under their own had an impact on the research findings. complementary/alternative medicine steam from humble and ultimately Of a sample of articles submitted to the sector, pointing out that from the originally inorganic origins. I was also British Medical Journal, every one funded public’s point of view medicine might interested to observe that the scientific by industry found that there was no link, have reached a fork in its development proponents of ID present came from and every one funded by public money with traditional, evidence based, western engineering backgrounds, people who found there was. Other studies have medicine on the one hand and were professionally used to having to found similar correlations in other areas complementary/alternative medicine on actively engineer things to create such as papers on tobacco. Declarations the other. New conflicts of interest issues artefacts. Needless to say they were of interests is one strategy to combat can be expected to arise in smaller given a hard time by all the life scientists this, but even with the best of personal companies working on the fringes of present. So I was left thinking that as a intentions, authors can have imperfect medicine. In his view, medical bioscience community we really need to insight into their own potential conflicts publications have a duty of trust in explain in simple, understandable terms of interests. Many doctors fail to declare providing reliable information to the to the general public (that ID is currently a conflict because they are confident it public. Perhaps we will see new forms of trying to influence) the mechanisms of has not caused them to behave in a clinical trials appearing to address this how complex organic life forms can arise different way. Double-blind randomised need? without active intervention. trails are important, not because researchers are consciously dishonest, In the ensuing discussion it was generally Conflicts of interest – does but because bias is pervasive and felt that increased regulation of clinical money influence scientific unconscious. The BMJ has found that in trials would be a good idea, and that the declarations you have to ask very specific UK would benefit from copying the publication? (15 January) questions to help draw pertinent Italians to create an independent public Our President, Ole Petersen, came with information out on, for example, body whose findings the public could me to this session. The speakers were symposium expenses, stockholding, etc. trust. Industry for its own long term Richard Smith (United Health Europe), Sir An issue is that although it is now survival needed to address loss of public Iain Chalmers (Editor, James Lind common to ask authors of potential confidence arising from perceived Library), and Clive Wilson (Strathclyde journal articles to declare their interests, conflicts of interest and put its house in University and Royal Pharmaceutical less attention is often paid to checking order. Complacency in industry will not Society of Great Britain). Some very out the editors and editorial boards. He be tolerated, with the mass media keen interesting key points came up in the summed up by saying that we need clear to expose conflicts of interest when they presentations and subsequent disclosure systems at all levels in the arise. Ole stressed that the biggest discussion. The session defined a conflict publication process, from the authors, problem was the interpretation of of interest as a set of conditions in which through the editorial boards to the results, effective peer review processes professional judgement concerning a presidents of the learned societies are vital in this, but are increasingly primary interest (such as patients’ connected with the journals. under threat from many quarters

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including from changes in the RAE. We ‘ extremely unsatisfactory’. From the being addressed. Teachers are now need to look at bolstering peer review ASE’s point of view, all students should encouraged to avoid taking a particular and rewarding it so that people are experience a broad, relevant science line on any debate, but 14 year olds often motivated to engage in it. Our Society’s curriculum which puts the prefer clear direction. Surveys of student journal publisher, Blackwell Publishing, understanding of science and its attitudes show that their confidence in also got a positive mention in the applications in a social context. Students scientists drops after scientific literacy discussion, with editors clearly separated should experience a variety of teaching debates, for example discussions on from the financial side of the journals, and learning approaches including animal research or GM foods can put kids and published guidelines on practicals. Teachers are the essential off careers in science based industries. transparency. resource in this, but often struggle to We must be very careful about raising juggle the curriculum, assessments, ethical issues in classrooms and leaving Science education for the 21st admin, etc. Facilities are also often them unresolved, as students will be left inadequate – there is an urgent need to with a negative perception of science. century (21 May) invest in modern labs. Teachers need to David felt that traditional models of The speakers were Robin Millar (Salters be qualified for the specialties they teaching science can provide a better Professor of Science Education, teach. Having a relevant degree doesn’t solution, can inspire students more even University of York), Derek Bell (Chief always indicate breadth of knowledge. if they don’t fully understand it, and can Executive, Association for Science We need to think about how to prepare be many students only experience of Education), and David Perks (Head of teachers to teach the curriculum. academic science. It is difficult to teach Physics, Graveney School, Tooting). Experienced teachers need CPD to keep scientific method to students through them up to date. A very big issue is that presentations, students can only learn by Robin Millar noted that the proportion of we may not be able to hold onto the doing. Students love to do practicals but students choosing to study science teachers we’ve got, surveys show a lot of get less chance to do them these days. beyond GCSE is falling. A House of Lords professional dissatisfaction. Teaching to Select Committee report has emphasised the test has been a concern with many In the subsequent discussion I raised the that the role of science education in people now perceiving assessment as issue of the importance of practical schools has a dual mandate, it must not being part of the problem, but if training in schools, and our Society’s only be to prepare students wishing to approached properly it can raise concern at its apparent decline. Practical study science at university, but also to motivation and standards. Students’ training is needed to initially enthuse develop general science literacy skills in initial experiences are very important in students, to reinforce learning (much the population. The UK needs a getting them interested in science, it social science research has highlighted population that can understand scientific needs to connect to their personal the importance of learning by doing), issues, the MMR scare is a good example circumstances, and include looking at and to feed through to the practical skills where failure to achieve this led to many exciting new discoveries, potential needed by academia and industry. I got a parents refusing to vaccinate their applications and ethics. We need to get lot of support for this. One discussant children on the basis of perceived risk. away from ‘can’t do that, it’s not on the from a Small and Medium Sized However, the dual mandate is difficult to curriculum’ attitudes and engage with Enterprise (SME)) said that practical skills get to work in practice, students tend to events in the real world such as what are vital for SMEs which can’t fall back on see much of the science curriculum as students and their families see on the in-house training resources like large being irrelevant to their daily needs. news. He concluded by saying that there companies. Someone from the Teachers Teaching academic science to the whole have been so many curriculum changes Science Network in Norwich said that population often doesn’t work. Under that we need to stick with it now to give practical training is essential, we need the dual mandate, a single science course it a chance to work. Constantly chopping properly equipped labs. They have for everybody is an unsatisfactory and changing brings many problems of received a lot of feedback from students compromise, different sorts of science its own. saying that they want more practicals. courses are needed for students with Baroness Joan Walmsley (Lib Dem), a differing aspirations. The new GCSE David Perks then gave us a very thought former biology teacher, said that she science syllabus has attempted to provoking view from the teaching coal liked the idea of teaching science for provide this. Although still too early to face, challenging some of the science sake, and the importance of see if it works, there has been some good assumptions of the other speakers. The practicals in helping them learn by doing. feedback from teachers on how prepared dual mandate can’t be addressed in the Another discussant raised the interesting students are for A-Level. Robin finished same curriculum. We need to see science issue of the need to inspire students at by saying that the 21st century science education as being worthwhile in its own primary school, get them interested in syllabus needs to become more creative terms, there is a danger of science science before the hormones kick in at in developing practical skills, with more education in schools becoming puberty and they become interested in access to ICT, etc. The choice structure politicised as different lobbies try to give other things. also needs to allow students to pick up it a sense of purpose. There is a particular science at any stage in order to danger of education being used to I was lucky enough to be able to encourage older students to pick up address social issues where young people continue the discussion with David on science again. are perceived to be making the ‘wrong animal research, when he made a choice’. For example the Government is subsequent presentation at a meeting of Derek Bell emphasised the vital role of currently struggling with how to ‘sell’ the Coalition for Medical Progress. He teachers. Debates on the parlous state of nuclear power to the general population, stressed that speakers in schools were education are anything but new, a 19th promoting scientific literacy in schools is useful, but not if they came to try to give century Royal Commission described supposed to address this. It could also be a ‘balanced’ view, leaving ethical issues science education in schools as a problem in terms of the age group unresolved. It is better for speakers to

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nail their colours to the mast, and make a defining a core curriculum in case for whatever lobby they represent as physiological principles to support the The Physiological Society Council students find it easier to engage with publication already produced in this area 2007–2008 this. I was pleased to note from this that by the BPS (Teaching safe and effective Trustees our new Society DVD, Animals in research: prescribing in UK medical schools: a core David Eisner (International Secretary, make up your own mind, which focuses curriculum for tomorrow’s doctors) by University of Manchester) strongly on the case for biomedical Simon Maxwell and Tom Walley in 2003. Prem Kumar (Meetings Secretary, research, does seem to fit the bill here. It is hoped that this will help in the University of Birmingham) Please contact me if you’d like a copy design of courses in medical, dental, William Large (Editor-in-Chief, The ([email protected]). nursing and other health sector training Journal of Physiology, St George's University schools, and that we might eventually of London) Liz Bell follow this up by looking at how our Graham McGeown (Treasurer, Queen's societies can help develop parallel University Belfast) systems of assessment. There may even Ian McGrath (Chairman of the Executive Joint PhySoc/BPS eventually be a niche for new Committee, University of Glasgow) professional qualifications in medical Clive Orchard (Vice-Chairman of the Executive Committee, University of Bristol) physiology and pharmacology, which medical training Ole Petersen (President, University of could be attractive for qualified medical Liverpool) initiative professionals to pursue through The Physiological Society’s Executive continuing professional development. Jonathan Ashmore (University College Committee has paid considerable We will be kicking off this work with a London) thought to the issue of how our short survey of schools over this summer Valerie Gladwell (University of Essex) discipline is represented in medical to try to identify particular needs. Paul Greenhaff (University Nottingham) training, and identified this area for John Hanrahan (McGill University) action at its ‘Prioritisation’ meeting last |If you’d like to contribute to the work of Anne King (University of Leeds) October. Ole Petersen and I then this Group, please contact me Stafford Lightman (University of Bristol) attended a lively Hot Topics meeting of ([email protected]). Christof Schwiening (University of physiology and pharmacology Heads of Cambridge) Departments (HoDs) in Manchester Liz Bell Godfrey Smith (University of Glasgow) (28–29 March) which focused on medical David Sugden (King's College London) training issues. The HoDs meeting asked Alexei Tepikin (University of Liverpool) us to set up a joint Physiological Annual General Teresa Tiffert (University of Cambridge) Society/British Pharmacological Society John Winpenny (University of East Working Group to discuss and potentially Meeting Anglia) David Wyllie (University of Edinburgh) make recommendations about the future The Annual General Meeting of The content of physiology and pharmacology Physiological Society took place in Affiliate representatives in the medical curriculum. We’ve now Glasgow on 11 July. Jane Cleal (University of Southampton) set up this Working Group, chaired by Patrick Howorth (University of Bristol) Ole, with the following members: Paul Bromley, Austin Elliott, John Lee, Eugene Elections Lloyd, Amanda Mackenzie, Simon This year saw the introduction of K Michael Spyer (University College Maxwell, Ian McGrath, Richard Naftalin, online voting for the Council London) was appointed an Honorary Clive Orchard, Peter Roberts, Dafydd election. This proved to be very Member. Walters and Jeremy Ward. popular, with more than double the number of votes cast compared to Membership rates HoDs were concerned that the teaching last year. Godfrey Smith (University Basic embership rates for Ordinary of scientific principles may need to be of Glasgow) and John Winpenny and Affiliate Members will remain reinforced in medical training. It was felt (University of East Anglia) have been unchanged in 2008. There will be a that the teaching of physiology and 5% increase for those Members pharmacology might have become a elected to Council. Two new Affiliate requiring hard copies of The Journal particular issue, because understanding representatives have been of physiological principles is important appointed, Jane Cleal (University of of Physiology or Experimental for medical diagnosis and insight into Southampton) and Patrick Howorth Physiology. Trial rates will apply to disease processes, and pharmacological (University of Bristol). new membership categories – knowledge is vital to safe and effective Associate (£45), School and College prescribing. Doctors are also becoming Doug Corfield, Sarah Hall, Patrick Associate (£15) and Undergraduate increasingly under pressure because they Harrison, Sergey Smirnov and Keith Associate (£15). are having to assimilate the rapid Thornbury have retired from Council expansion in scientific and medical and Patricia de Winter has retired as Subscriptions are due on knowledge. In addition patients are an Affiliate representative. The 1 January (Ordinary Member) and becoming, quite correctly, better 1 September (Affiliate). For all new informed about their illnesses and the Society is extremely grateful for all risk of medical litigation is increasing. their contributions. Members who joined on or after 1 January 2007, subscriptions will In the first phase of the Group’s work, A full list of Council members for run on for 12 months from the the two societies will be looking at 2007–2008 appears above right. month of acceptance.

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Where our money came from (£3.3m) Balance sheet • Investments (fund and property) doing Publications well; the capital value growing by £464k and £510k respectively; • cash balances were high at year-end. Investment income This was mostly to do with the timing of a VAT payment collected in Membership December 2006 and paid to HMRC in subscriptions January 2007.

Meetings and The Benevolent Fund of The education Physiological Society – 2006 Other income financial statements As at 31 December 2006, the net assets of the Fund were £29,314 (2005: £30,004), a fall of £690. Although income exceeded Where our money has gone (£3.1m) Publications expenditure by £484, the fund saw a large drop (£1,174) in the value of its Meetings COIF Investment Fund (formerly the Charities Official Investment Fund). Membership services Income Governance Three new annual standing orders International for regular giving were received in the year. £1,874 was received in External relations donations and regular giving (2005:

Education £1,505) during the year and income from raffles was £495 (2005: £330). Cost of generating funds Interest fell by £421 although this was due to a book-keeping For full details visit £3.3m). However, expenditure correction in 2005. The COIF interest http://www.physoc.org/membership increased by £0.1m to £3.1m (2005: yield is between 5.3% and 5.6%. £3.0m) and, as a result, net incoming 2006 Annual Report and Accounts resources fell by £0.1m to £0.2m Expenditure The 2006 Annual Report and (2005: £0.3m). Thanks to the good Two grants totalling £3,000 (2005: Accounts were approved by the performance of our investments in £5,050) were awarded in 2006. Trustees on 17 May 2007 and 2006, The Society’s reserves School-age children in families of subsequently laid before the increased during the year by £1.2m. current and recent beneficiaries were Members of The Society at the sent book tokens or Marks & Spencer Annual General Meeting. The report Key points vouchers worth £200 in total (2005: is now fully compliant with the new Income £225) for Christmas 2006. Charity Commission reporting • Journal income is stabilising but the Applications for assistance are requirements. We have created a real surplus is falling because of sporadic and the Fund has no document that, I am sure you will inflationary effects; predictable future liabilities or agree, is rather more professional • membership income diminished due commitments. and user-friendly than in previous to free Ordinary Retired subscriptions years. (subscriptions also frozen in 2008); The financial position of the Fund is • investment income will be reinvested reasonable. The performance of the from the middle of 2007 to build up All Members were sent an Annual the reserves. These can supplement COIF Fund is a cause for concern and Report incorporating summary Society income in future years. alternatives will be considered in financial statements. The full 2007. statements, as filed with Companies Costs House and the Charity Commission, • Major exceptional items in year: Please contact me if you have any rebranding (£43k) and web project can be found at questions about the reports in (£85k); general or the accounts in particular. http://www.physoc.org/downloadfil • notable savings were made in direct es/AR2006.pdf. costs of publishing due to the Blackwell Publishing Singapore Summary of accounts operation; C R Early The Society’s income remained • there was a 3.5% increase in total staff Finance Manager constant in 2006 at £3.3m (2005: costs;

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problems with insurance and staff recruitment if we ask technicians or PhD students to retrieve tissue samples from the viper pit, and the necessary supplies of anti venom might add considerably to the cost. However, a suitable claw-ended retrieval pole might provide an adequate A mouse speaks: solution. One hidden advantage of the pit ‘Schedule 1 so lacks technique – but for obvious reasons panache’ please keep this strictly entre nous – if you had a trainee Home Office inspector Last week I had a dream. In the dream I workings of the mouse mind. Following who was underperforming, but was took some hallucinogenic drugs. And I an extended philosophical discussion, a difficult to remove from duty by the took them at work in the university talking mouse and I have come to a standard mechanisms, perhaps a little mouse-house. unique inter-species agreement. We are accident could be arranged: “Honest in clear accord that the current legal officer, he slipped. The side of the pit was There is a logical reason why I confined methods of killing mice in the lab are wet”. my altered state of consciousness to boring and lack a certain “je ne sais quoi”. work. I would like you to think it was We therefore wish to suggest an We think this method has many positive because I am a responsible law-abiding alternative Schedule 1 method that we aspects – ritual (a vital aspect of the end adult, and this applies to my dreaming would like added to my animal licence. of life for humans), spectacle, and even self too. I suspect, however, that my We feel that this technique would bring a the possibility of ticket and video sales. subconscious thinks nobody notices certain extra something to scientific However, if you feel it is unworkable, the when you are hallucinating in a university research and have the potential to mouse and I do have other ideas we neuroscience department. You wouldn’t engage bored scientists, sentient mice would welcome the chance to discuss stand out, let’s put it that way. and members of the public in a whole with you. An electrified running wheel is new philosophical debate about the one – clean, quiet, and carbon neutral if In the dream I used my newly enhanced nature of a good, or at least purposeful, converted to solar or even to “running cognitive state to begin a serious death. mouse” power. And I sense that we are philosophical conversation with a only scratching the surface. The mouse transgenic mouse. The method, in its essentials, is to throw has pointed out, rather perceptively I the mouse into a pit of vipers. This was a think, that humans have devised ‘I don’t understand the regulations favoured liberal alternative to prison in enormous numbers of creative ways of relating to the euthanasia of mice’, I said. early medieval times, and was notably disposing of one another throughout ‘ Neither do I’, said the mouse, ‘If I had employed by King Einar of history. So there must be many methods to do all that paperwork every time I ate Northumberland to dispose of a we could seek to adapt. a beetle I’d be a basket case. And apart troublesome Danish relative, King from that, the current methods are so Ragnar. To close, if you are happy with our boring – no theatrical finesse at all. suggested method, please amend both When I go, I want to go with a bit of I suspect that the Home Office would my project and personal animal licence style. A friend of mine feigned death and have had reservations about the method with immediate effect. It is our escaped from the freezer last week - in its original historical use for human understanding that there is a longish which is a pretty neat trick, but he said subjects. While the vipers are nibbling lead time on orders for poisonous his near death experience was a bit the ankles of their intended victims they reptiles, and the mouse and I are keen to boring. It’s cold in the freezer and when could get trodden on; this is obviously start testing and refining the method as you shut the lid the light goes off. unacceptable from an animal welfare soon as possible.' Personally I want spotlights - a bit of perspective. Using a pit of vipers to spectacle.’ dispose of mice avoids these concerns, And then, just as I was contemplating the however. The mice are no threat to the best place to source half a dozen pit The conversation carried on for a while, vipers; mice are despatched; vipers are vipers, I woke up. And remembered I had until my 5-HT receptors returned to fed. to get to work. normal (a process which surprisingly rendered me unable to communicate Pragmatically, I could see this method A Home Office inspection is due, and we effectively with or read the mind of my raising a number of minor legal and have to scrub the place from top to furry rodent friend). I then wrote to the technical problems. The pit itself might bottom, make sure all the forms and Home Office inspector asking for a need special Home Office approval, and records are in order (all three filing number of amendments to my animal there could be problems if a confused cabinet drawers of them), and check that licence: escapee snake began wandering around everyone’s licences are complete and up the lab, overexciting the Health and to date. So back to reality. ‘ Dear Home Office Inspector, Safety people. The other problem Yesterday, for scientific purposes only, I concerns organ retrieval. For our But a man can always dream. took some LSD. The ensuing expansion research, mice are often killed and their of my consciousness has given me a organs harvested for histology and other Keith Cormorant number of unique insights into the inner experimental purposes. We may have

Physiology News | No. 68 | Autumn 2007 | www.physoc.org BOOK REVIEWS PN 55

The biochemical basis providing lots of information as it may, it's an interesting fact that leavened by a healthy dose of only one in every 200,000 neurones of the health effects of schematics. The trouble is that there in the human central nervous system is so much data from diverse is a motor neurone, so it's not exercise sources, that it becomes difficult or surprising that these rather special Essays in biochemistry No. 42 perhaps impossible to make much cells, mediators of the CNS ‘final Edited by AJM Wagenmakers sense of it in relation to individual common pathway’ should have 2006. Portland Press, London. patients, except to say ‘take more excited a lot of interest. In fact, they 214 pp, £21.95 exercise’. While one can't disagree are among the most intensively with the blurb writer's assertion that studied and best characterised of all ISBN 978 1-85578 159 7 this volume will ‘be a unique mammalian neurones. They have information source for medical large cell bodies which are relatively If you are someone who likes doctors, health professionals, easy to get a microelectrode into, schematic diagrams with lots of dieticians and public-health they can be clearly identified by arrows, and various blobs or policymakers’, I doubt many of them stimulation of their peripheral axons, polygons representing genes, will read it, or would find it and they have clear functional tasks enzymes, substrates and so on, then comprehensible if they did (the idea to perform on their also well you will love this book, which of public health policy being directly characterised effector cells the contains loads of them. To my mind influenced by a volume such as this is muscles. A search for relevant papers they rather highlight the problems terrifying). We should be honest from the last 55 years deluged the we face when trying to understand about this sort of research. The main author with 19,700 references, complex systems. On the one hand reason why we do it is not medical, which increased to 22,900 when he they are an undoubted help to it's cultural – it's because we like to included the term 'motor unit'. learning. On the other, they spotlight try and figure out how things work. Whew! Even though Daniel Kernell how un-joined-up our thinking and If something medically useful comes has been working in the field for 40 analysis tends to be, so that once out of it, so much the better, but the years, that still amounts to 11 papers you've looked at more than a few likelihood is that it will in the end be every single week, including you start to question whether you do subsumed by ‘take more exercise’. Christmas and school holidays. in fact know anything worth The real audience for this book is not His aim in writing this monograph knowing about the system after all. the blurb list, but researchers was to ‘give a critical, balanced and The blurb tells us that this volume working in the field of muscle and reasonably complete survey of the ‘gives clear mechanistic insights into exercise biochemistry and most essential facts about the multitude of enzymes, signalling physiology. For them there is a lot of motoneurone and muscle unit pathways and tissue and bodily up-to-date material in this book, physiology, including both new and functions that benefit from relatively with a more than average amount of older observations, provided that modest increases in physical attempted synthesis. For them this they are all still valid’ and to exercise, making exercise a unique volume represents good value for ‘summarise the present state of and incredibly efficient therapeutic money and is worth reading. affairs in a generally understandable treatment.’ Leaving aside the manner’. Given the huge volume of question of whether enzymes and John A Lee work he has had to sift through (the signalling pathways can really book itself contains about 1,300 ‘benefit’ from anything, this shows references), I think Kernell has done why you should never leave blurb The motoneurone and an excellent job. Introductory writing to publishers. But is also its muscle fibres chapters deal with basic properties reinforces the problem noted above. of neurones, neuromuscular If all the book really says is that a bit Monographs of The transmission, muscles and motor of exercise is good for you, then you Physiological Society No. 50 units. Then follows more detail on don't really need to read it. But, of By D Kernell motor neurone morphology, course, there is more than this. There 2006. Oxford University Press, organisation, electrophysiology and are 13 chapters (essays?) dealing synaptic control. Further chapters with a variety of subjects related to Oxford. 341pp, £55. consider more integrative aspects of the title, though principally focusing ISBN 0-19-852655-5 motor neurone physiology including on the effects of exercise on gene motor neurone pools and the expression, insulin action, fat In order to get things done, all our gradation of muscle force, fatigue metabolism and so-called metabolic thoughts converge on motor and potentiation, denervation and its syndrome. There are also neurones or, as they are for some recovery, long term plasticity, and contributions on muscle adaptation, reason called here, motoneurones genetic control and lifespan mitochondrial biogenesis and muscle (raising confusing crosstalk in my development. The result is a close atrophy/hypertrophy. All of this is a mind at least of mobile phones and read which gives a pretty solid well set out, if rather technical, read motorway service stations). Be that overview of the field. Although

Physiology News | No. 68 | Autumn 2007 | www.physoc.org 56 PN BOOK REVIEWS people will be able to point to many book. In cycles 2 and 3, György packages’ lasting 15-30 ms which extra details which could have been Buzsáki discusses form and function, may be involved in perceptual included in their own specialist fields, indicating that preferentially binding of object features. Buzsáki the overall result is impressive and connected areas of the cortex form then goes on to show that will be of considerable interest and the basis of higher order cortical perceptions and actions are brain- use to a wide range of readers, from systems, e.g. for movement and/or state dependent (cycle 10), which those new to the field looking for a vision. He points out that the adds to his argument that a given detailed introduction, to established diversity of cortical functions can environmental perturbation leads to researchers looking for new ideas or only be achieved by inhibition and by modification of ‘a perpetually a wider context for their results. complex networks of interneurones evolving network pattern in the offering the basis for temporal brain’s landscape’. Cycle 11 talks of John A Lee coordination, often accomplished by navigation in real and memory space oscillations. In Cycle 4 (Windows on and how the hippocampus is the the Brain), he outlines the currently search engine for the retrieval of Rhythms of the brain available monitoring techniques archived information with theta By György Buzsák most frequently used to investigate oscillations related to episodic and Oxford University Press, the oscillatory behaviour of neuronal semantic memory, path integration networks, including EEG, positron and ‘map-based’/landmark Oxford. 448 pp, £42 emission tomography, optical navigation. Further transient ISBN 978 0 19 530106 9 imaging, recordings from single oscillations are used to transfer this neurones, and high density information to the neocortex, when György Buzsáki has written an recordings with silicon probes. cortical assemblies are transiently excellent, scholarly book on brain György Buzsáki’s fundamental entrained to the theta rhythm (cycle oscillations, his speciality. The work argument is that most of the brain’s 12). The final cycle investigates the is dense but very readable and is all activity is generated from within and relationship between structural the better for being by a single that external inputs cause only minor connectivity and global function. author rather than an edited departures from its internal It is difficult to do justice to György collection of review articles. programme. Thus the brain ‘does Buzsáki’s tour de force in a short Appropriately, the book is divided not simply process information but review. I can only recommend that into 13 cycles rather than chapters also generates information’, those with an interest in the and each cycle ends with a brief and observable in the EEG as a blend of neuroscience should read and learn useful summary. He combines ideas rhythms unable to phase-lock with from it. from the neurosciences with those each other because their mean from chaos theory and non-linear frequencies are not integers. These Bill Winlow dynamics, pointing out in the oscillations are metastable and result introduction (p. 13) that ‘complexity from the physical architecture of can be formally defined as neuronal networks (cycle 5). In cycle Other books received nonlinearity and from nonlinear 6 he discusses synchronization by Regulatory mechanisms of striated equations, unexpected solutions oscillation based on self-organized muscle contraction. Advances in emerge’. Put simply complex interactions among neurones, which experimental medicine and biology behaviour of a dynamic system such he argues may be the source of No. 592. By S Ebashi and I Ohtsuki. as the brain cannot be predicted cognitive function. Cycle 7 discusses from the behaviour of individual the self-organized oscillatory Oxford handbook of clinical examination neurones or small neuronal rhythms connected with rest and and practical skills. Edited by James ensembles. sleep – the default pattern of the Thomas and Tanya Monaghan. György Buzsáki promotes the view brain in the absence of Oxford handbook of medical sciences. By that the inside-out approach to environmental inputs. In cycle 8 the Robert Wilkins, Simon Cross, Ian neuroscience enhances our perturbation of various default Megson and David Meredith. understanding of relatively patterns by experience is explored unperturbed brain states because and it is shown that sensory Peer review and manuscript ‘ self-generated behaviour and representations in the brain acquire management in scientific journals. emergent large-scale oscillations real-world metrics early in Guidelines for good practice. By Irene tend to occur in the unperturbed development by first acquiring Hames. brain’. In the introductory cycle he information about the three- Insulin murders. By Vincent Marks and argues that during exploration of the dimensional nature of the skeletal Caroline Richmond. brain, experimental perturbation of muscle system. Cycle 9 considers the network interactions and emergent “Gamma Buzz” in the waking, Neuro-ophthalmology. Edited by A functions will yield hints of causality. activated cortex through which Straube and U Büttner. He then successfully adopts this neuronal assemblies organize approach for much of the rest of the themselves into ‘temporal Reviews will be carried in future issues.

Physiology News | No. 68 | Autumn 2007 | www.physoc.org Photos by Ivor Williams Estrogen receptor in breast cancer. ER positive cells are stained brown and the section is counterstained with haematoxylin (blue). Photo by Ms Korsa Khan, UCL

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