PHYSIOLOGYNEWS

spring 2007 | number 66

Meetings Edinburgh Belfast Brazil

Also featuring Peter Stanfield’s 10 key papers ... and some music A critical look at Lord Adrian’s 1933 classic Tim Bliss and LTP Physiologists having fun on the road The Journal of Physiology symposia Warning: ethics can kill Education – new feature

A publication of The Physiological Society Joint International Meeting with the Brazilian Physiological Society Ribeirao Preto, Brazil 27-30 August 2006 PHYSIOLOGYNEWS Editorial 3 Meetings Perinatal physiology: from uterus to brain Alison Douglas, 4 Mike Ludwig The Society’s dog. ‘Rudolf Magnus gave 5 me to Charles Sherrington, who gave me Ion channels and the microcirculation Graham McGeown, to Henry Dale, who gave me to The Tim Curtis Physiological Society in October 1942’ Images of Brazil inside front cover My 10 key papers Peter Stanfield selects his top 10 ion channel papers ... and 6 Published quarterly by The Physiological Society a piece of music

Contributions and Queries Living history Executive Editor What can clinical medicine give back to physiology? 10 Linda Rimmer John Dickinson The Physiological Society Publications Office P O Box 502 A week in the life of ... Cambridge CB1 0AL Frivolous days in the life of physiologists having fun 13 UK Christof Schwiening

Tel: +44 (0)1223 400180 From the archives Fax: +44 (0)1223 246858 Afferent impulses in the vagus and their effect on respiration 15 Email: [email protected] John Widdicombe The Society web server: http://www.physoc.org Features Magazine Editorial Board Reactive oxygen species and glucose transport during exercise 16 Editor Marie Sandström, Shi-Jin Zhang, Joseph Bruton, José Silva, Austin Elliott (University of Manchester) Michael Reid, Håkan Westerblad, Abram Katz Members Patricia de Winter (King’s College London) The amazing versatility of hPEPT1 Monica Sala-Rabanal 18 Sarah Hall (Cardiff University) Where is my arm? Uwe Proske 20 Munir Hussain (University of Liverpool) Thought to action: development of temporal signals from 23 John Lee (Rotherham General Hospital) Thelma Lovick (University of Birmingham) topographic maps David Waitzman, Jason Cromer Bill Winlow (Prime Medica, Knutsford/University of Store-operated calcium entry in adult skeletal muscle fibres: the 26 Liverpool) missing clue Bruno Allard, Vincent Jacquemond © 2006 The Physiological Society Peripheral muscle fatigue from hyperoxia to moderate hypoxia – 28 ISSN 1476-7996 a carefully regulated variable? Markus Amann, Jerome Dempsey The Society permits the single copying of individual articles for private study or research. For Going with the flow: just say NO to oxygen radicals 30 copying or reproduction for any other purpose, Henning Morawietz written permission must be sought from The Letters to the Editor 32 Physiological Society ([email protected]). Reports Opinions expressed in articles and letters submitted Special Symposium – Tim Bliss and LTP Samuel Cooke 33 by, or commissioned from, Members, Affiliates or outside bodies are not necessarily those of The World Congress to focus on advances in research methods 35 Physiological Society. and strategies Jon Richmond Affiliate News The Physiological Society is registered in England as a company limited by guarantee: No 323575. Let’s talk about science Rehana Jawadwala 36 Registered office: PO Box 11319, London WC1X To be strong – a Chinese PhD student’s story Meihua He 36 8WQ Registered Charity: No 211585. Education Physiology for schools and colleges Donna Brown 37 Printed by The Lavenham Press Ltd CASE Opinion Forum Liz Bell 38

Cover photos Memorable Members Bernard Katz Liam Burke 39 The Society’s journals Image from The Journal of Physiology Symposium The cortex, interneurones The Journal of Physiology 40 and motoneurones in the control of Experimental Physiology 42 movement to take place in Darwin on Society News Thursday 19 July 2007. See page 40 for details What’s happening in The Society Michael Collis 43 Society Meetings Prem Kumar 44 Parliamentary and Scientific Committee Are patients safe with the NHS? Liz Bell 46 Biosciences Federation Richard Dyer 48 Images from A week in the life of ... (p. 13) Unbelievable! 49 Book Reviews 31, 50 Noticeboard 52 PHYSIOLOGYNEWS

Action points Guidelines for contributors In this issue Grants These guidelines are intended to assist Welcome to the first Physiology For full information on Members’ authors in writing their contributions and to News of 2007. and Affiliates’ Travel Grants, reduce the subsequent editing process. The Network Interaction Grants, Non- Editorial Board of Physiology News tries to The best bit of being an editor is to Society Symposia Grants, Vacation ensure that all articles are written in a see new features inaugurated, and I Studentship Scheme, Departmental journalistic style so that they will have an am delighted to say this issue has Seminar Scheme, Centres of immediate interest value for a wide two. The first is a regular column Excellence and Junior Fellowships readership and will be readable and aimed at teachers in schools and visit: http://www.physoc.org/grants comprehensible to non-experts. In colleges, kicked off by The Society’s particular, scientific articles should give a Education Officer Donna Brown. As with all new features, volunteers to Membership applications good overview of a field rather than focus Applications for Full and Affiliate entirely on the authors’ own research. write articles will be needed sooner Membership are received throughout or later (usually sooner), so contact the year and have no deadlines. A Format of articles Donna if you would like to be decision is normally made within The main message or question posed involved. 7 days of the Administration Office should be introduced in the first paragraph. The second new feature is ‘From the receiving the application. For full The background for the topic should then be Archives’, where John Widdicombe details please visit: established, leading up to the final looks back at a classic paper, http://www.physoc.org/join conclusion. recalling when he first read it and comparing his reactions then and Change of address Length of articles now. If you fancy writing about a Members should inform the This will be determined by the subject matter paper that stands out in your Administration Office of any changes and agreed with the Executive Editor. memory, or if you have mused about of address, telephone, fax or email writing a ‘My 10 Key Papers’ but address. Submission of articles felt 10 was 9 too many, now is your Changes can be emailed to: Authors should submit articles as a Word chance. Again, volunteers please! [email protected] or updated online document attached to an email. Illustrations This issue also has a 10 Key Papers, at http://www.physoc.org should be sent as separate attachments (see below) and not embedded in the text. this time ion channel papers chosen by Peter Stanfield, and a Living Illustrations and authors’ photographs History – not for the squeamish! – Authors are encouraged to submit diagrams, from John Dickinson. We also have Physiology News drawings, photographs or other artwork with seven scientific News and Views Deadlines their articles or to suggest appropriate features, a Week in the Life of a illustrations. A photograph of the author(s) physiologist on the road, plus Letters and articles and all other should also accompany submissions, if meeting reports, Society news and contributions for inclusion in the possible. Illustrations and photographs may book reviews. Summer 2007 issue, No. 67, should be colour or black and white, prints, reach the Publications Office transparencies or tif/jpeg files with a Finally, I am a great fan of historical ([email protected]) by 23 April minimum resolution of 300 dpi. articles, and the longer I work in 2007. Short news items are Electronic colour figures should be saved in physiology, the more amazed I am encouraged, and can usually be CMYK mode. by just how much the pioneers in included as late copy if space various fields achieved with permits. References primitive and often self-built Suggestions for articles Authors are requested to keep the number equipment. But historical articles Suggestions for future articles are of references to a minimum – preferably no also provide wonderful unexpected welcome. Please contact either the more than two or three. Please cite all glimpses of people. For us normal Executive Editor or a member of the references in the style of The Journal of bunglers it is good to know that even Editorial Board of Physiology News Physiology (see Instructions to Authors 2005 the scientific immortals couldn’t do (see contents page for details). at http://www.physoc.org) everything perfectly, so I treasure the revelation that Bernard Katz wasn’t the greatest micropipette puller (see Physiology News Online Liam Burke’s memoir). Heroes Physiology News is now available on should be human too. The Society’s web site: http://www.physoc.org. Austin Elliott EDITORIAL PN 3

Real science needs you much as a matter of routine, misquoted, most cases the original source – press misunderstood, and misappropriated. And that release or published paper – of a ridiculous people on the receiving end of it – the public – media science story is easy to find, and the As 2007 dawns, a straw poll of the issues are misinformed and misled. errors in how it has been misreported are not facing The Physiological Society and its that subtle.. However, unless there is Members might include, inter alia: the The usual reaction from scientists is a weary something of a change of heart it seems upcoming Research Assessment Exercise; the shrug of the shoulders. unlikely that the UK scientific establishment impact of full economic costing for grant will ‘go public’ in quite this way, so we will applications to government–funded bodies, I would like to offer a counter-view. Rather probably have to rely on bloggers like the particularly the Research Councils; and the than shrugging, we should be doing excellent Ben Goldacre in The Guardian (3) or looming Tsunami (at least for learned societies something. And I mean each of us. our own David Colquhoun (5), the occasional that run journals) of open access and the courageous editor like the FASEB Journal’s potential loss of journal subscription income. First, though, one has to ask: why are we scientists so apathetic about junk science? Gerald Weissmann (6), and the people at All of these issues are worth an editorial Sense About Science (4). apiece, and I hope Physiology News will come One can justify the prevailing apathy in a But there is something we can do ourselves – back to them all during the year in one form or number of ways. The first is the view that the take some individual action, at the grass roots another. However, for this editorial I want to misreporting of science, and even more the level, to promote real, evidence-based, talk about one of my other recurring themes; full-on pseudoscience, is so crazy that no-one science. Why not resolve, in 2007, to try one the ever-growing tide of scientific could possibly believe it. To which one might or more of the following: ‘disinformation’, and how this potentially cite the poll on creationism, or the accounts shapes the public’s view of science, scientists, from tropical medicine specialists indicating • sign a petition against pseudo-science, or for and scientific issues. that some people travelling to malarial regions the real thing. There are online petitions to can, and do, believe that homeopathic sign, sometimes flagged up by The Society This topic needs highlighting, I think, because preparations will offer malarial prophylaxis (4). but also often via internet newsgroups it is something of a Cinderella issue. What I devoted to debunking bad science, or Another viewpoint is that it doesn’t matter if mean by this is that it does not impact on us promoting ‘informed scepticism’. day-to-day in the same direct way as the lots of people believe utter nonsense, as long • do something in your local school. This issue others listed above do. For instance, I would as the people who matter listen to the experts. of Physiology News kicks off a new regular guess that many Members have spent some To which one might cite the homeopathic feature directed at school teachers. But time this last year cursing while they filled in a medicine labelling debacle, where the initiatives directed at schools need people – pre-RAE census form, trying to track down interests of the homeopathic ‘industry’ clearly you – to get involved to give them life. The someone who can tell them how to fill in an weighed heavier for the government than the universities are finally waking up to the need FEC-costing sheet, worrying about whether scientific and medical opinion. to get more involved with secondary school The Society might have to charge a hundred A third view is that we cannot do anything science, but how many Society Members, pounds a go for meeting registration fees if full about what people believe. Well, we can. It is even those with secondary school age kids, open access publishing comes in, or even called explanation – or education. It may only actually offer to go and talk about working in pondering whether to publish something in an have an effect on people whose current views science? Or about science stories in the author-pays online open access journal. are based on misunderstanding but, as we news? In contrast, you probably haven’t worried that have seen, there is an awful lot of • email your MP. You can do this in minutes much about any of the following: the Human misunderstanding about. via sites like writetothem.com. For instance, Fertilization and Embryology Authority (HFEA) the HFEA has defended its decision on hybrid The final viewpoint, which is where I suspect prohibiting scientists from making new stem cell cloning as ‘sending the issue back to most of us end up, is that we deplore all this experimental ‘hybrid’ stem cells by injecting the politicians for more public consultation’. but feel there is nothing much we can do human somatic cell nuclei into enucleated The final decision will come in the autumn. So about it. animal eggs (1); the new UK rules on labelling now is your chance to tell your MP what you homeopathic ‘medicines’ discussed in our last Which is where I beg to differ. think. You may be quite sure those opposed to issue’s editorial; the opinion poll a year ago stem cell research will be making their voices that suggested nearly half of Britons felt So what can we do? heard. ‘intelligent design’ should be taught in science • write to a newspaper. If you see a piece of It would be nice to think that the Royal classes (2); the mass experiment in Durham scientific nonsense in a paper you read, don’t Society, or the learned societies in concert, feeding omega-3 fish oil supplements to all just sit there – write and tell them exactly why might set up a ‘science nonsense rapid O-level pupils, which has no control group or it is wrong. blinding but has been widely described as a rebuttal unit’, bashing out quick and scientific trial (3); or the alarming prominence scientifically authoritative press releases Because if you don’t, no-one else will. on British TV of self-styled ‘nutritionists’ and debunking the current idiocy du jour. Actually ‘diet doctors’ who find a lack of any formal it would not be as hard as it sounds, since in Austin Elliott scientific qualifications no bar to lecturing members of the public about what is 1 http://www.guardian.co.uk/science/story/0,,1989990,00.html 2 http://news.bbc.co.uk/2/hi/science/nature/4648598.stm supposedly going on in their bodies. 3 http://www.guardian.co.uk/life/badscience/story/0,,1873857,00.html 4 http://www.senseaboutscience.org.uk/index.php/site/project/73 If you were a pessimist you could look at the 5 http://www.ucl.ac.uk/Pharmacology/dc-bits/quack.html issues just cited and say that science is, pretty 6 Weissmann G. (2006) The FASEB Journal 20,405-407.

Physiology News | No. 66 | Spring 2007 | www.physoc.org 4 PN EDINBURGH FOCUSED MEETING

Invited speakers Perinatal physiology: from Andrew Blanks (Warwick, UK) uterus to brain Cathy Dwyer (Edinburgh, UK) A Physiological Society Abby Fowden (Cambridge, UK) Focused Meeting at the Dimitris Grammatopoulos (Warwick, University of Edinburgh UK) Vivette Glover (London, UK) on 12 and 13 February Dave Grattan (Dunedin, New Zealand) The meeting Mark Hanson (Southampton, UK) The focus of this 2 day meeting, on 12 Kelly Lambert (Richmond, USA) and 13 February, at the University of Edinburgh is perinatal physiology. We Harry McArdle (Aberdeen, UK) aim to draw together researchers from Simone Meddle (Edinburgh, UK) various active groups in the fields of Quentin Pittman (Calgary, Canada) neuroendocrine, placental and uterine John Russell (Edinburgh, UK) physiology from within the UK and understanding of human and abroad. Julia Szekeres-Bartho (Pecs, mammalian physiology, development Hungary) and disease. Recent research in the field is Rachel Tribe (London, UK) highlighting important emerging issues Research in the Laboratory of Joanne Weinberg (Vancouver, Canada) such as the balance between brain and Neuroendocrinology focuses on Susan Wray (Liverpool, UK) uterine/placental control of birth and networks of neuroendocrine neurones perinatal behaviours, and the roles that that control all aspects of reproduction, neurohormones and immune signals as well as growth and metabolism, fluid play in regulating both elements. and electrolyte balance, and physiological responses to stress, which The Centre for Integrative are all of key importance to health and Physiology (CIP) welfare. The meeting will be hosted by Alison Douglas and Mike Ludwig from the The city Laboratory of Neuroendocrinology in The University of Edinburgh is located the Centre for Integrative Physiology within the centre of Edinburgh. (http://www.cip.ed.ac.uk), which was Edinburgh was established as a founded in 2005 as a focused research UNESCO World Heritage City in 1995 centre within the School of Biomedical and contains many visitor attractions, Sciences. The scientific remit of the including Edinburgh Castle, Holyrood CIP is to investigate key physiological Palace and the Georgian New Town. mechanisms from genes and cells to Additionally, Edinburgh is known for whole organisms. Investigators exploit its Festivals and hosts Scotland’s 6 appropriate model systems and focus Nations International Rugby games at activities that directly facilitate the Murrayfield stadium. In fact, on the Saturday before the meeting (10 February) Scotland will be playing against Wales.

We look forward to welcoming you to The University of Edinburgh in February.

Alison J Douglas Mike Ludwig Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh

Above: Meeting organizers Alison Douglas (right) and Mike Ludwig. Far left: Sir Walter Scott monument. Left: Edinburgh seen from Holyrood Park.

For further information and online registration please visit http://www.physoc.org/meetings/edin2007.asp

Physiology News | No. 66 | Spring 2007 | www.physoc.org BELFAST FOCUSED MEETING PN 5

Ion channels and the microcirculation A Physiological Society Focused Meeting at Queen’s University Belfast on Above: Local organisersTim Curtis (left) and Graham McGeown. Right: Retinal arteriole showing smooth 4 and 5 April muscle cells and endothelial layers (provided by Norman Scholfield). Below: Queen’s University Belfast (top) and the Students’ Union This new growth and confidence has been paralleled with new academic Regard this as a personal invitation to appointments in the area of physiology, Belfast in the spring-time! I know and five full-time staff have joined us over Easter 2007. This will explore the Belfast hasn’t always been the most within the last 2 years. For the first role ion channels play in the attractive of destinations; indeed, the time in 20 years we have a truly microcirculation and follows the Belfast of the 1970s featured as one of international team of young researchers Annual Meeting of The British the ‘hotspots’ in PJ O’Rourke’s book and teachers, mainly concentrated in Microcirculation Society. The Holidays in hell. Thankfully, the 8 the newly refurbished laboratories of international speakers will describe years since the signing of The Good the Cell and Metabolic Signalling recent findings based on techniques Friday Agreement have been marked by Research Group. ranging from the molecular to in vivo ever-increasing political stability and physiology. The aim is to understand remarkable economic growth. Belfast is It is a great privilege for us to host one what makes the microcirculation, booming, and in a good way this time! of The Society’s Focused Meetings particularly resistance arteries and arterioles, so responsive to both the local needs of metabolically active tissue and the central requirements of cardiovascular homeostasis. Considerable emphasis will be placed on both K+- and TRP channels but one sub-theme will be how changes in ion channel expression and control may contribute to vascular disease. Poster sessions will allow delegates to present their own results and several of the submitted abstracts will be selected for oral presentation, allowing younger researchers to discuss their work before a wider audience. Send in an abstract and it could be you!

There will be plenty of opportunity to meet people in a more informal setting as well, and there are good bars and restaurants all around the University area. The Meeting dinner is definitely not to be missed, as it will be held in Parliament Buildings at Stormont Castle, an imposing venue with plenty of history. Past experience suggests the food should be good too.

The last time The Society was in Belfast was September 1990, when 44 communications were presented. Let’s see whether we can’t double that score in April 2007.

Graham McGeown Tim Curtis Meeting Organisers

Physiology News | No. 66 | Spring 2007 | www.physoc.org 6 PN MY 10 KEY PAPERS

Peter Stanfield selects his top 10 ion channel papers ... and a piece of music

You know you are getting old when Linda as shorthand and in finding that the Rimmer asks if you would contribute your top formulations (n4 for example) resonate 10 papers to Physiology News. The task is in the channel structures now known. easily accepted, but choosing only 10 papers In IT terms, these were early days to among so many is more difficult, and I am have computed the propagating action sure if I had done this next week some, at potential from the descriptions of least, of my choices would have been current. But the paper also contained a different. Since the 1960s, when I did my most interesting insight, distinguishing PhD, the ion channel field has changed the unitary event from the transfer of markedly. Then, the concept of ion channels as membrane proteins was only in its infancy. ions. Rejecting the hypothesis that And the great diversity of channels that we sodium ions cross in simple now know, first from electrophysiology but combination with a charged carrier, now more fully from molecular biology, was a Peter Stanfield because the carriers would carry initial strange, even heretical notion. The past 40 outward current as they moved to the years have also seen a change in thinking point where they picked up Na+, the from the domination in the early days by ideas bilayer. We would not then be asking authors wrote: from electrical engineering to an approach students to write essays distinguishing ion ‘Changes in ionic permeability more familiar to biochemists. Nonetheless the channels from other transport proteins. depend on the movement of some seeds of current thinking were laid some time Indeed, natural selection has not drawn the ago and a handful of papers generated component of the membrane which distinction, making a family of transporting behaves as though it had a large hypotheses that have survived the proteins – the CLC family – that includes examination even of structural biology. charge or dipole moment. It is proteins we might classify as channels and necessary to suppose that (the) density those we might think of as transporters Ion channels seem special in that they have a (of these components) is relatively low (Jentsch, 2006). high turnover rate. We know from single and that a number of sodium ions channel recording that they carry current in Some, at least, of the papers I have chosen cross the membrane at a single active 6 the order of 1pA, equivalent to 6 × 10 seem to me to be those that sowed the seeds patch.’ monovalent ions in 1s. Chris Abrams, a of current understanding. But as well as former, gifted PhD student of mine, wrote in being influential, they are attractive in the way Use of the word ‘patch’ seems prescient his thesis (Abrams, 2000) comparing an ion the experiments are done and in the way they too. channel to the ticket barrier of a London are written. Sometimes I can remember first underground station. The barrier bears about reading the papers; often I have had the 2 Hodgkin AL & Keynes RD (1955). the same relation in size to the people going privilege of knowing the authors at least The potassium permeability of a to catch their train as a channel does to the slightly. giant nerve fibre. J Physiol 128, permeating ions. The barrier acts as a 61-88 selectivity filter, permitting only those in 1 Hodgkin AL & Huxley AF (1952). The jostling of passengers on the possession of a ticket to pass through. Their A quantitative description of underground is more annoying than luggage compares with the hydration shell of membrane current and its an ion and is temporarily given up during helpful. But repulsion between ions is application to conduction and passage through the barrier. The jostling that needed for fast permeation. This paper excitation in nerve. J Physiol 117, occurs during rush hour is similar to the is the first description of single filing of 500-544 electrostatic repulsion that helps ions ions through ‘active patches’ and permeate. One difference is that the barrier Alison Brading also started with this almost certainly the first to propose that opens and shuts each time a passenger goes paper (Brading, 2006). It is beautifully ‘K+ ions cross the membrane through through. A second is that if passage occurred written, of course, but it is a more narrow tubes or channels’ whose at the same rate as it does in channels, the difficult read now because the diameter was ‘little bigger than the entire population of Greater London could go convention used to ascribe a sign for hydrated potassium ion’. Here through a single barrier in little more than 1s. current and voltage is no longer used. unidirectional fluxes were measured in This is not an experimental paper, but metabolically poisoned axons, but a Now although the speed of transfer can seem is a mathematical description of astonishing it is actually comparable to the mechanical model (Fig. 1) was also currents recorded under voltage clamp turnover rates of the fastest enzymes, constructed to help illustrate what was catalase and carbonic anhydrase. And I often and shown in other members of the going on. In the axon, the ratio of wonder whether, if ionic transfer by channels series of papers that won the Nobel unidirectional fluxes is very different had been discovered by biochemists rather Prize for Physiology or Medicine in from what is expected from the than by those who are more attracted to the 1963. The description is so powerful independence principle, where the concepts of physics, they would simply have that it dominated thinking for a very movement of one ion is quite classed them as enzymes, catalysing the long time, and indeed still does. I am unaffected by the presence of other downhill movement of ions through the lipid sure I am not alone in using m, h, and n ions. The unidirectional flux from high

Physiology News | No. 66 | Spring 2007 | www.physoc.org MY 10 KEY PAPERS PN 7 to low concentration is much greater than is expected, compared with the unidirectional flux in the opposite direction. Further, the flux ratio changes much more steeply with voltage than expected from independence. If the pore contains n ions on average, the mathematical description is:

where jo/ji is the flux ratio, z is valency,

E is membrane potential, EK is the potassium equilibrium potential, and R, T, and F have their usual meanings. n turned out to be about 2.5.

3 Armstrong CM (1969). Inactivation of the potassium conductance and related phenomena caused by quaternary ammonium ion injected in squid axons. J Gen Physiol 54, 553-575 Figure 1. The mechanical model used by Hodgkin & Keynes to illustrate single filing of ions through a potassium channel. Small (3mm), coloured ball bearings were introduced into the two chambers as indicated, which were The quaternary ammonium ion then shaken using a motor. Model A comes close to mimicking the independence principle, with flux from left to tetraethylammonium, which is similar right 2.7 fold greater than from right to left (compared with the 2 fold difference expected). In Model B, a spacer is in size to a hydrated potassium ion, introduced so that the channel through which balls move contains several at any one time. Now the flux is 18 blocks potassium channels in squid times greater from left to right. Reproduced from Hodgkin & Keynes (1955). axon only from inside. This paper from Clay Armstrong shows blockage by gates close (Kamiya et al. 2006), just as methylamine does not. The dimensions TEA+ and other quaternary ammonium quaternary ammonium ions can be of the slot can be set at something like × ions to depend on channels being open. trapped by gates shutting. In this paper, 3 5Å. A later paper in the series Depolarisation produces potassium Armstrong also made the proposal for (Hille, 1973) looked at selectivity of currents that are initially normal in potassium conductance of muscle – that potassium channels, suggesting a pore + + appearance, but then inactivate as TEA+ ‘metabolism of one class of TEA -like of 3 – 3.5Å diameter envisaging K moves into the channel to block. The compounds’ by muscle was responsible ions giving up their hydration shell to inner, cytoplasmic end of the pore is, for the gating of what are now known permeate. So Hodgkin & Keynes + then, wider and less selective than the to be channels of the inward rectifier (above) were wrong only in thinking K outer part and access to this inner part (Kir) family and for the inactivation ions would retain their hydration shell. of the pore is controlled by a gate, under depolarisation of the voltage situated at its cytoplasmic end. The gated potassium channels. 5 Armstrong CM & Bezanilla F conclusion that ‘a channel is either (1973). Currents related to fully open or fully closed’ echoes the 4 Hille B (1971). The permeability movement of the gating particles of notion of Hodgkin & Huxley that the of the sodium channel to organic the sodium channels. Nature 242, unitary event is the formation of an cations in myelinated nerve. J Gen 459-461 active patch. In this paper also there is Physiol 58, 599-619 Hodgkin & Huxley had predicted a dissection of the channel into parts This paper is not Hille’s first paper on gating currents and the fact that they that confer selectivity and parts that selectivity, but is the first on selectivity could not measure them told them that gate between open and shut states. The of a voltage gated ion channel. The the unitary event must be the creation paper is the first of a brilliant series of selectivity filter of an ion channel is of an ‘active patch’ through which great influence on thinking, particularly here seen at its simplest as working many ions would pass. This paper was about how drugs act on ion channels. rather like the slot of a post (mail) box, one of the first to measure these For example, the hERG channel in permitting molecules of the right size to currents, which was also done at much heart binds drugs rather promiscuously, get through. But size alone is not the same time by Keynes & Rojas causing acquired long QT and enough and the permeating molecule (1974). At about the same time also, potentially causing death through interacts with the lining of the slot. In Chandler & Schneider (1973) were ventricular fibrillation. Drugs bind in particular, molecules can be larger if measuring charge movements the wide inner vestibule of the channel they can hydrogen bond to the pore. associated with the activation of and are potentially trapped there when Thus hydroxylamine permeates, but excitation-contraction coupling in

Physiology News | No. 66 | Spring 2007 | www.physoc.org 8 PN MY 10 KEY PAPERS skeletal muscle. The discovery of gating currents was aided by the ability to work on line to a computer, which could be used to subtract residual leakage currents digitally as well as the linear capacity currents (owing to charging of the lipid bilayer). This left the current associated with movement of the ‘gating particles’. In terms of its timing, this current precedes the ionic current it permits (Fig. 2). Gating current is not blocked by the sodium channel poison tetrodotoxin, consistent with the separation of selectivity filter and gating; has an appropriate dependence on voltage; and has appropriate amplitude, with about 300 charges moving in each µm2 of squid axon membrane, giving some 50 channels in this area. Later work established that the charge was immobilised with long depolarisations – i.e. the charge movement causing Figure 2. Gating current (above), measured in a squid axon at 3.5oC and in the absence of permeant cations . activation was itself inactivated by The holding potential was -70mV and the gating current is measured here at 0mV. Below is shown the sodium depolarisation. Thus activation and current from a squid axon in artificial sea water at the same temperature and voltage. (Reproduced from Armstrong & Bezanilla (1973) © 1973 Nature Publishing Group). inactivation of sodium current were not completely separate gating phenomena as Hodgkin & Huxley had proposed, great job of widening access to the The first 19 residues might be thought occurring independently in parallel with method, partly through their book on of as forming an inactivating ball, with each other. Instead there was a linkage Single-Channel Recording (1995) and the next 64 residues tethering it to the between the two. in many other ways. Getting your first channel. Deletions of or insertions into seal in the 1980s was actually quite the tethering sequence have the effect 6 Hamill OP, Marty A, Neher E, thrilling. of speeding or slowing inactivation. Sakmann B & Sigworth FJ (1981). Improved patch-clamp techniques 7 Hoshi T, Zagotta WN & Aldrich 8 Kubo Y, Baldwin TJ, Jan YN & for high-resolution current recording RW (1990). Biophysical and Jan LY (1993). Primary structure from cells and cell-free membrane molecular mechanisms of Shaker and functional expression of a mouse patches. Pflügers Archiv 391: 85-100 potassium channel inactivation. inward rectifier potassium channel. Science 250, 533-538 Nature 362, 107-108 This is a paper concerned with method, and some are a bit sniffy about This paper described what has now The choice of this among the many methodological papers. But patch come to be known as N-type inactiva­ wonderful papers that have come out of clamp revolutionised electrophysiology tion and is a most elegant experimental the Jan laboratory reflects my private and brought it into the mainstream of approach relating structure to function passion for Kir channels – channels that biological sciences. The 1970s saw in Shaker channels, which activate and set the resting potential of skeletal electrophysiology a bit in the doldrums, then rapidly inactivate under muscle and other cells and that are + at least in the UK, and the late Ebbe depolarisation. The findings only gated by both voltage and [K ]o. The Petersen once told me that someone partly fulfil Clay Armstrong’s paper describes the cloning of IRK1 or (who shall remain nameless) in a very prediction that a TEA+-like metabolite Kir2.1 from mouse macrophage. It was senior position in the administration of would move into the pore to prevent K+ the second paper to describe a UK science had told him that ion flux. Rather, a cytoplasmic domain potassium channel with a different ‘electrophysiology no longer (had) interacts with the open channel to cause structure to that of voltage gated anything to contribute to new blockage, though the principle is channels, but it confirmed the existence knowledge’. This statement was made remarkably similar to what Armstrong of a new family. As well as the in 1981 by someone who failed to had proposed (see above). As its name molecular biology, there is clear notice a renaissance under way. Neher – N-type inactivation – tells us, the N­ electrophysiological analysis of the & Sakmann and their collaborators, terminus is the domain involved. Its expressed channel protein, including people like David Colquhoun digestion with trypsin abolishes demonstration of its distribution in and Alan Hawkes who pioneered the inactivation as does truncation of the various tissues, and a correct prediction treatment of channel kinetics, also did a N-terminus or appropriate mutation. of the membrane topology. For better

Physiology News | No. 66 | Spring 2007 | www.physoc.org MY 10 KEY PAPERS PN 9 or worse, I used the information from this paper to move my laboratory into the use of molecular approaches to channel function.

9 Lopatin AN, Makhina EN & Nichols CG (1994). Potassium channel block by cytoplasmic polyamines as the mechanism of intrinsic rectification. Nature 372, 366-369 If Clay Armstrong was only partly right about how K+ channels might inactivate, he was pretty accurate in his prediction as to how Kir channels are gated. Excision of patches containing Kir channels resulted in loss of channel + gating by voltage and [K ]o, but moving the patch back close to the oocyte from which the patch had been torn restored gating. Soluble factors were therefore important and these turned out to be polyamines, including spermine. These blockers move into the channel under depolarisation but are repelled from their blocking site by extracellular K+ ions. We had established that an aspartate residue in the inner part of the pore was important to gating (Stanfield et al. 1994), and had thought it a Figure 3. The selectivity filter of a K+ channel as revealed by X-ray crystallography. The channel subunit voltage sensor. Instead the residue was immediately in front of the reader has been removed to show the lining of the filter. K+ ions were confirmed as important as part of the receptor for moving in single file through a series of binding sites formed by the backbone carbonyl oxygens (red) and the hydroxyl of a Thr side chain in the sequence (from intracellular) TVGYG. Extracellular is at the top. Three K+ ions spermine. are shown, though the two lower sites are unlikely to be filled simultaneously, owing to electrostatic repulsion. A water molecule occupied the space between the two uppermost K+ ions in the original description (Fig. 8 of Doyle 10 Doyle DA, Cabral JM, Pfuetzner et al. 1998). K+ permeates in part because of its neat fit. Na+ is too small and Cs+ too big. Rb+ can make it RA, Kuo A, Gublis JM, Cohen SL, however. Figure courtesy of Michael Sutcliffe, University of Manchester. Chait BT & MacKinnon R (1998). The structure of a potassium permeant ions. All this understates the choose music rather than science. So, channel: molecular basis of K+ achievement of crystallising and Mozart’s Marriage of Figaro – Act 2 if I conduction and selectivity. Science solving the structure of a membrane could have only part of it. 280, 69-77 protein. Additional references Finally, though it is still from the last MacKinnon was awarded the Nobel Abrams CJ (2000). PhD Thesis, University of Leicester. century, I choose the solution of the Prize for Chemistry in 2003 and Bezanilla F & Armstrong CM (1972). J Gen Physiol 60, 588-608. structure of a bacterial potassium Armstrong, Hille & MacKinnon the channel, KcsA. This confirmed early Lasker Prize for Basic Medical Brading AF (2006). Physiology News 63, 9-12. ideas about how potassium ion Research in 1999. Hille B (1973). J Gen Physiol 61, 669-686. channels select. The ‘narrow tube or channel’ through which ions move has Peter Stanfield Jentsch TJ (2006). J Physiol 10.1113/jphysiol.2006.124719. the kind of diameter Hille had Department of Biological Sciences, University of Kamiya K, Niwa R, Mitcheson JS & Sanguinetti MC (2006). Mol predicted, and is lined with carbonyl Warwick, Coventry, UK Pharmacol 69, 1709-1716. oxygens as Bezanilla & Armstrong Keynes RD & Rojas E (1974). J Physiol 239, 393-434. (1972) had also predicted in the 1970s. Coda The selectivity filter contains two or As Richard Naftalin pointed out in his Naftalin RJ (2005). Physiology News 61, 10-13. three K+ ions at any one time (Fig. 3). contribution (2005), this series seems to be Sakmann B & Neher E (1995). Single channel recording, 2nd edn. The structure was described as an The Physiological Society’s equivalent of Plenum Press. inverted tepee, and the apex of the Desert Island Discs. So perhaps, if forced, Schneider MF & Chandler WK (1973). Nature 242, 244-246. tepee is what is opened and shut to I have to make one choice. To take with me Stanfield PR, Davies NW, Shelton PA, Sutcliffe MJ, Khan IA, permit or prevent the movement of to a desert island, however, I would have to Brammar WJ & Conley EC (1994). J Physiol 478,1-6.

Physiology News | No. 66 | Spring 2007 | www.physoc.org 10 PN LIVING HISTORY

What can clinical medicine give back to physiology? human high blood pressure seemed to have been largely sorted out. John Dickinson gives a personal account My scientific career was interrupted by At school I was lucky to have had an a year at UCH as Resident Medical inspiring biology teacher who got me Officer, in administrative charge of interested in animal physiology. At medical and surgical admissions. This Oxford my tutors were David gave me an unrivalled experience of Whitteridge and Hugh Sinclair, both of acute medicine and surgery. Then whom were medically qualified. Both followed 2 years in the British Army as said that exposure to clinical medicine a medical officer and junior medical had helped them understand specialist. I had time to read widely and physiology. They also pointed out John Dickinson to think more about essential (wryly) that a medical degree was hypertension. This gave me my first useful for getting good preclinical jobs observations stimulated Ernest Starling physiological idea, which came by in medical schools. Both recommended to note that high blood pressure could thinking about human disease. The idea University College Hospital for clinical result from 'gross lesions of the arterial was ludicrously simple: perhaps the training. But before I left Oxford, trunks (which) might diminish the normality of cerebral blood flow in David invited me to spend a research average arterial pressure in the circle of essential hypertension simply meant year in his lab, working on vagal Willis or in the small arteries of the that the human brain had been afferents related to distension pressures brain. This condition is well known' successful in getting and keeping an in cats' atria. (Starling, 1925). But at around the adequate blood flow for itself – by same time Corneille Heymans raising systemic blood pressure – David encouraged me to make all my discovered the systemic arterial despite some obstruction to the brain's own equipment. This had to include a baroreceptors. These could detect and blood supply. Atheromatous deposits sensitive capacitor manometer, correct any fall of blood pressure. The are widespread in the larger arteries of associated circuitry, high gain Cushing response seemed not to be human adults. They usually narrow the amplifiers and recording equipment. needed to protect the brain's blood arterial lumen and must impede blood The experience hooked me into a supply. And in the late 1940s Seymour flow in some measure. Was it even physiological career. But later on I Kety devised a clever and non-invasive possible that essential hypertension became equally fascinated by clinical way of measuring cerebral blood flow could actually be the body's response to medicine, and found that I really in man. He reported that it was normal increased cerebrovascular resistance? enjoyed looking after patients. This in essential hypertension. leads me to my first example of the I wanted to test this idea, but I knew type of contribution that clinical Attention then turned towards the from the literature that it was fiendishly medicine can make to physiology. kidney. People with longstanding difficult to keep large cerebral arteries hypertension usually had small fibrosed in animals constricted or clamped, to 'Essential' hypertension kidneys. Harry Goldblatt had noted the see whether this would make blood When I became Max Rosenheim's widespread narrowing of the afferent pressure rise and reach the stable house physician at UCH I looked after glomerular arteries in people who had operating condition that I had many of Max's patients with high blood died with longstanding hypertension. envisaged might comprise essential pressure and wanted to find more about He simulated this by putting hypertension. Collaterals vessels always this strange condition. Most patients constricting clips on the main renal opened up in animals. Blood pressure were diagnosed as having 'essential' arteries of dogs. This produced soon went back again to normal levels. hypertension, i.e. high blood pressure sustained hypertension, which closely of unknown cause. resembled human essential But clinical medicine could provide a hypertension. The idea for this brilliant different approach. In hospital post­ I read all the hypertension literature I physiological experiment came from mortem rooms I had often seen people could get hold of. The most potentially clinical medicine. whose main cerebral arteries were relevant early animal work had been narrowed or occluded by atheroma. On done by Harvey Cushing, around 1900. Ischaemic kidneys were found to leaving the Army I was appointed a He was later to become the world's secrete the hormone renin, which acted medical registrar at the Middlesex most famous neurosurgeon, but in his on a circulating precursor to produce Hospital. I had access to the post­ early days he had done some angiotensin. This was later identified mortem room there and was lucky to physiological experiments. He observed and characterised by Stan Peart – a meet a friendly, interested and that when he compressed the brain of a clinician working in a department of cooperative pathologist (the late Drew dog, to make it ischaemic, the blood medicine. Angiotensin raised blood Thomson). His charm bewitched the pressure went up. This phenomenon has pressure spectacularly when infused post mortem room attendants, who been known ever since as the 'Cushing into a vein. By the time I qualified in helped us. They gave us time and response'. Twenty-five years later his medicine in 1952, the aetiology of facilities to study nearly 100 cadavers.

Physiology News | No. 66 | Spring 2007 | www.physoc.org LIVING HISTORY PN 11

A B Two examples of the two main cerebral arteries which we examined are shown in Fig.1. Each vertebral and internal carotid artery has been tied at its distal end and filled with a hot suspension of powdered barium sulphate in gelatine, held at an injection pressure of 140 mmHg until the gelatine had set. Both arteries illustrated on the right show many areas of gross atheromatous stenosis.

These observations did not, of course, prove that cerebral vascular disease caused human essential hypertension, but they were compatible with my idea. They provided a starting point for further research.

With a Rockefeller Travelling Fellowship, awarded by the MRC, I pursued the Cushing response in dogs, in Jim McCubbin's department in the Cleveland Clinic Research Division. Jim and I observed that the response was almost eliminated by general Figure 1. X-rays of the main brain arteries on one side of the neck removed from two human cadavers, showing anaesthetics, but that the brain stem of the routes of the two arteries in relation to the bones of the neck (vertebrae) and the base of the skull. The vertebral arteries take a twisting looping course from their origin at the top of the chest to their termination inside conscious or only lightly sedated dogs the skull (at the top of the x-rays). A, shows a normal vertebral and internal carotid artery in a 43 year old could increase sympathetic woman with a near normal blood pressure. B, is from a woman of 59 with severe hypertension and gross vasoconstrictor tone and blood pressure stenosis of both arteries by atheroma. The perfusion rates for each artery were measured, then a hot solution of when made ischaemic (Dickinson gelatin containing x-ray-opaque barium sulphate powder was pumped in and allowed to set while a pressure of 140 mmHg was maintained until the x-rays had been taken. Reproduced from Dickinson (2005). &McCubbin, 1963). Since then an exquisitely sensitive Cushing response All these former patients of the hospital Our results surpassed my wildest has been reported in unanaesthetised had ante-mortem blood pressures dreams. fetal sheep, in utero (Harris et al. recorded in the hospital notes – 1989). I have been kept awake with fortunately before hypotensive drugs In our crude measuring system, the excitement recently by hearing from had come along to confuse the picture. flow resistance of the neck arteries Julian Paton, in Bristol, of his work on Another friend (Jack Howell) kindly varied over a more than 10-fold range. single chemosensitive neurones in the read all the relevant hospital notes and When the flow rates of the two brainstems of decerebrate rats. He is independently recorded a value in each vertebral arteries were taken together engaged in a comprehensive study of case which he thought best represented their average effective resistance was the neural organisation of the what had been the average ante-mortem closely and directly related to each mammalian brainstem, with particular blood pressures of each of our subjects. individual's ante-mortem blood reference to chemosensitive structures After each cadaver's skull had been pressure. The relationships were less serving the autonomic nervous system. opened and the brain removed, we for the two internal carotid arteries, and dilated the four main cerebral arteries less still for the two femoral arteries in These adventures in clinical physiology in the neck with dilute ammonia (to the same cadavers, perfused by the led to many original papers and to my relax post mortem arterial spasm). Then same technique (Dickinson & two monographs on Neurogenic we cannulated the proximal ends of Thomson, 1960). The main renal hypertension, one published by each vertebral artery in the upper chest, arteries were too short to perfuse, but Blackwell in 1965 and the other by and the origins of the two internal we estimated their maximum diameter Chapman & Hall in 1991. Fellow carotid arteries in the neck. Using a with graduated round glass rods. There hypertensiologists remain mostly measuring jug held within the skull, was some (inverse) relation of renal sceptical, though none has so far and a stopwatch, we measured the artery diameter to ante-mortem blood disproved my idea – which is surely the maximum rate that water flowed along pressure, but nothing to suggest that best that any scientist can hope for. And the length of each artery from a high main renal artery stenosis was a there is increasing and widespread reservoir providing a constant perfusion frequent or important cause of human general interest in neurogenic theories pressure of 140 mmHg. hypertension. of human hypertension.

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The progressive pressor response to small amounts of angiotensin I have already said that angiotensin raised systemic arterial pressure when it was infused intravenously. After sensitive analytical methods had been developed for measuring renin and angiotensin concentrations in blood, a problem appeared. Although intravenous infusions of angiotensin into human subjects could raise the blood pressure, there was not nearly enough angiotensin circulating to account for the sustained hypertension of people with obvious 'renal' causes of hypertension, e.g. those with severe stenosis of a main renal artery.

Could a physiological approach solve the problem? Perhaps the same type of reasoning which I applied to increased cerebrovascular resistance causing human hypertension might help. Once Figure 2. Top, a 6 day record of the mean blood pressure of a rabbit made with a servo-manometer. During the 3 days indicted by the signal marker angiotensin II was infused intravenously at a high constant rate. The blood blood pressure had stabilised at an pressure went up rapidly by about 40 mmHg, remained steady for 3 days, then dropped immediately when the elevated level, further angiotensin infusion was stopped. Damped oscillations with a 4 h period continued as the blood pressure slowly returned to might not be needed to keep it there. its control level over the ensuing 2 days. Above, a 4-5 day record made in the same way, but showing the Control systems might have been reset. contrasted and different effect of infusing a low concentration of angiotension at a rate which had no immediate effect on blood pressure. The average blood pressure slowly climbed up by about 35 mmHg over 3 days, but Jim McCubbin and John Green had dropped sharply when the infusion was turned off. Reproduced from Dickinson (2005). observed that the carotid artery baroreceptors of dogs with chronic renal hypertension had reset themselves We continuously infused very low scientist', and to have been able to to operate at and sustain the higher concentrations of angiotensin into describe, study and, occasionally, blood pressure level (McCubbin et al. rabbits, and saw blood pressure rise account for some 40 more clinical and 1956). So I devised a piece of steadily over some 3 days to a level as fascinating Medical mysteries, always machinery which continuously high as that which was immediately from a physiological standpoint measured the arterial blood pressure of reached by the acute infusion of (Dickinson, 2005). a rabbit and controlled the rate of angiotensin at concentrations twenty or administration of synthetic angiotensin. more times higher (Dickinson & References Lawrence, 1963). Fig. 2 compares the Dickinson CJ (2005). Medical mysteries: the testament of a clinical My servo manometer controlled three scientist. Lewes, Book Guild. different intravenous infusion rates of blood pressure responses to 3 days intravenous infusion of synthetic Dickinson CJ, McCubbin JW (1963). Pressor effect of increased angiotensin, in inverse proportion to the cerebrospinal fluid pressure and vertebral artery occlusion with and current level of my rabbit's blood angiotensin II into a rabbit at constant without anesthesia. Circ Res 12, 190-202. rates of 0.13 and 0.006 µg.kg-1.min-1. pressure. Dickinson CJ, Thomson AD (1960). A post mortem study of the main Our observations seemed to explain in cerebral arteries with special reference to their possible role in blood The results were immensely exciting. a convincing way how angiotensin pressure regulation. Clin Sci 19, 513-538. Jim Lawrence and I first raised a could cause human renal hypertension Harris AP, Koehler RC, Gleason CA, Jones MD Jr & Traystman RJ rabbit's blood pressure 30-40 mmHg by despite there being only minute (1989). Cerebral and peripheral circulatory responses to intracranial hypertension in fetal sheep. Circ Res 64, 991-1000. infusing angiotensin at a moderately amounts of the hormone in the blood. high rate. Then we switched on the McCubbin JW, Green JH & Page IH (1956). Baroreceptor function in chronic renal hypertension. Circ Res 4, 205-210. servo system. Although blood pressure Conclusion remained at the high level we had set I have been delighted by the striking Starling EH (1925). Physiological factors in hyperpiesia. Br Med J ii, the control system to maintain, the success of the original hypothesis, and 1163-1165. infusion rate of angiotensin steadily the other which I have described. declined over the next 3 days until it Whether they eventually prove to be In a future issue, John Dickinson was only about 5% or less of the rate right or wrong, they have brought continues this account with another initially needed to sustain hypertension. clinical observations and physiology clinical/physiological example: This result stimulated us to perform the together in mutually satisfying ways. I Fainting: a ‘most intriguing mystery in obvious and much simpler experiment. am proud to have been a 'clinical cardiovascular physiology’.

Physiology News | No. 66 | Spring 2007 | www.physoc.org A WEEK IN THE LIFE OF ... PN 13

Frivolous days in the life of physiologists having fun Christof Schwiening and Andy Newport discover the true significance of low TRH

During the first few minutes of 2006, in a moment of recollectable merriment, I agreed to accompany an old friend (Andy Newport, who did a PhD at Bristol with the late Don Lewis) on a road trip. Unfortunately, the following morning, before I could wriggle out of it, my wife had scornfully dismissed the idea at the breakfast table. In the cold light of day I had considered the permanent postponement of the trip the best option, but there is hardly a more Zigzagging up through the Alps without any doors – potent stimulus than scorn to harden loud, but extremely good fun. one’s resolve.

The road trip was ostensibly a last farewell for a fellow physiologist’s investment – a bright yellow sports car purchased in more affluent times – before it was transmuted from base metal to gold and placed in the pockets of builders. By February plans for a trip around the Mediterranean or to the Having flown over one of these ridges I slammed on Artic circle had been replaced by a mad the brakes – now we had two more to negotiate. The oil sump sticks out under the car (just behind the dash to the Black Sea and back – Above: Repairs. Earlier that day on the motorway I number plate) about 4 inches from the road surface – maybe even into Asia via Istanbul. had tried to clean the windscreen using the wash-wipe one knock could finish the trip. Whilst I had driven to Warsaw in 1991 system. All I managed to do was squirt Andy in the face with hot water as the tubing below the dashboad I was unfamiliar with much of Eastern blew apart. It was now my job to get in there and fix Europe – beyond Prague. the leak. Below: Nice legs, but just a bit too small for our Part I Thus, we began to make plans – practicals! insurance, breakdown cover, accommodation, currencies, maps etc. It is not easy to insure a sports car for much of Eastern Europe – indeed Serbia, Bosnia and the Ukraine, amongst others, proved to be We had overtaken these carts about 15 min before, impossible. Then in May we realized – now we were stuck working out how to get over an area of poor road. in a rare moment of lucidity – that I had never driven a sports car – could I do it? My 16 year old Volvo can be safely driven with the right foot flat to the floor for minutes on end. However, Andy’s Caterham was a different matter – something I found out much later. The 1.8 L Rover engine is light, freely revving and prone to stalling – the driving position could be best described as low and laidback. Andy brought his car to Cambridge from near Bristol and A pressure wash in Turkey after going through mud­ covered roads in Bulgaria. At this point the car was I had a go. My first challenge was to clean, and the garage mechanic was eager to do an reach the pedals: slouching as engine/oil check. With the police watching and taking instructed, I could hardly see over the pictures, we felt sure he would do a good job! I was a ridiculously long bonnet. It was raining bit worried about taking this picture of the police, and Apparently you can squeeze a couple more litres of just after it they stiffened up. that day, so my progress was slow – I fuel into your tank if you jack up one side of your car.

Physiology News | No. 66 | Spring 2007 | www.physoc.org 14 PN A WEEK IN THE LIFE OF ... may actually have reached 40 mph at monastery. It was, without doubt an one point. But my performance was just adventure – my diary for half the trip good enough to allow our plans to covers over a dozen pages: pot-holes continue. the size of coffee tables, on-coming lorries on the wrong side of the road, We had decided that we would also try metal-rimmed horse-drawn carts, main and raise money for a lightweight new roads with the surface of farm tracks, leg for Nikki Britton, who had lost one solitary tower blocks in the middle of of hers in a car accident. The story was the countryside, ludicrous local taxes at particularly tragic since the accident borders, the smell of chips from diesel occurred as her brother was attempting Andy’s Serbian brother! He had just given Andy a nice engines, the ravages of communism, to rescue her after she slid off the road kiss – I don’t think Andy was expecting that! They glaciers and men with rough chins in icy conditions. Thus, we began exchanged telephone numbers despite having no breathing the word ‘money’ just too collecting sponsorship. language in common ... close.

At 4.30 a.m. on 30 June we were off. I am glad I went. The bug-eyed Initially I took the role as navigator and Caterham, with a testicular ride height soon began to regret my earlier (TRH) of only a few inches, was the enthusiastic start to the day – two cups perfect car for a trip down to Istanbul – of strong coffee – as I sat both reliable and silly enough to cause uncomfortably contemplating the likely nearly everyone to smile. trajectory for orally ejected fluids in an open topped car. We took the tunnel We got back in one piece having had across to France, and sped through the most amazing set of experiences in Belgium and Germany putting rapid succession. My lasting memories considerable distance between us and Above: At the top (~2.5 km high) of the are of laughing faces, toothless grins, Andy’s credit cards (that’s another Grossglockner Hochalpenstrasse we found a small, the vast differences between people and steep road with a no entry sign. After a quick story!) … reconnoitre we headed straight up it in first gear. In places only a few hundred miles apart the background you can see the glacier making its and the willingness of strangers to help In Germany I took over the driving. way slowly down the mountain. if asked. Much to my surprise, I found that the Below: A Romanian campsite. Perfect – quiet with soft ground, but we had to cook by torchlight. car wouldn’t go much faster than 120 In the end we raised a total of £2,300 mph before the rev limiter cut in. for Nikki’s leg – many thanks to all of However, it accelerated faster than you who contributed. anything else on the road – if there was sufficient grip! The lack of decent Christof Schwiening aerodynamics caused the fuel Department of Physiology, Neuroscience and consumption to increase dramatically Development, University of Cambridge, Cambridge, UK when cruising at speed – and the noise was horrendous. The wind constantly threatened to rip anything held above See outside back cover for more waist height out of the car. Fortunately, images of Christof’s epic road trip there was little to hand to lose, other than the GPS, since the cockpit was incredibly cramped and the seat harness held us firmly in place. Whilst the lack of space in the cockpit was inconvenient, the small fuel tank was a blessing, making frequent stops a necessity. It was impossible to eat or drink whilst driving.

We took 5 days to get down to Istanbul (France, Belgium, Germany, Czech Republic, Slovakia, Hungary, Romania, Bulgaria, Turkey), and then 5 more to Trans-European fuel costs plotted in sequence from UK to Turkey and back to the UK. Fuel was very cheap in get back (Turkey, Bulgaria, Romania, both Romania and Bulgaria, but not in Turkey. From the horizontal spacing between the data points you can see that after the fourth refuelling we stopped more frequently (141±34 miles, putting in 18.3±5.0 L, n=33) – largely Hungary, Austria, Switzerland, France). because we were almost stuck on the motorway with an empty tank. The fuel tank was about half the size of that We camped most nights, except for one found in a normal small car (29 L) and the fuel gauge was hopelessly inaccurate. In total we bought 134 gallons stay in a hotel, and another in a of petrol costing just over £500.

Physiology News | No. 66 | Spring 2007 | www.physoc.org FROM THE ARCHIVES PN 15

Afferent impulses in the vagus and their effect on respiration John Widdicombe launches our occasional series of highlights from The Journal of Physiology online archive with a critical look at E D Adrian’s classic 1933 paper

E D Adrian’s 1933 paper is rightly regarded as Coleridge & Coleridge (1964), list over 40 Adrian to study the literature more closely, and a classic. It is over 50 years since I first read it references published before 1933 which are to relate already published results to his own and I have frequently quoted it and regarded it directly relevant to Adrian’s paper. Of course I new findings. I assume that Adrian’s as magnificent (correct) and almost beyond am not suggesting that he should have written reviewers were not influenced by the fact that criticism (wrong). He was the first to do a review article, but only that he should not he had received a Nobel Prize (shared with afferent single-fibre recording from the vagus have omitted papers basic to his thesis. He Sherrington) the previous year, and that he nerve and thus inspired a plethora of similar does say ‘a brief discussion cannot hope to do was on the Editorial Board of The Journal of studies, still continuing today. He was one of justice to earlier work’, and then goes on with Physiology! the first to use the cathode-ray oscillograph, 11 pages of discussion! Amazingly he does soon to be replaced by the oscilloscope. The not refer to Breuer’s paper in 1868, the This paper was one of a series in which technical difficulties must have been foundation of our understanding of the Hering- Adrian studied afferent pathways in many formidable. Breuer inflation reflex and the basis of mainly somatic nerves. He published many Adrian’s study; nor does he mention the reflex papers on this topic in the years 1929–1934 Adrian established the afferent pathway for as so-named. He completely misses the point alone but subsequently no more on vagal the Hering-Breuer inflation reflex that of two important papers he cites. Head (1899) reflexes. The papers were a turning point in originates in pulmonary stretch receptors and established that the ‘deflation reflex’ had an neurophysiology and contributed to a great controls the pattern of breathing, and afferent pathway different from that of the career which made him one of the most described its characteristics. Until his paper inflation reflex of Breuer; collapse of the lungs distinguished physiologists of the last century. there was still some dispute as to the nature caused a stronger inspiratory reaction than and significance of this reflex. After his paper cutting the vagi, and therefore the His neglect of the literature was shared by there was little argument. His illustrations phenomenon could not have been due solely another great British neurophysiologist, show, for the first time, beautiful single-fibre to removal of the inhibitory pathway for the Charles Sherrington; in the Integrative action nerve impulses from vagal afferents (Fig. 1). inflation reflex. Breuer had suspected this but of the nervous system (1906) he devotes only The only previous records of vagal activity not proved it. But Adrian, who described six lines to the Hering-Breuer inflation reflex, were multifibre; some looked like wind-swept ‘deflation fibres’, does not relate them to the although it was one of the best-established sand dunes and others like seismographs of a ‘deflation reflex’, which he does not mention; examples of negative feedback, and only Richter Scale 1 earthquake. After his paper its afferent pathway was only analysed many three lines to Head’s paradoxical reflex, an every reviewer of respiratory neurophysiology years later. He cites Keller and Loeser (1929) established and rare example of positive quotes him first in their alphabetical reference but misses the point that they recorded from feedback. list (if I am quoted it is usually last, a just vagal fibres from ‘deflation receptors’ and If Adrian could not maintain an interest in position based on our relative distinctions). concluded that they mediated cough, the most vagal reflexes he was in good company. powerful of all the pulmonary vagal reflexes; Breuer, Head and Kratchmer (upper airway The paper displays a precious jewel, both Adrian does not mention cough. However, reflexes) (1870) each published essentially a valuable for its insight into lung reflexes and Adrian was loyal to his university (Cambridge) single paper on the subject, which laid the beautiful for the elegance of Adrian’s expertise and its printing house (CUP); 12 of the 16 foundation of airway and lung reflexes, and and experimental techniques. But the gem is papers he cites were in J Physiol. each then went on to achieve great distinction mounted in a rather unworthy setting. Adrian in other fields. A wonderful quartet! lists 16 references, of which only five are Let me be emphatic; this is a very important relevant to vagal respiratory reflexes. The paper that stimulated much research and led John Widdicombe others are concerned with his interest in non­ to better understanding of respiratory reflexes. University of London, London, UK vagal somatic reflexes. Later reviews, e.g. But a critical reviewer might have asked References Adrian ED (1933). Afferent impulses in the vagus and their effect on respiration. J Physiol 79, 332-358.

Breuer J (1868). Die Selbststeuerung der Athmung durch den Nervus Vagus. Sber Akad Wiss Wien 58, 909-937.

Coleridge HM & Coleridge JCC (1986). Reflexes evoked from the tracheobronchial tree and lungs. In Handbook of Physiology, Section 3, The Respiratory System, Vol II, ed. Cherniack NS & Widdicombe JG, pp 395-429. Bethesda, American Physiological Society.

Head H (1889). On the regulation of respiration. Part I. Experimental. J Physiol 10, 1-70.

Keller CJ & Loeser A (1929). Der zentripetale Lungenvagus. Z Biol 89, 373-395.

Kratschmer F (1870). Uber reflexe von der nasenschleimhaut auf athmung und kreislauf. Sber Akad Wiss Wein 62, 147-170.

Figure 1. Record from single fibre of vagus (decerebrate cat) showing discharges at different lung inflations by Sherrington CS (1906). The integrative action of the nervous system, pump. A 65 ml, B 115 ml, C 230 ml. Upper trace moves upwards on inflation. From Adrian (1933). pp 11-411. Charles Scribner & Sons, New York.

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Reactive oxygen species and glucose transport during exercise

Glucose transport is an essential metabolic event that is characteristic of all eukaryotic cells. With respect to skeletal muscle, contraction is the most potent physiologic stimulus for glucose transport, resulting in up to a 50-fold increase during maximal exercise in humans (Katz et al. 1986). Whereas the full sequence of reactions underlying the activation of glucose transport during exercise has not been elucidated, there is good evidence that the activation of AMP-activated protein kinase (AMPK) plays an integral role in this process (Hardie & Sakamoto 2006).

Reactive oxygen species (ROS) consist Figure 1. NAC inhibits contraction-mediated glucose uptake in mouse EDL muscle Values are means±SEM for 6-8 muscles. Unfilled bars, control; filled bars, NAC (20 mM). *P<0.05 vs control. of the superoxide anion and several of its derivatives, including hydrogen hypothesis was recently made, stimulated to perform repeated peroxide (H2O2). Skeletal muscle following the observation that addition contractions and analyzed for glucose produces ROS at a low rate in the basal of exogenous H2O2 to isolated muscle uptake. Repeated contractions increased state and markedly higher rates during preparations at rest resulted in the glucose uptake almost 3-fold, as exercise (Murrant & Reid, 2001). activation of glucose transport and measured with the glucose analogue: Considering the evidence that AMPK (Toyoda et al. 2004). 2-deoxyglucose (2-DG) (Fig. 1). If the exogenous ROS stimulate glucose muscles were exposed to a general transport in skeletal muscle and that Now, we have tested this hypothesis antioxidant, N-acetylcysteine (NAC), contraction stimulates ROS production, (Sandström et al. 2006). Fast-twitch, the contraction-mediated glucose it would seem intuitive that endogenous extensor digitorum longus (EDL) uptake was diminished by about 50%. ROS production would play an muscles were isolated from mice and This indicated that endogenous ROS important role in contraction-mediated incubated in a physiological salt production played a significant role in glucose transport. Indeed this solution. The muscles were then contraction-mediated glucose uptake. To assess whether the NAC effect was specific for contraction, additional modes of glucose uptake activation were investigated. However, NAC did not affect insulin or hypoxia-mediated glucose uptake (Sandström et al. 2006). This suggested that the ROS involvement in glucose uptake was specific for exercise and not other physiologic stimuli.

To establish that the NAC effect was associated with ROS metabolism, additional experiments were performed. We found that both intracellular ROS accumulation and alterations in glutathione status (reflects increases in Figure 2. Scheme for ROS-mediated glucose transport during muscle contraction Following the release of Ca2+ ROS production) were blocked by from the sarcoplasmic reticulum, actomyosin interaction occurs resulting in muscle contraction, ATP breakdown NAC (Sandström et al. 2006). Thus and ADP and P increases. ADP and P stimulate mitochondrial respiration, which can also be stimulated by i i NAC was functioning as an anti­ increases in Ca2+ that activate mitochondrial dehydrogenases. Increased respiration results in superoxide anion -. -. oxidant. (O2 ) formation through NADH dehydrogenase and semiquinone components; O2 formation can also occur by 2+ -. extramitochondrial mechanisms (eg., via a Ca -mediated activation of phospholipase A2). O2 is then dismutated by superoxide dismutase to H2O2, which results in increased LKB1-mediated phosphorylation and activation of To confirm the species of ROS AMPK, followed by a translocation of Glut-4 to the surface membrane and an increased glucose transport. involved in contraction-mediated

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one can imagine a situation where excessive amounts of ROS are produced during heavy exercise resulting in premature fatigue (i.e. a decrease in cell function). In this situation anti-oxidants would be expected to delay fatigue and hence have a positive effect on cell function, as has been demonstrated elsewhere (Medved et al. 2004). However, in a situation where one relies heavily on glucose transport (eg, prolonged, submaximal exercise) and during which physiological amounts of ROS are produced, anti-oxidants could have deleterious effects.

So what can one conclude from the data? The conclusion is that, depending Figure 3. Scheme for biphasic relationship between cell function and ROS levels on the conditions, antioxidants can have Blue bulge on left denotes resting state. Relationship is based on a model regarding muscle function and cellular either positive or negative effects on et al. redox balance (Andrade 1998). muscle performance. glucose uptake, we performed two available in the literature, we proposed Marie E Sandström additional experiments. In one, we used the sequence of events depicted in Shi-Jin Zhang another anti-oxidant, ebselen, which Fig. 2 to explain how ROS stimulate Joseph Bruton functions as a glutathione peroxidase glucose transport during exercise. José P Silva1 mimetic that removes H O in the 2 2 2 presence of reduced glutathione (GSH). To study the mechanism whereby ROS Michael B Reid Ebselen also inhibited contraction­ mediate their effect on glucose Håkan Westerblad mediated glucose uptake and to an transport, we measured the Abram Katz extent similar to that seen with NAC activity/phosphorylation state of Department of Physiology and Pharmacology, (Sandström et al. 2006). This suggested AMPK. We found that NAC also Karolinska Institutet, Stockholm, Sweden 1 that the ROS species involved in inhibited the contraction-mediated Laboratory of Metabolic Diseases, The Rockefeller contraction-mediated glucose transport increase in activity and phosphorylation University, New York, NY, USA 2 was H O . (represents activation) of AMPK by Department of Physiology, University of Kentucky 2 2 Medical Center, Lexington, KY, USA about 50% (Sandström et al. 2006). We also studied muscles from mice that Thus the ROS effect appeared to References over-expressed manganese-dependent involve activation of AMPK. Andrade FH, Reid MB, Allen DG & Westerblad H (1998). Effect of superoxide dismutase, which is the hydrogen peroxide and dithiothreitol on contractile function of single mitochondrial isoform of the enzyme Generally, ROS are associated with skeletal muscle fibres from the mouse. J Physiol 509, 565-575. that converts the superoxide anion to negative effects on body function, Hardie DG & Sakamoto K (2006). AMPK: a key sensor of fuel and H2O2. Assuming that the production of including muscle fatigue (Medved et al. energy status in skeletal muscle. Physiology 21, 48-60. superoxide anion is not altered 2004). However, recent studies have Katz A, Broberg S, Sahlin K & Wahren J (1986). Leg glucose uptake compared with the wild type condition, also implicated ROS as essential during maximal dynamic exercise in humans. Am J Physiol 251, this would result in an increased signaling molecules for normal E65-E70. production of H2O2 and hence an physiological processes. The apparent Medved I, Brown MJ, Bjorksten AR, Murphy KT, Petersen AC, Sostaric S, Gong X & McKenna MJ (2004). N-acetylcysteine increase in contraction-mediated paradox may be resolved by enhances muscle cysteine and glutathione availability and attenuates glucose transport. Indeed, muscles from considering that excessive levels of, or fatigue during prolonged exercise in endurance-trained individuals. J mice over-expressing the enzyme prolonged exposure to ROS exert Appl Physiol 97, 1477-1485. exhibited a glucose uptake rate deleterious effects on cell function and Murrant CL & Reid MB (2001). Detection of reactive oxygen and following contraction that was about viability, whereas low/physiological reactive nitrogen species in skeletal muscle. Microsc Res Tech 55, 236-248. 25% higher than in wild type muscles levels appear to be requisite for proper (Sandström et al. 2006). Taken cell signaling and function. To this, one Sandström ME, Zhang SJ, Silva JP, Reid MB, Westerblad H, & Katz A. Role of reactive oxygen species in contraction-mediated glucose together, these results indicated that can add the possibility that different transport in skeletal muscle. J Physiol 575, 251-262. 2006. either H2O2, or one of its derivatives, species of ROS affect various Toyoda T, Hayashi T, Miyamoto L, Yonemitsu S, Nakano M, Tanaka was the ROS species involved in the metabolic/structural targets to varying S, Ebihara K, Masuzaki H, Hosoda K, Inoue G, Otaka A, Sato K, activation of glucose transport during degrees depending on the conditions Fushiki T & Nakao K (2004). Possible involvement of the alpha1 isoform of 5'AMP-activated protein kinase in oxidative stress­ contraction. Based on our recent studied. A scheme to depict this view is stimulated glucose transport in skeletal muscle. Am J Physiol results, as well as other information given in Fig. 3. To illustrate the point Endocrinol Metab 287, E166-E173.

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The amazing versatility of hPEPT1 hPEPT1 is the port of entry into enterocytes of all possible di- and tri-peptides resulting from the digestion of dietary proteins. Since the mid-1990s, it has been exploited as a tool to enhance the oral availability of an ever-increasing number of drugs and prodrugs –both peptidic and non-peptidic. Recently, Monica Sala-Rabanal and colleagues uncovered the molecular mechanism by which peptides and drugs alike make their way into the human enterocytes

The human proton-coupled presence of a low affinity, high capacity oligopeptide cotransporter hPEPT1 transport system for di- and tripeptides, (gene SLC15A1) is expressed in the but that would not take longer peptides brush border membrane of the or single amino acids (see Adibi, 1997). enterocytes, the S1 segment of the renal During the 1980s, extensive work in proximal tubules and the hepatic bile intestinal brush border membrane ducts. In addition to being responsible vesicle (BBMV) preparations and the for the uptake of all natural di- and tri­ human colon cancer cell line CaCo-2 peptides, this all-purpose transporter confirmed the existence and basic has been implicated in the absorption of kinetics of the system, and unveiled key everyday drugs, such as β-lactam features of the mechanisms involved in antibiotics. Here, I will highlight the Monica Sala-Rabanal short-chain peptide absorption. In milestones of oligopeptide transport particular, evidence collected by research and review the key molecular, predominant view was that dietary Leibach and coworkers on rabbit functional and pharmacological aspects protein was absorbed primarily in the BBMV demonstrated that transport of of hPEPT1. form of free amino acids. This was di- and tripeptides is electrogenic and challenged when it was observed that coupled to an inwardly-directed proton The search patients suffering from genetically gradient (see Ganapathy & Leibach, The first evidence that intact peptides impaired amino acid transport, as 1985). A major breakthrough came with are transported across the intestinal occurs in cystinuria and Hartnup the expression cloning of the first epithelium was obtained in the late disease, did not develop protein mammalian gene that encoded peptide 1950s (Newey & Smyth, 1959). Until malnutrition. In vivo absorption studies transport activity, the rabbit PEPT1 (Fei the early 1970s, however, the in human volunteers suggested the et al. 1994); cloning and functional characterization of the human isoform followed (Liang et al. 1995; Mackenzie et al. 1996b; Sala-Rabanal et al. 2006).

Mechanisms of hPEPT1 function Fig.1 illustrates the standard model of intestinal peptide absorption. After a meal, proteins are hydrolyzed by pancreatic proteases, and subsequently broken into short-chain peptides by peptidases located in the apical membrane of enterocytes. Di- and tripeptides are then carried into the cytoplasm by hPEPT1, against a concentration gradient and together with protons. Peptides are then released unmodified to the blood –through an unidentified basolateral transporter– or hydrolyzed by the action of endogenous peptidases into amino acids, which then Figure 1. Model of intestinal peptide absorption. Dietary proteins are hydrolyzed by pancreatic proteases, and subsequently broken into short-chain peptides by peptidases in the apical membrane of enterocytes. Di- and leave the cell via specific transporters. tripeptides are transported into the cytoplasm by PEPT1, against a concentration gradient and with protons. The overall electrochemical balance is Peptides are then released through an unidentified basolateral transporter or hydrolyzed by endogenous maintained by the apical Na+/H+ peptidases into amino acids, which then exit via specific transporters. The overall electrochemical balance is exchanger NHE-3 and the basolateral maintained by the apical Na+/H+ exchanger NHE-3 and the basolateral Na+/K+-ATPase (Daniel, 2004). (Reprinted, + + with permission, from the Annual Review of Physiology 66 ©2004 by Annual Reviews, www.annualreviews.org). Na /K -ATPase (Daniel, 2004).

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To address the molecular mechanism of apical H+/oligopeptide cotransport, we expressed the cloned hPEPT1 in Xenopus laevis oocytes and performed comprehensive voltage-clamp electrophysiological assays. We found that transport by hPEPT1 is electrogenic, H+–coupled, and voltage dependent (Mackenzie et al. 1996b; Sala-Rabanal et al. 2006). hPEPT1 is capable of transporting neutral and charged substrates; in all cases, transport is associated with the generation of inward cationic currents, regardless of the net charge of the substrate (Mackenzie et al. 1996a). Figure 2. Schematic representation of the kinetic model for H+/dipeptide cotransport by hPEPT1. The + In addition, hPEPT1 responds to step model assumes that the empty carrier is negatively charged. In a transport cycle, one H binds to the outside­ oriented empty transporter (state C ) to form the proton-carrier complex (C ). Then the substrate binds, and the jumps in membrane potential with 1 2 substrate-loaded protein (C3) undergoes a conformational change (C4) that results in cotransport. On the + transient presteady-state currents or cytoplasmic side, the substrate dissociates (C5), and the H is released (C6). The partial reactions C1 ↔ C2 and charge movements (Mackenzie et al. C6 ↔ C1 are voltage-dependent, and are responsible for the electrogenicity of the transporter (adapted from 1996a; Sala-Rabanal et al. 2006), that Sala-Rabanal et al. 2006). have been postulated to be due to changes in the conformation of the β carrier protein as it goes through the Surprising substrate substrates. The list includes -lactam transport cycle (Loo et al. 1993). selectivity: peptide bond not antibiotics (penicillins and a must! cephalosporins), inhibitors of the By simultaneous analysis of the Over the last decade, the substrate angiotensin-converting enzyme kinetics of steady-state dipeptide­ specificity of hPEPT1 has been subject (captopril, enalapril), antineoplastics induced inward proton currents –to to intense scrutiny, driven by the and prodrugs (valacyclovir). monitor substrate transport– and of prospect of using the transporter as a presteady-state currents –to monitor the way to enhance oral bioavailability of Drug absorption and structure-affinity protein conformations during the drugs and prodrugs. Recently, studies have been largely based on competition assays (Daniel, 2004; H+/dipeptide cotransport–, we comprehensive three-dimensional Biegel et al. 2005), mainly because established a kinetic model for hPEPT1 quantitative structure-activity these compounds are not commercially function (Sala-Rabanal et al. 2006). relationship (3D-QSAR) studies have led to the identification of the minimum available in radiolabelled form. The ordered model, summarized in structural requisites for hPEPT1 Competition assays, however, do not Figure 2, assumes that cotransport substrates, among which, remarkably, a allow discrimination between substrates happens through a series of peptide bond is not included. Thus, the and inhibitors –that is, whether a given conformational changes induced by the essential features for recognition drug is transported or simply comprise a simple three-point model: recognized and bound to the carrier. binding of ligands (H+ and substrate) the presence of hydrogen-bond donor Using our electrophysiological and membrane potential. In a transport and acceptor sites and an electrodense approach, we demonstrated that β­ cycle, one H+ binds to the outside­ region at given positions within the lactams ampicillin, amoxicillin, oriented empty transporter (state C ) to 1 molecule are sufficient to grant access cephalexin and cefadroxil, and the form the proton-carrier complex (C2). to the peptide transporter binding site antineoplastics bestatin and δ­ Then the substrate binds, and the (Biegel et al. 2005). aminolevulinic acid are indeed substrate-loaded protein (C3) undergoes transported by hPEPT1, by the same a conformational change (C4) that One direct implication of such alternating-access mechanism as results in H+/dipeptide cotransport. On unrestrictive steric requirements is that dipeptides (Fig. 2). These drugs are the cytoplasmic side, the substrate virtually all possible natural di- and transported with lower affinity and dissociates (C5), and then the proton is tripeptides composed by L-α-amino turnover rate than dipeptides. Our released (C6). A rate-limiting step of the acids may be transported by hPEPT1 – findings implicate that drug absorption transport cycle is the reorientation of an impressive 8,400 different by hPEPT1 may be compromised by the empty carrier within the membrane substrates. In addition, a large number the presence of physiological

(C6 → C1). Variations in dipeptide and of pharmacologically active concentrations of dietary peptides in the drug transport by hPEPT1 are due to compounds, both peptidomimetic and gut. Thus, oral delivery drugs should be differences in affinity and in turnover non-peptidic, satisfy the minimums and taken on an empty stomach (Sala- rate. have been tested as putative hPEPT1 Rabanal et al. 2006).

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Future directions Where is my arm? Despite the unquestionable progress that has been made, there are still gaps The subject of proprioception is concerned with the body’s in our knowledge about hPEPT1­ ability to sense its own actions. One aspect that Uwe mediated drug absorption. Given the Proske, below, has been studying recently is the pharmacological importance of kinaesthetic sense, the sense of position and movement of hPEPT1, solving the crystal structure would validate and complement the our limbs computational studies and provide a movements about the joint. There are gigantic leap towards the rational two pieces of evidence in support of the design of oral delivery drugs and view that muscle spindles provide prodrugs. information about limb position. The first were the ground-breaking Acknowledgements observations of Goodwin et al. (1972) The author wishes to thank Bruce who described illusions of movement Hirayama, Donald Loo and Ernest and changed position of the elbow Wright for their advice in the writing during vibration of elbow muscles. At of this manuscript. that time it was already known that The present-day view for muscles muscle spindles were exquisitely Monica Sala-Rabanal acting about the elbow joint is that an sensitive to vibration (Brown et al. Department of Physiology, David Geffen School of important source of positional 1967). The second observation Medicine at UCLA Los Angeles, CA, USA information comes from the muscle supporting a role for muscle spindles as spindles of elbow flexors and extensors. kinaesthetic sensors uses the muscle We believe that muscle spindles signal property called thixotropy. This is the References muscle length. During rotation of the change in passive tension of skeletal Adibi SA (1997). The oligopeptide transporter (Pept-1) in human intestine: biology and function. Gastroenterology 113, 332-340. joint, as a muscle is stretched, spindle muscle following conditioning discharge increases in direct proportion contractions and length changes. Since Biegel A, Gebauer S, Hartrodt B, Brandsch M, Neubert K & Thondorf to the size of the length change. In the intrafusal fibres of muscle spindles, I (2005). Three-dimensional quantitative structure-activity relationship analyses of beta-lactam antibiotics and tripeptides as substrates of other words, signals of muscle length on which the spindle sensory endings the mammalian H+/peptide cotransporter PEPT1. J Med Chem 48, change are interpreted by the brain as lie, also exhibit thixotropy, it means 4410-4419.

Daniel H (2004). Molecular and integrative physiology of intestinal peptide transport. Annu Rev Physiol 66, 361-384.

Fei YJ, Kanai Y, Nussberger S, Ganapathy V, Leibach FH, Romero MF, Singh SK, Boron WF & Hediger MA (1994). Expression cloning of a mammalian proton-coupled oligopeptide transporter. Nature 368, 563-566.

Ganapathy V & Leibach FH (1985). Is intestinal peptide transport energized by a proton gradient? Am J Physiol Gastrointest Liver Physiol 249, G153-G160.

Liang R, Fei YJ, Prasad PD, Ramamoorthy S, Han H, Yang-Feng TL, Hediger MA, Ganapathy V & Leibach FH (1995). Human intestinal H+/peptide cotransporter. Cloning, functional expression, and chromosomal localization. J Biol Chem 270, 6456-6463.

Loo DDF, Hazama A, Supplisson S, Turk E & Wright EM (1993). Relaxation kinetics of the Na+/glucose cotransporter. Proc Natl Acad Sci USA 90, 5767-5771.

Mackenzie B, Fei YJ, Ganapathy V & Leibach FH (1996a). The human intestinal H+/oligopeptide cotransporter hPEPT1 transports differently-charged dipeptides with identical electrogenic properties. Biochim Biophys Acta 1284, 125-128.

Mackenzie B, Loo DDF, Fei Y, Liu WJ, Ganapathy V, Leibach FH & Wright EM (1996b). Mechanisms of the human intestinal H+-coupled oligopeptide transporter hPEPT1. J Biol Chem 271, 5430-5437. Figure 1. The technique of muscle conditioning. The two diagrams at the top show a human forearm with one flexor and one extensor muscle drawn in. On the left, the arm is held flexed (dashed lines) and the flexors are Newey H & Smyth DH (1959). The intestinal absorption of some dipeptides. J Physiol 145, 48-56. contracted (conditioning flexed). Once the arm has relaxed it is moved to an intermediate angle (test). This leaves biceps and its spindles in a ‘taut’ state. When the arm is held extended (dashed lines) and elbow extensors are Sala-Rabanal M, Loo DDF, Hirayama BA, Turk E & Wright EM contracted (conditioning extended), moving the arm to the intermediate angle (test) leads to development of ‘slack’ (2006). Molecular interactions between dipeptides, drugs and the in biceps and its spindles. The lower diagram shows an instantaneous frequency display of the responses of a human intestinal H+ -oligopeptide cotransporter hPEPT1. J Physiol soleus spindle in the cat following conditioning of the muscle leaving the spindle taut (red) or slack (blue). 574, 149-166. Redrawn, in part, from Wood et al. (1996).

Physiology News | No. 66 | Spring 2007 | www.physoc.org FEATURES PN 21 that by conditioning the muscle it is possible to alter spindle responsiveness without changing the length of the muscle. That, in turn, means subjects make conditioning-dependent errors in a forearm matching task (Gregory et al. 1988).

To explain how we use muscle conditioning to explore position sense I have drawn a simple diagram (Fig. 1). Contracting elbow flexors with the arm held flexed leads the intrafusal fibres in elbow flexor spindles to lie ‘taut’, generating strain on sensory endings and producing high levels of resting discharge in the spindles. When the relaxed arm is placed at an intermediate test angle, activity levels in flexors will continue to be high, in extensors they will be low. The subject interprets the high discharge levels as a muscle that is more stretched than it really is. It leads subjects to make matching errors in the direction of arm extension.

If now the contraction is repeated but with the arm held extended, during the subsequent movement to the test angle, flexor muscles and their spindles fall slack, leading to a low resting discharge (Fig. 1). By contrast, extensor spindle activity will be high. It means that after extension conditioning subjects perceive their forearms to be more Figure 2. Position sense in the horizontal plane. Panel A shows data when subjects were required to support a load at the test angle. In panel B, following muscle conditioning the subject moved the loaded arm to the test flexed than they really are. By using the angle. Traces in red, means (± SEM) for nine3 subjects following flexion conditioning (FC), traces in blue, values two forms of conditioning, total errors after extension conditioning (EC). in position sense of 20º can be Position errors have been calculated as the angular difference between reference and indicator arms. Positive achieved, representing about a quarter errors, placement of the indicator arm in the direction of extension relative to the reference, negative errors placement in the direction of flexion. Dashed line, zero error. Values are shown for the unloaded reference arm, of the full range of elbow movements when it was supporting 10% MVC (maximum voluntary contraction) and when it was supporting 25% MVC. available to the subject under the Asterisks indicate significant differences (p < 0.05) between errors from the two forms of conditioning. Redrawn conditions of our experiment. So the from Ansems et al. (2006). effects of conditioning are considerable.

The usefulness of the conditioning support them against gravity, or when intrafusal contraction? It is really that method is that is provides evidence for they are bearing a load? The important question which fascinates me. a role for muscle spindles in position consideration here is that whenever we sense that is quite different from the carry out a voluntary contraction to Rather than go through the various effects of muscle vibration. It is support our limbs the intrafusal fibres hypotheses that have been put forward unlikely that other potential of muscle spindles are contracted as in an attempt to solve this problem, I contributors to position sense, joint well. This is called co-activation would like to describe some recent receptors and skin stretch receptors, (Vallbo, 1971). It means that as soon as observations from our laboratory will show muscle conditioning­ limb muscles become active, the relevant to the topic (Ansems et al. dependent effects. spindle signal fed back to the brain 2006). from those muscles increases The question that has consumed me in dramatically. Now we face a new We chose to carry out the recent times is how does position sense problem. How is the brain able to measurements of position sense about work when limb muscles are distinguish between spindle impulses the elbow joint in the horizontal plane. contracting? For the forearms, how do generated as a result of muscle length The reason for doing this was that we we know where our arms are when we changes from impulses generated from did not want our observations to be

Physiology News | No. 66 | Spring 2007 | www.physoc.org 22 PN FEATURES complicated by the effects of gravity. During load bearing, the fusimotor To conclude, we have made a number The arm was supported by a cradle that activity would be expected to produce a of observations on position sense at the rotated about a pivot point coaxial with large increase in spindle discharges, yet forearm during contraction of elbow the elbow joint. Movement of the position errors remained unchanged. muscles. While the picture remains relaxed arm was almost effortless. Nor was there any evidence of subjects fragmentary, we have provided new Position of one arm, set by the becoming more erratic in their directions for future experiments. We experimenter, was matched by the matching ability. Standard errors of the no longer believe that the sense of other, moved by the subject. In mean remained about the same (red effort accompanying support of a load addition, by means of a series of trace, Fig. 2A). So whatever theory is provides positional information in any pulleys arm muscles could be made to used to explain position sense during simple way (Walsh et al. 2004). support a load, or to move it. load bearing, it must take such a result into account. Our current working hypothesis is that The first thing we found was that when when we move a loaded arm the brain elbow muscles began to contract to There is one more clue to add to the listens to the feedback during support a load, the conditioning effects puzzle. When a passive muscle is placement of the arm and compares it disappeared. They don’t disappear vibrated, as mentioned earlier, it leads with feedback levels generated in the immediately at contraction threshold, to illusions of limb movement and past from similar movements. This but become progressively smaller as the changed position. We measured the information is used in deciding where contraction grows until, typically with a position error from vibration of the to place the other arm in a position strength of a quarter of maximum for passive muscle and compared it with matching task. elbow flexors, they are no longer errors during vibration of a contracting significant. For a group of subjects, muscle. Interestingly the position errors Uwe Proske Department of Physiology, Monash University, Clayton, position errors of 4.5º from muscle from vibration were gone at 25% MVC Victoria, Australia conditioning in the relaxed muscle (Ansems et al. 2006). We believe that reduced to 0.8º at 25% MVC fusimotor-activated spindles are still References (maximum voluntary contraction, Fig. vibration sensitive (Brown et al. 1967) Ansems GE, Allen T & Proske U (2006). Position sense at the 2A). but they do not seem to generate any human forearm in the horizontal plane during loading and vibration of illusions. Is it possible that fusimotor­ elbow muscles. J Physiol 576, 445-455. We explain this result by proposing that activated spindles no longer have Brown MC, Engberg I & Matthews PB (1967). The relative sensitivity where muscles and their spindles were access to consciousness? to vibration of muscle receptors of the cat. J Physiol 192, 773-800. slackened by conditioning Goodwin GM, McCloskey DI & Matthews PB (1972). The contribution (conditioning extended for elbow Finally, we tried a slightly different of muscle afferents to kinaesthesia shown by vibration induced illusions of movement and by the effects of paralysing joint afferents. flexors in Fig. 1), the fusimotor activity approach. Following muscle Brain 95, 705-748. accompanying a contraction leads to conditioning, the subject was required Gregory JE, Morgan DL & Proske U (1988). Aftereffects in the removal of the slack and to to move a load from the conditioning responses of cat muscle spindles and errors of limb position sense in sensitisation of spindles. Therefore position to the test angle. This time the man. J Neurophysiol 59, 1220-1230. during a contraction the errors from difference in conditioning effects did Vallbo AB (1971). Muscle spindle response at the onset of isometric flexion and extension conditioning not disappear on loading the arm (Fig. voluntary contractions in man. Time difference between fusimotor and skeletomotor effects. J Physiol 218, 405-431. converge towards the flexion 2B). It was as though moving a load conditioned state, where spindles are introduced an additional signal that Walsh LD, Hesse, CW, Morgan DL & Proske U (2004). Human forearm position sense after fatigue of elbow flexor muscles. J sensitised. produced errors which added to the Physiol 558, 705-715. errors from conditioning, particularly Wood SA, Gregory JE & Proske U (1996). The influence of muscle So the distribution of position errors at when the conditioning had sensitised spindle discharge on the human H reflex and the monosynaptic the forearm during loading supports the spindles (red trace, Fig. 2B). reflex in the cat. J Physiol 497, 279-290. ideas that during a voluntary contraction the fusimotor and The Babraham Institute Established with initial funding of €1.8M over skeletomotor systems are co-activated. co-ordinates new European 4 years, ‘ProteomeBinders’ is co-ordinated by What, perhaps, is a little unexpected is infrastructure in proteomics Dr Mike Taussig, Head of Babraham’s that co-activation is distributed over Technology Research Group and brings The Babraham Institute, Cambridge is the co­ about a quarter of the muscle’s working together 26 European partners from 12 ordinating partner for a new European range. countries, and two from the USA. research infrastructure, ‘ProteomeBinders’, which aims to understand how the human As one of the largest genome-scale projects None of this helps us, of course, in genome functions by studying its proteins. in Europe, this resource will impact on understanding how position sense healthcare, diagnostics, target discovery for The project, funded through the European works during load bearing. What we drug intervention and therapeutics and will Commission’s 6th Framework Programme, considered to be a clue was that when consequently deliver advantages to the sets the stage for an open-access resource of flexor spindles were in their sensitised research, medical and biotechnology binding molecules directed against the entire state (conditioned flexed, Fig. 1), communities. loading flexor muscles did not human proteome, the full set of over 100,000 proteins specified by the human genome. www.proteomebinders.org introduce additional position errors.

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Thought to action: development of temporal signals from topographic maps

where light falls on the retina (a spatial system is transformed into the time code). In contrast, single motor neurons varying spike train of the motor that drive the muscles of the eyes neurons that is necessary to drive the encode the amplitude of muscle eye muscles. This article summarizes contraction via the number of spikes in recent data suggesting how the change their burst and the speed of contraction from spatial to temporal coding occurs. by the rate at which spikes are emitted (a temporal code). To perform the task The superficial layers of the superior of repositioning the eye with a high colliculus (SC) located in the dorsal portion of the midbrain receive direct David Waitzman (left) and Jason Cromer degree of accuracy, the central nervous system must provide a rapid and retinal and visual cortical input and Maintaining the stability of the eye accurate mechanism via which activity contain a topographic map of the during vision and shifting the eye related to a sensory perception is contralateral field of vision comparable rapidly to view different locations are translated into appropriate movements. to that in the visual cortex (see Wurtz two of the major tasks of the In neuronal terms, this question can be & Goldberg, 1989 for review). Below oculomotor system. Different rephrased into understanding how the the superficial layers, neurons in the populations of neurons in the visual activity of topographically arranged, intermediate and deep layers of the SC pathways become active depending on spatially encoded neurons of the visual are activated just before the occurrence of rapid eye movements that shift the fovea a specific amplitude and direction relative to its previous position. In analogy to the sensory receptive field of the visual system, the array of eye movements which activate a SC neuron describes a ‘movement field’ (Fig. 1A).This structural arrangement of a pure sensory region above and a ‘movement associated layer’ below sparked considerable interest and suggested an opportunity to explore the transformation of visual information into motor activity, a so-called spatial to temporal transformation or STT (Fig. 1C) (Sparks & Mays, 1990).

However, despite an exhaustive evaluation of the SC activity, the underlying nature of this transformation remains elusive. Indeed, most investigators agree that the discharge of neurons in the intermediate and deep layers of the SC encode the intended target of a saccade, but do not encode the metrics of the movement (i.e., neither the number of spikes nor the rate of discharge is related to movement amplitude or velocity) (Bergeron et al.

Figure 1. Schematic showing the elements of a sensory to motor transformation. A A series of superior colliculus (SC) cells positioned from rostral to caudal along the horizontal meridian of the SC have closed movement fields with response areas (grey color indicates the size of the movement field) for progressively larger amplitude saccades (cells 1, 2, and 3, see panel C). Small horizontal saccades would activate cell 1, medium amplitude saccades would activate cell 2, and large horizontal saccades would activate cell 3. Note that the discharge of each cell is the same regardless of amplitude (spike discharges shown below the eye velocity traces) and only occurs if the intended movement is into its movement field. B Single neurons in the cMRF and PPRF have activity that increases in duration with saccade amplitude and whose peak frequency increases with saccade velocity (compare the discharge of the single cell in this panel to the three cells associated with the same amplitude saccades in panel A). Both of these features are not evident in the discharge of neurons in the intermediate and deep layers of the superior colliculus (A). Thus, temporally coded neurons have movement fields which have no limit with respect to amplitude and encode the metrics of saccades in the timing and number of spikes in their bursts. C The SC is topographically arranged. The activity of a particular locus of SC neurons defines the intended amplitude of the saccade that will be generated. The rostral pole is to the right and the dashed line indicates the horizontal meridian. Neurons located further from the rostral pole have movement fields associated with larger movements. For example, the colored loci correspond to the location of cells (1-3) in panel A. From this population of closed movement field cells, the temporal activity of the downstream cMRF and PPRF neurons must be generated by a spatial to temporal transformation.

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2003). Thus, one of the major questions in oculomotor control has been to understand how temporal signals like those of the neuron shown in Fig. 1B that encode the dynamics of saccadic eye movements are developed.

Location of temporally coded neurons Temporal signals encoding eye movement dynamics are the end result of the STT. Over the last three decades a number of laboratories have searched for evidence of such signals in the structures targeted by neurons of the intermediate and deep layers of the SC (see Moschovakis et al. 1996 and Scudder et al. 2002 for reviews). Areas of particular interest are positioned downstream of the SC and include portions of the mesencephalic and Figure 2. Schema for the sensorimotor transformation between the spatially coded superior colliculus and the pontine reticular formations (MRF and temporally coded PPRF. The direct pathway uses anatomic weighting to generate an estimate of the ideal PPRF) and the nucleus reticularis saccade trajectory. Indirect pathways refine the metrics of the movement. One potential indirect pathway is shown tegmenti pontis (NRTP), the primary (SC � cMRF � Omnipause � PPRF), whereby recursive, excitatory loops between the SC and the cMRF and gateway to the cerebellum for the between the cMRF and the omnipause neurons can modulate the anatomic weight provided by the colliculus to the PPRF. Abbreviations: SC, superior colliculus; OPNs, omnipause neurons located in the raphe interpositus; oculomotor system. These structures cMRF, central mesencephalic reticular formation; PPRF, paramedian portion of the pontine reticular formation. provide either direct or indirect access Dashed arrows indicate inhibitory connections while solid lines depict excitatory connections. to abducens motor neurons. with the SC and the omnipause neurons as to how a topographically defined The paramedian portion of the pontine The majority of cMRF neurons provide locus of activity in the superior reticular formation (PPRF) forms part a burst of spikes that are most closely colliculus that occurs approximately 40 of the direct pathway. The PPRF associated with contralateral saccades. ms in advance of saccades is molded receives anatomically weighted, Recent recordings from cMRF neurons into a burst of impulses related to contralateral projections from the SC have demonstrated that the number of saccade amplitude, duration, and (Grantyn et al. 2002) and the axons of spikes and frequency of discharge in instantaneous velocity that can activate its burst neurons impinge directly upon the saccade associated bursts are extraocular motor neurons 20 to 25 ms abducens motoneurons (Fig. 1C, Fig. correlated with saccade amplitude and later? 2). The number of spikes in each burst instantaneous velocity similar to the of a PPRF neuron is monotonically bursts in PPRF neurons (Fig. 1B) While neurons in the SC do not related to the amplitude of each saccade (Cromer & Waitzman, 2006). Indeed, typically display relationships to while the discharge frequency of the many of the neurons had a saccade metrics, their discharge PPRF burst neurons is directly related monotonically increasing relationship duration may reflect changes that occur to the instantaneous velocity of the between spike number and saccade in downstream structures (Goossens & saccade (Fig. 1B) . The duration of the amplitude and burst duration was Van Opstal, 2000; Soetedjo et al. PPRF burst is tightly regulated by a closely correlated with saccade 2002b). However, the close relationship group of inhibitory neurons located duration. While the correlations for between the discharge of cMRF and along the midline of the pons in the cMRF burst neurons are generally PPRF neurons to instantaneous eye raphe interpositus (Buttner-Ennever et weaker than those in the PPRF, velocity requires a physiological al. 1988). Since these neurons have a nevertheless, these temporal signals mechanism that can utilize the locus of tonic level of activity and pause for could influence motor neurons via SC activity, which is poorly associated saccades in all directions, they have direct projections from the cMRF to the with the metrics of the saccade, to been dubbed ‘omnipause neurons’ abducens nucleus (Ugolini et al. 2006) generate the highly correlated time (OPNs) (Fig. 2). or via an indirect path mediated via varying signals related to eye amplitude reciprocal connections with the and velocity (Fig. 1C). While the The central Mesencephalic Reticular omnipause neurons (Fig. 2). density of projections between the SC Formation (cMRF), located just lateral and the PPRF likely contributes to the to the oculomotor nuclei and ventral to The spatial to temporal generation of these temporal signals the superior colliculus (Horn, 2005), transformation (Fig. 2), it cannot be the only receives ipsilateral afferents from the Despite the identification of temporally mechanism via which these tightly SC and it forms reciprocal connections encoded neurons, the question remains controlled signals are created.

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A number of physiologic models have and monitoring the time varying signals Horn AK (2005). The reticular formation. Prog Brain Res 151, 127­ been postulated to explain how the STT for saccades downstream from the SC. 155. occurs. One suggestion is that a series Moreover, this approach would permit Keller EL & Edelman JA (1994). Use of interrupted saccade paradigm to study spatial and temporal dynamics of saccadic burst of SC neurons projecting onto neurons topographically organized cortical cells in superior colliculus in monkey. J Neurophysiol 72, 2754-2770. in the PPRF are sequentially activated regions such as the frontal eye fields Moschovakis AK, Scudder CA & Highstein SM (1996). The at a particular rate to develop not only access to the same eye movement microscopic anatomy and physiology of the mammalian saccadic the correct spike number, but the time generator utilized by the superior system. Prog Neurobiol 50, 133-254. variation associated with velocity found colliculus. Munoz DP & Wurtz RH (1995). Saccade-related activity in monkey in these target neurons (Munoz & superior colliculus. II. Spread of activity during saccades. J Neurophysiol 73, 2334-2348. Wurtz, 1995). However, physiological David M Waitzman1,2 evidence for such a spread of activity 1,2 Ohtsuka K & Noda H (1991). Saccadic burst neurons in the Jason A Cromer oculomotor region of the fastigial nucleus of macaque monkeys. J across the primate SC has not been Department of Neurology1 and Program in Neurophysiol 65, 1422-1434. found (Keller & Edelman, 1994; Neuroscience,2 Quaia C, Lefevre P & Optican LM (1999). Model of the control of Soetedjo et al. 2002a). An alternative University of Connecticut Health Center, Farmington, saccades by superior colliculus and cerebellum. J Neurophysiol 82, idea suggests that the SC provides an CT, USA 999-1018. idealistic drive and that the exact Robinson FR & Fuchs AF (2001). The role of the cerebellum in metrics of the pontine burst are shaped References voluntary eye movements. Annu Rev Neurosci 24, 981-1004. Bergeron A, Matsuo S & Guitton D (2003). Superior colliculus by cerebellar outflow that also encodes distance to target, not saccade amplitude, in multi-step Scudder CA, Kaneko CS & Fuchs AF (2002). The brainstem burst impinges on the PPRF neurons (Quaia gaze shifts. Nat Neurosci 6, 404-413. generator for saccadic eye movements: a modern synthesis. Exp Brain Res 142, 439-462. et al. 1999). This model shifts the idea Buttner-Ennever JA, Cohen B, Pause M & Fries W (1988). Raphe of spreading activity away from the SC nucleus of the pons containing omnipause neurons of the oculomotor Soetedjo R, Kaneko CR & Fuchs AF (2002a). Evidence against a system in the monkey, and its homologue in man. J Comp Neurol moving hill in the superior colliculus during saccadic eye movements to the cerebellar vermis, for which 267, 307-321. in the monkey. J Neurophysiol 87, 2778-2789. again there is little physiological evidence (Robinson & Fuchs, 2001). Cromer JA & Waitzman DM (2006). Neurones associated with Soetedjo R, Kaneko CR & Fuchs AF (2002b). Evidence that the saccade metrics in the monkey central mesencephalic reticular superior colliculus participates in the feedback control of saccadic formation. J Physiol 570, 507-523. eye movements. J Neurophysiol 87, 679-695. A different approach has posited that a recursive excitation loop between the Fuchs AF, Robinson FR & Straube A (1993). Role of the caudal Sparks DL & Mays LE (1990). Signal transformations required for the fastigial nucleus in saccade generation. I. Neuronal discharge generation of saccadic eye movements. Annu Rev Neurosci 13, 309­ cMRF and the SC could prolong the pattern. J Neurophysiol 70, 1723-1740. 336. collicular outflow (Cromer & Goossens HH & Van Opstal AJ (2000). Blink-perturbed saccades in Ugolini G, Klam F, Doldan Dans M, Dubayle D, Brandi AM, Buttner- Waitzman, 2006). In this schema monkey. II. Superior colliculus activity. J Neurophysiol 83, 3430­ Ennever J & Graf W (2006). Horizontal eye movement networks in activation of a collicular locus would 3452. primates as revealed by retrograde transneuronal transfer of rabies virus: Differences in monosynaptic input to "slow" and "fast" trigger excitation in this recursive Grantyn A, Brandi AM, Dubayle D, Graf W, Ugolini G, Hadjidimitrakis abducens motoneurons. J Comp Neurol 498, 762-785. pathway and possibly a similar loop K & Moschovakis A (2002). Density gradients of trans-synaptically labeled collicular neurons after injections of rabies virus in the lateral Wurtz RH & Goldberg ME (1989). The Neurobiology of saccadic eye between the cMRF and the omnipause rectus muscle of the rhesus monkey. J Comp Neurol 451, 346-361. movements. Elsevier, New York, NY. neurons (Fig. 2). These recursive loops could generate a persistent burst whose Pearls from Society minutes model which gave the impression that the number of spikes and duration W D M Paton, who was Meetings Secretary speakers were in the deadly embrace of a corresponded with the desired saccade gigantic surrealist spider.’ amplitude as long as a second signal in the early 1950s, produced minutes that captured the humour which permeated appeared to appropriately shut down The advent of PowerPoint has undermined Meetings in those relaxed days before the loop thereby ending the saccade. The Society rule that no Communication Teaching Quality Assessments, Research should be read. Until relatively recently, The origin of this ‘shut-down’ signal is Assessment Exercises and other reading was severely condemned since it unclear, but could arise via a second bureaucratic horrors. The Mill Hill Meeting in makes for boring presentations and goes indirect pathway that utilizes 1954 included discussion of the suggestion counter to the training in communication projections from the SC to the NRTP from R C Garry and J S Gillespie that the The Society seeks to provide. which projects in turn to the fastigial term ‘orthosympathetic’ be adopted as the oculomotor region of the the cerebellar twin for ‘parasympathetic’. B Katz made an The degree of disapproval engendered in vermis whose cells are activated with alternative suggestion: ‘sympathetic’ and one audience was recorded in the minutes saccade end (Ohtsuka & Noda, 1991; ‘unsympathetic’. of a Meeting in the 1950s. Reporting on a Fuchs et al. 1993; Quaia et al. 1999). In the same minutes Paton mentioned the Communication about LSD, the Secretary While the exact mechanism for the STT latest aids to audibility. He reported that said that the drug ‘in an oral dose of a few remains an area of active research, ‘Each speaker, when he reached the dias, micrograms induces in about 20 minutes generation of the burst in PPRF was invested with electronic regalia, which certain mescalin effects such as distortion of neurons that is tightly coupled to amplified all the noises (intended and the bodily image and loss of interest in the saccade dynamics probably occurs via unintended) emanating from him and surrounding (sic). The latter of these actions modulation of the direct tecto-pontine allowed the control engineer to produce was also produced even more rapidly in projection (Fig. 2, direct pathway) by some interesting effects.’ On another Members of The Society by the five or six indirect pathways. This idea is occasion a Secretary recorded that ‘Last authors who read their papers. attractive since it keeps most of the year’s Mayor’s chair-type of microphone was Culled by Ann Silver from Bynum WF (1976). A short history of machinery necessary for developing this year replaced by a more fearsome The Physiological Society 1926-1976. J Physiol 263.

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Store-operated calcium entry in adult skeletal muscle fibres: the missing clue

through the plasma membrane is not pathology. Interestingly, the unitary relevant to this process (see Melzer et activity of the corresponding ion al. 1995). Actually even the most well channel appeared well resolvable with known Ca2+ entry pathway in skeletal the cell-attached patch-clamp technique muscle (through the voltage-dependent and actually was very similar to a slow Ca2+ channels) has no clear single channel activity previously established function. Still, and although shown to be particularly high in the store-operated Ca2+ entry concept is dystrophin-deficient cells by several Bruno Allard (left) and Vincent Jacquemond mostly popular in non-excitable cells, groups (see Gillis, 1999). This is the possibility was there too, that SR important because in many other Changes in cytoplasmic Ca2+ Ca2+ depletion would trigger a specific instances, store-operated calcium entry was proven easier to reveal with concentration are of ubiquitous Ca2+ influx through the plasma fluorescent methods than with importance to the function of living membrane of skeletal muscle fibres. membrane current measurements. At cells. A rise in cytoplasmic [Ca2+] can This was supported by a series of that point we thought that a further in­ 2+ experimental data by Kurebayashi & occur from either Ca entry through depth characterization of the store 2+ Ogawa (2001), showing in particular the plasma membrane or Ca release dependent Ca2+ influx in control and that the rate of Mn2+ entry into muscle from an intracellular store, mainly the dystrophin-deficient muscle fibres fibres (measured by a fluorescence endoplasmic reticulum. One obvious could bring precious information into quenching approach) was increased difference between the two mechanisms the field. More specifically, we were when the SR was severely depleted. is that the store has a finite content and very interested in the possibility of This study was an encouraging piece of will, to some extent, get depleted upon directly measuring the store-dependent 2+ work, prompting further analysis of the substantial activation of a Ca release membrane current under acute physiological properties of store­ process. In the past 20 years conditions of SR Ca2+ depletion, in an operated Ca2+ entry in muscle. The considerable evidence has been intact muscle fibre under voltage­ interest of this quest further gained in accumulated supporting the existence clamp. This latter condition is of 2+ intensity when it was suggested that of a specific plasma membrane Ca critical importance as membrane dysfunction of store-operated channels entry pathway meant to refill emptied polarization is a non-avoidable 2+ belonging to the TRPC (transient (or partially emptied) Ca stores. parameter if one wishes to study the receptor potential canonical) family Although there is sparse indication that, physiological properties of either trans­ was responsible for an abnormal, in certain cell systems, a direct pathway plasma membrane or trans-SR potentially detrimental, influx of Ca2+ between the extracellular medium and membrane Ca2+ fluxes in muscle cells, in dystrophin-deficient muscle the lumen of the store could do the job, and thus a fortiori when studying a (Vandebrouck et al. 2002). One could the most widely accepted view is that possible relationships between the two, then put a name to an ion channel the way is through the cytoplasm. Then, as is the case for an SR-operated Ca2+ 2+ protein with an identified gating store depletion-induced Ca entry entry mechanism. Since voltage-clamp generates a cytoplasmic [Ca2+] mechanism in relation to the dystrophic elevation, the role of which goes in fact well beyond replenishment of the store as it appears to be strongly relevant for various cell signalling processes. The study of ‘store operated calcium entry’ has become an extensive field of research, covered recently by a number of comprehensive reviews (see, for instance, Parekh & Putney, 2005).

The adult skeletal muscle fibre is a robust archetype of a cell relying on an intracellular Ca2+ store for its function: Ca2+ release from the sarcoplasmic reticulum (SR) is activated by Figure 1. Simple scheme illustrating the possibility of a store-operated Ca2+ entry in skeletal muscle. Under 2+ membrane depolarization and generates physiological conditions, membrane depolarization triggers sarcoplasmic reticulum (SR) Ca release through an interaction between the dihydropyridine receptors (DHPr) in the plasma/transverse-tubule membrane and the 2+ the cytoplasmic [Ca ] elevation that ryanodine receptor (RyR) in the junctional SR membrane; the resulting rise in cytoplasmic [Ca2+] triggers triggers contraction, whereas Ca2+ entry contraction. Consecutive Ca2+ depletion in the SR would turn on a Ca2+ influx through the plasma membrane.

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depolarization, the role of which is unknown. This makes the physiological relevance of this putative store-operated Ca2+ entry very much questionable. There are several other detailed aspects of the problem as well that may be discussed but overall it seems that in the absence of new related experimental data the controversy will stand.

Acknowledgements The preparation of this manuscript and the related work done in our laboratory were supported by grants from Université Lyon 1, Centre National de la Recherche Scientifique and Association Française contre les Myopathies. Figure 2. Illustrative examples of the different signals that were collected simultaneously from the same muscle fibre when looking for the store-operated Ca2+ current. The plasma membrane ion channel activity was followed at Bruno Allard the unitary level with the cell-attached patch-clamp technique (single channel current) and at the macroscopic Vincent Jacquemond level (whole-cell current) with the silicone voltage-clamp technique. Records were taken while the fibre was depolarized by a 2 s-long depolarization from -80 to +20 mV. The change in intracellular Ca2+ concentration was Physiologie Intégrative, Cellulaire et Moléculaire, followed from the fluorescence of fluo-3. The cell-attached pipette contained Tyrode and the external solution Université Lyon 1, CNRS, Villeurbanne, France. contained only calcium as permeant cation. The cell-attached patch-clamp record shows the activity of channels carrying inward current at -80 mV before the pulse and of the delayed rectifier K+ channels during the pulse. The References whole-cell current trace shows the slow inward calcium current that activates and inactivates during the depolarization. Allard B, Couchoux H, Pouvreau S & Jacquemond V (2006). Sarcoplasmic reticulum Ca2+ release and depletion fail to affect sarcolemmal ion channel activity in mouse skeletal muscle. J Physiol 575, 69-81. had so far not been used in previous operated Ca2+ influx (Allard et al. 2+ Gillis JM (1999). Understanding dystrophinopathies: an inventory of studies of store-operated Ca entry in 2006). the structural and functional consequences of the absence of muscle fibres, we thought this may be a dystrophin in muscles of the mdx mouse. J Muscle Res Cell Motil 20, key to a wide, unexplored aspect of the Now why is that? How could it be that 605-625. 2+ problem. We worked things out trying the Ca influx would not show up Kurebayashi N & Ogawa Y (2001). Depletion of Ca2+ in the under these conditions, when SR Ca2+ sarcoplasmic reticulum stimulates Ca2+ entry into mouse skeletal to gather the best possible sets of muscle fibres. J Physiol 533, 185-199. experimental conditions so that we depletion was assessed and membrane 2+ 2+ current measured at both the Melzer W, Herrmann-Frank A Lüttgau HC (1995). The role of Ca would not miss the store-operated Ca ions in excitation-contraction coupling of skeletal muscle fibres. current. This included, on the same macroscopic and unitary levels? Why Biochim Biophys Acta 1241, 59-116. could not we detect any sign of an muscle fibre, a combination of either Parekh AB & Putney JW (2005). Store-operated calcium channels. two or three techniques: whole-cell inward current? One could speculate Physiol Rev 85, 757-810. voltage-clamp (allowing control of SR that, for obscure reasons, SR content­ 2+ Vandebrouck C, Martin D, Colson-Van Schoor M, Debaix H & Gailly Ca2+ release and measurement of the dependent Ca entry did not operate P (2002). Involvement of TRPC in the abnormal calcium influx under this specific set of conditions. observed in dystrophic (mdx) mouse skeletal muscle fibers. J Cell total membrane current), cell-attached Biol 158, 1089-1096. patch-clamp (for tracking the above­ Conversely we tend to believe that mentioned store-dependent-suspected assessing the existence of a store­ unitary channel activity) and detection depletion induced Ca2+ influx in a Come and join us of the fluorescence of a calcium dye muscle fibre out of voltage control is Would you like to join the injected within the cytoplasm of the quite hazardous. Another possibility Physiology News editorial team and fibre. Well, despite our efforts, all this would be to consider that the influx is get involved in The Society’s highly failed! We tested a vast array of too small to be detected as a current regarded Members’ magazine? If so, experimental protocols and conditions with electrical methods whereas it please contact Editor Austin Elliott at aimed at depleting the SR such as would be detectable with fluorescent [email protected] repetitive large membrane quenching techniques. Still, then what depolarizations, use of SR Ca2+ uptake would be the physiological relevance of We also welcome articles, news, blocking agents or of SR Ca2+ releasing this non-electrically detectable current meeting reports and any other agents, but never detected any when, for instance, we know that there information which you think may be 2+ reproducible change in either unitary or is a clear well-detected Ca entry of interest to our Members. Send whole-cell membrane current that through the voltage–dependent Ca2+ your contributions to Linda Rimmer would be consistent with a store- channels upon membrane at [email protected]

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Peripheral muscle fatigue from hyperoxia to moderate hypoxia – a carefully regulated variable?

How does the central nervous system (CNS) regulate athletic performance in different environmental conditions from below sea level exercise to exercise at moderate altitudes? What is the role of peripheral muscle ‘fatigue’ in endurance performance – is it a major Members of the John Rankin Laboratory of Pulmonary Medicine. From the left: David Pegelow, Markus Amann, determinant? Jerome Dempsey and Anthony Jacques.

Fatigue is defined as the reduction in Peripheral muscle fatigue can be CaO2 time trial (FIO2 1.0) and weakest force/power generating capacity of the assessed objectively and reproducibly during the condition of reduced CaO2 neuromuscular system that occurs using, for example, supra-maximal (FIO2 0.15). Accordingly, the highest during sustained exercise and is motor nerve stimulation. However, the average power output and the best subclassified into a ‘peripheral’ and a evaluation of central motor output (and exercise performance (i.e. shortest time ‘central’ element. It is generally agreed central fatigue) during dynamic whole to finish the time trial) was achieved in that much of the loss of force/power body exercise, must rely on more the high CaO2 trial and vice versa. The results from biochemical changes indirect measures of the muscle striking finding of this study was that, within the working muscle (i.e. electromyogram, which are prone to despite marked differences in central peripheral fatigue) (Fig. 1A). However, artifacts. motor output, power output and the loss of force/power can also result exercise performance time, the level of from inadequate muscle activation – We have previously demonstrated a peripheral muscle fatigue induced by often, but not exclusively, in highly sensitive effect of arterial the various time trials was almost combination with failure of contractile oxygen content (CaO2) on the rate of identical (Amann et al. 2006a). mechanisms – resulting from a reduced development of peripheral muscle Together, these data indicate that as the motor drive by the CNS to the working fatigue during dynamic whole body level of arterial oxygenation was muscle (i.e. central fatigue) (Fig. 1B). exercise (Amann et al. 2006a) (Fig. altered during exercise the CNS Several mechanisms which are not 1G). Even relatively small reductions received sensory input which was used mutually exclusive have been suggested in hemoglobin saturation (SaO2) below to up- or down-regulate central motor to underlie central fatigue (Gandevia, resting levels (as occurs during heavy drive to adjust for the respective rates 2001). For example, afferent neural sustained exercise at sea level or at of peripheral muscle fatigue feedback mechanisms originating in moderate altitudes (-6 to -10% SaO2)) accumulation. Therefore, an ‘excessive’ various peripheral organs (Fig. 1C), exaggerated the rate of development of development of end-exercise peripheral including the working muscles (Fig. peripheral muscle fatigue, whereas muscle fatigue beyond a critical 1D) might affect brain cortical increases of CaO2 significantly threshold or ‘sensory tolerance limit’ processes and the CNS might in turn attenuated this rate. In a subsequent (Gandevia, 2001) was prevented. We modulate central motor output investigation (Amann et al. 2006b) we then tested (and confirmed) this accordingly to ensure a specific level of varied levels of CaO2 via changes in the hypothesis in the same subjects using a organ system homeostasis and protect inspired O2 fraction (FIO2 0.15 to 1.0) to high intensity constant load exercise the organism from damage. manipulate the rate of fatigue test to exhaustion at varying FIO2 Alternatively, exercise-induced changes accumulation during bicycle ergometer (Amann et al. 2006a; Romer et al. in cerebral neurotransmitter activities time trial performance tests in which 2006). (i.e. serotonin) (Fig. 1E) (Meeusen & trained athletes attempt to cover 5 km De Meirleir, 1995) and/or the effects of in the shortest time possible. This type How did the CNS know how to various environmental/physiological of exercise performance test mimics regulate motor drive and match conditions (e.g. heat stress or hypoxia) real-life competitions wherein the contractile activity to the functional (Gandevia, 2001) (Fig. 1F), per se, performer must make second by second capacity – which was determined by might affect the control of motor decisions concerning the magnitude of CaO2? How might CaO2-dependent activity in the brain and thus whole his power output. Average central effects on the rate of development of body exercise performance, motor drive, estimated by integrative peripheral muscle fatigue be ‘sensed’ independent of any peripheral sensory electromyography of the locomotor and in turn impact central motor feedback mechanism. muscles, was strongest during the high output? In other words, what provides

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example, in situations where expiratory flow limitation and lung hyperinflation occur during sustained exercise (highly trained subjects at maximum exercise, fit elderly and COPD patients), excessive respiratory muscle work or respiratory muscle fatigue are also likely to occur. In turn, reflex-induced supra-spinal sensory feedback occurs which will not only intensify cortical perceptions of effort but may also

influence blood flow and O2 transport to exercising limbs thereby exacerbating limb fatigue (Fig. 1H). We are currently investigating the relative influence of hypoxemia severity and respiratory muscle work on central and peripheral fatigue during exercise in health and in COPD patients. In conclusion we need to emphasize that the physiologic determinants of central and peripheral fatigue and exercise performance are highly

Figure 1. Hypothetical scheme linking a reduction in arterial O2 content (i.e., acute exposure to moderate altitude) complex and controversial and certainly and exercise performance via its effects on fatigue. The solid lines graphically illustrate our proposed hypothesis. situation- and subject-dependant. Our The dashed lines indicate other potential factors capable of affecting central motor output and exercise correlative findings in healthy humans performance. Alterations in arterial O content (C O ) occur throughout the organism and affect various organ 2 a 2 have provided only a first indication – systems. Consequently, various organs might affect exercise performance via inhibitory feedback mechanisms controlling central motor output. Based on our measures of peripheral quadriceps fatigue and our estimates of albeit we believe a strong one – that central motor output (from quadriceps EMG), we propose that peripheral muscle fatigue is carefully regulated via exercise-induced peripheral muscle modulations of CNS motor output to ensure muscle homeostasis during exercise from hyperoxia to moderate fatigue is likely to play a significant hypoxia. The relative importance of peripheral fatigue might diminish at more severe levels of hypoxemia and role in this process under many cerebral hypoxia might gain in relative influence on central motor output and the termination of exercise. circumstances in health and in certain disease states. feedback to the working athlete contractile performance is now allowing him to exercise close to his extended by showing a connection highest endurable rate of fatigue between peripheral locomotor muscle Markus Amann development without significantly fatigue and central motor output during Jerome A Dempsey exceeding it which would result in whole body exercise. The John Rankin Laboratory of Pulmonary Medicine, University of Wisconsin Medical School, Madison, WI, premature ‘excessive’ peripheral fatigue USA and jeopardize his maximal It is important to emphasize that the performance? We propose that rate of peripheral fatigue accumulation References metabolite accumulation (e.g. inorganic is certainly not the only potential Amann M, Romer LM, Pegelow DF, Jacques AJ, Hess CJ & phosphate) whose rate of accumulation source of inhibitory influences on Dempsey JA (2006a). Effects of arterial oxygen content on peripheral locomotor muscle fatigue. J Appl Physiol 101, 119-127. in contracting muscle is CaO2 central motor output and thus exercise dependent (Hogan et al. 1999) activates performance. Significant influences of, Amann M, Eldridge MW, Lovering AT, Stickland MK, Pegelow DF & sensory nerve endings which project for example, cerebral hypoxia on Dempsey JA (2006b). Arterial oxygenation influences central motor output and exercise performance via effects on peripheral the rate of fatigue accumulation in the central drive have been indirectly locomotor muscle fatigue. J Physiol 575, 937-952. peripheral muscle to higher areas of the implicated in several investigations. Gandevia SC (2001). Spinal and supraspinal factors in human CNS (Taylor et al. 2000). Based on this Based on these reports, we predict that muscle fatigue. Physiol Rev 81, 1725-1789. afferent feedback the CNS will the relative influence of our proposed Hogan MC, Richardson RS & Haseler LJ (1999). Human muscle modulate central motor drive to feedback effect from fatiguing muscle performance and PCr hydrolysis with varied inspired oxygen optimize exercise performance while on central motor output (Fig. 1A) will fractions: a 31P-MRS study. J Appl Physiol 86, 1367-1373. concurrently ensuring locomotor diminish as CaO2 is reduced below Meeusen R & De Meirleir K (1995). Exercise and brain muscle homeostasis. The data point to normoxic levels (i.e. exposure to higher neurotransmission. Sports Med 20, 160-188. the rate of peripheral muscle fatigue and higher altitudes) and CNS hypoxia, Romer LM, Haverkamp HC, Amann M, Lovering AT, Pegelow DF & development as an important per se, gradually increases its inhibitory Dempsey JA (2006). Effect of acute severe hypoxia on peripheral fatigue and endurance capacity in healthy humans. 10.1152/ajpregu. determinant of central motor drive and influence (see Fig. 1F). Furthermore, Am J Physiol Regul Integr Comp Physiol, 00269.02006. of exercise performance. Thus, the there are surely systemic sources of Taylor JL, Petersen N, Butler JE & Gandevia SC (2000). Ischaemia classical view which emphasizes the inhibitory feedback – other than from after exercise does not reduce responses of human motoneurones to direct effect of peripheral fatigue on fatiguing limb locomotor muscles. For cortical or corticospinal tract stimulation. J Physiol 525, 793-801.

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Going with the flow: just say NO to oxygen radicals Endothelial cells are permanently exposed to shear stress by the flowing blood. Shear stress increases the endothelial formation of nitric oxide. But what happens to oxygen radicals during flow? Henning Morawietz and colleagues analyzed the flow-dependent regulation of the NADPH oxidase as a major source of endothelial oxidative stress

We all know the good advice of our expression in human endothelial cells physician to exercise on a regular basis. (Duerrschmidt et al. 2006). Short-term From the physiological point of view, a application of shear stress transiently - major beneficial effect of this everyday induced ·O2 formation in human challenge could be an increase in blood endothelial cells. This was inhibited by flow. As the inner layer of our blood the NAD(P)H oxidase-specific inhibitor vessels, the endothelial cells are gp91ds-tat, but NAD(P)H oxidase permanently exposed to shear stress subunit expression was unchanged. In throughout their lifetime. A well-known contrast, long-term arterial laminar beneficial effect of increased shear ­ Henning Morawietz shear stress downregulated ·O2 stress is the augmented endothelial formation, mRNA and protein formation of nitric oxide (NO). NO low-density lipoprotein thus promoting expression of NAD(P)H oxidase does not only mediate endothelium­ foam cell formation and atherosclerosis. subunits Nox2/gp91phox and p47phox. In dependent vasodilation, but also anti­ parallel, endothelial NO formation and inflammatory and anti-thrombotic While several studies have addressed eNOS, but not Cu/Zn superoxide processes (Landmesser et al. 2004). the impact of shear stress on NO dismutase expression was increased. Therefore, formation of NO by the formation, much less is known about Interestingly, downregulation of ·O ­ endothelial NO synthase (eNOS) is a 2 the impact of shear stress on phox phox critical determinant of endothelial endothelial formation of reactive formation, gp91 and p47 function. The NO availability can be oxygen species. Our lab established a expression by long-term laminar shear limited by enhanced formation of cone-and-plate viscometer as an stress was blocked by eNOS inhibition. reactive oxygen species like superoxide experimental model to simulate Furthermore, an NO donor - phox - downregulates ·O2 formation, gp91 anions (·O2 ) (Bachschmid et al. 2005). different levels of shear stress on phox - and p47 expression in static NO and ·O2 can form peroxynitrite in a cultured endothelial cells more than 10 very rapid reaction, thus reducing the years ago (Fig. 1). Because the endothelial cells. Our data suggest a - available NO. An increased formation NADPH oxidase has been identified as transient activation of ·O2 formation by of reactive oxygen species has been a major source of reactive oxygen short-term shear stress, followed by a - considered as a major determinant of species like ·O2 in human endothelial downregulation of endothelial endothelial dysfunction (Harrison et al. cells (Rueckschloss et al. 2003), in a NAD(P)H oxidase in response to long­ 2003). Another detrimental effect of recent study we analyzed the impact of term laminar shear stress. NO-mediated - downregulation by shear stress vascular oxidative stress is the laminar shear stress on ·O2 formation increased oxidative modification of and NAD(P)H oxidase subunit preferentially affects the gp91phox/p47phox-containing NAD(P)H oxidase complex. This novel mechanism might be involved in the shear stress-dependent regulation of the - endothelial NO/·O2 balance (Fig. 2). ­ An increased NO and decreased ·O2 formation could also contribute to the vasoprotective potential of physiological levels of laminar shear stress. This would further support an intact and healthy endothelial function.

How can this be translated into cardiovascular physiology and pathophysiology? Short-term and long­ Figure 1. Application of shear stress to endothelial cells using a cone-and-plate viscometer. Human endothelial cells can be cultured under static conditions or exposed to shear stress using a cone-and-plate viscometer. The term endothelial NO formation by shear apparatus consists of a cone with an angle of 0.5° rotating on top of a cell culture dish. The degree of shear stress can involve different stress τ depends on the viscosity of the medium µ, the angular velocity ω, and the angle of the cone α. Long­ mechanisms. While the first phase -2 term application of laminar shear stress (24 h, 30 dyne cm ) results in elongation of endothelial cells in the mainly represents a functional direction of flow.

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Human Physiology BIOS Instant Notes By Daniel McLaughlin, Jonathan Stamford & David White 2006, Taylor & Francis. £18.99. ISBN 978 0 415 35546 9 This book does exactly what it sets out to do; it distils the richness and complexity of physiology down to the essentials. The question remains: is this a good thing or a bad thing? The publisher’s claim that the book explains fundamental concepts and major physiological systems ‘without overloading the reader with information’ - Figure 2. Laminar flow can regulate the endothelial NO/·O2 balance and endothelial function. speaks for itself. The book should not be mistaken for a full textbook, despite its 460 activation of eNOS, the second phase is The bad news for all couch potatoes: pages; rather it should be viewed as a revision accompanied by an upregulation of the beneficial effects of exercise are aid, which would act as a prompt for the reader who has access to that extra information, or as a eNOS expression (Fleming & Busse, only transient. We have to move on. complement to extended texts which treat the 2003). Similarly, short-term shear stress topics in more detail. seems to activate NADPH oxidase Acknowledgments activity. In contrast, long-term This study was supported by the The difficult task of identifying core information is application of laminar shear stress German Federal Ministry of Education tackled admirably by the authors. The text is downregulates ·O - formation and and Research (BMBF) program NBL3 organised in a traditional, linear format. The 2 material is presented using a cellular and NADPH oxidase subunit expression. of the University of Technology Dresden. systems-based approach with 13 sections, This makes physiological sense because divided into 85 bite-sized topics. Specific topics both processes improve the vascular are found easily using the table of contents, NO availability in response to increased Henning Morawietz which is important for a revision text. ‘Key notes’ laminar flow. Interestingly, NO even Department of Vascular Endothelium and are contained in a box at the start of each topic seems to be involved in the Microcirculation, Medical Faculty Carl Gustav Carus, and provide a summary of the information on downregulation of oxidative stress by University of Technology Dresden, Dresden, Germany. that topic; the information is equivalent to the long-term laminar flow. This is not just minimum ‘take home’ message from a lecture on the topic. Signposts to other ‘related topics’ at a simple scavenging of ·O - by NO, References 2 the end of the key notes acknowledge the because transcriptional downregulation Adams V, Linke A, Krankel N, Erbs S, Gielen S, Mobius-Winkler S, Gummert JF, Mohr FW, Schuler G & Hambrecht R (2005). Impact of integrated nature of the subject. The book also of NADPH oxidase subunit expression regular physical activity on the NAD(P)H oxidase and angiotensin has a good index and a useful list of common by long-term laminar shear stress receptor system in patients with coronary artery disease. Circulation abbreviations and acronyms, although the 111, 555-562. involves an NO-dependent pathway as suggestions for further reading appear at the end well. Which NO-dependent Bachschmid M, Schildknecht S & Ullrich V (2005). Redox regulation of the book rather than at the end of a section. of vascular prostanoid synthesis by the nitric oxide-superoxide transcription factors are involved in this system. Biochem Biophys Res Comm 338, 536-542. process is currently not known. The didactic presentation is in contrast to the Duerrschmidt N, Stielow C, Muller G, Pagano PJ & Morawietz H interactive, multimedia style of most recent (2006). NO-mediated regulation of NAD(P)H oxidase by laminar publications, and the lack of colour is also Coming back to the initial advice of our shear stress in human endothelial cells. J Physiol 576, 557-567. conspicuous. The diagrams are clear and physician, should we also exercise to Fleming I & Busse R (2003). Molecular mechanisms involved in the concise, however, so the basic black and white − regulation of the endothelial nitric oxide synthase. Am J Physiol balance our NO/·O2 ratio? The answer presentation is to its advantage; the minimal Regul Integr Comp Physiol 284, R1-12. is definitely yes. Experimental studies style of the line diagrams should make it easy for in flow-adapted coronary arterioles and Harrison D, Griendling KK, Landmesser U, Hornig B & Drexler H students to reproduce them under exam (2003). Role of oxidative stress in atherosclerosis. Am J Cardiol 91, conditions. aorta support this concept. Increased 7A-11A. blood flow in mice subjected to − Landmesser U, Hornig B & Drexler H (2004). Endothelial function: a This book is aimed at students studying voluntary training reduces vascular ·O2 critical determinant in atherosclerosis? Circulation 109, II27-33. physiology as the foundation for degrees in the release and NADPH oxidase subunit biomedical sciences or in the early stages of Laufs U, Wassmann S, Czech T, Munzel T, Eisenhauer M, Bohm M expression as well (Laufs et al. 2005). & Nickenig G (2005). Physical inactivity increases oxidative stress, medicine; however, students with a primary Finally, chronic exercise training of endothelial dysfunction, and atherosclerosis. Arterioscler Thromb focus on physiology would require a more Vasc Biol 25, 809-814. patients with coronary artery disease extensive textbook. The optimist in me hopes increases flow, decreases generation of Rueckschloss U, Duerrschmidt N & Morawietz H (2003). NADPH that all students would demand more than this oxidase in endothelial cells: impact on atherosclerosis. Antioxid book has to offer; the cynic in me realises that reactive oxygen species and expression Redox Signal 5, 171-180. many students may neither want, nor even need, phox of gp91 in internal mammary more than this. arteries, and improves endothelial function (Adams et al. 2005). More book reviews appear on p. 50 Sarah Hall

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My first CONference physiologists occupying their bastions in the new and old quarters of the city waged a war MICROELECTRODE which often went beyond the realm of TECHNIQUES FOR CELL Recent letters in Physiology News (64, 22) academics. brought back vividly the memories of the first PHYSIOLOGY conference I attended! Tired after an The evening meal was delicious with an th overnight journey, five of us were crammed assortment of choice local foods. I could 24 Plymouth Workshop into a room meant for three at the guest meet and introduce myself to many senior 5-19 September 2007 house. After a quick wash we hurried to the physiologists(balding pates, protuberant venue for the free breakfast that went along bellies and the fluid levels in their glasses The Marine Biological the inauguration. Festoons and banners and being the indicators). Association of the UK, Citadel young volunteers with badges, greeted us. Hill, Plymouth, PL1 2PB To my surprise I found policemen holding Next day the attendance dwindled by half. back the delegates from rushing to the Obviously the Delhi crowd had caught the Microelectrode recording and tables, as the chief guest has night flight. As I was early, I found time to injection, voltage clamp, patch meet the sage. This time he asked me clamp single channel and whole not yet arrived. The Minister who could reach whether I belonged to any Navratnas (a term cell, slice recording, ion selective the venue only half an hour later, looked applied to well funded, star studded institutes electrodes, fluorescent indicators, confused about the distinction between of research, established by the government). capacitance, amperometry, physiologists and physicians and exhorted The day belonged to them the sage informed electronics, microscopy us to serve the rural poor! After the me, and gently reminded me of a free tour of Application details and poster at registration and a heavy breakfast, I beaches arranged for the late afternoon. marched to the venue armed with the gift Some of the papers were quite interesting, www.mba.ac.uk/courses bag containing all the papers and some the beaches far more. or by email to thrills like a packet of Pan Masala (now [email protected] banned). The venue was full of people from Further decline in numbers was evident on all walks of life – press with cameras and the last day but new banners of drug Fee £1,200 including notepads, khaki-clad politicians who followed companies appeared on the scene and the accommodation (bursaries the Minister, defence personnel boldly papers on pharmacology were due. I available) displaying their decorations and, of course, confessed to the sage that I felt a bit odd at physiologists. Included in the morning the presence of politicians and Deadline for applications 30 April session were workshops on yoga and pharmacologists. ‘We need them’, the sage medical education. While contemplating said. ‘The conference hall was given free of which to attend, I noticed an elderly, sage­ charge and the dinner where you ate Fools rush in looking gentleman with a greying beard and chicken xacuti with relish was hosted by a J L Linzell, who did pioneering work on turban approaching me, and asked for his pharmaceutical company’. lactation using surgically prepared goats, once suggestions. With a smile he replied that it defined a physiologist as someone who all depended on whether I was a meditator Since the few remaining delegates were in a chopped rubber tubing into short lengths that (philosophically oriented, statistically hurry to catch trains, only a few papers were couldn’t be re-used in any other experiment. disinclined) or a meducator (lab detesting, presented by physiologists like me. Another essential for many experiments in tongue twisting). Being neither, I chose to According to the sage they may be called systems physiology was Plasticine. This was attend both, slipping in and out. In the first ‘generalists’ spending a life time ideal for anchoring the tubing, and for propping workshop I heard the benefits of breathing demonstrating simple muscle curves on up glass connectors, taps, etc. through the left nostril and of energy moving smoked drums to mediocre medical up from one chakra to the other, starting students! In 1952 I spent part of the summer vac from the sacral spinal cord and ascending all working in Edinburgh with Catherine Hebb. the way to the cerebral cortex! The second J Prakasa Rao This coincided with a Meeting of the British workshop debated the acceptance of MCQs Department of Physiology, Kasturba Medical College, Pharmacological Society at which we Manipal, India by medical students who pursued their high demonstrated a perfused heart-lung preparation. I was standing beside the sealed school education in native tongues. Excellent PS More than three decades have gone by and perfusion chamber – a set-up that required tea served after the workshops prepared me I have attained a fairly senior level. Although I many, many bits of tubing, all with their for the next session. I noted with dismay that did not learn much physiology at my first attendant Plasticine (which happened to be conference, the contacts I made proved the entire day was dedicated to the dark purple). One rather distinguished-looking presentation of papers dealing with extremely useful. With their help I managed some small scale research. From smoked drums man pointed through the lid at the lungs and hypothalamus or hypoxia! Puzzled, I said disparagingly ‘Huh! Very cyanosed’. I approached the sage for explanation. He many labs moved to physiographs and some could obtain data acquisition systems. I still unhesitatingly replied ‘But that’s Plasticine.’ said the day belonged to the capitalists enjoy attending conferences and am encouraged This was greeted with glee by the surrounding (physiologists from Delhi who arrived on the to note the increasing participation of young audience – the complainant was an eminent morning flight). They followed two different people and the freshness in their approach. For Member of both Societies. paths of enlightenment – Anand Marg and with them lies the future of physiology in this Autar Marg. These two great schools of country! Ann Silver

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early nomadic journey into the cortical outrageous socks. Tim Bliss and LTP substrates of learning. Yes – it appears he was looking for something akin to Before we could ‘slap him in irons’ what he found! This settled him to his O’Keefe left the stage to Graham task and he became a staff member in Collingridge (University of Bristol) the Neurophysiology Division at the who went on to give us two distinct National Institute for Medical Research lessons in metrics. The first involved (NIMR) in Mill Hill. Safely ensconced highlighting the outrageously in his permanent home LTP became a successful LTP review he had co­ driving force for many experiments authored with Tim in 1993 and the conducted by Tim and co-workers. The incredible number of citations that this research effort has also extended into article had received. Based on citations the wider community in behavioural, alone it might well be screening soon systems, cellular and molecular as a classic adaptation in the BBC’s On 22 September they travelled from neuroscience. Perhaps most impressive, Sunday Night drama spot. In the far and wide to pay homage to the man, even to those who have not been bitten second, Graham described the distinct his three letter acronym and more. by the LTP bug, is the way in which role that sub-types of the NMDA Timothy Vivian Pelham Bliss, or Tim, LTP has been at the heart of numerous receptor play in particular forms of is to retire after over 40 years service to research efforts and careers that have synaptic scaling, based on his and the field of neuroscience. Organized tried to integrate investigation across collaborators’ work in Bristol. with support from The Physiological distinct organizational levels of the Society and the British Neuroscience nervous system. It is through Graham was followed by the meeting’s Association (BNA) to celebrate Tim’s collaboration and the direct effort of his furthest-travelled attendee – Cliff career, the symposium and following own lab that Tim’s efforts have Abraham (University of Otago, New party were a delight. continued to shape the field and this Zealand). Cliff has been a regular sentiment was broadly reflected in the visitor to NIMR and a long-standing Tim’s pre-eminence among the contributions made to his retirement contributor to the debate about the international neuroscience community symposium. existence and role of LTD in the mature reflects his seminal description of the nervous system. Cliff has pondered phenomenon of long term potentiation The event took place at Tim’s current why plasticity can be so variable in (LTP). However, the assembled hoards, great passion, the aforementioned slice and in vivo preparations and the breadth of contribution from NIMR, and was centred on a highlighted, with the support of attendees encompassing cleaning staff, symposium at which collaborators and mathematical modelling, why tonic former artist in residence and a friends each gave some perspectives on activity or its loss in the slice may veritable collective noun of research their current work and how their confound studies of LTD. Indeed, the scientists reflects affection and esteem personal interactions with Tim over the supporting photographic homage to that goes beyond just the key scientific years have affected some of their Tim on trips to the southern hemisphere contribution. Indeed, the ambience and research. John O’ Keefe (University will likely lead to a long queue for spirit of the meeting truly reflected the College London) set the standard in sabbatical leave to New Zealand. contribution of one of the most British describing the role of CaMKII in of neuroscientists. refining place fields in the After Cliff we left the hippocampus and hippocampus while simultaneously delved into a world of pain as viewed His description of LTP (we assume it regaling us with tales of two seafarers. by Steve Hunt (UCL). Steve touched on naturally exists so will not argue for its In this vein, the photographic evidence the existence of LTP among several discovery) provides an experimental suggested that, despite his nautical other plasticity paradigms that might model of a long- lasting synaptic heritage, Tim did well to discover his sub-serve a role in pain transmission in plasticity that has captured the liking for synaptic plasticity and, as the spinal cord. Despite his long­ imagination and we may yet see the keenly scored by John O’Keefe, his standing collaboration with Tim, it was day when such synaptic plasticity is penchant for bright shirts and not clear who introduced who to whom. proven to be the very basis of memory. The phenomenon, which has its roots in two seminal papers published over 30 years ago in The Journal of Physiology, the first with Terje Lømo and the second with Tony Gardner-Medwin, both of whom happily were present at the celebration, and arose out of Tim’s

Above: Tim Bliss at the meeting. Right: John Garthwaite, Graham Collingridge and John O’Keefe.

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Nevertheless, Steve highlighted the contribution their collaboration had made in pointing towards the role of gene transcription in LTP. Steve reminded us of the charm that was and is Bliss before the pain of hunger kicked in. Participants retired to the pavilion for lunch.

The post lunch session opened with Serge Laroche (Université Paris Sud, Orsay) taking guard and hitting us with insights into the role of transcription factors in LTP and, by experimental extension, memory and learning. Serge Above: Tim Bliss adds his own words before stepping into retirement. Below: Serge Laroche built up from here and highlighted that, at the time of the silver anniversary of deprecation about her own work it was on Bliss, or at least its ancestral line. his collaboration with Tim, there was clear to the audience that it is in the plenty of scope to investigate how arena of addiction, stress and Tea was duly taken before the gathered neuronal remodelling and neurogenesis neurodegenerative biology that LTP throng returned to hear from an Ashes­ supports brain plasticity. will continue to feature in the future. less visitor from the University of Melbourne. Chris Reid’s talk focused Our next speaker, Marina Lynch Post-Marina we were schooled in the on optical investigations of that less (Trinity College, Dublin), informed us optical imaging of synaptic Bliss-ful form of LTP seen at mossy that she had required all her convent transmission from a host of Tim’s fibre synapses. Chris described the training to dodge questions about Saint collaborators and one-time co-workers. potential unsilencing of active zones Paul during the interview she had been These talks focused on the development during this form of LTP, which might subjected to on applying for a post­ and use of optical methods to decipher strike a cord with those searching for doctoral position at NIMR. In true the cellular basis of LTP. The first of unifying theories of synaptic plasticity ‘Bliss’-style, the interview, and thus the these was from Alan Fine wherever it might happen. More selection of Marina as co-worker, had (NIMR/Dalhousie University) who importantly, Chris reminded us all of not actually been conducted by Tim. detailed how live and sequential what is clearly a remnant of Tim’s His views on Saint Paul remain imaging of neuronal structure and halcyon days (i.e. his Mini). Chris’s unknown. Nevertheless, Marina assured function could be used to re-open the recollection of that first car ride with us that she had been delighted with her long standing debate over the Tim struck a cord with those who were time with Tim and she illuminated how presynaptic component to the privileged or unlucky enough to her investigations of a potential role of expression of LTP, and the degree to accompany the renowned arachadonic acid in LTP had led to her which structural re-organisation hippocampologist as he ‘scooted’ from current focus on neuro-inflammation in contributes to synaptic plasticity. Alan’s the heights of Mill Hill into Town for a the aged brain. Like many, Marina has talk also reminded us of Tim’s long social and/or scientific meeting. successfully used hippocampal LTP as affiliation with Canada and its a robust assay of synaptic transmission universities, having gained his PhD at Our final speakers were certainly and scores perturbation in its induction McGill. However, most revealing was among the best dressed and were much and maintenance as a measure of Alan’s assertion that Halifax, the home more restrained in a sartorial sense than dysfunction. Despite Marina’s self- of his own university, was a town built our retiree. Antonio Malgaroli (Universita’ Vita-Salute San Raffaele, Milan) described peptide-based reagents that could be used to fluorescently mark important synaptic compartments with a view to achieving further real time images of synaptic function. The finale came from Nigel Emptage, who further evidenced Tim’s penchant for the life at sea by providing pictures of a wet- suited Professor. Nigel’s talk described work honed during his time as a post-doc with Tim and he detailed how variations in the optically recorded pre-synaptic responses could be used to provide

Physiology News | No. 66 | Spring 2007 | www.physoc.org SPECIAL SYMPOSIUM ON LTP/WORLD CONGRESS PN 35 further insights into NMDA receptors. World Congress to focus on The 3Rs in practice The observations discussed by Nigel Many replacement alternatives are developed led him to make the case that NMDA advances in research initially to obtain general insights or to inform in­ receptors, the post-synaptic guardian of house decision making (with the methods are LTP induction, may also be present in methods and strategies often quicker and cheaper than animal studies). the pre-synaptic compartment. Overall, The use of the term ‘reduction’ is misleading and the presentations, scientific content and The 6th World Congress on Alternatives and wrong – what is actually meant is to minimize or ambience of contributions made for a Animal Use in the Life Sciences optimize animal numbers. Even if fully most satisfying and educational (www.knt.co.jp/ec/2007/wc6) will be held in implemented, minimization and optimization can symposium and one worthy of Tim’s Tokyo from 21 to 25 August 2007, providing a be consistent with a rise in the number of contributions to the field. platform for advanced research strategies animals used if more or better science is the and methods with the potential to enhance product. biomedical research and make better However, as intimated above, the day Taking care to optimize and minimize the provision for animal welfare. It is an was to reflect more than the sum of numbers of animals used is part of good opportunity for the international scientific Tim’s scientific contribution. scientific practice. Using too many animals is to community to celebrate, publicise and share Accordingly, the science was followed be avoided – but using fewer than are required its successes and continue to make progress to draw sound conclusions is a much more by a most cordial social soiree that in these areas. included Pimm’s served by ‘boater clad serious problem in scientific terms. At best using too small a sample size will, if recognized, dandies’, a jazz band, a Shakespearean Fundamental and applied research are essential require additional studies are undertaken if valid play (Melvyn Sherwood Productions) to provide new insights and to devise and deliver conclusions are to be drawn. At worst the and the acceptance speech from the improved healthcare technologies and other problem will not be apparent and misleading societal benefits, and animal research continues ‘belle of the ball. One would be failing statements will be accepted at face value: to the to play a vital part in achieving these ends. the wider community if one did not detriment of science if, for example, differences It is generally accepted that good animal welfare mention the outstanding thespian reported as not reaching statistical significance and good science are inseparable, and that one performance of Mick Errington, the are the result of too small a sample size rather of the hallmarks of good science is that than there being no true meaningful difference. young Bliss’s long-standing able unintended variables such as animal welfare assistant and doyen of in vivo LTP. issues do not go unrecognized or uncorrected. Mick had come out of his own There is a still a tendency to consider refinement only to be the measures, such as the retirement to tread the Mill Hill boards. Whilst we seek every opportunity to present new implementation of humane endpoints, taken to His performance was only surpassed by scientific findings, the constant improvements to reduce or minimize the pain, suffering distress or research methods are often given insufficient the beautiful and vivacious pantomime lasting harm caused by animal experiments – prominence in the mainstream literature. dame Ophelia, as played by Abdul that is minimizing the harm done. We must look Sesay, who reduced many a watching wider than this in considering refinement and Asking scientists how progress with alternatives man to tears. consider it to embrace the promotion of good and the 3Rs are relevant to their research often animal welfare – not simply removing the produces only defensive general statements Having received thanks and a gift from negative, but seeking to add additional positive relating to abstract potential benefits, but few measures to further enhance animal welfare and John Skehel (Director, NIMR), Tim concrete examples: whereas asking how improve the science. was left to add his own words to the research methods have evolved or improved day. The premise of the speech was that often produces enthusiasm and practical Closing remarks he would speak for longer than his examples of technical progress that can be former colleague, the recently retired cross-referenced to the 3Rs. Investment in and All scientists must keep abreast of technical progress and continue to innovate; and continued progress with alternatives does not impede Errington. Anecdotes were told, points professional development must look beyond scientific progress – it promotes it. of contention clarified, collaborators individual scientific disciplines into other areas and co-workers thanked, mentors where new ideas, knowledge and practices can The 3Rs – Replacement, improve scientific outputs. ‘Alternative’ methods are homaged, absent friends remembered Reduction, Refinement and loved ones bowed to. It was well more often existing good practice, or ‘advanced’ Developing and employing improved research methods destined to become integral parts of good received, warmly applauded, its wit, methods, which reflect elements of the 3Rs, are science. The 6th WC will focus on aspects of length and grammatical precision noted. an essential component of mainstream science. training, experimental design, animal and non­ The scientific contribution of the ‘Alternatives’ is not a separate discipline or animal models, and data analysis with the potential speaker is clear. But importantly, as agenda led by those with an anti-science or to improve science and animal welfare. It is an Tim stepped into retirement, the good ethical agenda. Progress in the 3Rs is led by opportunity to celebrate and publicise the progress manners and charm that go with his the scientific community - seeking to look that is made and the scientific and societal benefits beyond the scope and limitations of existing scientific contribution will be among this brings. If you think you have already made research methods, to overcome technical significant progress, or have nothing more to learn, the longest lasting of memories. problems, and produce more relevant and timely then come to the 6th WC to contribute and tell outputs. It is science led and science driven. others how to do as well. If you can see room for Samuel Cooke improvement come to 6WC to listen and learn. Massachusetts Institute of Technology, Cambridge, Even in the absence of ethical and animal MA, USA welfare considerations, scientific progress Jon Richmond Vincent O’Connor requires that the 3Rs should be embedded in the Home Office Animals Scientific Procedures Division, University of Southampton, Southampton, UK planning and conduct of biological research. London, UK

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Let’s talk about science… made aware of ways in which we can language and my accommodation; all participate through the Science and these things made my whole world Rehana Jawadwala Engineering Ambassadors and blue. The university accommodation I experiences a Science Researchers in Residence schemes, and lived in when I arrived had no internet Communication Workshop National Science Week (9-18 March). access, no radio, no TV and no telephone in the room. I had no friends For those of us interested in alternative or relatives in this country, so I have I am on the train returning back from a scientific careers, science journalism never felt so desperate and lonely as 2 day workshop on science was suggested as a stimulating career during that period and I thought I communication, held in London by The choice. Most of the professional science would not be able to stay here any Physiological society. My mind is journalists had some sort of a longer. The only thing I wanted to do overloaded with information, ideas, background degree in a science field was to pack up all my stuff and go back inspiration and an immense sense of and that had facilitated their to China forever. Fortunately, I have enthusiasm. In the past 2 days I have understanding of the concepts about two nice supervisors who helped me heard interesting thoughts and debates which they wrote. The view that the get through that horrible period. My life on the roles and responsibilities PhD is an over qualification for such became brighter when I got familiar scientists ought to have in educating the jobs is rapidly changing and most with my research project and my public, informing them, motivating employers are reaping the benefits of surroundings as time went by. But still, them and, most of all, encouraging a the transferable skills we learn during I cannot help sometimes feeling lonely. healthy debate among the general our research training. Daytime here is evening in China and public. vice-versa so I can only call my family Even though the workshop lasted only during the day. The evenings are the This workshop was conducted jointly in 2 days, we all made some really good worst because I cannot call home at association with Sense about Science, friends and, most of all, bonded with times when I am alone. Voice of Young Science, UK GRAD people with similar ideas, concepts, and other organisations. To most of us fears and aspirations. The intellectual Culture conflict is another difficulty. I young participants it was time well debates, laughs and quirky, geeky moved to a flat with six other spent in the company of professionals habits that we shared over wine and postgraduate students coming from six who are out there doing active work Italian food in a lovely pizzeria, tucked different, mainly European, countries. with the public, communicating their behind the Thames is an evening I will The first conflict happened when I put own science and that of the national cherish. a notice up asking my flatmates not to and international scientific community. talk loudly in the kitchen after midnight Rehana Jawadwala because my room is just opposite and The biggest take home message was University of Central Lancashire, Preston, UK the noise affected my sleep. This that we, as early career scientists, irritated them; they thought that putting matter. I think most of us came with an up a notice was rude and that I should idea that the media are interested in To be strong have confronted them face to face. But huge discoveries, novel and ground Chinese PhD student Meihua for me, the notice was the best way to breaking inventions, and that they He’s story solve the problem as well as avoid would like to cover people who occupy embarrassment. the higher echelons of science, such as, If you are an overseas student here in John Mather, Richard Dawkins and UK, and at the same time, a mother Loneliness and culture conflict are, James Watson. But that is far from with a 3 year old daughter that you however, nothing compared to the reality. Most science journalists we have left behind in your home country, guilty feeling I have as a mother. chatted with were in search of grass you will understand the feelings that I Leaving my daughter behind was the root level scientists who would be able will try to describe in this article. It is most difficult thing for me. It is not to explain new ideas and processes not easy to get supported by the easy for them to visit me or for me to easily to them; they were interested in Chinese government to study abroad; it go back home often because of finances our view points as much as they were is also difficult to make the decision to as well as time – it’s a long way to in those of celebrated scientists. leave the family behind. If you were in China. The only thing I could do was this situation, what would you do? to promise my daughter, as well as my It was refreshing to note that most of Family or career, which one is the most husband, that we would meet every 3-4 the delegates still cherished those early important thing in our life? On 10 months. school days and the teachers who October 2005, when I took the plane infused such enthusiasm into us; the from Beijing to London, it seemed that To live through the entire PhD journey, triggers that made us pursue a career in I had made my choice. support is necessary – from supervisors, science. By being informed of various as well as colleagues. Fortunately, I government initiatives and programmes Life in London is not as easy as I had have both, and that makes me feel that to increase motivation for children to imagined before I came. I was very living in London is something can be take up science as a career, we were homesick, I had problems with the enjoyable.

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Association of Science Diabetes: from Egypt to global obesity. Physiology for schools and Education (ASE) Annual Stephen Gough’s presentation was colleges Conference 2007 excellent. He had a true passion for the subject, and the teachers who attended Welcome to our new were enthused by his presentation and education section were lining up to ask questions. For more details of speakers, and several I was recently approached by our speaker presentations that can be used Physiology News Editor, Austin Elliot, in the classroom, please visit about running an education section for www.physoc.org/education/ase. this magazine (and writing articles if the volunteers dry-up!). If I’m honest Research on animals DVD it’s always been high on my ‘to-do’ list, The Physiological Society and Biochemical Society Make up your own mind so with a little push from Austin and stand where the Research on animals DVD Make up your own mind was demonstrated. The Society, along with several other the next three articles already lined-up, organisations, has produced a DVD to the first edition of 2007 seemed a great The ASE Annual Conference is a address the on-going issues of animal time to start. school educator’s paradise with an research, which can be used for extensive programme of workshops, teaching: How science works – The education section, for 2007 at least, courses and lectures, and an exhibition. applications and implications of will focus on secondary education with The Physiological Society, with a science. It includes achievements in articles specifically for teachers, number of other organisations, put medical research, animal welfare and technicians and advisors, but in the together a one day programme Biology the reduction, refinement, and future I hope to expand this section to in the real world which took the theory replacement of animal testing. Extras include undergraduate education – any of science and put it into the context of include a suggested lesson plan, volunteers? This first article is a mish­ every day life. The aim of the classroom activities, topics and mash of a number of things, so if programme was to extend teacher resources, and web sites which add to you’re interested in becoming a School knowledge, providing them with the the ethical debate. The DVD received and College Associate of The opportunity to talk to the experts and excellent reviews from teachers at the Physiological Society, hearing about the give them something to take back to the ASE and will be sent to UK schools in Association of Science Education classroom. March. If you would like to receive a Annual Conference, finding out more free copy please let me know. To help about The Society’s new Research on Our speaker, co-sponsored by the launch the DVD, scientists will be animals DVD Make up your own mind, Biochemical Society, talked about visiting schools during National or careers in science for students, Science and Engineering Week (9-18 please read on. March) to demonstrate the DVD and School and College facilitate debate. If you are interested in Associate membership inviting a scientist to your school, or Physiology is a major component of the are a scientist who would like to go secondary school biology curriculum, into a school, please get in touch. and The Physiological Society recognises the need to support its Careers from science teaching. While The Society is already It is widely recognised that there isn’t engaged in a number of activities for enough science and engineering careers teachers and students, we thought advice available to school students. In introducing School and College November 2006 the Campaign for Associate membership would be a great Science and Engineering (CASE) held way of targeting our resources, an opinion forum event on Information encouraging interactions between our and advice on careers in science and scientists and schools, and also help us engineering for students, which was to find out what resources school and attended by The Physiological Society. colleges would like us to develop. For A report follows on p. 38. The £15 per annum schools and colleges Physiological Society is also supporting can enjoy attendance at various teacher Top: Glenn Clack (left) explaining the process of drug Careers from science, a Science discovery. Annie Duckworth (right) preparing the and student workshops, receive hard audience for some hands-on participation. I never Council initiative which has just been copies of Physiology News, career thought ecology could be so much fun! awarded significant DfES funding. The advice, access to scientists (willing to Above: Stephen Gough telling the audience about the primary aim of this project is to give presentations), online access to first recording of diabetes by Ebers Papyrus in 1500 develop a web resource, aimed at BC, ‘A wasting disease in which the sufferer produces Society journals, and more. For further sweet tasting uring’. Yuck ... someone must have students aged 11-19, to increase their information please contact me. tasted it! awareness of the wide range of career

Physiology News | No. 66 | Spring 2007 | www.physoc.org 38 PN EDUCATION paths available from studying science, interests of future non-scientists. students is that studying science and and importantly, make students (and technology opens up 80-90% of the job their parents) comfortable about opting The House of Lords report Science market, with science graduates being in for science. A detailed summary of this teaching in schools identifies careers demand in a very wide range of industry project will be included in the next advice as a problem. Students tend to see sectors. issue and a full report will be available science and technology as ‘hard’ subjects, on our web site shortly. and anxious to get high grades, choose to The meeting then split into workshop study ‘easier’ subjects. Lord Jenkin groups to discuss the roles of central and What’s next? concluded that students need high quality local government and schools and When is a boring class practical not a careers advice long before they reach A colleges, and the responsibilities of industry boring class practical? Answer, when a level as it is very difficult to change track and the wider scientific community. scientist can tell you how to use a afterwards, but many teachers don’t feel simple piece of equipment (already qualified to provide this – we need advisors A lively debate ensued. It was felt that available in many classrooms) to get to support the advisors! government had an important information your students thinking and dare I say it co-ordinating role. Employers and young ‘having fun’. This was followed by a presentation from a people were confused by many different chemistry undergraduate, Danielle Miles, sources of information. SETNET was Donna Brown whose strong interest and commitment to regarded as being a model national Education and Membership Manager studying chemistry had not been facilitated scheme, and could become the central [email protected] by the careers advice she had received in vehicle for providing careers advice and school and elsewhere, or the decline in support to young people and teachers. A CASE Opinion Forum properly resourced science teaching in simple pack of information on science for The Campaign for Science and Engineering schools and universities. There was a teachers to help dispel myths might be very (CASE) regularly holds Opinion Forums on strong message here, that had she not effective, with a strong message about the a variety of issues affecting science, the been so personally committed to studying wide variety of careers open to people who output of which is the creation of a report of chemistry, the present system would not do science subjects at school and policy findings and recommendations to have acted to encourage her into it. Many university. Strong role models, preferably help them in their lobbying of Government. potential students must be falling by the highlighting young scientists to make them The event on 21 November, Information wayside through similar difficulties. accessible, should be promoted to help challenge stereotypes. and advice on careers in science and The final presentation was from Mike Hill of engineering for students, sought to Prospect Services who talked about his examine the anecdotal consensus within Older people’s needs should also not be many years of being a careers advisor in forgotten; we should aim to re-attract the scientific community that young people several different industries. It is important to often lack good information and advice people to science by offering re-training for share good practice and support teachers career changes. about careers in science, or have problems who are trying to provide an advice service accessing information that already exists, in schools, often as a part-time addition to Parents need to be encouraged to be more throwing up barriers to attracting potentially their many other roles. In his experience involved in the careers advice process, good students into science and job markets can change radically, and after all parents are already established in engineering. careers advice needs to keep up with this. a wide variety of different careers and could be a good resource. The first presentation was from Lord Jenkin The reasons why people select particular of Roding, the former Chair of the House of careers are very complex. Peer and Careers advice in schools needs to Lords Science and Technology Sub- parental pressure are very important. become a central part of the schools Committee, who chaired the influential Careers advisors can also be influenced by activity, not just an add-on. Teachers need report Science in Society. The Select the apparent glamour of certain careers, more training in providing careers advice, Committee had looked at why the public overselling options such as studying law, perhaps this could be consistently provided seemed to be getting disenchanted with the media, or sports science, without through the network of Science Learning science. The Committee had not initially having a sufficient grasp about the real Centres? Careers advice for students intended to cover education, but found level of job opportunities that are likely to needs to start as early as possible and be when they looked at the evidence that be available. Careers advice needs to accessible at each stage of the learning public distrust of science starts in schools, provide this, so that students can make process. Companies are often keen to work where we had failed to engage the interest informed decisions about the levels of with schools in offering careers advice but of many pupils who saw science as being competition that they are likely to face in don’t know how to access the school stodgy, authoritarian and dogmatic. trying to attain their chosen careers. system. A one stop shop facilitating that access, such as SETNET, would be very Schools therefore had a dual role, in Hill stressed that when he is offering useful. enthusing future generations of people who careers advice, he tries to encourage want to practice science, and to engage the people to keep their options open as much Liz Bell understanding and concerned citizen as possible. A very important message for Head of Policy and External Affairs

Physiology News | No. 66 | Spring 2007 | www.physoc.org MEMORABLE MEMBERS PN 39

enough, a sharp pull produced two Bernard Katz electrodes. Too soon or too late in pulling Liam Burke recalls an ‘annus was disastrous. Our best electrode maker mirabilis’ during his time in was del Castillo, a very relaxed Spaniard. Bernard Katz' laboratory Katz strove valiantly to make electrodes but his temperament was a major obstacle and In September 1952 Bernard Katz invited me with each failure he would get more and to join his laboratory in the newly created more angry, eventually abandoning the Biophysics Department at University attempt and stalking off fuming. Otherwise College London. I had just completed my Katz was not often angry. Indeed, I BSc at UCL and was uncertain what my remember clearly only one other occasion, future would be. I was Katz' second choice, when a paper was published claiming that his first choice having turned the job down. the records in the 1951 Fatt & Katz paper That I was even in second place was due to were artifacts. Katz hit the roof. a recommendation from G L Brown, Head of Physiology, with whom I had a good Everyone has their foibles. When I was in relationship (we had a similar sense of his laboratory Katz would not send a reprint Bernard Katz in 1952 when Liam Burke joined his to anyone unless the request was hand­ humour, somewhat larrikin). I could not laboratory (© Godfrey Argent, for the Royal Society) believe my good fortune but I was written. This reflects an old-world courtesy apprehensive about my performance under So this was the setting for my initiation into which has now almost disappeared. I don't the eagle eye of Bernard Katz. neurophysiology. I could truly say, with know what Katz would make of the present­ Wordsworth, ‘bliss was it in that dawn to be day world of emails when even members of 1952 was an 'annus mirabilis'. This was the alive’. Katz had attracted some brilliant your own family send you computer­ year in which Hodgkin and Huxley people to his laboratory, for example, generated letters with no signatures. published their seminal papers on the ionic Ricardo Miledi, Jose del Castillo, John Katz was a refugee who became more theory of the action potential. It was the Nicholls, Ove Sten-Knudsen, Bernard English than the English. He modeled year in which Eccles and colleagues Ginsborg, Bob Martin, Ian Boyd, Don himself on A V Hill under whom he did his published their equally important papers on Jenkinson, Ed Furshpan and many others PhD at UCL. A V assisted Katz (and many synaptic transmission at the motor neurons after I had left. I made many good friends other refugees) before, during and after the of the spinal cord. It was the year of among that group and still maintain contact Second World War. At one time A V Eccles' Waynflete Lectures in Oxford, with them today. The 4 years I spent in decided to sell his car, an old Austin A40. subsequently published as The Katz' laboratory were among the happiest of Katz bought it. His reverence for A V was neurophysiological basis of mind. That year my life. saw a series of important meetings, most such that he would have paid a fortune for notably one at the Royal Society in which all Katz was a very kind person, aware of his that car. If he had been given a choice of these recent advances were described, ability but also aware of his limitations, quite between that car and a Nobel Prize he discussed and celebrated. It was also the humble, not in the least bit arrogant. He might have chosen the car (but A V wouldn't year in which Charles Sherrington died and was also rather shy so that it was often have allowed that). Katz couldn't drive but somehow his departure was fitting because difficult to maintain a conversation. At first I soon learned under the tutelage of Bob the first half of the 20th century had been asked rather a lot of questions, but if he Martin. When A V died in 1977 Katz wrote dominated by the Sherringtonian revolution thought I could have worked out the his obituary for the Biographical Memoirs of and this was now over. Sherrington's work, answers by myself he wouldn't give me the the Fellows of the Royal Society. Many of encapsulated in two epoch-making books, answer. He would say ‘You can look that the expressions Katz used about AV could Integrative action of the nervous system up in …’. Like most students I was lazy and be applied to himself. ‘ … he was intolerant (1906) and Reflex activity of the spinal cord was always looking for the easy way out. and scornful only of pretentiousness and (1932), the latter written in collaboration But Katz' attitude was good pedagogy. It intellectual snobbery.’ ‘(he) was held in the with Creed, Denny-Brown, Eccles and reflected his own upbringing. He was the greatest affection … for setting … an Liddell, based largely on his work on spinal epitome of the self-taught man. Sometimes example of uncompromising integrity in reflexes, brought order out of chaos for the I felt he did not know the answer to my personal and social relations.’ ‘(he) was a physiology of the central nervous system. question but it was more likely that I was person of old-fashioned tastes and virtues, Now, in 1952, just half-way through the not expressing myself well. addicted to simple commonsense and century, there was to be another change of straight dealings, and very allergic to paradigm. The second half of the 20th Katz was always rather tense, rarely pomposity.’ century was to be dominated by ionic relaxed. In those days we had to make the Liam Burke mechanisms and facilitated by the invention microcapillary electrodes by hand. This Emeritus Professor of Physiology of the microcapillary microelectrode. This was done by holding a piece of glass University of Sydney, Australia electrode, developed in Ralph Gerard's capillary tubing with two hands and placing This article appeared originally in the laboratory, was used to brilliant effect by the centre of the tubing in the small hot Proceedings of the Australian Neuroscience Katz and Paul Fatt in their famous 1951 flame of a Bunsen burner. At a critical Society (2004, 15) and is reprinted here with the paper, ushering in the new age. moment when the glass had softened permission of the Society.

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SYMPOSIA Symposia 2007

Friday 2 March SYMPOSIA Regulation of ion channels For further information go to Regulation of ion channels and and transporters by www.jphysiol.org phosphatidylinositol or email transporters by 4,5-bisphosphate (PIP ) [email protected] 2 phosphatidylinositol Friday 2 March 2007 from 1200 to 1700 st at the 51 Biophysical Society Annual Meeting 4,5-bisphosphate (PIP2) Room 316/317, Baltimore Convention Center, Baltimore, MD, USA At the 51st Biophysical Society Annual Chairmen Nikita Gamper (University of Leeds, UK) Meeting Mark S Shapiro (University of Texas Health Science Center, TX, USA) Organising Editor Room 316/317, Baltimore Convention Brian Robertson (University of Leeds, UK) Speakers Center, Baltimore, MD, USA David A Brown (University College London, UK)

Regulation of M(Kv7.2/7.3) channels in neurons by PIP2 and products

of PIP2 hydrolysis: significance for receptor-mediated inhibition Tamas Balla (National Institutes of Health, MD, USA) Imaging and manipulating phosphoinositides in living cells Monday 30 April Donald Hilgemann (University of Texas Southwestern, Dallas, TX, USA)

Direct and indirect regulation of ion transport by PIP2 metabolism Bertil Hille (University of Washington, Seattle, WA, USA) Obesity and the central nervous Phosphoinositide requirements of ion channels probed with translocatable enzymes system Leslie M Loew (University of Connecticut Health Center, CT, USA) At Experimental Biology 2007 Where does all the PIP2 come from? Mark S Shapiro (University of Texas Health Science Center, TX, USA) Room 146B, Washington DC Regulation of voltage-gated Ca2+ channels by phosphoinositides Thomas Voets (KU Leuven, Leuven, Belgium) Convention Center, Washington, DC, Regulation of TRPs by PIPs Diomedes Logothetis (Mount Sinai School of Medicine, NY, USA) USA The signalling phospholipid PIP2 is a central regulator of potassium channel function

Call for related papers Symposium proceedings will be published in a special issue of The Journal of Physiology. To submit a related manuscript for inclusion in the issue, please visit www.jphysiol.org Wednesday 2 May

The Journal of Physiology is published by Blackwell Publishing on behalf of The Physiological Society in 24 fortnightly issues in eight volumes. For further information go to www.jphysiol.org Exercise hyperemia. Are there any answers yet? At Experimental Biology 2007 Washington DC Convention Center, Washington, DC, USA SYMPOSIA Obesity and the July central nervous Brain adaptations for a successful system

Monday 30 April 2007 from 1030 to 1230 pregnancy at Experimental Biology 2007 At the IBRO World Congress of Room 146B, Washington DC Convention Center, Washington, DC, USA Neuroscience (12-17 July) Melbourne, Australia Chairs Steven Mifflin (University of Texas, San Antonio, TX, USA) Alison Strack (Merck Research Laboratories, Rahway, NJ, USA)

Speakers Barry Levin (New Jersey Medical School, East Orange, NJ, USA) Thursday 19 July Why some of us get fat and what we can do about it

Mary Dallman (University of California, San Francisco, CA, USA) The cortex, interneurones and Glucocorticoids and insulin both modulate caloric intake through actions on the brain motoneurones in the control of

Greg Morton (University of Washington, Seattle, WA, USA) movement Hypothalamic leptin regulation of energy homeostasis and glucose metabolism At the IBRO World Congress of Michael Tuck (Veterans Affairs Medical Centre, Sepulveda, CA, USA) Neuroscience Sympathetic nervous system in obesity

Call for related papers Darwin, Northern Territory, Australia Symposium proceedings will be published in a special issue of The Journal of Physiology. To submit a related manuscript for inclusion in the issue, please visit www.jphysiol.org

For further information go to www.jphysiol.org For forther information go to or email [email protected] www.physiol.org

The Journal of Physiology is published by Blackwell Publishing on behalf of The Physiological Society in 24 fortnightly issues in eight volumes. For further information go to www.jphysiol.org or email [email protected]

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important source issue in the field. The metabolic dilations along the deadline for submission of original microvascular wall in situ. Her second research papers for this issue is 1 July interest is in leukocyte-endothelial Symposia 2007. communication during inflammation, Since 1999 The Journal of Physiology including regulation of permeability. has run symposia at major international Carol Huxley Ingrid's laboratory has a long-standing Managing Editor meetings interest in microvascular (http://jp.physoc.org/misc/symposia.shtml). hemodynamics, particularly as this These have been successful in raising New Editor relates to understanding the role of the profile of The Journal and the shear forces in adhesion molecule resulting Symposium Reports have expression and leukocyte interactions been amongst the most-read and -cited with the microvessel wall. in The Journal. One of the dilemmas of the Editorial Board of a journal that covers all areas of physiology is where to focus attention. The Symposium Issues are markers for specific areas of Sleep apnoea and expertise on the Board and emerging topics. In 2007 six symposia in hypertension: physiological different areas are being sponsored by The Journal (see facing page). The New Journal of Physiology Editor bases for a causal relation Journal is increasingly interested in Ingrid Sarelius (above) graduated with attracting high-quality related research a PhD in Physiology from the In the spirit of Experimental Physiology’s papers to accompany these reports, with University of Auckland, New Zealand, commitment to address integrative and the aim of creating an informative issue in 1978. She was a Fogarty translational physiology, the January that covers a number of approaches and International Exchange Fellow at the themed issue provides a series of review includes the latest research results on a University of Virginia from 1979-1981, articles which bridge cellular and molecular particular topic. Calls for related papers and joined the University of Rochester mechanisms of physiological adaptations to are put out on the web site in 1981 as Assistant Professor in intermittent apnoea to the strong clinical (http://jp.physoc.org/misc/callforpapers.shtml ) Biophysics and in Physiology. Ingrid is association between sleep apnoea and and email alerts, and are sent out to currently Professor in Pharmacology hypertension (http://ep.physoc.org). relevant email lists. Society Members and Physiology and also in Biomedical can act as ambassadors for The Journal Engineering at the University of Sleep apnoea, once thought of as a disease by passing on information about the Rochester, Fellow of the Cardio­ of morbid obesity, but now recognized as a symposia and the calls for related vascular Section of the American prevalent disease that is a significant risk papers to colleagues who may be Physiological Society and a Fellow of factor for many serious comorbid conditions interested, and indeed should consider the American Heart Association. Ingrid with cardiovascular disease. This field of attending the symposia and submitting has also served as a Past President of investigation has evolved from the clinical related research papers for inclusion in the Microcirculatory Society, and is observation of a strong association between the Symposium Issues themselves. currently Chair of the Microcirculation sleep apnoea and hypertension, to When the new Society web site is Section of the IUPS Commission on epidemiological data reported in the 1980s. unveiled the Editorial Board hopes that Circulation and Respiration. She From these clinical observations several opportunities for further interaction served on the US National Committee with Members about The Journal’s of the IUPS from 1996-2005 and symposia and overall content will arise. serves, or has served, on the Editorial Boards of the American Journal of The Journal is also planning an Physiology: Heart and Circulatory Olympics Special Issue for January Physiology, Microvascular Research, 2008, which will take advantage of, and and Microcirculation. enhance, The Journal's reputation as the top journal in integrative (especially Ingrid's research focus is on cell human) physiological research. There communication in the microvasculature, will be a number of invited reviews with two major areas of interest. First, focusing on issues in integrative mechanisms of metabolic responses in physiology with a strong link to human small arterioles, focusing on the role of performance. A call for related research endothelium, and endothelial cell papers for inclusion in this issue is calcium, in metabolic vasodilation and being made on The Journal’s web site the exploration of mechanisms and it is hoped that this will be an underlying the axial communication of

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by microneurography) that is present during investigators also provide compelling sleep and wakefulness. This often rivals the evidence for an important role of reactive activity seen in patients with congestive oxygen species and hypoxia-inducible heart failure. Acutely, apnoea leads to factor-1 in the cellular and molecular increased sympathetic nerve activity by signalling mechanisms linking intermittent activating the arterial chemoreceptors and hypoxia to sustained sympathoexcitation. by withdrawing the respiratory modulation of sympathetic discharge. This has led to the Considerable data from humans also hypothesis that the chemoreflex is, in part, confirm that chemoreflex control of responsible for the chronic elevation of sympathetic activity is altered with sympathetic activity. Consequently, a major intermittent hypoxia or apnoea. The focus of this themed issue is on the manner potential mechanisms that have been in which the chemoreflex adapts to explored include altered gain, resetting and intermittent hypoxia or apnoea. A hallmark sustained chemoreceptor activation. These of essential hypertension is vascular potential mechanisms and how they may dysfunction, and there is now a growing contribute to the chronic elevation of body of evidence suggesting that sympathetic activity are reviewed by Smith intermittent hypoxia can lead to vascular & Pacchia and Weiss et al. For these dysfunction. Last, since hypertension is a changes in neural control to translate into core disease process integral to the essential hypertension, sustained metabolic syndrome, the possible links alterations of cardiac, renal and/or vascular between sleep apnoea and the metabolic function must occur. Consistent with most syndrome are addressed. forms of hypertension, evidence is accumulating to suggest that endothelial The clinical link between sleep apnoea and dysfunction and impaired vascular control hypertension involves partly the comorbid are a consequence of intermittent hypoxia states associated with sleep apnoea; and thus are likely to comprise a causative however, evidence is growing to support a outcome linking sleep apnoea to causative role of sleep apnoea. The hypertension. Foster et al. review the evidence for this and some of the potential evidence supporting this premise. Finally, mechanisms, including the role of altered the relationship of sleep apnoea to chemoreflex function in patients and the hypertension combined with its association potential link to specific neuromodulators with obesity and diabetes implies that sleep such as angiotensin II and endothelin, is apnoea is likely to grossly increase the risk reviewed by Weiss et al. Brainstem of the metabolic syndrome. In fact, sleep processing of chemoreceptor afferent input apnoea should perhaps be considered a is the primary target for both short-term and component of the metabolic syndrome. The long-term adaptations of respiratory control. final review by Wolk & Somers explores the Long-term facilitation of respiratory control strong evidence linking sleep apnoea to is a model of central adaptation which obesity, insulin resistance, diabetes, lipid appears to play a role in the occurrence dysfunction, inflammatory disorders and and/or protection against apnoea as hypertension, and thereby provides a lines of investigation have emerged to test reviewed by Mahamad & Mitchell. Since compelling argument for its role in the whether there is a causal relationship. The sympathetic efferent activity is chronically metabolic syndrome. resulting literature has consistently shown elevated with non-sustained intermittent hypoxia, it is likely that altered brainstem that intermittent apnoea, in particular This themed issue provides a foundation of processing may be a contributing factor. intermittent hypoxia, is the primary culprit in the primary mechanisms that appear to link How the adaptive mechanisms for the physiological changes accompanying sleep apnoea to hypertension and to the respiratory control and sympathetic neural sleep apnoea which provoke the increased metabolic syndrome. As future research control are related is an important target for risk of hypertension. How this unique extends these findings, this foundation of future mechanistic investigations. The stimulus leads to physiological adaptations knowledge will provide not only the catalyst evidence that chemoreflex function is that can culminate in hypertension has for better understanding of these causative affected by intermittent hypoxia or apnoea been the focus of intense investigation over relationships, but also the potential for new is consistent in both animals and humans. the past 15 years. strategies for treating hypertension and the Prabhakar et al. review the specific other disease processes of the metabolic adaptations which occur at the carotid body The primary physiological mechanism syndrome. linking sleep apnoea and hypertension is receptors and demonstrate that there is the well-established chronic elevation of altered afferent neural regulation from the Michael L Smith sympathetic nerve activity (whether chemoreceptors and altered processing University of North Texas Health Science Center, Fort measured by circulating catecholamines or within the central nervous system. These Worth, TX, USA

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What’s happening in The Society A number of you will be only too familiar with The first of a regular series of short updates to keep you, the problems we have had with the PO Box used for Society correspondence. In this age the Members, informed of the priorities and activities of the of technology, it is amazing that a simple Council and Executive Committee of The Society mechanism such as a PO Box can lead to so much misdirected mail! Despite numerous Two projects that were approved last to monitor what effects this will have. phone calls of complaint to the Post Office, we have concluded that the drawbacks of the use year are now coming to fruition. You There are many challenges approaching of a PO Box number outweigh its benefits and will have seen the new Society logo in in the publishing arena; the introduction the new web site will give the Peer House the last edition of Physiology News and of new technologies, the steady street address for all correspondence. The PO it will be appearing on all Society decrease in requirements for hard copy Box will continue to ‘operate’ in parallel with documents in the coming year. publications and the threats from open direct addressing for a period of time. Development of the new web site is access (see previous Physiology News). well advanced with launch expected in The Publications Committee will significant risk for our future finances early 2007. address all these issues and develop an is the loss of journal income, if open overall strategy for publications from access dramatically reduces At its recent meeting, the Council The Society. In parallel with this subscriptions. To protect the future approved a streamlined committee revised structure, committee activities of The Society, we plan to structure for The Society which aligns membership is also being reviewed and supplement our reserves by depositing with the various functional groups in modified in order to have the required additional sums and re-investing the London and Cambridge offices (see spread of expertise and to keep income from our current investments to Fig. 1). A significant change is to numbers to an optimal level. build a fund sufficient to generate about combine the International and Meetings £500,000 p.a. This would enable The committees into one, which will cover An important topic at the recent Society to continue some of its core all such scientific events whether held Council meeting was Society finances activities in the face of a precipitous in the UK or abroad. The formation of and the budget for 2007. Our financial fall in journal income. A working party a new Publications Committee is also state is reasonably healthy with income has also been formed to evaluate other an important step, prompted by the showing a small rise, however, this is alternative sources of income for The need to take an overall view of The less than inflation. There are a number Society. Society`s publishing activities. We of financial exposures and risks on the produce two prestigious journals, horizon for which we need to budget. As a Society we are always looking for Physiology News magazine and are The Council agreed to put aside ways to improve the quality of our planning a textbook series. This new £400,000 this year into a contingency activities, to be more efficient and to committee will take a strategic view of fund for the IUPS meeting we are provide better services to our all our publication activities and of our hosting in 2013. The plan is to put membership. Some of the projects interactions with publishers. The latter further sums in reserve in coming years underway to achieve this are: a review is particularly timely as our current until we have a total fund of £1 million, of our strategic objectives and of the publisher, Blackwell, has just been to underwrite potential commitments role of Council, a project to develop taken over by Wiley and we will need associated with this meeting. A very physiology teaching resources for secondary and tertiary levels and a new DVD on the importance of animal experiments in advancing medical advances. Pilot projects have also started to evaluate new membership categories, which could build the critical mass of Society membership and increase the awareness of physiology as the fundamental science of life. Plans are well advanced for our main meeting in the summer which will be the first combined event with our colleagues from the Biochemical Society and the British Pharmacological Society. It will be the Bioscience meeting in Europe next year and one that you cannot afford to miss!

Summary of the new committee structure and chairpersons. The activities of the Membership Services Committee will be continued by the Membership and Grants Working Parties, which will report to the Executive Committee. Michael Collis Other committees also have associated working groups, which are not shown on this figure for simplicity. Chief Executive

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Society Meetings New Society Meetings Secretary Prem Kumar looks to the future

In July 2006 at the AGM of The Physiological Society, I was elected Meetings Secretary – a post that I am very proud to hold. This followed ‘shadowing’ Bridget Lumb during her last year in this position and I am grateful for her time and energy in helping me move smoothly into the role. It doesn’t seem so long ago that I gave my first oral communication to Figure 1. The Meetings Secretary, Prem Kumar (on the left) and the ex-Chair of The Society, Giovanni Mann do The Society (although I suppose 22 their Deputy Dawg impressions at the foot of the Great Wall of China on a break during an invited visit to the years is a long time!) and the Chinese Association of Physiological Sciences Meeting in Beijing, November 2006. responsibility can still sometimes seem daunting. Certainly, academic life is The Society held its main meeting in But I would expect that any fee charged quite different now than it was back in Bristol in 2005 and UCL in 2006. This after Glasgow would not be substantial the 1980s. I am aware that, with time year we will meet in Glasgow (9–12 (i.e. relative to the costs incurred in now being such a precious commodity, July) as part of the LifeSciences travel and accommodation). Presently, a only high quality meetings will be well meeting (www.LifeSciences2007.org), in registration fee of £50 for full Members attended and I hope that I am able to collaboration with the Biochemical and and £25 for Affiliates is something that produce these on your behalf. British Pharmacological Societies. Free the Meetings Committee is considering Fortunately, an excellent events team in oral and poster communications will be for main meetings. I understand that the London office, headed by Nick run alongside high quality international any increased cost is unlikely to be Boross-Toby, provides all the support I symposia and the range of themes welcomed and I shall keep you all need. Nick (whom I am sure many of should cover most of our Members’ informed of developments. you have met or corresponded with) interests. This exciting new venture will and his team look after the day-to-day be viewed by all three societies as a 2007 also sees a series of excellent running of meetings, freeing me up to possible template for future focused meetings – in Edinburgh, concentrate on strategic developments collaborations and I hope that our Belfast, Manchester and Bristol – in consultation with my colleagues on Members will make every effort to covering topics that include perinatal The Society’s Executive Committee attend to ensure its success. It is the physiology, ion channels, cardiac and and Council. hope of the LifeSciences Scientific renal function. I strongly recommend Committee that all symposia will be anyone who has not yet attended a Meetings are the most obvious facet of attended by some members from all focused meeting to make an effort to do The Society’s many functions. We now three societies, as the distinctions so, as they are well worth the time, and have an established system, with an between biochemistry, pharmacology the opportunity for interaction with annual main meeting complemented by and physiology become increasingly colleagues is a particular strength of the smaller, focused meetings, and this blurred. There will be a cost to all those format. I have attended several system is, I believe, slowly bedding attending the meeting. I appreciate that recently and I am grateful to all the into your consciousness. A clear list of this is something we have not had to local organisers for their efforts and scheduled Society meetings, and also of consider previously, but as both the BS enthusiasm. Speak to someone who has meetings that we are associated with and BPS always charge a registration attended a focused meeting - they will (through The Journal of Physiology, fee, we have been requested to follow be very supportive of the concept, as it collaborations with other societies or suit. That said, Society meetings have appears to fill an important niche part sponsorship of other physiology­ stood out for being the last of the free between the major meetings on the related meetings) is available at (i.e. no registration fee) meetings on the international circuit (e.g. EB, http://www.physoc.org/meetings. The list is international circuit (at least to my Neuroscience, ATS, etc.) and the much long and covers a wide range of topics. knowledge). It may be that we should smaller, often invitation-only, ones that Together with a generous grant support consider this carefully in the future if not everyone can attend. scheme, it should be possible for all we wish to produce high quality Society Members to attend some meetings in light of any potential Looking ahead, the main meeting in meetings of interest each year to which shortfalls in our income due, for 2008 will be at the University of The Society has contributed. example, to open access publishing. Cambridge and the deadline for

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Table 1. Consolidation of Special Interest Groups (SIGs) of The Physiological Society into themes. The present list of SIGs are shown, abbreviated in rows, and each is associated (with a X) to a number of themes (listed in columns) that cover the range of interests of Members. Each SIG is associated with two or more themes and each theme has a significant number of SIGs associated with it. This matrix is not definitive, but should provide a starting template for how future, non-main, meetings might be organised around themes rather than SIGs.

BBB Blood brain barrier; CRAC Cardiovascular, respiratory & autonomic; CN Cellular neurophysiology; CS Cellular signalling; CIN Comparative & invertebrate neuroscience; CP Comparative physiology; DP Development & plasticity; EMT Epithelia & membrane transport; GIT Gastrointestinal tract; HCM Heart & cardiac muscle HP Human physiology; IC Ion channels; L Locomotion; MEP Microvascular & endothelial physiology; MC Muscle contraction; NE Neuroendocrinology; PP Placental & perinatal physiology; RP Renal physiology; Resp Respiratory physiology; SMC Sensorimotor control; SF Sensory functions; SM Smooth muscle; SSP Somatosensory physiology; TW Teaching workshops. symposia applications will have passed your SIG to be more active, pester your main meeting) four, 3 day meetings by the time this magazine is published. SIG convenors – or me! each year, based around a single, We have already begun preparations focused symposium but, in addition, and I am very hopeful for an excellent A call for a venue and host for the 2009 with space allocated for free meeting in attractive surroundings. main meeting will go out during March communications to be presented within More details nearer the time, but please 2007 and I hope that we are able to a physiological ‘theme’. Table 1 shows try to keep 14–16 July 2008 free in attract a number of high quality bids. If a matrix with all current SIGs in rows your diaries. Although the annual you want The Society to spend some and a smaller set of themes in columns. meetings may appear to be symposia­ sunny days at your site, please Themes have been determined on the driven, there are many free oral and download the forms in March, talk to basis of our Members’ interests and are poster communications that are the relevant people in your institution not as arbitrary as they might seem at organised through our Special Interest and send in an application. Please don’t first glance! From the matrix, you can Groups (SIGs). We have recently held a hope that someone else will do it for see that all SIGs fit into two or more number of SIG convenor elections and you and remember that our events team themes (Xs in rows) and each theme I am looking forward to working with now handles much of the organisation has a minimum of six associated SIGs all the convenors to ensure high quality and administration and your department (Xs in columns). Bids to hold themed sessions. I expect to increase the need no longer close down for the meetings will be selected by scientific number of slots available for oral duration of the meeting! quality and timeliness of the communications at Cambridge as this is symposium proposed. I believe strongly something that some Members have Some Members have raised concerns that the scientific quality should take requested and it seems reasonable to try about a reduced opportunity to present priority in our selection process and to accommodate this. If you wish to oral communications within the new will be using external review processes present on any topic, I can guarantee format of meetings. I hope that a subtle to ensure the quality is as good as it can (provided it is ethical and has scientific change might begin to address this. be, perhaps, for example, by suggesting merit) that it will be timetabled. There Thus, from 2008, we will begin to see alternate or additional speakers. Of the is no reason why any Member should what will be called ‘themed meetings’ 3 days of a themed meeting, the not be able to present original work at rather than ‘focused meetings’. Briefly, symposium element will fill no more the annual meeting and if you wish the aim is to run (in addition to the than two thirds of the time available,

Physiology News | No. 66 | Spring 2007 | www.physoc.org 46 PN SOCIETY NEWS/PARLIAMENTARY AND SCIENTIFIC COMMITTEE with the remaining time devoted to free attend! Themed meetings should thus communications from any SIG linked provide an opportunity, in addition to with the theme. One aspect of themed the main meeting, for free meetings is that there will be no communications to be presented to a parallel sessions and attendance is large, knowledgeable audience and in limited to between 100–200 people. In an environment that encourages an addition, themed meetings need not be exchange of ideas. They should also held at a university if a cost effective contain cutting edge science and be fun alternative (and, hopefully, attractive) to attend. The aim would be, within any venue can be found. There are many of 2 year period, for any Member to be these places around the UK and it able to present original work at the two should make for greater interest if we main meetings plus at least one, if not meet in different surroundings from two, themed meetings with a mean gap those in which we usually congegrate. of around 6 months between attendances. Are patients safe with the Perhaps an example may make things clearer. Let’s say someone was In progress are plans to hold a joint NHS? successful in a bid to hold a themed meeting with the Chinese Physiological This debate was inspired by recent meeting in 2008 under the theme of Society in Beijing during October or House of Commons Public Accounts Cardiovascular, respiratory and November 2008 (see Fig. 1) and a joint Committee comments on safety aspects autonomic with a symposium on, for meeting with FEPS (perhaps in within the National Health Service: example, Ion channels, mitochondria Scandinavia) during 2010 as well as the IUPS meeting in the UK in 2013. These and O2 sensing. This might involve Every day over one million people are around 12 speakers being invited to talk large-scale ventures are an exciting treated successfully by the NHS. at the symposium – selecting from a opportunity for our Society to interact Although patient care is generally of a range that includes not only the key, on an international scale and to high standard, the scale and complexity recognised physiology PIs in this field showcase our strengths. of patient interventions means that but also young investigators and patients can sometimes suffer Of course, the success of the meetings perhaps clinical staff and researchers unintended harm, and official estimates depends, ultimately, upon Members from other disciplines (biochemistry, show that one in 10 patients admitted submitting great ideas for symposia, for biophysics, engineering, mathematics, to NHS hospitals is unintentionally themed meetings and free etc. as appropriate) to produce an harmed. There were 940,000 reports of communications arising from original interesting mix of cutting-edge talks incidents and near misses last year, work and I hope that many of you will that should enable full discussion on which include blunders ranging from be encouraged to apply or to submit the topic. In addition, posters and oral medication errors and drug interactions original work to either the main communications would be submitted to missing emergency equipment and meeting and/or the themed meetings. I that allied with the symposium topic, the wrong limbs being amputated. am optimistic for the future of our but also any posters and oral Even more patients are at risk since this meetings and hope that optimism is communications from the eight SIGs does not include 300,000 reports of shared by many of you. The annual associated with this theme (see Table 1) hospital-acquired infections each year calendar of meetings (see the Society would be appropriate. It would be my including MRSA. Around 50 per cent web site) contains information on the job – with Nick Boross Toby and Heidi of all actual incidents might have been dates of all calls and I will ensure that Adnum in the London Office, the avoided if NHS staff had learned reminders are sent out when symposium organisers and related SIG lessons from previous ones. There are appropriate. The forms are very simple convenors – to produce a programme big differences between similarly-sized indeed to fill in as the London Office that accommodated all submissions trusts in the number of incidents does much of the work regarding appropriately. If, for example, one day reported. Massive under-reporting of budgets, etc. What is required is the were put aside for free oral deaths and serious incidents means the continued, creative input from the communications only, this would NHS has no idea how many people are membership to generate high quality provide around 28 15 minute slots in dying each year from patient safety sessions. I look forward to meeting addition to the posters and any selected, incidents. symposia-related orals. If this were to Members and listening to any views on how we might improve what we can be held at Birmingham, for example, However it was noted that these offer in terms of meetings, but ask only the meeting might be held within the startling statistics are not significantly that you appreciate that it isn’t possible conference facilities of our excellent different from those reported in several to please everyone – at least all the City Botanical Gardens with the main other developed countries. dinner perhaps on a canal boat. I time! promise you, I haven’t arranged such a Prem Kumar The debate at the Parliamentary and meeting – but it does sound like one I’d Meetings Secretary Scientific Committee on 20 November

Physiology News | No. 66 | Spring 2007 | www.physoc.org PARLIAMENTARY AND SCIENTIFIC COMMITTEE PN 47 asked ‘How can the further application very good surgeons tend to work manufacturers, etc. It is important to of science, technology and engineering regular daytime hours, with less get people together from different parts help to improve a situation arising experienced surgeons handling the of the system to map out and predominantly as the result of human difficult emergency cases that tend to understand each other’s problems. We failure?’ Lively discussion of this appear during anti-social hours. need to really understand what happens important issue was kicked off by However, it is possible to judge the in healthcare systems and build in more presentations from Bill Murray (Acting overall performance of individual safety. Ergonomists believe that we Chief Executive of the National Patient surgeons against expected success rates should never train people in a system Safety Agency), Tom Treasure (General and to challenge ‘bad’ surgeons. This that is intrinsically unsafe. Thoracic Surgeon, Guy’s Hospital) and needs to be a confidential process to Peter Buckle (Robens Centre for Health encourage surgeons to admit to The ensuing discussion agreed that Ergonomics, University of Surrey). mistakes and seek further training etc. improving systems was a good idea, but if necessary. There are also inherent asked where is the balance if we are not Bill Murray, an engineer by problems in trying to establish an to increase NHS overheads too much? background, said that the National effective national monitoring system, The speakers responded by saying that Patient Safety Agency, a separate and in particular in trying to set the improved safety systems are not organisation from the DoH, was ‘alarms’ to flag where action needs to necessarily expensive, and are likely to founded in July 2001 in recognition of be taken. Like a burglar alarm system, prove value for money as a litigation the fact that although NHS safety it can’t be too sensitive in triggering culture increasingly takes hold in the records were respectable by false alarms, but has to be capable of UK. It was acknowledged that good international standards, improvements detecting genuine intruders. He doctors share knowledge of risks with were possible, and it was important to concluded that the NHS needed more their patients to promote patient buy-in implement systems where patient safety safety to be in-built into its equipment and informed consent. Engineers in could be improved by learning from and processes. other industries emphasise the experience. The NHS is a very importance of training to cultivate complex system, but it should be Peter Buckle stressed the importance of attitudes where safety is always kept in possible to learn from other industries. taking an ergonomics approach, mind. BPS raised the issue of medical For example, it has often been found in designing safety systems with the end students no longer being trained in a the analysis of major accidents such as user firmly in mind. He works with rigorously scientific manner how to the Challenger disaster, that the systems engineers, cognitive prescribe, this was likely to eventually problems arose from the complex psychologists and designers. He gave a lead to more errors in doctor’s interactions of multiple factors rather very thought-provoking example of surgeries. For patient safety and ease of than a single cause of failure such as how to build in potential errors into use, medical equipment should be one individual. Similar systems failures prescribing systems, many of which standardised, but this runs counter to can strike the NHS. The NHS is regularly occur. This includes giving manufacturers’ desires to differentiate currently trying to emulate the sort of medicines similar names and their products. Linguistic problems also sophisticated safety processes packaging, not putting the name of the arise, medical staff recruited from developed in the airline industry, with a drug onto the pills so people forget abroad may not have good English, and focus on trying to build a no-blame what they are when separated from many patients also cannot speak culture to increase reporting of their packaging (e.g. by patients putting English. The meeting concluded with a incidents in a national reporting and them into personal pill bottles), putting strong feeling that the NHS was learning system. New integrated risk vital contra-indications information on generally doing a good job but that management approaches also seek to sheets of paper separate from organisations like the National Patient involve patients, their families and the packaging which patients then throw Safety Agency needed to be supported general public in improving systems. away, using small font sizes that people in their efforts to improve safety with poor eyesight can’t read, etc. etc. systems. Tom Treasure noted that hospitals, by Yet we expect the right patient to take their very nature, are high risk places. the right life-saving drug at the right Liz Bell They concentrate sick and dying people dose at the right time! This can be a big alongside strong medicines and sharp problem for elderly people trying to Scientists and the UK instruments. We should focus on the manage multiple medications, and can Parliament positive – the nation is far safer with an have appalling results when it goes Established in 2001 by The Royal Society NHS than without one. Analysing what wrong. How do we change this? Buckle as part of the Science in Society goes wrong in individual cases can be felt that the NHS doesn’t see itself as a Programme, the MP/Scientist Pairing very complex. Surgical cases can be high risk industry, yet it needs to if Scheme aims to build bridges between very complicated, and it can be difficult safety issues are to be effectively some of the best UK research workers and to see which of a long series of managed. He noted that the NHS is a MPs. To date over 80 scientists and MPs treatment steps caused the problem. very complex system with incomplete have taken part.For more information visit The system is also skewed in that the feedback between medics, patients, http://www.royalsoc.ac.uk.

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excellent but grant income is low and thoughts about important matters to outputs may be relatively sporadic. address in the next year or so please let Research in systematics is an example us have them via your Council. Another New Year has arrived. I hope where these anxieties are relevant. that it brings you all the important We are quite pleased by the number of things you seek and few of those that Third, and following from the previous ‘hits’ our jobs link page received during you do not. point, the BSF thinks it likely that vice 2006. You may remember that this was chancellors will inevitably move to a new initiative for us and is aimed to From a political point of view I fear support most those areas of the provide a resource for postdocs. I write that the latter will not be true. The biosciences most suited to whatever ‘quite pleased’ because we are fully discussions about the future of the RAE algorithm that emerges. These areas aware that all web sites can be have now reached a critical point. The will, of course, ‘do well’. improved. If you – or junior colleagues momentum towards the abolition of not members of the Society – have a peer review panels and the introduction And finally, and personally, because I thought about how improvements could of a metrics only based RAE continues. have had too many computer generated be made please contact Dr Emma This change is supported strongly by letters from non-existent bank Southern ([email protected]). In many of your employers! External to managers based on incorrect fact, please contact us about any bright Government, the main supporters of the information or a ‘mistake’. I have ideas that you may have concerning the metrics only approach are university always managed to receive an apology BSF. I don’t promise to pursue them vice chancellors and The Academy of and charges reimbursed. I doubt that all, but I do promise to ‘cherry pick’ the Medical Sciences. All other you will get (m)any apologies out of very best for consideration! ‘academies’, including The Royal the RAE! Society, the Royal Society of Once again my best wishes for 2007. Chemistry, the Institutes of Physics What can you do about this situation? and Biology, and – of course – the Well, of course, you can continue to Richard Dyer Biosciences Federation are strongly support the BSF and I would welcome Chief Executive Officer opposed to the abolition of peer review your ideas about how costs can be panels. We want these panels reduced effectively and peer review Editor’s note: Congratulations to Richard maintained and we want them informed panels maintained. If you do decide to Dyer (below) on his OBE in the New Year by robust metrics including those write to me, please make it brief and let Honours List for services to biology while relating to output. me have your views by the 21 working as Director of the Babraham February. Some of you could also start Institute in Cambridge. The main argument for change is to an interesting discussion with your reduce costs – including those costs employer! associated with time. We agree that strenuous efforts should be made to There are quite a few issues emerging implement clear and substantial that will have an effect on your reductions in the bureaucracy professional lives. By the time that you associated with the RAE and believe read this, I will have met with a task that there should be serious discussion force to discuss the BSF response to a about how can this be achieved. A paper published by the Research metrics only approach will achieve a Councils’ on peer review and our cost reduction but this is not at all the response will be on our web site. If right route to follow. Why do I write you haven’t seen the Research this? Councils’ proposals, you might like to BSF database download them The BSF will be creating a database of UK First, because the BSF holds the view (www.rcuk.ac.uk/research/peer/efficiencypr.htm). scientists who have high level expertise in that it is potentially dangerous to rely I don’t wish to prejudge our response to policy work, who can be contacted when on an algorithm for an activity as these proposals, but I am 100% relevant expertise is needed. The database critically important as the RAE. We confident that we will not be 100% will be for BSF use and will not be made think it essential that there is some wise supportive – and nor will you! available to others. We are looking for evaluation of the quality of the data fed Members of The Physiological Society who into the formula. I am anticipating a busy year. have top level experience of policy work However, I don’t want all the activity to that may be useful for the BSF. Examples Second, because the BSF thinks that a be reactive. A proactive position, taken of the experience that we seek might metrics based formulaic approach will at the right time, can often be more include membership of a Royal disadvantage some areas of the influential than ‘fire fighting’. Ideally, Commission, Chair of an RAE Panel or a biosciences. We are particularly I should like some of the issues where Research Council Committee. If you are concerned about those important we should trigger debate to come from interested please contact Liz Bell disciplines where research is truly our member organisations. If you have ([email protected]) as soon as possible.

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glowing as this you might get a job as a molecular biology advisor to the Chetchen government. Ethics kills! Take scientific ethics Can you prove it, and if you can you win but actually you too seriously and kiss your career lose goodbye Proving wrong-doing is difficult, make an allegation and management’s instincts will be to protect the money supply (i.e. your boss). Scientific institutions are circulating guides naïve and looked at some air tickets brought Just suppose you can provide cast iron on ethical behaviour. But before developing with some grant money. I didn’t realise that evidence of fraud, and management have a conscience and becoming a ‘grass’, junior my boss’s wife and 9 year old children were been unable to hide the evidence or discredit staff should think about the consequences researchers who could present posters at an you. You win. But your boss is discredited, very carefully. international conference. Then I realised it he resigns or is sacked. Then your Reading recent articles about fraud, a young was in the West Indies. Even minor ego laboratory is closed scientist might be tempted to report any driven irrelevancies including consumables malpractice. But, if you would like your and staff need money. If the money What do you do now? Try writing on your cv career to survive and your PhD to enable disappears, you will be public enemy number in the key skills section ‘responsible for the you to perform research and not land a one. Scandal will also damage the money­ molecular destruction of my last laboratory’ tenure track position stacking shelves in a making potential of other labs in your or ‘I uncovered fraud. My last boss is now supermarket, don’t breathe a word. institute. Nobody will like you, not your boss, living in the Cayman Islands under an your co-workers, management and assumed name, nobody will speak to me, At an institution where I once worked a especially your boss’s ‘associates’. frightening incident occurred. It began three Science papers have been retracted innocently enough. A researcher was and my last employers had to pay me a What about your boss’s fortune in compensation. Oh, you can now accused of fraud and ‘persuaded’ to resign. ‘associates’? Then a sinister document called On being a read the entire thing on the front page of this scientist, responsible conduct in research Nobody likes a ‘grass’ – it’s not the weeks Nature.’ landed on our desks. Published by the Sopranos, you won’t be shot dead in the squeaky clean, United States National woods by a fat sociopath wearing white What should you do if you find out anything Academy of Sciences, it describes a range socks but your career will be. In any field ‘scientifically unethical’ of unethical situations. It doesn’t specifically there are usually about 10 people you could mention cloning a range of domestic pets but work for – our boss will know them all. As an insurance policy, collect as much it does mention fraud, and what to do about Cause a scandal and every single one of written or computer evidence as you can. it. This usually involves going to see a them will be informed. Nobody will be silly Make copies and secrete them where they responsible adult in a senior position who enough to put anything in writing but without cannot be recovered and ‘lost’. You might will sort things out in a professional manner. the support of the National Security Agency think I am paranoid, but at one place I This was accompanied by a letter oozing your boss’s telephone conversations will be worked a disgruntled former employee tried patrician contempt suggesting that junior very hard for you to legally monitor. Every to sue. A day later my boss smugly staff were moral neophytes who needed time you apply for a job your boss’s announced that he had been told to shred reminding of our ethical responsibilities. So, ‘associates’ will be quietly reminded that you and delete anything incriminating by the we just chucked it on our desks and forgot are untrustworthy, a source of trouble, and a head of the institution. about it. When we did get round to reading ‘nutter’. You will also acquire a number of it, we all came to one overwhelming bizarre and unpleasant sexual peccadilloes, If you witness fraud say absolutely nothing, conclusion: taking this document seriously especially if you are female. In a tribunal or just quietly get out and get another job – it’s will lead to a fast tenure track career path – court case every single one of your boss’s’ cowardly but the repercussions of a straight to your local unemployment office. ‘associates’ will step into the witness box conscience could be devastating. This is a and perjure themselves senseless. Went to cynical, dishonest but realistic view. If you Before ‘grassing’ or ‘reporting an incident Oxford with Professor Johnny Fraudulent, are lucky enough to obtain hard evidence using the correct procedure’, consider the ‘diamond geezer’, lovely rower, mainstay of and you are threatened as a result of wrong­ consequences. Will you have a job to go to, my local Masonic lodge, research assistants doing simply use it to cut a deal, get will you be victimised, so you won but will making allegations should be strung up. management to provide you with some good you still have a lab to work in? Consider this references or redundancy money and – everything about scientific research is Can you afford the legal fees? Your continue to pay your mortgage. dependent on one thing: money. institution will be spending a bottomless pot of other people’s (tax payers) money on Derick Guillemot* Specifically the money your boss and extremely expensive barristers, if you are *Derick Guillemot is a nom de plume. Derick has worked in five institution can bring in. The expensive swivel lucky you might get a dodgy legal aid labs in the last 20 years and has witnessed fraud in two. In both chair that your boss parades in front of solicitor. Who is likely to lose? If you are cases the culprit was the head of the lab. In one case 10 members of a lab all developed amnesia. Derick’s current boss visitors. Their ‘little perks’! Years ago I was really lucky, with an employment history as is entirely clean.

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The trouble with medical reality more journalistic than scientific journals, providing that it does not (when was the last time you cited an debase the value of what the journal journals article in a medical journal in a publishes. Press releases on high impact By Richard Smith scientific manuscript?) topics can be valuable as long as they are kept under control. 2006, Royal Society of Despite his long career in medical Medicine Press. 292 pp. publishing, Smith has a critical I found the sections of the book dealing with open access and the future of £19.95 viewpoint on many of its aspects: ‘All publishing particularly interesting as ISBN 1 85315 673 6 publication is theft!’ He does not believe that peer review is of value, in they are issues of direct relevance to The trouble with medical journals is an its current form. He suggests it is an Society publications. Smith outlines a authoritative, well written book based unproven system that involves bias, the number of pros and cons for the open on the author`s many years of potential for theft of ideas, undue access/author pays model: experience as Editor and Chief influence of the author’s name or Executive of the British Medical institution on reviewers’ decisions and For open access: Journal (BMJ). It covers the nature and a bias against negative results. One • greater dissemination of ideas values of medical journals, the wonders whether he is really criticising generates more ideas processes and problems of publishing, the system or particular reviewers and • the public (?) should not have to pay relationships with the media and editors. To my mind a scientific twice for research results pharmaceutical companies, ethics and publication lives or dies by the quality • the added value of peer review and future scenarios for medical publishing. and impartiality of its reviewers and distribution of publications is limited Reading the book made me realise how editors. Encouragingly, Smith does • publishers make too much money different medical journals are from the make some useful suggestions to from scientific publications scientific journals published by The improve the peer review process, e.g. • academic credit for the quality of Society and that some of the problems blinding of author name/institution, research will become uncoupled from the author raises are specific to the training for reviewers and their publishing in ‘high impact’ journals. former. Medical journals are essentially identification to the author. Against open access: magazines for doctors and, • publishers do add value increasingly, for patients. They can, The book deals in some detail with the • peer review maintains quality occasionally, publish articles that would relationship of medical journals with • open access as a business model is be unlikely to pass peer review in a the pharmaceutical industry and the untried and may collapse scientific journal worth its salt and this media. The former is regarded as an • open access ‘journals’ may not can have disturbing consequences. The essentially unhealthy relationship. Most survive and archival data will be lost author cites the paper by Wakefield medical journals derive a significant • many researchers cannot pay to have (published in The Lancet) on autism part of their income from their research published and this and the MMR vaccine, as an example pharmaceutical advertising. This allows model penalises high productivity of how publication of a scientifically the journals to be provided free to labs and those in developing flawed study can have a major impact many doctors. Doctors should not countries on public perception. However, he goes expect the pharmaceutical industry to • authors paying for publication on to suggest that publication of articles support their education through encourages ‘vanity publishing’. containing little supportive evidence is provision of journals. However, this appropriate for medical journals culture of interdependence, with both Overall he comes down on the side of because they provoke debate. The parties being willing participants and open access for research papers, but problem is that the public and the beneficiaries, will be hard to change. sees a changing role for medical and media interpret what is published in a One wonders how many doctors would scientific journals. He suggests that the medical journal as always being pay to receive medical journals? The future role of journals will be to add scientifically sound! dependency of medical journals on the analysis and interpretation to the pharmaceutical industry isn’t just research data. This analysis, review and Smith suggests that, although the financial, they need to publish the latest interpretation will add value and should original audience for medical journals clinical trials (supported by industry) to therefore justify subscription fees to was doctors and medical students, it is maintain their relevance and impact. It journals. This is the reverse of the increasingly the public and the patient is unlikely that this relationship will be current approach for many scientific that are accessing these sources for broken, but Smith suggests that it could journals, which charge for access to medical information. He sees the role be improved by making it more ‘at research papers but make review and of medical journals as being arms length’. With respect to relations analysis articles available for free. educational, provoking debate and with the media, he provides a number Another interesting suggestion is that in laying the background for political of cautionary tales but concludes that an open access world, authors change where it relates to medicine and interactions with the media are often submitting manuscripts for review public health. Medical journals are in valuable to the public and to the could pay for the peer review process

Physiology News | No. 66 | Winter 2006 | www.physoc.org BOOK REVIEWS PN 51 on a sliding scale. Thus, a minimum This book is probably unique in the oesophagus, liver, stomach and bladder, payment would be required for initial depth of analysis it provides into the among others. It's enough to stop you triage and payments would ramp up if world of medical publishing. It is also going out until the smoking ban is the manuscript went for editorial relevant in a number of areas to (finally) introduced, and then only to review and would be the highest if the scientific journals. It doesn’t make places serving mineral water and author requested detailed comments ‘comfortable’ reading for those cranberry juice. from the reviewers. involved in the publishing or editing of medical journals, but is challenging and But for those with a strong constitution, Smith concludes his book by thought provoking. Has the author this useful book brings together current considering various future scenarios: written this book now that he has thoughts on the mechanisms by which 1 No change to the current system retired from the BMJ as a ‘swansong’ alcohol and tobacco initiate and (unlikely). for medical journals? I don’t think so. promote cancer. 2 All research data open access and What is certain is that the publication author pays for publication. Peer and dissemination of medical and other The first chapter gives a very brief review is an open process. Magazines scientific information is changing overview of general mechanisms of (journals ?) provide added value by rapidly and we are just at the beginning carcinogenesis. This is followed by 11 providing comment and analysis and of this process. chapters discussing the role of alcohol are funded by subscription and in cancer, including epidemiology, interactions between alcohol and advertising. Scientific prowess will Mike Collis be assessed by the number of ‘hits’ tobacco, reactive oxygen radicals, on a research paper and by the pancreatitis and pancreatic cancer, practical benefits of the research Alcohol, tobacco and cancer breast cancer risk, and liver cancer. The final seven chapters discuss aspects of (improved healthcare practise in the Edited by C H Cho and V case of medical research). tobacco and cancer, including Purohit. 2006. Karger epidemiology, the role of nicotine 3 All scientific information exchanged (Basel). 312 pp. US$207.25 (which is a cellular mutagen, via the internet within specialist user carcinogen precursor and mitogen, as groups. No role for publishers or ISBN 3-8055-8107-6 well as being addictive), and an journals (archiving would be a real Of the estimated seven million cancer approach to prevention based on problem in this scenario). deaths in 2001, 2.5 million or 35% developing a vaccine to nicotine. It's 4 Large companies control and were associated with potentially good to see the latter. disseminate all medical information modifiable risk factors, prominent (a big brother scenario which also among which are alcohol and tobacco. When as much money is being spent on seems unlikely). Excessive alcohol consumption is research into primary and secondary associated with cancers of the mouth, prevention, as is currently spent on In addition to the topics I have pharynx, larynx, oesophagus, liver and investigating the arcana of established discussed in this review, the book also colon. Smoking, in addition to causing (but incurable) disease, we'll know that has extensive sections on the ethical cancers of the mouth, phaynx, larynx, real progress is being made. accountabilities of authors and of trachea, bronchi and lungs, is also publishers. associated with cancers of the John A Lee

Would you like a free book for your bookshelf? The following recently published books are available in The Society’s Publications Office and offered free to any readers who would like them. Please apply to [email protected]

• Programming the cerebral cortex (Stephen Lomber and Jos Eggermont) • The nuclear envelope (Edited by D E Evans, C J Hutchison, J A Bryant) • Wellcome Witnesses to Twentieth Century Medicine The MRC Applied Psychology Unit (Volume 16) The rhesus factor and disease prevention (Volume 22) Prenatal corticosteroids for reducing morbidity and mortality after preterm birth (Volume 25) • Electric fields of the brain - the neurophysics of EEG (Paul L Nunez, Ramesh Srinivasah) • Diversity in the neuronal machine - order and variability in interneuronal microcircuits (Ivan Soltesz) • Brain development - normal processes and the effects of alcohol and nicotine (Edited by Michael W Miller) • Neuroglycobiology (Edited by Minoru Fukuda, Urs Rutishauser, Ronald Schnaar) • Long-term potentiation - enhancing neuroscience for 30 years (Tim Bliss, Graham Collingridge, Richard Morris)

Physiology News | No. 66 | Spring 2007 | www.physoc.org 52 PN NOTICEBOARD

Notices for the Summer 2007 issue of Physiology News should reach the SOCIETY MEETINGS/INTERNATIONAL WORKSHOPS Publications Office by 23 April. Please Krakow, Poland send contributions to [email protected] 9–12 May 2007 International Workshop Endothelium: the determinants of cardiovascular health AMERICAN THORACIC SOCIETY or disease San Francisco Glasgow, Scotland, UK – Life Sciences 2007 18–23 May 8–12 July 2007 International Conference for clinicians Joint Meeting of The Physiological Society, Biochemical Society and British and basic science researchers Pharmacological Society (see details, below). Honorary Member Denis Noble specialising in various areas of (University of Oxford) will give the Paton Lecture pulmonary, critical care and sleep Manchester, UK medicine. 5–6 September 2007 http://www.thoracic.org Focused Meeting Cardiac electrophysiology: with a special celebration of the centenary of the discovery of the sinoatrial and atrioventricular nodes TRAVEL GRANTS Bratislava, Slovakia New travel grant deadlines for 2007 are 10–14 September 2007 now available at Joint Meeting of The Physiological Society, the Slovakian Physiological Society http://www.physoc.org/grants and FEPS Lviv, Ukraine SOCIETY FOR ENDOCRINOLOGY 18–23 September 2007 An essay-writing competition for International Workshop Molecular physiology of membrane transport and undergraduates, with a first prize of cellular signalling £1,000 and two runner-up prizes of Bristol, UK £250 each (deadline 23 March) 17–18 December 2007 http://www.endocrinology.org Focused Meeting Renal cortex: physiological basis of glomerular and tubular diseases Cambridge, UK For news updates visit our online 14–16 July 2008 noticeboard at Main Annual Meeting http://www.physoc.org/news http://www.physoc.org/meetings (for Meetings) http://www.physoc.org/international (for International Workshops)

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