PHYSIOLOGYNEWS

spring 2006 | number 62

Meetings Manchester Portugal Brazil Beijing, China

Also featuring: A clinical scientist’s week Physiology in the extreme Letter from Korea An only transporter is a lonely transporter Dying for a good night’s sleep

A publication of The Physiological Society The Journal . To submit a . To of Physiology For furtherFor information go to: http://jp.physoc.org or email: [email protected] related Call for papers: Symposium proceedings will be published in a special issue of http://jp.physoc.org related manuscript for manuscript for related in the issue, inclusion please visit: SYMPOSIA www.jphysiol.org www.jphysiol.org ang (Secretary is published by Blackwell Publishing on behalf of the Physiological Society in (Ireland) Hikaru Suzuki and G David S Hirst David S Hikaru Suzuki and G Tadao Tomita Tomita Tadao President: Chairmen: Speakers: (Japan) Komuro Terumasa tract in GI Structure and organization of ICC Hirst (Australia) David S G stomach Role of ICC in generation of organized movements of the Hikaru Suzuki (Japan) muscle Factors modifying the frequency of slow waves in gastric (USA) Sean Ward transmission in GI tract Involvement of ICC-IM in neuroeffector Kenton Sanders (USA) ICC at the clinical and scientific interface Noel McHale (Ireland) in urinary tract Organization and function of ICC Rick Lang (Australia) Role of ICC in upper urinary tract Hikaru Hashitani (Japan) Interaction between interstitial cells and smooth muscles in the lower urinary tract and penis Gerard Sergeant Ca imaging in urethral ICC Involvement of interstitialInvolvement cells of Cajal in the control of excitability smooth muscle 2006 22 July, Saturday, at the Japanese Society for Smooth Muscle Research, Okayama, Japan The Journal of Physiology 24 fortnightly issues in eight volumes. For further information go to Representatives of The Physiological Society and the Chinese Representatives of Association of Physiological Societies meet to discuss a joint scientific meeting in Beijing, China in 2008 (see related article on From the left: p. 11). Secretary elect), Prem Kumar (Meetings Bridget Lumb (Meetings Secretary), Xiao-min W General of the Chinese Association of Physiological Sciences), General of the Chinese Yao Tai Giovanni Mann (Chairman of the Executive Committee), Association of Physiological Sciences) (President of the Chinese and David Eisner (International Secretary). PHYSIOLOGYNEWS Editorial 3 Meetings Manchester Focused Meeting – New university, new buildings, new The Society’s dog. ‘Rudolf Magnus gave staff Maynard Case 4 me to Charles Sherrington, who gave me Portugal Focused Meeting Margarida Amaral, Mike Gray 5 to Henry Dale, who gave me to the Physiology in Brazil – Andy Ramage, Ted Taylor, Thelma Lovick 7 Physiological Society in October 1942’ Joint Meeting of the Chinese Association of Physiological Sciences and The Physiological Society in Beijing, China 11 Giovanni Mann, David Eisner Published quarterly by the Physiological Society A week in the life of ... Contributions and Queries A clinical scientist Tim Lang 12 Executive Editor Letter from ... Korea Insuk So, Sung Joon Kim 14 Linda Rimmer The Physiological Society Publications Office Physiology in the extreme P.O. Box 502 John Coote, Thelma Lovick 16 Cambridge CB1 0AL Features UK How ion channels and transporters affect metastasis Christian Tel: +44 (0)1223 400180 Stock, Albrecht Schwab 19 Fax: +44 (0)1223 246858 Multimerisation – an only transporter is a lonely transporter Email: [email protected] David Meredith, Richard Boyd 20 The Society web server: http://www.physoc.org A new muscle sense? Uwe Proske 23 Magazine Editorial Board Sympathetic nerve activity and cardiac output: an integrated Editor balance with implications for blood pressure regulation 25 Austin Elliott (University of Manchester) Nisha Charkoudian, Michael Joyner, Gunnar Wallin Members 2+ Lesley Anson (Nature) Ca sparks – SOS signals of struggling muscle Elena Isaeva, Patricia de Winter (King’s College London) Vyacheslav Shkryl, Natalia Shirokova 27 Sarah Hall (University of Cardiff) Dying for a good night’s sleep Victoria Cooper 29 Munir Hussain (University of Liverpool) Vagal nociceptors in the oesophagus Martin Kollarik, Bradley John Lee (Rotherham General Hospital) Thelma Lovick (University of Birmingham) Undem 31 Bill Winlow (Prime Medica, Knutsford) Calcium signalizing in developing mouse skeletal muscle fibres Joana Capote, Pura Bolaños, Carlo Caputo 33 © 2006 The Physiological Society A racing start for the heart in exercise Valerie Gladwell 35 ISSN 1476-7996 Light up the signal fires – imaging calcium’s protein partners The Society permits the single copying of Stephen Bolsover 37 individual articles for private study or research. For Noticeboard 32, 36, 39, 40 copying or reproduction for any other purpose, written permission must be sought from The Obituaries Physiological Society ([email protected]). A Murray Harper Sheila Jennett, James McCulloch 38

Opinions expressed in articles and letters submitted Letters to the Editor 39 by, or commissioned from, Members, Affiliates or Nobel Prize 2005 39 outside bodies are not necessarily those of The Physiological Society. Unbelievable! 40 The Society’s journals The Physiological Society is registered in England The Journal of Physiology Carol Huxley 41 as a company limited by guarantee: No 323575. Registered office: PO Box 11319, London WC1X Experimental Physiology John Coote, Peter Hunter 42 8WQ Affiliate News Registered Charity: No 211585. Where are all the women going? Patricia de Winter 44 Printed by The Lavenham Press Ltd Young Physiologists’ Symposium Melissa Grant, Richard Siow 44 Medical education and the arts Mary Forsling 46 Society News Cover photos Celebrity diets, obesity and hormones Liz Bell 46 Meetings Bridget Lumb, David Eisner 47 Parliamentary and Scientific Committee Liz Bell 49 Competing with football in Dublin Society for Experimental Biology 50 A word from the Education Officer Donna Brown 51 Teachers’ Workshop at Coventry University Ray Carson 51 Science learning with a difference Donna Brown 52 Biosciences Federation Clockwise from top left: caiman, capabari, iguana and a group of caiman. Student employability – whose job is it? Sarah Blackford, 53 From Ramage A, Taylor T & Lovick TA. Physiology in Brazil. pp. 7-10. Dariel Burdass, Sue Assinder Book Reviews 55 PHYSIOLOGYNEWS

Action points Guidelines for contributors In this issue Grants These guidelines are intended to assist Welcome to another issue of For full information on Members’ authors in writing their contributions and to Physiology News – 56 pages again, reduce the subsequent editing process. The and Affiliates’ Grants, Intercalated incidentally, as we were once more Editorial Group of Physiology News tries to BSc Bursaries, Network Interaction spoilt for choice for content. Grants, Non-Society Symposia ensure that all articles are written in a Grants, Postgraduate Support Fund journalistic style so that they will have an immediate interest value for a wide There is a short list of adjectives information and the Vacation readership and will be readable and magazine editors like to use about Studentship Scheme visit: comprehensible to non-experts. In their magazine and its content. http://www.physoc.org/grants particular, scientific articles should give a ‘Packed’, ‘exotic’ and ‘global’ are good overview of a field rather than focus three good ones. I like to think they Membership applications entirely on the authors’ own research. all apply. I don’t think I have seen Applications for Full and Affiliate another issue with quite such a Membership are received throughout Format of articles The main message or question posed should be breadth of features. Take the list of the year and have no deadlines. A introduced in the first paragraph. The background places where we have reports from, decision is normally made within 8­ for the topic should then be established, leading or about. Meeting previews for 10 weeks of the Administration up to the final conclusion. Portugal, Brazil and Beijing (not to Office receiving the application. For mention Manchester), a letter from Length of articles full details please visit: This will be determined by the subject matter and Korea, and Extreme Physiology from http://www.physoc.org/join agreed with the Executive Editor. the Himalayas. The features have geographic range as well – four UK Submission of articles vs six non-UK, six Old World vs four Change of address Authors should submit articles as a Word Members should inform the document attached to an email. Illustrations New World, plus Australia for good Administration Office of any changes should be sent as separate attachments (see below) measure. It all goes to emphasize, of address, telephone, fax or email and not embedded in the text. once again, the global nature of scientific endeavour. address. Illustrations and authors’ photographs Changes can be emailed to: Authors are encouraged to submit diagrams, [email protected] or updated online drawings, photographs or other artwork with their Finally, and closer to home, we have articles or to suggest appropriate illustrations. A at http://www.physoc.org a dozen pages this issue relating photograph of the author(s) should also broadly to another topic important to accompany submissions, if possible. Illustrations and photographs may be colour or black and scientists – education of the wider white, prints, transparencies or tif/jpeg files with a world, including but not limited to minimum resolution of 300 dpi. Electronic students, about science and scientific Physiology News colour figures should be saved in CMYK mode. research. Scientists always need to Deadlines References keep in mind both the global and the local. I hope this issue gives you Letters and articles and all other Authors are requested to keep the number of references to a minimum – preferably no more something to think about on both contributions for inclusion in the than two or three. Please cite all references in the fronts. Summer 2006 issue, No. 63, should style of The Journal of Physiology (see reach the Publications Office Instructions to Authors 2005 at Austin Elliott ([email protected]) by 21 April http://www.physoc.org) 2006. Short news items are encouraged and can usually be included as late copy if space permits.

Suggestions for articles Suggestions for future articles are welcome. Please contact either the Executive Editor or a member of the Editorial Group of Physiology News (see contents page for details).

Physiology News Online Physiology News is now available on I’m a leading scientist – the Society’s web site: get me out of here. http://www.physoc.org. Unbelievable! (p. 40) EDITORIAL PN 3

research papers. The modern trend in This is all as may be, but I think that Not complex, but vintage the UK seems to be to make this a part we as physiology teachers are not of the 2nd undergraduate year, the helping ourselves here. To give theory being that students will then be students a better chance of grasping the In the last couple of years The Journal ready to apply these interpretative process of science, rather than just of Physiology has had the excellent skills to the scientific papers that they adding modern methods to their idea of publishing occasional read as part of final year dissertation or ‘portfolio of the heard-about’, we commentaries on landmark papers project work. I am sure I am not the should start by leafing 30-plus years from its archives, together with web only university teacher who has the back into our journal collections. access to a PDF version of the original impression that students often struggle Papers of this vintage are far more paper. I would like to suggest that to get past the Methods section of likely to employ a single methodology, similar commentaries should become many papers analysed in this way. thus cutting the time needed to be more widespread, with the specific Given the tendency for papers to use spent on looking up ‘hydropathy purpose of using older papers in multiple complex modern techniques, analysis’ or ‘SHG two-photon undergraduate physiology teaching. each with its own description in microscopy’, or whatever. The controls condensed jargon, this is hardly will often be extensive, and extensively The American Physiological Society, surprising. described, while the statistics will be which like our own Society is in the simple. There is also an enormous process of making all the back Although it is often possible to choice of papers available, to enable us numbers of its journals – primarily the interpret data without a detailed to pick ones that stand out as examples American Journal of Physiology – understanding of the methods used to of lucid reasoning, or which have come available online, has recently called for derive it (‘what do the Figures tell to be regarded as classics. Once articles along just these lines for its us?’), my subjective impression is that students have mastered critically journal devoted to physiology teaching, most students feel very insecure about reading papers of this type, they will Advances in Physiology Education doing this. The all-too-common result have a firm foundation in scientific (Raff, 2005). is a disconnect in their thinking reasoning and a ‘toolbox’ of analytical between the experimental results and skills to bring to more complex modern A major point of this idea is that papers the methodology used to obtain them. papers, with their proliferation of from the older literature often use techno-methods. relatively straightforward methods that The end result is that the interpretation students can comprehend readily. This they derive from any paper is, in effect, So here is a challenge to any enables their reading of the paper to likely to be no more and no less than physiologists out there who feel they concentrate on following the logic of what the paper’s authors tell them it is, have witnessed the ‘methodology the experiments, their interpretation, with little sense of whether this overload’ I describe in their and the deductive reasoning applied by interpretation is truly supported by the interactions with their students. Go the authors, rather than struggling to data, or of whether other alternative back to the earlier days of your work out exactly what a Cftrtm1Unc- interpretations could equally well discipline and find a J Physiol paper TGN(FABPCFTR) mouse is, and how it apply. It is not clear to me what the that does not contain five different differs from a common-or-garden gain is in this over just reading the techniques, but which makes careful Cftrtm1Unc mouse. There is also a abstract. While it is clearly assimilating observations, interprets them logically suggestion that the authors of literature, “interpreting” is stretching it, and clearly, and reaches a well­ yesteryear, perhaps because they had and we are hardly talking critical reasoned conclusion. Then ask yourself more time to contemplate their analysis. how that paper could be used as a experimental interpretation and their teaching tool. And finally, write in and writing, communicated what they had Well, many academics will say, what tell us about it. While I suspect J done rather more lucidly than is do you expect? Off the record, many Physiol is unlikely to introduce an sometimes now the case. Finally, as I scientists will offer the opinion that it education section any time soon, have commented before, I also suspect is not until some time during a PhD Physiology News would be happy to they were more likely than nowadays course that most learners these days oblige by bringing readers’ selections to discuss alternative interpretations to begin to acquire the skills of reading for classic physiology teaching papers their preferred line. papers critically, and then gradually. of this type to a wider audience. And these are typically students Together with our occasional feature on So I think the suggestion has real derived from the top 10-20% of the Ten Favourite Papers, I am hoping we promise. Helping students get to grips undergraduate first degree intake. We can mine some real gold out of the rich with the primary literature remains a can all agree that full critical seams of the past. stated aim of most undergraduate interpretation of scientific papers takes Austin Elliott science degree courses, and large many years to learn, hence the fact that chunks of (especially) tutorial time are journal referees are typically principal Reference devoted to analysing and interpreting investigator-level scientists. Raff H (2005). Adv Physiol Educ 29, 138.

Physiology News | No. 62 | Spring 2006 | www.physoc.org 4 PN MANCHESTER FOCUSED MEETING

New university, new buildings, new staff

Welcome to the new look University of Manchester. Since The Physiological Society last visited in September 2003, the merger of the Victoria University of Manchester with UMIST has been finalised; bioscientists have moved into three new buildings (with a fourth about to be built); and an exciting group of young physiologists (and some not-so-young) has been appointed.

Merger officially took place in October Above: The latest new bioscience building, which opened in February 2006, houses a Core Technology Facility on 2004, with the creation of four the ground and 1st floors, the Channels and Transporters Group on 2nd floor and the Cardiovascular Group on Faculties. Life Sciences, the smallest, the 3rd floor. but most beautifully formed, of these Faculties, is where most physiologists are located, but there is a significant number in the Faculty of Medical and Human Sciences, most notably in the Division of Cardiovascular Studies.

Life Sciences was created by a merger of staff in the School of Biological Sciences (Victoria University), the Departments of Biomolecular Sciences and Optometry & Neuroscience Above: Mark Boyett, Professor of Cardiac Electrophysiology in the Cardiovascular Group, (UMIST) and the Centre for the History Faculty of Medical and Human Sciences. Above: Alison Gurney, Professor of Pharmacology, of Science Technology and Medicine, Faculty of Life Sciences. most of whom are historians of Left: Some of the new Neuroscience staff (left to right): biomedical science. In terms of Denis Burdakov (brain circuits which control sleep and physiology, the most obvious benefit is appetite), Ingo Schiessl (non-parametric analysis of functional brain imaging); Rasmus Petersen (coding the coming together of neuroscientists tactile information in the CNS). from the two institutions. Below: New staff in the Channels and Transporters Group: back row (left to right) Jason Bruce (signalling The Faculty of Life Sciences acts as a cross-talk in non-excitable cells), Ian Fearon (oxygen single financial unit (School); but for sensing and the regulation of cell excitability), Donald Ward (extracellular Ca2+-sensing receptors); front row administrative purposes is divided into Ita O’Kelly (left) (regulation and expression of three sections: Molecules to Cells membrane proteins) and Holly Shiels (cardiac (M2C), Cells to Tissues (C2T) and physiology of ectotherms). Tissues to Organisms (T2O), with most physiologists in T2O. Our Society President, Alan North, moved from Sheffield in 2004 to preside over the new Faculty as Dean and University Vice-President.

Most molecular and cellular bioscientists have moved into new buildings, namely the Michael Smith Building (opened December 2004) and the Manchester Interdisciplinary Biocentre (opened December 2005). A few physiologists work in the Michael Smith Building, but many will be

Physiology News | No. 62 | Spring 2006 | www.physoc.org MANCHESTER FOCUSED MEETING/PORTUGAL FOCUSED MEETING PN 5 moving into a third new building (yet Portugal Focused Meeting to be named) early in 2006, at which time construction of a fourth building An invitation to come to to house the neuroscientists will begin. Portugal to talk, hear and discuss current research about Ignoring any barriers created by cystic fibrosis, as well as enjoy Faculties, Sections, Buildings (which are in any case very low), the strength the delights of the Algarve of physiology in Manchester is generally focused on three overlapping This April in Portugal sees The areas: channels and transporters, Physiological Society venturing into cardiovascular physiology and what we believe represents an exciting neurophysiology. The two former new forum for Society-sponsored groups are moving into adjacent floors Focused Meetings, when the European of the third new building. During the Cystic Fibrosis Society (ECFS) joins past 3 years, all these areas have been forces with The Physiological Society strengthened by new appointments. In to host an exciting conference on New terms of professors, in addition to Alan frontiers in the basic science of cystic North, we have gained Mark Boyett, fibrosis. The meeting will take place who moved from Leeds in February from 19-23 April in Carvoeiro, once a 2005, and Alison Gurney from small fishing village, but today still one Strathclyde in January 2006. We have of the most picturesque and flourishing also appointed a dozen young seaside resorts on the south coast of the physiology staff, many of whom are Algarve. featured in the accompanying photographs. Our aim in organizing this unique venture was to broaden the scope of The meeting in April is a Focused past basic cystic fibrosis (CF) science Meeting on the theme Frontiers in meetings (held since 2003), and help to epithelial transport. This continues to foster new research interactions towards a better understanding of the be a significant area of research within Top: Two more newcomers to the Channels and the Channels and Transporters group, Transporters Group. Liz Fitzgerald (left) (molecular pathogenesis of CF and of other related and has been strengthened by the recent and cellular physiology of voltage-dependent Ca2+ disorders. Of course we hope to appointment of Jason Bruce, Gavin channels) and Kath Hinchliffe (right) (inositol lipid maintain the important characteristics Stewart and Donald Ward. The line-up function and regulation). of past meetings by encouraging Above: Two of our four Research Council UK Fellows. speakers to present their most recent of speakers for the meeting is first-rate Catherine Lawrence (left) (energy balance and – and, maintaining the tradition of neuronal function) and Natalie Gardiner (right) unpublished results and ensuring a Manchester meetings, we can assure (sensory nerve regeneration). lively discussion of data and ideas at you excellent hospitality. Below: Epithelial physiologists studying channels, the forefront of research, all in an transporters and signalling in choroid plexus, gut, informal, co-operative atmosphere. exocrine glands, kidney and placenta. From left to Maynard Case right: Maynard Case, Gavin Stewart, Peter Brown, Faculty of Life Sciences, University of Manchester, UK Martin Steward, Donald Ward and Craig Smith. New frontiers in the basic science of cystic fibrosis Symposia • Lung physiology • Calcium signalling • SLC26 family of transporters • Role of sodium channels in epithelial transport • Post-genomics • Biogenesis of membrane proteins and the ER quality control • CK2 and epithelial biology • The basic defect of CFTR in CF and how to correct it • Epithelial cell biology, inflammation and pathogens

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ECFS/Physiological Society 2006- Basic Science Conference. We welcome all scientists, not just from the field of CF, but also from a diverse range of related disciplines to an exciting conference of high scientific quality in the spirit of traditional Portuguese hospitality.

Looking forward to meeting you in Carvoeiro in the Spring.

Margarida D Amaral Department of Chemistry and Biochemistry Faculty of Sciences, University of Lisboa, Portugal Mike Gray School of Biomedical Sciences, University of Above, left: Algar Seco-Carvoeiro Newcastle upon Tyne, UK Above, right: Carvoeiro beach Conference Chairpersons Left: Tivoli-Almansor Below: Carvoeiro grottes Additional information (important deadlines, provisional programme, etc.) The programme consists of nine The conference will be open to a available online at: symposia which will bring together 28 maximum of 120 scientists (invited http://www.europeancfconference.org/ internationally recognized experts, guests and registrants). There will be no covering key aspects of cystic fibrosis parallel sessions and we strongly research and related themes, and will encourage all participants to attend the include a full day of physiological­ full duration of the conference. The based symposia that are at the cutting registration fee (1,000€ for regular edge of current epithelial research (see registrants, 750€ for Physiological list of topics on p. 5). Society Members and 650€ for registrants under 30 years) covers hotel There will also be an opening keynote accommodation (4 nights), all catering, lecture by Alan Verkman (UCSF, USA) participation in the social functions and as well as several special interest group airport transfer on the pre-arranged discussions in the evening. In addition, shuttles. One day registration for designated poster presentation sessions Physiological Society Members only is plus oral communications (chosen from also possible (225€). submitted abstracts, in particular from young researchers) will run throughout It is thus with great pleasure that we the meeting. We expect to bring invite you to attend this joint together the best of European and International experts, and strongly Carvoeiro encourage post-graduate students Carvoeiro, probably born as a Moorish village, has a local history going back to mediaeval engaged in cystic fibrosis and epithelial times as it was integrated into the kingdom of Portugal through King Afonso III who re­ physiology research, to attend. Also of conquered the Algarve in the 13th century. We hope that, besides participating in a cutting­ note during this conference, are edge conference, you will be able to experience some of the flavour of the inspiring and presentations and discussions (open to graceful village of Carvoeiro and of its beautiful blue waters, as described below: all scientists) held by EuroCareCF, the recently EU-funded network of ‘On one of those late afternoons when we feel that spring is already arriving and we researchers aimed at coordinating dream of summer, I found myself having a pleasant walk through the Carvoeiro streets. It research efforts in this area across was one of those aimless trips with no set schedule, where turning each corner is a new Europe. experience. There the panorama spreads out as if one were on a flight over the sea and the small cozy beach, an area of golden sand shaped like a shell, still practically deserted In addition to generous support from in the lukewarm March sun. On this day, the strong smell of the sea rises up over the cliff, The Physiological Society and the and my gaze casts over the blue vastness but always returns to become fixed on the ECFS, we would also like to thank the attractive group of white cottages that cling to the hill over the opposite side of the beach. US Cystic Fibrosis Foundation (CFF) Although most of the small cottages have been modified, they still remind one of the times for their sponsorship, which has when the daily routine of Carvoeiro's inhabitants was determined by the departure and enabled the attendance of a arrival of the fishing boats. In those days the Carvoeiro beach was a place for hard work considerable number of outstanding and not a cosmopolitan meeting and leisure place.’ researchers from the US this year. [By: Maria José Pires. Tribuna do Algarve, 31July 1996]

Physiology News | No. 62 | Spring 2006 | www.physoc.org BRAZIL MEETING PN 7

Physiology in Brazil In August this year, The Physiological Society holds its first joint meeting with the Brazilian Physiological Society. Brazil might seem remote to many, but for pharmacologists and physiologists it can be quite an attractive place as Thelma Lovick found out by talking to two Society Members who have active collaborations with Brazilian labs

Andy Ramage is Reader in Systems Pharmacology at University College London.

Thelma Lovick (TL) What took you to Brazil in the first place?

Andy Ramage (AR) It was one of those odd combinations of coincidences. It all started with a Brazilian, Henrique Futuro-Neto, doing a PhD in Birmingham in 1977 alongside Mike Gilbey. They were both doing their PhDs under John Coote and the two became good Figure 1. Andy Ramage (centre) studying the effect of 5-HT1A receptors in the control of the upper airway evoked friends. Mike then moved to the then reflex bradycardia in 1992 with José GP Pires (left) and Gilton (right), an MSc student. Royal Free Medical School (now UCL) and Henrique to the Departamento de went well. In 1992 Mike decided to a chance to see my in-laws (!) and get Ciências Fisiológicas, Centro skip his trip as Gill, his wife, was my son to know his cousins. Figure 2 Biomêdico, Universidade Federal do pregnant. So, I went out to finish the is a view of the beach from my Espìrito Santo in Vitória which is on work off (see Fig. 1) and it was during proposed retirement home. the coast about 250 miles north of Rio. that trip that I became fully involved In 1988 they set up an exchange with Jussara whom I married. TL I suppose most people’s perception programme under the auspices of the of Brazil is carnival, rain forest, girl British Council and CAPES and invited TL So the Brazilian connection was the from Ipanema, delicious beef, nuts, that me and José Pires to join them. The start of something good? sort of thing; what’s it really like being uniting area of research was the role of there? central 5HT in cardiovascular AR Oh yes, in more ways than one! I regulation. I started in 1991 by going have been returning to Brazil for AR When I first went there, it was a bit to the Departamento de Ciências periods of collaborative work ever daunting. I did not speak any Fisiológicas and carrying out since. In December 1992 I was made a Portuguese and it is a fiendishly experiments on the role of central 5-HT Professor Emérito of the Universidade difficult language to get your head in control of the diving reflex. I Federal do Espìrito Santo. But now, round. Things were OK in the lab enjoyed the time there and the work with family ties there as well, it is also because everyone wanted to practice their English on me, but English was not widely spoken outside, unlike nowadays. One thing that really took a bit of getting used to was the concept of hyperinflation, which was rampant at 200% a month when I first went. During an experiment people would be popping out to the bank to check their balance – and not just once a day!

TL And what about the science?

AR There is some very good stuff going on in the central autonomic area. I am continually impressed by the level of commitment and in the number of skills that the labs possess, especially Figure 2. Life’s a beach – the view from Andy’s proposed retirement home in Brazil. regarding in vivo work. There are some

Physiology News | No. 62 | Spring 2006 | www.physoc.org 8 PN BRAZIL MEETING great young scientists but there is a log jam on the jobs front so there are more and more itinerant post docs touring the world. One great thing about working there, from a Brit’s point of view, is that rats are free – well, the particular university I worked at supplies them free. It reminded me of those happy days in the UK, when the departmental budget could cover basic research needs. Also, Brazilian universities are not (yet!) run like a business, as they are becoming in the UK, and that is very refreshing. On the other hand, facilities were not that great 15 years ago, although the labs are now much better equipped and up to international Figure 3. Andy with Henrique A Futuro-Neto (left) and Benedito Machado after a lecture given at the Brazilian standards. At the start I used to Physiology Society, Águas de Lindóia, Sao Paulo State on 25 August 2004. Centre front is Frederico, 8 years old, struggle through customs carrying another product of the long term Brazilian collaboration. stereotaxic frames and stuff like that. But there was always a genuine interest their cook will be doing it. The middle Ribeirão Preto to work with Benedito in what I was doing and an appreciation classes still have live-in servants. Machado (who is in the picture taken at of why it was important. Now they the 2004 Brazilian Physiology Society think I am going to blow up the plane! TL Andy, what about the safety side of Meeting) (Fig. 3). We arrived at the life – do they all live in gated international airport in São Paulo, TL And what about the lifestyle? communities? Guarulhos at 6.30 a.m. (the time most international flights arrive – from AR The standard of living for AR Well safety is a problem. However, London it takes just under 12h) and academics is far higher than here in the it depends what areas you go to and caught a taxi to the bus station UK. It took me a while to realise that whether you look like a rich gringo; not (Rodoviaria). A very nice bus, better when people invite you round and offer a problem for UK academics! Two than the airplane and a lot cheaper, took to cook you a meal, they mean that years ago Dan Kellett and I went to us to Ribeirão Preto, the place where the joint meeting will take place in The science… August this year. The bus station seemed to be a fairly safe place. It took I am particularly interested in the role of central 5-HT pathways in the control of about 4h so we had a good sleep. the autonomic nervous system. Brazil has experts in hypertension and Ribeirão Preto is very quiet and does cardiovascular reflexes and it is their expertise in whole animal experimentation, not get a lot of tourists, so it’s fairly especially the use of conscious animals, that makes Brazilian physiology, for me, cheap. very exciting. With Professors Futuro-Neto, Pires, Cabral & Mauad at the Universidade Federal TL So would you recommend a trip to do Espìrito Santo I have been investigating the role of central 5-HT receptors in Brazil, to collaborate etc? the control of the sympathetic nervous system. We found recently that central AR Yes and yes. I love Rio de Janeiro 5-HT2 receptors are involved in the control of vasopressin release and that vasopressin is essential for the development of DOCA-salt hypertension. We had and Salvador – great places to visit and you only need a Hepatitis A hypothesised that this 5-HT system is involved in the central control of blood vaccination. Keep your eyes open in volume, thus we believed that by blocking it with mianserin (a non-selective Rio though, but the vista from 5-HT2 receptor antagonist) we could prevent the development of DOCA-salt Corcovado (with its statue of Christ) is hypertension (Silva et al. (2005). Eur J Pharmacol 518, 152). This system is fantastic. Ipanema is the better beach probably also responsible for the hyponatraemia seen with selective serotonin to stay. Working there is great, reuptake inhibitors (SSRIs) in the treatment of depression. At present I am especially in my area of central writing up a paper with Professors Cabral amd Mauad showing that activation of autonomic research. However, collaborations usually occur depending 5-HT3 receptors in the NTS causes diuresis and selective inhibition of renal nerve on circumstances, the future activity in conscious rats. In another collaboration with Benedito Machado experiments one is particularly (University of São Paulo, Ribeirão Preto, where the joint meeting is to be held) we interested in carrying out and also the have been studying in conscious rats the baroreflex and chemoreflex. This led to nature of the collaborator. At present I a paper (Kellett et al. (2005). Brain Res 1054, 61) that showed that 5-HT want to learn how carry out in vivo depletion causes attenuation of baroreceptor reflex gain in conscious rats. voltammetry.

Physiology News | No. 62 | Spring 2006 | www.physoc.org BRAZIL MEETING PN 9

Ted Taylor is Professor of Animal Physiology in the School of Biosciences at the University of Birmingham Thelma Lovick (TL) Being a comparative physiologist must be one of the best excuses for travelling to exotic locations, but why Brazil?

Ted Taylor (TT) You have to go where the animals are, and Brazil is one of the best known biodiversity hotspots on the planet – it has possibly the most diverse Ted at work with flora and fauna of anywhere else in the Hamish Campbell. world so it is the place for comparative and I are cardiovascular physiologists animals but already very snappy and physiology. and reptiles are really fascinating getting bitten is routine. TL So how did you get to go there in because they typically have TL Isn’t it a bit dangerous trying to the first place? incompletely divided circulations. They can shunt blood from the pulmonary to work with some of these exotic species? TT Well I first went to Brazil in 1995 to the systemic circulation and we are a meeting in Manaus. I’d had a Brazilian studying the control and possible TT Yes, of course, but you just have to postdoc working with me in functional roles of cardiac shunting. In be careful. In fact reptiles are relatively Birmingham who had recently returned 2005 I was joined by Hamish Campbell, slow compared to us as mammals, home, so after the meeting I went to São a post-doc from Birmingham, and we particularly when they are cool, first Paolo to visit her. Then I came back in used dataloggers to detect respiratory thing in the morning, which is when we 1999 to work with Tobias Wang. Tobias sinus arrhythmia in rattlesnakes. are normally handling them in is a research Professor at the University preparation for experiments. of Aarhus, Denmark but he has spent a TL Tell me about the lab environment. I lot of time in Brazil and speaks imagine you don’t send a requisition to TL What are the facilities like? Portuguese. He introduced me to the animal house a week in advance to Augusto Abe at UNESP who has a order a caiman for Tuesday, say, like we TT The animal holding facility is wonderful animal holding facility with a have to do here with rats. unbeatable – the best I’ve seen huge collection of reptiles. There are anywhere in the world. The animals are captive breeding populations of three TT Right. We do have to catch our own very well kept. There are good labs ­ species of caiman, 2 species of turtle, animals. The caiman, which I’m doing a loads of space. There are some very tegu lizards, green iguanas and Burmese lot of work on at the moment, live in good Brazilian physiologists, mostly pythons. He is also able to obtain large huge pens with concrete walls and a easy-going, friendly people. Standards numbers of rattlesnakes because of his moat to simulate their natural are high too, and I find Southern Brazil links with the Butantan Institute in São environment. The breeding population a great place to work. The weather is hot Paulo, famous for its work on antisera lay their eggs in a sort of compost heap, of course – too hot for some – during against snake venom. However, our which keeps the eggs warm and from the southern Summer (December interest in these animals has nothing to this heap masses of tiny caiman hatch through to March). There is tropical rain do with them as biohazards. Both Tobias out. They are very attractive little in the afternoon, making it hot and humid, so it can be quite tiring trying to work, but most labs I work in have air conditioning and in the evening we normally enjoy a cold beer.

We used to have to take much of our Ted Taylor (far left) own equipment, things like blood flow with some of his meters, but now they have their own so collaborators in Brazil. From left: we don’t need to take so much. Funding Jim Hicks (University for research is patchy across the country, of California, Irvine), most generous in southern Brazil and in Mogens Glass (USP particular São Paulo state via FAPESP. Ribeirão Preto), Augusto Abe In 2004/5 I held a visiting Professorship (UNESP), Tobias for 6 months, sharing my time between Wang (Aarhus) and UFSCar and UNESP. This was funded Tadeu Rantin by FAPESP, which paid my travel and (UFSCar). subsistence costs. We worked on

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respiratory and cardiovascular some students from poor backgrounds The science ... coordination in fish and reptiles. There do their whole degree at night as they are also federal funds available from have a day job to fund themselves. Our work in Sao Carlos centred on control CNPq and active Brazilian researchers Although Brazil is a rapidly developing of cardiorespiratory interactions in fish. At can obtain funds to travel abroad for country, 40% of the Brazilian population UNESP in Rio Claro we are making a collaborative work. is very poor. Academics are part of a comparative neuroanatomical study of the small middle class, with a lifestyle vagal motor column and doing physiolog­ Brazilian academics work quite hard – reminiscent of the Edwardian era in ical investigations of cardiac shunting, teaching loads are high, although student England. venous filling pressures and intrinsic numbers are not as high as is typical in vasomotion in the lung in reptiles including the UK. The physiology teaching is TL And what about life outside the lab? turtles, lizards, caiman and snakes. fairly fundamental and broad based – Where do you live? Pharmacological approaches are being students come in from a lower used to uncover of the classic roles of the educational background than here. Many TT Both Tobias and I enjoy rent-free autonomic nervous system in the courses are taught in the evening, accommodation for ourselves and sometimes 9-11 at night. This is because associates provided by our friends and cholinergic and adrenergic control of the colleagues at UNESP, primarily Augusto cardiovascular system as well as bradykinin, neuropeptide G and histamine In September 2005 Ted Taylor took a Abe. Some visitors are placed in local hotels or rented apartments, which are (Skovgaard et al. (2005); Galli et al. party of 16 undergraduates (some of (2005a,b). Using data loggers to measure whom are pictured below) from cheap for anyone on a European or North American salary. heart rate variability, we have recently Birmingham to Brazil to study animal identified respiratory sinus arrhythmia in physiology. From the original 65 TL That brings me to the social scene. the rattlesnake and caiman. students who were keen to go, 16 were What’s it like? chosen on the basis of the standard of Galli LJ, Skovgaard N, Abe AS, Taylor EW, Conlon JM & Wang T their academic performance. Each (2005a). Cardiovascular actions of rattlesnake bradykinin ([Val1, TT Unbeatable. In big cities like Rio or Thr6]bradykinin) in the anaesthetised South American rattlesnake Crotalus durissus terrificus. Am J Physiol 288, R456-R465. student needed to raise £1,000 and a Salvador the beaches, scenery and further £10K was provided by the nightlife are among the best in the Galli LJ, Skovgaard N, Abe AS, Taylor, EW & Wang T (2005b). University of Birmingham. The role of nitric oxide in the regulation of the systemic and world, but even where I work, in small pulmonary vasculature of the rattlesnake Crotalus durissus towns in the interior, there are nice bars terrificus. J comp Physiol. 175, 201-208. and restaurants serving good food, Skovgaard N, Galli LJ, Taylor EW, Conlon JM & Wang T (2005). which is always fresh and very cheap. Haemodynamic effects of neuropeptide γ in the anaesthetised The cost of living is about 25% of that python, Python regius. Regulatory Peptides, 128, 15-26. in UK. Brazilians are very sociable – a lot of fun to be with. get it impounded by customs in some obscure office somewhere – and it’s a TL Do you speak Portugese ? big country with a virtual absence of anything typically ‘British’ about it. It TT Not much, but I can order a beer and wouldn’t suit everyone. find my way around. I plan to take lessons this year. I can interact socially TL So far so fabulous. Have you bought Ted Taylor comments: They were a mixed via my Brazilian friends so that we are your retirement home there yet? group in terms of personality and background able to get out to samba bars, drink and but all proved to be very able students. They dance on our weekends off work. TT I’m thinking about it. When I do worked extremely hard on a range of animal finally retire from the day job in species, including terminally anaesthetised Birmingham, this September, I’m turtles, measuring blood flows etc. and TL Surely there must be some planning about a 50/50 split between the chronically instrumented frogs, lizards and frustrations? caiman, studying heart rate and blood pressure UK and Brazil. Brazil suits my after pharmacological blockade. The level of TT Well, for me there’s the language personality – work hard, play hard (well animal experimentation was far in advance of barrier. Also, things take time, it’s fairly hard!). I have an open invitation to anything the students had previously sometimes difficult to obtain some stay with friends whenever I go, so I’m experienced and would have been impossible things like drugs for the lab, for pretty lucky. to sustain without the expertise of Tobias Wang example, especially in small towns, but and his two demonstrators, Nini and Marianne communication is OK, just so long as Brazilian acronyms from the University of Aarhus. All experiments you rely on email. So life is not quite so were closely supervised by one of us and CNPq Conselho Nacional de Pesquisa straightforward as here in the UK. You followed the general ethical standards applied FAPESP Fundação de Amparo à have to be a certain sort of person – you in the UK and Denmark, and according to the Pesquisa do Estado de São Paulo controls exerted in Brazil. We instructed the need to be fairly laid back. There can be UFSCar Universidade Federal de São students to write up their experiments like a problems with transporting equipment – Carlos (a campus of a federal university) paper in a journal. Some may indeed prove you might get a swingeing customs worthy of publication. ‘duty’ levied on new equipment or even UNESP Universidade Estadual Paulista

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Joint Meeting of the Chinese Association of Physiological Sciences and The Physiological Society in Beijing, China in 2008

In a recent article (Physiology News reactive oxygen radicals in cell 59, 10), David Eisner highlighted that signalling. Professor Angelo Azzi the International Committee of our (Secretary General of SFRR- Society is committed to building closer International) replied that 'a joint links with China. This process began symposium between the Physiological with a visit to China by Giovanni Societies and SFRR-International will Mann in 2004. Our Executive certainly be welcome'. The dates for subsequently met with Professor Tai their XIV Biennial Meeting of the Yao (President) and Professor Xiao­ SFRR-International in Beijing are 15­ min Wang (Secretary General) of the 19 October 2008. Giovanni Mann Chinese Association of Physiological hopes to further discuss a joint Sciences at the IUPS meeting in San symposium with their Council during Diego in 2005, and we agreed to hold the forthcoming SFRR-International a joint scientific meeting in Beijing, meeting in Davos, Switzerland from China in the autumn of 2008. 15-19 August 2006 (for further details see: http://www.sfrr-congress.org/). We then invited Tai Yao and Xiao-min Wang to the FEPS meeting in Bristol Prior to the FEPS meeting in Bristol, in July 2005 and to a planning meeting Tai Yao, Xiao-min Wang and Giovanni chaired by David Eisner (International Mann visited Windsor and on the way Secretary) and attended by Bridget back to London with Richard Siow Lumb (Meetings Secretary), Prem spent a pleasant afternoon in Bath Kumar ( Meetings Secretary elect) and sampling English tea and coffee! The Giovanni Mann (Chairman of the photographs highlight the FEPS Executive Committee). Xiao-min meeting in Bristol and visits to Wang kindly agreed to explore Windsor and Bath. potential venues/costs for holding the joint meeting in Beijing and has We are delighted that The Society will recently informed us that the meeting be strengthening its research/academic would need to be held after 10 October links with colleagues in China, and it 2008. In Bristol, we also discussed the was a personal pleasure to have possibility of inviting the American welcomed Tai Yao and Xiao-min Wang Physiological Society to sponsor a to the UK on behalf of The designated symposium at this joint Physiological Society. We look meeting, and David Eisner will be forward to an exciting scientific liaising with Marty Franks, their Chief meeting in Beijing in 2008! Executive. Giovanni Mann Chairman of The Executive Committee Coincidently, the Society for Free Radical Research International (SFRR) David Eisner will be holding its 2008 meeting in International Secretary Beijing, China. The Physiological From the top: Society has previously sponsored Tai Yao (President of the Chinese Association of research symposia at SFRR meetings Physiological Sciences) with Experimental Physiology in May 2004 in Buenos Aires, Chair John Coote. Argentina (Physiology News 57, 31) Tai Yao, Xiao-min Wang (Secretary General of the and in July 2005 in Leicester, UK, and Chinese Association), and Society President Alan it may be possible to schedule our joint North. meeting in Beijing back-to-back with Tai Yao, Xiao-min Wang and Giovanni Mann in New the SFRR International meeting. As a Hunt's House Library, King’s College London. member of SFRR, Giovanni Mann has Tai Yao and Giovanni Mann outside the gates of asked their Council to consider co­ Windsor Castle. sponsoring a symposium on the role of Richard Siow (KCL) with Xiao-min Wang in Bath

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A week in the life of a clinical scientist Case conferences, ward rounds, mass spectrometry and unspeakable things in jars are all in a week's work for Tim Lang

When Austin Elliott first asked me to patient presents to the doctor to when write about my work as a clinical the test results are reported. This is scientist – more accurately, when he especially true in paediatric cornered me at the wedding of a mutual biochemistry. More often than not we friend of ours and two drinks past the can find ourselves being sought out for point of remembering to say I was too an opinion early on in a particularly Less ‘ER-like’, of course, are the times busy – it had been 5 years since I had difficult case or emergency, and having when you are presented with dubious finished my PhD. In the intervening an input into how the patient is looking samples in jars and tubes, years I trained as a clinical scientist, investigated. ranging from the particularly offensive and am currently in a Principal Clinical faecal sample (sadly a hazard of the Biochemist post in the Regional Once, for instance, I had just sat down job) to various strangely-coloured Paediatric Biochemistry Laboratory in in my office when there was a bang on urines! I remember one particularly odd Belfast. This lab is the regional centre the glass – there, stationed outside, request from A&E relating to an for the investigation of inborn errors of were the consultant paediatric unconscious patient with suspected metabolism and has strong links with neurologist and both specialist alcohol poisoning. The patient had been the Royal Belfast Hospital for Sick registrars, wanting to talk about an working in the garden shed and had Children and Royal Maternity Hospital. acutely urgent case. Two registrars and consumed an amount of mysterious It was here that Nina Carson and a consultant definitely screams ‘triple lime coloured liquid, which Casualty Desmond Neill described the first case urgent’ – people who know medicine thought may have contained anti-freeze. of homocystinuria in1962. will tell you that outside of a ward Luckily it turned out that it was only round or a departmental meeting it is lime cordial. So what does a clinical biochemist nearly impossible to get this many actually do? Well, some days we do doctors this senior in one place at one Clinical liaison/co-operation between ‘frantic’. I definitely never thought, time! In this particular case the patient the clinical scientists and clinicians is when I was a graduate student, that one had presented with severe something that is essential and really is day I would be involved in some of the encephalopathy, and the biochemical actively encouraged. This type of diagnostic storylines you see in dramas investigations needed to be performed relationship is probably not seen like ER. There are times when the urgently to provide the diagnosis that between academic scientists and pressure is on to deliver an urgent would aid with management and physicians, as their joint subject of result, similar to the pressures of prevent irreversible brain damage. investigation is less likely to be actual submitting a grant application with an Rarely does a child present with patients with symptoms, and more ever more rapidly looming deadline. textbook symptoms, so it is up to likely to be bits of data, or other pieces Delivering a result is not just a matter clinical scientists to work in partnership of a scientific jigsaw. However, it is of giving the clinicians a number. with the clinicians to facilitate the important to remember that the time­ Clinical scientists are involved in a investigations. It is in this sort of case frames are very different. It may take number of processes from when the where you still feel like an investigator. years of research to answer a particular question (if you’re lucky!), whereas in the clinical situation it might be hours, or days, or sometimes weeks before a firm diagnosis is reached. Like everyone else, I had heard the ‘war stories’ about friction between the different professions in hospitals, but my personal experience has been quite the opposite. In fact, I would say the most pleasant surprise for me, working as a clinical scientist in paediatrics, has Tim Lang been the healthy partnerships that are (above) established between the different professional groups. Royal Belfast Hospital for Sick Children So what do I actually do in a typical (left) week? This is harder to answer than

Physiology News | No. 62 | Spring 2006 | www.physoc.org A WEEK IN THE LIFE OF ... PN 13 you might think as, due to the specialist case my ex-supervisor is reading this). the development of the service, and nature of paediatrics, no day or week is You will have to try to solve the there are links in most hospitals for ever the same. But there are a few fixed problem, or make alternative provision, supporting clinical research and trials. points. as most hospital labs provide a 24 hr At the moment some of my time is service. spent preparing and developing an One day a week I participate in the assay for the measurement of acyl­ duty biochemist rota for clinical On Tuesday mornings I have the carnitines using tandem mass validation/authorisation of tests opportunity to attend the weekly special spectrometry, which we hope will performed in clinical biochemistry, so I care baby unit (SCBU) ward round, improve the investigation of patients am on-call to offer advice or where cases of the recent and current with suspected fatty acid oxidation interpretation of results for clinicians admissions are discussed in the defects. Just as in The Physiological and other healthcare professionals. presence of all those involved in their Society, we are expected to present our Being on duty can be very busy at management, from clinicians to nurses finding and interesting cases for peer times and you soon learn how to to biochemists. Very occasionally there review. The Association of Clinical prioritise tasks. It can be quite a may be a case where a neonate has Biochemistry (www.acb.org.uk) challenge, especially when you are presented at birth with a suspected organises a number of regional and trying to locate a doctor who is not metabolic disease of unknown cause. national scientific meetings, where answering their bleep (yes, that bit is When this happens I offer advice and junior members are especially true). You are not just there to deal with liaise with the clinicians in order to encouraged to do oral and poster clinical problems, as analysers in the pinpoint the suspected metabolic presentations. This week I am spending hospital biochemistry lab are just as condition. some time preparing a clinical case prone to failure as patch clamp rigs, or history for presentation at a national imaging systems, or centrifuges. One thing that appeals to me about my meeting on inborn errors of metabolism Unfortunately, when something breaks job is the opportunities available to – a bit like a Phys Soc communication. you can’t just end the experiments for participate in research without next So there are the usual PowerPoint the day and go to the pub (not that I year’s grant application hanging on the slides to be prepared, and figures to ever did that as a PhD student, just in outcome. Most of the research relates to check for errors.

Whilst preparing the talk I get a call Careers in clinical science from a clinician in a local district Career entry is through the NHS Clinical Scientist Training scheme, which recruits a general neonatal ward requesting number of scientists into a variety of disciplines every year through a process similar to advice on the possible diagnosis of a the annual graduate milk round. Trainees are recruited to regional centres, normally sick baby who has presented with large teaching hospitals, where they spend 2 – 4 years in training, depending upon the recurrent episodes of hypoglycaemia. discipline. After taking a clinical history of the baby I am able to suggest the Training involves: appropriate biochemical investigations • on-the-job training in the laboratory to be performed and discuss a possible • a taught MSc course differential diagnosis. The following • opportunities to attend other training events day we receive specimens, which we • a 3-6 month secondment to a district general hospital. analyse urgently. Normally before the results are released to the clinicians I During the early part of your career you are expected to be mobile - similar to being a review them and, if necessary, add post-doc, but with the security of a permanent, or at least a 3-5 year, post. However some interpretative comment or suggest compared with post-doctoral work there is a structured career path, which can eventually further investigations. In this case I lead to consultant clinical scientist status, equivalent to a medical consultant. contact the requesting doctors and Progression through the path is dependent upon experience and, for more senior posts, discuss the results with them in light of obtaining membership of the Royal College of Pathologists (MRCPath) through any change in the child’s condition. examination. This is the only Royal Medical College to admit non-physicians to its ranks. On a Friday morning I attend the Things to do if interested: multidisciplinary paediatric ward • visit a local laboratory or department meeting in the Children’s Hospital. • speak to a clinical scientist Here difficult cases are discussed and • work shadowing/experience in a hospital lab any outstanding results followed up. I • contact the appropriate professional body normally come back with a number of cases to follow up or read up on. As it Useful web sites: is such a wide topic you can never http://www.nhscareers.nhs.uk (NHS Careers) know everything and there are always http://www.nhsclinicalscientists.info (NHS Clinical Scientists Recruitment Service) developments occurring in the field. http://www.acb.org.uk (Association of Clinical Biochemistry) The current reference textbook for

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Letter from ... Korea

‘Land of morning calm’ was the name by which we previously called our country. Nowadays, however, it is hard to find a ‘calm’ place in Korea. Since the Korea-Japan World Cup games in The Regional Paediatric 2002 a more popular, and probably Biochemistry more exact, portrayal would be Laboratory in ‘dynamic Korea’. Dynamic and rapid Belfast (left) changes have occurred, not only in the Royal Victoria modern industry, but also in physiology Hospital, research in Korea. Most of the changes Belfast (below) are progressive and, every year, state­ of-the-art techniques are introduced to the field. In addition, one of the inborn errors is composed of four very whether the right staff are available to influential slogans from the Korean heavy volumes. Definitely not analyse it over the weekend. Ministry of Science & Technology is something that would fit in the pocket of your white coat! Last minute crises sorted, I head for home and a different kind of ‘busy Friday afternoons are always quite busy working environment’ … those with so sadly there is no chance of slipping young children will know exactly what off early to the local pub – almost I mean! Anyway, I hope this has given makes me nostalgic for my PhD student you a snapshot of a week in the life of days. There will be results to be a clinical scientist. I have found my 6 reported to clinicians before the years in the career very rewarding and weekend, and batches of tests to varied – every day really is different authorise. Friday afternoon is also and challenging. PhD students and normally when you get the phone call postdocs who don’t think a career in Insuk So in his smooth muscle research laboratory. from a clinician wanting a test academic science is for them, but performed urgently, typically at 4.30 would still like to use their scientific knowledge hands-on, could do a lot the development of so-called Fusion p.m. when you are finishing off an Technology (like Biotechnology and assay and looking forward to going worse. If I have convinced any of you, the box on p. 13 gives some info on Information Technology, BIT). home. Depending on the clinical history Infiltration of ideas, as well as of the case you have to decide whether how to look into careers in clinical science. technology from other fields of science, it can be assayed. A big consideration is has greatly changed the themes and whether the patient’s management Tim Lang titles of presentations at the Annual would change depending upon the Regional Paediatric Biochemistry Laboratory, Belfast, Meeting of the Korean Physiological result. There is also the question of N Ireland Society (KPS). Although awkward at first, the progressive effects of such changes will become obvious in the near future. The most popular food in Korea is ‘Bibimbap’, a steamed rice with assorted mixtures of vegetable, minced beef, and hot sauces. (I have to say that we really mix them well with a spoon just before we eat it. A spoon of sesame oil is an important ingredient). Hopefully, the KPS can be the large ‘bowl’ for a Bibimbap of life science.

Here, we would like to briefly look back upon the recent history of the Physiology Department at Seoul National University. Our Department is located on University Road in central Seoul. For the last 30 years, electrophysiology of excitable tissue

Physiology News | No. 62 | Spring 2006 | www.physoc.org LETTER FROM ... PN 15 has been the main theme of our research. We started in 1976 by recording action potentials from frog atrial muscle with very primitive hand­ made equipment. Between 1978 and 1985, two-electrode voltage clamp techniques and patch clamp methods were introduced for the study of cardiac muscles, smooth muscles and neuronal cells. Through this period, the support from Denis Noble (Oxford) Hiroshi Irisawa (Okazaki) was a great advantages to us. The introduction of patch clamp techniques to Korean physiologists was a very successful story and it became the most popular research technology for the last 20 years. Combined with fluorescence imaging technique, confocal microscopy and molecular biological methods, we are widening our research focus into various tissues and organs. At present, the major research in our Department includes response of cardiovascular sensing mechanisms for hypoxia and mechanical stress, learning and memory mechanisms of neuronal system, molecular nature of pain, pacemaking activity in gastrointestinal tract, exocytosis and the role of calcium Top, left: Insuk So (left) and Sung Joon Kim in the old quadrangle building of Seoul National University College of in presynaptic terminals. In most of Medicine. those studies, the physiological roles of Top, right: Sung Joon Kim on top of the mountain in Moo-ju ski resort where the 2005 KPS meeting was held on ion channels have been focused at October 20. various levels. Above: Annual winter symposium for ion channel research in Korea. It is usually held in a mountain resort and, With the development of the Korean after the symposium, climbing is our tradition. This photo was taken from an old Buddhist temple in Jiri mountain. economy, government support has also From left to right, Chae-Hun Rheem (Ulsan Uniersity), Myung-Kyu Park (Sungkyunkwan University), Hyo-Won Bang (Chung-Ang University), Min-Goo Lee (Yonsei University), Sung-Joon Kim (Seoul National University), and increased. Approximately 5% of the Tong-Mook Kang (Sungkyunkwan University). national budget was allocated to research and development projects. Although the present government meeting to present their work, and FAOPS is a first experience for KPS, places too much emphasis on the lively discussions took place with and all the members and the Council of application of research, the total Korean physiologists. The main themes KPS are trying their best to host the allocation is much increased. In of the Joint Meeting were guest scientists and speakers. Professor general, the number of scientists who cardiovascular ion channels, epithelial Ki Whan Kim (Seoul National work for life science is increasing, and membrane transport and University) was nominated as a especially in the area of molecular neurophysiology. chairman of The Organizing Committee biology. The rate of expansion in of the 6th FAOPS meeting. With the physiology is rather slower than that of 2006 has a very special meaning for Organizing Committee, KPS is doing other fields of life sciences. Around 400 our Society. KPS hosts the 6th Congress their best to ensure a successful physiologists attended the KPS Annual of the Federation of Asian and meeting. Please try to visit Korea at this Meeting last October. Traditionally, the Oceanian Physiological Societies time and enjoy the 6th FAOPS meeting. main topics are ion channels, molecular (FAOPS, www.faops2006.org) on 15-18 ‘Kam-Sa-Ham-Ni-Da’ (Thank you very physiology, system physiology and October. This meeting consists of three much!) neurophysiology. In 1995, a joint plenary lectures, eight special lectures symposium with The Physiological and 22 symposia. This Congress was Insuk So Society was held to celebrate the 50th approved at the 4th FAOPS meeting in Sung Joon Kim Anniversary of the KPS. Around 35 Brisbane, Australia in 1998. In fact, Department of Physiology, Seoul National University physiologists from the UK attended this hosting an international meeting like College of Medicine, Seoul. Korea

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Physiology in the extreme Thelma Lovick talked to another intrepid physiologist who takes his science into the extreme. Below, John Coote, Professor Emeritus in the Division of Neuroscience at the University of Birmingham, shares some of his experiences of doing physiology in the extreme environment encountered at high altitude

Thelma Lovick (TL) I understand you’ve worked in the Peruvian Andes as well as in Chile, the Italian and Swiss Alps, Karakoram in N Pakistan and in Nepal in the Everest region and Himulchuli. How did you get started on all this?

John Coote (JC) Well as you probably know, I used to be quite a keen climber. When I first went to East Africa to climb the north face of Mt Kenya, I experienced severe headaches and nausea and it took me several days to recover. Within our group, though, some weren’t affected, and I began to wonder about the reasons for this individual variability in the ability to adapt to low pO2. There are also more prosaic reasons for needing to understand our reactions to low pO2. The military is obviously very interested in ways to keep the troops in John Coote pedals up Everest peak condition if they are flying them in over long distances to drop them into in terms of mending equipment in the there are often queues of guys waiting a high altitude combat zone. Skiers, field. to be selected. too, can be badly affected by low pO2 . TL How do you transport all this stuff? TL Let’s take one of your trips to Presumably there are no roads. TL So why do you need to take your Everest. Is it really the mess we hear lab to the mountain when there are about? perfectly good altitude labs around the JC Well, you helicopter everything in world where you can live and to give you a start. Then it goes on to JC I’m afraid it was, although attempts experiment at low pO ? pack animals or on to the backs of 2 porters. Always when going above are now being made to clean it up. When I was last there, which is now 10 JC I thought you’d ask me that! My 18,000ft you have to use local porters. years ago, the route in was littered with interest is in the response of lowlanders In fact, portering provides quite a boost the debris left by Westerners. to long periods at altitude and the best to the local economy in many areas and way to simulate this is to actually be there. Also, altitude chambers aren’t Extract from John Coote’s diary that comfortable to be in. And compared to the mountains the view is July 12 (18,000 ft) terrible! 4.30 a.m. Wake after good night’s sleep to see it’s snowing heavily. Temp outside TL Tell me how you set up one of minus 30 degrees. I feel warm and cosy in sleeping bag. I have all my outside these expeditions. clothes on, 2 pr socks, woollen long-johns and salopettes, wool vest, shirt and pullover, balaclava and hood of bag pulled tight to leave small breathing hole JC There’s months of planning through which 13 leads connected to Medilog recorder and Bioximeter pass. involved. Inevitably, when you go to remote areas with poor access, you Generator worked throughout night, no doubt thanks to Pete and Neil keeping the have to take your whole lab in a fuel supply going every 2 hrs. So biox worked all night. Alveolar oxygen now at 52 portable form. You have to take spares mmHg. It snowed all day, about 18 inches, tents completely submerged 2 and be prepared to be quite resourceful collapsed. Clear some of the snow but not much else done today.

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TL And are you guilty of adding to The scientific question that? As we fall asleep our brain responds less to the outside world, yet it does not JC We do our best to bring everything switch off. The sleeping, but active, brain actually requires increased amounts of out with us, but I must confess there are oxygen compared to the resting awake brain. To supply this, blood flow increases. occasionally things that fall down Studies in sleeping animals suggest that the blood flow changes are finely tuned crevices when we’re at high altitudes. by the arterial chemoreceptors, which are one of the few afferent inputs that maintain a strong influence on brain activity during sleep. At sea level, where the TL Tell me about a typical day. blood is fully saturated with oxygen, the blood flow increase in sleep is sufficient to supply the needs of the brain even though ventilation is slightly decreased. JC We live in tents in the snow and the day starts when one of the porters However, at high altitude the barometric pressure can be low enough to seriously brings you hot sweet tea to get you decrease SaO2 and an alteration in oxygen delivery to the brain during sleep can going. Then you get out of your severely affect brain activity. It is not surprising, therefore, that hypoxic insomnia sleeping bag, have something to eat and is a common complaint amongst trekkers, skiers and mountaineers sojourning set to work. above 10,000 ft. So what are the physiological changes in visitors to high altitude and, even more interesting, how have residents at high altitude adapted? These The days are very organised – everyone are questions that have kept drawing me back to the mountains. has a designated task and nobody is idle. We may all have to attend the TL What about meals? usually have more than about 1500 medical tent to be weighed, measure Kcal so consequently I lose around a body fat, heart rate, blood pressure, JC Lunch and tea breaks are organised stone or more over a month. give saliva, blood samples, etc. If by the porters and Sherpas. But you you’re doing a sleep study your don’t eat a lot. You’re busy, it’s cold, When you stop working you just want electrodes for EEG, ECG and you have no appetite and it’s actually to get into your sleeping bag to keep ventilation will need removing or quite hard work to make the effort to warm. You go back to your two-man replacing along with your Medilog eat. The whole environment is not tent once you’ve finished your work recorder. In an exercise study we take exactly conducive to eating and the and maybe chat to your companion for along a bicycle ergometer and test food is mainly dried stuff. Above a bit before the final meal of the day, or people at different workloads. The bike 18,000 ft we exist mainly on tea, you just have a snooze. This can is heavily used and takes a lot of porridge, chapatis, jam and actually be quite worrying if the other punishment. We often have to use it reconstituted soup and stews – it’s not a person remains awake at this time outside so it’s very unpleasant if you’re great culinary experience. You need because at altitude you go into periodic the minder of the bike! about 3000 Kcal per day, but I don’t breathing and you may stop for quite long periods of time. There have been incidents when non-medical scientists have panicked because they thought their partner had died!

TL If you’re living at altitude in a hypoxic environment, presumably you are functioning at less than 100% mental capacity. How can you be sure that the science you do is actually any good?

JC Well we plan everything in detail before we go and we’re all pretty experienced scientists and highly motivated, so this helps. The organisers of the trip take diamox (a carbonic anhydrase inhibitor) and this helps quite a bit too. We have on occasions had to send people down, though, because they got so ill. Once we were in the Alps just below the Matterhorn at about 11,000 ft. We were using a mountain hut as a lab and on the second night one guy, an experienced David Paterson measuring a Sherpa’s blood oxygen saturation mountaineer, developed pulmonary

Physiology News | No. 62 | Spring 2006 | www.physoc.org 18 PN FEATURES oedema. Fortunately, we had some furosemide (a diuretic) with us. So we started him on that and then had to get him down the mountain in the dark and snow whilst collecting his copious urine output in lemonade bottles! He recovered OK, I’m pleased to say.

TL It all sounds a bit grim to me. Are there any good bits?

JC Being in such remote environments, you notice that it is absolutely pristine – stunning in fact. And this offsets the unpleasantness of the rest of the time. But it’s not everyone’s cup of tea by The team waiting for signs of a helicopter any means. our path was blocked by a huge pile of Although I do have to admit that for me TL Any scary moments? stones, which turned out to be a it’s an excuse to visit the high terrorist road block. We had to mountains as a break from my main JC There have been a few. I suppose dismantle it stone by stone, not lines of research. We have still the most hazardous time was in a knowing whether we’d be killed at any published some important original village in Peru when we came in the moment. observations on altitude sickness and way of the Shining Path guerrillas and sleep, though! had to spend most of the night under Finally, after waiting nervously in this the bed as the bank outside the lab was field with our kit, the helicopter arrived Publications arising from John blown up and bullets started flying very low, just about skimming the Coote’s ‘holidays’ at altitude when the army was sent in! mountain tops. Flights in Nepal are include: monitored by the military so it could Coote JH, Nicholson AN, Smith PA, Stone BM & Bradwell AR (1988). Altitude insomnia studies during an expedition to the Then there was the famous episode of land only for a short time out of radar Himalayas. Sleep 11, 354-361. the dodgy Russian we met in a bar in surveillance. We bundled our stuff in Smith PA, Coote JH, Nicholson AN & Stone BM (1989). Sleep Kathmandu. We needed to move our and got out OK. But it was all a bit during an alpine expedition. Aviat Space Eviron Med 59, 478­ gear to Lukla (9,400 ft) and he said he hair-raising. 481. had a helicopter and could do it for us. Coote JH, Stone BM & Tsang G (1992). Sleep of Andean high David Paterson (University of Oxford) TL It all sounds very British and gung­ altitude natives. Eur J Appl Physiol 64, 178-181. began negotiations and we ended up ho. Coote JH, Stang G, Baker A & Stone BM (1993). Respiratory handing over a pile of cash and striking changes and structure of sleep in young high altitude dwellers in a deal to meet him at night in a remote JC Perhaps, but nevertheless good the Andes of Peru. Eur J Appl Physiol 66, 249-253. field. We hired a Sherpa and a battered science does get done. You have to be Coote JH (1993). Sleep at high altitude. In Sleep, ed. Cooper R, bus to get our stuff there but on the way very determined and single-minded. pp 242-264. Chapman Hall, London.

Nobel Laureate to give medical imaging techniques, with an keynote lecture at KCL in associated exhibition on imaging National Science Week techniques currently used in the diagnosis of heart disease. This exciting event is National Science Week (10-19 March) is targeted towards sixth form students and an annual event run by The British undergraduates, although anyone with an Association for the Advancement of interest is welcome to attend. The event Science to provide people with an will begin at 1 p.m. with lunch and opportunity to take part in science, demonstrations of medical imaging engineering and technology activities. This equipment will be available during the year The Physiological Society is Physiology/ Medicine. The lecture will afternoon. Sir Peter Mansfield will give his sponsoring an event organised by Richard include background on his pioneering lecture at 4 p.m. followed by a reception Siow at the Guy’s Hospital Campus of achievements in magnetic resonance for all participants. King’s College London on 17 March. The imaging. A major emphasis for this event session will focus on recent advances in will be on the diagnosis of heart diseases For further programme details please medical imaging techniques, and the and Professor Peter Weissberg, the contact: keynote lecture will be given by Sir Peter Medical Director of the British Heart Mansfield FRS (pictured right), who was Foundation, will give a short presentation Richard Siow ([email protected]) or awarded the 2003 Nobel Prize in on biomedical and clinical applications of Donna Brown ([email protected])

Physiology News | No. 62 | Spring 2006 | www.physoc.org FEATURES PN 19

How ion channels and transporters affect metastasis Cell migration is an important mechanism in metastasis. Ion transporters such as the Na+/H+ exchanger NHE1 control migration of tumour cells by, among other things, modulating cell adhesion. NHE1 creates a pH nanoenvironment at the cell surface that allows a coordinated formation and release of cell-matrix contacts during cell migration

Cell migration away from the primary • a coordinated formation and release tumour is a major step in metastasis. of focal adhesion contacts to the This multistep process requires extracellular matrix mediated by sequential interaction between the receptor molecules such as integrins invasive cell and the surrounding enables the migrating cell to grab and extracellular matrix as follows: loose its hold on the extracellular matrix. • migrating cells release matrix metalloproteinases in order to cleave Our interest is focused on the roles ion their way through the dense, fibrous network of the extracellular matrix transporters and channels play in cell migration. One of these transporters • a directed reorganisation of the whose role in cell migration is well cytosekeleton, especially actin studied is the Na+/H+ exchanger filaments, is needed for the isoform NHE1. The primary task of continuous renewal of protrusive the NHE1 is the regulation of structures at the front of a motile cell intracellular pH and cell volume. Its • the simultaneous action of the Na+/H+ housekeeping activity is of particular exchanger NHE1, the importance for many tumour cells. - - Christian Stock (top) and Albrecht Schwab Cl /HCO3 exchanger AE2, the Insufficient tumour vascularization aquaporin AQP1 and possibly the leads to a diminished O2 supply, so + - Na -HCO3 cotransporter NBC1 that anaerobic glycolysis leads to an NHE1 activation enhances the mediate local salt and water uptake at accumulation of protons in the cytosol. invasiveness of tumour cells (Reshkin the leading edge of the lamellipodium Excess protons are extruded into the et al. 2000; Cardone et al. 2005) while which induces gradual cell swelling extracellular space by blocking NHE1 inhibits cell migration and causes the leading edge to grow the NHE1 which then causes an in several cell types. The fact that (Schwab, 2001, Fig. 1) acidification of the tumour tissue. NHE1 and integrin dimers colocalize at the focal adhesion contacts led us to hypothesize that NHE1 creates a pH nanoenvironment at the surface of the plasma membrane which then affects cell migration.

To prove this hypothesis we studied the migration of human melanoma cells that utilize a2b1 integrins for establishing reversible cell-matrix contacts (Maaser et al. 1999). Migration of these cells depends on both NHE1 activity and the extracellular proton concentration (Stock et al. 2005). Cells reach their maximum motility at extracellular pH values of about 7.0 to 7.2. They hardly migrate at pH 6.6 or 7.5, when NHE1 is inhibited, or when NHE1 activitiy is Figure 1. Model demonstrating the function of ion channels and transporters in migrating cells. At the leading + + - - stimulated by loading cells with edge of the cell salt uptake mediated by Na /H (NHE1) and Cl /HCO3 (AE2) exchange and osmotic water entry facilitated by the aquaporin AQP1 occur. They contribute to the extension of the lamellipodium. Increasing volume protons. Under these different 2+ 2+ and membrane tension eventually trigger a rise in intracellular Ca ([Ca ]i) concentration by activation of conditions characteristic changes in 2+ mechanosensitive cation channels. This rise in [Ca ]i induces the retraction of the rear part of a migrating cell intracellular pH are observed. The accompanied by massive K+ efflux and shrinkage of the posterior cell pole (modified after Schwab 2001). changes in the intracellular pH,

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Multimerisation – an only transporter is a lonely transporter

David Meredith (left) and Richard Boyd.

The Oxford English Dictionary definition of a multimer is ‘An aggregate of molecules held together by Figure 2. Model of the functional interrelation of NHE1 activity and integrin-mediated cell adhesion in human relatively weak bonds, such as α β melanoma cells (MV3). NHE1 and integrins (e.g. 2 1) are colocalized at the leading edge of the lamellipodium. hydrogen bonds’. Protons stabilize the collagen-integrin bond. A, normal NHE1 activity leads to suitable cell adhesion and to the formation of a lamellipodium with a leading edge. B, a lack of protons (alkalosis) or an inhibited NHE1 activity prevent adhesion and cells become spherical (modified after Stock et al. 2005). As all biological systems include water, by this definition all proteins would be however, cannot account for the rats with this drug prevents them from multimers – hence the need for a more changes in migratory behaviour. dying of cancer. Only time and more physiologically relevant definition. This Migration instead correlates with the research will tell if NHE1 will really would not be confined to a molecular strength of cell-matrix interactions, as provide a new angle of attack on aggregate held together by weak bonds, adhesion is strongest at an cancer, but the signs are promising. but would include ‘salt bridges’ and extracellular pH of 6.6 and weakens at covalent bonds; but critically in this basic extracellular pH values, upon Christian Stock new definition the aggregation must be NHE inhibition or upon blockage of Albrecht Schwab between protein molecules. the integrin α2β1. Institute of Physiology II, The University of Münster, A monomer transport protein is a Münster, Germany At this point a direct interrelation single polypeptide chain that possesses the intrinsic capability of between NHE1 activity, extracellular Acknowledgements proton concentration, cell migration transporting its substrate(s) and This work was supported by grants additionally exists in the membrane and adhesion begins to appear (Fig. 2). from the Deutsche Forschungs­ The extracellular protons and NHE1 without interacting with other gemeinschaft (Schw 407/7-1, 407/9-1 proteins (Fig. 1A). activity affect migration of human and Re 1284/2-1). melanoma cells by modulating cell­ matrix interactions. Migration is It is surprisingly difficult to find References hindered when the interaction is too examples of membrane transport Cardone RA, Casavola V & Reshkin SJ (2005). The role of disturbed proteins cited in the literature as being strong (acidic extracellular pH) or too pH dynamics and the Na+/H+ exchanger in metastasis. Nature Rev shown to be monomers. One example is weak (alkaline extracellular pH or Cancer, 5, 786-795. the bacterial lactose transporter, lac NHE1 inhibition). Maaser K, Wolf K, Klein CE, Niggemann B, Zänker KS, Bröcker E-B & Friedl P (1999). Functional hierarchy of simultaneously expressed permease (reviewed in Kaback, 2005); Implications adhesion receptors: integrin a2b1 but not CD44 mediates MV3 another is the mammalian melanoma cell migratiojn and matrix reorganization within three­ Ion transporters such as NHE1 might dimensional hyaluron-containing collagen matrices. Mol Biol Cell sodium/glucose cotransporter SGLT1, be potential targets for 10, 3067-3079. shown by Eskandari et al. (1998), with freeze fracture electron microscopy chemotherapeutics within the scope of Reshkin SJ, Bellizzi A, Albarini V, Guerra L, Tommasino M, Paradiso the treatment of cancer. A & Casavola V (2000). Phosphoinositide 3-kinase is involved in the allowing measurement of the particle tumor-specific activation of human breast cancer cell Na+/H+ size of the cloned transporter expressed exchange, motility, and invasion induced by serum deprivation. For instance NHE1 inhibitors such as J Biol Chem 275, 5361-5369. in Xenopus oocytes. However, even cariporide (also known as HOE642), these two examples are not have been shown to have low levels of Schwab A (2001). Function and spatial distribution of ion channels unchallenged: the lac permease has and transporters in cell migration. Am J Physiol Renal Physiol 280, toxicity, so that they might be useful as F739-F747. been suggested to be a dimer by a anti-cancer agents. Cariporide has been number of researchers, with the Stock C, Gassner B, Hauck CR et al. (2005). Migration of human shown to have antiproliferative activity melanoma cells depends on extracellular pH and Na+/H+ exchange. experimental conditions (such as the in vitro, and long-term treatment of J Physiol 567, 225-238. presence or absence of a physiological

Physiology News | No. 62 | Spring 2006 | www.physoc.org FEATURES PN 21

Figure 1. Cartoon to show different types of multimerisation of membrane proteins (see text for details). electrochemical gradient (Golkorn et al. identical transporter polypeptides, might act as a transporter if in the 1984), or the detergent used (Houssin et based on the way the identical subunits (albeit unphysiological) monomeric al. 1984) being proposed to affect the interact, irrespective of whether they state. subunit interactions. Earlier reports are in a heteromultimer or a from radiation inactivation experiments homomultimer (where all the subunits In a functional multimer each are consistent with proposals that are identical polypeptide sequences). transporter protein subunit does not SGLT1 exists as a multimer (Lin et al. have the intrinsic capability of 1984), while a decade later Koepsell & In a structural multimer each transporting its substrate, but has to Spangenberg (1994) reported that ‘the transporter protein subunit has the be associated with (at least) other functional Na+-glucose cotransport intrinsic capability of transporting its polypeptides of sequence identical to systems in mammals are composed of substrate, but in the membrane the that of the subunit in order to two SGLT1-type subunits’ (as well as a protein is found associated with (at function (Fig 2C, D). regulatory protein) using similar least) other polypeptides of sequence techniques. identical to that of the subunit (Fig. The ability of a mutant subunit of a 2B). transporter multimer to inhibit the A heteromultimer is a multimer (as activity of a wildtype one indicates that defined above) where the subunits For example, each individual subunit of the interaction between the subunits in are not all identical. Thus it could SGLT1 is thought to have its own the multimer is essential for the either consist of a number of (all) substrate binding site and translocation functioning of the individual subunits, different subunits/ polypeptides, or of pathway, based on the finding that that is, the individual subunits do not a number of identical subunits plus SGLT1 transports glucose when have intrinsic transport capability. Thus one or more other distinct protein. expressed in Xenopus oocytes yet the mutant protein exerts a dominant appears as monomers in freeze-fracture negative effect on the wildtype The topic of heteromultimeric transport electron microscopy. Thus it would proteins, and this can be measured by a proteins is too large to be given more appear that if/when the proteins are drop in activity when the mutant and than the briefest treatment here, but present as a dimer, this is because they wildtype proteins are co-expressed in a includes: are physically more stable in this form. heterologous expression system such as Xenopus oocytes. There are a number • proteins which modify the function of While at the present time mammalian of explanations for why a dominant others e.g. the NHERF family transport proteins are virtually negative phenomenon might be (reviewed by Shenolikar et al. 2004); impossible to crystallise, more progress observed, e.g. the binding site is made has been made with those from • true multi-subunit transport proteins up of parts of a number of subunits, or bacteria. For example, the bacterial (e.g. amino acid transporters, reviewed a single subunit protein does not have multidrug resistance transporter EmrE by Verrey et al. 2004); or the correct shape to be functional. has been shown to be an asymmetric • proteins required (at least) for homodimer (Ubarretxena-Belandia & Analysis of the reduction of transport expression (e.g. MCT1 and CD147, Tate 2004), with each subunit when known ratios of mutant and reviewed by Halestrap & Meredith, crystallised with a tetraphenyl­ wildtype protein are expressed, with an 2004). phosphonium ion (TPP+) substrate assumption of a binomial distribution bound to it. As the binding sites were of mutant and wildtype protein There are two ways of defining virtually central to the protein, it would complexes, allows modelling of the multimers that contain two or more be logical to speculate that each subunit data to estimate the number of subunits

Physiology News | No. 62 | Spring 2006 | www.physoc.org 22 PN FEATURES in the multimer. This approach was A used by Casula et al. (2001) for the KCC1 K-Cl cotransporter, and in our laboratory for the proton-coupled peptide transporter PepT1 (Panitsas et al. 2006). Data from such an experiment on PepT1 is shown in Fig. 2A. The model that best fits the data (shown by the solid line) represents a tetramer, with at least two wildtype subunits (Fig. 2B). One conclusion would be that the mutant PepT1 shows a dominant negative effect, and that the tetramer actually consists of a dimer of B functional dimers (Fig. 2C).

Why is it important to know whether a transport protein is a monomer or a multimer, and, if the latter, of what type? There is a paucity of high resolution structures for membrane transporters, and computer modelling is one way of providing a working model. Therefore, if the protein of interest is for example a functional multimer, this C will be crucial information. In a very recent paper by Jen et al. (2005), a heterozygous mutation was identified in a neurotransmitter reuptake system for glutamate (EAAT1) in a patient with episodic ataxia, seizures, migraine and alternating hemiplegia. When the mutant EAAT1 was expressed with the wildtype (as would happen in a heterozygous individual) the function of the wildtype was severely compromised. The decreased glutamate uptake is predicted to result in the Figure 2. A, Data modified from Panitsas et al. (2006) showing the uptake of dipeptide into oocytes (filled bars) neuronal hyperexcitability and the and the membrane surface expression of PepT10FLAG )open bars) with injection of increasing amounts of cRNA symptoms reported. for the non-functional mutant PepT1 transporter (W294F-PepT1) and a constant amount of cRNA for the functional PepT1 (PepT1-FLAG). The line represents the model that best fits the data, which is that of a tetramer Therefore, multimerisation is not just of with at least two functional subunits. B, Cartoon to explain data in Figure 2A. C, Cartoon of a possible model of PepT1 in the membrane, forming a dimer of functional dimers. academic but also of clinical importance. Eskandari S, Wright EM, Kreman M, Starace DM & Zampighi GA Koepsell H & Spangenberg J (1994). Function and presumed (1998). Structural analysis of cloned plasma membrane proteins by molecular structure of Na+-D-glucose cotransport systems. J Memb freeze-fracture electron microscopy. Proc Natl Acad Sci USA 95, Biol 138, 1-11. Acknowledgement 11235-11240. The authors are grateful to the Lin JT, Szwarc K, Kinne R & Jung CY (1984). Structural state of the Goldkorn T, Rimon G, Kempner ES & Kaback HR (1984). Functional Na+-D-glucose cotransporter in calf kidney brush-border membranes. Wellcome Trust for supporting their molecular weight of the lac carrier protein from Escherichia coli as Target size analysis of Na+- dependent phlorizin binding and Na+­ work. studied by radiation. inactivation analysis. Proc Natl Acad Sci USA dependent D-glucose transport. Biochim Biophys Acta 777, 201-208. 81, 1021-1025. Panitsas KE, Boyd CAR & Meredith D (2006). Evidence that the David Meredith Halestrap AP & Meredith D (2004). The SLC16 gene family from rabbit proton-peptide co-transporter PepT1 is a multimer when monocarboxylate transporters (MCTs) to aromatic amino acid expressed in Xenopus laevis oocytes. Pflugers Arch (in press). Richard Boyd transporters and beyond. Pflugers Arch 447, 619-628. Department of Physiology, Anatomy & Genetics, Shenolikar S, Voltz JW, Cunningham R & Weinman EJ (2004). Houssin C, le Maire M, Aggerbeck LP & Shechter E (1985). The Regulation of ion transport by the NHERF family of PDZ proteins. University of Oxford, South Parks Road, Oxford, UK lactose permease of Escherichia coli: evidence in favor of a dimer. Physiology 19, 362-369. Arch Biochem Biophys 240, 593-606. Verrey F, Closs EI, Wagner CA, Palacin M, Endou H, Kanai Y (2004). References Jen JC, Wan J, Palos TP, Howard BD & Baloh RW (2005). Mutation CATs and HATs: the SLC7 family of amino acid transporters. Casula S, Shmukler BE, Wilhelm S, Stuart-Tilley AK, Su W, in the glutamate transporter EAAT1 causes episodic ataxia, Pflugers Arch 447, 532-542. Chernova MN, Brugnara C & Alper SL (2001). A dominant negative hemiplegia and seizures. Neurology 65, 529-534. mutant of the KCCl K-Cl cotransporter: both N- and C-terminal Ubarretxena-Belandia I & Tate CG (2004). New insights into the cytoplasmic domains are required for K-Cl cotransport activity. J Biol Kaback HR (2005). Structure and mechanism of the lactose structure and oligomeric state of the bacterial multidrug transporter Chem 276, 41870-41878. permease. C R Biol 328, 557-567. EmrE: an unusual asymmetric homo-dimer. FEBS Lett 564, 234-238.

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A new muscle sense? Uwe Proske proposes that, whenever movement of our limbs is accompanied by an effort sensation, this information can be used by the brain to determine the location in space of the limbs In a previous report (Physiology News firmly based on experimental As far as we know, it has not been 60, 14 ), I described our work on observations. In 1972, Goodwin, specifically claimed before that the muscle exercise and how intense McCloskey and Matthews showed that motor command can also provide exercise of arm muscles, be it eccentric muscle vibration produced illusions of positional information. In 1988 Peter or concentric, can lead blindfolded both movement and changed position Matthews declared, ‘… the interest now subjects to make positional errors in a of the forearm during vibration of is not in asking simply whether forearm matching task. The elbow flexors (Goodwin et al. 1972). corollary discharges are involved in the observations prompted us to propose Since the primary endings of spindles genesis of human position sense, for it that the muscle activity required to hold were known to be selectively sensitive seems to me that they must be’ up the arm against the force of gravity to vibration, the observations led to the (Matthews, 1988). By corollary provides us with information about present-day view that the kinaesthetic discharges Matthews meant a copy of where the arm is in space (Walsh et al. sense (position and movement) is the central motor command. Be that as 2004). That is our new sense! generated by signals of a peripheral it may, there have been few specific origin. Our observations, if confirmed, proposals put forward which At the present time the generally will require these ideas to be modified. incorporate a central command signal accepted view is that muscle receptors, in the perception of limb position. Thus specifically the muscle spindles, When we say that subjects derive Worringham and Stelmach (1985) provide us with our sense of limb spatial information from their sense of concluded that torque sensation was an position and movement. This view is effort we mean that a certain amount of accessory source of information in effort is required to hold the arm in a limb positioning. Other reports have given posture against the force of tended to interpret their observations in gravity. If the arm is more horizontal, terms of an exclusively peripheral the gravitational vector will be larger, origin of the positional signals (Rymer requiring more muscle activity to hold & D'Almeida, 1980). it there. The extra activity is perceived as more effort (Walsh et al. 2004). The We propose that positional information actual relationship between effort and from the sense of effort is available position is complicated by the fact that only when positioning of the limb is muscle force and torque at the elbow accompanied by muscle contraction. joint don’t change in parallel with Does that mean the sense of effort plays change in angle, since the moment arm a role in kinaesthesia only when the changes and muscle length changes too. limb is held against the force of In any case, we propose that for a given gravity? We think not. We are coming effort required to support the arm to the view that for all limb placements against gravity, the brain is able to that involve muscle contraction, even in derive information about its position in circumstances which are gravity­ space. How the sense of effort is neutral, such as moving the arm in the calibrated is another matter. horizontal plane, effort plays a role in position sense. The idea that our muscle senses may have a central origin is not new. Von What happens when there is no muscle Helmholtz proposed a ‘sensation of activity and the muscle remains Figure 1. Forearm position errors. Blindfolded innervation’ back in 1867. Since then relaxed? If a blindfolded subject places subjects had their forearms taped to paddles which the question of whether a their arm at a set angle on a support were hinged at a point coincident with the elbow joint. Elbow angle was recorded with potentiometers. The proprioceptive signal is associated with and the arm remains relaxed, position experimenter placed one forearm at a given angle and the motor command has been sense is rather poor, with subjects the subject matched its position with their other arm. repeatedly raised. For example, the routinely making large matching errors Errors for 11 subjects were calculated from the present-day view of the sense of force (Winter et al. 2005). However, as soon differences in angles between the two arms. Upper panel: Mean position errors (±SEM). Blue histogram, or of heaviness is that it is derived as they support their arm themselves, subjects held the reference arm unsupported at the centrally. The evidence is that force and their matching performance improves test angle. Red histogram, the relaxed reference arm heaviness matching can be disturbed by significantly (Fig. 1). was placed on a support during position matching. weakening the muscles with partial Lower panel: Mean standard deviations of position errors. Blue, unsupported, red supported (Redrawn paralysis or fatigue. For a review, see In another experiment we have been from Winter et al. 2005). (McCloskey et al. 1983). able to provide evidence that the crude

Physiology News | No. 62 | Spring 2006 | www.physoc.org 24 PN FEATURES position signal available to subjects powerful argument for spindles as the increases. Fusimotor-activated spindles when their arm is relaxed is coming receptors responsible since other would not be expected to show muscle from muscle spindles (Winter et al. sensory receptors that might contribute, conditioning effects, since any slack 2005). The evidence is based on the skin and joint receptors, are unlikely to introduced by conditioning would be observation that conditioning the show such history-dependent behaviour. taken up by the fusimotor activity muscle at different lengths leads Effort cannot play a role since the (Gregory et al. 1988). During a subjects to make systematic errors in muscle has remained relaxed. contraction, while the effects of muscle position sense (Fig. 2). The reason for conditioning are significantly less, for a this pattern of errors is that the So, to summarise up to this point, when submaximal contraction (15% of contraction has conditioned the our limb muscles are relaxed, positional maximum in Fig. 2), some small responses of the muscle spindles. information is coming from muscle conditioning effects persist. This spindles. However, as soon as the task suggests that the few remaining passive When a muscle is contracted requires some muscle contraction, spindles are still able to manifest voluntarily, both skeletomotor and additional information from another themselves as position errors. fusimotor neurones are co-activated source begins to contribute. We claim (Vallbo, 1974). This means that the that this source is the sense of effort, What we are saying is that evidence of intrafusal muscle fibres of spindles generated centrally in association with a spindle contribution to position sense contract. If that is done in a posture the motor command. in the passive muscle, and for low where the muscle is short, and levels of contraction, is clearly afterwards the muscle is stretched to an Our current area of research concerns discernible. Then, as the contraction intermediate length, the intrafusal fibres the changes in position sense observed grows, a new influence becomes will be taut and spindle resting when the limb is bearing a load. As apparent. Our experiments suggest it is discharge levels will be high. already mentioned, during a voluntary the sense of effort. In an alternative Alternatively, the muscle is contracted contraction spindles become co­ view, spindles continue to provide the while holding the limb in a posture activated. The fusimotor activity might position signal but after some kind of where the muscle is long. On moving it be expected to produce a sudden central processing of their input, where to a shorter length, the intrafusal fibres change in the position signal. Yet the fusimotor-related activity is subtracted will fall slack and therefore resting observations are of a smooth transition out (McCloskey et al. 1983). To resolve discharge will be low (Gregory et al. from passive position matching to this issue is a challenge for the future. 1988). Such contraction history­ where the muscles are contracting (Fig. dependent changes in spindle activity 2). We place particular importance on Uwe Proske are reflected in the observed errors in the observation that the conditioning Department of Physiology, Monash University, Clayton, position sense (Fig. 2). This is a effects gradually disappear as load Victoria, Australia

References Goodwin GM, McCloskey DI & Matthews PB (1972). The contribution of muscle afferents to kinaesthesia shown by vibration induced illusions of movement and by the effects of paralysing joint afferents. Brain 95, 705-748.

Gregory JE, Morgan DL & Proske U (1988). Responses of muscle spindles depend on their history of activation and movement. Prog Brain Res 74, 85-90.

Matthews PBC (1988). Proprioceptors and their contributions to somatosensory mapping: complex messages require complex processing. Can J Physiol Pharm 66, 430-438.

McCloskey DI, Gandevia S, Potter EK & Colebatch JG (1983). Muscle sense and effort: motor commands and judgements about muscular contractions. In Motor Control Mechanisms in Health and Disease, ed. Desmedt JE, pp. 151-167. Raven Press, New York.

Rymer WZ & D'Almeida A (1980). Joint position sense. The effects of muscle contraction. Brain 103, 1-22.

Vallbo A (1974). Human muscle spindle discharge during isometric voluntary contractions. Amplitude relations between spindle frequency and torque. Acta Physiol Scand 90, 319-336. Figure 2. Effects of muscle conditioning on position sense. Upper panel: Distribution of position errors for a single subject after a conditioning voluntary contraction of the Walsh LD, Hesse CW, Morgan DL & Proske U (2004). Human forearm position sense after fatigue of elbow flexor muscles. J reference arm with the arm held extended (blue dots, EC) or held flexed (red dots, FC). After conditioning, the Physiol 558, 705-715. relaxed reference arm was placed on a support at the target angle. Trials alternated between the two forms of conditioning and each pair of measurements has been joined by a line. Errors are scored as positive in the Winter J, Allen T & Proske U (2005). Muscle spindle signals combine direction of extension and negative in the direction of flexion. The dotted line is zero error, i.e. where reference with the sense of effort to indicate limb position. J Physiol 568, 1035­ and matching arms were exactly aligned. Lower panel: similar measurements made while the reference arm was 1046. held by the subject themselves at the test angle, unsupported. The paddle to which the arm was strapped had 2kg Worringham CJ & Stelmach GE (1985). The contribution of of weight attached with it, meaning that an elbow flexion force of approximately 15% of maximum was required to gravitational torques to limb position sense. Exp Brain Res 61, 38­ maintain arm position (Redrawn from Winter et al. 2005). 42.

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Sympathetic nerve activity and cardiac output: an integrated balance with implications for blood pressure regulation Sympathetic vasoconstrictor nerves have an important role in blood pressure regulation in humans via control of peripheral vascular resistance. Recent findings of a balance between cardiac hemodynamics and control of sympathetic activity at rest provide insight into integrated mechanisms of blood pressure regulation in individuals with widely varying sympathetic activity

We recently set out to investigate this shown in Figure 1B. Taken together, apparent paradox by testing the these relationships suggested a balance hypothesis that a balance exists between the two main contributors to between CO and MSNA that is arterial pressure: CO and TPR important to normal blood pressure (Charkoudian et al. 2005). The regulation. We further hypothesized findings provide strong evidence that a that this balance would involve an major reason why individuals with inhibitory influence of CO on higher sympathetic nerve activity do baroreflex control of MSNA. To not have higher blood pressures is address these hypotheses, we measured because of a balance between cardiac Gunnar Wallin (left), Michael Joyner and Nisha MSNA (peroneal microneurography), hemodynamics and control of Charkoudian CO (acetylene uptake) and arterial peripheral vascular resistance. pressure (directly via radial artery Sympathetic vasoconstrictor neural catheter) in 18 normotensive men Previous microneurographic recordings activity (SNA) is a major contributor to (Charkoudian et al. 2005). Our most of human MSNA have revealed that, in blood pressure regulation in humans: a striking finding was a strong inverse individual subjects, the arterial rise in SNA increases vasoconstriction relationship between CO and MSNA, baroreflex exerts substantial control and vascular resistance, resulting in an such that individuals with high CO over MSNA. Thus small changes in increase in blood pressure. It has long tended to have low mean levels of blood pressure elicit marked opposing been considered paradoxical, therefore, MSNA, and vice versa. Figure 1A changes in MSNA, which tend to that humans with higher resting SNA shows the relationship between CO and correct, or ‘buffer’, the original changes do not necessarily have higher blood MSNA at rest among our subjects. in pressure (Kienbaum et al. 2001; pressures than those in whom SNA is Furthermore, MSNA showed a positive Charkoudian et al. 2004). Given this very low. Indeed, there is wide inter­ correlation with TPR in our subjects, as strong baroreflex control, it is quite individual variability in SNA among normotensive humans with similar arterial pressures. Furthermore, muscle SNA (MSNA, often measured in humans) is extremely reproducible over time (Fagius & Wallin, 1993), and correlates well with resting SNA in other vascular beds (Wallin et al. 1996). Yet MSNA can vary 5-10 fold among individuals (Fagius & Wallin, 1993; Charkoudian et al. 2005). Thus if we consider that mean arterial pressure is determined by the product of cardiac output and total peripheral resistance (MAP = CO x TPR), we must ask the question: how can all this variability exist in normal healthy individuals with similar blood pressures?

Figure 1. A Inverse relationship between cardiac output (CO) and MSNA at rest among normotensive subjects, such that individuals with high resting MSNA have low CO, and vice-versa. B Direct relationship between MSNA at rest and total peripheral resistance (TPR), showing that MSNA is probably a good indicator of total ‘net’ sympathetic vasoconstrictor tone at rest.

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individuals are ‘out of balance’ in this regard – their level of CO is too high for the level of MSNA, or vice-versa. Taking both elements of the CO-MSNA balance into account may help to explain previously contradictory reports regarding whether individuals with hypertension have higher SNA compared to healthy controls (Gudbjornsdottir et al. 1996). In a broader sense, better understanding of the integrated balance of the mechanisms presented here (and other Figure 2. Schematic diagram showing the balance between cardiac output (CO) and total peripheral resistance potential contributors) will not only (TPR) in regulation of blood pressure. Represented in the figure is the major role our data suggest for a balance improve our understanding of the between sympathetic nerve activity (SNA) and CO in this overall regulation. Other potential influences on the integrated regulation may include stroke volume (SV), rate of change of pressure (dP/dt), and factors that may complex physiology involved, but may, influence vascular responsiveness to SNA, such as nitric oxide (NO). in the future, lead to more individualized diagnostic assessment striking that the large inter-individual et al. 2004), and/or by its effects on the and treatment of certain forms of variability in MSNA in normotensive rate of change of pressure (dP/dt) cardiovascular malfunction. humans results in a complete lack of which could alter afferent firing of correlation between mean levels of arterial baroreceptors (Chapleau & Nisha Charkoudian nerve activity and blood pressure across Abboud, 1989). The relationship Michael J Joyner individuals (Skarphedinsson et al. between SNA and total peripheral B Gunnar Wallin 1997; Charkoudian et al. 2005). In our resistance (TPR) in this balance may be Departments of Physiology and Anesthesiology, Mayo recent study, we reasoned that this lack affected by one or more of numerous Clinic College of Medicine, Rochester, MN, USA of correlation might be explained by an influences on vascular tone. For and influence of CO on baroreflex control example, Skarphedinsson et al. (1997) Institute of Clinical Neuroscience, Göteborg University, of MSNA (Charkoudian et al. 2005). reported a direct relationship between Göteborg, Sweden We assessed this possibility using a circulating nitrite/nitrate (a plasma technique called ‘threshold analysis’, marker of nitric oxide activity) and References Chapleau MW & Abboud FM (1989). Determinants of sensitization of which gives information about how resting MSNA among normotensive carotid baroreceptors by pulsatile pressure in dogs. Circ Res 65, likely it is that a given level of blood males. This suggests that individuals 566-577. pressure will elicit a burst of with higher SNA also have higher Charkoudian N, Joyner MJ, Johnson CP, Eisenach JH, Dietz NM & sympathetic activity. The midpoint circulating nitric oxide, and that its Wallin BG (2005). Balance between cardiac output and sympathetic (T50) of a threshold diagram provides a vasodilator effects may offset nerve activity in resting humans: role in arterial pressure regulation. J Physiol 568, 315-321. measure of the blood pressure value vasoconstrictor influences of high which elicits a burst of sympathetic sympathetic activity. Charkoudian N, Martin EA, Dinenno FA, Eisenach JH, Dietz NM & Joyner MJ (2004). Influence of increased central venous pressure on activity 50% of the time (for detailed baroreflex control of sympathetic activity in humans. Am J Physiol discussion, see Kienbaum et al. 2001). Our recent results do not address the Heart Circ Physiol 287, H1658-1662. We found that CO and stroke volume origin of the inter-individual variability Eisenach JH, Barnes SA, Pike TL, Sokolnicki LA, Masuki S, Dietz (SV) were each inversely related to T50 in MSNA or CO. Some evidence NM, Rehfeldt KH, Turner ST & Joyner MJ (2005). Arg16/Gly {beta}2­ adrenergic receptor polymorphism alters the cardiac output response among our subjects, suggesting that suggests that the variability in the to isometric exercise. J Appl Physiol 99, 1776-1781. high resting CO and SV may inhibit MSNA/CO relationship may be genetic Fagius J & Wallin BG (1993). Long-term variability and reproducibility sympathetic outflow at rest via the in origin. For example, identical twins of resting human muscle nerve sympathetic activity at rest, as baroreflex. have very similar levels of resting reassessed after a decade. Clin Auton Res 3, 201-205. MSNA (Wallin et al. 1993) and genetic Gudbjornsdottir S, Lonnroth P, Sverrisdottir YB, Wallin BG & Elam M The inverse relationship we observed variation in genes encoding the beta­ (1996). Sympathetic nerve activity and insulin in obese normotensive between CO and MSNA, and the adrenergic receptor cause differences in and hypertensive men. Hypertension 27, 276-280. apparent inhibitory influences of CO CO and hemodynamic responses Kienbaum P, Karlssonn T, Sverrisdottir YB, Elam M & Wallin BG (2001). Two sites for modulation of human sympathetic activity by and SV on baroreflex control of (Eisenach et al. 2005). It will be arterial baroreceptors? J Physiol 531, 861-869. MSNA, suggest that a balance between interesting to see whether it is possible CO and SNA is an important element Skarphedinsson JO, Elam M, Jungersten L & Wallin BG (1997). in the future to identify genetic factors Sympathetic nerve traffic correlates with the release of nitric oxide in of normal blood pressure regulation. which contribute specifically to the humans: implications for blood pressure control. J Physiol 501, This is shown schematically in Fig. 2, balance of factors described here. 671-675. along with factors that may influence Wallin BG, Kunimoto MM & Sellgren J (1993). Possible genetic this balance. From the cardiac The existence of a balance between CO influence on the strength of human muscle nerve sympathetic activity at rest. Hypertension 22, 282-284. perspective, the influence of SV may be and MSNA leads to the intriguing important, via afferents from the possibility that the bases for some Wallin BG, Thompson JM, Jennings GL & Esler MD (1996). Renal noradrenaline spillover correlates with muscle sympathetic activity in cardiopulmonary region (Charkoudian forms of hypertension may be that humans. J Physiol 491, 881-887.

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Ca2+ sparks – SOS signals of struggling muscle Ca2+ sparks are rare in mammalian skeletal muscle under physiological conditions. Our recent studies reveal an important role for mitochondria in suppression of these localized Ca2+ signals

The primary function of skeletal muscle is to produce shortening and force for movement of our bodies. A complex From left: series of events, known as excitation­ Elena Isaeva, contraction coupling (ECC), links Vyacheslav Shkryl nerve-mediated electrical excitation of and Natalia Shirokova the skeletal muscle membrane to muscle contraction. A key step in ECC Direct experimental evidence for CICR 2+ 2+ difference in Ca signalling between is the release of Ca from intracellular function in normal skeletal muscle mammals and amphibians? Ca2+ stores (sarcoplasmic reticulum, physiology was provided only in 1995, SR) to activate the contractile when Ca2+ sparks were found in In the search for answers, several machinery. Ca2+ release occurs through amphibian skeletal muscle. Sparks, hypotheses have been considered, but specialized Ca2+ channels, called transient localized elevations of most turned out to be dead-end roads. ryanodine receptors (Ryrs). For several cytosolic [Ca2+], represent SR Ca2+ Initially, it had been suggested that the decades it was believed that Ca2+ release events through a small cluster expression of the Ryr3 isoform might release channels are opened by of Ryrs, and are considered to be be necessary for skeletal muscle to mechanical interactions with the elementary events of CICR. They are produce Ca2+ sparks, because most voltage-sensing molecules of the T­ abundant in frog muscle fibres and their amphibian, but not adult mammalian, tubular membrane (dihydropyridine frequency is greatly increased by muscles express Ryr3. However, this receptors) and that Ca2+ released from electrical stimulation, suggesting a hypothesis did not survive experimental the SR by this voltage-dependent substantial contribution of CICR to challenge as spontaneous Ca2+ sparks mechanism subsequently activates ECC. Was the missing link of ECC were found in developing skeletal additional Ryrs via Ca2+-induced Ca2+ definitively found? No! In mammalian muscle of Ryr3-knockout mice. release (CICR), thereby amplifying the muscle, spontaneous Ca2+ sparks are Alternatively, in Shirokova et al. contractile signal. rarely seen and depolarization does not (1999), we proposed that a functional induce Ca2+ sparks, but Ca2+ ‘embers’, interaction between DHPrs and Ryrs The phenomenon of CICR was which probably result from the opening prevents CICR. But this idea was discovered in mechanically skinned of a single Ryr channel and do not subsequently challenged by Kirsch et fibres in the early1970s (Endo et al. involve CICR. The latter observations al. (2001), who demonstrated abundant 1970) but for a long time there was no left us with burning questions: why are sparks in mechanically skinned direct evidence of its involvement in there no Ca2+ sparks in mammalian mammalian fibres, where the coupling Ca2+ signaling during ECC. muscle? Is there a fundamental between DHPrs and Ryrs is presumably preserved. This indicated that mammalian fibres are capable of producing Ca2+ sparks, but these are normally suppressed, and immediately raised another question: why would skinning of the cells lead to the appearance of Ca2+ sparks?

Our recent studies revealed an important role of mitochondria in the suppression of sparks in mammals. For a long time, the almost exclusive function of mitochondria in skeletal muscle was considered to be production of the energy (ATP) supply necessary for the key muscle function – contraction. However, increasing evidence indicates that mitochondria Figure 1. Membrane depolarization produces Ca2+ sparks in amphibian, exert a multifactorial influence on cell but not mammalian, skeletal muscle. physiology: the organelles can

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may be required for muscle adaptation. In particular, increased cytosolic Ca2+ concentration could lead to a mild Figure 2. Ca2+ sparks appear increase of the mitochondrial Ca2+ load. earlier in skinned mammalian This, in turn, can counteract the muscle fibres containing fewer decreased mitochondrial metabolism by mitochondria. A, B Images of NADH stimulating ATP synthesis, thereby fluorescence obtained with two­ improving muscle contractility. Under photon confocal microscopy from pathophysiological conditions EDL and soleus muscle fibres, associated with mitochondrial respectively. C Development of sparks in 17 dysfunctions, acute and exaggerated EDL (black circles) and 17 soleus Ca2+ spark activity could be a precursor (white circles) fibres. Frequency of of muscle degeneration. sparks was determined from sets of 40 sequential fluo-3 images acquired with a confocal It still remains to be clarified exactly microscopy at different times after which mitochondrial mechanisms fibre permeabilization. normally suppress CICR in mammals, accumulate Ca2+, produce reactive Moreover, the appearance of sparks to what extent this suppression can be oxygen species (ROS), balance was delayed or sped up by the addition impaired in muscle diseases, and how a cytosolic redox potential, etc. Each of of exogenous ROS scavengers or ROS failure of this suppression is involved these functions is influenced by, and generators, respectively. These findings in muscle pathophysiology. It may turn can in turn influence, intracellular Ca2+ strongly implied that Ca2+ sparks occur out that some of these mechanisms homeostasis. Importantly for the when ROS increase in the cytosol as could be targets for pharmacological interactions within these Ca2+ the redox potential falls upon interventions to slow down, or prevent, dependent feed-back loops, in impairment of mitochondrial the progression of degenerative mammalian muscle, mitochondria are metabolism. In agreement with this muscular conditions. strategically located close to the SR view, sparks were reported in intact Ca2+ release sites, where they are mammalian muscle cells in response to Acknowledgements Our work was supported by the NIH capable of interfering with and sensing osmotic stress or strenuous exercise and MDA. SR Ca2+ release (Shkryl & Shirokova, (Wang et al. 2005), conditions in which 2005). the cytosolic ROS balance is likely to be compromised. Interestingly, it also Elena V Isaeva How can mitochondria suppress CICR? turned out that stress-induced Ca2+ Vyacheslav M Shkryl In Isaeva & Shirokova (2003) we first spark activity was significantly Natalia Shirokova suggested that a degradation of augmented in muscle fibers dissected Department of Pharmacology and Physiology, mitochondrial function following from mdx mice lacking dystrophin, a University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ, USA muscle permeabilization and widely used model of muscle consequent washout of cytosolic dystrophy. This last observation constituents is a proximate cause for suggests that Ca2+ sparks, although not References 2+ 2+ Endo M, Tanaka M & Ogawa Y (1970). Calcium induced release of the appearance of Ca sparks in the mediator of Ca signaling in calcium from the sarcoplasmic reticulum of skinned skeletal muscle. permeabilized mammalian fibers. normal ECC of mammals, may play an Nature 228, 34-36. Experiments with several mitochondrial important role in muscle pathology. Isaeva EV & Shirokova N (2003). Metabolic regulation of Ca2+ uncouplers and Ru360, a specific release in permeabilized mammalian skeletal muscle fibres. J Physiol 547, 453-462. inhibitor of mitochondrial Ca2+ uptake, In summary, it is clear that CICR is less revealed a potential role of important for mammalian skeletal Isaeva EV, Shkryl VM & Shirokova N (2005). Mitochondrial redox 2+ 2+ muscle ECC under physiological state and Ca sparks in permeabilized mammalian skeletal muscle. mitochondrial Ca buffering in the J Physiol 65, 855-872. inhibition of CICR, as impairment of conditions than for amphibian muscle. 2+ Mammalian fibres have two triadic Kirsch WG, Uttenweiler D & Fink RH (2001). Spark- and ember-like mitochondrial Ca uptake boosted elementary Ca2+ release events in skinned fibres of adult mammalian spark activity. In search of other junctions per sarcomere whereas lower skeletal muscle. J Physiol 537, 379-389. mechanisms for mitochondria to affect animals have only one. Ca2+ released Shkryl VM & Shirokova N (2005). Transfer and tunneling of Ca2+ cytosolic Ca2+ signals we next studied from the SR in mammals thus needs to from sarcoplasmic reticulum to mitochondria in skeletal muscle. J the appearance of sparks in travel a shorter distance to activate the Biol Chem Oct 10; [Epub ahead of print] contractile machinery of the muscle. permeabilized skeletal muscle fibres Shirokova N, Shirokov R, Rossi D, González A, Kirsch WG, García with different mitochondrial content Therefore, a further amplification of the J, Sorrentino V & Ríos E (1999). Spatially segregated control of Ca2+ 2+ release in developing skeletal muscle. J Physiol 521, 483-495. (Isaeva et al. 2005). The results were initial voltage-induced Ca signals by striking: in all fibre types, Ca2+ sparks CICR may not be necessary. Under Wang X, Weisleder N, Collet C, Zhou J, Chu Y, Hirata Y, Zhao X, developed in parallel with the decay of stress, however, a moderate Pan Z, Brotto M, Cheng H & Ma J (2005). Uncontrolled calcium 2+ sparks act as a dystrophic signal for mammalian skeletal muscle. the mitochondrial redox potential. augmentation of cytosolic Ca signals Nat Cell Biol 7, 525-530.

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Dying for a good night’s sleep Obstructive sleep apnoea, characterised by excessively loud snoring is not only embarrassing for the patient who falls asleep in public but has much more serious consequences – an increased risk of cardiovascular morbidity and mortality

Obstructive sleep apnoea (OSA) is a may be greater than 50%, and the common, and yet often under­ incidence of OSA in hypertensive diagnosed and under-recognised, patients is greater than 25%. The clinical disorder. It is more common in incidence of OSA in resistant men aged 30-65 years, but can occur in hypertension is even greater, with one all age groups, and is estimated to study reporting that 87% of affect approximately 4% of middle­ hypertensive patients refractory to aged men and 2% of middle-aged maximal medical therapy had women in the UK. OSA is defined as a Victoria Cooper undiagnosed OSA (Logan et al. 2001). cessation in airflow for at least 10 seconds during sleep despite continuing clinical definition of OSA) to more The mechanisms by which OSA leads respiratory effort. It occurs as the result than 100 times per hour of sleep. to hypertension and other of obstruction to the upper airways, Clearly this leads to severe sleep cardiovascular disorders have most commonly caused by excess fat fragmentation, which is more undergone much research in recent due to obesity. During sleep, upper deleterious than sleep deprivation. years. Although there is no apparent airway muscles relax and their tone is The most common symptom of this consensus, the mechanisms are clearly reduced. Inspiration also helps to condition is excessive daytime multi-factorial. Episodes of OSA result favour airway collapse due to negative sleepiness (Fig. 1). in large swings in intrathoracic pressure within the airway. These pressure, arterial oxygen desaturation, factors combined, together with excess Aside from the impact sleepiness has in hypercapnia and acidosis. Events parapharyngeal fat or some other social functioning, work performance terminate in arousal and are obstructive factor, result in closure of and driving ability, there are more accompanied by marked surges in the airways. As a result hypoxia and sinister consequences to OSA. There is arterial pressure, preceded by an hypercapnia develop, with oxygen increasing evidence that OSA has direct increase in sympathetic vasoconstrictor saturation levels falling below 50% in and deleterious effects on cardiac and tone. All these factors probably have severe cases. Fortunately, this leads to vascular structure and function, with some role to play in the development of an arousal which acts to increase OSA patients at increased risk of cardiovascular complications. muscle tone and open up the airways so arterial hypertension, heart failure, breathing can resume. Sleep then cardiac ischemia, arrhythmias and One of the first mechanisms to be ensues and the cycle starts over. This stroke. The prevalence of hypertension considered in the link between OSA cycle can occur from five times (the in patients with severe untreated OSA and hypertension was that both are manifestations of a common cause, e.g. obesity. This is an attractive hypothesis since there is a known association between obesity and both hypertension and OSA. However, numerous studies have shown that even after adjustment for body mass index, although the strength of the association is predictably reduced, there is still an independent link between OSA and hypertension. Also against this hypothesis is the finding that successful treatment of OSA, particularly using nasal continuous positive airway pressure (nCPAP), reduces blood pressure despite no alteration in weight.

Frequent arousals result in abnormal electrophysiological sleep structure, in particular a reduction in the deep sleep Figure 1. Pathogeneis of obstructive sleep apnoea. stages 3 and 4. Arousal also results in

Physiology News | No. 62 | Spring 2006 | www.physoc.org 30 PN FEATURES transient increases in heart rate, blood affect vascular remodelling, reactivity alterations, through a number of pressure, ventilation and surges in and resistance vessel tone, all factors mechanisms, will promote hypertension sympathetic output. It has been which may promote hypertension. and cardiovascular disease. Whatever suggested that movement arousals also the underlying mechanism, the influence daytime sympathetic tone Another point to consider is the effect increased risk of cardiovascular independently of respiratory of night-time surges in blood pressure morbidity and mortality in patients with disturbance index (the number of >3% on arterial baroreceptors. Baroreflexes OSA is real. Therefore early diagnosis desaturations per hour of sleep) and act to maintain blood pressure at a and treatment is essential in reducing night-time saturation (Loredo et al. given level, but may reset when this risk. 1999). However, animal models have pressure is altered for a prolonged not shown arousal in itself to lead period, so that pressure is maintained at Victoria Cooper sustained hypertension (Brooks et al. the new prevailing pressure. A canine Institute for Cardiovascular Research, University of 1997). model of sleep apnnoea suggested that Leeds, Leeds, UK the baroreflex curve is shifted to the Probably of more importance than right without a change in slope (Brooks References arousal is the effect of repetitive et al. 1999). We have also recently hypoxia and hypercapnia. Animal Brooks D, Horner RL, Kozar LF, Render-Teixeira CL & Phillipson EA found something similar in patients (1997). Obstructive sleep apnea as a cause of systemic models have suggested that intact with OSA. The baroreflex ‘set point’ hypertension. Evidence from a canine model. J Clin Invest 99, 106­ carotid chemoreceptors, sympathetic (the pressure corresponding to maximal 109. nervous system, renal nerves and slope) is shifted to the right first thing Brooks D, Horner RL, Floras JS et al. (1999). Baroreflex control of activation of the renin-angiotensin in the morning in OSA patients, heart rate in a canine model of obstructive sleep apnea. Am J Respir Crit Care Med 159, 1293-1297. system are all critical to the rise in whereas the reverse is true in healthy blood pressure in sleep apnoea-induced control subjects who have a reduced Cooper VL, Bowker CM, Pearson SB, Elliott, MW & Hainsworth R hypertension. We have recently shown (2004a). Effects of simulated obstructive sleep apnoea on the human blood pressure during sleep (Cooper et carotid baroreceptor-vascular resistance reflex. J Physiol 557, 1055­ that brief periods of asphyxia or al. 2004b). We propose that night-time 1065. hypercapnia result in resetting of the reductions in blood pressure during Cooper V, Bowker C, Elliott M, Pearson S & Hainsworth R (2004b). carotid baroreflex to maintain arterial normal sleep act to reset baroreceptors Baroreflex resetting in obstructive sleep apnoea – a mechanism for pressure at a higher level, and that this towards lower levels, and that this may promoting hypertension. Clin Auton Res 337. is sustained after the removal of the be a protective mechanism. This Cooper VL, Pearson SB, Bowker CM, Elliott MW & Hainsworth R stimulus (Cooper et al. 2004a, 2005). mechanism is absent in OSA and is (2005). Interaction of chemoreceptor and baroreceptor reflexes by This is also true for sympathetic hypoxia and hypercapnia – a mechanisms for promoting actually reversed, which would hypertension in obstructive sleep apnoea. J Physiol 568, 677-687. activation (Morgan et al. 1995). Indeed, therefore promote hypertension. augmented resting (waking) Logan AG, Perlikowski SM, Mente A, Tisler A, Tkacova R, Niroumand M, Leung RS & Bradley TD (2001). High prevalence of sympathetic activity and a potentiated Other possible factors to be considered unrecognized sleep apnoea in drug-resistant hypertension. J chemoreflex response to hypoxia have are changes in endothelial cell function Hypertens 19, 2271-2277. been found in patients with OSA and also insulin resistance, which is a Loredo JS, Ziegler MG, Ancoli-Israel S, Clausen JL & Dimsdale JE (Narkiewicz et al. 1999). Renal known risk factor for atherosclerosis (1999). Relationship of arousals from sleep to sympathetic nervous handling of sodium and water is also and thus cardiovascular and system activity in obstructive sleep apnoea. Chest 116, 655-659. impaired in OSA. Hypoxia leads to a cerebrovascular disease. Morgan BJ, Crabtree DC, Palta M & Skatrud JB (1995). Combined deficit in renal sodium excretion and hypoxia and hypercapnia evokes long-lasting sympathetic activation this may lead to volume expansion and In summary, OSA causes alterations in in humans. J Appl Physiol 79(1), 205-13. hypertension. Hypoxia also has cellular chemoreflex and baroreflex function, Narkiewicz K, van de Borne PJH, Pesek CA, Dyken ME, Montano N effects, particularly on vascular sympathetic tone, insulin resistance and & Somers VK (1999). Selective potentiation of peripheral chemoreflex sensitivity in obstructive sleep apnea. Circulation 99, endothelial cells. This may directly endothelial cell function. These 1183-1189.

Rob Clarke Members or their departments with Benevolent Fund Alison Marshall, Rob Clarke’s sister, space to accommodate them. The Annual General Meeting of the ran the Robin Hood half marathon to The first set offers issues of The Benevolent Fund will be held on raise funds for Cancer Research UK Journal from 1995-2003. Anyone Wednesday, 26 April 2006 at 2 p.m. in memory of Rob Clarke who died interested should contact Atticus H at The Society’s London in August 2004 (Physiology News Hainsworth at De Montfort Administration Office. 2004, 57, 49). Alison raised £587 University ([email protected]). for the charity. All those who have donated to the The second set runs from Fund are welcome to attend. The Journal of Physiology 1940-2002. Anyone interested back issues should contact Jane Mellanby at the Further details are available from Two sets of The Journal of University of Oxford Elfa Wilmot at the London Office Physiology are on offer to any ([email protected]). ([email protected]).

Physiology News | No. 62 | Spring 2006 | www.physoc.org FEATURES PN 31

Vagal nociceptors in the oesophagus Nociceptors, in Sherrington’s classic definition, are now exactly one hundred years old, but they keep turning up in new places. Here Marian Kollarik and Bradley Undem describe one example

In his timeless text on the integrated naturally would be useful for the action of the nervous system, organism if organs other than the skin Sherrington discussed specific types of also have a ‘specific sense of their own sensory nerve fibres in the skin that injuries’, and indeed nociceptors have ‘Instead of but one kind of stimulus been identified in virtually every being their adequate excitant, they may visceral tissue. In modern usage the be regarded as adapted to a whole term ‘nociceptor’ is often, explicitly or group of excitants, a group of excitants implicitly, narrowed to include only which has in relations to the organism sensory nerves that mediate pain. This one feature common to all its change in characterizing nociceptors, Marian Kollarik (left) and Bradley Undem components, namely a nocuous from the nature of their activators to the character’ (Sherrington, 1906). He consequences of their activation, has a can overtly lead to pain, yet it would reasoned that such nerve fibres ‘under major influence on the type of afferent seem clear that there are vagal afferent selective adaptation, attach to the skin a nerves that are categorized as nerves that can be accurately so-to-say specific sense of its own nociceptors. It is unknown at this time characterized as nociceptors. Our injuries’. The term given to this special whether stimulation of any type of recent studies have served to add type of afferent nerve is nociceptor. It vagal afferent nerve in the oesophagus support for this contention (Yu et al. 2005).

It has long been recognized that airways and lungs receive large numbers of vagal afferent C-fibres (often termed bronchopulmonary C­ fibres) (Coleridge & Coleridge, 1984). These nerves nicely fit into Sherrington’s definition of nociceptors. They are quiet during normal activity of the respiratory system but respond vigorously to a long list of noxious stimuli with, again using Sherrington’s words, ‘the common feature of having a nocuous character’. These stimuli include noxious airborne irritants, inflammatory mediators, and excessive tissue distension. The bronchopulmonary C-fibres, like the somatosensory nociceptors in skin, express the capsaicin receptor TRPV1, rendering them also sensitive to a variety of noxious chemical stimuli including vanilloids and acid. In addition, although bronchopulmonary nociceptors may not mediate pain, their Figure 1. Vagal oesophageal nociceptors, but not tension receptors (low threshold mechanosensors), discriminate innocuous and noxious levels of oesophageal distention. (A) Extracellular recordings were made from the vagal activation has been associated with sensory neurones in nodose and jugular ganglia with mechanosensitive nerve terminals in oesophagus in the unpleasant sensations such as dyspnoea guinea pig isolated innervated oesophagus preparation. Both nodose and jugular ganglia supply nocieptors to and can lead directly to protective oesophagus, while tension receptors are derived exclusively from nodose ganglion. Note that in the guinea pig reflexes that include apnoea, cough and (and larger mammals) the vagal nodose and jugular ganglia are readily identified as separated structures. In some mammals, such as rat and mouse, vagal sensory ganglia can fuse into a single elongated structure perhaps best mucus hypersecretion (Coleridge & described as a jugular/nodose complex. IX, X, XI and XII – glossopharyngeal, vagus, accessory and hypoglossal Coleridge, 1984). nerves, respectively. (B) Distention pressure-activity curves of vagal sensory nerve fibres in oesophagus. Distention of proximal gut > 60 mmHg is reported to cause responses consistent with pain in rodents. Note that Textbooks and review articles often the activity of tension receptors, but not nociceptors, saturates at presumably innocuous pressures. Vagal associate vagal afferent nerves in the oesophageal nociceptors, but not tension receptors, express the capsaicin receptor TRPV1 that confers sensitivity to a variety of noxious chemical stimuli (not shown). oesophagus exclusively with the

Physiology News | No. 62 | Spring 2006 | www.physoc.org 32 PN FEATURES autonomic regulation of homeostasis. differ in their expression of neurokinin This implies that the afferent nerves peptides. The spinal afferent nerves Noticeboard designed to respond to actual or innervating the oesophagus, many of impending tissue damage are limited to which are nociceptors, also originate SOCIETY MEETINGS the spinal nerves with their cell bodies from neural crest. Based on some For a full list of Physiological Society in the dorsal root ganglia. This preliminary data, we speculate that their Meetings during 2006, see the tear-out hypothesis finds credence in studies phenotype will prove to be more Meeting card on p. 48 or visit where few, if any, vagal sensory nerve similar to jugular than to nodose vagal http://www.physoc.org fibres in the oesophagus had nociceptors. 2007 characteristics consistent with Glasgow, Scotland (8-12 July). nociceptors (e.g. Sengupta et al. 1989). Although it seems clear that the vagus Joint Meeting of The Physiological nerves innervating the oesophagus It has been recognized that noxious Society, Biochemical Society and comprise large numbers of nociceptors, British Pharmacological Society. stimuli in oesophagus can amplify the consequence of their activation is vagal reflexes such as cough. This and less clear. It can be reasoned that these Bratislava, Slovakia (10-14 certain similarities in the pattern of the nerves should cause effects consistent September). Joint Meeting of The vagal innervation between lungs and with the oesophagus ‘being informed of Physiological Society, the Slovakian oesophagus led us to hypothesize that its own injury’. Some recent work Physiological Society and FEPS. the vagus supplies nociceptors to the indicates that vagal afferent fibres are oesophagus in a fashion similar to the required for aversive responses to International Workshops bronchopulmonary C-fibres in the noxious gastric stimulation in the rat Margarita Island (19-24 March neighboring respiratory tract. Our (Lamb et al. 2003). There has been 2006). Membrane transport in recent paper experimentally addresses speculation that vagal nociceptors may health and disease. this hypothesis in guinea pigs (Yu et al. contribute to the emotional components 2005). that accompany pain perceptions Kiev, Ukraine (4-7 June 2006). (Berthoud & Neuhuber 2000). It is The study of nociception from We found that the guinea pig also likely that vagal nociceptors may periphery to brainstem. oesophagus is indeed supplied by a serve to coordinate defensive reflexes large population of vagal nociceptors. Charles University, Prague aimed at diluting or ridding the tissue (21-23 September 2006). Lung In fact, based on functional and of the potential noxious stimuli. histological assessment, nociceptive function in health and disease. nerves may represent the predominant Marian Kollarik Full details at type of vagal afferent nerve in the Bradley J Undem http://www.physoc.org/international/ oesophagus. The vagal nociceptors are The Johns Hopkins School of Medicine, Baltimore, MD, readily distinguishable from vagal non­ USA EXPERIMENTAL BIOLOGY 2006 nociceptive low threshold Moscone Convention Center, San mechanosensors (also termed tension References Francisco, CA, USA (1-5 April 2006) receptors). Like spinal nociceptors, but Berthoud HR & Neuhuber WL (2000). Functional and chemical anatomy of the afferent vagal system. Auton Neurosci 85, 1-17. http://www.faseb.org unlike vagal tension receptors, vagal nociceptors discriminate noxious Coleridge JC & Coleridge HM (1984). Afferent vagal C fibre innervation of the lungs and airways and its functional significance. FEDERATION OF EUROPEAN distension of the oesophagus (Fig. 1) Rev Physiol Biochem Pharmacol 99, 1-110. NEUROSCIENCE SOCIETIES and they express the TRPV1 receptor Vienna, Austria (8-12 July 2006) that confers sensitivity to variety of Lamb K, Kang YM, Gebhart GF & Bielefeldt K (2003). Gastric inflammation triggers hypersensitivity to acid in awake rats. http://www.fens.org noxious chemical stimuli. Moreover, Gastroenterology 125, 1410-1418. we found that vagal nociceptors in the Sengupta JN, Kauvar D & Goyal RK (1989). Characteristics of vagal 8th INTERNATIONAL SYMPOSIUM oesophagus are not a homogeneous esophageal tension-sensitive afferent fibers in the opossum. population, but can be divided into two J Neurophysiol 61, 1001-1010. ON NEUROBIOLOGY AND groups based on their embryonic origin. Sherrington SC (1906). The integrative action of the nervous system. NEUROENDOCRINOLOGY OF Nociceptors derived from the Yale University Press, New Haven. AGING embryonic placodes, whose cell bodies Yu S, Undem BJ & Kollarik M (2005). Vagal afferent nerves with Bregenz, Austria (23-28 July 2006) nociceptive properties in guinea-pig oesophagus. J Physiol 563, For the current list of speakers and other are situated in the vagal nodose ganglia, 831-842. can be activated by a broad spectrum of information visit http://www.neurobiology­ autacoids, including 5-HT, ATP, and and-neuroendocrinology-of-aging.org or adenosine. Oesophageal vagal contact Andrzej Bartke ([email protected]) Noticeboard or Richard E Falvo ([email protected]). nociceptors derived from the neural crest, whose cell bodies are located in Notices for the Summer 2006 issue of vagal jugular (supranodose) ganglia, are Physiology News should reach the IUPS rather unresponsive to these autacoids. Publications Office by 21 April. Kyoto, Japan (27 July-1 August 2009) Placodes- and neural crest-derived Please send contributions to UK (July 2013) vagal oesophageal nociceptors also [email protected]. http://www.iups.org

Physiology News | No. 62 | Spring 2006 | www.physoc.org FEATURES PN 33

Calcium signalizing in developing mouse skeletal muscle fibres Mice are born immobile and develop the ability to move over the first 2-3 weeks of life. Here Carlo Caputo and co-workers explore the underlying processes in skeletal muscle

Recently-born mice lack the capacity time course of Ca2+ transient is for movement, which is slowly characterized by a fast rising phase, Clockwise from above left: acquired during the 2-3 weeks completed in about 1.5 ms, followed by Joana Capote, following birth. During this period, a bi-exponential decay phase, with time Pura Bolaños and Carlo important changes take place at level of constants of about 2 and 16 ms Caputo the molecular entities, schematically respectively. In 7 day old mice, the diminished by 25% in the former and listed in Fig. 1, responsible for the magnitude of Ca2+ transients is about by 11% in the latter. series of events that start with one third while the raising phase of the membrane excitation and lead to transients is double that in adult fibres, In principle the prolonged duration of massive calcium release and contractile while the bi-exponential decay phase is the Ca2+ transients in young animals activation in skeletal muscle fibres much slower, with time constants of 5 could be due to prolonged duration of (Capote et al. 2005). and 105 ms respectively. action potentials caused by incomplete development of the K+ delayed rectifier The records in Fig. 2 compare Ca2+ 2+ Ca currents in recently- born mice and by the presence of Ca2+ currents. transients obtained with enzymatically (Beam & Knudson, 1988) appear to However, optical measurements with dissociated flexor digitorum brevis 2+ contribute more to Ca signalizing than the potentiometric dye Di-8-ANEPPS muscle fibres from 7 and 42 day old in adult animals; thus in the absence of indicate that the duration of action mice, respectively. In adult animals the 2+ external Ca the transient amplitude is potential is practically the same in young and adult fibres, precluding this possibility.

Alternatively, the slow decay of Ca2+ transients in young fibres could be attributed to poor development of the Ca2+ clearance mechanisms. The two components of the transient decay,

Figure 1. A schematic representation of the elements involved in Excitation-Contraction Coupling, (ECC). These comprise: Na and K channels responsible for membrane excitability (1,2). L-type Ca2+ channels, identified as dihydropyridine receptors (DHPr), that serve as voltage sensors for ECC and are disposed in tetrads in the t-tubule membrane (3). This DHPr together with RyR (4) that are Ca2+ release channels located in the SR membrane, may form Ca2+ release units (5) at the junctional region between the TT and SR membrane system. Calsequestrin (6), present in the SR lumen, controls the intraluminal Ca2+ concentration. PV (7) present in the myoplasm, serves as a fast Ca2+ buffer, with high affinity and relatively low capacity, binding Ca2+ at two sites normally occupied by Mg. Ca2+-ATPase present in the SR membrane (8), with high capacity for Ca2+ is 2+ responsible for maintaining a low intracellular [Ca ]i, and together with PV is responsible for Ca2+ clearance after contractile activation. The contractile machinery formed by different proteins (9). Notice that non­ junctional RyR (10) may also be present in the SR membrane. All these elements are not completely developed at the moment of birth. The isoform RyR3 is present at the moment of birth and markedly diminishes during the first two weeks. PV is almost absent at birth and starts increasing after birth.

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involved in contractile activation, in particular myofibrils. This in turn indicates that Ca2+ signals may have a role in myofibrillogenesis (Li et al. 2005).

Acknowledgement Supported by FONACIT Grant S1-2000000504.

Joana Capote Pura Bolaños Carlo Caputo Centro de Biofisica y Bioquimica, Instituto Venezolano Figure 2. Comparison of Ca2+ de Investigaciones Cientificas IVIC, Caracas, transients in fibres from young and Venezuela mature mice. The upper records compare Ca2+ transients in two fibres References from 7 and 43 days old animals, Beam KG & Knudson CM. (1988). Effect of postnatal development respectively. The records have been on Calcium currents and slow charge movement in mammalian skeletal muscle. J Gen Physiol 91, 799-815. scaled to better show the difference in their time courses. The lower Capote J, Bolaños P, Schuhmeier RP, Melzer W and Caputo C records show a similar comparison (2005). Calcium transients in developing mouse skeletal muscle after poisoning the fibres with fibres. J Physiol 564, 451-464. cyclopiazonic acid to block the SR Ca2+ ATPase activity. Close R (1964). Dynamic properties of fast and slow skeletal muscle of the rat during development. J Physiol 173, 74-95. characterized by the two time constants, slowness of movement in young Franzini-Armstrong C (1991). Simultaneous maturation of transverse tubules and sarcoplasmic reticulum during muscle differentiation in could be associated with the operation animals may be caused by a poorly the mouse. Dev Biol 146, 353-363. of the myoplasmic Ca2+-sequestering developed Ca2+ uptake systems, both 2+ Leberer E & Pette D (1986). Neural regulation of parvalbumin protein parvalbumin (PV) and of the PV and SR Ca ATPase, and also by expression in mammalian skeletal muscle. Biochem J 235, 67-73. sarcoplasmic reticulum (SR) Ca2+ the the fact that the myosin isoform in Li H, Cook JD, Terry M, Spitzer NC & Ferrari MB (2004). Calcium ATPase activity respectively. Poisoning young animals is of the slow muscle transients regulate patterned actin assembly during of the SERCA pump by cyclopiazonic type (Whalen et al. 1981). Thus it is myofibrillogenesis. Dev Dyn 229, 231-42. 2+ acid reveals the presence of an initial, clear that the capacity to develop Ca Whalen RG, Sell SM, Butler-Browne GS, Schwartz K, Bouveret, P & fast, poison insensitive recapture transients is acquired prior to the Pinset-Harstom I (1981). Three myosin heavy-chain isozymes appear sequentially in rat muscle development. Nature 292, 805­ component in adult, which is much complete development of structures 809. reduced in young animals. This is consistent with the notion that PV Memorable Members enough to have met him need no reminder content is very low at birth and of his ebullient character. Stories about increases during postnatal development him, some printable, some not, are legion. (Leberer & Pette, 1986).

2+ Two examples concern David Whitteridge Interestingly, robust Ca transients who succeeded him as Waynefleet appear in muscle fibres early after birth Professor in Oxford. David was another of (6-7 days) indicating that at this time The Society’s greats who, though he the mechanisms underlying ECC are mellowed much with age, had a reputation sufficiently developed to produce for acerbity. This led G L to describe him 2+ sizeable Ca release. This is even as the physiologist with the highest IQ and though the Ca2+ release units formed by the lowest pH. At my first ever Phys Soc ryanodine (RyR) and dihydropyridine Meeting (Edinburgh 1952), Whitteridge receptors (DHPr) at the level of the mentioned in a discussion that Paintal had junctional region between T-tubules evidence for a cast iron ventricular (TT) and SR are completed only 2 or 3 baroreceptor afferent fibre. ‘Oh’, said G L weeks after birth (Franzini-Armstrong, ‘Perhaps Professor Whitteridge would care 1991). to tell us the conduction velocity in cast G L Brown (pictured above) died over 30 iron.’ In spite of robust Ca2+ release, motility years ago, but his name remains familiar is much reduced and slow in young to physiologists of all ages in the UK and Ann Silver animals (Close, 1964), indicating that RoI. He is commemorated annually in the the development of the contractile G L Brown Lectures that The Society The 2006/7 G L Brown Prize Lectures have apparatus is the limiting factor. The established in 1975. Those of us lucky been awarded to C A R Boyd (see p. 38).

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A racing start for the heart in exercise At the onset of exercise the heart rate changes within one second to bring about a 25% increase in the heart rate, but what initiates these changes? Valerie Gladwell takes a closer look at the mechanisms involved, focusing on how feedback from the muscle alters the heart rate via cardiac vagal activity

The brain’s command to exercising stretching of the muscle whilst the skeletal muscles undoubtedly subject was in a semi-supine position simultaneously initiates appropriate (Gladwell & Coote, 2002). Heart rate cardiovascular changes (Secher, 1999). increased rapidly and the increase was However, feedback from the sustained during the stretching period, contracting muscles also contributes whilst there was only a transient significantly. Recent data suggest a increase in blood pressure. special role for one type of afferent Valerie Gladwell Additionally, it was identified that fibre in inhibiting cardiac vagal activity. rhythmic passive stretching did not initiation of contraction, with the elicit any cardiovascular response, Studies in animals show that removal of stimulation causing the fall suggesting that larger afferent spindles stimulation of the small afferent nerve in heart rate at the termination of and Golgi tendon organs did not play a fibres within the muscle cause increases contraction. role. Interestingly, the cardiovascular in heart rate and blood pressure (Coote response to stretch performed following et al. 1971). Similar effects have been Although experiments have been muscle contraction with occluded shown in humans with electrical conducted in animals to look at the circulation was not sensitized by the stimulation to induce muscle selective influence of type III afferents, metabolic conditions within the muscle. contraction. This evokes changes in it has proved to be more difficult in (Fisher et al. 2005). heart rate and blood pressure of a humans. However, recent experiments similar magnitude to those contractions in humans have been conducted to try In animal models, passive stretch of the which are voluntary in nature. to stimulate mechanoreceptors muscle has been shown to elicit a Furthermore, when circulation is selectively. Leg compression to reduction in cardiac vagal activity occluded at the end of involuntary increase intramuscular pressure has (Murata & Matsukawa, 2001). In contraction, blood pressure remains been used and caused increases in both humans, the increase in heart rate elevated, whereas heart rate falls heart rate and blood pressure brought about by the stimulation of rapidly to baseline levels (Bull et al. (Williamson et al. 1994). This stimulus mechanoreceptors is also likely to be 1989). (Fig. 1). is likely to stimulate both type III and vagally-mediated, judged by the IV afferents or polymodal afferents. rapidity of the change and a decrease in Two types of slow conducting muscle heart rate variability, which is an index afferent fibres (type III and IV) have We considered that a ’purer‘ method of of vagal activity. Further, as animal been shown to contribute to the muscle mechanoreceptor stimulation experiments have shown that the cardiovascular changes via feedback would be to use sustained passive baseline level of vagal activity is mechanisms; type IV have been shown in humans and animals to respond to accumulation of metabolites, whereas type III respond to mechanical stimuli. It is likely that there is some overlap between these receptors with some responding to both types of stimuli. As heart rate increases rapidly at the initiation of contraction and rapidly falls to baseline at the end of contraction, particularly if metaboreceptors continue to be stimulated at the end of the contraction (by occlusion of the blood supply and thus trapping metabolites), it is unlikely that the metaboreceptors are the major contributing factor to the changes in heart rate. It is more probable that mechanoreceptor stimulation is Figure 1. Schematic drawing showing heart rate changes (dashed line) and blood pressure changes (solid line) responsible for the rapid rise at the during contraction period and occlusion of the blood supply following isometric muscle contraction.

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The mechanoreceptors that are probably responsible for this immediate reduction in vagal activity are likely to be those Group III afferent fibres that respond to stretch. We suggest that these could be called ’tentonoreceptors‘ (from the Greek ’tentono‘ meaning stretch) to distinguish them from other types of mechanoreceptors found elsewhere. The stimulation of these tentonoreceptors is likely to be important to ensure close matching of cardiac output and oxygen delivery to the exercising muscle in the early stages of exercise, prior to the re­ distribution of blood flow.

Valerie Gladwell Figure 2. Factors controlling heart rate and blood pressure during exercise. It illustrates the mechanoreceptors (III, IV and Polymodal), baroreceptor and central command inputs and possible sites of interaction where arrows Department of Biological Sciences, University of converge NTS= nucleus tractus solitarus; RVLM= rostroventrolateral medulla; NA =nucleus ambiguous. Essex, Colchester, UK important in the heart rate response to activity brought about by the neck References Bull RK, Davies CT, Lind AR & White MJ (1989). The human pressor contraction, we performed additional suction is not overcome by the response during and following voluntary and evoked isometric experiments which altered the level of stimulation of the mechanoreceptors. It contraction with occluded local blood supply. J Physiol 411, 63-70. vagal activity just prior to the stretching is likely that this indicates that the Coote JH, Hilton SM & Perez-Gonzalez JF (1971). The reflex nature period. Drug induced vagal blockade stimulation of the mechanoreceptors is of the pressor response to muscular exercise. J Physiol 215, 789­ and rhythmic hand-grip, both of which not great enough to overcome the 804. reduce vagal activity, significantly increase in cardiac vagal activity by the Fisher JP, Bell M, White MJ et al. (2005). Cardiovascular responses decreased the response to passive baroreceptor afferents. Neck pressure, to human calf muscle stretch during varying levels of muscle stretch (Gladwell et al. 2005). on the other hand, resulted in a slight metaboreflex activation. Exp Physiol 90, 773-781. augmentation of the response to stretch. Gladwell VF & Coote JH (2002). Heart rate at the onset of muscle An additional way of altering vagal The results of both neck pressure and contraction and during passive stretch in humans: a role for mechanoreceptors? J. Physiol 540, 1095-1102. activity is to alter the input from the neck suction may provide additional baroreceptors using brief pressure or evidence to support an argument that Gladwell VF, Fletcher J, Patel N, Elvidge L, Lloyd D, Chowdhary S & Coote JH (2005). The influence of small fibre muscle suction over the baroreceptors which the two opposing inputs mechanoreceptors on cardiac vagus in humans. J Physiol 567, 713­ are located in the carotid sinus in the (mechanoreceptor and baroreceptor 721. neck. An increase in pressure mimics a afferents) interact at a common Murata J & Matsukawa K (2001). Cardiac vagal and sympathetic decrease in blood pressure, leading to a neuronal pool. efferent discharges are differentially modified by stretch of skeletal decrease in vagal activity, whereas muscle. Am J Physiol 280, H237–245. suction mimics an increase in blood Studies to date have shown that the Secher NH (1999). Cardiovascular function and oxygen delivery pressure causing an increase in vagal stimulation of muscle afferents has a during exercise. In Physiological determinants of exercise tolerance in humans. Eds Whipp B J & Sargeant AJ, pp 93-114. Portland activity. Interestingly, neck suction specific functional role in exercise, with Press. London. which results in a decrease in heart rate mechanoreceptors (alongside central significantly reduced the increase in command) inducing the rapid increase Williamson JW, Mitchell JH, Olesen HL, Raven PB & Secher NH (1994). Reflex increase in blood pressure induced by leg heart rate caused by passive stretching. in heart rate at the onset of exercise by compression in man . J Physiol 475, 351-357 and erratum J Physiol This suggests that the increase in vagal a reduction in vagal activity (Fig. 2). 476, 554-555.

The 8th Meeting of the European • Autoimmune diseases Federation of Autonomic Societies • Quantitative physiology (EFAS), Physiology and • Diabetes physiopathology of the autonomic • Sleep and disautonomy nervous system, will take place at the • Hypertension Lisbon Faculty of Medicine, Lisbon, • Deposit diseases Portugal from 24-27 May 2006. • Neuro-ophthalmology • Disorders and physiology of the The main topics to be covered include: autonomic nervous system • Parkinsonism European Federation of • Obesity Full details available at Autonomic Societies • Receptor dysfunction http://www.efas2006.fm.ul.pt/

Physiology News | No. 62 | Spring 2006 | www.physoc.org FEATURES PN 37

Light up the signal fires – imaging calcium’s protein partners

In Victorian times, almost all calcium signal that is largest at the cell microscopes sold came with an periphery (B). In contrast, stimulation attachment to facilitate the observation of mast cells releases calcium from of blood flow in the tail of a tadpole. intracellular stores causing a relatively Using this, the paterfamilias could uniform calcium increase (E), but demonstrate to his family the opaque calmodulin is concentrated at the red blood corpuscles coursing through periphery (D). Stimulation of both otherwise invisible vessels that types of cell generates a high branched and anastomized. More concentration of active calmodulin at advanced microscopists killed, fixed Stephen Bolsover the periphery, as revealed by imaging and stained the tadpole to reveal the of a reporter calmodulin (C). various tissues in more or less detail. imaging technologies has changed this situation dramatically. We can now see Because the calcium transient and the Ten years ago our study of calcium where particular proteins or organelles spatial distribution of the target protein signalling in cells was at a similar are in living cells, and watch how this have to overlap for a response to be stage. Thanks to the indicator dyes pattern overlaps with, or changes in elicited, the system constitutes an ‘and’ created by Roger Tsien and others we response to, calcium signals. The most gate. For example, the neurotransmitter could see where calcium ions advanced protein constructs go further glutamate will cause the calcium accumulated, and the paths through and report not only their location but concentration to increase in the nuclei which they moved through the also their conformation. of hippocampal neurones, but this cytoplasm. By killing and fixing the calcium increase can only activate the cell we could see its organelles and The immediate targets of calcium are nuclear transcription factor CREB if even the location of individual proteins the calcium binding proteins, among calmodulin has previously been caused – at the time of fixation – in exquisite which calmodulin dominates. Figure 1 to move to the nucleus by electrical detail. However, we could not watch shows two ways in which calcium and activity (Mermelstein et al. 2001). the interaction between calcium and calmodulin can interact spatially. In other components in a living cell. The nerve cell bodies calmodulin is The movement of calmodulin to the development of green fluorescent distributed relatively uniformly (panel nucleus of electrically active neurons is protein and other novel live cell A) while electrical activity evokes a one example of calcium-evoked translocation. The mechanisms that cause proteins to move in response to a calcium signal are many, and vary in complexity. Some proteins use calcium ions as part of the coupling that attaches them to a cellular location. A rise of calcium concentration in that cell region will therefore recruit the protein. Examples are protein kinase C (Fig. 2A, B) (Bolsover et al. 2003) and annexin. Other proteins are post­ translationally modified in response to a calcium signal. Their subsequent movement need not, therefore, be dependent on where the calcium signal occurred. The transcription factor NFAT behaves in this way (Fig. 2C, D). It bears a nuclear localization signal that is only active when the protein is dephosphorylated by the calmodulin dependent phosphatase calcineurin (PP2B). Thus NFAT can be dephosphorylated at the location where calcium increases (assuming that Figure 1. Two strategies to one end. A-C: rat sensory neurones showing respectively endogenous calmodulin (by calcineurin is present); its subsequent immunofluorescence) then calcium and Ca:calmodulin concentrations after 200msec of voltage clamp depolarization. From (Milikan & Bolsover, 2000; Milikan et al. 2002). D, E: RBL cells showing respectively a movement to the nucleus will be calmodulin-GFP chimaera, and calcium after 30 seconds of stimulation. calcium-independent. Since the time

Physiology News | No. 62 | Spring 2006 | www.physoc.org 38 PN FEATURES/OBITUARY

A Murray Harper 1933-2005

For 25 years from the mid 1960s, the elucidation of the physiology of cerebral blood flow owed more to Murray Harper than to any other investigator in Britain or, indeed, internationally. As a medical graduate in Glasgow, he developed a particular interest in brain blood flow in the context of cardio-pulmonary bypass, Figure 2. In RBL cells one calcium signal sends proteins to two distinct targets. A, B: the same cell expressing a and he was to become leader of a PKCα-GFP chimaera before and after stimulation. C, D: populations of cells expressing a GFP-NFAT chimaera at rest and after stimulation respectively. Red in D indicates the otherwise invisible cell margins. From (Bolsover et research team in laboratories established al. 2003; Pandey et al. 2004). for the purpose at the Wellcome Surgical Institute, University of Glasgow where constant of NFAT rephosphorylation is domain in the translocation of protein kinase Calpha to the plasma Murray was ultimately Professor of membrane. J Biol Chem 278, 10282 - 10290. of the order of 7 minutes (Tomida et al. Surgical Physiology. He pioneered 2003), even low frequency calcium Mermelstein PG, Deisseroth K, Dasgupta N, Isaksen AL & Tsien RW radioactive inert gas methods for brain transients can cause a maintained NFAT (2001). Calmodulin priming: nuclear translocation of a calmodulin complex and the memory of prior neuronal activity. Proc Natl Acad blood flow measurement and, from his translocation (Pandey et al. 2004). Sci USA 98, 15342-15347. MD thesis in the 1960s onwards, his publications developed the concept of the Milikan JM & Bolsover SR (2000). Use of fluorescently labelled With the help of GFP and other calmodulins as tools to measure subcellular calmodulin activation in local regulation of the smaller brain blood fluorescent labels, achieving our goal of living dorsal root ganglion cells. Pflügers Archiv 439, 394-400. vessels by metabolic and chemical rather mapping the interactions of calcium Milikan JM, Carter TD, Horne JH, Tzortzopoulos A, Török K & than neural control. His definition of the and its downstream targets in living Bolsover SR (2002). Integration of calcium signals by calmodulin in influence of sympathetic nerves on brain cells is literally in sight. rat sensory neurones. Eur J Neurosci 15, 661-670. blood flow and the interplay between blood pressure and carbon dioxide Stephen Bolsover Pandey V, Mihara S, Fensome-Green A, Bolsover SR & Cockcroft S (2004). Monomeric IgE stimulates NFAT translocation into the tension are seminal contributions. Murray nucleus, a rise in cytosol Ca2+, degranulation and membrane ruffling Department of Physiology, University College London, championed multidisciplinary research UK in the cultured rat basophilic leukemia-2H3 mast cell-line. J Immunol 172, 4048-4058. and, although he focused on basic References Tomida T, Hirose, K, Takizawa A, Shibasaki F & Iino M (2003). NFAT research, he was also actively involved in Bolsover SR, Gomez-Fernandez JC & Corbalan-Garcia S (2003). functions as a working memory of Ca2+ signals in decoding Ca2+ human studies along with neurosurgeons, Role of the Ca2+/phosphatidylserine-binding region of the C2 oscillation. EMBO J 22, 3825-3832. anaesthetists and clinical physicists. He was one of the founders of the 2006 Prize Lectures International Society of Cerebral Blood The Physiological Society has awarded the following Prize Lectures: Flow and Metabolism and was the first editor of its journal. In 1987 we were Mark Fishman (Annual Review Prize Lecture) privileged to arrange with him a Mark J Dunne (Australian/UK Visiting Lectureship Scheme) Rod Flower (Bayliss-Starling Prize Lecture) symposium on this topic at a Matthew Bailey (Biller Prize Lecture) Physiological Society Meeting in C A Richard Boyd (G L Brown Prize Lectures*) Glasgow, with later publication of the Thomas Jentsch (Hodgkin-Huxley-Katz Prize Lecture) proceedings as a Study Guide. He was Susan Wray (Joan Mott Prize Lecture) indeed a physiologist of major Neville McClenghan (Sharpey-Schafer Lecture and Prize) international and historical significance. Helen Kennedy (Wellcome Prize Lecture) Sheila Jennett * See G L Brown – a memorable Member (p. 34) James McCulloch

Physiology News | No. 62 | Spring 2006 | www.physoc.org LETTERS TO THE EDITOR PN 39

The Dolmetsch business founded in 1883 continues to flourish in Nobel Prize 2005 Haslemere, Surrey and Members interested in our history are invited to Rather than look to a basic research discovery, the 2005 Nobel Prize Committee visit our web site www.dolmetsch.com for Physiology or Medicine honoured what Brian Blood the British Medical Journal described as Dolmetsch Music Instruments, Haslemere, Surrey, UK ‘old-fashioned medical detective work’ by awarding the Nobel to two Australians, The Society’s ‘mascot’ Editorial note: Our sincere apologies pathologist Robin Warren and Through the magic of the World Wide to Brian Blood for misrepresenting the gastroenterologist Barry Marshall, of the Web I have been reading with great work of Dolmetsch Musical University of Western Australia in Perth. interest the article in Physiology News Instruments Their achievement was to discover (or (60, 37)) about the loss and recasting of rediscover) the stomach-dwelling bacterium The Society's ‘mascot’ – the little dog. Stem cell rush Helicobacter Pylori and to recognise the Congratulations to J Prakasa Rao link between infections with H Pylori and I am the Brian Blood (bass recorder (Physiology News 61, 42) for having inflammation of the stomach lining player rather than tenor) who was a the guts to point out the folly of the (gastritis) leading to ulcers (Marshall & research student with Denis Noble and lemming-like rush to stem cell Warren, 1984). This insight has led directly who arranged, through the good offices technology! The UK Stem Cell to the successful medical treatment of of my wife (Marguerite Dolmetsch) and Initiative has been lobbying very ulcers with antibiotic regimes. Previously, the Dolmetsch family musical effectively for this bandwagon. the many patients with troublesome ulcers instrument making company, the Between £650m and £820m will be had little option for a ‘cure’ other than turning of the circular plinth to which invested over the next 10 years, and surgical vagotomy or even gastrectomy, the dog was to be attached. total public sector funding for stem cell drastic solutions which were nonetheless research over the 2 year period 2006 to widely practised well into the late 1980s. If my memory serves me right, the 2008 is now up to £100m. circular stand was made in 1976 the Many of the reports on Marshall and year of the centenary celebrations of Part of the excitement is because Warren’s Prize have rightly emphasised the The Society which culminated in a restrictions on the use of stem cells in struggle they had to get their observation of dinner in Trinity College, Cambridge. the US make this one of the few fields bacteria in the gastric mucosa accepted in which the UK can compete – if we through the 1980s. As Warren notes in his We were asked to make this new plinth don't get overtaken by Korea, Spain, Nobel lecture (Warren, 2005), the because the dog tended to fall off the Israel, etc. observation of such bacteria in stomach Victorian stand on which it only rested. sections was at least a hundred years old It would be funny if it were not for the when they started their work, and had been Your photographs are therefore fact that research funds from all sources ‘re-discovered’ periodically (see Marshall, confusing. We did not make the are being diverted into this area at the 2002). However, the dominant consensus Victorian stand which is shown at the expense of worthwhile science that has in the early 1980s was that the stomach top of column two on page 37 but we more immediate prospects of conferring lumen was sterile, due to its acidity, and did make the base that is just visible in therapeutic benefit. that no bacteria could grow there. the picture (above) taken from R Chapman's article in the 1994 Stanley Salmons The difficulty the two had getting their ideas Physiological Society Magazine. Department of Human Anatomy & Cell Biology, accepted ultimately led Marshall to University of Liverpool , UK undertake a celebrated self-experiment where he drank an H Pylori culture to give The Xth Oxford Conference himself acute gastritis, which was subsequently cured with antibiotic therapy. Modeling and control of breathing - integration in Another widely-reported facet of the story respiratory control: from genes to systems was the serendipitous way in which the culture conditions for successfully growing Lake Louise, Alberta, Canada H Pylori were arrived at. They had been culturing gastric biopsy specimens for the 19-24 September standard 48 h, but the 1982 Easter weekend, and/or an epidemic of MRSA at the Royal Perth Hospital which backed up Further information is available at the pathology labs, meant that one sample http://www.ucalgary.ca/~oxford06 was left for over 5 days before being or email [email protected] examined. Unlike the samples examined and thrown out after 48 h, when bacterial

Physiology News | No. 62 | Spring 2006 | www.physoc.org 40 PN UNBELIEVABLE! growth was scarce to invisible, the ‘old’ specimen showed an abundant growth of I’m a leading scientist – get the (slow-growing) H Pylori. In fact, up to me out of here 50% of humans are colonized with H Pylori, typically being infected in early childhood, Science is often accused of being although most people have no symptoms of inaccessible to the general public. Scientists the bacterium’s presence. H Pylori is able counter that this is because scientists don’t to induce multiples changes, including get enough media exposure. This includes proliferation, in gastric epithelium, and is a both real scientists, and people playing key factor in the development of many scientists in TV dramas. We can all agree gastric cancers. Much research now that there are less TV shows with scientists focuses on why only some people who are in them than shows about policemen, or places [May be difficult to fill this role with infected develop the severe changes in doctors. scientists, but you never know] mucosal (patho) physiology that lead to But I think I have come up with a solution. • one monosyllabic youth person given to cancer and ulcers. Since the public’s appetite for reality TV mumbling ‘Yeh, wicked’ at random intervals seems to be insatiable, let’s give them what [male PhD students are the obvious So what lessons are there for physiologists they want AND get ourselves some much­ candidates here] in the story? Perhaps the main one is that needed exposure. • one or more people who are pathologically the normal, as well as abnormal, argumentative physiology of an epithelium may actually I give you: Celebrity Scientist Big Brother involve co-resident microorganisms. This • one person teetering on the edge of a The beauty of this is that this idea can be public mini-nervous breakdown [Given the emphasises the topicality of symposia like franchised; you could have different proximity of RAE2008 any Head of that on Epithelia-Microbe Interactions held versions for different scientific disciplines, or Department or RAE2008 Submission Task­ a couple of years ago in Newcastle. one for just your own Department, or a force Leader should be a good bet] national all-star version, or an international • at least one person who even the other Another lesson is the timeless one of not one. The possibilities are endless. letting one’s scientific curiosity be blinded contestants find weird and unsettling by an apparent consensus. Barry There are, however, some easy rules to • one person who you thought would never Marshall’s Nobel lecture (Marshall, 2005) enable you to select the contestants for be seen dead on a show like this. This quotes the historian David Boorstein: ‘The maximum viewing figures. The people person should subsequently storm out in a greatest obstacle to knowledge is not inhabiting the house/jungle/island should cloud of invective and denunciations (think ignorance – it is the illusion of knowledge’. include: Germaine Greer or Johnny Rotten) • at least one person recently dramatically • several people who used to be vaguely Austin Elliott publicly disgraced and in search of well-known, typically for having once rehabilitation appeared on television, but have now References largely faded from view. Marshall BJ (2002). Helicobacter pioneers: firsthand accounts from • a person who has undergone extensive the scientists who discovered helicobacters, 1892-1982. Blackwell, cosmetic surgery or dental work This mix should ensure plenty of good Victoria, Australia. • a minor member of the aristocracy, or a reality TV, including shouting, swearing Marshall BJ & Warren JR (1984). Lancet 8390, 1311-1315. Lord, Sir or Right Hon arguments, tears and perhaps even a fight Marshall BJ. http://nobelprize.org/medicine/laureates/2005/marshall­ • one person who is faking the whole thing or two. lecture.html. • one or more relentless self-publicists Of course, some contestants may fulfil Warren JR. http://nobelprize.org/medicine/laureates/2005/warren­ • one or more people who are extensively several of the above criteria at the same lecture.html tattoo-ed, and/or pierced in improbable time. If so, so much the better. Finally, all the participants need to share MICROELECTRODE TECHNIQUES FOR CELL PHYSIOLOGY some basic personality traits. They should 23rd Plymouth Workshop, 6-20 September 2006 be able to talk tirelessly about themselves The Marine Biological Association of the UK and their work until the small hours, and Citadel Hill, Plymouth, PL1 2PB should believe unquestioningly that their merest utterance is deeply fascinating and Microelectrode recording and injection, voltage clamp, patch clamp, slice recording, ion demands the rapt attention of all those selective electrodes, fluorescent indicators, capacitance, amperometry, electronics listening. Application details and poster at www.mba.ac.uk/courses ‘They’ll all be professors, then’ commented email [email protected] a friend on hearing this.

Fee £1,200 including accommodation. Bursaries available. Hmmm. You might think that. I couldn’t possibly comment. Deadline for applications 30 April 2006 Mark Cain

Physiology News | No. 62 | Spring 2006 | www.physoc.org THE SOCIETY’S JOURNALS PN 41

when there is no free access to the final paper at The Journal’s own web site. Special Issues

The cost to authors of colour figures in A number of Special Issues of The New for 2006 research papers is now lower – £200 Journal are planned for 2006. These Nine new sections now appear on the for the first figure and £60 for each include: back cover and contents page of The subsequent figure. As previously, • AMP kinase: metabolic sensing in Journal of Physiology in place of the online-only colour figures and colour health and disease previous four: figures in Topical Reviews and • The mammalian transcriptome and the • Molecular and genomic Symposium Reports are free. cellular complexity of the brain • Cellular • The cochlea • Neuroscience In the news There will be a call for related papers • Cardiovascular A paper published in volume 569.2 of ahead of each Special Issue. • Alimentary The Journal of Physiology by Combaret • Renal and endocrine et al. (2005), together with a Wellcome Trust funded • Respiratory Perspective by Michael Rennie, • Skeletal muscle and exercise received wide media coverage research • Integrative following a pilot project by The Wellcome Trust funded researchers are Journal’s Executive Committee to Pdf files of published papers and pre­ reminded that they can publish in The promote suitable papers in this way. publication manuscripts from the web Journal of Physiology and Among the coverage received, the BBC site now include a front and back cover Experimental Physiology. produced a well-informed report of the with branding. research and its relevance to the general The Wellcome Trust requires electronic public, namely that older people should The copyright line at the bottom of the copies of any research papers that have keep eating protein in order to maintain page now acknowledges the authors been accepted for publication in a peer­ their muscle mass. Promotion in the rather than The Society as holding the reviewed journal, and are supported in press of papers that have clear copyright. The Journal’s Exclusive whole or in part by Wellcome Trust relevance to human health not only 1 funding, to be deposited at PubMed Licence Form should be consulted raises the profile of The Society’s for full details, but rights to publication Central (or UK PubMed Central once journals, but also helps to fulfil the established). of reviewed and copy-edited articles are mission of The Society to ‘contribute to assigned to Blackwell Publishing, the progress and understanding of acting on behalf of The Society. The This requirement will apply to all biomedical and related sciences and the grants awarded after 1 October 2005 final Journal of Physiology pdf cannot detection, prevention and treatment of be posted online by the authors at any and, from 1 October 2006, to all grants disease, disability and malfunction of regardless of award date. The Trust time. Authors may only make their physical processes in all forms of life’. own manuscript available online for the will provide grant holders with period before acceptance and from one Combaret L, Dardevet D, Rieu I, Pouch M-N, Bechet D, Taillandier additional funding to cover the costs of year after final print publication: it D, Grizard J & Attaix D (2005). A leucine-supplemented diet restores open access publishing so that they can the defective postprandial inhibition of proteasome-dependent post their articles on PubMed Central cannot be made available by the proteolysis in aged rat skeletal muscle. J Physiol 569, 489-499. authors during the one year period immediately on publication. This funding will be provided for articles Archives reporting research that was part-funded The Journal of Physiology symposia The NLM/Wellcome Trust archiving by the Wellcome Trust. project is on track and it is hoped that Involvement of interstitial cells of all articles published in The Journal Both journals offer authors an open Cajal in the control of smooth from 1878 will be available online at access publishing option through PubMed by May. Blackwell Publishing’s Online Open muscle excitability service.2 Saturday, 22 July 2006 Letters To apply for funding to make your at the Japanese Society for Smooth In addition to Perspectives and paper in The Society’s journals open Muscle Research, Okayama, Japan Classical Perspectives, Letters to the access through Online Open, please Editor and the focus articles of contact your institution’s Research For further information go to Perspectives will be made freely Office or The Physiological Society http://jp.physoc.org available online and identified using Publications Office for advice. ‘free article’ icons. ([email protected]).

1http://www.blackwellpublishing.com/pdf/tjp_caf.pdf Carol Huxley 2http://www.blackwellpublishing.com/static/onlineopen.asp Managing Editor

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on the use of viral vectors in (Chair of the Editorial Board from neuroscience. Translational and July), Andrew McCulloch and Peter integrative physiology has also been Hunter. Contributing authors include highlighted in three symposia with Chris Bradley, Martin Buist, Kelly The rise of Experimental published articles covering Heart­ Burrowes, Neil Cherniack, Richard kidney interaction, Structure of blood Clayton, Justin Fernandez, Martin Physiology vessels and a third on Obesity-related Hayward, Eric Hoffman, Darren Hooks, The journal started by Sharpey Schafer hypertension. This focus was Panny Kallis, Peter Kohl, Ian LeGrice, in 1908 continues to play an important continued in the 67 original research Guy Longobardo, Martyn Nash, Peter role in communicating scientific papers also published in the six issues Taggart, Natalia Trayanova, Marcus discoveries to a world-wide audience. of 2005. This year there will be Pandy, Andrew Pullan, Bruce Smaill, In 2005 its recent upward progress has Themed Issues on Cardiovascular Peter Sutton, Merryn Tawhai and Mark been maintained with a further rise in aspects of exercise and Computational Trew. impact factor to 1.88, and this when modelling in physiology. In July 2006 I most other physiological-type journals step down as Chair of the Editorial Nearly all of the papers in the Themed declined. An increasing world-wide Board. David Paterson has been Issue describe mathematical models of readership can be attributed to its elected to replace me, whilst Julian organs or organ systems based on mixture of popular content, including: Paton becomes Deputy Chair. These biophysical equations solved on three­ two, together with Nadurai Prabhakar, dimensional (3D) finite element • Hot Topic reviews our USA Deputy Chair, represent a representations of the organ anatomy. featuring articles pertinent to the heart, the formidable team which will ensure the The finite element method is a circulation and the brain continued progress of the journal computational technique that is widely • Prize Lectures through its centenary year in 2008. I applied in the analysis of complex covering respiratory control, exercise and wish them well and hope that Members engineering structures but is equally metabolism, and tissue engineering of The Society will maintain their applicable to modelling the complex • Review articles whole-hearted support for the journal. anatomy of organ systems and the on the latest developments in non-invasive anisotropic, inhomogeneous and highly measurement of blood pressure and stroke John H Coote nonlinear properties of biological volume tissues. The organ systems considered • Exchange of Views articles in this Themed Issue are the heart, the which, in the latest issue, feature differing Themed Issue – Modelling lungs, the digestive system and the views on central chemoreceptors. of biological systems musculo-skeletal system. Part of our mission to publish papers The March issue of Experimental Many of the papers have a clinical ascribing physiological function to Physiology (Vol 91. 2) develops the focus. Fernandez and Pandy, for genes and proteins in the context of translation and integration theme of the example, propose a framework for integrative systems has been met by journal by presenting a Themed Issue incorporating lower limb gait analysis themed sections, one on aspects of on Modelling of biological systems. data, ground reaction force data and cardiovascular genomics and another The issue is edited by David Paterson EMG data into subject specific models of walking based on solving the Experimental euthanasia of rodents. We also disseminate equations of continuum mechanics on Physiology is delighted our research results by developing training models that incorporate the 3D to announce the materials for research workers anatomy of the major muscle groups of appointment of Paul (http://www.digires.co.uk and the leg. The paper by Buist et al. links Flecknell as an adviser http:www.ahwla.org.uk). gastric slow wave activity on to the Editorial Board.. anatomically-based models of the I graduated from Cambridge in 1976, and Paul (pictured right) stomach to clinical measurements of started my career as a clinical veterinarian at writes: the electromagnetic fields produced by the University of Bristol. I became involved in these waves under conditions of ‘My research interests are the welfare of medical research at the MRC Clinical Research cellular uncoupling induced by animals used in biomedical research and, in Centre in London, while acting as their ischaemia. particular, issues associated with pain and laboratory animal veterinarian. After distress. I am also interested in comparative completing a PhD in physiology, I moved to Tawhai et al. consider structure­ aspects of pain assessment and allevation, Newcastle where I was able to develop my function relations in the pulmonary animal anaesthesia and the neurophysiological major interests in the science underpinning circulation within the context of a 3D effects of anaesthetics. Current research animal welfare. I am responsible for the overall projects aim to develop methods of pain management of the university research animal anatomical model of the lungs that was assessment and alleviation for use in animals facilities and I am also the University’s ‘Named illustrated on the cover of the inaugural and in human neonates. My group is also Veterinary Surgeon’. I head a research group issue of the new Experimental investigating neurophysiological effects of whose main objectives are strongly linked to Physiology launched in January 2004 anaesthesia, and assessing methods of improving the welfare of laboratory animals.’ (Crampin et al. 2004). The model

Physiology News | No. 62 | Spring 2006 | www.physoc.org THE SOCIETY’S JOURNALS PN 43 predicts the patterns of perfusion in models that represent molecular events wave propagation). The approach to response to different lung orientiations within the context of solving modelling heart physiology with cell under gravity loading for both normal biophysical equations at the tissue level processes incorporated into the and diseased conditions. A different level. Four examples of this in the physical equations governing function approach to modelling the lung is taken March Themed issue are the at the tissue and whole organ level by Cherniack and Longobardo, who use incorporation of models of ion channel owes much to the pioneering cardiac a control theory model to examine the electrophysiology in cardiac tissue ion channel modelling work by Denis role of periodic breathing in simulations by Kohl et al. (the role of Noble in the UK (Noble, 2002). understanding cardiovascular and mechanically sensitive ion channels), This Themed issue can be seen as respiratory disorders. Trayanova (mechanisms of representative of a major new direction defibrillation), Nash et al. (action in physiology that holds considerable Another important theme of potential restitution properties of promise for integrating experimental Experimental Physiology is integration cardiac tissue) and Trew et al. (the role data at the protein, cell and tissue levels via multi-scale models – these are of cardiac tissue structure in electrical into whole organ function. Changes to The Physiological Society and publication of The Proceedings Peter Hunter Bioengineering Institute, University of Auckland, New Informal discussion with Members of The Society suggests that many are not fully aware of the Zealand changes that have happened to The Society over the last few years. These include the governance changes and, with regard to our Scientific Meetings, the move to an Annual Main References Meeting plus Focused Meetings. Information on pages 47-48 aims to address some of these Crampin, EJ, Halstead M, Hunter P, Nielsen P, Noble D, Smith N & uncertainties. The page is designed to be removed and posted somewhere convenient. Tawhai M (2004). Computational physiology and the physiome project, Experimental Physiology 89, 1-26, Members should also be aware of changes to the publication of the Proceedings of our Scientific Meetings. Meetings abstracts are no longer published as part of The Journal of Physiology but will Noble D (2002). Modeling the heart: from genes to cells to the whole organ. Science 295, 1678-1682. form a separate online-only publication entitled Proceedings of The Physiological Society. Volume 1 will comprise the abstracts from the Focused Meeting held in December 2005 at University College Free EP archive 1908-2004 London. Citations will be in the following format: Back copies of Experimental Physiology from 1908 to 2004 Smith A & Jones B (2006). Proc Physiol Soc 1, C53. are now freely accessible at http://ep.physoc.org/contents-by-date.0.shtml In practice, the change will make very little difference. The Proceedings will continue to be hosted The archive contains searchable pdf files of all manuscripts on The Society’s web site, and there will still be a link from The Journal home page; they remain and material published in The Quarterly Journal of accessible via search engines. As meetings abstracts, The Proceedings will not be listed in ISI Experimental Physiology 1908-1989 and Experimental (they have not been since 2003 when they went online only). Physiology from 1990.

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Where are all the women going? New Affiliate representative Patricia de Winter ponders the increasing popularity of scientific writing as a career choice

I was rather surprised to be asked to that he was not about to rock the boat replace Laura Blackburn as the Affiliate by legally forcing his employer to take representative on the Physiology News him on permanently. So, although this in Nature noted that both men and group, as I currently serve on The law is supposed to assist contract women rated women’s research ability Society’s Council and thought that workers, it is unenforceable, as no one as inferior to that of similarly qualified there might be some conflict. wishes to start their career with a men, when the gender is known However, when I was reassured that reputation as a troublemaker. (Nature 438, 1 Dec 2005). there was none, I realised that this Furthermore, female post-docs had to would be an excellent opportunity to Whilst browsing through the Higher perform twice as well as males to communicate with Affiliates, having Education Statistics Agency (HESA) achieve an equivalent peer-review score previously begged for them to contact web site, I picked out a couple of (Nature 387, 22 May 1997). me to no avail. statistics that supported my perception of there being proportionally fewer In the next issue, one of my colleagues, There are two things that I would like women as one progresses up through Dola Akanmu, mother-of-two and to concentrate on in the Affiliate section levels of seniority. In the academic currently PhD student-awaiting-viva of the next few issues as I feel that they year 2003-2004 69% of anatomy, examines if babies and benchwork are are of utmost importance to young physiology and pathology students compatible. If you wish to contribute physiologists: retention of PhD­ were female. At the undergraduate your views (you don’t have to write a educated scientists and women in level 56% of students obtaining a first full article) email me at science. Has anyone else noticed the degree were female, but at the doctorate [email protected] increasing popularity of level this fell to 43% – unfortunately, medical/scientific writing as a career the completion figures for science Patricia de Winter choice? In our department three PhD subjects alone are not available so these King’s College London graduates/post-docs have left research percentages are for all subjects. By the for writing jobs over the past 3 months, time we get to women academics, only and one is currently looking for such a 35% of full-time staff are female Young Physiologists’ post. Coincidentally, all are female. I although, again, I have data only for all Symposium asked them all why they no longer subjects. I am pretty sure that the wished to work at the bench and the proportions are even lower in science. The first Young Physiologists’ unanimous answer was that medical Let’s take our Society as an example: Symposium to incorporate a European writing offered a permanent position five of the 28 Council Members are Society for Free Radical Research and career opportunities that are hard to female (18%). I don’t think that this (SFRR) ‘Free Radical School’ was held come by in academia or industry. The necessarily reflects inherent sexism at Aston University and The Belfry on perception is that in industry, job within The Physiological Society, but Friday, 8 July 2005 security is non-existent, and in rather that Council membership simply academia permanent positions are mirrors the fact that there are far fewer Young scientists from across the globe scarce. One academic said medical women at the senior level from which were given the opportunity to present writers would probably spend an to select. Is female gender a barrier to their work and 18 oral and eight poster average of only 2 years in their job, a career in science or do the stats communications were presented by making the length of the contract reflect a self-selecting academic participants from several European comparable to that of a post-doc population? A recent correspondence countries, the USA and Japan. anyway. Although this might be true, with a permanent contract the choice of whether to move on or not is the employee’s, hence he/she retains control of future employment. This same academic also pointed out that by law, if an institution employs someone Kelvin Davies for 5 years on short-term contracts, it is (University of subsequently obliged to offer them a Southern California, 3rd permanent contract. I passed this from right) with comment on to a post-doc who has YPS delegates been at King’s for 5 years on a contract following his talk that is nearing expiry. His reply was at Aston University.

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Considering that this YPS was held on the day after the tragic terrorist events in London, all participants should be congratulated on their perseverance in negotiating the ensuing transport chaos to arrive in good time!

As the meeting was held immediately before the 2005 annual SFRR meeting, the topics mainly covered physiological responses to oxidants and antioxidants, and ranged from the benefits of enriching human diets with vitamin C, soy or almonds to the modulation of gene expression, cell signalling and DNA damage. We were especially honoured that Kelvin Davies, Professor of Gerontology and Biological Sciences at the University of Southern California Above: Some of the YPS delegates at the evening and outgoing President of the SFRR barbeque reception held at The Belfry. Right: PhD students Amos Fatukun (University of International SFRR, delivered the Glasgow), left, and David Rowlands keynote lecture on oxidative stress­ (King’s College London) at the YPS poster session. related diseases and ageing to close the L McLellan (University of Dundee), YPS. All of the young physiologist’s (King’s College, University of London) M David-Dufilho (CNRS, France), presentations were of an extremely high who shared his views on cardiovascular F Etienne (University of Louvain, standard and it was only after much diseases. Despite the early start, these France) and A Banning (German deliberation that an overall winner for sessions were very well attended and Institute of Human Nutrition). the best YPS presentation could be spawned lively discussions between the finally selected. Milos Filipovic, young scientists and the mentors, but Finally, we would like to thank (University of Belgrade, Serbia and time was limited and the main meeting everyone who made the YPS such a Montenegro) won this award for his always came too quickly. great success – all the organisers and enthusiastic talk on nitric oxide and generous sponsors, but especially the manganese superoxide dismutase. All The Physiological Society also YPS delegates themselves for attending participants appreciated the opportunity sponsored a symposium at the SFRR and presenting their work. It only to share their research experiences meeting on Lipid peroxidation, remains for us to urge more societies to during the poster sessions held over oxidative stress and cardiovascular promote such dedicated symposia for lunch and coffee breaks. disease organised by Giovanni Mann young scientists alongside their main and Enrique Cadenas (University of meetings and to encourage international Following our successful symposium, Southern California). In addition to the networks of younger scientists. YPS delegates joined the main SFRR organisers, speakers in this well meeting for an evening barbeque, attended session included G Poli Melissa Grant reception and sessions over the (University of Torino, Italy), Aston University, Birmingham, UK weekend held at The Belfry near P Thornalley (University of Essex), Richard Siow Birmingham. Apart from the unique A Martinez-Ruiz (CINC, Spain), E King’s College London, UK opportunity to play golf at the home of Halligan (Leicester Royal Infirmary), Co-organisers the PGA and Ryder Cup, a novel aspect of this YPS was that it continued over the next 3 days as part of the Free National Science Week Radical School ‘breakfast club’, held every morning at 8 a.m. before the Science knees up! Medical engineering of the joints main sessions! These early morning Dr Martin Knight will host a hands-on lecture at Queen Mary, University of sessions allowed young scientists to London, Mile End Road on 13 March at 3 p.m. This stimulating lecture is th have informal discussions with experts targeted towards 6 form students, although anyone with an interest in medical in the field, and were led by Angelo engineering is welcome to attend. For further details please contact Irrum Magre Azzi (University of Bern, Switzerland) ([email protected]) or visit http://www.physoc.org/education/ who discussed his work on vitamin E, Jose Viña (University of Valencia, Related information Spain) who examined free radicals in Nobel Laureate to give keynote lecture at King’s College London in National Science Week (p.18) the ageing process and Giovanni Mann Science learning with a difference (p. 52)

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Medical education and the Celebrity diets, obesity and arts hormones: what does science have to say? There is increasing interest in the inclusion of the arts in the medical Donna Brown, The Society’s Education Officer, curriculum. It was recently reported and I ran a session at the British Association’s that almost half the medical schools in Festival of Science in Dublin on 8 September the United States involve the arts in 2005 aimed at young people. A lively learning activities (Strickland et al. discussion ensued with our speakers, after 2002). Use of the arts is said to serve a their presentations exploring various current number of functions such as myths about dieting, metabolism, exercise and improvement of clinical skills, managing weight control. The session was promotion of humanism and as a chaired by Stuart Warmington (Trinity College learning tool. Dublin), and the line up of speakers included Claire MacEvilly (Medical Research Council), Medical students are often gifted David Haslam (National Obesity Forum), Nicole Lowe (University of Central Lancashire) musicians or artists and arts and Karen Birch (University of Leeds). related-activities allow the students opportunities to express their creativity Thorny issues tackled included the dangers of in a way they can seldom do during the The Tales of Hoffman (Royal Opera House) from the various extreme, and often celebrity undergraduate medical course. Sarah Lenton’s talk promoted, diets including Atkins, nutritional (photo by Clive Barda) myths promoted in the media, the extent of the At the School of Medicine, King’s rising tide of obesity in the UK and the College London, I have developed two Music), Ian Noonan (Nursing and diseases such as diabetes and cancer that are special study modules focusing on the apparently linked to it, and the need to engage Midwifery at St Thomas' Hospital) who links between medicine and the arts. in physical activity to protect your health. The speaks on madness in music with a live The first, Bodyworks: Images of the latter had a particularly strong message for performance of some of the songs Body in Western Art, has at its women and girls – taking enough exercise is discussed, and Sarah Lenton foundations the basic science discipline vital for healthy weight control approaches, (broadcaster and writer) who anatomy, and is for second year however health and the female reproductive examines the representation of doctors medical students. The course explores hormones are all strongly connected. Women and disease in opera. One student was and girls who over-diet or over-exercise to the thematic imagery and concepts so inspired that, although she had never extent that their menstrual cycles shut down involved in the representation of the been to the opera, she chose can lose the protective effects of oestrogen and body in art and draws parallels with tuberculosis in music as the theme for progesterone, with consequent health aspects of medical practice. It includes her assessment, presenting the 'case implications for maintaining a healthy heart and lectures, seminars, tutorials and visits to notes' of Violetta (Verdi's La Traviata) bones, and the risk of bringing on health art galleries enabling students to and Mimi (Puccini's La Boheme). problems normally only seen in menopausal explore the themes in the context of Overall the students produce women. The attendant media lapped all this up visual art theory and practice and to and we had good coverage of the event in the imaginative high quality work with consider connections to the medical papers next day. topics ranging from ‘Sex, drugs and context. Dr Rosa Maria Letts, an art Schubert’ to ‘Musical Savants’. historian who lectures at the Victoria And what did a middle-aged lady like myself and Albert Museum, has given two learn from this? Moderation is the key, i.e. don’t A number of colleagues have expressed informal presentations, one on eat more than you can burn off, take more interest in putting on such a course, but Renaissance sculpture and one on the exercise, but don’t overdo it (not a big risk in are unable to find time to put the my case!) and eat a nutritionally balanced diet bodies at Pompeii. material together. I plan to make the to promote health without being obsessive courses available on CD/DVD and about weight control. Since this module proved to be very would be grateful if anyone who is popular with the students, a second interested or who has any ideas on the Donna and I love doing these sort of events on module was developed on music and project would contact me. behalf of The Society. Next year we are medicine, focusing on psychology. We planning to attend the BA Festival in Norwich in look at the origins of music, how music Mary L Forsling September with an event for young people on is perceived and processed by the brain Department of Medicine, St Thomas' Hospital, London, Regenerative Medicine. If you would like to and the physiological and psychological UK. contribute, you are very welcome to contact responses to music. This led on to Donna or myself at [email protected] or Reference [email protected]. consideration of psychotherapy and Strickland MA, Gambala CT, Rodenhauser P (2002). Medical music therapy. Speakers include Dr education and the arts: a survey of US medical schools. Teach Learn Aaron Williamon (Royal College of Med 14, 264-267. Liz Bell

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Administrator and two Publications Interaction, Non-Society Symposia, Vacation The Physiological Society Administrators (The Journal of Physiology), Studentships and International Centres of Executive Editor/Editorial Administrator Excellence and Junior Fellowships can be found Founded in 1876, The Physiological Society is (Physiology News/The Journal of Physiology) on The Society’s web site. Grants are also a learned society with approximately 2,500 and a Publications Executive (Experimental available to Members and Affiliates to attend Members (including 14 Nobel Laureates) and Physiology). scientific meetings and to collaborate with other Affiliates (younger scientists) drawn from over laboratories in the UK and abroad. 50 countries. The majority of Members are Activities of The Society http://www.physoc.org/grants engaged in research, in universities or Scientific Meetings and industry, into how the body works or in International activities How can I join? teaching of physiology. The Society's main Activity at scientific meetings is driven largely by Joining The Society is a straightforward and aims are to promote the advancement of the Special Interests Groups (SIGs)), each of transparent process with clear guidelines. For physiology and to facilitate communication, which is led by one or two SIG Convenors. The further information go to: Society supports an Annual Main Meeting in July both between scientists and with other http://www.physoc.org/join each year, four or five Focused Meetings, interested groups. To achieve these Special Symposia and Non-Society Symposia. How can I benefit? objectives, The Society supports 4-5 scientific Scientific meetings and symposia may be held meetings annually, organises International jointly with other societies, in the UK or As a Member you: Workshops, publishes two journals and internationally. As part of its international • are provided with information about The awards grants to allow Members to travel to activities The Society supports International Society’s activities via the web site, the scientific meetings and to carry out research Workshops that are aimed at physiologists at an Newsletter and Physiology News collaborations. Interaction with outside bodies early stage in their careers. The Society supports • can have online access to The Society’s is encouraged through representation on the scientific meetings of the Federation of journals various councils and committees, and active European Physiological Societies • can become a member of one or more of The membership of the Biosciences Federation (http://www.FEPS.org) and International Union of Society’s Special Interests Groups, which will and the Federation of European Physiological Physiological Sciences (http://www.IUPS.org). It enable you to participate more actively in the Societies. hosted the annual FEPS meeting in Bristol in scientific meetings of The Society http://www.physoc.org 2005 and will co-host it jointly with the Slovakian • can apply to the various grant schemes. Society in 2007 in Bratislava and will host the Structure of The Society scientific meeting of IUPS in 2013. How can I contribute? As detailed is its governance documents, the http://www.physoc.org/meetings As a Member activities of The Society are overseen by an http://www.physoc.org/international • organise Research Symposia at Main Meetings Executive Committee of seven members and a • organise Focused Meetings, Special Symposia, Council of 28 members Much of the Publications and Non-Society Symposia development and implementation of The The Society produces a monthly electronic • nominate Prize and Public lecturers Society’s activities is devolved to a number of Newsletter for Members and a quarterly • vote at AGMs and EGMs to help shape the committees, each of which focus on a particular magazine Physiology News, which keeps workings of The Society, develop its policies and area of interest. The Society is supported by an Members and others informed about interesting determine the membership of Council and Administrative Office in London and a science and Society news. The Society Executive Committee. publishes two journals, The Journal of Publications Office in Cambridge (with 10 As a SIG Convenor Physiology ( ) and employees in each office). http://jp.physoc.org • organise special interest sessions at Focused http://www.physoc.org/members/committees/ Experimental Physiology (http://ep.physoc.org), and Main Meetings http://www.physoc.org/contacts/ and a series of Monographs. The abstracts of • coordinate the process of scrutineering of work presented at scientific meetings are abstracts, in order to help maintain scientific Executive Committee published electronically as The Proceedings of The Executive Committee comprises a excellence and integrity within your subject area the Physiological Society. • meet annually with the Meetings Secretary and President, Chairman and Vice-Chairman, http://www.physoc.org/publications Treasurer, International Secretary, Meetings other members of the Meetings Committee to help formulate the strategic development of The Secretary and Editor-in-Chief of The Journal of Outreach activities Physiology (ex officio). Society’s scientific meetings The Society supports workshops for teachers of • liaise with members of your SIG to develop Administrative Office (London) physiology and participates in UCAS Education scientific initiatives within your subject area. The staff in the London Office comprise a Chief Conventions and BSF careers events. Executive Officer, Deputy Executive Publications of The Society include a number As a Committee Member Secretary/Head of External Affairs, Personnel that aim to enthuse undergraduates and • play an active role in implementing The Officer/Accounts Administrator, Committee schoolchildren about physiology as a subject and Society’s objectives within a given area of Secretary/Office Administrator, Accountant, to provide information about the use of animals activity Education Officer, Membership & Grants Officer, in biomedical research. The Society also lobbies • play an active part in developing strategy and Meetings Administrator, Events & Membership Government and other organisations on issues shaping the budget within a given area of Assistant and International Programme relevant to its Members and promotes activity. awareness of physiology in the media. Administrator. As a Council Member/Trustee http://www.physoc.org/education Publications Office (Cambridge) • play an active part in the strategic development The staff in the Cambridge Office comprise a of The Society’s activities Managing Editor, IT Manager (The Journal and Funding opportunities • ensure good governance of The Society The Society), three Production and Copy Editors Information about grants available, including the • play a role in the selection of the Executive (The Journal of Physiology), Senior Publications Departmental Seminar Scheme, Network Committee and of Honorary Members.

Physiology News | No. 62 | Spring 2006 | www.physoc.org 48 PN SOCIETY MEETINGS 30 Apr 31 Oct 29 Feb 29 Feb 30 June 30 June Deadline Deadline 18 Feb 06 31 Dec 05 31 Dec Application Application scheme*** scheme*** Affiliates’ Grant Affiliates’ Meeting specific Grant 31 Jan 31 Jan 31 Jan 31 Jan 31 Mar 31 July 30 Sept specific Meeting of registration. For For of registration. Deadline Deadline Members’ 31 Jan 06 Application scheme*** scheme*** 18 Feb 2006 . Applicants will be . Applicants No No No No Yes Yes Yes Society Published as Published Physiological Physiological Proceedings of Proceedings TBC 3 Mar 9 Aug 4 Nov 1 June 1 June On-line available available Jan 2006* Jan 2006* Jan 2006** Jan 2006** Programme April 5 July closes closes 18 Jan 18 Jan 6 Sept 13 Mar 24 Feb Abstract submission submission 12 Jan 2006 http://www.physoc.org/meetings/ http://www.physoc.org/meetings/ 9 Jan opens opens March 26 Jun 26 Jun 13 Feb 28 Aug Abstract ed.uni-muenchen.de/dpg06/ Dec 2005 Dec 2005 Nov 2005 Nov submission submission Main Type FEPS Focused Focused Focused Focused Focused Focused Focused Focused Joint Intl http://www.europeancfconference.org http://physinst.web.m The Physiological Society Meetings Calendar 2006 Date 20 Apr 6-7 Apr 13 Sept 5-7 July 4-5 Dec 26-29 Mar 27-30 Aug UCL Bristol Munich, Algarve, Algarve, Ribeirão Portugal Germany Germany Germany Heidelberg, Heidelberg, Manchester Manchester Preto, Brazil * For further information please visit please information * For further visit please information ** For further *** A limited number of travel grants to attend the meeting in Brazil will be available. Up to 50 individuals may be supported individuals may Up to 50 will be available. in Brazil to attend the meeting of travel grants *** A limited number evidence to produce will be required for the meeting and to submit they are intending of the work an abstract to submit required further information and a meeting specific application form please visit specific application and a meeting further information � � � Meeting Place Frontiers in Epithelial Transport of Basic Science Fibrosis Cystic Physoc Main Meeting German Physiological & FEPS Society Control and Modification of Excitation- Contraction Coupling in Healthy and Diseased Muscle New in Developments Stress Physiology Joint International Meeting with The Brazilian Physiological Society

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Parliamentary and Scientific proven benefits to patients, so Bills their training to include anatomy and regulating these had already been physiology, and that clinical trials Committee passed through Parliament. Other should be conducted. The UK also CAMs that showed self regulatory needed centres of excellence in our I attended two interesting meetings of cohesion, provided training and had universities looking at CAMs. The the Parliamentary and Scientific some evidence that they were useful findings of the Inquiry had been Committee this Autumn – one on included herbalism, acupuncture and debated by the Lords in 2001and complementary medicine with homeopathy. Lord Walton defined these subsequently accepted by Government. Giovanni Mann, Chairman of The as his category 1 therapies. Category 2 Society’s Executive Committee, and therapies, such as reflexology, seemed Professor Holgate reported his interest one on African science and technology to have some evidence of usefulness in in clinical trials and the complexities of development with our new International complementing main stream medical human health. The debate between Programme Administrator Laura treatments. Category 3 therapies, conventional medicine and CAMs had Pinson. The Society is a member of the including ayurvedic and ancient often been unhelpfully polarised and it Committee, established in 1939 as a Chinese medicine needed a great deal was important to try to move beyond primary focus for liaison on scientific of further investigation, as although this and find the common ground. and technological issues between well established in their communities, Conventional medicine was struggling Parliamentarians and scientific bodies, their founding paradigms were not well in some areas, notably the management science-based industry and the understood. There had also been some of chronic disease, with patients’ academic world. The main aim is to concerns about known harmful increasingly stressful lifestyles leading focus on those issues where science and ingredients such as heavy metal poisons them to feel fragmented and politics meet, informing Members of in some Chinese medicines. We disempowered, and increasingly both Houses of Parliament by suggested that the Committee might concerned about the perceived possible indicating the relevance of scientific approach the Chinese mainstream side effects of mainstream drugs. and technological developments to medical establishment to see if they had Health services now need to address the matters of public interest and to the made any headway in analysing their question of an integrated approach to development of policy. The Committee own traditional medicines. Lord Walton health, looking at diet and lifestyle meets once a month, when Parliament also had an ‘unclassified’ category for issues, and going beyond treating is sitting, to debate a scientific or those CAMs where there seemed to be illness to promoting the improvement technological topic and its relationship little or no evidence of any efficacy, of health and well being in the with political issues. such as crystal therapy population. Humans are very complex animals, with health being a holistic Complementary and alternative Lord Walton summed up by saying that self regulated state where the whole is medicine (CAM): should it be provided the Inquiry had concluded that the more than the sum of its parts. on the NHS? took place on 17 October. social role of the therapist and placebo Conventional medicine may have taken The speakers were The Lord Walton of effects could explain some of the too disaggregated an approach, Detchant (Chairman of the Inquiry into benefits obtained by CAMs, it was well attempting to focus on the individual CAM by a sub-committee of the House known that busy GPs could often not components of disease. In contrast to of Lords S&T committee), Professor give their patients the same levels of this, the intelligent body hypothesis Stephen Holgate (MRC Clinical quality time as CAM practitioners, but views the body and the brain as a self Professor of Immunopharmacology, not all of the observed therapeutic organising, self regulating system. The University of Southampton) and David benefits could be explained away by placebo effect may well prove to be an Tredinnick MP (Joint Chairman, All- this. The important policy question for important therapeutic principle in Party Parliamentary Group for Government now was whether any treating the whole system and research Integrated and Complementary CAMs should be funded through the is beginning to highlight this. Brain Healthcare). The debate looked at the NHS and, with limited budgets, what imaging has demonstrated that placebos issue of the increasing number of GPs should be given priority. He considered can mimic active drugs and activate the who recommend CAM therapies to that introducing some therapies into the same brain areas. His conclusion was their patients (40% recommending and NHS might lead to some cost savings. that the NHS needs to move to some 20% offering CAM services at For example the herb St John’s Wort is integrate a spectrum of approaches to their surgeries). known to be useful in treating the management of complex disease, depression and can be cheaper than and that it was in this area that CAMs Lord Walton emphasized that his prescribing some main stream drugs, and conventional medicine might Inquiry had taken a long hard look at and osteopathy and chiropracty could effectively interact. the various CAMs on offer and make inroads into the treatment of considered evidence of efficacy. chronic back problems. He thought that David Tredinnick emphasized that he is Osteopathy and chiropracty had been the next step should be to encourage well known as an enthusiastic advocate found to be reasonably well each CAM area to rigorously self for CAMs, to the extent that he has institutionalized and seemed to offer regulate, develop core curriculums in even been called the MP for health food

Physiology News | No. 62 | Spring 2006 | www.physoc.org 50 PN SOCIETY NEWS retailers Holland and Barrett. He had foreign solutions to African problems. materialise,1 John had to abandon his noted that in the past CAM This gave us the opportunity to say that PowerPoint illustrations and change the practitioners had been relatively the new aid initiatives being developed emphasis of his talk to engage his isolated, even from each other. He had should liaise closely with the UK audience with a good deal more brought practitioners together from the learned societies, as most societies had discussion than they had been various areas to debate their African members who could help with expecting. Taking as his initial example involvement in health provision. The grassroots initiatives. Laura and I will the topic of embryonic stem cells that general public also seem to be voting be following this up with DFID and the had been highlighted by the BA's with their feet with a sharp rise in their Royal Society for Chemistry. President, Robert Winston, he use of CAMs. CAM remedies are now compared the actual current state of the If any Members have an interest in on sale in high street chemists. He art with scientists' statements about the helping us to develop new programmes considered that CAM should be used to promise of stem cell technology. He in Africa, please contact us. plug effectiveness gaps in conventional went on to analyse in more depth the medicine, such as in the treatment of whole topic of Science and the spin, Liz Bell back pain, stress, and nausea. illustrating this with several comparisons of the way that mid-20th After much lively debate, the meeting Competing with football in century and early 21st century concluded with a general feeling that discoveries were presented. some CAM therapies should be offered Dublin on the NHS to plug existing With the welcome arrival of weaknesses in provision. However, this refreshments (which included, might best be done by offering a small according to Chris Willmott of number of the well regulated ones first, Leicester University, the best spicy notably chiropracty and osteopathy. chicken wings he had tasted since his Others might then be added to the NHS time as a post-grad in New York2), John menu at a later date when they are handed the initiative to the audience considered appropriate. who were encouraged to work in The importance of science, engineering groups to discuss the possible reasons and technology to a sustainable that scientists in the 21st century are economy on the African continent took much more likely to make bold public place on 12 December. The speakers claims about the applications of their were Sir Crispin Tickell (Former work than earlier generations. This was Ambassador to the UN), Professor followed by a general discussion as the Frank Rijsberman (Director General of groups presented their views. We all the International Water Management agreed that in an age where sound­ Institute), Professor Richard Carter bytes and hype are increasingly the (Institute of Water and Environment, John Bryant (immediate past-president norm, scientists faced with such Cranfield University) and Professor Sir of the Society for Experimental headlines as Gene discovery brings Gordon Conway (Chief Scientific Biology, pictured above) represented hope for millions or GM crops can feed Advisor to the Department for the Biosciences Federation recently the world have a responsibility to help International Development (DFID)). All when he spoke at their Café the wider public understand the of these presentations emphasised the Scientifique event which was held difference between science fact and Government’s current drive to help during the British Association for the science fiction. Overall, despite the Africa develop in the science and Advancement of Science’s Festival of problems, the audience seemed to enjoy technology area to tackle its manifold Science in Dublin in early September. the evening, as did the local organisers economic, environmental, educational of Dublin's Alchemists' Café, who and health problems. The presentations Bravely contending with the Ireland vs hosted the event. specifically focused on issues of water France World Cup qualifying match development which were not which was being shown in the bar Education and Public Affairs, particularly newsworthy in below (and from which we could hear Society for Experimental physiological terms. However, all every cheer and groan), John gave a Biology speakers did emphasise that western aid brilliant performance with his talk to Africa needed to build on home entitled Science promise vs science Deceased Honorary Member grown expertise and talent, rather than reality. When the promised data The Society reports, with regret, the attempting to unthinkingly apply projector and screen failed to death of A David M Greenfield. David was elected as a Member in 1944 and 1 A clear example of the difference between promise and reality! 2 Did this, John wondered, give a whole new dimension to the term 'winging it', an activity that had an Honorary Member in 1987. A been forced on him that evening by the lack of a data projector. Was the talk spicy enough to qualify tribute will be carried in the next issue for a similar accolade? of Physiology News.

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A word from the Education Teachers’ Workshop at After a coffee break, while the gels ran, Officer… the gels were stained with coomassie Coventry University blue to show the protein bands. All the I now have 8 months experience working as gels produced a nice array of bands, the Education Officer for The Physiological which the teachers were justifiably Society and I think I can finally say that I have Physiology is fun was the approach for proud of, with particularly prominent found my feet! Not being one to tiptoe around, a recent teachers’ workshop hosted at bands for actin and myosin. There were within my first month I agreed to brave a Coventry University. The idea behind number of sixth form events, present to clearly visible differences between the the event was to offer a refresher course postgraduates, mingle with teachers, and protein bands for the different species spent a considerable amount of time for biology teachers in some laboratory of fish, which Melanie cleverly linked networking. techniques and to provide ideas for back to evolution. I couldn’t help biology A-level practical classes. The thinking that the remains of the fish The year 2005, from an Education event was organised in collaboration samples would have made a nice perspective, was very successful. The with Society Education Officer Donna bouillabaisse! Physiological Society was represented at a Brown and Melanie Hanna from Bio- number of schools’ events, UCAS Rad Laboratories Ltd. We then moved on to a nice conventions, and workshops for teachers and demonstration of size exclusion sixth formers (see reports on opposite and on After a welcome cup of coffee the chromatography, using a coloured p. 52). We ran a ‘sell-out’ session at the BA teachers were straight into the lab, and solution and simple, cheap columns. Festival of Science in Dublin (see report on they had all remembered to bring their p. 50) which was subsequently featured in a The two coloured components were labcoats, unlike the students. Melanie number of newspapers. During the later part visibly separated by the column and of the year, in collaboration with The ran the practical sessions superbly well fractions were collected. In doing this, Biochemical Society, The Institute of Biology, with the able help of Palak Heywood. the teachers had an insight into The Society for General Microbiology, The Initially, Melanie produced a variety of research: 5% inspiration, 95% British Pharmacological Society, The Institute fish and the teachers may have been perspiration! of Horticulture, and supported by The forgiven for thinking it was Ready, Biosciences Federation, we ran a biosciences Steady, Cook. After lunch (fish was definitely off the careers conference and gave over 500 menu) we moved on to an entertaining graduate/postgraduate students and postdocs The idea behind the first practical on introduction to ELISA. This involved the opportunity to hear about, and tips on protein finger-printing was to extract role play as travelling sales pursuing, a variety of careers. the proteins from fish muscle and run representatives exchanging bodily an electrophoresis gel to separate the fluids! Each person selected a tube of I am hoping that 2006 will be just as eventful. proteins. Melanie had provided a We are already putting together a session for solution and went round the lab merrily the BA Festival of Science (as detailed in comprehensive booklet on the lab mixing their fluid with that in other Celebrity diets, obesity and hormones) and sessions and gave clear introductory people’s tubes, to an accompaniment of we are sponsoring an event at King’s College, talks on the underlying theory. The disco music! We all then ran a simple London, during the BA National Science teachers got to work on mashing up the and quick ELISA, using the fluids in Week (see Nobel Laureate to give keynote tissue, boiling, extracting and running our tubes as samples. Some of the lecture at King’s College London during the gels. The Bio-Rad electrophoresis samples were found to be positive in National Science Week on p. 18). The equipment was affordable and easy to the ELISA and some were negative. bioscience careers conferences will be held set up for school labs and the teachers The protein is question was supposed to on 4 and 18 November and 2 December. For proved adept at loading the gels. be from an infective agent. By further details see the BSF website from September (http://www.bsf.ac.uk/careers.htm). We have tentative dates for sixth form and teachers’ workshops; however, there are still grants available to run additional workshops – if you have a physiology-based activity appropriate for sixth formers or secondary school teachers (one they can take back into their classroom), and you are interested in running a workshop please contact me ([email protected]).

If you would like to get involved with any of our educational activities, or have ideas of your own or an interest in helping to redevelop our education web pages, I would love to hear from you. Getting to grips with protein Donna Brown finger-printing

Physiology News | No. 62 | Spring 2006 | www.physoc.org 52 PN SOCIETY NEWS analysing the number of positive and earlier lecture. With heads full of facts, negative results it was possible to and desperate to start moulding illustrate epidemiology in action and plasticine, the students were split into identify the two original culprits, one of groups with the objective of developing whom was the initial ‘Typhoid Mary’. a short animation to describe one of the following elements of the lecture: the The day was rounded off nicely with a structure of the knee, articular cartilage, tutored wine tasting by our resident cartilage injury and diagnosis, total wine expert, Steve Smith (I can joint replacement, chondrocyte personally recommend the wine courses transplantation and future tissue at Coventry University). Very positive engineering treatments. feedback on the day was provided by the teachers, with comments like: The students started off by drawing a challenging, exciting, stimulating, story board to explain their given topic. relevant, an excellent day really well The idea was to be as creative as delivered, excellent in terms of quality possible, and as creativity rose so did and the hands-on opportunities, highly the noise levels! Quotes such as ‘This enjoyable. Some of the teachers asked is going to be fun man’ and ‘Arrrr that’s for a similar future event, but based on wicked’ clearly showed how much fun exercise physiology. .Girish Pattappa performs a hoof joint dissection. they were having. And amongst the fun and laughter the students were learning; their coming-together animations Ray Carson started the next part of his lecture with Physiology and Sport Science, University of Coventry, clearly showed that they understood the a picture of a rugby player having his UK science. knee bent backwards during a match (not one for the faint hearted), and this Not wanting to spoil the show (the Science learning with a led nicely onto knee arthroscopy and animation will eventually be posted on keyhole surgery used to examine, and our website) I thought I would just difference in some cases treat, joint injury. A mention a few highlights: a physco­ ‘used’ knee replacement implant was style knee replacement operation, a With only 24 places on offer for this passed around the group whilst we giant smiley knee after a bouncing 1 day interactive sixth form workshop, heard about how this surgery was chordrocyte transplantation and a visit I was overwhelmed by 150 requests for performed. Martin then described to the ‘bioreactor spa’ and ‘detox clinic’ places. The workshop was organised chondrocyte (cartilage cells) for cartilage tissue generation – the and run by Martin Knight a researcher transplantation and revolutionary future ... With the animation complete and lecturer at Queen Mary University cartilage tissue engineering. the students recorded the voice-over of London, and held at Tower Hamlets and the final film was left in the City Learning Centre in December With a dramatic change of topic Reza capable hands of Adele Goodwin (City 2005. Designed for sixth form students Ben Gajra (animation support) gave the Learning Centre) to edit. The day was a with an interest in medicine, biology, group an introduction into animation, a huge success; all those involved physiology or medical engineering, the subject which the students were thoroughly enjoyed themselves and, workshop focused on joints such as the particularly knowledgeable about and more importantly, the students went knee and hip, examining joint injuries even knew that it took the creators of away having learnt about the knee and associated with trauma or disease, and Wallace and Gromit 5 years to make at current, and indeed future, treatments the clinical repair techniques including 18 shots/second, 5 seconds a day! The of knee joint injury. tissue engineering. idea was to use animation to explain the science they had learnt during the Due to popular demand Martin also ran Martin Knight started the workshop an interactive lecture attended by with a short lecture describing the approximately 50 students from schools anatomy of the knee, function of the surrounding Queen Mary University of cartilage and the necessity for exercise. London. After the lecture the students The initially shy sixth-formers were were given the chance to chat to Martin eventually coaxed out of their shells and some of his colleagues, and fuelled when Girish Pattappa (PhD by drinks and snacks this part of the student/demonstrator performed a hoof session was also well received. joint dissection and asked them all to put on gloves and feel the cartilage. We are hoping to run a similar event Despite the protest of ‘yucks’ and ‘you during 2006. Do please contact me for must be joking’ even the most more information ([email protected]). squeamish of students had a quick touch. With the dissection over Martin Martin Knight helps students create their animation. Donna Brown

Physiology News | No. 62 | Spring 2006 | www.physoc.org BIOSCIENCES FEDERATION PN 53

Student employability – whose job is it? Colloquium organisers (from This was the title of the Biosciences left to right): Dariel Federation’s second Education Burdass, Sarah Blackford, Sue Colloquium in October 2005, where Assinder, Jane professionals from the education, Taylor, Donna careers and employment sectors came Brown, Olga Zolle together to discuss employability issues and Hannah Baker and to answer this topical question. The bulk of the delegates were academics evaluate evidence, consider the • Directed trajectory where students have a and careers advisers from higher implications of science on society and long-term desire for a career in science. education, but there was also demonstrate knowledge of how science They tend to be inspired by highly visible representation from school teachers and is practiced including explaining, professions such as sports science. educational and policy professionals. theorising and modelling. The • Partially resolved: these students are still Disappointingly, the industry sector was framework is flexible and students are experimenting between science and the arts. represented by only two delegates, one able to choose from GCSE Science, • Funnelling where a student is slowly from English Nature, the other from GCSE Additional Science and also gaining interest in science over time due to AstraZeneca, but the presence of separate GCSEs in Biology, Chemistry the topics and the quality of teaching (this recruiting firms and organisations such group was poorly represented). and Physics. Those that choose to as the Bioindustry Association and study GCSE Science alone will not be • Multiple projection: these students are bioKneX allowed us to share an overall very indecisive about their career choices able to study science at A-level. In wide variety of viewpoints for the and favour different careers at different addition, 360Science also includes the discussion sessions. times. BTEC First Certificate and Diploma, • Precipitating trajectory: these students are which allows students to study for a But what exactly is ‘employability’? generally good at most things so they are vocational qualification. What do employers want, and how spoilt for choice and find it difficult to should employability skills be decide which subjects to take. In terms of employability, concerns provided? During her introduction, Sue were raised by the audience that maths Assinder (Colloquium Chair) noted the One alarming fact that emerged from is still not embedded into the science various descriptors that have entered the survey was that, even amongst high curriculum and field work is not the everyday language of the teaching achieving students with A grades for mandatory as it is for geography. The world: core skills, toolkit, graduate GCSE science, there was an overall multiple-choice examination system qualities, key skills, tertiary literacies, image that science is too hard and that remains, which some in the audience springboard competencies. She left the they are not clever enough to study it to believed would compound the audience with the questions ‘How are A-level. increasing problems of poor literacy these skills being provided?’ and ‘Is it and essay-writing skills. working?’ Anna finished her talk with a number of suggested ways forward: keep Anna Cleaves (Anglia Ruskin The morning was split into three improving science teaching, provide University) reported on some extensive sections (Schools, Higher Education bursaries for ‘real science teachers’, research which she carried out on the and Employers), each containing two utilise careers advisers who know about formation of science choices in talks. science careers, and encourage secondary school (International exploration about science careers. Journal of Science Education 27 471­ Schools 486). Her work was driven by the drop Higher education Kath Skillern (Edexcel) explained in uptake of science in schools and the ‘What is a bioscientist?’ was the Edexcel’s new GSCE science increasing tendency for biology to be opening gambit for Jane Taylor’s curriculum, which was developed to taken with a range of other subject (Lancaster University) talk. She make science accessible to all students. combinations. Students were surveyed suggested that there are three types of It enables students to experience the longitudinally at the beginning and end bioscience student: those who want to science that affects them in their of year 9, the end of year 10 and become a practising scientist, those everyday lives in a relevant and directly after they had made their wishing to apply their knowledge to a interesting manner using either a choices in the spring of year 11. content or context-orientated approach. bioscience-related industry and those The specifications are based on the Anna divided the student’s choice into who enjoy biology but do not want to QCA criteria. The students have to various ‘trajectories’: use the knowledge directly in their

Physiology News | No. 62 | Spring 2006 | www.physoc.org 54 PN BIOSCIENCES FEDERATION future employment. This creates a specialist knowledge, advanced IT and Andrew divided the skills and qualities dilemma for the average academic who commercial awareness. most in demand into five main is left wondering how to meet categories: everyone’s needs, and specifically how Quotes such as ‘You come out of uni expecting to walk into a job but in • self-reliance skills (self-promotion, self­ to balance specific knowledge and awareness, networking) generic transferable skills in their actual fact all graduates have the same experience and so the realisation that • people skills (teamworking, course material. In addition, many communication, leadership) students are now coming to university you need more at an early stage would be good’ will probably make most • general skills (problem-solving, with insufficient knowledge of maths entrepreneurial, numeracy, commitment) and chemistry, an assessment-driven course providers and careers advisers • specialist skills (specific occupational motivation and low level literacy skills. throw their hands up in exasperation as skills, technical skills) All of these are problems that are they strive to introduce students to the having to be redressed by academics Careers Service as they arrive at • commercial awareness. during the degree course. university. Similarly, another quote ’The hardest part was customer Whilst a good percentage of bioscience graduates enter occupations directly or The other major issue for academics is contact, day after day, question after indirectly related to their degree, student awareness of what transferable question‘, illustrates that students come statistics show that over 70% do not. skills are and why they need them. In out of university unable to make the This emphasises the need for general an assessment-driven culture many connection between part-time employability skills in the curriculum. students will not be motivated to temporary and full-time employment. undertake these parts of the course Ian’s final take-home message was unless they are embedded. Even if this Discussion ’There are easy ways in which we can Following these formal talks, the is the case, students invariably are improve employability aspects of our delegates came back together for the unable to identify which transferable courses. Use the existing tools and discussion session, ably and efficiently skills they do have. In addition, Jane don’t re-invent the wheel.’ managed by Sue Assinder. Sitting at pointed out other short-comings of new round tables, the delegates were given students who arrive at the university Employers three of the following questions to with their heads stuffed full of discuss and then feedback informally: information but with little Kay Wardle, managing director of understanding or the ability to express science recruitment company RSA • how can we improve communication their own ideas and thoughts either Consulting, was able to give the between stakeholders? verbally or in writing. employer’s perspective setting out the • are transferable skills really transferable? wide variety of jobs available within • how can students take responsibility for the bioscience industry. These include Jane concluded by saying that a long­ their own employability skills? term and concerted effort is currently research, clinical trials, toxicology, • what could employers do? needed to overcome some of these regulatory affairs, sales and marketing. dilemmas, including reducing the The three main requirements employers • is there a ‘core’ knowledge base for a bioscience graduate? If so, what is it? amount of assessment and testing in look for are a good degree in a relevant schools, fostering critical thinking, and subject, practical work experience and • how do you give students experience of a better communication between transferable skills (see below). Her the workplace? schools and universities. concluding remarks led on very well to • how can we break the mould of the next talk as she told the audience assessment-driven learning? Ian Hughes (HE Academy Centre for that a good degree is not enough. The results of the discussion and Bioscience) reported on a survey which feedback are not reported here but a he conducted recently and which is Our concluding talk of the morning formal document will be published published in the Centre for Bioscience’s from Andrew Whitmore (Careers early in 2006. This will make online journal, BEE-J, at Centre, University of Manchester) recommendations that complement the www.bioscience.heacademy.ac.uk/journal/vol6 began with some professional findings and recommendations of the /beej-6-2.htm. The conclusions of his definitions of the word ‘employability’, Biosciences Federation’s Enthusing the findings from a longitudinal study of the most poignant of which was a quote next generation group which was students who had graduated 1-2 years from Peter Hawkins: ’To be employed published in November. We welcome previously showed that graduates felt is to be at risk, to be employable is to any input and comments from our they had been well prepared by their be stable’. Competition for graduate members about their views and university course with respect to theory jobs is tough, illustrated by information experiences on student employability. and knowledge, presentations and which says that from a pool of 160,000 communications skills, basic IT needs, graduates entering employment in Sarah Blackford, Dariel confidence, organisation and time/self­ 2005, only 18,000 will enter formal Burdass, Sue Assinder management. However, they felt they ‘graduate training programmes’, Education Committee, Biosciences Federation were ill-prepared for practical aspects leaving 142,000 entering junior roles The PowerPoint slides for all the talks can of their jobs, career management, within a wide range of employers. be viewed at www.bsf.ac.uk/edu.

Physiology News | No. 62 | Spring 2006 | www.physoc.org BOOK REVIEWS PN 55

Ribeiro da Silva) and mechanisms of Zuckerman: scientist The neurobiology of pain modulation and central sensitization Molecular and cellular (Salter and Woolf). Mechanisms of extraordinary neurobiology neuropathic pain and its relentless persistence are then considered by Edited by Stephen Hunt and By Bernard Donovan Koltzenburg, who concludes that BioScientifica Ltd, Bristol. Martin Koltzenburg peripheral and central mechanisms for 2005 Oxford University the generation and maintenance of 506 pp, £24.95 Press. 403 pp, £60.00 neuropathic pain remain largely ISBN 1-901978 24 9 unexplored. A chapter on targets in ISBN 0-19-851561-8 One day in May 1966, shortly after the pain and analgesia (Dickenson and general election, I was sitting on the top This is an interesting collection of 15 Suzuki) follows and is succeeded by deck of a London bus travelling down invited papers dealing with the chapters on ascending pain pathways Oxford Street towards my laboratory in molecular and cellular aspects of the (Hunt and Bester), spinal delivery of Drury Lane. Having narrowly failed to neurobiology of pain, but very little drugs in pain control (Yaksh and get elected to the House of Commons data on central processing of data in the Mantyh) and an excellent chapter on as a supporter of Harold Wilson’s brain is included, perhaps reflecting this the development of pain systems by ‘white heat of scientific and field of research. There is, however, an Fitzgerald and MacDermott. This is technological revolution’, I was interesting chapter on central imaging followed by a good review of visceral thinking about science and politics, and of pain (Flor and Bushnell) towards the and deep somatic pain (Laird and the new Government the PM was end of the book and good chapters on Schaible). The final two chapters are on forming, when a news-bill caught my organization of periaqueductal grey headache (Goadsby and Ferrari) and eye. ‘Atom wizard called to Number matter, including integration of pain control of cancer pain (Mantyh and 10’, it said. Intrigued, I leapt off the bus behaviours (Lovick and Bandler) and Yaksh). at the next stop and bought a copy of descending control of pain processing the Evening Standard, to find that the by Gebhart and Proudfoot . The book is Production is quite good, but four wizard in question was Sir Solly not divided into sections, making colour plates are placed in the centre of Zuckerman, then the Government’s relationships between chapters more the book, all but one of them Chief Scientific Adviser. opaque than necessary. dissociated from their text. Perhaps more use of colour throughout the book Lord Zuckerman OM, FRS, as he The first two chapters are good would have resolved this problem. became, was an early exemplar of those overviews of the molecular biology There are the usual weaknesses of bright young South Africans who left (Caterina et al.) and plasticity edited books, but the chapters are their homeland for postgraduate work (McMahon and Priestly) of nociceptors. interestingly written by people deeply in Europe or America, never to return. Two chapters are devoted to studies of involved in the subject. Sydney Brenner, Bennie Kaminer and the dorsal horn giving details of its Lewis Wolpert are more recent molecular architecture (Todd and Bill Winlow members of the same group. Born in 1904, Zuckerman arrived in London in 1925 with first class honours, and a Other books published Masters degree in Anatomy, to do the clinical part of his medical training New titles in the Wellcome Witnesses to Twentieth Century Medicine series (which could not then be done in South Africa). Hardly an ‘atom’ wizard – I No 23 The recent history of platelets in thrombosis and other disorders. Edited by LA think the sub-editor had confused him Reynolds & EM Tansey. with Sir William Penney, another ISBN 0-85484-103-2 Government Adviser – but wizard he No 24 Short-course chemotherapy for tuberculosis. Edited by DA Christie &EMTansey. certainly was. ISBN 0-85484-104-0 In the 1920s and 30s young Zuckerman No 25 Prenatal corticosteroids for reducing morbidity and mortality after preterm birth. made his way in scientific circles in Edited by LA Reynolds & EM Tansey. London and Oxford. In the manner of ISBN 0-85484-102-4 the times he also met many luminaries These edited and annotated transcripts of meetings cover major topics in modern medical in science, politics, literature and the science, including monoclonal antibodies, NMR and MRI, heart transplant surgery in the UK, arts, making contacts and friendships haemophilia, medical research and education in Africa, childhood asthma, leukaemia, several useful to him later on. Like many MRC research units, genetic testing, obstetric ultrasound and maternal care. young scientists he disagreed with some of his mentors, in this case about Volumes 1-25 are freely available to download at http://www.ucl.ac.uk/histmed following the links to Publications/Wellcome Witnesses. the anthropology of human and ape skulls that he had begun to study in

Physiology News | No. 62 | Spring 2006 | www.physoc.org 56 PN BOOK REVIEWS

South Africa. These controversies offensive air power, considering that, largely because the Prime Minister helped make his scientific reputation, with the limited bombing accuracy then considered herself to be her own and a substantial section of the book is possible, empirical evidence science adviser. concerned with both the arguments and demonstrated that attacks should be the long-term outcome of the work. He concentrated on rail marshalling yards The index of this book is a roll-call of also worked on human and ape and engine repair facilities so as to the science and defence questions that endocrinology, particularly of the paralyse the enemy’s transport system. came before post-war Governments; reproductive cycle, studies that These opinions, developed in the Skybolt, TSR2, ‘independent’ nuclear foreshadowed the later discovery of the Sicilian campaign, often disagreed with weapons, Thor missile deployment, contraceptive pill. The endocrine field military wisdom, particularly with that Hawker-Hunter VTOL aircraft, the was then still in its infancy, and of the United States Air Force in the Thames Barrier and so on. Many of Zuckerman fostered it by founding and run up to the D-Day landings. these were costly failures, but some editing a major journal (The Journal of Zuckerman’s views seem largely to were outstanding successes. Endocrinology). At the outbreak of have been vindicated when enemy Zuckerman’s advice was sought on all World War Two he was appointed records later became available. of these, but in the culture of amateur Professor of Anatomy in the University Ministers was not always taken in full. of Birmingham. This comprehensive biography by There were few, if any, empirical Bernard Donovan, covering all aspects (biological) scientists in the Commons When the war came, and in the of Zuckerman’s professional and public during the period; after my failed aftermath of the Fascist bombing of life, is well-written and well-researched attempt in 1966 it was more than 30 Guernica, there was much concern and should surely be of interest to years before Dr Ian Gibson was elected about probable bombing casualties. I many members of The Physiological in 1997, though sadly he has never once heard J D Bernal, another major Society. It is organised in blocks been given Ministerial rank. British scientific figure and one of my covering the different aspects, so that it personal heroes, tell the story as is occasionally difficult to detect the It is appropriate to end a review of this follows: chronological life of the man. In a book excellent book by remembering two ‘Solly Zuckerman knew all about of more than 500 pages, with copious particular achievements of Zuckerman monkeys, so we staked out some on references and quotations, there are the man. Among all his other activities Salisbury Plain at various distances inevitably parts that will be of more or he achieved the reform of the from a 500lb bomb and detonated it. less interest to an individual reader, but Zoological Society in a Promethian Then we tried to extrapolate the effects this does not detract from the worth of struggle against long-established on humans.’ the book. From my personal privilege, involving two cases in the perspective I was fascinated by the High Courts. Sadly, though, despite his Practical science, no doubt, and surely wartime accounts, and the post-war advice the London Zoo remains one of necessary at the time, though one political experiences. the few national zoos in Europe not to shudders to think of the reaction of have Government funding. Perhaps his today’s animal protection lobby. crowning moment, though, was his After the war Zuckerman continued as reaction to the Cecil King-Hugh Chief Scientific Adviser under Bernal and Zuckerman went on to carry Cudlipp coup-conspiracy in 1968; I am successive Conservative and Labour out (for the Ministry of Home Security) delighted that it was a scientist who Governments, first to the Ministry of a seminal study of the economic and declared ‘this is rank treachery’, which Defence and later to the whole morale effects of air raids on it certainly was (pp 500-501). It is no Government, on a three-days-per-week Birmingham, showing that long­ exaggeration to call Solly Zuckerman basis. His academic life in Birmingham anticipated disaster and panic should ‘scientist extraordinary’, and this book meanwhile continued in the remainder not occur with the attack levels then does justice to his multiple roles, and of his time. In the 1960s he resisted possible. I can testify personally to the many achievements. accuracy of their conclusions, having Harold Wilson’s attempts to bring him directly into the political process as a spent the war years in London through Gerald Elliott both Blitz and V-weapons. We Minister in the House of Lords. Nuffield Laboratory for Ophthalmology, Oxford Londoners were certainly scared, Remembering the lack of political cowering nightly under staircases or in impact of those who succumbed to such cellars while bombs fell and guns blandishments, including Patrick Zuckerman: scientist Blackett, Alun Gwynne-Jones and CP raged, but in the mornings most of us extraordinary Snow, this was probably a very wise came out alive and got on with our is available to Society members normal lives. decision. As a consequence, Zuckerman survived in Whitehall until formal at the specially discounted price Zuckerman subsequently joined retirement and remained as a part-time of £18.50. Combined Operations, becoming an adviser, with a room in the Cabinet For full details of how to order Office, into his eighties. Only in the adviser on bombing policy. He had your copy, see p. 43 clear ideas on the optimum way to use Thatcher years did his influence wane,

Physiology News | No. 62 | Spring 2006 | www.physoc.org 23–27 July 2006, Glasgow, UK BJ Centenary Symposium: Focus topics: Literature, Legacy, Life… • Nuclear receptors • Transcription Monday 24 July 2006 • Control of immune responses celebrating 100 years of biochemistry • Proteins - structure and function • Ion channels Organized by: George Banting, • Information processing and Peter Parker and Guy Salvesen molecular signalling • Coordination of cellular processes Centenary speakers: Award lectures: • Mina Bissell • James Barber • Fred Goldberg • Simon Boulton • Steve Huber • Phillip Hawkins • Louise Johnson • Seamus Martin • Stephen O’Rahilly • Kim Nasmyth • Donny Strosberg • Martin Raff • Mike Waterfield • Sir Gregory Winter • Lewis Wolpert

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