PHYSIOLOGYNEWS

autumn 2004 | number 56

Featuring: Cork Meeting Bristol & Oxford Focused Meetings

Living history New series

Adaptations to marathon training Training and competition stress A week in the Zambian bush Learning to smell Making old muscles young again Neuroscience books special

A publication of the Physiological Society PHYSIOLOGYNEWS Contents Editorial 3

The Society’s dog. ‘Rudolf Magnus gave Cork Meeting Edward Johns 4 me to Charles Sherrington, who gave me Bristol Meeting Sergey Kasparov, Julian Paton 6 to Henry Dale, who gave me to the Alan Garny, David Gavaghan, Peter Kohl, Physiological Society in October 1942’ Oxford Meeting Philip Maini 6

Living History Published quarterly by the Physiological Society A moment of excitement Geoffrey Burnstock 7 Contributions and Queries Executive Editor Features Training and competition stress: effects on immune function and health Linda Rimmer The Physiological Society Mike Gleeson 9 Publications Office Inside the ‘black box’ Henning Wackerhage, Philip Atherton 11 Building 4A, The Michael Young Centre A week in the Zambian Bush Tristan Pocock 13 Purbeck Road Role of villus microcirculation in intestinal absorption: coupling of Cambridge CB2 2HP epithelial with endothelial transport John Pappenheimer, Charles Michel 16 Learning to smell Tim Jacob 18 Tel: +44 (0)1223 400180 Conditions under which systemic lactate may act as a metabolic substrate Fax: +44 (0)1223 246858 for the brain Angus Brown, Malcolm Prior 20 Email: [email protected] Our shape is elastic, modular and held together by carbohydrate strings The Society web server: http://www.physoc.org John Scott 22 Elastin and hypertension: is there a link? Silvia Arribas, Ana Briones, Magazine Editorial Board José González 25 Editor The leaky mitochondrion Kent Sahlin, Michail Tonkonogi, Maria Austin Elliott (University of Manchester) Fernström 27 Members The contribution of steric and electrostatic factors on distribution of Lesley Anson (Nature) macromolecules in the interstitial space Helge Wiig, Christina Gyenge, Laura Blackburn (University of Cambridge) Olav Tenstad 29 Munir Hussain (University of Liverpool) What limits jaw movements during vigorous head movements? John Lee (Rotherham General Hospital) Timothy Miles, Stanley Flavel, Michael Nordstrom 31 Thelma Lovick (University of Birmingham) Making old muscles young again James Ryall, David Plant, Gordon Bill Winlow (Prime Medica, Knutsford) Lynch 33 Maternal stress in pregnancy may affect the cardiovascular system of © 2004 The Physiological Society the child Natalya Igosheva, Vivette Glover 36 ISSN 1476-7996 Affiliate News The Society permits the single copying of Annual Molecular Techniques Workshop, Cork Patricia de Winter 35 individual articles for private study or research. For copying or reproduction for any other purpose, written permission must be sought from the International News Physiological Society. Physiology in Belarus Bill Winlow 37 Cardiovascular Physiology Andrzej Beresewicz, David Eisner, Gerrit Opinions expressed in articles and letters submitted Isenberg, Alex Verkhratsky, Susan Wray, Natalie Middleton 38 by, or commissioned from Members, Affiliates or outside bodies are not necessarily those of the Benevolent Fund Physiological Society. Ella and the Ben Fund Ann Silver 40

The Physiological Society is registered in England Editorial Boards as a company limited by guarantee, Experimental Physiology at FASEB John Coote 43 No 323575. Registered office: PO Box 11319, London WC1X 8WQ Registered Charity No Letters to the Editor 43 211585. Symposium Report Printed by The Lavenham Press Ltd Nociception in vertebrates: anatomy, electrophysiology, genomics and behaviour Lynne Sneddon 44

Transfer News/Promotions 44 Cover photo A hippocampal pyramidal Society News neurone expressing green Biosciences Federation Maggie Leggett 45 fluorescent protein targeted Moving on Maggie Leggett 45 using an adenovirus with a Publications Office 46 neurone-specific promoter in organotypic slice culture. Obituaries Fluorescent neurones remain James Ryder David Cotterrell, Lars McNaughton 46 viable for weeks in vitro and allow superb conditions for live cell confocal imaging and other types of experiments Unbelievable! 47

Neuroscience books special 48

Noticeboard 52 PHYSIOLOGYNEWS

Action points (p. 9), molecular adaptations to In this issue endurance exercise (p. 11), and leaky Grants Welcome to the Autumn 2004 mitochondria (p. 27). Muscle Grant schemes have changed. For full Physiology News. physiology is not just for the young information on Members’ and and fit, of course – in age we want to Affiliates’ Grants, Pfizer in vivo One of the most gratifying things for keep our muscle tone, as James Ryall Physiology Grants, Intercalated BSc an editor is to see new features up and and friends discuss on p. 33. Bursaries, Network Interaction Grants, running. This issue we introduce what I Non-Society Symposia Grants, hope will be a recurring feature, Living A second theme is inner – or rather Postgraduate Support Fund information History. History – and physiology has intercellular - space. In this age of cell and the Vacation Studentship Scheme a rich one – is perhaps best heard and molecular physiology, please visit: through the voices of those who were physiologists can be accused of http://www.physoc.org/grants there. Scientists prize their moments of neglecting the spaces between cells. discovery – times when you saw However, we do so at our peril. The Membership applications something new, or first realised structures and macromolecules in these Applications for Full and Affiliate something was going to work – and spaces give us our shape (p. 22), Membership are received throughout Geoff Burnstock kicks off the Living influence the composition of the fluid the year and have no deadlines. A History series on p. 7 by recalling just within the spaces (p. 29), and help decision is normally made within 8-10 such a moment. This issue also sees determine how solute uptake occurs (p. weeks of the Administration Office our second diary (p. 13), where Tris 16). Finally, mis-programming the receiving the application. For full Pocock tells us how a physiologist structures filling these spaces in early details please visit: ended up teaching secondary school life may lead to adult disease (p. 25). science in Zambia – a marked contrast http://www.physoc.org/join to Alan North’s working week that we Plenty of meat and fibre there then! heard about in the last issue. And we have not neglected the body’s Change of address most (self?) important organ, the brain, Members should inform the It is fun to try and spot scientific since on p. 48 we review five recent Administration Office of any changes themes in the magazine, and I think I books in the field of neuroscience. All of address, telephone, fax or email spy at least two this time. One is the in all, we hope, something for address. continuing Olympic-year strand on everyone. Changes can be emailed to: muscle and exercise physiology, where [email protected] or updated online at we learn about exercising in the heat Austin Elliott http://www.physoc.org A moment of excitement ... Physiology News Deadlines Letters and articles and all other contributions for inclusion in the Winter 2004 issue, No. 57, should reach the Publications Office ([email protected]) by 20 September, 2004. 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 our website: http://www.physoc.org. EDITORIAL PN 3

whopping 0.1%, although of course a government do whatever is necessary to Talking to the public - percentage of my time/salary should encourage you to leave your whose responsibility? also be factored in. laboratories. What can the Society do to help you? Many of these activities will So what do I think we should be doing? be local, and depend on local networks Not mine! I hear you cry. Or: ‘Isn’t that The Society’s best resource is you, our (talking to local media, participation what we pay you for?’ as a grumpy Members. Much as there exists a with café scientifiques, visiting Council member asked me recently. ballooning‘science communication’ schools/local clubs etc). Rather than try Well, perhaps, but there are an awful lot community, the best people to to reinvent the wheel and set up of ‘the public’, and there is only one of communicate about science are active complicated national networks, the me, or my successor. scientists. In my experience ‘science Society should help to raise awareness communicators’ can be anything from of local schemes, share success stories, I should explain. As I am leaving the retired professors who fancy getting on and flexibly provide small amounts of Society to take up a new post with their soapbox, to some kid who has money for Members to use to help you BBSRC (if you’re interested, find out read and possibly failed to understand take part. Perhaps funds for some what on p 45), Austin Elliott asked if I the latest New Scientist. Both can be admin help to free up your time to would like to write this piece. ‘Say good or hopeless, but until that organise/ participate in an event, to what you think needs saying after five community thinks up some way of contribute to a projector for giving years as our External Affairs person’ regulating itself – and even if it does – school talks, or help with course fees if was the commission, which explains then it is you who should be out there. you want training in some form of why you are hearing about Public communication skills. Communication two editorials running. There are two obvious main problems. First, you all have a day job to do. Nationally, there are already several In case you didn’t know, the Society’s Secondly, talking to a lay audience can organisations with which we could strategic plan singles out ‘educating the be a bit daunting. There have been work more closely. The Science Media public’ as a particular aim of ours. And various suggestions about ways in Centre does an excellent job of in the near future we may get asked which public engagement activities can proactively badgering journalists to talk what we have done about it. The be ‘rewarded’ - anything from it being a to researchers to get their slant on Charity Commission is busy casting its box to tick on a PhD report, to taken as particular stories. I have already beady eye over learned societies (ours value in the RAE exercise, to suggested we support this organisation, included), asking if these organisations universities forcing paid staff out for a but so far without success. Likewise, really should be charities. A quick couple of days a year. Some people are the British Association for the aside: historically charities have been better at communicating than others, so Advancement of Science has networks able to say they ‘served the public’ (one I personally don’t think the last option of members and holds events regularly. of their key duties) by serving their would be the right way forward. I also The Royal Society seems to be doing members, since their members are part fear that the RAE is complicated ever more in this field and, following of the public – see e.g. private schools. enough already without trying to add in criticism from the government, the However, those days are clearly some kind of measurement of success BBSRC has stepped up activities. numbered. When this happens, in public engagement activities. Helping these organisations with their fulfilling stated objectives like Personally, I would favour making efforts, both financially and by ‘educating the public’ will be critical to public engagement work part of PhD involving our Members, has to be better holding on to our charitable status, training as, whichever method one than striking out on our own. Although which, if nothing else, saves us a lot of chooses, it should lead to good funding a Prize or two, as Nancy money. I also feel quite strongly that transferable skills. Also, I think Rothwell suggests on p 43, would also we – you – have a duty to share your universities should view these activities be one way for the Society to put its knowledge. People really do want to alongside all the others academics do – money where its mouth is. know who you scientists are and what so, for instance, if you were the person you do. The intricacies of some minor responsible in your department/group None of this is revolutionary. I am ion channel might be beyond your for working with the public, you should merely suggesting the Society does average layperson, but why you started be relieved of some admin or similar. what it says it will in its (now rather your research, what the aim is, and how However, these are just my views. A elderly) strategic plan, by formulating a you spend your time will prove consensus among the academic policy through which Members can surprisingly interesting to Joe Public. community is needed. As your learned engage, linking up with other society, we should be actively organisations and using a small amount If you read the last editorial you will be canvassing your views and then of its budget. However, I have been aware that the Society already engages lobbying for whichever is your banging this drum for the last five years with the public to some extent. Frankly, preferred solution. and I haven’t got very far. Maybe it’s though, this is a drop in the ocean – in time to buy a bigger soap box. my time the amount of the budget spent Let’s suppose a strategy is agreed and on these activities has risen from 0 to a universities/funding agencies/the Maggie Leggett 4 PN CORK MEETING

Welcome to University College Cork Edward Johns details changes in Cork since the Society last met there in 1995

and he is reinforcing the teaching of molecular physiology in the different programmes. Vincent Healy is a graduate of UCC and, having returned from a fellowship in UCD, is contributing to the cellular physiology courses. Therese Ruane-O'Hora is undertaking teaching in the nursing programmes and is ensuring that there is emphasis on integrative physiology. Along with the increase in personnel, there has been an expansion in quality research space for Physiology on the first floor of the Biosciences Institute – Above: The Boole Library and Lecture Theatre complex, venue for the Society Meeting a brand new building which came on Below: Patrick Harrison and his molecular physiology research group (top) and the University quad (bottom) stream in October 2003. There are a Queen’s College Cork, along with its Physiology remains an independent number of research themes being sister colleges in Galway and Belfast, budget unit within the Faculty of developed within the Department at was brought into existence by the 1845 Medicine and Health and is responsible present. Patrick Harrison, with Tara Act of Parliament under the direction of for the delivery of physiology teaching Kelly (Research Fellow), Dave the Prime Minister, Sir Robert Peel. to its constituent Schools – Medicine O’Sullivan (PhD student) and Rowan The building of the College complex in (250 students), Dentistry (80), Nursing Flynn (PhD student), together with Cork began in 1847. It was completed and Midwifery (400), Pharmacy (50) collaborators in the Departments of in 1849 and, having been seen by and Clinical Therapies (50). Courses in Anatomy and Microbiology, are Queen Victoria in August, was physiology are also delivered to developing virus vectors for gene officially opened on 7 November of undergraduates in the Faculty of delivery. At the molecular level projects that year. The educational processes of Science (160 students) who provide our are underway to investigate the link the College were based on that of the final year Honours BSc Physiology between mutant forms of CFTR and University of London rather than the class of 10-15 students. It is from these mechanisms of infection in cystic tutorial system of the Oxbridge students that a number progress to read universities. Such were the political for a PhD. In all, just over 1,000 sensitivities of the time that initially the undergraduates each year are exposed position of ‘Professor’ was a Crown to the ‘Physiology experience in Appointment made from London. Cork!’. It is Anne Harris who co­ Medicine was a foundation Faculty coordinates the teaching and learning with a first year enrolment of 12 approaches which are an essential students. The demand for teaching in element of the curriculum. medicine was so great that in the 1860s funds were released for the construction The Society last met in Cork in 1995 of the Windle Building which to this and since that time the Department has day houses the Departments of changed substantially. John Hall Physiology and Anatomy. It is retired, with the new Head arriving in therefore a singular coincidence that January 2002 (narrowly escaping the this meeting of the Physiological demise of the Department of Society in University College Cork Physiology in Birmingham), while coincides with the 150th anniversary of Brian Harvey has moved on to Dublin. the graduation of the first cohort of There have been three new academic medical students who received their appointments recently to cope with the physiology education in Cork. increased teaching required as a consequence of the opening of the new The provision of teaching and research Schools, bringing the Department in physiology today is very different complement to eight permanent full from the early years of University time academic staff. Patrick Harrison College Cork. The Department of arrived from the University of Glasgow CORK MEETING PN 5 fibrosis, and a separate study to identify The large mammal physiology group is the aquaporin and NHE isoforms led by Mike Snow and his collaborators expressed in Rana temporaria bladder are Therese Ruane-O’Hora and Roisín (in collaboration with Liz Gebruers). Kelly (PhD student) who are Patrick Harrison also organizes the undertaking acute studies in the pig. Physiological Society/Wellcome Trust Together they have two areas of Molecular Techniques Workshop hosted interest; the first concerns in the Department since 2000. Each understanding the relationship between year, the 10-day workshop provides shear stress and the generation of nitric training for 16 physiologists in oxide in large conducting arteries in molecular biological techniques such as vivo. The second area is the sub-cloning, siRNA technology, RT- contribution of local factors, for PCR, site directed mutagenesis and example VIP and NO, in modulating transfection techniques. The next the impact of the vagus on the control workshop will be held in UCC in of the heart. Spring/Summer 2005. Gerry O’Regan and Fionnuala Ni Vincent Healy leads a group Chiardha together form a team investigating the mechanisms mediating investigating respiratory control in noradrenaline-induced uptake of humans. They have been assessing sodium in the renal proximal tubule. It how CO2 together with tidal volume would seem that there is intracellular may determine the degree of respiratory trafficking of the NHE3 from sinus arrhythmias. In this work they endosomal stores into the apical are aided by a number of final year BSc membrane which requires students, who effectively recruit other phosphorylation of intermediates to Above: Gerry O’Regan with Fionnuala Ni Chiardha undergraduate subjects. (top); Anne Harris (centre); Mike Snow and Roisin occur. The impact of the noradrenaline Kelly (bottom). The Society Meeting will take place on both these processes is a relatively Below: Edward Johns (red jumper) with his team of within the Boole lecture theatre Chunlong Huang, Ahmad Ahmeda and Rob Gaffney unexplored area, and Vincent and complex, and administrative and Claire Thompson (PhD student), are (top); Vincent Healy and Claire Thompson (centre); the new Biosciences Institute which came on stream in technical staff will be on hand to ensure applying not only cell culture October, 2003 (bottom) that audio visual, orientation and any techniques but whole animal studies to other local issues are dealt with elucidate the mechanisms involved. efficiently. There are four symposia organized for the Members to enjoy, Edward Johns’ team is concerned with ‘Cardiovascular-renal interactions’ investigating the mechanisms whereby which aims to provide an up-to-date the sympathetic nerves to the kidney view of central and peripheral determine both vascular and tubular regulatory mechanisms; ‘Adenosine, function and how their regulatory purine and nitric oxide in the regulation mechanisms may be deficient in of kidney function’, which is part pathophysiological states. Together supported by Pfizer; ‘Cellular and with Chunlung Huang (Research integrative aspects of water balance’, Fellow) renal sympathetic activity is which is of particular relevance in being measured in conscious rats to see relation to this years’ award of the how baroreflexcontrol is altered by Nobel Prize in Medicine; and, finally, different dietary sodium intake. there is the Molecular Techniques Teaching Symposium; a chance to In acute studies in the rat, Rob Gaffney brush up on the basics and get updated (PhD student) is investigating how on the latest topics. leptin within the central nervous system can determine the sensitivity of We at the Department of Physiology are baroreflex control of renal nerve looking forward to having the Society activity, both normally and in rat visit us in Cork in September. models of obesity. Ahmad Ahmeda (PhD student) is assessing the Edward J Johns Department of Physiology, University College Cork importance of reactive oxygen species in determining renal blood flow distribution and how this may be For further information and registration altered in rat models of hypertension. details visit: http://www.physoc.org/ 6 PN BRISTOL/OXFORD MEETINGS

Bristol Meeting Viral gene transfer in neuroscience: new tricks of the trade

A Physiological Society Focused experts speaking at this Meeting will Meeting will take place at the cover such families as alphavirus, University of Bristol, Bristol, UK on adenovirus, adeno-associated, lentivirus 4-5 September, 2004 and baculovirus-derived vectors, and demonstrate their use to address various During the last decade, viral vectors physiological and biomedical problems. have become reliable tools for gene Special attention will be paid to laboratories in the University of Bristol manipulation in the brain. This Meeting targeting transgenes to the diverse where viral gene transfer is carried out will focus on viral gene transfer as one cellular populations present in the brain (site visit places are strictly limited). of the powerful techniques in a rapidly and to the future of viral vectors in both growing field of physiological basic science and gene therapy. This meeting will provide a great genomics. In the context of opportunity to learn, meet the experts, neuroscience, viral gene delivery helps In addition to the talks there will be an and discuss and establish new to determine the roles of individual open poster session where participants collaborations between all those genes and their families under normal are invited to demonstrate any piece of interested in viral gene transfer and and pathological conditions. recent work using viral gene transfer. neuroscience.

Several types of vectors are currently Finally, on the second day of the Sergey Kasparov being used and all offer distinct Meeting, interested participants will Julian F R Paton advantages for neuroscience. The have a chance to visit several University of Bristol

Society, while lectures will also be Oxford Meeting featured in a 2005 focused issue of the Proceedings of the Royal Society. The city of dreaming spirals The focus of this workshop is to bring A Physiological Society Focused during the last few decades), the ‘career together specialists who are actively Meeting at the University of Oxford, change’ of a pioneer of our field is conducting biomathematical modelling Oxford, UK on 1-3 October, 2004. certainly worthy of special celebration. in physiology. The lecture format (20 min talk + 10 min discussion), lunch Dreaming spirals? No, the Special Fittingly, the workshop will be arrangements (in the poster area), and Meeting of the Physiological Society, launched by the Physiological Society’s social activities are tailored to provide devoted to Biocomputation and Hodgkin-Huxley-Katz Prize Lecture ample time for discussion and informal Modelling in Physiology, will not focus titled From the Hodgkin-Huxley Axon interaction. Fitting with the concept of entirely on modelling cardiac re-entry to the Virtual Heart, which Denis will a ‘workshop’, the meeting will be in the shape of spirals. It will address a deliver on Friday, 1 October at the Saïd limited to 160 participants, so early whole range of data-based simulation Business School. This will be a public registration is encouraged. of biological behaviour, from molecule and highly publicised event, which to man. coincides with the first day in office of In anticipation of a focused and Oxford’s new Vice Chancellor, John productive Special Meeting, we look There will be 18 invited lectures on Hood, who will open proceedings. forward to welcoming you to the City topics as diverse as molecular of Dreaming Spires. dynamics, developmental biology, The following 2 days will be devoted cancer, the respiratory system and – to lectures by international leaders in Alan Garny well, of course – the heart! the field of biomathematical modelling, David Gavaghan covering a wide range of topics from Peter Kohl The meeting is timed to coincide with sub-cellular to whole organ and Philip Maini the retirement of Denis Noble from his systems modelling. Departments of Physiology, Mathematics and Computing, University of Oxford Burdon Sanderson Chair in Cardiovascular Electrophysiology. In addition, there will be a dedicated Even though we do not expect to see poster session (all posters will be on For up-to-date information and much – if any – reduction in his display throughout the event). registration details for the Bristol and scientific activities (many predict that Oxford Meetings please visit the he will find more time in future to All abstracts will, as usual, be Physiological Society website: conduct his research than at any point published on-line by the Physiological http://www.physoc.org/ LIVING HISTORY PN 7

A moment of excitement To launch our Living History series, Geoffrey Burnstock recalls the discovery of non- adrenergic, non-cholinergic autonomic neurotransmission

I remember vividly the day that we discovered non-adrenergic, non­ cholinergic autonomic neurotransmission.

Together with Ralph Straub at the National Institute of Medical Research, the sucrose gap technique for recording continuous, correlated changes in electrical mechanical activity of smooth muscle was developed (Burnstock & Straub, 1958). I moved to Edith Bülbring’s lab in the Department of Pharmacology, Oxford, and completed studies of classical adrenergic and cholinergic responses of the guinea-pig taenia coli (Burnstock, 1958a,b).

From Oxford, I moved to Melbourne, Australia where, with the help of an NIH grant held jointly with Mollie Holman, whom I had met in Oxford and whose work I had admired there, I set up the sucrose gap apparatus in my laboratory.

Graeme Campbell, a postgraduate research assistant and Max Bennett, at that time a part-time electronics technician who was completing a degree in Electrical Engineering, were working with me, and one day in 1962 we decided to look at the direct responses of the smooth muscle of the taenia coli after blocking the responses of the two classical neurotransmitters, Figure 1 (top). Sucrose gap records from smooth muscle of guinea pig taenia coli showing inhibitory potentials in acetylcholine and noradrenaline. response to stimulation of intrinsic nerves. Frequencies of stimulation: (A) 1/sec; (B) 10/sec; (c) 20/sec. Upper trace, tension; lower trace, membrane potential. Note the phase of excitation (B and C) which follows cessation of Graeme and Max came into my office stimulation (from Burnstock, Campbell, Bennett & Holman (1963). Nature 200, 581-582) to show me the remarkable responses to stimulation, which were rapid Figure 2 (above). Effects of adrenergic neurone-blocking drugs on responses to stimulation of the taenia or of hyperpolarisations and associated -6 the perivascular nerves after atropine. Perivascular nerve taenia preparation. Bretylium (BRET, 5x10 g/ml.) relaxations in response to single abolished mechanical responses to stimulation of the perivascular nerves at 30 pulses/sec (P, at dots), but only reduced responses to stimulation of the taenia with 10 pulses/sec (T, at triangles). Time marker 10 min (from electrical pulses. This was a very Burnstock, Campbell & Rand (1966). J Physiol 182, 504-526) exciting moment – we all felt instinctively that this unexpected result was going to be important.

Later we, and others, showed that tetrodotoxin, which had just been discovered in Japan and which blocked nerve conduction but not muscle responses, abolished these Max Bennett (left) with Graeme Campbell, hyperpolarisations and we realised that about 1983 we were looking at inhibitory junction 8 PN LIVING HISTORY potentials (IJPs) in response to a non­ adrenergic, non-cholinergic (NANC) inhibitory neurotransmitter (Burnstock et al. 1963, 1964). This was followed by a detailed study of the mechanical responses of the taenia coli to stimulation of intramural and sympathetic nerves while I was on sabbatical leave at the School of Pharmacy in London, working together with my friend Mike Rand (Burnstock et al. 1966). Nearly a decade later, after much work, we published a paper that suggested that the NANC transmitter in the taenia coli was ATP (Burnstock et al. 1970).

Geoffrey Burnstock Director, Autonomic Neuroscience Institute, Royal Free & University College Medical School and Professor of Anatomy in the Department of Anatomy & Developmental Biology at University College London

References Burnstock G & Straub RW (1958). A method for studying the effects of ions and drugs on the resting and action potentials in smooth muscle with external electrodes. J Physiol 140, 156-167.

Burnstock G (1958a). The effects of acetylcholine on membrane potential, spike frequency, conduction velocity and excitability in the taenia coli of the guinea-pig. J Physiol 143, 165-182.

Burnstock G (1958b). The action of adrenaline on excitability and membrane potential in the taenia coli of the guinea-pig and the effect of DNP on this action and on the action of acetylcholine. J Physiol 143, 183-194.

Burnstock G, Campbell G, Bennett M & Holman ME (1963). Inhibition of the smooth muscle of the taenia coli. Nature 200, 581­ 582.

Burnstock G, Campbell G, Bennett M & Holman ME (1964). Above Innervation of the guinea-pig taenia coli: are there intrinsic inhibitory Top: Mollie Holman and Geoff Burnstock, 1960 nerves which are distinct from sympathetic nerves? Int J Neuropharmacol 3, 163-166. Above: Edith Bülbring and Geoff Burnstock, about 1985 Burnstock G, Campbell G & Rand MJ (1966). The inhibitory innervation of the taenia of the guinea-pig caecum. J Physiol 182, Right: Geoff Burnstock in 2003 504-526.

Burnstock G, Campbell G, Satchell D & Smythe A (1970). Evidence Below: that adenosine triphosphate or a related nucleotide is the transmitter Left: Geoff Burnstock with Mike Rand, about 1992 substance released by non-adrenergic inhibitory nerves in the gut. Br J Pharmacol 40, 668-688.

Biographical notes about all those featured in the article appear on the next page LIVING HISTORY/FEATURES PN 9

Biographical notes Ralph Straub was a visiting scientist in Training and competition stress: effects on immune Feldberg’s Department at the National Institute of Medical Research in the late function and health 1950s. He returned to Switzerland in the Mike Gleeson continues our series of articles on exercise 1960s to become Professor of physiology in the run up to the Olympics by considering the Pharmacology at the Centre Médical Universitaire, Geneva. He died in April health implications of hard training by endurance athletes 1988 when only 60 years old. these changes has not been established, it has been suggested that the post­ Edith Bülbring was born in 1903 in Bonn. exercise period may provide an ‘open She joined the Department of Pharmacology window’ for infection representing the in Oxford in 1937 and between 1950 and most vulnerable time for athletes in 1990, when she died, established her terms of their susceptibility to infection. laboratory as the leading international laboratory in smooth muscle pharmacology The impairment of immune function and physiology; she had a major influence following a prolonged bout of exercise on many working in this field today. Mike Gleeson is associated with decreased expression of the Toll-like receptors on monocytes Athletes dread the thought of catching a that detect pathogens, decreased killing Mollie Holman was born in 1930 in cold or the ’flu. Infections can interfere capacity of neutrophils and natural Australia. She joined Edith Bülbring’s with training, impair performance and killer cells, decreased cytokine group in Oxford to work on the even prevent an athlete from electrophysiology of smooth muscle, production by type 1 T-helper cells competing. Unfortunately, athletes completing a DPhil in 1957, and then together with the disappearance of returned to Melbourne and was eventually engaged in heavy training programmes, these lymphocytes from the circulation, appointed as Professor of Physiology at particularly those involved in decreased lymphocyte proliferative Monash University. She retired in 1995. endurance events, appear to be more responses to antigens and increased susceptible than normal to infection. apoptosis under the influence of For example, several epidemiological cortisol. The secretion of cortisol Graeme Campbell was born in Australia studies in the 1990s indicated that sore and completed a PhD in Zoology supervised during exercise is stimulated by by Geoff Burnstock in 1965. In 1976 he throats and flu-like symptoms are more muscle-derived interleukin-6 (IL-6). took over the Chair of Zoology in common in endurance athletes than in Studies from Bente Pedersen’s group in Melbourne vacated by Geoff Burnstock on the general population. The immune Copenhagen indicate that the release of his move to UCL Anatomy, but is now system protects the body against IL-6 from contracting muscle can be retired. infection but the functioning of the attenuated by carbohydrate ingestion immune system is affected by stress during exercise and by long-term and there is some evidence that the Max Bennett was born in 1939, completed antioxidant supplementation. This a degree in Engineering in 1963 and increased susceptibility to infection in group has argued that this, however, switched to Zoology, completing a PhD in athletes actually arises from a may be a two-edged sword, as IL-6 has 1967 under the supervision of Geoff depression of immune function. several metabolic effects and shared Burnstock. He was appointed as a Lecturer Although impairment of immune mechanisms exist regarding immune in Physiology at Sydney University in 1969 function sometimes leads to the impairment and training adaptation. and rose to Professor of Physiology in reactivation of a latent virus, the The concern for athletes is that 1983. He is now one of the most active and development of a new infection distinguished neuroscientists in Australia. although these nutritional interventions generally requires exposure to a may reduce their risk of infection, pathogen, and there are many training another effect may be to limit their Mike Rand was born in 1927 in England, and competitive situations in which the hard-earned adaptation to training. but moved with his mother to Australia in athlete’s exposure to pathogens is 1941. He completed his PhD in increased. Pharmacology in Sydney University and then accepted a postdoctoral position in Heavy prolonged exertion is associated Oxford Pharmacology with J H Burn in with increased levels of stress 1957. After a period of 5 years at the School of Pharmacy in London he accepted hormones (e.g. adrenaline and cortisol) the Chair of Pharmacology in Melbourne and cytokines (e.g. interleukins 6 and University in 1965 and after ‘retirement’ 10) which inhibit some aspects of took up an appointment as Adjunct immune function. Several changes Professor at RMIT University, also in during early recovery from exercise Melbourne. He was a marvellous scientist would appear to weaken the potential and had a major international influence; immune response to pathogens and sadly, he died in 2002. Figure 1. Monitoring of saliva immunoglobulin A in although the clinical significance of swimmers can provide an idea of mucosal immunity 10 PN FEATURES

Both heavy exercise and nutrition exert pressures, international travel, selection separate influences on immune pressures, funding pressures and other function; these influences appear to be major life events. Chronic greater when exercise stress and poor psychological stress is also known to nutrition are present together. Exercise depress immune function. The aim of training increases the body's the coach, working with a sport requirement for most nutrients and, in psychologist, should be to anticipate many cases, these increased needs are these additional stressors and, through met by increased food consumption, appropriate evaluation and planning, though for some athletes this may eliminate or minimise as far as possible conflict with their weight restriction their impact upon the athlete. Sleep goals. Athletes can help themselves by disturbance is not uncommon in eating a well balanced diet that includes athletes who are training hard, and it is adequate energy, carbohydrate, protein important to realise that chronic lack of and micronutrients. Ensuring sufficient sleep is itself associated with impaired carbohydrate intake to restore glycogen immunity. Athletes should be stores on a daily basis will minimise encouraged to get adequate sleep and 6 the stress hormone response to training hours sleep per night is probably the and delay the onset of symptoms minimum required by most. Other Figure 2. High levels of air pollution may impair lung associated with overreaching. function in athletes behavioural lifestyle changes, such as good hygiene practice, may limit Hard exercise is associated with an oxidant compounds, such as vitamins C transmission of contagious illnesses by increased level of free radicals because and E, that are involved in the reducing exposure to common sources of the high rate of oxygen consumption. quenching of free radicals. of infection including airborne The superoxide radical is formed Supplementation with vitamins C and E pathogens and physical contact with during the passage of electrons through appears to alleviate the effects of ozone infected individuals. Medical support, the mitochondrial respiratory chain. on exercise performance and, although including regular check ups, Free radicals are also formed in the there is some controversy regarding the appropriate immunisation and blood and tissues by activated effects of anti-oxidant vitamin prophylactics, may be particularly phagocytic white blood cells. Finally, supplements on immune function and important for athletes who are at high the reperfusion of tissues such as the resistance to infections, a handful of risk of succumbing to recurrent gut after exercise may also give rise to studies have reported fewer infectious infection. increased free radical production episodes in athletes supplemented with through the actions of endothelial vitamin C prior to long distance foot Finally, do not take this as a message xanthine oxidase. Some immune cell races. that exercise is bad for you! Of course, functions can be impaired by an excess it is well established that regular of free radicals and so this is another The other big environmental problem in moderate exercise is good for health possible mechanism of exercise­ Athens is, of course, the heat. and is associated with reduced induced immune function depression. Exercising in these hot environmental incidence of both cardiovascular and In Athens, the high level of air temperatures is associated with an metabolic diseases. Even immune pollutants (particularly ozone) is likely increased stress hormone response and function may benefit from regular to exacerbate oxidative stress and may greater perception of effort. The general exercise, provided that you don’t over also impair lung function. This, of consensus is that exhaustive physical do it. A recent study found that the course, affects athletes more than activity and severe environmental stress incidence of respiratory infections was sedentary people because of the high generally have at least an additive 30% lower in people who exercised level of pollutant exposure with high effect on stress responses and moderately for 1-2 hours per day rates of ventilation during exercise (as immunodepression. Limiting initial compared with those with a coach high as 200 litres per minute in very fit exposure when training or competing in potato lifestyle! To have any chance of individuals). Obviously, the longer the adverse environmental conditions, and winning an Olympic medal, though, event, the greater the exposure to acclimating or acclimatising where athletes have to train much longer and ozone, and asthmatic athletes such as appropriate, will reduce the effects of harder than this. Paula Radcliffe will be more environmental extremes on the stress susceptible to airborne pollutants. To hormone response to exercise. This Mike Gleeson protect against the harmful effects of should be beneficial for the School of Sport and Exercise Sciences, Loughborough University, Loughborough, UK oxidative stress, the body contains maintenance of immunocompetence. numerous anti-oxidant compounds (e.g. glutathione) and enzymes (e.g. In addition to physical stress, there is The final article in this series, to be superoxide dismutase), along with the the added psychological stress of published in issue 57 of Physiology ability to absorb several dietary anti- competition, team and commercial News, will look at doping issues. FEATURES PN 11

The marathon run is a benchmark increase. As a result, marathon runners Inside the ‘black box’ endurance test. It was born during the save their relatively small glycogen Henning Wackerhage and first modern Olympic Games in Athens store and rely more on the plentiful fat Philip Atherton explain the in 1896, and subsequently stretched in reserves. steps to today’s 42.195 km or 26.2 molecular adaptations to miles. The jogging and running boom Classical exercise physiologists used a marathon training of the 70s and 80s, and improvements ‘black box’ approach to study the in endurance training, have changed it adaptation to endurance training. Their from something that was seen as a model was: dangerous, over-exhaustive, males-only endurance training → black box → activity to a serious test that anyone can adaptation. do – including the young and old, heart patients and disabled people. Marathon Molecular exercise physiologists now running was also an important stage for seek to open the black box and to female emancipation in sport, starting identify the mechanisms that regulate with unofficial attempts in the 60s up to the well-described adaptive responses the present day record of 2:15 h held by to endurance training. Their aim is to Paula Radcliffe. identify the chain of events, starting with an exercise-related signal such as The high fitness of marathon runners calcium or muscle tension, followed by and other endurance athletes, and the activation of a signal transduction phenomena such as ‘hitting the wall’, pathway and its effect on gene have stimulated a generation of regulation and ending with a known exercise physiologists to study adaptation to exercise. marathon running and endurance training. They focused on the The major breakthrough in this new determinants of marathon running field was made by Eva Chin and co- performance and on the adaptations that workers in 1998. Chin et al. found that are stimulated by endurance training. ‘We are now well on the way to characterising the the immunosuppressant drug An early, major finding was that mechanisms that make athlete’s hearts grow, their cyclosporin A increased the percentage endurance training promoted ‘healthy’ muscle capillaries sprout and their bones and their of fast muscle fibres in rodents. cartilage more resistant to mechanical impact’ – cardiac growth, resulting in the Cyclosporin A is known to inhibit the Henning Wackerhage (above) and Philip Atherton ‘athlete’s heart’. The endurance (below) calcium-activated calcineurin pathway. athlete’s larger heart can increase its pumping of blood to a maximum of 40 This and other findings suggested that litres per minute (compared to about 20 activated calcineurin stimulated the litres in untrained subjects). The higher production of proteins such as capacity for blood transport also means myoglobin and slow troponin that are a higher capacity for oxygen and known to be upregulated by endurance nutrient transport round the body. training. The findings could be summarised as a mechanistic model Skeletal muscles adapt as well: (Fig. 1): endurance training promotes a limited fast-to-slow exchange of motor endurance training → calcium proteins. That is one reason why concentration increase → calcineurin marathon runners are poor sprinters. activation → increased expression of Marathon runners, however, have a proteins known to increase in response very high capacity for producing ATP to endurance training. by oxidative phosphorylation because mitochondrial biogenesis is stimulated Soon after, it became clear that the by endurance exercise. The fuel supply calcineurin pathway was only part of for oxidative phosphorylation also the story. Murgia et al. (2000) showed changes, which enables the runner to that the activated ERK1/2 pathway also better sustain the fuel supply during increased the percentage of slow long duration exercise. As a rule of muscle fibres (Fig. 1). thumb, the concentrations of enzymes that use glycogen decrease, whereas the Other studies showed that the ERK1/2 concentrations of enzymes that pathway is activated by endurance synthesize glycogen and utilize fat exercise and thus both pathways are 12 PN FEATURES likely to co-operatively regulate the adaptive response to endurance exercise.

Much progress has also been made in identifying the mechanisms that regulate the exercise-induced increase in the division of mitochondria, termed mitochondrial biogenesis. Mitochondria are the sites of oxidative phosphorylation. The majority of mitochondrial proteins are encoded in nuclear DNA, but mitochondria have their own 16,600 base pair-long DNA which encodes some of the proteins. This is an evolutionary ‘leftover’ and was the target of the first major human DNA sequencing project. Because of the existence of mitochondrial DNA, the regulation of mitochondrial biogenesis must involve the activation of the expression of genes that are Figure 1. Major signalling events that mediate the adaptation to endurance training encoded in nuclear and mitochondrial DNA.

Scarpulla (2002) has identified so- might be formalised as (Fig. 1): Acknowledgements called nuclear respiratory factors that We should like to thank the Wellcome endurance exercise → ‘energy stress’ were important for the expression of Trust, the University of Dundee and the → AMP kinase activation → mitochondrial genes encoded in the University of Central Lancashire for upregulation of PGC-1 → expression of nuclear DNA. Tiranti et al. (1995) then supporting our research. a) nuclear DNA-encoded mitochondrial identified the mitochondrial genes (including mtTFA) via PGC-1 transcription factor A (mtTFA or 1 and b) mRNA and mitochondrial DNA- Henning Wackerhage TFAM), which is encoded by nuclear encoded mitochondrial genes via Philip J Atherton1,2 DNA but switches on the expression of mtTFA → synthesis of all mitochondrial 1School of Life Sciences, University of Dundee genes encoded in mitochondrial DNA. 2 proteins and mitochondrion assembly Department of Biological Sciences, University of → Central Lancashire A breakthrough was the discovery of (more mitochondria) higher capacity the transcriptional co-factor PGC-1. for ATP synthesis by oxidative Puigserver & Spiegelman (2003) found phosphorylation. References Chin ER, Olson EN, Richardson JA, Yang Q, Humphries C, Shelton that the overexpression of PGC-1 JM, Wu H, Zhu W, Bassel-Duby R & Williams RS (1998). A stimulated mitochondrial biogenesis. The above findings show that calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type. Genes Dev 12, 2499-2509. Interestingly, mice that overexpress molecular exercise physiology has PGC-1 not only have a very high entered its golden era fuelled by Murgia M, Serrano AL, Calabria E, Pallafacchina, G, Lomo T & technological advances such as Schiaffino S (2000). Ras is involved in nerve-activity-dependent mitochondrial content but also express regulation of muscle genes. Nat Cell Biol 2, 142-147. large amounts of other slow fibre antibodies against phosphoproteins and microarray technology. We are now Puigserver P & Spiegelman BM (2003). Peroxisome proliferator- proteins such as myoglobin (their activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): muscles appear red) and slow troponin. well on the way to characterising the transcriptional coactivator and metabolic regulator. Endocr Rev 24, mechanisms that make athlete’s hearts 78-90. Recently Terada et al. (2002) have grow, their muscle capillaries sprout Scarpulla RC (2002). Nuclear activators and coactivators in shown that endurance exercise and the and their bones and their cartilage more mammalian mitochondrial biogenesis. Biochim Biophys Acta 1576, 1- 14. activation of the AMP kinase increased resistant to mechanical impact. In PGC-1 expression. AMP kinase is addition, genotype chips are available Terada S, Goto M, Kato M, Kawanaka K, Shimokawa T & Tabata I (2002). Effects of low-intensity prolonged exercise on PGC-1 mRNA activated by increases in the that allow researchers to link an expression in rat epitrochlearis muscle. Biochem Biophys Res concentration of AMP which is individual’s genotype to performance- Commun 296, 350-354. related characteristics. associated with the ‘energy stress’ Tiranti V, Rossi E, Ruiz-Carrillo A, Rossi G, Rocchi M, DiDonato S, during exercise and with low glycogen, Zuffardi O & Zeviani M (1995). Chromosomal localization of The future will show whether this mitochondrial transcription factor A (TCF6), single-stranded DNA- which results from endurance training. binding protein (SSBP), and endonuclease G (ENDOG), three increase in knowledge can be exploited human housekeeping genes involved in mitochondrial biogenesis. To summarise, the major regulating for guiding marathon runners at all Genomics 25, 559-564. events during mitochondrial biogenesis levels towards better performances. A WEEK IN THE LIFE OF ... PN 13

A week in the Zambian Bush In May 2002, Physiological Society Member Tristan Pocock left the Physiology Department at the University of Bristol, where he was a senior post-doc researching the microcirculation, to spend 2 years as a VSO1 volunteer teaching high school biology in the Zambian bush

A typical week begins with the Monday morning staff briefing. I usually emerge from under my mosquito net at 6.15am, having dozed since being awoken by chickens crowing at 4.00 (everyone in rural Zambia seems to own at least one chicken and they are usually let out well before dawn). The water is turned on at 5.30 in the morning for 30 minutes – if I want a wash, I have to jump in the cold bath for a few minutes and then refill it for washing clothes, plus filling bottles for drinking. Getting up this early was not part of my routine as a PhD student or postdoc! However, it is much easier to get up at such an unearthly hour with the sun streaming Tristan Pocock with pupils from the Mambwe High School, where every day offers something new through the curtains 360 days a year. longer as the morning progresses and feeling that it was not a career for me Being better at getting up than my VSO the temperature rises (in the hot season, in the long term, although I had no housemate, Jenny, I make breakfast for it is 30oC at 7 am and often over 40oC clear idea what to do instead. Having us both (imported porridge oats), unless by 12.40 pm!) Many pupils get up in glimpsed different cultures around the I am ‘Teacher on Duty’, in which case I the middle of lessons and lean against world as a tourist, including South am obliged to go to the dining hall to the wall. It took me a while to realise Africa, I knew I wanted to learn more. taste the ground maize porridge which that this is to stop them from falling When I contacted VSO, they decided I the pupils get for breakfast. I leave the asleep! was made to be a biology teacher! I do house for the 6.45 staff briefing, feel privileged to have received such a invariably arriving 2 minutes late. I am the only biology teacher, but also good education in the UK (honestly!), Other teachers arrive over the course of teach chemistry sometimes. It was a bit and VSO offered me a chance to use the next half an hour. With the staff of a shock having to dig deep into the my knowledge to benefit others, as well suitably up-to-speed (or more likely memory banks for my long-neglected as to live in a different culture for a confused) as to what lies in store for GCSE knowledge of atomic structure! couple of years. Having made the the week, we proceed to assembly. The Most of the higher education level decision, I finished my contract, and best thing about assembly is listening to biology I learnt is pretty irrelevant here. then went, within the space of about a the very talented choir and joining in At the beginning I occasionally had to week, from the lab in Bristol to the with the National Anthem (provided it’s stop myself getting carried away and bush. sung in English, rather than the local ranting on about growth factors when language, Chinyanja). The worst thing teaching blood vessel structure and I first arrived at the school after an is that it delays the start of teaching function. In fact, it is the sometimes- arduous journey from the Zambian (often to the extent that the first lesson derided ‘transferable skills’ from my capital, Lusaka, where I had spent a is lost entirely!). On other days of the time in higher education and research few days acclimatising and learning week lessons start at 7.00 and go that are the most useful here – the about Zambian culture. From Lusaka I through until 12.40. ability to judge the appropriate level of boarded the ‘chicken bus’ (so-called explanation for the audience/class, to because of the ever-present chickens, Before lessons, I take my class register. decide how detailed to make a diagram, and with hundreds of people crammed With 56 pupils in my class this often and so on. into every available space) for the long takes up all 10 minutes of registration. journey to Chipata, my ‘local’ town. Lessons are generally 80 minutes in So how did I end up here? After nearly After that, I endured a further 3 hour length, but seem to get longer and 10 years in research, I had the growing journey to the school along a heavily

1 Voluntary Services Overseas (VSO) is an international development charity, started in 1958 and currently has over 2,000 volunteers working in ‘developing countries’ worldwide. 14 PN A WEEK IN THE LIFE OF ...

dragged out of lessons to draw water, collect firewood, mend the diesel generator (which powers the water pump and supplies lighting in the evening) or for punishment. Punishment usually involves an extended stint cutting the long grass on the school compound. This is useful because the long grass is where the (malarial) mosquitoes breed. Cutting the grass is also an important part of impressing visiting dignitaries from the Education Ministry! Just as back in the UK, whistle-stop tours by the Great and the Good mean a frenzy to get things Classroom lessons generally last for 80 minutes, but seem to get longer as the morning progresses and the looking right, since visiting Big-wigs temperature rises to over 40oC. Pupils often get up in the middle of lessons and lean against the wall - to stop are rarely around long enough to do them from falling asleep! more than look. pot-holed dirt track, perched a privilege many children here cannot Back to the teaching. Due to the large precariously on the back of a truck with afford. My experience as a physiology class sizes, science practicals are a all my worldly possessions and several tutor at Bristol, and of presenting at logistical nightmare. However, I nonchalant locals (with their luggage, national and international scientific decided to take the plunge and teach bags of maize and, inevitably, more meetings, helped me to come to terms groups of 20-25 in the afternoons for chickens). with teaching - just as well, since my practicals. The lab is surprisingly well- only previous experience at this level stocked for an African school – plenty My school, Mambwe High School, is a came from a week of shadowing of glassware and a cupboard full of government-run mixed boarding school teachers in a Gloucestershire secondary chemicals, although most of them with almost 400 pupils, aged between school. Learning the names of over 300 inappropriate for the level of teaching. 14 and 25. The pupils study in classes pupils was infinitely more difficult. All Many of them are the kind of solvents ranging in size from 22 to 60 (!) and sit teaching is conducted in English, but it you still find in UK university biology exams similar to British GCSEs. The is not the first language (there are labs, but which were long ago banned teachers (all Zambian except for Jenny around 70 tribal languages in Zambia). from British schools for being too and I) live on the school compound. Although pupils must pass an English dangerous, like xylene and phenol. The nearest post office, bank and exam at a fairly high level, for many There are no COSHH regulations to supermarket are 87 km away in their lack of English understanding is a worry about, though, and most of the Chipata. Fortunately, the local BOMA major stumbling block to learning. pupils would be happy to dissect (administrative centre), a mere 7 km Another hindrance is pupils being whatever wildlife they can get their down the road, has a few shops (which stock a wide range of biscuits and soap), a market (which sometimes has fresh vegetables) and even a bar (which, until electricity arrived in the District last year, served only warm beer!) There is a mission hospital 3 km away, which has one doctor (when he’s not called away to town) and several nurses, an X-ray machine and an operating theatre. My only experience of treatment there was when I got plastered after breaking my arm playing football.

I settled into teaching quickly – in contrast to my experiences of British schools (and universities!), the pupils are extremely respectful of teachers and were very willing to accept me. Unlike Classes of up to 60 pupils make science practicals a logistic nightmare, but the lab is surprisingly well stocked for in the UK, secondary school teaching is an African school A WEEK IN THE LIFE OF ... PN 15 hands on! Lack of running water and many local communities. The pupils with walking back from a British pub electricity is a hindrance, but not an know far more about the local wildlife after closing time! All in all, a far cry insurmountable one – examples of than I do, and many are keen to work from my life in Bristol, where I had a practicals we do include testing the as guides when they finish school. choice of six pubs within 10 minutes local produce for fats, proteins or walk from home. Weekends away start carbohydrates, or comparing the Typical early evening activities include with hitching to Chipata on the back of features of local flora. badminton or tennis, on a specially a truck – a journey which can take constructed court in front of the house, anything from 1 to 6 hours, depending Morning tea break is a chance to re- followed by a cold bath (shared – but on the state of the pot-holed road, the energize with a cup of Zambian tea one at a time!) to coincide with the recklessness of the driver and the (more like a concentrated sugar water being turned on, again for just 30 degree of overloading. solution with a hint of tea) and a scone. minutes. Dinner is a combination of This probably saved me on a number of tomatoes, onions (plus peppers if we Leaving research, after completing a occasions from collapsing in the heat of can get them), and pasta or rice from Pharmacology degree, a PhD and then the late morning! At 12.40, I return the supermarket in Chipata. Dinner is 4 years as a post-doc, to teach home for further vital rehydration and followed by at least one game of secondary school biology in Zambia lunch (bread buns bought from a local Scrabble (by candlelight if the was perhaps not the most obvious village and sometimes tomato, followed generator is not working), often career move, but I have no regrets. by local bananas, all washed down with interrupted by having to remove a Instead of being cooped up in a dark warm squash). Over lunch I play gigantic insect or turf out noisy frogs. lab looking down a microscope at Scrabble with Jenny. This rapidly These latter might be Xenopus, capillaries fluorescing (or not, on a bad became an addiction, and we recorded although I couldn’t swear to it. I day), I get to stand up in an open over 150 games in one term! occasionally find myself wondering classroom in front of a large crowd of whether they have interesting muscle teenagers explaining how blood moves Apart from the practicals, afternoons fibres, oocytes, or microcirculatory around the body. Like other teachers, I are spent marking, or on extracurricular vessels, or whether I could ship them to have more responsibilities concerned activities, such as coaching the girls’ the UK for experimental purposes. with the well-being of other people and football team or meeting with the Anti- hope that I have made a lasting impact AIDS Club. AIDS is probably the If I’m feeling brave, I might venture up on some of those I have met. If only major health issue facing the population to school in the dark (no outdoor light one of my pupils decides to use here. The proportion of Zambians except moon and stars here) to condoms as a result of my attempts to infected with HIV is around 25%, and supervise evening ‘prep’, or do some explain how the HIV virus is about 1 million Zambian children have marking before the power is switched transmitted, then several people might lost at least one parent to AIDS. Just on off at 9.30 pm. After that, the be spared infection with HIV. Aside the laws of statistics, a significant compound is silent, except for the from teaching, I’m sure I have learned proportion of my pupils must be HIV- (often ear-piercing) sounds of cicadas as much from the people I have met in positive. It is therefore very important and the occasional distant howl of a Zambia as they have from me. Every that this generation of Zambian youth hyena or wild dog. day has offered something new, and I are active in instigating the behaviour have had some amazing adventures. changes necessary to reduce the Weekends are usually spent at the infection rate. Fortunately, Mambwe school, preparing lessons, taking the My experiences in Zambia have High School has an enthusiastic Anti- Anti-AIDS Club on visits, watching the certainly changed my outlook on life. AIDS Club. My involvement, as club school football team play or relaxing. Teaching has been a refreshing change ‘Patron’, is to facilitate discussion and Perhaps the most unusual after-school from the confines of a lab, and I am to organise visits to other schools and activity so far was getting roped in to keen to continue teaching in some villages. The pupils perform drama and judge a pupils’ modelling contest! A capacity when I return to the UK. poetry, sing and dance to raise downside of being on-site is that the Perhaps as a teaching fellow or awareness and educate other people pupils have no qualms about knocking demonstrator in a university about HIV/AIDS. The other Club I on the door at 6 am on a Sunday department, or even as a secondary supervise is the Wildlife Conservation morning to request a book. Lie-ins are a school teacher. Anyway, it has been Club. The school is in a ‘Game rare luxury given the intense heat great fun (if exhausting), and I would Management Area’, so it is important during most of the year. Sometimes on heartily recommend VSO to any young for the pupils to understand that, while Saturday nights I join the ‘drinkers’ on physiologist contemplating a career poaching is a way of life for many the 7 km excursion to the ‘local’ bar. If change from research to teaching. people here, conservation of rare transport can’t be commandeered then species is imperative for maintaining we have to walk back in darkness, Tristan Pocock running the risk of meeting the odd Since this piece was written, Tris Pocock has returned the National Park (South Luangwa) as a to the UK and is now a Teaching Fellow in popular tourist destination. This then hunting hyena en route – probably an Pharmacology and Physiology at Manchester provides income and employment for insignificant risk, though, compared University 16 PN FEATURES

Role of villus microcirculation in intestinal absorption: coupling of epithelial with endothelial transport Capillaries in jejunal villi can absorb glucose at rates several hundred times greater per gram of tissue than in brain or contracting skeletal muscles. These high rates are made possible by delivery of glucose in high concentration from epithelium to capillaries via paracellular diffusion and solvent drag combined with increases of villus capillary blood flow and surface area

investigators have assumed that the lateral membranes immediately below basement membrane and capillary walls the tight junctions. Subsequent offer little resistance to absorbed transport to the abluminal surfaces of solutes, and that the concentration the capillaries is by convection and differences across them are negligible. diffusion through the post-junctional Our recent analysis of glucose intercellular channels. Thus paracellular absorption shows that this assumption transport is the connecting link between is far from correct (Pappenheimer & epithelium and capillaries, and there is Michel, 2003). The capillaries present a strong anatomical and electro­ barrier comparable with that of the physiological evidence that the epithelium, and increases in villus channels are widened during capillary blood flow and surface area Na+-coupled transport of sugars and during absorption are an important part amino acids (Madara & Pappenheimer, of the absorptive mechanism. 1987; Pappenheimer & Volpp, 1992).

John Pappenheimer (top)and Charles Michel A schematic diagram of the transport We have estimated glucose pathways is shown in Fig. 1. Glucose concentrations along the pathway as a Investigations of nutrient absorption enters the epithelial cells with Na+ on function of glucose absorption rates in from the small intestine have focussed the SGLT-1 transporter and leaves by unanaesthetised rats and in normal almost entirely on transport into and facilitated diffusion through the lateral human subjects. Only small out of the epithelial cells. However, the membranes on Glut-2. It is seldom concentration gradients are necessary to transport pathways extend beyond the appreciated that the nucleus, account for diffusion-convection in epithelial absorptive cells to villus mitochondria, and other membranous intercellular channels. However, large capillaries so that, in addition to the organelles occlude most of the cross trans-endothelial concentration apical and lateral epithelial cell sectional area of the epithelial cells gradients are required to account for membranes, transport continues through (Buschmann & Manke, 1981). observed absorption rates of glucose the epithelial basement membrane and Consequently, diffusion into the basal into villus capillary blood. Figure 2 the walls of the villus capillaries into regions of the cell is hindered and the shows our estimates of glucose flowing capillary blood. Previous preferential pathway lies through the concentrations at the epithelial basement membrane immediately outside the capillaries as a function of glucose load and villus blood flow. With normal hyperaemic responses to glucose absorption the concentrations in abluminal fluid required for diffusion into capillary blood are in the range 60 -100 mM; without the normal hyperaemic response, concentrations exceeding 400 mM would be required to sustain observed absorption rates.

In addition to the large concentrations required for transport across villus Figure 1. Diagrammatic representation of pathways for transport of glucose from lumen of small intestine to villus capillaries, there may be significant capillary blood. The pathways are shown as thick arrows passing through apical regions of the epithelial cells into gradients across the lateral membranes the paracellular spaces and into the capillary. To the right of the diagram are listed the estimated glucose of epithelial absorptive cells. concentrations at various points along the pathway during glucose absorption at a moderate rate (40 µ-moles h-1 Calculation of these gradients, using cm-2) under normal conditions in unanaesthetised rats. Note that the fall in concentration across the capillary walls is more than twice that needed for transport between the apical cytosol of the epithelial cells and the abluminal available kinetic parameters of Glut-2 surface of the capillaries. (Kellett, 2001), has led to estimates of FEATURES PN 17

The low rates of absorption found in anaesthetized animals (Ugolev, 1987) may be attributed to inhibition of the normal microcirculatory responses associated with Na+-coupled transport by the epithelium. In anaesthetised animals with low villus blood flows, glucose concentrations outside the capillaries may exceed 150 mM (Fig. 2) and with increased gradients across the lateral membranes (Fig. 3) the intra­ cellular concentrations will rise to 250­ 300 mM. Total osmolarity, including the Na+ brought in with glucose, would then exceed 600 m-Osmolar, a value comparable to that found experi­ Figure 2. Effects of blood flow on glucose concentrations immediately outside villus capillaries at different rates of mentally by Hällback et al. (1991). glucose absorption. Cb is mean glucose concentration at the abluminal surface of the capillaries under conditions where the increase in blood flow is normal (middle curves •), twice as great as normal (lower curves ∆) and only half as great as normal (upper curves, o). Glucose absorption rates are expressed in µ-moles h-1 cm-2 of smooth August Krogh (1922) appears to have luminal surface of small intestine. Panel A shows data for unanaesthetised rats and panel B shows data for been the first to recognize the special conscious human subjects. problems posed by nutrient transport within the villi after absorption by the intracellular glucose concentrations as resistance to glucose transport between epithelium. The hypothesis outlined shown in Fig. 3. From this it is easy to the apical cytosol of the epithelial cells briefly in this essay provides a solution see how failure of blood flow to and the capillary blood during normal to these problems in terms of villus increase during absorption could lead to rates of absorption. Increases in villus capillary permeability, surface area and cellular glucose concentrations that capillary blood flow and permeability­ blood flow on the one hand, coupled compromise the efficiency of SLGT-1 surface area product are thus essential with properties of the epithelium on the upon which all glucose absorption for sustaining high rates of glucose other. depends. absorption. Na+-coupled concentrative transport of sugars and amino acids J R Pappenheimer1 Conclusions must trigger these increases in blood The jejunal epithelium of normal 2 flow and permeability-surface area C C Michel animals can present the villus 1 product; otherwise, concentrations in Department of Biology, Harvard University, capillaries with absorptive loads that Cambridge, MA, USA the sub-junctional fluids and within the are several hundred times greater (per 2 epithelial cells would rise to levels that Division of Biomedical Sciences, Imperial College, gram tissue) than found in capillaries London, SW7 2AZ, UK. would compromise carrier mediated elsewhere, including contracting transport. Signals that trigger the skeletal muscle and brain. Far from References microcirculatory responses remain to be being negligible, the villus capillary Buschman RJ & Manke DJ (1981). Morphometric analysis of the discovered. membranes and organelles of the small intestinal enterocytes. I walls account for 50% or more of the Fasted hamster. J Ultrastruct Res 76, 1-14.

Hallbäck DA, Jodal M, Mannischeff M, & Lundgren O (1991). Tissue osmolality in intestinal villi of four mammals in vivo and in vitro. Acta Physiol Scand 143, 271-277.

Kellett JL (2001). The facilitated component of intestinal glucose absorption. J Physiol 531, 585-595.

Krogh A (1922). The Anatomy and Physiology of Capillaries. pp 244-249. Yale University Press, New Haven.

Madara JL & Pappenheimer JR (1987). The structural basis for physiological regulation of paracellular pathways in intestinal epithelium. J Memb Biol 100, 149-164.

Pappenheimer JR & Michel CC (2003). Role of the villus microcirculation in intestinal absorption of glucose: coupling of epithelial with endothelial transport. J Physiol 553, 561-574.

Pappenheimer JR & Volpp K (1992). Transmucosal impedance of small intestine: correlation with transport of sugars and amino acids. Am J Physiol 263, C480-C493.

Ugolev AM (1987). Membrane transport and hydrolytic enzymes Figure 3. Effects of blood flow on estimated glucose concentrations in the apical cytosol of rat epithelial cells at under physiological vs acute experimental conditions. News in different rates of glucose absorption. The three curves show the relations when the increase in blood flow with Physiol Sci 2, 186-190. absorption rate is normal (•), twice as great as normal (∆) and half as great as normal (o). 18 PN FEATURES

Learning to smell The human olfactory system can ‘learn’ to smell androstenone. Why this should occur is uncertain and, because androstenone can have different smells to different people, it challenges the relationship between odour and receptors. There is perhaps more to this smelling business than meets the nose, says Tim Jacob per trillion and who find the odour age can become sensitized to extremely unpleasant (urinous), and b) benzaldehyde and citralva, something a group who are not only less sensitive that does not happen to men or pre- but perceive the odour in different ways pubertal or post-menopausal women. such as ‘sweet’, ‘musky’, ‘perfume- Another odorant commonly used in like’. The distribution of thresholds for smell research is amyl acetate and it Tim Jacob androstenone, unlike most other does not induce the same sensitivity odorants, is not normally distributed, increase (Dalton et al. 2002). There is a long-standing debate about but heavily skewed toward the high how much, if any, of the olfactory threshold end. Initially, it was thought that the system is hard-wired and therefore proportion of people that couldn’t smell whether the discrimination of certain Androstenone is thought to be formed androstenone had a ‘specific’ anosmia smells is innate or, alternatively, from non-odorous precursors (perhaps and were lacking the gene that coded whether we have to learn to smell. This testosterone and progesterone) by the for the receptor that bound article concerns the phenomenon of action of bacteria that inhabit the androstenone. Examples of supposed induced sensitivity to the steroid axillae (armpits). Since the type of specific anosmias have been reported; androstenone which may give some microflora present will depend on the one person in 10 cannot smell the insights into the process of acquisition immune sensitivity of the individual poisonous gas hydrogen cyanide and of smell discrimination. this is one of the proposed mechanisms about one in 1,000 people are immune for how immunotype is related to an to the smell of skunk (butyl mercaptan). Androstenone is a member of the 16- individual’s unique smell or ‘odortype’. But the idea of specific anosmias has androstene family of steroids, one led people to underestimate the source of which is the testes in pigs. In the 1980s, Charles Wysocki, a smell complexity of odour detection and The steroids gain access to the systemic researcher anosmic to androstenone, discrimination. It is now known that circulation via the spermatic vein. In noticed in the course of an experiment there is not one receptor type for a the salivary gland the steroids are involving the steroid what appeared to given smell but that an odorous stored and concentrated to be released be induced sensitivity. After months of compound will activate a range of into the saliva at moments of intermittent exposure he found that he different receptors. These receptors and aggression or sexual activity. The could detect a distinct odour (Wysocki their respective glomeruli to which they response of the sow is to take up the et al. 1989). He went on to study this project in the olfactory bulb are mating position (‘lordosis’, Fig.1). phenomenon and found that subjects molecular ‘feature’ detectors. An odour Such a rapid response is typical of a initially insensitive to androstenone is recognised because of the unique releaser (or signalling) pheromone could be induced to smell it by pattern of activation of these feature effect. repetitive exposure. Subsequent studies detectors – the odour code. have shown that even those who can Cooks have long known that an smell it can lower their threshold by Recent work on the threshold for unpleasant odour emanates from the this treatment. androstenone has shown that far fewer meat of mature boar when it is cooked. people than previously thought are This is the so-called ‘boar taint’ and This phenomenon of sensitization to an really anosmic to it. When signal one of the compounds responsible is odour is actually quite rare. Mostly detection studies are performed, only 5α-androstenone. repetitive exposure to odours leads to a between 2-6% of people seem to be decrease in responsiveness as the unable to detect androstenone Androstenone also occurs in human olfactory system adapts and/or (Bremner et al. 2003). Detection saliva, urine and sweat. It is found in habituates. Adaptation is a peripheral thresholds are more similar among much higher concentrations in men process and habituation is a central identical twins as compared to than women (Gower & Ruparelia, process, both involving an attenuation dizygotic twins; hence insensitivity to 1993). of the reponse to the repeated stimulus. androstenone appears to have a genetic basis. One might expect it therefore to A proportion of people (∼30%) cannot To date this sensitization phenomenon be stable over time. Early explanations smell androstenone and those who can has only been shown to occur with put forward to explain the androstenone fall into two groups: a) a very sensitive androstenone in humans, and it occurs sensitization process invoked clonal group, who can detect less than 10 parts in both sexes. Women of reproductive expansion of the olfactory receptor FEATURES PN 19 cells containing the receptors for androstenone. An implication of this is that there must be a few cells that respond from which the expansion originates. This is difficult to reconcile with the notion of an odour code that requires the activation of many different receptors per odour. For example, one crucial receptor for the discrimination of androstenone might be missing, leading one to miscode it.

But how, if that receptor is missing, is Reproduced with permission from Wayne Singleton, Purdue University sensitivity induced? The only Figure 1. The pig pheromone androstenone is released into the boar’s saliva at moments of sexual activity and explanation that fits the facts is that causes the sow to adopt the mating position. there is a set of androstenone receptors, We set out to monitor the response of cells express more androstenone but they are expressed at such a low the olfactory system during the receptors? Is just one population of level that their activation does not acquisition of increased androstenone cells stimulated to divide or make more result in perception. This argues against sensitivity by measuring the evoked receptors, or are all cells that detect the existence of specific anosmias, at potentials of the olfactory epithelium androstenone’s molecular features least for androstenone. (EOGs), simultaneously with the event- stimulated to divide? Does this related potentials (OERPs) recorded on phenomenon extend to other steroids The search for specific anosmias was the scalp using EEG electrodes. We or, indeed, other compounds? What begun by John Amoore in an attempt to correlated the results with the detection exactly is the significance of exposure- prove his ‘molecular shape theory’ of thresholds for androstenone. The EOG dependent smell learning? Once olfactory transduction. He believed that represents solely peripheral events, learned, is it reversible? there were primary odours, much like whereas the OERP reflects the activity the visual system, each with its own of both peripheral and central elements Further study of this phenomenon may particularly shaped receptor. Odours of the olfactory system. It is thus answer some of these questions but, for fitted into one or more sites with possible to dissect out the location of the moment, androstenone-sensitization varying affinities and the combination any induced changes. We found that the gives an indication of the kind of of binding gave rise to the multiplicity androstenone-evoked EOG increased processes that might occur in babies as of smells that we can detect. Amoore with increasing sensitivity and the they learn to smell their new world and, thought that the known types of OERP followed the EOG suggesting most importantly, learn the smell of specific anosmias would represent the that this is a peripheral change their own mothers – something they are start of a list of primary odours occurring at the level of the olfactory able to do within 3 days of birth. A (Amoore, 1967). But his definition of receptors (Wang et al. 2004). timescale that, coincidentally, is about specific anosmia was arbitrary, a the same as that taken for androstenone detection threshold greater than two The fact that androstenone sensitivity sensitization. standard deviations from the population can be induced or enhanced by mean. The ‘specific anosmics’ detected exposure tends to militate against the Tim Jacob the odour, but at much higher current wisdom of the involvement of School of Biosciences, Cardiff University, Cardiff, UK concentrations. multiple receptors which ‘analyse’ the References molecular features of androstenone (i.e. Amoore JE (1967). Specific anosmia: a clue to the olfactory code. How this phenomenon of induced the odour code for androstenone), for Nature 214, 1095-1098. sensitivity occurs is unclear. Yee and one would have to postulate a Bremner EA, Mainland JD, KhanRM &Sobel N (2003). The Wysocki (2001) provided evidence of concurrent increase in a number of prevalence of androstenone anosmia. Chem Senses 28, 423-432. the involvement of the olfactory different receptors or receptor cells, and Dalton P, Doolittle N & Breslin PAS (2002). Gender-specific induction of enhanced sensitivity to odors. Nature Neuroscience 5, 199-202. epithelium by repetitively exposing rather suggests that a single receptor mice with olfactory nerve transection to Gower DB & Ruparelia BA (1993). Olfaction in humans with special type or receptor cell is involved. Two reference to odorous 16-androstenes: their occurrence, perception, androstenone and demonstrating plausible alternatives, those of rapid possible social, psychological and sexual impact. J Endocrinol 137, increased sensitivity (compared to pre- adaptation or central inhibition, were 167-187. surgery levels) upon regrowth of the ruled out by our finding that if there is Mainland JD, Bremner EA, Young N, Johnson BN, Khan RM, Bensafi olfactory nerves. However, Mainland et M & Sobel N (2002). One nostril knows what the other learns. no sensitivity then there is no EOG. Nature 419, 802. al. in a recent study (2002) on humans Wang L, Chen L & Jacob, TJC (2004). Evidence for peripheral in which they exposed only one nostril Many questions remain: is there just plasticity in human odour response. J Physiol 554, 236-244. to repetitive stimulation and showed one receptor for androstenone? Are new Wysocki CJ, Dorries KM & Beauchamp GK (1989). Ability to perceive acquisition of sensitivity by the other, androstenone-sensitive olfactory androstenone can be acquired by ostensibly anosmic people. Proc unexposed nostril, suggested that this receptor cells formed by clonal Natl Acad Sci USA 86, 7976-7978. learning occurred in central brain expansion of a small number of pre- Yee KK & Wysocki CJ (2001). Odorant exposure increases olfactory sensitivity: olfactory epithelium is implicated. Physiol Behav 72, 705- regions of the olfactory system. existing receptor cells, or do existing 711. 20 PN FEATURES

Conditions under which systemic lactate may act as a metabolic substrate for the brain

Ask any student what substrate the improvement of cognitive function brain uses as a fuel and the answer will when compared to volunteers who were invariably be glucose. So ingrained is deprived lactate infusion, implying that the concept of glucose as the brain’s lactate can freely pass into the brain only energy substrate that it is the and be oxidatively metabolised. In central dogma of brain energy addition, the counter-regulatory metabolism and can be summarised as responses to systemic hypoglycaemia follows: the brain contains insignificant were substantially diminished. Under energy reserves, and is thus entirely normal physiological conditions the a-v dependent on the blood to deliver a difference of lactate is negative, i.e. the constant, uninterrupted supply of brain produces lactate which then glucose in excess of the brain’s passes into the venous circulation. At demand. Malcolm Prior (left) with Angus Brown physiological pH (pH 7.4) lactate is 99% ionised, and is co-transported with The reasons for this universally pyruvate oxidation. It should be stated H+ ions by monocarboxylate accepted assumption of glucose as the quite clearly at this point that in vitro transporters. The transport is freely sole substrate for the brain include: brain tissue preparations can survive for reversible with equilibrium reached extended periods of time on a host of when: • complex homeostatic mechanisms non-glucose substrates (including the + + have evolved that ensure a stable sugars mannose and fructose, the [lactate]i [H ]o [lactate]brain [H ] blood ––––––– = –––––+ i.e. ––––––––– = ––––––+ concentration of glucose in the blood monocarboxylates lactate and pyruvate, [lactate]o [H ]i [lactate]blood [H ]brain

([glucose]blood) of ~ 6 mM, thus the and the ketone bodies acetoacetate and delivery of glucose to the brain is β-hydroxybutyrate), but in these Under physiological conditions blood + constant; preparations the blood brain barrier pH is 7.4 ([H ] = 40 nM) and brain pH + • non-glucose substrates in the blood (BBB) is circumvented and substrates is 7.2 ([H ] = 63 nM), the [lactate]brain is are converted to glucose by the liver in the perfusate have unlimited access ~2 mM and the [lactate]blood is ~1 mM and kidneys implying glucose is the to tissue. The topic of this review is the (Abi-Saab et al. 2002). Inserting these preferred substrate; viability of lactate in the systemic values into the equation demonstrates • the brain contains neurones which circulation supporting brain function. that the system is not in equilibrium, respond to decreases in [glucose]blood resulting in net efflux of lactate out of and promote compensatory mechanisms Lactate infusion improves the brain. Assuming that all the designed to elevate [glucose]blood; cognitive function during parameters except the [lactate]blood

• the a-v difference in [glucose]blood is systemic hypoglycaemia remain constant, [lactate]blood must always positive, implying that the brain An intriguing possibility that has increase above 3.2 mM in order for net takes up glucose; recently been proposed is that under lactate transport into the brain to occur, • NMR studies have shown that certain pathological conditions systemic i.e. [lactate]blood must reach a critical labelled glucose in the blood ends up as lactate can support brain function in threshold determined by the pH labelled glycolytic and oxidative adults. This concept flies in the face of gradient as well as the lactate gradient intermediaries in the brain; current convention, as it is widely before net lactate influx into the brain • insulin overdose which causes assumed that in adults lactate has occurs. This is illustrated in Fig. 1, systemic hypoglycaemia and results in limited access to the brain due to the where the [lactate]blood required to decreased delivery of glucose to the selective permeability of the BBB. reverse transport of lactate into the brain, results in deficits in brain Using human volunteers, Stephanie brain is plotted against brain pH, with function. Amiel’s group studied the ability of blood pH constant at 7.4, and

exogenously applied lactate delivered [lactate]brain constant at 2 mM. It can be These factors appear to present a cast- to the systemic circulation to support seen that as the brain becomes more iron case for glucose as the sole energy brain function when [glucose]blood had alkaline, the [lactate]blood required to substrate used by the brain. However, been rendered hypoglycaemic by the promote net reverse transport decreases. there are certain circumstances where infusion of insulin (Maran et al. 1994). It has been shown by several groups glucose is not the sole substrate used by In these carefully controlled that hypoglycaemia results in an the brain. In neonatal mammals the experiments when [glucose]blood was alkalisation of the brain, such that brain fatty acids derived from mothers’ milk driven to hypoglycaemic levels (~2.5 pH ~ blood pH (Fig. 2), implying that provide about half of the energy mM: < 4 mM glucose is considered all that is required for net lactate substrate metabolised by the brain, and hypoglycaemic) infusion of lactate, transport into the brain is for adult brain can survive on ketone leading to an eventual [lactate]blood [lactate]blood to exceed [lactate]brain. bodies derived from fatty acids or concentration of 3.5 mM, resulted in an Under hypoglycaemic conditions it is FEATURES PN 21

3.5 mM) is matched by an equivalent The data presented in this article to

increase in [lactate]blood (8 mM - 1 mM support the hypothesis that systemic = 7 mM ~ 3.5 mM glucose)? lactate is transported across the BBB and metabolised by the brain, although Of considerable interest is the fact that convincing, are entirely circumstantial. during exercise-induced hypoglycaemia there is no activation of counter- The extensive magnetic resonance regulatory mechanisms suggesting that facilities at the University of the glucose-sensing neurones in the Nottingham offer an ideal environment Figure 1. The relationship between brain pH and brain are not activated due to the in which to address some of the key [Lactate]blood. At physiological brain pH (7.2) it is increased [lactate]blood. This has been points raised in this article, and calculated that [Lactate]blood must rise to 3.2 mM in order for net transport of lactate into the brain to occur. verified in a separate study in rats experiments are currently underway in However as the brain becomes more alkaline, this subjected to systemic hypoglycaemia which NMR spectroscopic detection of concentration decreases such that at brain pH = 7.4 (Borg et al. 2003). Animals in which metabolites derived from systemically (~ blood pH), [Lactate] must only exceed blood lactate was infused into the injected labelled lactate will determine [Lactate]brain in order for net lactate transport into the brain to occur. ventromedial hypothalamus exhibited a conditions under which systemic lactate reduction of 80 - 85% of the counter- crosses the BBB and is metabolised. regulatory hormonal response, implying likely that the [lactate]brain stays constant or decreases, further lowering that these glucose-sensitive cells sense Angus M Brown1 glucose through glycolysis, as occurs in 2 the [lactate]blood required to drive net Malcolm J W Prior pancreatic β cells. However, in this 1 lactate transport into the brain. Thus the MRC Applied Neuroscience Group, School of study it was argued that the lactate was response of the brain to hypoglycaemia Biomedical Sciences generated within the brain parenchyma, lowers the [lactate] threshold at 2 blood rather than transported across the BBB. The Sir Peter Mansfield Magnetic Resonance Centre, which net movement of lactate into the School of Physics and Astronomy brain occurs. University of Nottingham, Nottingham, UK What is the fate of glucose and lactate once they have entered the brain? It is References Exercise-induced widely agreed that astrocytes, which hypoglycaemia and elevated Abi-Saab WM, Maggs DG, Jones T, Jacob R, Srihari V, Thompson J, comprise 50% of the brain volume, are Kerr D, Leone P, Krystal JH, Spencer DD, During MJ & Sherwin RS plasma lactate mainly glycolytic, taking up glucose (2002). Striking differences in glucose and lactate levels between Experiments under more physiological brain extracellular fluid and plasma in conscious human subjects: and converting it to lactate which is effects of hyperglycemia and hypoglycemia. J Cereb Blood Flow conditions support the hypothesis that subsequently released into the Metab 22, 271-279. systemic lactate can support brain extracellular space. Neurones, on the Borg MA, Tamborlane WV, Shulman GI & Sherwin RS (2003). Local function. During heavy exercise other hand, are clearly oxidative and lactate perfusion of the ventromedial hypothalamus suppresses [glucose] can fall to levels hypoglycemic counterregulation. Diabetes 52, 663-666. blood there is accumulating evidence that considered hypoglycaemic (~2.5 mM), they can take up and oxidatively Felig P, Cherif A, Minagawa A & Wahren J (1982). Hypoglycemia without producing the warning signs of during prolonged exercise in normal men. N Engl J Med 306, 895- metabolise astrocyte-derived lactate. Is 900. systemic hypoglycaemia that a non- it possible that there is cellular exercising individual would display Ide K, Schmalbruch IK, Quistorff B, Horn A & Secher NH (2000). compartmentalisation of the substrates (Felig et al. 1982). This is almost Lactate, glucose and O2 uptake in human brain during recovery from available to the brain during exercise, maximal exercise. J Physiol 522, 159-164. certainly correlated with the fact that and that the systemic glucose is used by [lactate] can increase to 8 mM Maran A, Cranston I, Lomas J, Macdonald I & Amiel SA (1994). blood astrocytes, whereas the muscle-derived Protection by lactate of cerebral function during hypoglycaemia. Lancet 343, 16-20. during extreme exercise. Under these lactate is used to fuel neurones? conditions the a-v difference in lactate reverses as the brain takes up lactate, presumably for oxidative metabolism to fuel brain function (Ide et al. 2000). As is the case with insulin-induced hypoglycaemia the response to exercise (i.e. acidification of the blood) lowers the [lactate]blood threshold at which lactate will enter the brain. These experiments are rather confused by the fact that there is still considerable glucose present in the blood, and it thus appears that the brain survives on a Figure 2. Net lactate transport under normal, hypoglycaemic or exercise conditions. Under normal conditions combination of glucose and lactate. Can there is a net efflux of lactate from the brain, implying that the brain generates lactate from glucose and transports it be a coincidence that the deficit in it into the venous circulation. Under hypoglycaemic conditions the alkalization of the brain reduces the threshold for net transport of lactate into the brain. It should be noted that this is an experimental paradigm in which [glucose] during exercise compared blood exogenous lactate is applied to the systemic circulation. During exercise [lactate]blood rises considerably to baseline levels (6 mM - 2.5 mM = accompanied by an acidification of blood, facilitating net lactate transport into the brain. 22 PN FEATURES

Our shape is elastic, modular and held together by carbohydrate strings Glycan strings tie collagen fibrils into shape-defining modules with intrinsic elasticity based on a springy sugar (Iduronate) and reversible intermolecular ratchets body, all that would remain would be a evolved to take the stresses of mass of slimy epithelium, quivering movement and the maintenance of muscle and frustrated nerve cells' shape’ (Scott, 1975). The fibrils are (Arcadi (1952) quoting his unnamed proteins - collagen and elastin. They are teacher). ropes, resisting and transmitting tensile (pulling) stresses, visible as such from Complete agreement! But these two John Scott the very thin (~10nm) collagen fibrils anonymous commentators are going in in vitreous humour to the huge tendons Bodies are supramolecular opposite directions. There is a third that support large animals. organisations, but we are not molecular way. Connective tissue (CT) (skin, Lego-men. We respond elastically to bones, tendon, cartilage, etc.) is shape. The soluble polymers are carbo- internal and external stresses. This Shape is one of the most important hydrates, anionic glycosaminoglycans enables us to move and to recover from issues in biology. Without a permanent (AGAGs, e.g. chondroitan, keratan and our encounters with the outside world. shape central functions (digestion, dermochondan sulphates). They are Much of this elasticity is proposed to circulation, etc.) could not have attached to proteins, thereby becoming reside in carbohydrate strings that tie us evolved. Ergo, CTs are of supreme proteoglycans (PGs). They resist together. importance. How do they do it? Is there compressive forces because they tend to a core concept? swell in aqueous solutions, as all Two views of connective polymers do in good solvents, thus tissues Nearly 30 years ago I proposed a global increasing their entropy. The many ‘Connective tissue is what you get rid definition, applicable to all CTs (or anionic groups (carboxylates, sulphate of in order to work with cells’ more precisely their extracellular esters) they carry repel each other, (anonymous physiologist). matrices, ECMs) in all species at all expanding the polymers they are stages in development as follows: covalently attached to. Also important 'If by some magic solution one could ‘animal CTs are systems of insoluble is the osmotic pressure of counterions dissolve all the connective tissues of the fibrils and soluble polymers that (Na+, etc.) associated with the GAG

Figure 1. A The shape module. Antiparallel AGAG aggregates (shown as duplexes) link collagen fibrils (in section). (p); proteoglycan protein. B Plan (left) and elevation of twofold helices preferred in solution by shape module AGAGs (chondroitins, keratans) and HA (hyaluronan) in which all glycosidic bonds are equatorial 1-3, 1-4; and hydrophobic patches (stippled) are identically placed, as are the waves and inter-residue H-bonds (dotted lines). Filled circles; N atoms. HA is illustrated. C Side views of tertiary structures of twofold helical AGAGs (see B). Hydrophobic patches (cross-hatched) form hydrophobic bonds and acetamido NH („†) H-bonds to carboxylate (z{) on the adjacent AGAG. Filled symbols are below, and open symbols above, the plane of the diagram. The waves in B complement each other in these antiparallel aggregates. Arrows (left) indicate reducing end (Scott, 2003 for review). Displacement of chain II vis-a-vis chains I and III (see also Fig 1D) is reversible, driven by the energy loss in reforming the broken hydrophobic and H-bonds (from Scott, 2003). D Elastic deformation (reversible slippage) within the shape module AGAG aggregates converts local compression into dissipated tensile strain. Collagen fibrils (verticals) are bridged by antiparallel AGAG chains (zigzags) covalently linked to PG protein (filled circles) which associate with fibrils at specific binding sites. Arrow (top left) indicates a ‘crimp’ within the fibril which takes up some slack under tensile stress. Horizontal lines indicate ECM into which the fibrils are anchored. Left, ‘REST’ shows AGAG chains, fibrils etc. in unstressed ECM.

In the right half; ‘COMPRESSED’, a compressive force (shown as a probe pressing in the direction of the arrow) impacts on the ECM. Tissue H2O is displaced into neighbouring spaces where it forces elongation of the axis of the AGAG aggregates via slippage between the participants, with stretching of the collagen fibril crimp.

Arrow (bottom) indicates reversal of the slippage to the resting state on releasing compressive stress, with return to the original position of the tissue H2O (see text). FEATURES PN 23 anions. The total swelling pressure inflates the fibrillar matrix. This was elegantly proved by precipitating the polyanions with cobalt hexammine or cetylpyridinium. The volume occupied by the precipitated polyanion is much less than that in solution, effectively removing it from the tissue. PG-rich tissues (e.g. cartilage or corneal stroma) then shrink, losing their turgor (Hedbys, 1961) and elasticity.

The anatomy How do the fibrils co-operate with the PGs? They cannot move independently or the shape of a CT would depend on its stressful history and a permanent shape would be impossible. The fibrils must be in a constant orientation. Collagen fibrils in, for example, tendons and corneal stroma, are in beautiful parallel arrays but Figure 2. A L-iduronate (IdoUA) in C1 (left) and 1C (right) conformations. Filled circles are oxygen-containing conventional electron histochemistry groups (OH and COO-). Arrow (top right) indicates the movement of the axial glycosidic bond towards the shows no interfibrillar connections, equatorial position in C1 under tensile forces acting along the polymer axis, thus converting 1C into the C1 although there must be structures which alternative conformation. C1 IdoUA is wider than 1C along the polymer axis (B and C, below) B Space-filling models of left) IdoUA C1, and right) IdoUA 1C, carboxylate at bottom. Red; oxygen, white; hold the fibrils in permanent hydrogen. The dermochondan longitudinal axis runs left ↔ right through the equator of each. 1C is the more orientations. compact on this axis. C Elevation views of stick-and-ball models of 2-fold helical dermochondan homopolymers comprising exclusively:- 4 1 In fact, collagen fibrils are tied together C1 Ido UA (top); C4 IdoUA (bottom). Carboxylate oxygens; red, sulphate ester sulphur; yellow. by PG AGAG bridges. These are in Compact IdoUAs confer shorter chain lengths (bottom) for the same number of sugar units. Under tension these elongate to longer (top) configurations. solution in vivo and consequently L-iduronate ‘springs’ in shape module dermochondan glycans enhance the elastic capacity of the AGAG bridge, invisible. They were discovered when which could stretch without slippage between glycans. (Based on Scott, 2003.) electron-dense reagents (e.g. Cupromeronic Blue) were developed to diameter are precisely well separated, (or be part of) elastic structures. stain AGAGs for electron microscopy and to 350 kDa in the very dilute (Scott, 1985). Cationic Cupromeronic vitreous humour. The bridge-fibril Fibrillar elastic properties are well Blue binds electrostatically to interaction repeats regularly along the described. Elastin elongates reversibly polyanionic AGAGs, precipitating them fibril, i.e. modularly. I therefore termed (up to 200%), driven by hydrophobic while preserving much of the shape, it the ‘shape module’. ECM cells and entropic interactions. It is ‘animal size and orientation of the AGAG. The unable to make the PG protein were rubber’. Collagen fibrils are elastic to a dermochondan sulphate-containing PG unable to form shape modules and the much smaller degree, elongating was called decoran because it decorates ‘ECM’ they produced was totally reversibly by ~10%, probably by the collagen fibrils in a beautiful disordered. rearrangements of collagen molecules regular pattern. Similar PGs containing within the fibrils. keratan sulphate are found in the Shape modules are found in all ECMs. corneal stroma. The PG protein is They are ubiquitous and PG AGAG elasticity is relatively attached non-covalently to the fibrils overwhelmingly dominant structures in uncharted. Polymers entangle and and AGAG chains aggregate head-to- animals as remote as holothurians. disentangle, thus contracting and tail across the interfibrillar gap (Fig. 1). Thus, animal shapes are stabilised by expanding, but there is little organised carbohydrate strings, i.e. the AGAG structure in this process and it is Not only are the PGs bound to collagen chains in interfibrillar bridges. probably not significant in tissue fibrils, thus stopping them from elasticity. wandering under stress, but they bridge The physiology and tie the fibrils together in register. Although CT ECMs provide a robust Two new mechanisms were proposed The lengths of the AGAG chains shape, they must deform reversibly in (Scott, 2003), one depending on the correlate with the interfibrillar response to internal and external spring-like behaviour of a specific separation, being short (e.g. about 15 stresses. 100% return to the original sugar (L-iduronate) in the AGAG chain, kDa in tendon) where fibrils are shape is mandatory, post stress. and the other in which shape module densely packed, rising to 50 kDa in Clearly, 99.9% will not do. Shape AGAG bridges partially disaggregate cornea, where fibrils of constant module components must therefore be under tensile stresses. 24 PN FEATURES

L-iduronate springs molecules were stretched while hydrophobic and H-bonds are broken. The AGAG sugars (D-galactose, observing the relationship between Slippage occurs along the AGAG D-galactosamine, D-glucosamine and lengths and applied force. Conversions bridge axis, in the direction of applied D-glucuronate) except one, from chair to boat forms were tensile stress. On releasing the stress 4 (L-iduronate), are stable C1 pyranose engineered by so-called ‘atomic levers’ slippage reverses as bonds originally conformers (Fig. 2). L-iduronate occurs (Marszalek et al. 1999), axial present are reformed into the optimal 1 4 2 glycosidic bonds which, when pulled, (lowest energy) structure (Fig. 1). in three conformers ( C4, C1 and S0) with almost identical energies (Casu et forced the pyranose ring into a al. 1988). One easily changes to conformation in which the stress is In this scheme compressive forces are another. Nevertheless, NMR shows that transmitted in a straight line along the converted into tensile forces distant from the compression, disseminated the 1C and 2S forms are preferred in polymer chain. It is deducible from the 4 0 work of Marszalek and co-workers that throughout the tissue. The scheme aqueous solutions of dermochondan chondroitan 4 & 6 sulphates, predicts that when slippage exceeds a sulphate, which is characteristic of hyaluronan and keratan sulphates will certain limit the tissue will disintegrate, shape modules. Molecular modelling not stretch under tensile stress since probably irreversibly. Indeed, when showed that 1C and 2S forms are more 4 0 their glycosidic bonds are equatorial corneal stroma swells beyond about compact (‘thinner’) along the AGAG rather than axial, offering no leverage 5-fold, the process becomes 4 chain axis than the C1 form, and a to force conformational changes. Their irreversible. 1 chain of C4 forms could stretch by sugars are fully extended anyway. On 4 1 2 7-10% under tensile stress to the C1 the contrary, the compact C4 and S0 Coda forms. On release the chain would forms of L-iduronate have axial The requirement for elasticity in blood shorten as L-iduronate contracted to the glycosidic links. These atomic levers vessel walls, for example, is well preferred compact forms (Fig. 2). enhance the effect of tensile stress on recognised. The properties of elastic the change between conformers (Fig. proteins (resilins, etc.) have been For the first time this schema provides 2), thus improving intrinsic elasticity. documented throughout animal biology. a mechanical raison d’etre for Heparan sulphate, which is not an ECM However, they are only part of the L-iduronate, which is formed by AGAG, nevertheless should show story. Their partners in shape-defining epimerisation in the polymer of L-iduronate elasticity, relevant to its connective tissue must also be elastic if D-glucuronate. This energy-expensive role in flexible cell membranes. the tissue as a whole is to be elastic. bit of biosynthesis was formerly The spring and dashpot properties of without a rationale. It suggests why the L-iduronate confers small scale carbohydrates are now seen to content of L-iduronate varies greatly in elasticity, but there are requirements for complement elastin, etc. in providing dermochondans from different tissues. larger scale reversible deformabilities. elastic linkages in modular ECM Corneal stroma swells reversibly 5-fold structures, playing a vital role in Flexible tissues such as skin are and the spring mechanism cannot maintaining shape. characterised by large scale accommodate that. An intermolecular epimerisation (> 90%), whereas in rigid mechanism was proposed to deal John E Scott Chemical Morphology, Manchester University, structures such as cartilage conversion elastically with large scale Manchester, UK stops at a much lower (~10%) level. deformations (Scott, 2003). Turgor in cartilages is high, so that References L-iduronate may normally be in the The PG sliding-filament Arcadi JA (1952). Book Review of Connective Tissues (Transactions fully stretched form, perhaps adopting mechanism of shape module of the first conference of the Macy Foundation). Bull Johns Hopkins compact forms under compression. elasticity Hospital 90, 334-335. L-iduronate/D-glucuronate ratios in AGAG bridge structure in the shape Casu B, Petitou M, Provasoli M, & Sinay P (1988). Conformational corneal stroma are higher than in module is based on non-covalent flexibility: a new concept for explaining binding and biological properties of iduronic acid-containing glycosaminoglycans. Trends cartilage, consistent with the idea that interactions. Electron microscopy, Biochem Sci 13, 221-225. cornea requires rigidity to maintain NMR and molecular modelling indicate Hedbys BO (1961). The role of polysaccharides in corneal swelling. shape and hence its optical properties, that the AGAG chains are probably Exp Eye Res 1, 81-91. but also elasticity to respond rapidly layered on top of each other, head-to Marszalek PE, Pang Y-P, Li H, Yazal JE, Oberhauser AF & and reversibly to stresses associated tail, which allows hydrophobic and Fernandez JM (1999). Atomic levers control pyranose ring with blinking and eye movements. H-bonds to form between neighbouring conformations. Proc Natl Acad Sci USA 96, 7894-7898. AGAGs (Fig. 1). This stringent lock- Scott JE (1975). Composition and structure of the pericellular Atomic levers may control and-key complementarity repeats along environment: physiological function and chemical composition of pericellular proteoglycan (an evolutionary view). Phil Trans Roy Soc elasticity in L-iduronate- the polymer chains. In the case of Lond B 271, 235-242. containing AGAGs hyaluronan the H-bonds were shown by Scott JE (1985). Proteoglycan histochemistry - a valuable tool for Direct physical evidence indicates that rheo NMR to break reversibly under connective tissue biochemists. Coll Rel Res 5, 541-598. tensile stress changes sugar shear stress. Thus aggregated AGAGs Scott JE (2003). Elasticity in extracellular matrix ‘shape modules’ of conformations. Using atomic force can be pulled apart in a slippage tendon, cartilage etc. A sliding proteoglycan-filament model. J microscopes, single polysaccharide process, during which the low energy Physiol 553, 335-343. FEATURES PN 25

Elastin and hypertension: is there a link? Recent work has highlighted the association between a defect in elastin synthesis, large artery abnormalities and hypertension development. Studies in spontaneously hypertensive rats also point in the same direction and suggest a link between a defect in elastin organization and resistance artery remodelling

(SVAS) and Williams-Beuren expected. However, we were very syndrome. Often individuals with these surprised to find that elastin also plays diseases are young children who are a critical role in the mechanical susceptible to peripheral vascular properties and structure of resistance disease, myocardial infarctions or arteries, where this protein is very Silvia Arribas (left), Ana Briones (centre) and José stroke (Milewicz et al. 2000). scarce. Small arteries play an essential González role in blood pressure regulation by A recent study of mice heterozygous contributing to total peripheral for the elastin gene (eln+/-) – a murine resistance. In fact, increased peripheral The physiological demands of the model of SVAS – has provided good resistance due to resistance-artery arterial system in vertebrates require evidence for a link between elastin and narrowing – termed ‘inward vascular that arteries store energy during systole hypertension (Faury et al. 2003). In this remodelling’ – is a key determinant for and release it during diastole, enabling study, Faury and co-workers the maintenance and progression of the system to maintain a continuous demonstrate that elastin haplo­ hypertension, and possibly its blood flow. This function is made insufficiency results in abnormalities in development (Mulvany, 2002). possible by vessel elasticity, which large artery mechanical properties depends largely on the presence of which lead to a hypertensive phenotype Our recent data demonstrate a link elastin in the vessel wall. Elastin is from birth. between altered elastin organization in synthesized by smooth muscle cells, mesenteric resistance arteries (MRA) and is secreted as the soluble monomer These data suggest that any factor that from spontaneously hypertensive rats tropoelastin, which is then cross-linked reduces elastin during a critical window (SHR, a model of human essential in the tissue space and associated with of vessel wall formation and alters large hypertension) and vascular remodelling microfibrillar proteins to form insoluble artery compliance could have a (Briones et al. 2003). Fluorescent elastin matrix. In large vessels elastin is modifying effect on the progression of, confocal microscopy enables organized into concentric rings of or susceptibility to, hypertension. As examination of relatively thick intact elastic lamellae around the arterial elastin is the dominant extracellular tissues without the need to cut sections. lumen. Each elastic lamella alternates protein in large arteries, the effects of We have taken advantage of this and of with a ring of smooth muscle, forming elastin defect on these vessels is to be the autofluorescent properties of elastin a lamellar unit that provides the compliance that arteries need to absorb and transmit hemodynamic forces (Parks et al. 1993).

The suggested link between a defect in elastin synthesis during early development and hypertension was proposed some time ago, and is based on the evidence that people with low birth weight tend to have higher blood pressure later in life. One mechanism that might underlie this association is impaired elastin synthesis when growth is retarded during a critical period of blood vessel formation in the fetus, leading to abnormal large artery compliance and finally higher blood pressure (Martin & Greenwald, 1997). Figure 1. The autofluorescent properties of elastin allows for visualization of the distribution of this protein with Hypertension is also present in a fluorescent laser scanning confocal microscopy. Transversal ring of a rat mesenteric resistance artery (MRA) proportion of patients with two clinical showing elastin distribution in external elastic lamina (EEL), internal elastic lamina (IEL) and some isolated fibres in the media (Fig. 1A). Figure 1B shows a confocal projection of the fenestrated IEL as well as some isolated conditions associated with elastin gene fibres through the wall. Below, higher magnification projections showing the differences in elastin distribution in the defects: supravalvular aortic stenosis IEL of a normotensive WKY (C) and a hypertensive SHR (D) rat (after Briones et al. 2003). 26 PN FEATURES

(excitation 488nm, emission 515 nm) to determine the organization and distribution of this protein in intact MRAs from SHR and from the normotensive reference strain, WKY, fixed at physiological pressures. In MRA elastin was restricted to a thin internal elastic lamina, a loose network of elastin fibres in the adventitia (external elastic lamina) and some fibres in the medial layer (Fig. 1). SHR MRAs showed altered internal elastic lamina organization with smaller fenestra when compared to the normotensive strain (Fig. 1).

However, elastin content, estimated from fluorescent intensities, was similar between strains. This altered elastin organization was associated with Figure 2. Lumen diameter-pressure (A,C) and stress-strain curves with β values (B,D) in pressurized mesenteric reduced lumen diameter and with resistance arteries from normotensive WKY and hypertensive SHR rats in the absence (A,B) and in the presence (C,D) of elastase (0.062 mg/ml, 60 min). *p< 0.05 when compared to WKY rats; +p< 0.05 when compared to increased stiffness in adult SHR, as arteries incubated with elastase; 2-way ANOVA. Elastase incubation abolished the structural and mechanical shown by the leftward shift of the differences between strains. β is a parameter directly proportional to Young’s Elastic Modulus and an indicator of stress-strain relationship and larger β arterial stiffness (after Briones et al. 2003). values (Fig. 2). dimensions are still similar between References The importance of elastin organization strains (González et al. 2003). These Briones AM, González JM, Somoza B, Giraldo J, Daly CJ, Vila E, in resistance arteries is emphasized by González MC, McGrath JC & Arribas SM (2003). Role of elastin in data suggest that abnormal elastin spontaneously hypertensive rat small mesenteric artery remodeling. the fact that elastin digestion with organization occurs prior to inward J Physiol 552, 185-195. elastase for 1 h induced a dramatic remodelling, and might contribute to it. Faury G, Pezet M, Knutsen RH, Boyle WA, Heximer SP, McLean SE, increase in lumen size and in β value, Minkes RK, Blumer KJ, Kovacs A, Kelly DP, Li DY, Starcher B & suggesting that elastin has an Mecham RP (2003). Developmental adaptation of the mouse All these data point to the potential cardiovascular system to elastin haploinsufficiency. J Clin Invest 112, unanticipated role in overall small importance of elastin or proteins related 1419-1428. artery dimensions and mechanical to elastic fibre assembly and González JM, Somoza B, Fernández-Alfonso MS, Gálvez B, properties. More interestingly, elastase organization, and the genes that control Abderrahim F, González MC & Arribas SM (2003). Elastin re­ abolished the structural and mechanical organization and vessels stiffness is an early event in the these, as critical issues in understanding development of vascular remodeling in resistance arteries from SHR. differences between hypertensive and vascular remodelling in essential Hypertension 42, 387. normotensive vessels, supporting the hypertension. Martin CN & Greenwald SE (1997). Impaired synthesis of elastin in hypothesis of a link between inward walls of aorta and large conduit arteries during early development as remodelling and a defect in elastin 1 an initiating event in pathogenesis of systemic hypertension. Lancet Silvia M. Arribas 350, 953-955. organization (Fig. 2) (Briones et al. Ana M. Briones2 2003). Milewicz DM, Urbán Z & Boyd C (2000). Genetic disorders of the José M. González1 elastic fibre system. Matrix Biology 19, 471-480. 1 Our recent data demonstrate that this Departamento de Fisiología Mulvany MJ (2002). Small artery remodeling in hypertension. Curr 2 defect occurs between the 2nd and 4th Departamento de Farmacología y Terapéutica Hypertens Rep 4, 49-55. Facultad de Medicina week of life, when SHR rats are in the Parks WC, Pierce RA, Lee KA & Mecham RP (1993). Elastin. Universidad Autónoma de Madrid Advances in Mol Cell Biol 6, 133-182. pre-hypertensive phase and small artery Spain

The Journal of Physiology Brian Robertson (The Journal of Physiology Ivan Soltesz (Irvine, CA, USA) Symposium Editorial Board) Alex Thomson (London, UK) Peter Somogyi (Oxford, UK) Kai Kaila (Helsinki, Finland) A Symposium in honour of the late Vincenzo Crunelli (Cardiff, Wales, UK) Stuart Cobb (Glasgow, Scotland, UK) Eberhard H Buhl will take place on Ole Paulson (Oxford, UK) André Fisahn (Stockholm, Sweden) John O’Keefe (London, UK) Friday, 10 September 2004 at the Roland Jones (Bristol, UK) Hannah Monyer (Heidelberg, Germany) University of Leeds, Leeds, UK. Miles A Whittington (Leeds, UK) Roger D Traub (Brooklyn, NY, USA) Istvan Mody (Los Angeles, CA, USA) Information and registration details Entitled ‘Structure/function correlates Katalyn Halasy (Budapest, Hungary) in neurons and networks’, speakers Gianmaria Maccaferri (Chicago, IL, USA) are available at: will include: Gabor Tamas (Szeged, Hungary) http://www.fbs.leeds.ac.uk/buhl/ FEATURES PN 27

The leaky mitochondrion Mitochondria use proton gradients to make ATP. Sometimes, however, proton ‘leak’ uses the gradient to produce heat instead. Here, Kent Sahlin and co-workers argue that the balance of these two consequences of fuel oxidation might be under physiological control significance of UCP3 as a determinant of UCR and basal metabolic rate is under debate. Concentrations of UCP3 increase in parallel with plasma FA during fasting and high fat diets and it has been suggested that the role of Kent Sahlin (left), Michail Tonkonogi (centre) and Maria Fernstrom UCP3 is to protect mitochondria from an overload of long chain FA (Hoeks et al. 2003). The high UCP3 content in The mitochondrion is the power plant Although the term leak indicates fast-twitch glycolytic muscles, where of the cell, where the energy derived deficiency in system design, UCR may the capacity for FA oxidation is from oxidation of fuels is converted to have, or may be associated with, reduced, supports such a role (Hoeks et ATP, i.e. oxidative phosphorylation. important physiological functions e.g. al. 2003). The process involves pumping of thermogenesis and body weight protons across the mitochondrial regulation, prevention of oxidative There is also evidence that UCP3 membrane and the proton gradient this stress, prevention of mitochondrial functions as a mild uncoupler and as forms drives the synthesis of ATP. damage induced by fatty acids (FA) and such reduces formation of reactive Although the major part of oxygen control of oxidative phosphorylation. oxygen species. Markers located near utilization is used for ATP synthesis the UCP2 and UCP3 gene are strongly The mechanism of UCR in skeletal (coupled respiration), the mitochondrial associated with basal metabolic rate muscle is not known but is currently an membrane is leaky and protons may (Bouchard et al. 1997) and suggest a extensive field of research. Proton leak leak back through the membrane. role of UCR in thermogenesis. Proton leak will increase oxygen may occur through membrane proteins consumption (uncoupled respiration, (e.g. uncoupling proteins, UCP) or by An approximate measure of UCR is the UCR) and the energy will be dissipated non-specific transmembrane flux, oxygen consumption of isolated as heat instead of being trapped as which is dependent on the lipid mitochondria and permeabilized fibres ‘useful energy’, i.e. ATP (Fig. 1). UCR composition of the mitochondrial under non-phosphorylating conditions. has been estimated to about 40% of membrane (Brand et al. 2002). In It has been known for a long time that basal metabolic rate in the rat (Brand et brown adipose tissue proton leak is FA stimulate UCR in isolated al. 1994) and will reduce the efficiency mediated by UCP1 and has a well mitochondria and that the effect varies of oxidative phosphorylation, which is described role in thermogenesis. A between different forms of FA typically measured as the yield of ATP homologous protein (UCP3) has been (Matthias et al. 1999). An intriguing per consumed oxygen (i.e. P/O ratio). found in skeletal muscle but the finding is that endurance training increases the sensitivity of UCR to FA (Tonkonogi et al. 2000). FA-evoked UCR increased two-fold after 6 weeks of training (Fig. 2). Diet-induced thermogenesis is increased in endurance trained subjects in

proportion to their VO2max (Lopez et al. 2000). It is possible that this relates to the increased mitochondrial uncoupling in the presence of FA and that endurance training may prevent obesity during overfeeding.

A well known adaptation to endurance training is an increased mitochondrial biogenesis. This would in itself increase UCR provided proton leak per mitochondrial volume remains constant. However, UCR, measured in the Figure 1. Schematic diagram of mitochondrial inner membrane indicating the mechanisms of coupled and uncoupled respiration. The driving force for proton influx is due to both an electrical and a concentration gradient absence of FA, was reduced after over the membrane. endurance training when related to 28 PN FEATURES mitochondrial volume (Fernstrom et al. 2004). The decrease in UCR was paralleled by reduced levels of mitochondrial UCP3 protein. The training-induced reduction in UCR may be a mechanism to avoid unnecessary waste of energy due to increased mitochondrial volume and may also increase efficiency during exercise. This idea is supported by the observed inverse correlation between mechanical efficiency during cycling and UCP3 protein in human skeletal muscle (Schrauwen & Hesselink, 2003).

UCR may contribute to the hitherto Figure 2. Effect of increased concentrations of long chain fatty acid (oleate) on uncoupled respiration in isolated unexplained excess oxygen mitochondria obtained before and after 6 weeks of endurance training. Measurements were performed with consumption during and after heavy pyruvate/malate in the presence of oligomycin (inhibitor of ATP synthase) and atractyloside (inhibitor of adenine exercise. During prolonged exercise at nucleotide translocase). a constant work rate there is a slow increase of VO2 (oxygen drift) expectations, mitochondria isolated performance during exercise. However, indicating a decreased mechanical from muscle samples taken transition from rest to exercise reduces efficiency. UCR, measured in immediately after prolonged exercise proton leak, and futile proton cycling permeabilized muscle fibres (i.e. after were more resistant to Ca2+-overload (pump and leak) may be a mechanism removal of the muscle cell membrane), than before exercise. Again this may to control oxidative phosphorylation was increased after prolonged exercise not give a correct picture of what is during rapid transitions in energy flux. (Tonkonogi et al. 1998), and the occurring in the working muscle since UCR is thus a parameter under oxygen drift may relate to increased the exercise-induced increase in physiological control and can be both uncoupling. However, UCR measured mitochondrial Ca2+ is likely to upregulated (overfeeding) and in isolated mitochondria (with and disappear during the preparation downregulated (exercise). The leaky without FA) as well as UCP3 protein process. However, the results suggest mitochondrion and the physiological both remained unchanged after that endurance exercise has a protective role of proton leak deserve further prolonged exercise (Fernstrom et al. role and increases Ca-tolerance of attention. 2004). mitochondria. Kent Sahlin1 2 Irrespective of the role of UCP3 in Michail Tonkonogi Measurements of UCR in muscle fibres 2 and in isolated mitochondria have a skeletal muscle, UCR is an important Maria Fernström number of limitations. During the factor in muscle energetics and as such 1Institute of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark preparation of mitochondria, potential important for body weight regulation 2 and work efficiency. The reduced Department of Physiology and Pharmacology, changes in UCR may be reversed due Karolinska Institutet, Stockholm, Sweden and to reversal of the exercise-induced efficiency in oxidative phosphorylation Stockholm University College of Physical Education perturbation of the cellular environment associated with UCR may impair and Sports, Sweden (e.g. acidosis, Ca-overload and hyperthermia). Only the effect of References Lopez P, Ledoux M & Garrel DR (2000). Increased thermogenic structural changes that remain in the Bouchard C, Perusse L, Chagnon YC, Warden C & Ricquier D response to food and fat oxidation in female athletes: relationship (1997). Linkage between markers in the vicinity of the uncoupling with VO(2 max). Am J Physiol Endocrinol Metab 279, E601-607. permeabilized fibres and the isolated protein 2 gene and resting metabolic rate in humans. Hum Mol mitochondria will be observed. In vivo Genet 6, 1887-1889. Matthias A, Jacobsson A, Cannon B & Nedergaard J (1999). The bioenergetics of brown fat mitochondria from UCP1-ablated mice. UCR may therefore be entirely different Brand MD, Chien LF, Ainscow EK, Rolfe DF & Porter RK (1994). Ucp1 is not involved in fatty acid-induced de-energization from that measured in vitro under The causes and functions of mitochondrial proton leak. Biochim ("uncoupling"). J Biol Chem 274, 28150-28160. Biophys Acta 1187, 132-139. standardized conditions. Schrauwen P & Hesselink M (2003). Uncoupling protein 3 and Brand MD, Pamplona R, Portero-Otin M, Requena JR, Roebuck SJ, physical activity: the role of uncoupling protein 3 in energy Buckingham JA, Clapham JC & Cadenas S (2002). Oxidative metabolism revisited. Proc Nutr Soc 62, 635-643. UCR may also relate to intermittent damage and phospholipid fatty acyl composition in skeletal muscle opening of large protein pores in the mitochondria from mice underexpressing or overexpressing Tonkonogi M, Harris B & Sahlin K (1998). Mitochondrial oxidative uncoupling protein 3. Biochem J 368, 597-603. function in human saponin-skinned muscle fibres: effects of mitochondrial membrane (i.e. prolonged exercise. J Physiol 510, 279-286. permeability transition pores; PTP). Fernstrom M, Tonkonogi M & Sahlin K (2004). Effects of acute and chronic endurance exercise on mitochondrial uncoupling in human PTP opening is stimulated by Ca- Tonkonogi M, Krook A, Walsh B & Sahlin K (2000). Endurance skeletal muscle. J Physiol 554, 755-763. training increases stimulation of uncoupling of skeletal muscle overload, oxidative stress and energetic mitochondria in humans by non-esterified fatty acids: an uncoupling- Hoeks J, Hesselink MK, van Bilsen M, Schaart G, van der Vusse GJ, protein-mediated effect? Biochem J 351, 805-810. stress, i.e. conditions prevailing during Saris WH & Schrauwen P (2003). Differential response of UCP3 to high-intensity exercise. Contrary to our medium versus long chain triacylglycerols; manifestation of a functional adaptation. FEBS Lett 555, 631-637. FEATURES PN 29

The contribution of steric and electrostatic factors on distribution of macromolecules in the interstitial space There is more to the space between cells than you might think - it is a crowded (if you’re a macromolecule) and highly charged environment. Helge Wiig and colleagues discuss the possible consequences

interstitial media is less than the total interstitial fluid volume, i.e. a given interstitial solute will distribute itself in the fluid space outside the meshwork or, alternatively, through those spaces of the meshwork that have dimensions larger than that of the solute. This phenomenon of geometrical, or sterical interstitial exclusion was first described by Ogston and Phelps ( 1961) and refers to the fact that two solid structures cannot occupy the same confined volume at the same time, as illustrated in Fig. 1B. The steric exclusion phenomenon is relevant only Helge Wiig (top), Christina Gyenge (centre) and Olav for species with high hydrodynamic Tenstad (above) sizes such as proteins and not for small molecules such as water, small ions and The present article focuses on the nutrients. interstitium, which is the physical and Figure 1. The interstitium and the exclusion biochemical environment of cells. The In addition to the steric exclusion, due phenomenon interstitial space consists of connective to the fact that glycosaminoglycans are A, schematic model of the interstitium. The interstitial and supporting tissues of the body and negatively charged at physiological pH space is located outside the blood and lymphatic is located outside the blood, lymphatic values, electrostatic factors might also vessels as well as parenchymal cells and may vessels and parenchymal cells. A be involved in selectively excluding essentially be divided into two phases: the interstitial fluid and the structural molecules (e.g. neutral collagen schematic of a generic interstitium is other negatively charged and negatively charged hyaluronan and provided in Fig. 1A. Although the macromolecules transported through proteoglycans) of the interstitial or extracellular matrix. composition and structure of this the interstitium (Fig. 1C). Data from There is a net filtration pressure across the capillary physiological space varies from tissue the lung have indicated that fixed resulting in a net fluid filtration into the interstitium. When the tissue is at steady-state an equal amount of to tissue, there are basic characteristics negative charges in the interstitial fluid is removed by the lymphatics back into the and functions that are representative of matrix significantly reduce the space circulation. interstitia of most tissues. Essentially available for anionic lactate B, sterical exclusion. The presence of structural the interstitium can be divided into two dehydrogenase 1 (pI ~ 5.0) as molecules results in macromolecular crowding of the phases: the interstitial fluid and the compared to the cationic lactate interstitial space. Consequently, the fluid space structural molecules of the interstitial or dehydrogenase 5 (pI ~ 7.9) (Taylor & available for other species diffusing through the interstitial media is less than the total interstitial fluid the extracellular matrix. As a Parker, 2003), suggesting a charge volume since two solid structures cannot occupy the generalized description, the interstitial effect on macromolecular probe same confined volume at the same time, a extracellular matrix can be thought of distribution. phenomenon called geometrical or sterical interstitial as a three-dimensional 'meshwork' exclusion. The centre of the spherical molecule (yellow) can only access the area inside the dotted composed of a complex aggregation of The magnitude of the excluded volume line, the available volume Va, and is excluded from the protein fibres and carbohydrate has important consequences in the area outside the dotted line, Ve. polymers. dynamics of transcapillary exchange. C, sterical and charge exclusion. Due to the fact that Due to exclusion, the effective protein glycosaminoglycans are negatively charged at The presence of numerous interstitial concentration in the interstitium is physiological pH values, in addition to sterical factors, macromolecules, particularly electrostatic factors are also involved in selectively much higher than the value that would excluding negatively charged macromolecules that are glycosaminoglycans (hyaluronan and be estimated if it were assumed that all distributed in and transported through the interstitium. proteoglycans) and collagen-based the fluid in the interstitium was Therefore, a negatively charged probe will have a species, results in macromolecular available. As stated in the review by higher apparent radius (light blue) than an uncharged crowding of the interstitial space. one. The case illustrated shows that, when the Aukland and Reed ( 1993), the combined effect of steric and electrostatic factors is

Consequently, the fluid space available physiological importance of the considered Ve is higher than in the case where only for other species diffusing through the exclusion phenomenon is two-fold; its steric factors were accounted for (see Fig. 1B). 30 PN FEATURES increase results in a more rapid emergence of new therapeutic tools like approach to a new steady-state after a monoclonal antibodies, the distribution change in transcapillary fluid flow and of macromolecular probes in tumours is less transfer of interstitial protein to of importance. Therefore, studies of plasma for a given capillary hyper- exclusion phenomena are of filtration. Interstitial exclusion thereby considerable interest in tumours since influences plasma volume regulation. the interstitium is a major barrier to Furthermore, the study of exclusion drug delivery in this tissue (Jain, 1997). phenomena provides information In preliminary studies in rat mammary regarding the organization of structural tumours we have shown a significant elements of the interstitium. Our recent effect of fixed negative charges on in vitro and in vivo experiments interstitial distribution of albumin, an involved testing the electrostatic effect that has to be considered when exclusion hypothesis and, moreover, studying uptake of macromolecular quantifying the magnitude of volume therapeutic agents. exclusion provided by these fixed negative charges in a given interstitium. In conclusion, it thus seems that a greater exclusion of more negative Together the interstitial fluid in skin Figure 2. Fractional excluded volume of cationized proteins is a general phenomenon and muscle accounts for almost 60% of human serum albumin (cHSA) and human serum occurring in normal as well as the total body interstitial fluid volume albumin (HSA) in lateral and medial muscle and pathological tissues. hindlimb and back skin (data from Gyenge et al, (Aukland & Reed, 1993). Therefore 2003). Cationization of albumin significantly affected these organs are of major importance its exclusion volume in skin as well muscle. From Helge Wiig for fluid balance studies, and have been these data we were able to estimate that on average, Christina C Gyenge the focus of our recent studies on the the contribution of fixed negative charges to albumin exclusion from skeletal muscle and skin interstitia is in Olav Tenstad effects of charge on the distribution the range of 25-40%. The number of rats is, n = 9. Division of Physiology, University of Bergen, Norway volume. Albumin is the most abundant Values are given as means ± SE. * P < 0.05 and ** P [email protected] plasma protein, and is an important < 0.01 compared to the corresponding tissue involving determinant of plasma and interstitial uptake of native albumin. References Aukland K & Reed RK. (1993). Interstitial-lymphatic mechanisms in colloid osmotic pressures. The in vivo experiments tested our the control of extracellular fluid volume. Physiol Rev 73, 1-78. hypothesis on albumin exclusion in Gyenge CC, Tenstad O & Wiig H. (2003). In vivo determination of Previous studies have stressed the skin and muscle of normally hydrated steric and electrostatic exclusion of albumin in rat skin and skeletal importance of steric exclusion and rats (Gyenge et al. 2003). A muscle. J Physiol 552, 907-916. shown that albumin is excluded from a prerequisite for this type of study is to Jain RK. (1997). The Eugene M. Landis Award Lecture 1996. large fraction of most interstitia Delivery of molecular and cellular medicine to solid tumors. establish a steady-state tissue tracer Microcirculation 4, 1-23. (Aukland & Reed, 1993). Because of concentration, which was done by its pI of ~5 the albumin molecule has a continuous intravenous infusion of Ogston AG & Phelps CF. (1961). The partition of solutes between buffer solutions and solutions containing hyaluronic acid. Biochem J net negative charge at physiological normal and cationized (net charge close 78, 827-833. pH. Accordingly, this substance is a to neutral) albumin for 5-7 days. highly relevant candidate to use as Taylor AE & Parker JC. (2003). Intersitial exluded volumes: the effect Another requirement is to isolate fluid of charge. J Physiol 553, 333. probe in interstitial exclusion studies. representative of interstitial fluid, and Wiig H, Kolmannskog O, Tenstad O & Bert JL. (2003). Effect of for this purpose we sampled fluid from charge on interstitial distribution of albumin in rat dermis in vitro. J An important step for conducting our wicks implanted in the tissues of Physiol 550, 505-514. studies was the possibility of modifying interest. the net charge of the anionic albumin to more positive values. Once this task As evident from Fig. 2, once again a Affiliate Members was achieved we performed an in vitro net change in the charge of albumin study involving fully swollen rat dermis significantly affected its exclusion See p 35 in this issue for the latest (Wiig et al. 2003). By quantifying the volume in skin as well as muscle. From Affiliate News article on the Annual contribution of negative charges to the these data we were able to estimate Molecular Techniques Workshop at volume exclusion of albumin we found that, on average, the contribution of University College Cork. that a decrease in the net charge of fixed negative charges to albumin albumin results in an increase in the exclusion from skeletal muscle and skin Don’t forget to send in your own interstitial distribution volume of this interstitia is in the range of 25-40%, a contributions for Physiology News to species. Thus, we demonstrated a contribution much higher than Laura Blackburn at: substantial influence of negatively previously believed. charged tissue elements on albumin [email protected] distribution, amounting to about 40% of The findings discussed above may also the albumin exclusion effect. have implications for therapy. With the FEATURES PN 31

What limits jaw movements during vigorous head movements? Tim Miles, Stan Flavel and Mike Nordstrom explain the mechanisms that keep the mandible in a fairly stable posture during exercises like running and jumping, in which the head moves vigorously up and down

pulsatile and alternates with pulses of low-level activation of the jaw-openers (Jaberzadeh et al. 2003).

How, then, is the position of the mandible maintained in the more challenging situation in which the head moves up and down during walking Stan Flavel, Michael Nordstrom and Timothy Miles and running? Figure 1 shows that in a subject who walks briskly (1.4 m.s-1), Ever wondered why your teeth don’t maxilla and/or mandible for cosmetic not only does the head move up and bang together when you run or jump, or reasons. down with every step, but the mandible even when you nod your head moves up and down relative to the rest violently? We all know that this does It has often been postulated that, when of the skull (i.e. the jaws open and not happen, and that it would be very the head is still, the mandible is close with each step). The downward uncomfortable if it did. Recent studies supported in its rest position by a mandibular movements must stretch the have demonstrated that the mechanisms stretch reflex in the jaw-closing jaw-closing muscles; however, there is that maintain mandibular posture under muscles, i.e. the mass of the mandible no burst of activity in the jaw-closer static conditions are different from stretches muscle spindles in these electromyogram (EMG) with each step those that restrain it when the head is muscles, which send signals to the that would indicate that the subsequent moving. brain to excite the motor neurones upward jaw movement was the result of innervating the jaw-closing muscles, a stretch reflex. This is seen clearly The mandible, of course, hangs below pulling the jaw upwards again (see when the EMG signal before and after the skull, hinged at the Woda et al. 2001 for review). A each landing is averaged for hundreds temporomandibular joints and problem with this notion is the fact that of steps (upper panels of Fig. 2). supported against gravity by soft tissues it is extremely difficult to demonstrate including the muscles of the face, the any activity in the jaw-closing muscles Not surprisingly, the head movements jaw-closing muscles and various when the mandible is in its rest are more vigorous when subjects run. ligaments. Consider first how it is position. We have recently shown that The greater impact of landing causes supported when its owner is sitting or there is an extremely low level of the mandible to move more briskly standing quietly with the head upright activity in the jaw-closers at rest, but downwards relative to the skull. This in the so-called rest position or postural that this is not the result of a stretch movement triggers a burst of EMG in position of the mandible. This position reflex. In fact, the muscle activity is the masseter which is evident in both is important in clinical dentistry and maxillofacial surgery because it is reproducible within a millimetre or two, and therefore can be used to establish the normal face height in situations such as the construction of artificial dentures in patients who have no remaining natural teeth. If the dentures are made too high, the teeth will click together when the subject speaks and eventually pain may develop in the masticatory muscles. If the dentures are too low, the face will have an unattractive, collapsed appearance. Surgeons also use the rest position of the mandible as a reference point for establishing the height of the face when Figure 1. Kinematic and jaw muscle EMG records recorded from a subject who was walking and running at various speeds on a level treadmill. The ankle accelerometer was on one leg only and therefore indicates only they are repairing the facial bones every second step. Note that although the jaw moves slightly during walking, the burst of EMG with every step following injury, or repositioning the began only when the subject began to jog at 2.1 m.s-1. Reproduced from The Journal of Physiology. 32 PN FEATURES

evokes reflex muscle excitation which then restrains the downward jaw movement. That is, when the stretch is sufficient to evoke reflex EMG activity, the muscle activation then prevents further downward jaw movement. Stronger stretches evoke more muscle excitation which result in smaller maximal downward jaw movement.

Thus, at rest, the mandible is supported not by reflex activity but by the visco- elasticity of the soft tissues in the masticatory system. This mechanism is sufficient to support the mandible during walking. However, the brisker downward movements of the mandible that occur when one lands on one’s heel during running evoke stretch reflexes in the jaw-closers that actively maintain Figure 2. Averaged kinematic and jaw muscle EMG records recorded from a subject who was running at various the posture of the mandible. Even speeds on a treadmill whose surface was horizontal, inclined downwards and inclined upwards in different trials. during running, the mandible usually The jaw movements and EMG responses were greatest in the downhill running which made the subject land on moves up and down less than a his heels, and least in the uphill running because he landed on his toes. Reproduced from The Journal of Physiology. millimetre, and the teeth do not crash together. This is a unique demonstration of how a stretch reflex the raw data in Fig. 1 and the averaged from the vestibular system, it should operates to maintain posture under data in the lower panels of Fig. 2. This still be present when the teeth are entirely natural conditions. muscle activity then causes the clenched. Landing on the heel (which mandible to move briskly upwards feels pretty uncomfortable, incidentally) Acknowledgment again. When subjects run uphill, they evokes strong reflex activation of the This work was supported by the land on their toes. This gentler landing jaw-closing muscles when the teeth are Australian National Health & Medical results in a slower, smaller movement unclenched. However, clenching the Research Council. of the mandible, which is often teeth abolishes the reflex (Miles et al. insufficient to trigger a reflex response. 2004). Thus we can be confident that Timothy S Miles However, during downhill running, the reflex is not vestibular, and, given Stanley C Flavel they must land on their heels, and the its latency, is a stretch reflex. Michael A Nordstrom larger mandibular movement that Research Centre for Human Movement Control, The results always triggers a reflex response The amplitude of this reflex response University of Adelaide, Adelaide, SA 5005, Australia in the jaw-closers. does not increase linearly with the [email protected] amplitude or velocity of stretch. To eliminate the possibility that the Instead, the amplitude of the EMG References EMG response was the result of a increases during brisker jaw Jaberzadeh S, Brodin P, Flavel SC, O'Dwyer NJ, Nordstrom MA & Miles TS (2003). Pulsatile control of the human masticatory vestibular reflex, our subjects also movements even when the maximum muscles. J Physiol 547, 613-620. hopped down from a step and landed amplitude and/or velocity of Miles TS, Flavel SC & Nordstrom MA (2004). Control of human on one heel, both with their teeth downwards jaw movement decreases or mandibular position during locomotion. J Physiol 554, 216-226. clenched together to prevent their jaws remains constant. This is because the Woda A, Pionchon P. & Palla S (2001). Regulation of mandibular from moving when they landed and downward movement of the mandible postures: mechanisms and clinical implications. Crit Rev Oral Biol without clenching. If the reflex arises stretches the jaw-closing muscles and Med 12, 166-178.

Fino to dinner your mouth may have been as less and the taste of bitter perceived Fino, a very dry, pale sherry drunk like assaulted by all sorts of contaminants, as greater. It helps explain why fino’s a white wine, is staging something of a from toothpase and coffee to exhaust slate-dry, nutty, savoury taste is good resurgence. Gonzalez Byass, the fumes. Roger Linden and his team are with smoked fish and salted nuts, and producers of Tio Pepe, have investigating the effect on the taste can be drunk with ‘difficult’ foods such commissioned Roger Linden, head of buds of the five basic tastes - sweet, as Asian and Indian cuisine. Research the Division of Physiology at King’s salt, bitter, sour and umami (Japanese, continues ... College London, to investigate why the approximately, for ‘rich in flavour’). Extracted from an article by Glyn Tucker drink is so versatile. His preliminary Preliminary results suggest the published in the Cambridge Evening News on 12 study suggests that when you sit down intensity of salt and sour are perceived June, 2004. FEATURES PN 33

Making old muscles young again – a therapeutic role for β2-agonists? β James Ryall and co-workers ask whether 2 anabolic enhancers might help prevent muscle loss in the elderly

handling, contributes to the slowing of Hormone replacement movement. Motor unit remodelling therapy for treating (whereby denervated fast fibres sarcopenia? subsequently become reinnervated by Ageing is associated with a so-called slow motoneurons) can also account for ‘somatopause’, defined as the decrease these changes. These age-related in circulating levels of anabolic changes in skeletal muscle can be hormones, including (but not limited to) attributed to a complex interaction of growth hormone (GH), insulin, insulin- ‘Exercise alone will not many factors that affect neuromuscular like growth factor I (IGF-I) and prevent sarcopenia. Other transmission, muscle architecture, fibre testosterone. These hormonal changes strategies, including composition, excitation-contraction (E- are thought to be responsible, at least in muscle anabolic agents, C) coupling, and metabolism (Plant & part, for the age-related loss of muscle must be considered’. Above, left: James Ryall, Lynch, 2002). mass and strength. Numerous clinical Above, right: David Plant trials on older adults have focused on and Gordon Lynch, left. The goal of any strategy for treating increasing circulating levels of sarcopenia, or any condition where hormones back to adult levels, as a way muscle wasting is indicated, is to to combat sarcopenia. However, recent What is sarcopenia? preserve and, ideally, increase muscle evidence from the US Women’s Health Some of the most serious consequences size and strength (Lynch, 2002a). One Initiative (combined Hormone of ageing are its effects on skeletal way to slow the progression of Replacement Therapy) trial indicated muscle. ‘Sarcopenia’ (derived from the sarcopenia is through regular exercise, that, for postmenopausal women, the Greek words ‘diminishing flesh’) is the particularly training programmes risks for side effects (such as heart term widely used to describe the slow involving resistance exercise or disease) from combined oestrogen and but progressive loss of muscle mass strength training (Singh, 2002). progestin appear to outweigh the with advancing age. Sarcopenia is Although resistance training is clearly benefits. Therefore, at this stage, it characterised by a loss of both muscle the best exercise to improve functional appears that this approach has only quantity and quality that leads to a strength, and there are many health limited therapeutic applicability. In the gradual decline in strength and a benefits associated with this form of absence of successful hormone slowing of movement. The loss of training that can improve quality of life replacement therapies, other muscle strength is so dramatic it can remove an in the elderly, it must be recognised that anabolic agents have been proposed to elderly person’s ability to carry out the exercise alone will not prevent treat sarcopenia. tasks of daily living and rob a person of sarcopenia. Also, there is a general β their functional independence, whilst reluctance to exercise, particularly in Role for 2-adrenoceptor also increasing the risk of sudden falls the elderly, and this further highlights agonists and fractures. As the number and the need for other therapeutic Although traditionally prescribed for proportion of older persons in the approaches. Elite Master’s level alleviating bronchospasm in the β population continues to escalate, athletes who train and compete year in treatment of asthma, 2-adrenoceptor sarcopenia will have a dramatic impact and year out for a large portion of their agonists (β2-agonists, such as the most on the quality of lives, and place ever- lifespan, simply do not perform at the widely described, clenbuterol), when increasing demands on public health same level when old that they did when given systemically at higher doses, systems. they were younger. Clearly, there are have potent anabolic effects on skeletal

other factors that contribute to the muscle. β2-agonists cause muscle The loss of muscle mass and strength is preservation of muscle quantity and hypertrophy via a cyclic AMP- thought to be due to the progressive quality. dependent mechanism that results in an atrophy and loss of muscle fibres increase in protein synthesis and a associated with a loss of motor units, Other approaches that are decrease in protein degradation (Fig. 1). and a reduction in muscle ‘quality’ due complementary to exercise also need to This hypertrophic effect, combined to the infiltration of fat and other non- be considered. Given the magnitude of with a known lipolytic action, has contractile material such as connective the growing public health problem proved desirable for those working in tissue. In some instances, there is a related to sarcopenia, there is enormous the livestock industry trying to improve preferential loss of fast muscle fibres, interest in the development and meat quality and yield. Unsurprisingly, leaving muscles with a greater evaluation of therapeutic strategies for β2-agonists have also been used/abused proportion of slow fibres which, along preventing or ultimately reversing age- by those engaged in competitive with alterations in intracellular calcium related muscle wasting and weakness. bodybuilding and soon after by other 34 PN FEATURES athletes competing in strength- and power-related sports.

As a therapy for treating muscle wasting and weakness β2-agonist administration has produced promising, although not entirely conclusive, results in many animal-based studies and some studies involving human patients (for review, see Lynch 2002b). When given to both young and old rats, the clenbuterol-induced increase in muscle mass was equivalent regardless of age, supporting the hypothesis that β2- agonists could be an effective intervention for countering sarcopenia (Carter et al. 1991). However, treating aged rats with a micromolar dose of clenbuterol, comparable to that used to treat asthma, did not prevent the age- Figure 1. β2-adrenoceptor signalling pathway responsible for skeletal muscle hypertrophy after β2-agonist related loss of muscle mass and stimulation. Binding of the β2-agonist to the adrenoceptor stimulates production of cyclic AMP by adenylate strength (Chen & Alway, 2000). A cyclase. This, in turn, activates protein kinase A leading to muscle hypertrophy via mechanisms controlling both more powerful β2-agonist, and/or at a protein synthesis and protein degradation higher dose, may therefore be necessary for treating sarcopenia effectively. attenuate (in part) the characteristic sarcopenia, one must prevent or reduce slowing of contraction in aged these detrimental effects on tissues We have recently shown that, at an mammals. other than skeletal muscle, and the equimolar dose to clenbuterol, another challenge is to devise treatments that β2-agonist, fenoterol, has a 10-15% Too good to be true? utilise different β2-agonists that are β greater anabolic effect on rat fast-twitch Despite the positive attributes of 2- capable of eliciting skeletal muscle (EDL) and slow-twitch (soleus) agonists for treating sarcopenia, they hypertrophy at extremely low doses, muscles (Ryall et al. 2002). In a have several deleterious side-effects, and following only a short treatment follow-up study we found that after just especially when administered in high duration. β 4 weeks of daily administration, doses. Given that 2-agonists act via fenoterol completely ameliorated the the β2-adrenoceptor, and there exists a Recently, new generation β2-agonists age-related loss of muscle mass and population of β2-adrenoceptors in the have been approved by the Food and strength in aged (28 month old) rats. heart, it is difficult (perhaps impossible) Drug Authority (FDA) for the treatment The fenoterol-induced increase in mass to separate the hypertrophic effect on of asthma. These β2-agonists, and strength was attributed to skeletal muscle from that on the heart. specifically salmeterol and formoterol, hypertrophy of existing fibres and not Cardiac hypertrophy has been observed have been developed specifically to to an increase in fibre number. To our in nearly all studies that have examined have an increased duration of action for knowledge, this was the first study to the effects of β2-agonist administration the treatment of asthma, and a greater demonstrate complete restoration of on skeletal muscle. Most of these β2-adrenoceptor selectivity (the both muscle mass and strength to studies have employed high doses in predominant skeletal muscle subtype) β (adult) control levels following 2- order to produce skeletal muscle compared with existing β2-agonists. agonist administration (Ryall et al. hypertrophy and therefore, not These new β2-agonists have the 2004). surprisingly, they have also resulted in potential to elicit skeletal muscle significant (and potentially deleterious) hypertrophy at very low (micromolar) One advantage of treating sarcopenia increases in heart size and, in some doses, due to their extended duration of β using 2-agonists rather than other cases, fibrosis. This has so far limited action, whilst at the same time β anabolic agents relates to the ability of the clinical potential of 2-agonists for minimising any unwanted side-effects, β some 2-agonists to cause a shift in sarcopenia, and also for other muscle due to the greater level of selectivity. muscle fibre type proportions, typically wasting disorders (such as muscular Their efficacy and safety for application from slow- to fast-twitch. Thus, dystrophy and sepsis). It is also to muscle wasting disorders remains powerful β2-agonists, such as fenoterol, important to note that many athletes are untested. are able to not only prevent, or reverse, not aware of these potentially the loss of muscle mass and strength, deleterious effects of chronic high-dose To sum up, there is a considerable need but might also help retain a higher β2-agonist administration. For for therapies that can slow the effects of proportion of fast-twitch fibres that will developing an effective therapy for aging on muscle function. Strategies FEATURES/AFFILIATE NEWS PN 35 are needed to restore muscle size and strength in the frail elderly so that Affiliate News quality of life can be maintained or Patricia de Winter unravels the mysteries of molecular improved. Physical activity must biology at the Annual Molecular Techniques Workshop in continue to play an important role in all Cork these therapeutic approaches; however, it must be realised that exercise alone will not prevent sarcopenia. For the uninitiated in the mysteries of confidence they needed to try using the molecular biology, attempts to techniques in their own labs, even in Consideration must therefore be given comprehend a paper that includes the labs where these techniques are not to other strategies including muscle use of such techniques can lead to the used routinely; and that the course feeling that the authors are speaking a provided them with a good grounding anabolic agents. Although β2−agonists show considerable potential as an completely different language to which in molecular techniques. Some people intervention for sarcopenia, much the reader is not privy. I was one of stated that they can access and research is needed to test their efficacy these poor unfortunates until I was critically assess literature which was and safety, especially the need to lucky enough to be accepted onto the previously unintelligible and that th separate skeletal muscle and cardiac 7 Annual Molecular Techniques attending the course broadened their effects. These issues need to be Workshop held at University College, research base. In some cases the focus addressed before they can be Cork. Recently the workshop of their research is now more recommended for clinical application. organiser, Patrick Harrison, sent out a molecular biology-orientated. feedback form to those who had Certainly, respondents felt that the Acknowledgements attended the workshop in 2002 and knowledge they had obtained would Supported by research grants from the 2003, with a view to obtaining longer- continue to serve them well in the Muscular Dystrophy Association term information on how the course future. (USA), Pfizer Pharmaceuticals (USA), has affected the subsequent research of and the Rebecca L Cooper Medical its attendees. Most physiologists who To end on a personal note, I attended Research Foundation (Australia). JGR attend are Affiliates rather than the workshop in 2003, during the latter is supported by a Postgraduate Members so this information is useful half of my PhD and, although I have as Biomedical Scholarship from the because it provides some evidence of yet been unable to employ any of the National Heart Foundation (Australia). the course’s effectiveness in training techniques I learnt, I do hope to be young physiologists for future practice. able to do so when I return to the James G Ryall world of work this autumn. For me, David R Plant A short feedback form (four questions) the boost in confidence was extremely Gordon S Lynch was sent to 31 course participants in important. Not only do I feel that I Department of Physiology, The University of early May 2004. Thirty forms will be able to tackle RNA/DNA Melbourne, Victoria 3010, Australia successfully reached their destinations isolation, restriction enzyme digests, and 18 (60%) were returned PCR, transfection etc. without my References completed. Nine respondents are former feeling of trepidation, but I no Carter WJ, Dang AQ, Faas FH & Lynch ME (1991). Effects of currently in post-doc/research associate longer look at articles containing clenbuterol on skeletal muscle mass, body composition, and recovery from surgical stress in senescent rats. Metab Clin Exp 40, positions, six are at various stages of strings of ATGC and phrases such as 855-860. their PhD and two are in permanent ‘we cloned a cDNA’ in utter horror. academic positions. Fourteen people Chen KD & Alway SE (2000). A physiological level of clenbuterol does not prevent atrophy or loss of force in skeletal muscle of old (47% of respondents) are currently Finally, I would like to add that the rats. J Appl Physiol 89, 606-612. using techniques learnt on the course, workshop was extremely well- Lynch GS (2002a). Novel therapies for sarcopenia: ameliorating age- and the others, predominantly PhD organised and evidently founded on an related changes in skeletal muscle. Expert Opin Ther Pat 12, 11-27. students, have not yet done so but will excellent knowledge of the subject. seek, or have obtained, a post-doc Lynch GS (2002b) Beta-2 Agonists. In Performance-Enhancing Some weeks after the course, Patrick Substances in Sport and Exercise, ed. Bahrke M & Yesalis C, pp 47- position that will involve the use of Harrison sent us all a superb written 64. Human Kinetics, Champaign Illinois. molecular techniques. Five report that he had compiled. It detailed Plant DR & Lynch GS (2002). Excitation-contraction coupling and participants have published at least one all our results with a rationale for the sarcoplasmic reticulum function in mechanically skinned fibres from paper or have papers in procedures and clear explanations of fast skeletal muscles of aged mice. J Physiol 543, 169-176. press/preparation that involve what we had expected to find. I am Ryall JG, Gregorevic P, Plant DR, Sillence MN & Lynch GS (2002). techniques learnt on the course. certain that none of us can thank him β2-agonist fenoterol has greater effects on contractile function of rat skeletal muscles than clenbuterol. Am J Physiol 283, R1386-1394. and the other course staff enough for Finally, participants were asked how their dedication, patience and Ryall JG, Plant DR, Gregorevic P, Sillence MN & Lynch GS (2004). their attendance on the course has willingness to impart their expertise. β2-Agonist administration reverses muscle wasting and improves muscle function in aged rats. J Physiol 555, 175-188. changed their research. Responses to this question were varied, but some Singh MA (2002). Exercise comes of age: rationale and Patricia de Winter recommendations for a geriatric exercise prescription. J Gerontol 57, major themes were predominant: most Birkbeck, University of London M262-M282. people stated that they have gained the 36 PN FEATURES

Maternal stress in pregnancy may affect the cardiovascular system of the child Prenatal stress of the mother has been shown to have long term effects on the cardiovascular reactivity of the child. When pregnant rats were mildly stressed in the last week of pregnancy, their adult offspring had increased systolic blood pressure responses to mild stress. Natalya Igosheva and Vivette Glover explain

after prenatal stress, by cross-fostering region of the brain (Matthews, 2002). all the offspring to new unstressed The link between antenatal maternal mothers (Schneider et al. 1999). anxiety and child behavioural problems has recently also been shown in In both rats and monkeys the humans. The children of mothers who underlying mechanisms are starting to were particularly anxious while be understood. It has been shown that pregnant (in the top 15%) were found Natalya Igosheva the exposure to prenatal stress re- to be at double the risk for later programmes the main stress response behavioural problems such as attention Our recent work (Igosheva et al. 2004) system of the offspring. The function deficit/hyperactivity (O'Connor et al. suggests that if the mother is stressed of the hypothalamic-pituitary-adrenal 2002) while she is pregnant this may axis, which makes the stress hormone permanently alter the cardiovascular cortisol, is permanently altered, and this Our recent research (Igosheva et al. reactivity of her child. This is probably is associated with changes in the 2004) suggests that these two areas of due to fetal programming. neurochemistry of the hippocampal study, prenatal stress and cardiovascular

This concept has become well known through the work of David Barker (Barker, 1995). He and his colleagues have shown that being small at birth is a risk factor for later cardiovascular disease and associated illnesses such as diabetes. Barker has proposed ‘the fetal origins of adult disease hypothesis’. This states that the physiological, neuroendocrine or metabolic adaptations that enable the fetus to adapt to changes in early life environment result in a permanent programming (or re-programming) of the developmental pattern of proliferation and differentiation events within key tissue and organ systems and have pathological consequences in later life. Barker and his group have mainly looked at the nutrition of the fetus to explaining the possible mechanisms underlying these findings.

A second field of work, originally in animal models, has shown that if the mother is stressed while she is pregnant this alters the later behaviour of her offspring. In particular, the offspring show an increased stress response when Figure 1. Changes in systolic arterial pressure (SAP) during 30 min period of restraint and for 30 min following exposed to a new stressor (Weinstock, return to the home cage in control and prenatally stressed female and male rats. Prenatally stressed (PS) rats 2001). showed an increased peak of SAP responses following the restraint stress and an extended duration of SAP responses during both acute stress and recovery. There were sex-related differences in SAP responses upon In animal studies it is possible to return to the home cage with PS females showing a higher SAP increase than PS males. Data are expressed as percentage changes from baseline values to the response for both stress and recovery periods. Control control for possible confounders, such offspring,ß, n = 7; PS, prenatally stressed offspring,ƒ, n = 7. Values are given as means – SEM. ∗ − P < 0.01 vs. as alterations in parenting behaviour basal values; • – P < 0.05; o – P < 0.01 vs. prenatally stressed group. Adapted from Igosheva et al. (2004) FEATURES/INTERNATIONAL NEWS PN 37 function, may be more linked than were more pronounced in the females Acknowledgments previously realised. In this study, than in the males. The research was supported by grants pregnant rats were mildly stressed from the Royal Society, CRDF and the during the final week of their Thus it seems that prenatal stress may Ministry of Education of the Russian pregnancy, by exposing them to light also have a permanent effect on the Federation. and restraint. A control group were cardiovascular system. As prenatal studied in parallel with no such prenatal stress can also cause smaller babies, it References stress. All the newborn pups were then is one possible mechanism underlying Barker DJ (1995). Fetal origins of coronary heart disease. BMJ 311, cross-fostered to new mothers and all the Barker findings. Such a pattern of 171-174. these offspring were studied when they haemodynamic responses to stress Igosheva N, Klimova O, Anishchenko T & Glover V (2004). Prenatal would have significant consequences stress alters cardiovascular responses in adult rats. J Physiol 557, were 6 months old. The basal 273-285. characteristics of all the offspring were for adult cardiovascular health if it also the same. However, when subjected to occurs in humans. Much more research Matthews SG (2002). Early programming of the hypothalamo- pituitary-adrenal axis. Trends Endocrinol Metab 13, 373-380. a new mild stress, those animals whose will clearly be needed to establish this. mothers had been exposed to stress However, it may be that a new way to O'Connor TG, Heron J & Glover V (2002). Antenatal anxiety predicts child behavioral/emotional problems independently of postnatal during pregnancy showed a much larger prevent the development of depression. J Am Acad Child Adolesc Psychiatry 41, 1470-1477. increase in systolic blood pressure than predisposition to a range of health Schneider M L, Roughton EC, Koehler AJ & Lubach GR (1999). did the controls (Fig. 1). Their blood problems will be to ensure that Growth and development following prenatal stress exposure in pressure also took longer to recover pregnant mothers have as stress free a primates: an examination of ontogenetic vulnerability. Child Dev 70, 263-274. back to normal. Prenatally stressed rats time as possible. also showed a greater increase in blood Weinstock M (2001). Alterations induced by gestational stress in brain morphology and behaviour of the offspring. Prog Neurobiol 65, pressure variability compared with Natalya Igosheva 427-451. control animals during exposure to Vivette Glover restraint stress, more prolonged heart Institute of Reproductive and Developmental Biology rate responses to acute stress and Imperial College London delayed recovery. Most of these effects London, UK

Physiology in Belarus The 50th anniversary of the Institute of Physiology of the National Academy of Sciences

Over the last few years I have visited hyperthermia and fever, physiology of Belarus and the Institute of Physiology the autonomic nervous system and of the National Academy of Sciences physiological mechanisms of of Belarus on several occasions. At the adaptation to environmental factors. end of the last year the Institute (which has been headed since 1984 by Valeri Currently the Institute of Physiology is Gourine – a member of the the leading scientific institution that Physiological Society and a personal coordinates physiological research in friend) celebrated its 50th anniversary. the Republic of Belarus. The staff of Valeri Gourine, Director of the Institute of Physiology the Institute consists of 72 full-time The Institute was founded on 7 of the Byelorussian Academy of Sciences researchers working in seven September, 1953 on the base of the laboratories and three working groups. Institute of Theoretical Medicine of the The major directions of research in the There is a postgraduate course and a Byelorussian Academy of Sciences. 1980s and 1990s were general council for defence of dissertations in Since the late 1950s the Institute had activities of the nervous centres which physiology and related disciplines. The been engaged in studies of the regulate the functions of internal research conducted at the Institute structural and functional organization organs, mechanisms of body conforms to modern trends in of autonomic ganglia, the role of temperature regulation, compensatory physiological sciences and to priority afferent pathways in local and systemic and recovery processes in tissues under directions of basic medical studies. reflexes, neurohumoral mechanisms of the influence of physiologically active vestibulo-visceral reflexes, causes of substances, and neural and humoral I hope all members of the disturbances of those processes of mechanisms of function regulation Physiological Society will join me in nerve myelination that lead to multiple under stress. At present the major sending our congratulations to all at the sclerosis, and the effects of ionising directions of research at the Institute Institute and wish them good luck in radiation on biochemical processes. In are central and peripheral mechanisms the next 50 years of their development the 1960s the Institute transformed into of thermoregulation, the control of an international scientific centre. body functions during hypo- and Bill Winlow 38 PN INTERNATIONAL NEWS

Cardiovascular Physiology Warsaw International Workshop for Young Physiologists through the eyes of the organisers... The 6th International Society Workshop for young physiologists dedicated to cardiovascular physiology was held in Warsaw from 13-16 May, 2004. The Workshop was organised by Andrzej Beresewicz, David Eisner, Gerrit Isenberg, Alex Verkhratsky and Susan Wray, and held at the Medical Institute for Postgraduate Education. As usual, the Workshop programme included lectures in the morning and laboratory sessions in the afternoon. Young researchers discuss their projects (above) and Gerrit Isenberg enjoys a compulsory ride at the Farewell The Workshop commenced with a Picnic (below) reception in the ‘House of Science’ where participants were welcomed by lectures covered various aspects of and the winners were given the International Secretary David Eisner cardiovascular physiology and opportunity to deliver 10 min oral and Andrzej Beresewicz. Altogether 42 pathophysiology. presentations at the beginning of the young scientists were selected from last session. In addition, the winners more than 80 applications; the selection The lectures were followed with were presented with Physiological was based on abstracts submitted. practical demonstrations which worked Society certificates and a small cash amazingly well, and no ’visitor effect‘ award. The poster winners were The participants came from 13 different was encountered. In parallel, speakers Alexander Bondarenko (Bogomoletz countries (registrants in brackets): ran ‘meet the expert’ sessions, which Institute of Physiology, Kiev, Ukraine), Poland (14); Ukraine (12), Slovak allowed for close interactions with Ole-Jakob How (University of Tromso, Republic (8), Czech Republic (6), students. Young researchers discussed Norway) and Thomas Simunek Russia (4), Hungary (2) Norway (1), their own projects as well as various (Charles University, Prague, Czech Estonia (1) Belorussia (1) Turkey (1), theoretical and practical questions. Republic). Israel (1) Romania (1) and the UK (1). These sessions worked very well, Students were exposed to a series of although they required a substantial On the second evening the whole lectures presented by Mark Boyett effort from both sides. On the second crowd was driven to the outskirts of (Leeds, UK), Bohdan Lewartovski day the parallel afternoon sessions were Warsaw where everybody was (Warsaw, Poland), David Eisner focused on research ethics, fraud and subjected to a compulsory ride (see (Manchester, UK), Alex Verkhratsky publication. Although not a ‘how to photo) on rather domesticated and (Manchester, UK), Susan Wray commit fraud’ session, it had the full forgiving horses. This was followed (Liverpool, UK) Maria Fiora Wendt- attention of all the students! with a session of archery and a gallitelli (Halle, Germany), Barbara magnificent rustic dinner which was Casadei (Oxford, UK), Gerrit Isenberg Each registered student presented a crowned with a roasted wild boar. (Halle, Germany), Gerd Hassenfuss poster, and the poster session was very Dances and informal communications (Goettingen, Germany) and Andzej lively. The three best posters were followed, yet the local organisers once Beresewicz (Warsaw, Poland). These chosen by a small evaluation committee more proved very careful indeed and at precisely 23.30 the bus delivered happy participants to their abodes.

Overall the meeting was an undeniable success, as corroborated by all the positive feedback from participants. (A student account, written by Natalie Middleton who represented Britain, follows). For this success the Society and all participants and lecturers are very much indebted to the absolutely flawless organization provided by Andrzej Beresewicz and his wonderful team of Warsaw colleagues. INTERNATIONAL NEWS PN 39

The full programme of the workshop is areas that were addressed varied from recording of single myocyte shortening available at: David Eisner’s engaging talk on aspects to investigating the Langendorff- http://www.physoc.org/international/warsaw of cardiac excitation-contraction perfused guinea-pig heart. Although 2004/programme coupling, to the concluding lecture on these demonstrations were beyond the where an extended collection of photos ‘Signal transduction mechanism of scope of my own research, they were can also be viewed in due course. ischemic preconditioning’ presented by fascinating to watch, and were the Workshop organiser – Andrzej accompanied by clear explanations Andrzej Beresewicz, David Beresewicz. which reinforced my physiological Eisner, Gerrit Isenberg, Alex knowledge. I am sure these sessions Verkhratsky, Susan Wray As a PhD student in exercise also sparked a few ideas for future physiology coming from a sport science experiments in many of the students! background, attending this workshop ...and through the eyes of a gave me a different perspective on my A further dimension of the workshop, own research, and enhanced my and one that was particularly student understanding of cardiovascular successful, was the ‘Meet the Expert’ mechanisms. Through presentation of sessions – an informal discussion my recent findings on ‘Impact of between a selected expert and a small marathon running on markers of group of students. Being unfamiliar cardiac damage’, I was particularly with experimental animal models, I interested to hear novel opinions and found a discussion on nitric oxide and ideas in this area. As the workshop was genetic knock-out mice with Barbara intended primarily for young scientists, Casadei extremely informative. This Natalie Middleton the lectures and demonstrations were also stimulated debate on experimental pitched specifically at this type of problems encountered in the lab and As the sole delegate from the UK, I audience. The visiting lecturers were some possible solutions. This session was clearly a minority amongst the approachable and supportive, with a also gave an insight into the cutting- diverse characters from Central and genuine interest in the students’ edge research work of an expert in the Eastern Europe that attended the research topics, and all were field, providing students with valuable Cardiovascular Physiology Workshop enthusiastic in providing suggestions information and a role model we could in Warsaw. However, they were a for future work. I believe this attitude aspire to. friendly and inclusive bunch and I was was fundamental in creating a rapport immediately made to feel part of the and facilitating interaction between the Despite inclement weather, the group at the ‘Welcome Reception’. This experts and the students. Farewell Picnic was thoroughly ambience suffused the Workshop from enjoyed by all. We experienced beginning to end, helping to make the During the allotted poster presentation generous Polish hospitality, and there event not only an invaluable learning sessions, there was also ample was no escaping the horseriding which tool and opportunity to meet experts in opportunity for discussion with other was apparently mandatory! Memorable the field, but also an enjoyable and students, which increased my images over the 4 days were captured highly entertaining experience! awareness of the current cardiovascular by an ever-present photographer, and physiology research being carried out CDs with photos on were presented to The theme of the workshop was ‘Signal across Europe. This time also served as delegates on the final day as a memento Transduction in the Cardiovascular a chance to establish new contacts and of the Workshop. I thought this was an System’. An international panel of foster potential collaborations for future excellent idea and this gesture reflected physiologists imparted their expert research projects. the great deal of time and effort that the knowledge in a series of lectures, which organisers had invested in the underpinned the experimental The laboratory demonstrations Workshop. laboratory demonstrations interspersed introduced a practical element to the throughout the programme. Specific Workshop, and ranged from the I am now looking forward to the next Physiological Society meeting, and hope that it will be as interesting and worthwhile as I found this one. As for Poland, with many invites from my new Polish acquaintances to visit, I will no doubt be back in the near future!

Natalie Middleton Sport Science, Brunel University Middlesex, UK Andrzei Beresewicz presents the poster winners with Society certificates and a small cash prize 40 PN BENEVOLENT FUND

Ella and the Ben Fund

Ella’s parents explain how the Society’s Benevolent Fund has helped her to cope with deafness caused by pneumococcal meningitis. The picture shows Ella on the day that her cochlear implant was switched on

Our daughter Ella contracted communication skills. Again the ladies, technicians, teachers – essential pneumococcal meningitis just before Benevolent Fund has helped out with a members of any physiologically her first birthday in January 2003. As a generous gift which will be used to pay involved department – are all eligible result she sustained profound hearing travel costs and donation fee to the for help, as are their dependants. loss as well as some movement and Foundation. As Ella’s mother has had to coordination problems and latterly give up work to care for Ella these gifts Calls on the Fund are erratic – some epilepsy. Soon after her deafness was have been very greatly appreciated and years are happily free of trauma and diagnosed she was fitted with powerful we would like to thank the donors to tragedy, others are not. When the 1976 hearing aids. At this time we were the Benevolent Fund for their Committee put its hands in its living in a flat with polished incredible generosity. collective pockets the £100 produced floorboards, and were advised by Ella’s made all the difference but, nowadays, teacher of the deaf that these conditions £100 doesn’t go that far. In the last 12 would be detrimental to the P.S. from the Chairman of months the Fund has paid out £5,250. development of her listening skills the Trustees Some of our beneficiaries may merit using her aids. further help. The Trustees of the Benevolent Fund The Physiological Society Benevolent are so grateful to Ella’s parents for We would like to be in a position to Fund very kindly provided funds for us sharing their story. Because we respect give worthwhile support whenever to have a carpet fitted to help lessen the the confidentiality of our beneficiaries genuine need arises. To do this we need echo in our living room. However, Ella it’s difficult to show Society Members to keep up our income. Some derived no benefit from these hearing that the Fund really works. Perhaps the Honorary Members are generously aids and was subsequently assessed for doubters who thought it was ‘some sort donating what would have been their a cochlear implant which was of slush fund for old physiologists’ now Society subscription. While big implanted at Great Ormond Street see what a difference it can make. donations are always very welcome, Hospital later that year. This incredible small donations from lots of you – say technology allowed her to begin to hear The Fund was established in 1976 £5.00, which equals £6.40 with Gift and identify environmental sounds when the Committee was asked if the Aid – could make a welcome difference before turning to her name and Physiological Society could help the to our bank balance without having beginning to understand a few words. widow of a young Member whose son much effect on yours. We have no doubt that the improvement had special needs. Itself a charity, the in the acoustics in our living room has Society may not give away its money Ann Silver made this easier for her. but it can support the administration of the Ben Fund. This means that all Since her implant Ella has been donations to the Fund can be used to There is a donation form opposite, attending the Elizabeth Foundation help what the Trust Deed calls those in and also on the Society web site once a week, a charity supporting pre- ‘necessitous circumstances’ whose (http//:www.physoc.org). Alternatively, school deaf children. Here she takes work, at any level, has contributed to you’ll be able to make a donation at part in nursery activities aimed at the ‘advancement of physiology’. ‘At the Ben Fund stand at the King’s developing listening and any level’ means just what it says: tea College Meeting in December. PN 41 42 PN EXPERIMENTAL PHYSIOLOGY/LETTERS TO THE EDITOR PN 43

Experimental Physiology at FASEB Public engagement Dear Editor, Awareness, by physiologists worldwide, to understand how genes/molecules I welcome your recent editorial of the mission and focus of determine or alter function of organs or discussing the importance of public Experimental Physiology is of systems. engagement, but also recognise the paramount importance for its future difficulties. We are all overworked success. This is why the recent FASEB Whilst in Washington we also had a and are rewarded for little that does meeting in Washington, USA was a meeting with our North American not contribute to external reviews of valuable opportunity to advertise the Editors. Eleven attended and included teaching and research – a serious journal, crucially to an American Mike Hogan, Julian Paton, Nandurai mistake in my view. But interactions audience. Washington greeted us with Prabhaker, Mohan Raizada, Peter with the public or school children can some lovely warm weather in April, Hunter, Jere Mitchell and John West, as take only a few hours each year, is together with an excellent venue. The well as myself, David Paterson and one of the best ways to improve our new convention centre is huge and in Alison Brown and Robert Harrington of presentation skills and is fantastically general the facilities are good. If I have Blackwell. There was a strong wish by enjoyable. a criticism it is the lack of social all to see the journal succeed even facilities close to each of the lecture though the inevitable question came up Yet – such activities carry little rooms and the fact that the large open ‘why do we need to publish in EP?’ recognition on our cvs or for RAE. space meant ‘bumping’ into colleagues Although there are presently no other One thing that does count is was less probable. journals with quite the same objectives, competitive prizes...so why doesn't the The Journal of Physiology does at Society offer a couple of prizes for The poster display and company stands present occasionally publish papers in science communication, perhaps one were excellent and Blackwell areas that I would hope will become for an early career scientist and one Publishing did a terrific job in more the province of EP. for a senior scientist? I am sure that displaying EP. Some 150 free copies of industry or other funders would EP (89.1) went like hot cakes and the Clearly the impact factor is important support this and it would send an and we need to show a sustained important message from the Society. increase in it. Whilst we seem to be on the right track, it was felt we could do Nancy Rothwell University of Manchester more. One important suggestion was to capture papers in the area related to understanding biological complexity by Nano – or anon modelling regulatory processes. We are Dear Editor, at a stage where the tools are becoming David Miller's exposition on available to take on the challenge of picograms and nanograms (Physiology making quantitative predictions to News, 55, 21) took me back to 1953 physiological outcomes from genomic when nanograms were still uncommon lunch reception got a lot of visitors knowledge. The article from Peter in biological usage. Volume 38 of The around the stand, although no doubt Hunter and Denis Noble’s group Quarterly Journal of Experimental some attended because of the ‘booze’. (Crampin et al. 2004) in the January Physiology contains a paper by JH There was a great deal of real interest issue of EP (89, 1-26), which Society Gaddum, CO Hebb, Ann Silver and and I think the message regarding what Members would do well to read, is a AAB Swan on the action of 5-HT in we are trying to achieve with EP got good indication of the importance of the perfused lung. The legend to Fig. across. People were encouraged to get this area that might be termed 4a, showing the assay of 5 H-T, their libraries to subscribe especially computational physiology. contains the words ‘Small figures give since they can get The Journal of doses in nanograms (ng.) of the base’. Physiology and Experimental Our North American colleagues were The assays were done in Gaddum's Physiology at a reduced cost, and both very supportive of our efforts to get EP lab and Catherine Hebb had left for are available electronically. Many moving forward and upward, not only Canada before he wrote the legend. thanks have to go to Alison Brown because of its aims, but because they (No requirement then for all authors to (Blackwell) for organising a very considered its great history made it certify they'd seen the final version.) successful reception and looking after imperative. On this point we are Soon after the paper appeared the stand so well. David Paterson and I presently trying to choose the best 10 Catherine was phoned by a colleague fielded lots of questions about ‘why papers published in EP over about 100 who said 'Catherine, what's a EP?’ and what we are trying to years. I would welcome any nanogram?' 'An anagram?' she achieve. Most enquirers were suggestions from Members. replied, ‘why, that's what you get in enthusiastically supportive of the main crossword puzzles.' aims regarding the publication of John H Coote Ann Silver papers using state of the art technology Chair, Experimental Physiology Honorary Member, Cambridge 44 PN SYMPOSIUM REPORT

Nociception in vertebrates: anatomy, electrophysiology, genomics and behaviour

The aim of this symposium, held in Edinburgh from 31 March to 2 April, was to bring academics, veterinarians and clinicians together to discuss the latest research on nociception and pain in mainly animal models. Speakers gave an up to date and fascinating insight into all of the major vertebrate groups including fish, amphibians, birds, mammals and the most highly evolved vertebrate – the human. From left: John Harris, Dale Sandercock, Mike Gentle (back), Bruce Lynn, Craig Stevens, Lynne Sneddon, Lynne Sneddon (Liverpool) discussed Johnny Roughan (back), Dorothy McKeegan, Sue Fleetwood-Walker and Carlos Belmonte research on the modern fishes as well as their predecessors, the lamprey and hagfish, and demonstrated that by peripheral and central examined glutamate receptors and their comparing results from the lower pathophysiological mechanisms. involvement in spinal cord sensitization vertebrates, many nociceptor properties Andrea Nolan (Glasgow Veterinary in chronic pain. Mouse knockouts and are evolutionary conserved. Bruce School) demonstrated that chronic pain their use in dissecting not only the Lynn (UCL) gave an excellent insight also occurs in many animal models molecular substrates of pain but the into the various types of nociceptors showing a need for the integration of complex ‘feeling’ of pain was elegantly that could be characterized by their clinical and fundamental science. discussed by Steve Hunt (UCL). anatomy and electrophysiological Carlos Belmonte (Alicante) and Finally, Turo Nurmikko, Director of the properties. Mike Gentle (Roslin Dorothy McKeegan (Roslin Institute) Pain Institute in Liverpool, displayed Institute) provided us with a fascinating took us to the trigeminal nerve and amazing images of brain activity from insight into the pathology of arthritis in discussed how corneal nociceptors are fMRI and PET scans demonstrating the birds and the associated pain-related stimulated by cold and nasal cerebral coding for the location, type behaviours. Sally Lawson (Bristol) and nociceptors show amazing sensitivity to and intensity of pain. Richard Morris took us deeper into the noxious gases, such as ammonia, in CNS and examined the highly complex mammal and bird models respectively. This was truly a fascinating symposium role of dorsal root ganglion cells and Pain assessment is problematic, as is with an integrative flavour spinal neurons. John Harris the efficacy of analgesics but Johnny encompassing techniques in (Nottingham) discussed how Roughan (Newcastle) and Julie neuroanatomy, electrophysiology, information from the spinal cord Fitzpatrick (Glasgow) showed us that it behaviour and genomics. I am grateful innervates reflex responses to painful is possible to assess pain by using to the Physiological Society for their stimuli. behavioural indicators. Mechanisms of generous contribution by supporting my nociception and pain can be assessed at application for a Non-Society Chronic pain is currently a major the molecular level and Craig Stevens Symposium Grant. clinical problem in humans and (Oklahoma) demonstrated that opioid Hermann Handwerker (Erlangen) gave receptors in amphibians are strikingly Lynne U Sneddon an enlightening presentation that similar to mammalian receptors. Sue University of Liverpool demonstrated the complex interplay of Fleetwood-Walker (Edinburgh) Liverpool, UK

Transfer News/Promotions Brian Robertson (Department of been elected Fellows of the Royal Physiology and Pharmacology at the Society. More coverage in the next R Angus Silver has been made Reader University of Strathclyde) has been issue. at the Department of Physiology, appointed to the Chair in Neurobiology University College London. and, on a personal note, to (Eberhard Buhl Chair of Biomedical ... Sciences) at the University of Leeds Craig Smith (currently a Royal Our Editor Austin Elliott and Anita on Society University Research Fellow) Congratulations to ... the birth of Sophie Marie (7 lbs) on 5 has been appointed Senior Lecturer in June. Molecular Physiology in the School of Nancy Rothwell (University of Biological Sciences at the University Manchester) and Graham Dockray Send your transfer and promotion news of Manchester. (Liverpool University) who have both for publication to [email protected] SOCIETY NEWS PN 45

Federation’s session is entitled ‘Fundamental research; what’s the point?’ and features talks on fish Policy activities hormones, deep sea vents and the first April saw another flurry of consultation breath of life. The session will take documents, including two of particular place at Exeter University on 9 note: the Commons Science and September. Contact Sai Pathmanathan Technology Committee follow-up ([email protected]) for free Time to say ‘goodbye’ - Maggie Leggett inquiry into the Research Assessment tickets. There will be a symposium on Exercise and the Treasury consultation the commercialisation of bioscience on The past 5 years have been, above all on a 10 year investment framework for 12 October at the Royal Society, and else, great fun. I joined you with a Science and Innovation. The main for younger scientists three careers career history in teaching and research, points of the first were to ask for more conferences, at King’s College London and had at that point no idea that a job details regarding the organisation of the (6 Nov), Leeds University (20 Nov) could actually be enjoyable. However, panel and sub-panel structure, to urge and Glasgow University (27 Nov) (see devising schemes with various against admin-heavy procedures and to separate advertisements for all events). committees, organising events for criticise the failure to integrate the For information on these and other academics, school children and review with the ongoing assessment of events, keep an eye on the website at members of the public, writing booklets dual support. The response to the www.bsf.ac.uk. and designing posters, overhauling Treasury document was long and policy and arguing with committees complex highlighting, among other Maggie Leggett that the status quo really did need to points, the need for academic freedom, change has been quite exciting. And, of the need for more funding for basic course, there is the eating and drinking research and for improvement to the Moving on for which the Society is famous. Lying career structure for scientists. All I can hardly believe the time has come by a pool in Budapest, dancing the consultation document responses are to say goodbye. As you read this, I night away in some dive in Cambridge available at http://www.bsf.ac.uk/recent.htm shall be preparing to take up a position and getting decidedly the worse for at the BBSRC. Much as I resigned a wear on a boat in Bristol – can this Future activities while ago – and am now serving a really be work? I hope to see those of you working in seemingly endless notice period – I or near Exeter at the British Association have still not accepted the fact that one It’s not all been great. I remember the Festival of Science in September. The day I shan’t be working for the Society. sinking feeling when I realised that, as 46 PN SOCIETY NEWS/OBITUARY a result of some ambiguous wording on the future there will be one Clarke, Prem Kumar, Chris Fry, Jeremy my part, Members who shared the same administration running a number of Ward, Dafydd Walters, Bridget Lumb, name also got to share a bedroom in a individual societies. As a Member this Malcolm Hunter, Stan White and hall of residence at a Society meeting. might be indistinguishable to you from Graham McGeown all come under this Luckily no Member has the surname the current system, although it could category, although there are many more ‘Leggett’, but there were some people reduce some flexibility. However, it who deserve gratitude. Good luck to who were, quite rightly, distinctly should be far more streamlined and less you all; I shall watch the progress of unimpressed. And there have been a expensive. Of course, I could be the Society with interest. few of you over the years who have influenced by my secondment to the shouted at me for not knowing your Biosciences Federation, but there is Maggie Leggett requirements for dinners or rooms undoubtedly duplication between stated on registration forms you or your offices of all the various societies and Publications Office secretaries forgot to send. Or who were an ever increasing need to reduce Jill Berriman, Managing Editor on the just bored and cross and wanted administration costs. Society’s journals, left the Publications someone to have a go at. But these Office at the end of June, after 13 years minor irritations are a small price to I am joining the BBSRC as ‘Head of with the Society, to join her husband, pay for a fun and rewarding job. Public Engagement’ – involving the John, who is now working in NewYork. public in how they allocate money to In her various roles with the Society – The Society has developed particular research areas. I shall, of Copy Editor, Senior, and then Chief, considerably in the last 5 years, and it’s course, need to retain close links with Production Editor and, since 2001, been interesting to be part of that the academic community, and hope that Managing Editor – Jill was involved in change. The governance structure, I come into contact with many of you format and content changes to both The membership application procedures, the again. If anyone would like to get in Journal of Physiology and organisation of Meetings and the grant touch I am sure the London office will Experimental Physiology, the schemes have all been overhauled. forward emails to me. Those with introduction of in-house DTP and Personally I think the Society is at the whom I have worked closely are really electronic submission of manuscripts beginning of a long process of too numerous to name, although I and, at the end of 2003, a move to complete transformation, which might would like to mention a few who not Blackwell Publishing after almost 125 be driven both by changes in the way only have been really supportive of me years with Cambridge University Press. scientific research is published and the but also have given up their time to the Our very best wishes for a bright new demands of government. I imagine in Society for little or no reward. Rob future go with Jill and John.

the department. Although only in Hull Sport and Exercise Science at James Ryder for a short period, he had established University College Chester completing excellent teaching and research his dissertation on the effects of 1974-2004 relationships with his students, hydroxy-methyl-butyrate colleagues in the Department and supplementation on muscle damage across the University. following eccentric exercise, work which he had presented to the James had completed his University of European College of Sports Science. Liverpool PhD at University College Chester, supervised by David As a young academic embarking on a Cotterrell, on a multidisciplinary teaching and research career in investigation into markers of physical exercise physiology he will be much fitness of elite young soccer players . missed by family, friends and He had presented his work on the colleagues in Chester and Hull. Our physiological aspects of fitness in his heartfelt condolences go to his parents, young soccer players to the Society on Ken and Sue Ryder. It is with great sadness we report that a number of occasions. He had also James Ryder, a promising and done a year as a post doctoral research David Cotterrell1 enthusiastic young physiologist, passed co-ordinator working on the Lars McNaughton2 away peacefully in his sleep in May physiological responses to exercise in 1 2004. post-myocardial infarct patients before University College Chester 2University of Hull moving to Hull. James had recently taken up a lectureship in the Department of Sports James graduated with a BSc in Sports The Society also reports, with regret, Science at the University of Hull and and Exercise Science from South Bank the death of Oliver Holmes and G was becoming established as a lively University as a student of Susan Eric Lamming, OBE since the last member of Lars McNaughton’s team in Ward’s. He then read for an MSc in issue of the magazine. UNBELIEVABLE! PN 47

them off the books so they need not be returned in RAE 2008.

Senior Teaching Fellow: staff member under 50 deemed non-RAE returnable who has been re-badged as ‘Teaching Only Staff’ so s/he need not be returned in RAE 2008. AAAAAAARRRRRRR … RAE Teaching Fellow (also ‘Demonstrator’): junior teaching-only staff member, typically ‘Universities UK chairman Ivor Crewe produces research output, typically peer- doing 20+ contact hrs/wk, hired to take warned the (House of Commons) reviewed research papers. teaching load off RAE-returnable staff. Science and Technology Committee that 2. (In recent RAEs, and in some less ‘Research-led teaching’ (also ‘teaching in a research-intensive universities): a staff game-playing (by universities) was research-rich environment’): teaching done by member who, over the RAE period, has likely to be worse rather than better in RAE-returnable staff. the next RAE.’ (THES, 21 May) produced four peer-reviewed papers. 3. (Current meaning in research-intensive Service teaching (colloq./slang ‘community As we approach the halfway point between Universities): a staff member who is likely to service’): teaching done by Senior Teaching the last and the next Research Assessment be graded 5* or better. Hence: a staff member Fellows, Honorary Senior Lecturers, Exercises (RAEs), we offer a helpful glossary who is first or corresponding author on four or Teaching Fellows and other non-RAE of RAE-related terminology. more peer-reviewed papers, who has £50K pa returnable staff. (or better £75K pa) research grant income, Pre-RAE readiness personal interview: (For non-UK based readers: just be grateful and who has been an invited speaker at (at expect a kicking. this doesn’t apply to you.) least) one international conference each year. RAE Review Team leader: chief hatchet Non-RAE returnable: any staff member RAE 2008: Self-explanatory. man. whose personal research profile is deemed Research-active: unlikely to score in the category their Pre-RAE mid-term review: expect more 1. (As used by academic scientists): a staff university has decided their Unit of kicking. member who participates in, and publishes, Assessment has to get (see RAE-returnable). scientific research. Colleague (RAE meaning): competitor. Unit of Assessment: whatever subject 2. (As currently used by UK University and category we can return this lot in where they Encouragement, support, help, mutual departmental managers): a staff member who will score the best rating. interest, scholarship: not in RAE dictionary. is considered to be RAE-returnable. Honorary (Senior) Lecturer: staff member Keep your head down. RAE-returnable: over 50 deemed non-RAE returnable and 1. (Original meaning): a staff member who ‘persuaded’ to take early retirement to get Mark Cain

Only too believable? syllabus, as it does for many of the other performed better than the locals. This was I would like to add my voice to that of the specialties. ascribed to a decrease in the teaching of ‘harassed doctor working in general basic physiology and pharmacology in UK medicine’ who complains about the lack of I, too, have noted a decline in the basic medical schools. science knowledge of our students but do physiological knowledge of undergraduates The knowledge required to pass the basic and junior medical staff (Physiology News, not know whether this is the result of Problem Based Learning (PBL) as science exams for the various specialties is 55, 46). I have been involved in teaching not much more than what used to be anaesthesia for over 25 years. We deal suggested by your correspondent. I had always assumed it was due to the required of undergraduates, but they do directly, and daily, with patients (both have to know it very well. They have to be healthy and many with pre-existing replacement of the biological sciences in the undergraduate curriculum with such able to ‘manipulate’ it, and be able to apply cardiovascular, respiratory, renal, hepatic it to rapidly changing situations, such as the and CNS impairment) undergoing surgery subjects as social science, psychology, management and the formal teaching of hypovolaemic patient ‘resuscitated’ with 5% of varying degrees of severity and extent. dextrose (sugar and water) referred to by This involves the physiological and ‘team working’, ‘communication skills’ and empathy. your ‘harassed’ correspondent. They also pharmacological manipulation of, have to persuade the (pre-PBL trained) predominantly, the cardiovascular and examiners that they can do so. Like the Something I have also noticed recently is respiratory systems to ensure they survive Obstetricians and Gynaecologists I believe that graduates from non-UK universities the attentions of our surgical colleagues their failure to do so reflects lack of (mainly Indian) have a better knowledge of who are attempting to cure their presenting sufficient exposure to basic physiology, physiology than our local people. This illness – cancer, fractures or whatever. As taught by physiologists, in their formative impression is supported by a recent article such it amounts to a very real exercise in undergraduate years. How else can they in Hospital Doctor (June 24) highlighting applied physiology and pharmacology with learn that we have salt and water circulating an increasing failure rate amongst UK the aim of maintaining homeostasis in the in our veins and not dilute Coca Cola? face of volaemic, thermal, nociceptive and graduates in the Part I (basic sciences) exam mechanical insults. Consequently for membership of the Royal College of Iain Campbell physiology and pharmacology constitutes a Obstetricians and Gynaecologists. Department of Anaesthesia, Wythenshawe Hospital, major proportion of our examination Graduates of Indian universities also Manchester, UK 48 PN BOOK REVIEWS – NEUROSCIENCE BOOKS SPECIAL

the index while reading about the price, which strikes me as a bit heavy The synaptic organization of cerebellum, you will find no entries for a paperback. under ‘olive’, ‘pons’ or ‘medulla’. the brain There is also a tendency to skate over The synaptic organisation of the brain the functional properties rather too is a classic text, and still very much Edited by Gordon M rapidly to make full sense of the great worth having and reading for anyone Shepherd. 2004, Oxford deal of detailed anatomical and cellular interested in the details of neuroscience. University Press. 719 pp, information included. Instead of I’m sure it will have many more editions. But I think a bit of an £42.50. explanation, the presentation sometimes seems more like a bit of overhaul in terms of coverage and ISBN 0-19-515956-X neurophysiological prestidigitation. context would make it a substantially This fifth edition of Shepherd’s well- ‘Roll up! Roll up! Ladies and better book. respected text is still worth having on gentlemen, watch closely as I place all John A Lee the bookshelf. It is not a complete brain these neurones, their connections, the book, since it concentrates on ‘the brain properties of their dendrites and the regions best understood for their shape of their action potentials inside The neuropsychology of synaptic organisation and functional this hat. I shake it gently and wave my correlates’. This means, for example, wand like so. And look! Here we have vision that you get two out of 12 chapters on a thalamus! A miraculous part of the Edited by Manfred Fahle & the olfactory system and nothing on the brain which allows us to love, feel, Mark Greenlee. 2003, brainstem, which strikes me as a bit move, see and a whole lot of other stuff Oxford University Press. odd, in spite of the pre-amble. too. Hold that for me madam, if you Nevertheless, the regions covered are will. There. Now, watch closely 344 pp, £ 65.00 dealt with systematically and clearly. everyone while I make a retina…’ ISBN 0-19-850582-5 Each chapter has a similar structure, Since we are highly visual animals, it is with sections on the neuronal elements Of course, this is the stuff of hardly surprising that the mechanisms present, their synaptic connections and neuroscience. Skilled practitioners have underlying our conscious experience of basic circuits, their intrinsic membrane been using the approach for years to seeing have occupied a prominent place properties, synaptic actions and extract large amounts of money from in brain studies. But it is difficult to dendritic properties, and the functional granting bodies, as well as occasionally know whether it is correct to add a properties of the circuits. This is all illuminating the way parts of the brain statement such as ‘and so the processes done clearly and thoroughly, packing a may work. But to some extent this underlying vision are among the best great deal of information into a small book, like many multi-edition texts, is understood aspects of cerebral space. beginning to show its age a little. In function’. On the one hand they have places, the density of its specifics is certainly been very intensively studied, Having said that, the book does have its starting to overwhelm the path from the but on the other ‘vision’ is probably the weaknesses. The general context tends synaptic building blocks to the most complex thing we do. Recent to be assumed rather than given, integrative aspects which got us all studies have revealed not just one or a expecting a considerable degree of interested in the first place. Another few cortical areas devoted to aspects of background knowledge on the part of slight oddity is the reference list, visual processing, but over 40 areas the reader for many aspects of the occupying 145 out of 719 pages, or distributed around the occipital, parietal discussion to make sense. The fact that over 20% of the book. It is certainly a and temporal lobes, and together this volume is not a complete brain worthwhile compilation and fulfills the accounting for as much as a third of the book also means that there are many editor’s wish to ‘prize a scholarly depth entire cortical machinery of our brains. loose ends dangling from the text, again behind our understanding’. But why requiring additional sources of isn’t it on the web, along with the other An originally unexpected finding is that information if the reader wants to tie useful web resources listed on page xi? most of these cortical areas represent them off. For example, if you turn to That might also have helped reduce the the entire visual field, giving rise to

Other books received. Reviews will be carried in future issues of Physiology News Free radicals: enzymology, signalling and disease. Edited by C Cooper, M Wilson & V Darley Usmar (Portland Press, £65.00. ISBN 1-85578-161-1) Long term potentiation: enhancing neuroscience for 30 years. By Timothy Bliss, Graham Collingridge & Richard Morris (Oxford University Press, £65.00. ISBN 0-19-853030-7) Textbook of endocrine physiology, 5th Edition. By James E Griffin & Sergio R Ojeda (Oxford University Press, £18.99. ISBN 0-19-516566-7) Basic and clinical neurocardiology. By Andrew J Armour & Jeffrey L Ardell (Oxford University Press, £50.00. ISBN 0-19-514129-6) MCQs and EMQs in physiology. (Hodder Arnold, £12.99. ISBN 0-340-81191-9 BOOK REVIEWS – NEUROSCIENCE BOOKS SPECIAL PN 49 multiple cerebral representations of our diagrams are well thought out and text appreciated by those in clinical, visual surroundings. This in turn boxes are used to highlight systems or cellular neuroscience, since indicates that different cortical regions physiological, pharmacological or there are chapters dealing with are specialised to analyse different anatomical details, when required, information flow through the nervous aspects of the visual world around us, without perturbing the flow of the main system and others considering neuronal and it follows that our experience of text. development and disease. I found the ‘seeing’ is actually the subjective chapters on protein trafficking and correlate of parallel processing in many, The book is aimed at medical students synapse to nucleus calcium signalling partly independent brain regions. The and successfully links basic and clinical particularly illuminating, but it is unfair evidence supporting this interpretation science together. It includes new to pick out particular chapters for comes from many different sources, chapters on the control of eye mention, since all of them are well ranging from single cell studies in movements and the vestibular system constructed. Perhaps in the next animals to detailed analysis of the often (entitled ‘the sense of equilibrium’) and edition, the publishers could improve strange subjective experiences of all the remaining chapters have been the book even more by the use of patients who have suffered damage to thoroughly revised and updated to colour to enhance the diagrams and various areas of their brains through include data from molecular biology to tables. trauma, tumour or stroke. Fahle and clinical psychology. Greenlee have done a good job in Bill Winlow pulling together contributions which This makes the book refreshingly easy span this spectrum of approaches, so to read and I would recommend it as an that anyone with an interest in this area informative text for medical students Ions in the brain is likely to find new and interesting with interests in the CNS. Normal function, seizures information in the book. Chapters cover anatomy and physiology, non-invasive Bill Winlow and strokes. By George C imaging and neurophysiological Somjen. 2004, Oxford techniques, lesion studies in monkeys University Press. £59.50 and humans, psychophysical studies Molecular biology of the ISBN 0-19-515171-2 including blindsight, agnosia and neglect, and finally a discussion of neuron In these times of publicity-seeking recovery and rehabilitation in cerebral Second Edition. Edited by scientists making escalating scientific visual disorders. Thinking clearly about RW Davies and BNJ Morris. claims of dubious credibility, it is vision requires a multi-disciplinary indeed refreshing to come across a approach and this volume is a welcome 2004, Oxford University scientific author who states that he one-stop-shop which collects up to date Press. £65.00 doesn’t know how the brain works. and well referenced discussions ISBN 0-19-850998-7 covering many important topics in the This edition of Molecular Biology of It is particularly enlightening when that field. the Neuron updates the first edition that author, George Somjen, whose name was published in 1997 and includes will be familiar to anyone with even a John A Lee many of the scientific advances made passing interest in the since that time. There are 16 chapters, electrophysiological properties of the each written by leading research brain, is a giant in the field who has The central nervous system workers. spent the last 30 years attempting to Structure and function, Third unravel the complexities of ion In their preface the editors state that disturbances associated with brain Edition. By Per Brodal. ‘this book provides a platform for malfunction. 2004, Oxford University knowledge, which allows new advances Press. 515 pp, £49.50 to be put into context, without being an In the present book Somjen has taken ISBN 0-19-516560-8 expert’. Having dipped into many of on the task of describing the regulation the chapters, I must concur with their of ions in the brain, and how that The third edition of Per Brodal’s book viewpoint. It is always difficult to regulation is disrupted during brain is beautifully produced and continues ensure a uniform standard of writing malfunction. the traditions of excellence set up by from a diverse group of authors, but the four editions of the same name these editors seem to have achieved it. The book is laid out in four sections: published by his father Alf Brodal Thus, each of the chapters provides a the first describes the regulation of ions between 1949 and 1982. The book is useful review of current knowledge of in the normal brain and how these ions clearly and concisely written and molecular data relating to neurons. affect neuronal function, with the manages not to lose the reader in subsequent three sections each anatomical detail, while explaining The book is clearly aimed at the containing several chapters that physiological mechanisms. The neuroscience community and will be describe alterations in ion levels 50 PN BOOK REVIEWS – NEUROSCIENCE BOOKS SPECIAL associated with epilepsy, spreading on ischaemic stroke and the toxic suggests possible scenarios that could 2+ depression and ischaemic stroke. accumulation of excess [Ca ]i. result in onset of spreading depression. However, Fig. 2-5 which illustrates the One interesting aspect raised is that As would be expected, Somjen corresponding [H+] versus pH should spreading depression may be related to + highlights his own input to the topics be memorised by all. incomplete buffering of elevated [K ]o, discussed, but never to the exclusion of which immediately suggests it may others, and I was gratified to see the I found the section on epilepsy the most occur in areas with low astrocytic respective key contributions of my two satisfying, as there is an extensive density. mentors in Seattle – Wayne Crill and review on the various theories of Bruce Ransom – duly acknowledged. seizure generation with exhaustive The final sections on stroke describe Each chapter has a summary of key evidence provided. As a rewarding the mechanisms of ischaemic cell points, but contained within each corollary, the section on mechanisms of death. Ischaemia can result in both chapter are helpful ‘in conclusion’ action of anti-convulsant drugs suggests necrosis and apoptosis and there are paragraphs summarising the previous that, if we know how ion channel multiple theories of how cells are topic. malfunctions contribute to epilepsy, killed, each of which shares to varying then targeting drugs to specific ion degrees the same combination of the Interspersed throughout the text are channels can result in a successful key factors - Ca2+ influx, glutamate technical notes bringing the reader’s preventative therapy. A computer model receptors, and zinc. I was disappointed attention to various key points which of seizure mechanisms is provided, but that there was no mention of the effects make understanding of the text easier, the model is based on an individual of ischaemia in white matter, as in all e.g. naming of the hippocampal layers, neurone. This may seem surprising cortical strokes, which are generally explanation of current clamp etc. As the given the widely assumed positive considered to affect only grey matter, book is the work of a sole author it has feedback mechanism whereby localized the underlying white matter is also a pleasing consistency of style that is excitability recruits more distant affected. Stokes can also occur purely lacking in the usual edited book chapter neurones, but Somjen does describe in white matter areas, e.g. lacunar format, and my only criticism is that multi-unit models and convincingly infarcts, and given the lack of synapses the figures are standard black and white argues that a one neurone model can and neuronal cell bodies in these areas that would not be out of place in a simulate seizure discharges. As an aside a different array of non-neuronal 1980s textbook. However, as most of I had always thought the depolarisation mechanisms has been described. It is the figures are reproductions of → increased Na conductance → further disheartening to note that there is no diagrams from published papers this is depolarisation cycle illustrated in Fig. chapter on the mechanism of understandable, and in only a few cases 9-8 was known as the Hodgkin cycle, neuroprotective drugs in stroke, as there where there are multiple overlaid traces rather than the Katz cycle as stated in are currently no clinically effective on a graph is the lack of colour the text. neuroprotective strategies. This is detrimental. particularly frustrating as the The section on spreading depression is contribution of ion channels to The first section on regulation of ions perhaps the least interesting, mainly as ischaemic damage is broadly in the brain is fairly detailed, but I feel it has not yet been positively associated understood, but unfortunately a novice would probably be better with any neurological condition; indeed successful laboratory results have not directed to a standard textbook (such as whether spreading depression actually been translated into effective clinical Kandel) as a lot of preliminary occurs in humans is unknown. Thus its applications. knowledge is assumed, e.g. by page 9 importance in neurological dysfunction of the chapter on regulation of brain is questionable, although it is a All in all this is an excellent book ions we are introduced to the GHK fascinating phenomenon. As with the which is a must read for all interested equations. To obtain the maximum epilepsy section all angles of in the fields covered. While not benefit from this book, it would be mechanisms are covered in great detail. claiming to tell us how the brain works, advisable for the reader to get the The final chapter illustrates a model of Somjen sticks with the facts and concepts of ion gradients, equilibrium spreading depression based on the describes in exquisite detail what potentials and the effects of ion epilepsy model, and as I read this happens when the brain malfunctions, transporters/exchangers, etc. securely chapter it became very apparent that it which is surely how successful under their belt. In this section the shares a remarkably similar mechanism strategies for combating devastating description of the effects of osmotic to a slow action potential. The model is neurological conditions will ultimately stress is particularly clear. I would not empirical as ‘appropriate be devised. A worthy testament to an argue that a better illustration of the adjustments’ were made, and although exemplary scientific career. + 2+ effects of reversibility of the Na -Ca the chapter is entitled ‘Solving the 2+ exchanger on [Ca ]i is Fig. 7 of Stys et puzzle of spreading depression by Angus Brown al. (1992) J Neuroscience 12, 430-439, computer simulation’, sadly this is not rather than the one shown (Fig. 2-4), the case, as the model merely particularly in light of the final section reproduces the experimental data and

52 PN NOTICEBOARD

YOUNG PHYSIOLOGISTS SYMPOSIA INTERNATIONAL WORKSHOP IN ION IUPS 2005 Channels to networks CHANNELS University of Leeds 35th Congress of the International Union of September 2004 Ion channels: from physiology to Physiological Sciences For further information contact Helen Garner pathology San Diego, CA, USA Email: [email protected] Universidad de Sevilla 31 March – 5 April 7-9 February, 2005 IUPS 2005 is being organised by the six member societies of the US King's College London This International Workshop will focus on the general aspects of ion National Committee of the IUPS, the American Physiological Society, 17 December 2004 channel molecular physiology and channelopathies. The meeting is the Society for Neuroscience, the Microcirculatory Society, the Joint with the Chilean Physiological Society sponsored by the Physiological Society and intended for young Society of General Physiologists, the Biomedical Engineering Society Theme free symposium, abstracts on all topics welcome scientists from the UK, Spain and Eastern European countries, and the Society for Integrative and Comparative Biology, under the For further information contact Charlotte Waters (KCL) though participants from other countries are also very welcome. Up auspices of the US National Academy of Sciences. Email: [email protected] to 40 applications will be accepted and preference will be given to or Paola Casanello (Chile) applicants who will present a poster. Interested applicants should Website: http://www.IUPS2005.org Email [email protected] submit a short cv and register online by 1 September, 2004. Journal of Physiology symposia will take place at the IUPS on 4 and Further information about these events will be circulated via email Website: http://www.physoc.org/international/seville2005 5 April. Full details will be available at www.jphysiol.org and published on the website.

BA FESTIVAL OF SCIENCE THE PHYSIOLOGICAL SOCIETY Noticeboard The responsibility of being a scientist CHANGE OF ADDRESS University of Exeter Notices for the Winter 2004 issue of Physiology News should 6-10 September, 2004 reach the Publications Office by 20 September, 2004 The Physiological Society Administration ([email protected]). Website: http://www.the-ba.net Office has moved to: Please note that whilst Members are welcome to advertise relevant events in Physiology News and on the Society’s website, PO Box 11319 advertisements via email will be restricted to events sponsored by the Physiological Society. ADVERSE REACTIONS TO DRUGS AND London WC1X 8WQ CHEMICALS: STUDIES FROM MOLECULES TO MAN University of Liverpool, Liverpool, UK THE PHYSIOLOGICAL SOCIETY 9-10 September, 2004 Meetings Joint meeting of the British Pharmacological and Toxicology Societies. 2004 email: [email protected] UNIVERSITY COLLEGE CORK AND ANNUAL GENERAL MEETING Website: http://www.bps.ac.uk 1-3 September (Wed-Fri) Abstract period closed EUROPEAN COUNCIL FOR CARDIOVASCULAR RESEARCH UNIVERSITY OF BRISTOL 9th Annual 4-5 September (Sat-Sun) (Focused meeting) Meeting Abstract period closed Nice, France 1-3 October, 2004 UNIVERSITY OF OXFORD The ECCR was formally established in 1997 to create within Europe 1-3 October (Fri-Sun) (Focused meeting) a unique forum for active clinical and pre-clinical researchers in the Abstract period closed important field of blood pressure and cardiovascular research. The annual meeting covers a broad range of subjects, including genetics of cardiovascular diseases, vascular biology, cardiac and renal aspects as well as modern strategies of prevention and therapy in KING’S COLLEGE LONDON cardiovascular disease. 18-20 December (Sat-Mon) Website: http://www.eccr.org Joint meeting with the Chilean Physiological Society Opening date for receipt of abstracts 20 September Closing date for receipt of abstracts 29 September INTERNATIONAL WORKSHOP IN CELL PHYSIOLOGY 2005 Transport mechanisms across cell SEVILLE, SPAIN membranes: channels and pumps 10-13 February (Thu-Sat) Russian Academy of Sciences and the Sechenov Institute of Sponsored symposia in association with the Spanish and Dutch Physiological Societies Evolutionary Physiology and Biochemistry, St Petersburg, Russia IUPS, SAN DIEGO, CA, USA 13-17 October, 2004 31 March-5 April (Thu-Tue) Focusing on the molecular mechanisms of membrane transport and experimental approaches. Sponsored by the Physiological Society UNIVERSITY OF BRISTOL and intended primarily for young scientists from Central and Eastern European countries and from other European countries. The 20-23 July (Wed-Sat) programme will include lectures, poster sessions and laboratory Opening date for receipt of abstracts 1 February demonstrations. Closing date for receipt of abstracts 15 March Website: http://www.physoc.org/international For further details please visit the Society’s website (http://www.physoc.org)