Oxford Medical School Gazette Issue 63(2) by Oxford Medical School Gazette

OMSG 63 (2)

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PRECOCIOUS PUBERTY 8

HIGH IMPACT CAREERS 42

GROWING PAINS 10

SOME LIKE IT HOT 46

ALL GROWN UP? 24

THINKING FAST & SLOW 50

EMPIRE & DISEASE 35

HOW TO GROW A KIDNEY 56

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OXFORD MEDICAL SCHOOL GAZETTE COMMITTEE Editors: Joshua Luck, Barnabas Gilbert Sub-editors: Stuart Mires, Laura Munglani, Nicholas Aveyard, Kevin Cheng, Bing Tseu, Nicola Kelly, Kiruthika Ananthan, Amrit Gosal, Giles Neal, Alex Barry, Lauren Passby, Suzanne Harrogate Peer Review editor: Thomas Hine Book Review editor: Edward Chesney Design: Rosalie Brooman-White, Hannah Thompson, Giles Neal, Lara Hibbs Design team: Alix Brazier, Simone Paulson, Richard Sykes, Dariush Micallef Patron: Professor Sir John Bell, Regius Professor of Medicine Honorary Treasurer: Mr Stephen Kennedy Senior Members: Dr Tim Lancaster, Dr Peggy Frith, Dr Sue Burge and Dr Vanessa Venning OMA Liaison: Dr Peggy Frith

Oxford Medical School Gazette (OMSG) is the oldest medical school journal in the world. OMSG is produced by the students of Oxford University Medical School for the enjoyment of students, doctors, alumni, academics and any other interested readers.

readers to subsidise production. If you are able to contribute in any way, all donations, either SUBMITTING ARTICLES TO THE GAZETTE The Gazette welcomes submissions from students, alumni, clinicians, other health professionals and members of Oxford University academic staff. Articles do not need to amend any copy received, following discussion with the author. If you would be interested in contributing please contact the editors at editors@omsg-online.com. SUBSCRIBING TO THE GAZETTE To subscribe directly to the Oxford Medical School Gazette please contact the editors by email at editors@omsg-online.com or by post at the address below. ACKNOWLEDGEMENTS The editors would like to thank the members of the senior committee, Jayne Todd, Karen thanks to Robin Roberts-Gant from the Medical Informatics Unit who has, as ever, given tremendous support in producing this issue of the OMSG. ILLUSTRATION AND PHOTOGRAPHY Many of the images used in OMSG are produced by members of the medical school and we thank all those involved in the modelling, photography, and illustration of this issue. Images COMMUNICATION Hospital, Oxford OX3 9DU. PRODUCTION Medical Informatics Unit, NDCLS, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU. Telephone +44 (0)1865 222746 COPYRIGHT NOTICE ÂŠ 2013 The editors of Oxford Medical School Gazette (OMSG) and the contributors to OMSG. All rights reserved. The contents of this publication may not be reproduced in whole or in part without the express prior written permission of the editors.

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The cancer patient

Precocious puberty

Laura Munglani asks what we can learn by viewing cancer from a patient’s perspective

Sophie McManus considers whether today’s children are growing up too fast

Growing pains

Grow up

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Bing Tseu gets a mother’s perspective on raising a child with cerebral palsy

The growing problem of cancer in Africa

Emma Fisher considers the challenge of ‘growing up’ in Medical School

Darkness within Alexander Allen talks about his personal experience with depression

Alice Buchan investigates if this could actually be neuropathic pain

Radiation proctopathy

Some like it hot

Unravelling the legend of David & Goliath

Shadows of the subplate Jennifer Millar evaluates the role of transitory cortical neurons in health and in neurodevelopmental disease

Dr Brian Phillips examines what is known about this emerging complication of pelvic radiotherapy Andrew Dooley reconsiders our relationship with the radiator...

Charles Coughlan Considers the medical truth behind the popular legend

All grown up but still growing Josephine Holland investigates neural changes in late adolescence and their potential psychiatric significance

Violence & schizophrenia

Targeting Toll Like Receptors in cancer therapy

High impact careers in healthcare

A perfect pick-and-mix me

Rosalie Brooman-White considers whether medication can be used to manage violent behaviour

Emily Duncan considers how plagues shaped the ancient Roman empire

Abbie Taylor asks how much good doctors really do

Type 2 Diabetes: Death or dedifferentiation?

Stunting the growth of medicine Molly Gilmartin reassesses the relationship between medicine and money

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Will Dace explores the theory that loss of beta cell identity may cause Type 2 Diabetes

Empire and disease

Cassie Aldrich considers the growing problem of cancer & non-communicable diseases on a continent still battling infectious diseases

Beth Kingston explores the scope of TLR targeting and the current limitations of this approach

Thinking FAST and slow

Smoking in Alzheimer’s

Cheat genes

How to grow a kidney

Tingewick round up

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Book reviews

Laura Munglani’s experiences with stroke patients remind us that we have to do more than just ‘Act FAST’... John Wilde looks at the self medication of nicotine by Alzheimer’s patients Genetically modified humans could soon be competing in top level sport. James Taylor investigates. John Castle details recent advances in 3D printing Rebecca Adams gives us the low down on all things Tingewick

Peer Review From our archives Crossword

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A Note from Design Welcome to the second Gazette of 2013. This issue saw the arrival of Lara Hibbs to the now well-established team. We hope that you might be able to detect her original style throughout the OMSG in front of you today. If you have any queries, or would like to get involved, do not hesitate to get in touch at: design@omsg-online.com - Rosalie Brooman-White, Giles Neal, Hannah Thompson & Lara Hibbs design@omsg-online.com

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63(2) EDITORIAL

Growth. It’s a strange notion, isn’t it? Just look at your average baby boy. He grows at such a rate in his first year that, if he could sustain it, he’d be as tall as Nelson’s Column by adulthood. Not only that – his middle fingernail would grow faster than the others, while all his toenails would grow three times slower than even the slowest growing fingernail. But what about growth in the more abstract sense?

the complex relationships between medicine, money, big pharma and the allocation of resources. If there remains a place for philanthropy then, perhaps it is in the better application of our own skills; a claim sensationally put forward by Abbie Taylor. In describing how the impact of the average doctor equates to less than one ‘life saved’, we certainly felt compelled to reassess our own career trajectories with the utmost concern.

We launch this second issue by examining personal growth in all its guises. Laura Munglani’s holistic take on cancer care, as viewed through the lens of modern literature, explores new territories in an all too familiar malady. Sophie McManus then considers the varied causes and implications of precocious puberty in an increasingly sexualised, consumerist society. Be sure, too, to reflect upon Emma Fisher and Alexander Allen’s very different – but equally humbling – accounts on life as a medical student.

If that all seemed a little serious, we’ve provided a rather winsome series of ‘new takes on old topics’ that you’ll be sure to enjoy, including Andrew Dooley’s witty and wise look at our reliance on the radiator. Charles Coughlan and Emily Duncan then transport us back in time, untangling the legend of David and Goliath and the speculation around the Antonine and Justinian plagues, respectively.

As for growth at the molecular level, we are grateful to Jennifer Miller for an excellent review of that ‘little researched brain structure’, the cortical subplate. Many of her ideas link elegantly with those in Josephine Holland’s expert précis of adolescent neural changes; together, these pieces afford us a better understanding of developmental and psychiatric disease. Looking elsewhere in the body, Will Dace negotiates Type 2 diabetes with forensic reductionism, while Beth Kingston reappraises our current theories of oncogenesis. And what about the growth of medicine as a whole? In a constantly changing environment, how can we optimise its progression? And how might knowledge, technology and politics act to limit its growth? These are fundamental questions posed by Molly Gilmartin as she investigates

We’ll look to the future too, as James Taylor scrutinises the science behind gene doping and John Castle critiques recent advances in the field of 3D printing, in the playfully titled “How to grow a kidney”. As the Original Research section continues to develop, we welcome Tom Hine to the team as our new Peer Review Editor, giving thanks to the departing Ben Stewart. Elsewhere, Lara Hibbs joins our magnificent Design Team, for whom hyperbole is wholly insufficient. We owe a titanic debt of gratitude to everyone on the OMSG Committee, who work with relentless diligence and enthusiasm to produce the magazine you now find before you. And, finally, we thank both our writers and our readers for continuing to support the oldest medical student journal in the world. When the reading is over, please do be in touch: we love to hear from you.

The OMSG Editors, Joshua Luck and Barnabas Gilbert

editors@omsg-online.com | www.omsg-online.com

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The Cancer Patient What can we learn by viewing cancer from a patientâ&#x20AC;&#x2122;s perspective?

IMAGE/ROBERT POPE

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‘Abandon hope all ye who enter here’. Dante’s words, written above the gate of hell, symbolise the initial feeling of fear felt by many patients when they are first diagnosed with cancer, according to Robert Pope in his book ‘Illness and Healing, Images of Cancer’ [1]. Pope himself suffered from cancer, and is one of many patients, including the late journalists John Diamond and Christopher Hitchens, who have depicted their perspective of living with this disease through autobiographies and poetry. Diamond, writing about his diagnosis of metastatic squamous cell carcinoma of the tongue in his column for The Times, asserted that ‘the rule…about life-threatening disease, is…that any response to the news of one’s own imminent death is a legitimate one’ [2]. As medical professionals, what can we learn from these accounts that can aid our care of patients living with cancer? More than 1 in 3 people in the UK will develop some form of cancer in their lifetime and currently half of all cancer patients survive with the disease for at least 5 years [3]. In addition, although cancer death rates in the UK have fallen by around 20% over the last 30 years, the overall cure rate is highly variable [3]. This means there are a larger number of people living with cancer than ever before. Poignantly, however, statistics are often meaningless to the individual. As Susan Sontag wrote whilst undergoing treatment for breast cancer, ‘cancer is a disease that strikes each person punitively, as an individual’ [4]. Very rapidly after the ‘cancer’ label is borne, a change occurs and in the words of Hitchens, ‘The novelty of a diagnosis of malignant cancer has a tendency to wear off. The thing begins to pall, even to become banal’ [5]. This sentiment was echoed by Diamond: ‘It doesn’t feel like cancer… [Cancer has] become so mundane that I thought of not mentioning it this week, save as a footnote to a tale of ordinary life’ [6]. Others postulate that it is not the cancer that brings suffering; rather the treatment of it. Indeed, Pope considered cancer treatment to be worse than the disease itself, noting that radiation ‘is equally effective in killing healthy cells as cancerous ones’ [1]. Alice Trillin, describing her experience of living with lung cancer, felt she was being thrust into ‘The Land of the Sick’ [7]. For the care team, this 2013 63:2

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Cancer is the number one fear for the British Public

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sense of frustration may be palliated through effective communication – thus empowering the patient with the liberty to make decisions during a course of treatment. Clearly, the diagnosis of cancer brings an uncertain future, an ‘ambiguous twilight’ in the words of Pope [1]. Patients diagnosed with terminal cancer often feel they are living under the constant threat of death, as echoed by Hitchens; ‘you spend a good deal of time preparing yourself to die with some modicum of stoicism…while being simultaneously and highly interesting in the business of survival’ [5]. This sense of stoicism epitomises Diamond’s mood too: ‘I wasn’t terrified at all: faced with death I was, rather, sad, angry, irritated’ [2]. A patient is not looking for certain facts but rather ‘some belief in themselves’ [8] and this is essential to understand when certain facts, regarding the prognosis for example, are unknown. By contrast, cancer may also be seen as a time for insightfulness, changing the way those with the disease view the world and indeed themselves. Virginia Woolf wrote that ‘[Illness is] like stepping into a different world, where there are different ways of behaving, ways of seeing’ [9]. Hitchens and Diamond made it clear in their writing that they did not want to be defined or changed by their illness. This approach contrasts starkly with that of the poet Jo Shapcott, who’s ‘Of Mutability’ highlighted the fundamental changes she experienced during her time living with breast cancer. Having successfully battled the ‘cellular madness’, she felt hope: ‘mutability’, suggesting death and decay, but also change, with apparent ‘twinklings of joy’. She realised that everything in life was more inse-

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cure, ‘but somehow that’s exhilarating’ [10]. As medical professionals we should note from these accounts the importance of treating our patients holistically as we journey with them through their illness, but never to define them by it. ‘Cancer’s a funny thing’, written by the geneticist Jack Haldane shortly before his death, has a markedly different tone from many other accounts. It highlights the possibility of taking a humorous attitude towards cancer: ‘I know that cancer often kills, But so do cars and sleeping pills …A spot of laughter, I am sure, Often accelerates one’s cure’ [11] Individuals’ views of cancer may often be shaped and influenced by the views of those around them. It is therefore important to understand how society views the disease. Of note, cancer continues to be the number one fear for the British Public, ahead of debt, knife crime, Alzheimer’s disease, or losing one’s job [3]. A patient’s fears may reflect those of the community in which he or she lives. Indeed, cancer is often perceived to be a stigmatised diagnosis. Diamond wrote ‘I had cancer yet I had to indulge others in their fear of it’ [2]. Society may sometimes, consciously or otherwise, view cancer as a diagnosis in which some blame or responsibility lies with the individual. This outlook is perhaps strengthened by research into the causes and risk factors for developing cancer. The opposite view is one in which those afflicted exhibit, above all else, bravery, although frustration at this latter senti-

More than 1 in 3 people in the UK will develop cancer

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The novelty of a diagnosis of malignant cancer has a tendency to wear off

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ment is evident in many patients’ accounts. To those around the patient, both their friends and family and the medical team, this reaction may be unexpected; unsurprisingly, perhaps, we don’t expect patients to be annoyed that we think they are coping well. Diamond offers an explanation for this: ‘The whole battlefield vocabulary suggested that the cure for cancer had a moral basis – that brave and good people defeat cancer, and that cowardly undeserving people allow it to kill them’ [6]. Trillin added, ‘I found the fact that I had cancer unacceptable…if I get sick, does that mean my will to live isn’t strong enough?’ [7]. Regrettably, then, this may leave patients feeling hopeless and even isolated because few can truly understand what they are going through.

- Christopher Hitchens

It is evident, then, that different people respond very differently to a diagnosis of cancer. Fear, frustration, hope, hilarity and anger are just several of the manifold emotions which patients might experience, and the combination influences their attitude towards the disease. We must appreciate that cancer also provokes varying reactions from those around the patient, often stigmatised by the fear of death of a loved one.

So what can we learn from these accounts? Foremost, that there is no right way to respond as medical professionals. We must try to understand the frustration felt by many patients, both from the disease itself, and at those around them. It is crucial that we treat the patient holistically, as an individual, as well as targetOur job as medical professionals should be to both un- ing their disease. We must give patients our time both derstand the disease and to empathise with each pa- to advise and to listen. Indeed, Robert Pope’s book tient and help them through their illness in the most is distributed as a gift to students in many Canadian appropriate way. One crucial element of this care lies medical schools, a testament to the importance of the in the breaking of bad news about a new or recurrent patient’s account. cancer diagnosis. Diamond wrote: ‘Doctors need to know how to bridge that two-second gap between Finally, although much of Shapcott’s poetry points opening the door of the room in which your terrified to the frustration felt by a cancer patient, she reflects patient is waiting with his wife and speaking the first that, in retrospect, ‘it seems, honestly, a trifle now’ words’. In Diamond’s opinion his oncologist demon- [10]. This portrays the fact that, once cured, many strated this best by simply saying ‘We’re going to have patients want to move on with their lives. They no to start treatment again’ [6]. Importantly the oncolo- longer wish to be treated as if they were still in ‘The gist didn’t say, ‘How are you, then?’ Land of the Sick’ [7]. Understanding between doctors and patients is still a problem; it is rather disconcerting that more than a third of patients ‘believe their palliative regimens are meant to be curative’ [8]. The failure of a doctor to communicate a prognosis effectively prevents the patient from making an informed choice about his or her course of treatment.

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Full references available at: www.omsg-online.com

Laura Munglani is a fifth year medical student at Balliol College

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PRECOCIOUS PUBERTY SOPHIE MCMANUS considers whether today’s children are growing up too fast. Certain times in puberty are pretty miserable for us all. Spots and self-consciousness are a couple of obvious hurdles. But at least the vast majority of us contend with the unpleasant aspects of growing up at the correct time. In cases of aberrant early development, there are multiple factors that the medical professional must consider; plus, recent figures indicate that the world’s children are growing up faster than ever before. This could be a cause for concern and begs the question why puberty is, on average, occurring earlier today than in history [1]. There are obvious uncomfortable consequences for a child growing up early – bullying and social exclusion by their peers, for example – but there may be even worse consequences. Young girls entering puberty early may have to deal with inappropriate adult sexual interest. An appalling example of this is evidenced by Lina Medina, the youngest mother on record, who gave birth aged just five [2]. Her parents first took the child to hospital when she presented with an abnormally swollen abdomen. Doctors suspected she had a grossly enlarged tumour but subsequent Xrays revealed she was heavily pregnant; a healthy sixpound baby was later delivered by emergency caesar-

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ean. The identity of the father was never verified, as the child “could not give precise responses” [2]. This is an obviously appalling extreme of precocious puberty but, as observed by clinicians worldwide, children today are entering puberty a few months, perhaps even a couple of years, earlier than the previous generation [1]. Perhaps it is the result of xenoestrogen exposure (found, for example, as bisphenol A in hard plastics), which has consistently been associated with ‘reproductive abnormalities’ [3]. Does increased exposure to chemicals necessarily result in shorter childhoods? Indeed, in 2008, the Canadian government classified bisphenol A as “toxic” under the Environment Protection Act, and is now considering a precautionary ban. This is not a new consideration; over ten years ago, Brown and Lamartiniere conducted animal experiments that implicate xenoestrogen exposure in mammary gland growth and proliferation [4]. Besides this chemical-induced fear however, we might also want to examine a more apparent change that has occurred in parallel with earlier puberty: that of our expanding waistlines.

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CHILDREN ARE GROWING UP FASTER THAN EVER BEFORE. WHAT ARE THE SOCIAL CONSEQUENCES?

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The bodily changes that precede puberty are stimulated by kisspeptins, critical protein regulators of the hypothalamo-pituitary-gonadal axis [5]. Before induction, the body’s lean-fat ratio must alter, increasing levels of the hormone leptin, which in turn leads to production of kisspeptins. These directly act upon GnRH neurons; hence LH and FSH are released, inducing female menarche; the link to male puberty is less well established, but is known to exist. A recent NHS programme recorded BMI values for the nation’s children and found a statistically significant increase in obesity prevalence, unsurprising in light of the problem in the adult population [6]. Indeed, only last year, a paper by Li et al. demonstrated a strong connection between high-fat foods and LH pulse frequency in rat models [7], further confirming the scientific community’s suspicion that modern diets may have repercussions beyond those that immediately spring to mind.

trend may well be tackled with tighter legislation regarding age-appropriate marketing, but it is not an easily soluble problem. Nevertheless, if children are simply maturing faster than before, a concerted approach will be necessary to offer requisite support. Attempts to tackle childhood obesity could be a simple solution in theory, but only time will tell whether they are actually as effective as we might hope. Full references available at: www.omsg-online.com

Sophie McManus is a third year Biomedical Sciences student at Magdalen College

IMAGE/ROSALIE BROOMAN-WHITE

So if the problem lies not in ingestion of chemicals, but obesity, what are the societal consequences? There has been a recent furore over the premature sexualisation of children: companies continue to market adult products to pre-teens, and teachers report that pupils are ever more fixated on body image and sex [8]. This

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GROWING PAINS Bing Tseu listens to a mother’s perspective on raising a child with cerebral palsy “He hardly ever stopped screaming, you know.” Sarah spoke faintly, as though she were talking to herself, “his elder brother would sleep through the night, but Michael used to scream and scream. It was a difficult time for the family. When we expected Michael to be able to sit up by himself he just couldn’t. He wouldn’t grab at things and so I’d just prop him up with a cushion and watch him.” Sarah crosses her legs and drums her fingers uneasily in her lap. “This was 48 years ago – it was a different age then. People told me to stop being a fussy mother, to stop comparing Michael with his elder brother and expecting them to advance at the same rate.”

never really voiced any questions. He was happy to do his own thing.” Sarah pauses, briefly closing her eyes to rouse tired memories, “none of this seemed to outwardly affect David. He was never jealous of the attention that Michael would get. David could talk the hind-leg off a donkey and, as Michael’s speech was never very good, David would just try to talk for him.” Sarah sighs, tilting her head to one side. “David would always make so many allowances for Michael, but I think I was just so busy coping that I didn’t notice at the time.” “When Michael was three, I gave birth to his sister, Catherine, and I have to say that having her around was a real positive influence on him. Cerebral palsy gave Michael such a competitive spirit – he always wanted to be able to do what everyone else was doing, and when Catherine came along, Michael made sure that he learnt to walk before she did.” Sarah breathes in slowly before continuing: “even with his condition, Michael was so keen to play his role as an older brother. He was so protective, and as Catherine was so young he felt that he could do so many things that she couldn’t. It did wonders for his confidence.”

I expect they never really understood how to treat Michael as an equal

“It was a struggle,” she continues, nodding her head gently to emphasise the point, “Michael was almost two when we finally went to see a paediatrician, and it was probably one of the worst experiences of my life.” Sarah purses her lips, pulling the edges of her mouth into a thin grimace. “He was the coldest doctor I’ve ever met. Children were meant to be his specialty but he treated Michael like a car going in for a service. Yes, he managed to pin down Michael’s diagnosis of cerebral palsy, but the meeting had such a terrible effect on Michael. For years afterwards, Michael would cry whenever he saw anyone behind a desk on the television.” “When we tried to explain Michael’s condition to his brother, David, I don’t think he really understood at first – he was only five after all. But David

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Sarah drums her fingers absent-mindedly against the naughtiest children. He made some friends and, her armrest, carefully considering her next sen- though I can’t quite describe it, they never seemed tence: “We did manage to send Michael to a to be close friends. They got on, but they were nevspecialised school – they used to refer to it as a er the kind of friends that would go down to the place for ‘delicate children.’ But we moved across pub together, if you know what I mean.” She softly the country when he was thirteen, and that was shakes her head – a small and solemn motion. “I supwhen we had a bit of trouble finding the right pose the other students weren’t used to dealing with place for him. It was about that time when we people like Michael when they’re all thrown ivn to the same environment. I expect they went to a children’s psychologist to get advice on choosing a school.” She Every day, he never really understood how to treat stops, frowning with a visible air of must wake up Michael as an equal.” frustration. “The psychologist recand ask: Why am Sarah cradles her head in her hands ommended that we should send MiI like this? and closes her eyes before she carries chael to a non-academic school. One on. “To be honest, I’m not sure how where they didn’t do O levels – the sort of school where you would do ‘arithmetic’, Michael has stayed so cheerful. Every day, he must not maths. Obviously I objected, and he respond- wake up and ask: “Why am I like this?” He’s never ed by telling me that I had too great expectations had a day where he’s woken up without his condition and it must be terrible.” Sarah readjusts her skirt for my son.” as she shifts in her chair. “Michael has really done so She inhales sharply, punctuating the pause with a well. I worry so much about him, but I try not to be steely expression. “Now I would take on anybody too protective – that’s the most difficult thing. What if I thought it would do my children good. So we I will say is that I am just fortunate to have a child managed to persuade a local school to take Mi- who is as tremendously determined as Michael is.” chael on – he had to board and it was hard to let him go like that, but we had to do what was best For the first time all morning, Sarah smiles. for him.” Sarah softens her gaze slightly, allowing Full references available at: www.omsg-online.com a small hint of pride to shine through. “Michael is Bing Tseu is a fifth year a coper. He settled well and he found that the best medical student at Christ way to stop the bullying was to be friendly with Church College

IMAGE/LARA HIBBS

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GROW UP EMMA FISHER considers the challenge of 'growing up' in medical school

tepping into the doctors' mess, dressed in new work clothes, coloured stethoscopes around our necks, shiny pen torches to hand and bright orange name badges shimmering in the light, there was no mistaking the new medical students. "Hello team! I'm, one of the consultants in geriatric medicine. They call me the falls guy," said a friendly-faced man with glasses and silver-grey hair. I immediately warmed to him. After his attempts to engage us with interesting questions were met with our blank expressions he proceeded to enlighten us to the world of clinical medicine. By lunchtime, I had already realised that there was a lot I needed to learn.

It was only when my parents left after a precarious drive in the snow to Stoke Mandeville, that I realised I really was going it alone. What if the doctors didn't like me? Worse â&#x20AC;&#x201C; what if the patients didn't? Where was I going to eat lunch? A whirlwind of worries! Mercifully, I found a fellow medical student to eat lunch with in the canteen. And a patient told me that my top brightened up the respiratory ward too. Now just for the doctors... It was on one of the ward rounds that the strang-

IMAGE/ISTOCK

It was 11 o'clock in the evening and I was hiding upstairs in my GP's house. I had arrived earlier that day and was greeted by the cheerful doctor who I was staying with for a week in Didcot. I had been left on my own in the house to bake cakes and had somehow upset the very old Labrador, who started to bark frantically downstairs. I was worried she

thought I was a burglar, so quickly retreated to my new room. But how frustrating! I'd been told to help myself to drinks from the bar in the pool room, but there was simply no way creeping past her. No one in Oxford had told me I would need infrared goggles and thermal imaging apparatus just to traverse the GP's kitchen for a martini and lemonade!

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No one in Oxford had told me I would need infrared goggles and thermal imaging apparatus just to traverse the GP's kitchen for a martini and lemonade!

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est thing happened. "Shall we go to ITU now?" said the SHO, as he bounded on ahead. And then, quite out of the blue, my slightly eccentric consultant sat down in a wheelchair at the side of the corridor in front of me, turned over his shoulder and gestured for me to go behind and push. I tried with all my might , but it just wouldn't budge! It was so heavy I couldn't move it! My consultant didn't look that heavy. How embarrassing!. The rest of the team traipsed back, confused as to why we hadn't followed. "I just wanted to see how much I weigh," explained my consultant. "Oh! I thought you wanted me to push you!" I replied, my cheeks flushing crimson. We all headed off to ITU, slightly bewildered by what had just happened. "It might help to take off the brakes next time!" he whispered in my ear. I gave him a meek smile and managed to avoid any further encounters with wheelchairs for the rest of the ward round. No sooner had I settled in on the respiratory ward, and I was off to another perplexing world of scrubs, gowns and unconscious patients. "Diathermy please!" the surgeon requested, as I braced myself for him to stamp on my toes instead of the pedal again. Fascinated by the intricate surgery before my very eyes, I barely noticed something flick onto my cheek. "Oh no!" yelled the

Scottish woman beside me. "I've covered the medical student with blood! Please can somebody wipe it all off her neck?" I finished the operation splattered with blood and walked back to the changing rooms with one scrub shoe higher than the other. At least it wasn't as bad as when I wore tights under my scrubs and did my face mask too tight. Rebreathing carbon dioxide and overheating under operating lights is never much fun... Despite patients telling me that 'doctors get younger and younger these days' and 'you look like you could be just 13 dear', I do feel like I have grown up this year, even if I have to stand on a stool to see in theatre! Admittedly much of my time has been spent smiling apologetically at bemused patients when I walk past them for the fifth time, still lost on the same ward. However, we're all on a steep learning curve as medical students – and, in fact, it's all part of the fun. We all have to grow up, and fast! And maybe one day, I'll even grow into a matching pair of scrub shoes... Full references available at: www.omsg-online.com

Emma Fisher is a fifth year medical student at Green Templeton College

"Diathermy please!" the surgeon requested, as I braced myself for him to stamp on my toes instead of the pedal again.

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Darkness Within

IMAGE/HANNAH THOMPSON

ALEXANDER ALLEN talks about his personal experience of dealing with depression

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“Depression” doesn’t really do it justice. A word denoting an economic fluctuation, a meteorological term, and used interchangeably with feeling ‘a bit blue’, is also the medical description of a state of abject psychological torment. William Stryon, an American author who suffered from depression, thought the term “brainstorm” would be the perfect description (were it not already taken) for the mental turmoil that embodies such illness. [1]

dangerous and debilitating condition.

My first experience of depression, only recognised with the benefit of hindsight, was when I moved to 6th form college. I was sixteen and the move was a big one; I didn’t have any classes with friends and was considerably more stressed than before. My depression didn’t present in the “typical” way. I was a bit down but not excessively so – there was no wailing or gnashing of teeth. There was simply a Depression is one of the most feeling of malaise that pervaded common chronic illnesses that most of my social activities. I young people can suffer from, enjoyed my hobbies less, felt it with suicide being the second was an effort to socialise with highest cause of death in this my friends, had no appetite or age group [2]. And yet psychi- libido, and I would over-analyse atric conditions (depression in every interaction looking for particular) get short shrift in faults in myself. It was exhaustthe public view. Stigma even ing. This is why I think brainextends into the medical field, storm would be a much more where one would hope accept- apt name. This is not a passive ance would be more forthcom- process but an ‘active anguish’, ing. Psychiatry as a speciality as American Psychiatrist Wilmay be looked down upon, or liam James described it. [3] overlooked entirely. Many depressed patients on the wards The cause, while I could put often have their mental wellbe- my finger on a few, was almost ing ignored; a not uncommon certainly the accumulation of opinion is that they need to many things. These would up‘snap out of it’. As someone who set most people for a little while has experienced depression, I but, with me, they lingered on. find that notion grossly offen- It was the small things too; for sive. It trivialises an extremely some reason these rankled and

festered where others would shrug them off. Not dissimilar to an infection, I suppose. But perhaps they are not that important to identify in retrospect: they were probably beyond my control before the depression and almost certainly were afterwards. In fact I think this lack of control probably underlies the mental paralysis that depression can inspire, seeping from the specific to the universal. More than once I felt my decisions and choices were pointless, that I was powerless to influence what was happening around me. After about a year it seemed to burn itself out and I thought no more of it. Unfortunately it returned at university, usually only for a few weeks at a time. I began to suspect something was wrong but it wasn’t until my 3rd or 4th year that I finally admitted it to myself. While it sounds rather clichéd, acknowledging the problem is the first and most difficult step towards a cure. It took another year before I actually sought professional help. The main reason was stubbornness: I was not immune to the stigma of psychiatric conditions, and part of me thought that I “should” be able to deal with this myself - not be-

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I felt my decisions and choices were pointless

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ing able to was a flaw in my character. It was only when my psychiatric and GP rotations showed me the potential interventions and treatments available that I felt able to act. When my next episode caused me to struggle with even getting out of bed or leaving the house, I realised things had gone too far. I visited my GP and emailed the University Counselling Service. My GP was very understanding and considerate. He didn’t push me to reveal more than I was comfortable with, didn’t attempt to push treatments, and gave practical advice for what the next steps could be. He provided the archetypal patient centred consolation, and was probably the most important person in my recovery. Counselling provided a shoulder to cry on but little else. The counsellor drew out a lot of issues, but failed to address them in a practical way. Solutions such as moving house or missing a year of Oxford were not feasible and almost certainly would have compounded my sense of failure. Anti-depressants provided minor relief (mainly due to reduced anxiety) but they caused insomnia. Combined with the poor quality sleep I was getting already, this was particularly non-ideal. Cognitive Behavioural Therapy was by far the most useful part of my treatment. Much of it was common sense, but by making me actively practice the thought techniques it dealt with the

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underlying problem: not the causes necessarily, but the self-destructive and catastrophic thinking patterns associated with them. I did an online course that allowed me to be flexible with my time commitments. Obviously what might work varies from person to person, but my overall message from this would be that at no point did I feel forced or coerced into any particular treatment. I hope that my story has given a small insight into depression, and how it feels to be on the other side of the system. It is not something that can be overcome over easily. It requires pro-action, effort, time and a lot support – sadly, the things that depression makes you mostly likely to think you lack. I do not feel fully recovered, but I do feel I have grown enormously and become more capable at dealing with my problems. My overriding regret is that I did not seek help sooner, and the hardship I endured because of that. I urge anyone who thinks they may be suffering from depression to tell someone about it; friend, family or GP. And I hope that if you suspect someone might be suffering from depression you’ll offer your ear and your support. After all, you’d hope they would do the same for you. Full references available at: www.omsg-online.com

Alexander Allen is a sixth year medical student at Brasenose College

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A perfect

'pick-and-mix' IMAGE/GILES NEAL

me.

EMMA THURSTON investigates the growing popularity of cosmetic labiaplasty.

Women’s bodies have long been vulnerable to scrutiny. However, in the modern era this is compounded by an increased openness and awareness of sexuality throughout society and a psychological drive for every element of one’s physique to be perfect. The ever-increasing provision of cosmetic surgery makes perfection seem attainable. There has been a radical increase in the number of labiaplasties performed in the UK over recent years. The aim

Some women have labial hypertrophy so extensive surgical intervention is advised to prevent chronic infection, pain and the restriction of sexual and sporting activities. However, the incidence of labia pathology has not increased over the same time frame as the growing demand for reconstructive surgery [2]. This suggests a cultural shift in either the desire for or awareness of female genital cosmetic surgery (FGCS). There is a general consensus within the field that the growing availability of pornography is involved in the increasing desire to go under the knife. Pornographic images are of-

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of the surgery is usually to make the labia minora smaller and/or more symmetrical. The exact number of surgeries performed is difficult to state as the majority are conducted by private sector. However, over the past ten years there has been a five-fold increase in the number of labial reduction surgeries conducted by the NHS [1]. This triggers the question of why so many women are electively undertaking such radical surgery.

ten altered and models can have undergone surgery themselves or been selected specifically for their ‘ideal’ anatomy. This can lead to the comparison of one’s self against the socially cultivated picture of perfection. With exposure often at an early age, this can cause an imbedded feeling of being abnormal or ‘sub-optimal’ which can grow into serious concerns causing great distress and a distinct lack of confidence. This issue is exacerbated by the lack of opportunity for comparison against un-modified or ‘enhanced’ women. There has also been an increasing social trend favouring a shaved pubis. A possible factor in this social trend is the

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increased prevalence of oral sex among heterosexuals; feasibly due to a change in societal attitudes beginning in the 1970s which made it acceptable before marriage, being previously considered more intimate than penetrative sex [3]. Regardless, a shaved pubis leaves genitalia far more visible than in the past, adding to concerns regarding its appearance, enhancing body-awareness and even seemingly exacerbating any protrusion of the labia [4].

IMAGE/ROSALIE BROOMAN-WHITE

Figure 1: Surgical technique: a) preoperative marking; b) de-epithelialisation of both sides of the upper labium and inferior wedge resection; c) wound closure: the labium is shortened in two dimensions - width and length; d) a narrow and shorter labium is attained [8].

The ever increasing availability of cosmetic surgery and ac-

ceptance of cosmetic enhancement can lead to an increase in internal and/or external pressure to conform. Such issues of ‘imperfection’ and self-esteem are often expressed as a fear of being intimate with someone. This fear is made all too clear when reading a responsive blog to an episode of the television programme Embarrassing Bodies, which filmed a woman who underwent a labiaplasty; “I have been in a relationship with my first boyfriend for a year and when we first had sex I was so terrified of what he would think I was actually shaking with fear” [5].

The age of those requesting cosmetic surgery on their genitals is a growing concern. One study documented a case in which an 11 year old was referred for labiaplasty and showed that the mean age of women seeking a labiaplasty was 23 (even when the proportion of women who wanted surgery for post-partum anatomical changes were included).

by the Guardian newspaper regarding her experience: “It was horrible. They didn’t explain how much it was going to hurt. I couldn’t walk for three days and I caught two infections. A lot of women who go for surgery don’t know what kind of pain they are putting themselves through. I never want to go through it again, but I’m glad I did it. It really helped my confidence” [7].

The external genitalia continue to develop throughout adolescence. Not only may this make initial asymmetries reduce over time (making interim surgery arguably unnecessary), if the labia continue to grow following surgery a second operation may be required [6]. Moreover, younger girls may not comprehend the potential complications and the painful, prolonged recovery the surgery entails.

This article not only highlights the naivety of some girls undergoing the procedure, but demonstrates that the risks of the operation are very real. The most commonly practiced surgical technique, the ‘straight amputation’, carries the risk that the scarred suture line, which replaces the edge of the labia, can cause chronic irritation and discomfort. However, a newer method involving deepitheilalisation and a small inferior wedge (represented diagrammatically in figure 1) could reduce these risks.

This raises the issue of informed consent. For example, a 22 year old who had undergone surgery was interviewed

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Moreover, the natural relationships of the labia minora to other tissues such as nerves and the clitoris may be disrupted, leading to reduced sensitivity and the risk of lifelong decreased sexual function [9]. These issues are exacerbated by social turbulence during adolescence; conflict and gross unsympathetic acts could worsen anyone’s feel-

ings of insecurity and intensify the social influences on a girl’s decision to ask for elective surgery.

The fact that the majority of young women requesting a referral for labiaplasty are within the presently defined anatomical norms implies that insecurities regarding body image need to be addressed [2,6]. The introduction of ‘body image’ education into our current education system has been proposed as a way of tackling issues of lowered self-esteem. Such lessons would be in addition to the current ‘sex education’ classes which concentrate on methods of contraception and sexually transmitted diseases, rather than on the more psychological aspects of relationships as a whole. In doing so, potential patients would become aware of the vast variation there is within the realms of normality. This would give girls a more natural basis for comparison than the images available from the pornographic industry, reducing the likelihood that they deem themselves abnormal.

wanting labiaplasties would be to modify the clinical assessment of women referred for FGCS. Adopting a more sequential strategy could improve outcomes. For example, it is possible to manage functional symptoms of labial hypertrophy with patient education in personal hygiene and the avoidance of close-fitting clothing [10]. Elective surgery could be offered only when these strategies fail to reduce a patient’s symptoms.

Another approach to meet the growing number of women

Striving for anatomical beauty is not a new issue in itself. However, perceptions of what beauty is and the social impacts of imperfections are dynamic. Even though many girls seeking labiaplasty are within the anatomical norm, they deem it necessary to conform to the social norm imposed upon them. With the ever increasing accessibility and acceptance of surgical cosmetic enhancement such criteria can be sought. It is a fundamental role of holistic medical practice to enhance both the physical and psychological wellbeing of a

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These concerns are highlighted by some practicing physicians who advocate a minimum age for the procedure, waiting until the patient is more mature and able to participate in informed consent [6].

Adapting the consultation to take a greater focus on the psychological wellbeing of the patient may be even more effective. A more holistic approach may raise issues which suggest that psychological rather than surgical therapy maybe a more effective initial management plan. Such non-surgical interventions could be undertaken in a primary care setting before referring to a surgical team. This could result in more long-term benefits, including an acceptance of normality and enhanced body perception.

patient and ensure they are not reduced to fragmentations of ‘perfect’ body parts. Although medically advisable at times, cosmetic surgery should not be considered a ‘quick fix’ for underlying psychological issues. Full references available at: www.omsg-online.com

Emma Thurston is a fifth year medical student at Worcester College

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Shadows of the subplate

JENNIFER MILLAR evaluates the role of transitory cortical neurons in health and in neurodevelopmental disease 20

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ubplate neurons never feature heavily in standard medical textbooks or articles on neurodevelopment and disease. However, this early born lamina has a powerful contribution in arranging the neocortex and coordinating thalamic inputs. Consequently, the subplate is beginning to be investigated in animal models of human brain disorders which feature widespread, subtle changes to cortical structure, such as schizophrenia and autism. The recent growth in studies identifying functional neuronal populations by their molecular genetic markers is beginning to reveal the subplate as a hotspot for the expression of genes implicated in disease. Although still an emerging field, subplate proteins with roles in axon pathfinding, cell signalling, cell-cell adhesion, synaptic plasticity and apoptosis hint towards mechanistic accounts behind altered thalamo-cortical projections. So what exactly is the subplate? Neurons of the subplate are some of the earliest born cells of the cortical plate, a layer of progenitor cells which gives rise to all neocortical glutamatergic neurons. Once the subplate is formed, neurons of cortical layers II to VI ascend from the ventricular zone, taking their positions between the subplate and the marginal zone in an inside-out manner. Initially described in Kostovich and Rakicâ&#x20AC;&#x2122;s Nissl-staining study in rhesus macaques (1980), subplate neurons are present from the first trimester of pregnancy [1], although the majority disappear in early infancy [2]. Remarkably, the number and thickness of neurons in the human subplate is substantially greater throughout embryonic development than in macaques. Such comparative work offers a tantalising suggestion that subplate expansion may contribute to enhanced human cognitive abilities. However, species specific accounts of subplate function remain a distant concept.

Since its discovery many researchers have dem onstrated that the subplate is essential for successful thalamic innervation of layer IV during the early postnatal period. An anatomical study from Oxford (1998) using fluorescent dye tracing in rat embryos found that thalamic axons associate with and grow alongside subplate neurons in the internal capsule before invading the cortex [3]. Interpreted within the Shatz [4] and Molnar [5] hypotheses of axon guidance, this finding supported a role for the subplate in thalamic axon pathfinding. More recently, Shatz and Kanold demonstrated the necessity of subplate-mediated guidance in thalamic axon ingrowth in the primary visual (cat) and somatosensory (rodent) cortices [6,7]. Ablation of the subplate in healthy embryos using an immunotoxin against p75, a protein expressed in subplate and cholinergic neurons, uncoupled electrophysiological recordings in the thalamus and layer IV. Furthermore, sensory input-dependent topological

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features known as ocular dominance columns and barrels, representing appropriate thalamic innervation, failed to develop. Although it is possible tnon-specific neuronal damage could account for some of these observations, such findings strongly support an active role for the subplate in specifying ascending input to the neocortex. Furthermore, the subplate may form a transitory relay between thalamic and layer IV neurons before synapses form directly. Electrophysiology experiments have shown that these microcircuits display sensitivity to thalamic inputs, responding to auditory stimuli [8]. Yet, the reach of the subplate extends beyond projections to layer IV. Its role in interneuron migration may allow a greater understanding of interneuron defects in schizophrenia, autism and mental retardation [9]. Attempts to pin down the mechanism behind subtle perturbations in migration have led to many theories, with inappropriate subplate activity a strong candidate. Kanold described

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Figure 1: Structure of the developing neocortex and subplate. Panel A shows a coronal section of a schematic developing embryonic human brain, highlighting the position of the neocortex and the route taken by invading thalamic fibres. Panel B shows a schematic cross section of the cortical plate at light microscope magnification. The subplate is visible between the growing cortical plate and the progenitor cell layers in the subventricular zone and ventricular zone. PWC stands for weeks post-conception. Taken from Molnar and Rutherford, Sci Transl Med (2013).

delayed expression of key GABAergic genes in subplateablated cats [10], including downregulation of GABAA receptor subunits and KCC2, the transporter essential for switching from GABA depolarisation to hyperpolarisation. These changes are likely to have a profound effect on cortical microcircuit development and oscillatory activity. Luhmann also reported a role for subplate GABAergic neurons in regulating early neocortical synchrony. Subplate interneurons fire powerful oscillatory bursts on excitation with acetylcholine [11], which may be crucial to the selective survival of cortical neurons [12]. Such importance in neurodevelopment supports further investigation of the subplate. Recent findings offer new directions for research, revealing the subplate as a heterog-

enous structure. The Molnar lab in Oxford has identified several subplate subpopulations which express overlapping genetic markers related to their location and persistence in the neocortex [13, 14]. These markers include the transcription factors complexin3 and Lpar1. Using bioinformatics to generate interactive protein networks could allow comparison against an array of developmental disorder risk genes. This approach could provide solid support for subplate driven neurodevelopmental disease theories, including a mechanistic explanation. Lpar1-expressing neurons are of particular interest. Born in the rostro-medial telencephalic wall [15], these progenitors produce cortical GABAergic interneurons and glutamatergic subplate neurons which may communicate during cortical organisation. In mice, this subpopulation is long-lived with long range projections [16].

Figure 2: Genetic markers of the subplate. Panel A shows the heterogeneity of transcription factor expression in the subplate neurons with regards to Lpar1 and CTGF. Panel B is a schematic of the overall pattern of gene expression with the top of the figure representing the superficial subplate in contact with the neocortex. Adapted from Hoerder-Suabedissen and Molnar, Cereb Cortex (2012).

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Work outside the mouse to confirm the conservation of these genes in other mammals and humans will be important before ambitious disease hypotheses are generated. Species comparison is especially important as the subplate persists into adulthood in rodents [17] whereas it almost completely disappears after infancy in primates. Continuous influences from the subplate throughout life in rodents may contribute a qualitatively different role compared to the thicker, transitory layer in humans. Despite this concern, evidence is emerging for a role of these genes in psychiatric conditions. Work from human [18] and rodent studies [19] suggests that the subplate preferentially undergoes apoptosis during ischaemic epi-

sodes in labour, a potential explanation for common cognitive issues in these children. Accompanying this has been a substantial shift towards neurodevelopmental accounts of many psychiatric disorders, including schizophrenia. Shadows of early subplate disorders have been suggested by robust findings in the postmortem schizophrenic brain [20]. A number of authors, including Paul Harrison, have identified changes in the density of interstitial white matter (the cells which initially accommodate the subplate) and the expression of reelin (a glycoprotein important in subplate neuron migration) in the brains of adult schizophrenics. This causal account has been expanded by an influential article identifying subplate-specific or enriched genes as-

Figure 3: Golli-GFP transgenic mouse Panel A shows the expression of the bright green Golli-GFP preferentially in the subplate in the mouse brain at embryonic day 17 (E17). This allows the subplate (sp) to be differentiated from the cortical plate (cp) and marginal zone (mz) above it and the white matter axon tracts below (wm). Panel B shows the substantial shrinkage of the subplate by post-natal day 0 (P0) in the same mouse construct. Panels C and D show the ingrowth of subplate marker expressing neurons into the cortical plate at P10. The red fluorescent protein stains for the 5HT transporter, expressed by thalamic axons on invading the cortex. Adapted from Molnar J Physiol (2009).

sociated with an increased risk of autism and schizophrenia [21]. 11 subplate genes were found to contribute a risk of sporadic autism (5 were fully subplate specific) and 10 for schizophrenia. The construct validity behind subplate disorganisation in developmental disorders has always been strong and such findings only signify the start of concrete molecular investigations that could provide useful mechanistic accounts. The origin of these disorders can only be understood if the

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developmental mechanisms are revealed. A fascinating, and little researched brain structure, the subplate may be hiding even more secrets about the assembly of a uniquely human cerebral cortex. Full references available at: www.omsg-online.com

Jennifer Millar is a fourth year medical student at University College

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All grown up but still growing… Neural changes in late adolescence and their potential

hen we think of the growing brain, we focus primarily on the changes in utero and early childhood. The transformation taking place throughout adolescence is comparatively overlooked. Humans have developed a markedly larger prefrontal cortex (PFC) than other primates [1] – reflected in a longer adolescence, during which time higher order processes are refined. Abnormalities arising during this important period can lead to social, emotional and cognitive deficits, as well as psychiatric illness. As Paus et al. argue, “moving parts get broken”, and adolescence (with its myriad of behavioural, hormonal and physiological changes) represents a vulnerable time for the brain [2]. The national comorbidity survey revealed that the peak age of onset of any psychological disorder is 14 years [3]. Schizophrenia was once considered to be a juvenile neurodegenerative disease, but unlike other such conditions there is little change following initial presentation. The changes in neural structure, self-related processing and higher order functioning are now thought to be neurodevelopmental in origin [4], and it follows that schizophrenia may manifest following the period in which these processes develop: adolescence. Feinberg first proposed that schizophrenia is due to an exaggeration of typical pubertal changes, showing that the normal trajectory of decreased delta wave sleep in adolescence was notably exaggerated in this population [5]. This theory is further supported by rare cases of childhood onset schizophrenia; in which the characteristic decrease in frontal grey matter is enhanced fourfold [6]. With the development of complex brain imaging methods, an understanding of both the linear and non-linear changes in cortical grey matter density is being developed [7-10]. Early detection of abnormal trajectories in these changes may help to identify those in the schizophrenia prodrome, potentially facilitating prophylactic intervention before the disease manifests itself. Currently, we rely on clinical detection of such individuals. The study of those identified as “at high-risk mental state*” has revealed a transition to psychosis rate of approximately 20% during a 1 year period [11]. Some argue that the use of cognitive behavioural therapy may reduce the psychological burden on these individuals, thus slowing or preventing progression. However, a recent multisite randomised controlled trial showed no difference in transition rate between those who received monitoring of mental state plus cognitive therapy compared to those who received monitoring of mental state alone [12]. Although these data appear robust, it should be noted that the overall transition rate in both groups was lower than expected, at 8%. The use of technology, alongside clinical monitoring may provide earlier and more sensitive detection of those at risk.

IMAGE/ROSALIE BROOMAN-WHITE

There is therefore a need for an interdisciplinary science of adolescence. This would incorporate epidemiology, social neuroscience and psychiatry in order to study genetic and environmental interactions and their impact on the adolescent brain, exploring how psychiatric disorders develop and become established [13]. This will aid us not only in detection and diagnosis of these conditions, but also in guiding more effective treatment and – perhaps – even prevention.

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*brief, intermittent or attenuated psychotic symptoms or genetic high risk combined with functional decline.

Full references available at: www.omsg-online.com

Josephine Holland is a third year graduate entry medical student at Somerville College

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Can medication be used to manage violent behaviour?

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ROSALIE BROOMAN-WHITE considers the problem of violence among schizophrenia patients in High Security Hospitals... Although violent behaviour is uncommon among schizophrenia sufferers in the community [1], it is a significant problem among patients in the forensic setting. Of note, schizophrenic men have a significantly higher rate of violent offending than men diagnosed with non-schizophrenic mental disorders [2]. Given that schizophrenia is known to be linked to violence, specific treatments to manage violent behaviour may be as important as those to treat the illness itself. This is especially important for patients with treatment-refractory schizophrenia in High Security Hospitals, who are considered to be at high risk of harm to others. CLOZAPINE: THE CURRENT GOLD STANDARD

One drug that has proven effective in managing treatment-refractory schizophrenia and associated violent behaviour is clozapine [3-5]. A 1996 study found that nearly half of these patients exhibited fewer episodes of physical aggression when treated with clozapine, with a concomitant reduction in verbal aggression noted in 70% of patients [6]. It remains uncertain, however, whether this reduction in aggressive behaviour is due to an overall reduction in the positive symptoms on schizophrenia or, rather, because of a specific anti-aggressive effect of clozapine [7, 8]. THE NEUROCHEMICAL BASIS OF AGGRESSION

The neurochemical basis of aggression is still poorly understood. Overall, serotonin (5-HT) seems to be the major neurotransmitter implicated in aggressive behaviours, including violent crimes [9]. However,neuroadaptive changes in dopamine levels (?) have also been reported following repeated aggressive experiences [10]. Clozapine is thus thought to mediate its anti-aggressive effects through a wide receptor profile, which includes both 5-HT and dopamine receptors. In the past, the D2-receptor antagonist haloperidol has been used to effectively treat aggressive patients, thereby implicating mesocortical dopaminergic neurons in aggressive behaviour [11]. Unfortunately, however, haloperidol is an unattractive long-term treatment for aggression due to its side effect profile.

NEW TREATMENT STRATEGIES: CLOZAPINE AUGMENTATION

One double-blind, randomized placebo controlled trial comparing amisulpride with haloperidol found that moderate to high doses of amisulpride attenuated hostility in acutely psychotic schizophrenia patients [12]. Augmenting clozapine treatment with amisulpride could therefore be a useful strategy for the treatment of aggressive and violent behaviours. For a subpopulation of treatment-resistant patients currently in high security hospital, this combination seems to be more effective at tackling these specific behaviours and reducing their risk of harm to others, compared to clozapine alone. This augmentation strategy may provide a new treatment avenue for aggressive behaviours in the forensic treatment-resistant population. SO WHAT?

Treatment-resistant patients are often highly symptomatic, requiring long periods of hospital care [13]. This may account for the disproportionately large percentage of the total cost of schizophrenia treatment represented by treatment-resistant patients [14]. Patients with a history of schizophrenia and violence in the forensic setting are also associated with higher treatment costs. On an individual basis, reducing a patientâ&#x20AC;&#x2122;s risk of harm to others and their incidence of violent behaviour facilitates participation in occupational, psychological and vocational therapies and should ultimately improve their treatment outcome and reduce their length of stay in high secure hospitals. Strategies to bring about improvement in this subgroup of patientsâ&#x20AC;&#x2122; symptoms and violence may therefore benefit both the individual and the health service at large. Full references available at: www.omsg-online.com

Rosalie Brooman-White is a fifth year medical student at Green Templeton College

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Targeting Toll Like Receptors in Cancer Therapy Too Little Research? Beth Kingston explores the scope of TLR targeting and the current limitations of this approach

ince the discovery that Toll-like receptors (TLRs) mediate the anti-tumour effect of Coley’s toxin (an early cancer immunotherapy comprised of bacterial toxins), there have been many attempts to manipulate TLRs in cancer treatment. However, limited success to date emphasises the need to reassess the therapeutic value of TLR targeting and to ascertain, for good, whether TLRs really justify their etymological origins (Toll; ‘Great’ [German]).

THE GOOD mmune evasion is a current trend in cancer research; pioneered as one of Hanahan and Weinbergs’ emerging characteristics of cancer [1]. TLR agonists stimulate dendritic cells and hence an immune response, but they also stimulate other immune cells. For example, TLR2 ligation decreases the threshold for T cell activation, enabling response to weakly immunogenic antigens [2]. This can negate the need for co-stimulatory molecules, allowing TLR agonists to be used as cancer vaccine adjuvants. Indeed, the only current phase III trial involving TLR agonists is such a vaccine – one based on the MAGE-A3 antigen Astuprotimut-R [3]. Further potential for TLR agonists comes in the form of combination therapies, since those targeting varying TLR isotypes have synergistic effects, decreasing T regulatory cell activation [4] and reducing radiation induced T cell apoptosis to increase anti-tumour activity [5].

THE BAD nwanted characteristics of TLR agonism in cancer cells often reflect those desired in T cell activation, particularly increased growth [7]. Harnessing specific anti-tumour effects of TLRs is therefore a major hurdle - but not an insurmountable one, as shown by manipulation of TLR3 signalling [8]. TLR stimulation can drive chemotherapy resistance, inhibiting treatment as well as undermining beneficial effects of TLR ligation [9]. Understanding how such resistance is initiated may allow avoidance of resistance to chemotherapy in general; to this extent, TLR agonists could enhance understanding of cancer pathogenesis, despite having a limited therapeutic effect.

HMGB1, expressed by tumour cells, increases tumour cell proliferation by ligating TLR4 and creating a positive feedback loop. Incorrect TLR agonism could therefore drive tumour progression, illustrating the need for understanding to improve safety [10]. TLR independent effects, which utilise TLR pathway components, are also important. For example, many melanoma cells express IRAK1 or 4, inhibition of which retards

IMAGE/LARA HIBBS

Direct effects on tumour cells also aid the therapeutic response. Imiquimod, a TLR7 agonist, causes tumour cell apoptosis, inhibits angiogenesis and facilitates

the immune response. Its action and efficacy may therefore be multimodal – exploration of which may provide new therapeutic targets. Of note, the inhibition of angiogenesis also reduces tumour interstitial pressure, thereby aiding drug delivery [6].

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py Expecting such a complex, ubiquitous system to be easily manipulated is perhaps naïve. tumour growth [11]. Understanding such downstream effects may aid segregation of hazardous and useful outcomes and facilitate manipulation of these separate effects therapeutically. Associations between TLR gene polymorphisms and several types of cancer [12] support the argument for TLR manipulation in cancer therapy. However, many agonists (e.g. Pfizer’s TLR9 agonist CPG7909) fail to show efficacy, despite combination with chemotherapy. Most successful TLR agonists have been anatomically localised - such as intravesical BCG immunotherapy in bladder cancer. As BCG targets both TLR2 and 4, it supports the need for TLR agonist combinations (indeed, the Astuprotimut-R trial uses such a combination, with TLR4 and 9 agonists in addition to the MAGE-A3 antigen). However, combinations can be detrimental; for example, TLR3 and 4 ligation increases production of the immunosuppressive factor IL-10 [13]. Thus, combinations must be carefully studied and not presumed to be effective – a worrying trend in TLR research. THE CONFUSION LR agonists have diverse effects that could inhibit tumour growth, but expecting such a complex, ubiquitous system to be easily manipulated is perhaps naive. Among factors limiting TLR manipulation are varying TLR expression in different tumours and different patients (suggesting a need for ‘TLR typing’ of tumours [7]) and variable effects of the same TLR agonist. Flagellin administration with tumour implantation increases tumour growth, but administration

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8-10 days afterwards reduces growth, suggesting that timing is an essential consideration in TLR targeting [14]. Further confusion is caused by cell type-dependent effects, with the same agonist inducing proliferation and limiting growth in different cell lines. Too much focus on moderately successful TLRs (ignoring more potent options) has also stifled progress [3]. Until pro-tumour effects of TLRs are elucidated, studies of highly effective agonists are potentially dangerous, illustrating the need for improved understanding before clinical use. THE CONCLUSION lthough frightening to look into the void of our current ignorance, without examining this knowledge deficit, clinical trials will continue to fail, jeopardising funding and the potential usefulness of TLRs. TLR agonist therapy is frequently compared to a double-edged sword; however, it is not TLR agonists that are dangerous, but our lack of understanding of the pathways they initiate. Optimising the response, using other treatments and combinations, localisation of the agonist, separation of pro- and anti-tumour effects and timing are important future considerations. TLR agonists have potential (albeit not perhaps as great as once thought), but greater understanding of the basic science is needed before transition to clinical practice can be safe and effective.

Full references available at: www.omsg-online.com

Beth Kingston is a second year medical student at Corpus Christi College

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Type 2 Diabetes – Death or Dedifferentiation? Will Dace explores the theory that loss of beta cell identity may cause Type 2 diabetes

ype 2 diabetes mellitus (T2DM) is characterised by dysfunction of pancreatic beta cells, alongside peripheral insulin resistance. Its prevalence continues to rise rapidly and by 2030, approximately 552 million adults will be living with T2DM worldwide [1]. How can we stem this seemingly inexorable increase? The recent explosion in T2DM is undoubtedly being driven by modern ‘Western’ lifestyle changes, and many struggle to improve their diet or undertake exercise. However, many obese people do not develop diabetes, and it is well recognised that a beta cell defect is central to the pathogenesis of the disease. Thus a critical step in unravelling the aetiology of T2DM will be to solve the ongoing debate regarding the pathogenesis of beta cell dysfunction. Both reduced beta cell mass and impaired insulin secretion are postulated to cause beta cell failure in T2DM, but their relative extent and importance is contested. Reduced beta cell mass is classically thought There is ongoing to reflect increased apoptosis, but more recently the idea debate regarding the has emerged that beta cells may dedifferentiate into propathogenesis of beta cell genitor-like cells and/or subsequently reprogram into alpha cells. The latter finding might help explain the dysfunction in T2DM bihormonal nature of T2DM, which is characterised by dysregulated glucagon release as well as reduced insulin secretion [2]. Preventing or reversing this reprogramming using “beta cell identity drugs” may therefore provide a powerful new therapeutic strategy.

IMAGES/LARA HIBBS

Current thinking suggests that beta cell failure, in the face of metabolic stress, results from increased beta cell apoptosis in the absence of adequate self-renewal. However, the evidence is controversial: increased apoptosis and loss of beta cell mass is indeed observed in human T2DM [3, 4], but the impairment of beta cell function substantially outweighs the rate of apoptosis [5]. In mice, beta cells replicate very slowly [6] but retain the capacity to increase their proliferation rate in response to physiological challenges such as gestation and peripheral insulin resistance [7, 8]. Surprisingly, near-total destruction of murine beta cells reveals the intrinsic ability of other differentiated pancreatic cells to reprogram and express insulin – a process known as transdifferentiation [9]. Thus it appears that under certain conditions, beta cells may reprogram into alpha cells and vice versa. Recently, Talchai et al [10] proposed that T2DM may result not from beta cell death, but from dedifferentiation. Genetic ablation of Fox01, a key beta cell transcription factor, caused reversion of beta cells in mice to an uncommitted endocrine progenitor-like stage. These dedifferentiated cells no longer expressed key beta cell genes (e.g. insulin, GLUT2) but instead expressed other islet hormones, including glucagon. This change may underlie not only the insulin deficiency but also the dysregulated glucagon secretion observed in T2DM. Furthermore, the observation of abundant “empty” (i.e. insulin-granule depleted) beta cells in two mouse models of T2DM suggests dedifferentiation may well be a common pathway to beta cell failure. The question, then – is dedifferentiation a mechanism of beta cell failure in humans, or is this phenomenon specific to mice? Although an increased proportion of glucagon-expressing cells has been reported in the islets of patients with T2DM [11], this appears to reflect the loss of beta cells rather than proliferation of alpha cells, or beta cells reprogramming into alpha cells. On the other hand, Spijker et al showed recently that primary human beta cells can spontane-

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ously convert into glucagon-producing alpha cells, in the absence of any experimental genetic modification [12]. This evidence for the plasticity of human pancreatic endocrine cells resonates well with Talchaiâ&#x20AC;&#x2122;s findings. Beta cell dedifferentiation and reprogramming may therefore cause T2DM in humans too. Currently, management of diabetes focuses on maintenance of glycaemic control (fasting and postprandial blood glucose, and HbA1c) to reduce complications, such as microvascular disease. A better approach would be to prevent disease progression by targeting the cause, not only the effects of T2DM. The United Kingdom Prospective Diabetes Study [13] demonstrated that neither sulphonylureas nor metformin provided any beta cell protective effect in newly diagnosed patients with T2DM, over the 15-year course of the study. Shortage of donor pancreata and requirement for toxic immunosuppressant drugs constitute obstacles to the clinical application of islet transplantation [14, 15]. Despite advances, stem cell development still faces significant hurdles and new therapies are urgently needed [16-18]. Exploiting the adult pancreasâ&#x20AC;&#x2122; ability to generate new beta cells, a phenomenon demonstrated in a myriad of experimental diabetes models [19], may constitute one avenue for development of novel, effective cell replacement therapies. Functional beta cells provide far better glycaemic control than any other therapy. Beta cells can be produced, under certain conditions, by three main processes - neogenesis [20-22], replication [23-27], and reprogramming [28, 29] - although much of the evidence is contradictory. Both exocrine cells [19, 29-32] and alpha cells [21, 33] are able to adopt the beta cell phenotype in vitro and in murine models in vivo, after genetic manipulation or near-total beta cell destruction [6]. These cells effectively undergo the same process suggested by Talchai, in reverse direction. If human beta cells dedifferentiate into progenitor cells and/or reprogram into alpha cells in human T2DM, one strategy might be to find a means to reverse this process, thereby enhancing beta cell mass. A number of molecules which promote beta cell expansion and function have been identified. Reg3 (INGAP), an endogenous peptide, ameliorates glycaemic control in T2DM patients [34]. Pharmaceutical analogues of the potent antihyperglycaemic hormone GLP-1, such as Exenatide, are currently used clinically to improve glucose-dependent insulin secretion and thus glycaemic control [35]. Intriguingly, evidence suggests GLP-1 may also promote beta cell proliferation and neogenesis, and inhibit apoptosis [36-38]. The hunt is on for more hormones harnessing the plasticity of the pancreas to facilitate beta cell function. Yi et al [39] recently identified betatrophin, a protein hormone secreted by the liver and adipose tissue, which is upregulated during gestation and in ob/ob and db/db murine models of insulin resistance. When this hormone was expressed transiently, it promoted beta cell proliferation (replication rates in some animals increased 33-fold), increased beta cell mass, reduced fasting glucose levels and improved glucose tolerance. Identification of this hormoneâ&#x20AC;&#x2122;s mechanism of action, receptor and cofactors will clarify the interaction between the pancreas, liver and adipose tissue in glycaemic control, and elucidate whether recombinant betatrophin is a realistic future therapy. Clearly, a number of important questions remain to be answered. Firstly, does loss of cell mass, function or identity cause beta cell failure? Does dedifferentiation occur in human T2DM, and does it underlie disease pathogenesis? If so, is dedifferentiation due to hyperglycaemia, hypoin-

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T2DM may result not from beta cell death, but from dedifferentiation to an uncommitted endocrine progenitor-like stage 29

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sulinaemia, or some other debates will ultimately should be chan- New

cause? And critically, can this process be reversed? Resolution of these determine the therapeutic avenues through which further research for nelled to target T2DM most effectively.

therapies T2DM are urgently needed

Type 2 diabetes mellitus (T2DM) is characterised by dysfunction of pancreatic beta cells, alongside peripheral insulin resistance. Its prevalence continues to rise rapidly and by 2030, approximately 552 million adults will be living with T2DM worldwide [1]. How can we stem this seemingly inexorable increase? The recent explosion in T2DM is undoubtedly being driven by modern ‘Western’ lifestyle changes, and many struggle to improve their diet or undertake exercise. However, many obese people do not develop diabetes, and it is well recognised that a beta cell defect is central to the pathogenesis of the disease. Thus a critical step in unravelling the aetiology of T2DM will be to solve the ongoing debate regarding the pathogenesis of beta cell dysfunction. Both reduced beta cell mass and impaired insulin secretion are postulated to cause beta cell failure in T2DM, but their relative extent and importance is contested. Reduced beta cell mass is classically thought to reflect increased apoptosis, but more recently the idea has emerged that beta cells may dedifferentiate into progenitor-like cells and/or subsequently reprogram into alpha cells. The latter finding might help explain the bihormonal nature of T2DM, which is characterised by dysregulated glucagon release as well as reduced insulin secretion [2]. Preventing or reversing this reprogramming using “beta cell identity drugs” may therefore provide a powerful new therapeutic strategy. Current thinking suggests that beta cell failure, in the face of metabolic stress, results from increased beta cell apoptosis in the absence of adequate self-renewal. However, the evidence is controversial: increased apoptosis and loss of beta cell mass is indeed observed in human T2DM [3, 4], but the impairment of beta cell function substantially outweighs the rate of apoptosis [5]. In mice, beta cells replicate very slowly [6] but retain the capacity to increase their proliferation rate in response to physiological challenges such as gestation and peripheral insulin resistance [7, 8]. Surprisingly, near-total destruction of murine beta cells reveals the intrinsic ability of other differentiated pancreatic cells to reprogram and express insulin – a process known as transdifferentiation [9]. Thus it appears that under certain conditions, beta cells may reprogram into alpha cells and vice versa. Recently, Talchai et al [10] proposed that T2DM may result not from beta cell death, but from dedifferentiation. Genetic ablation of Fox01, a key beta cell transcription factor, caused reversion of beta cells in mice to an uncommitted endocrine progenitor-like stage. These dedifferentiated cells no longer expressed key beta cell genes (e.g. insulin, GLUT2) but instead expressed other islet hormones, including glucagon. This change may underlie not only the insulin deficiency but also the dysregulated glucagon secretion observed in T2DM. Furthermore, the observation of abundant “empty” (i.e. insulin-granule depleted) beta cells in two mouse models of T2DM suggests dedifferentiation may well be a common pathway to beta cell failure. The question, then – is dedifferentiation a mechanism of beta cell failure in humans, or is this phenomenon specific to mice? Although an increased proportion of glucagon-expressing cells has been reported in the islets of patients with T2DM [11], this appears to reflect the loss of beta cells rather than proliferation of alpha cells, or beta cells reprogramming into alpha cells. On the other hand, Spijker et al showed recently that primary human beta cells can spontane-

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A c be

ously convert into glucagon-producing alpha cells, in the absence of any experimental genetic modification [12]. This evidence for the plasticity of human pancreatic endocrine cells resonates well with Talchaiâ&#x20AC;&#x2122;s findings. Beta cell dedifferentiation and reprogramming may therefore cause T2DM in humans too. Currently, management of diabetes focuses on maintenance of glycaemic control (fasting and postprandial blood glucose, and HbA1c) to reduce complications, such as microvascular disease. A better approach would be to prevent disease progression by targeting the cause, not only the effects of T2DM. The United Kingdom Prospective Diabetes Study [13] demonstrated that neither sulphonylureas nor metformin provided any beta cell protective effect in newly diagnosed patients with T2DM, over the 15-year course of the study. Shortage of donor pancreata and requirement for toxic immunosuppressant drugs constitute obstacles to the clinical application of islet transplantation [14, 15]. Despite advances, stem cell development still faces significant hurdles and new therapies are urgently needed [16-18]. Exploiting the adult pancreasâ&#x20AC;&#x2122; ability to generate new beta cells, a phenomenon demonstrated in a myriad of experimental diabetes models [19], may constitute one avenue for development of novel, effective cell replacement therapies. Functional beta cells provide far better glycaemic control than any other therapy. Beta cells can be produced, under certain conditions, by three main processes - neogenesis [20-22], replication [23-27], and reprogramming [28, 29] - although much of the evidence is contradictory. Both exocrine cells [19, 29-32] and alpha cells [21, 33] are able to adopt the beta cell phenotype in vitro and in murine models JO WJWP, after genetic manipulation or near-total beta cell destruction [6]. These cells effectively undergo the same process suggested by Talchai, in reverse direction. If human beta cells dedifferentiate into progenitor cells and/or reprogram into alpha cells in human T2DM, one strategy might be to find a means to reverse this process, thereby enhancing beta cell mass. A number of molecules which promote beta cell expansion and function have been identified. Reg3 (INGAP), an endogenous peptide, ameliorates glycaemic control in T2DM patients [34]. Pharmaceutical analogues of the potent antihyperglycaemic hormone GLP-1, such as Exenatide, are currently used clinically to improve glucose-dependent insulin secretion and thus glycaemic control [35]. Intriguingly, evidence suggests GLP-1 may also promote beta cell proliferation and neogenesis, and inhibit apoptosis [36-38]. The hunt is on for more hormones harnessing the plasticity of the pancreas to facilitate beta cell function. Yi et al [39] recently identified betatrophin, a protein hormone secreted by the liver and adipose tissue, which is upregulated during gestation and in ob/ob and db/db murine models of insulin resistance. When this hormone was expressed transiently, it promoted beta cell proliferation (replication rates in some animals increased 33-fold), increased beta cell mass, reduced fasting glucose levels and improved glucose tolerance. Identification of this hormoneâ&#x20AC;&#x2122;s mechanism of action, receptor and cofactors will clarify the interaction between the pancreas, liver and adipose tissue in glycaemic control, and elucidate whether recombinant betatrophin is a realistic future therapy. Clearly, a number of important questions remain to be answered. Firstly, does loss of cell mass, function or identity cause beta cell failure? Does dedifferentiation occur in human T2DM, and does it underlie disease pathogenesis? If so, is dedifferentiation due to hyperglycaemia, hypoinsulinaemia, or some other cause? And critically, can this process be reversed? Resolution of these debates will ultimately determine the therapeutic avenues through which further research should be channelled to target T2DM most effectively.

A number of molecules which promote beta cell expansion and function have been identified

Full references available at: www.omsg-online.com

Will Dace is a third year medical student at Hertford College The author would like to thank Professor Frances Ashcroft and Dr Melissa Brereton for their support.

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w o r G e h t g e n n i i t c n i u d t e S M The field of medicine is a constantly changing environment. Growth, development and discovery all contribute to a better outlook for patients. But how can we maximise progression? What are the limiting factors? Knowledge and technology, certainly. Yet, now more than ever, delivery of care is dictated by the bottom line. It’s an inconvenient truth: the pot isn’t bottomless; money doesn’t grow on trees after all. As the NHS bills continue to rise, the National Institute for Health and Care Excellence (or NICE) remains the arbiter in the rationing of resources. Ultimately, they decide whether the potential benefits of a new treatment are outweighed by its cost to the health service.

on the condition that they are provided at a discounted cost [1]. Yet pharmaceutical companies are, first and foremost, businesses. They must be capable of producing sufficient profits to reward owners and employees, with extra in reserve for future development. If the company fails to meet these objectives, it may be significantly compromised: unhappy shareholders and a devalued estimate of its worth. However, one important factor must not be overlooked. Huge profits mean greater investment in research and development – essential for new drug discovery. Many putative treatments are abandoned part way through production, with pharmaceutical companies having to foot the (often substantial) bill. This was demonstrated recently when Ziofarm’s new agent palifosfamide (for the treatment of soft tissue sarcoma) failed to meet the goal of a late-stage trial, causing a 66% drop in the company’s share price [2]. Whether we like it or not, if a company cannot derive sufficient profits from successful products to cover such losses it will be forced to close. Might it then be patients who ultimately suffer? Furthermore, the implications of price-cutting must

IMAGE/ROSALIE BROOMAN-WHITE

We are often quick to lay the blame upon pharmaceutical companies. Many argue that the market prices of new therapies are unnecessarily high, and hence unaffordable for health service providers. By way of evidence, drugs such as Vemurafenib and Ipilimumab fail to receive initial NICE approval, but are later accepted

f o th

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be considered. Continually slashing prices may have unexpected consequences and, eventually, something might be sacrificed. If this were the quality of drug testing standards, for example, it would only be a matter of time before the ill effects of such a change would materialise. One hardly needs reminding that patient safety is of paramount importance to our profession. But pharmaceutical companies are by no means innocent. Why have cures for the biggest killers in third world countries not yet been found? A cynic might suggest that it has something to do with profit – or a lack thereof. A recent study showed that the availability of public sector

QALY) index, many are not as effective as other, cheaper drugs. Indeed, NICE concede that a drug costing more than £20,000-£30,000 per QALY is unlikely to clear their costbenefit calculations [4]. As a result, pharmaceutical companies often work to this budget, increasing the likelihood of approval and maximising their future returns. Pharmaceutical companies have patents that last for a predefined number of years before others are allowed to enter the market. Competitors thus fight to lower production costs in a bid to attract more customers. Biosimiliar drugs are typically brought to the shelf at a far lower cost than the original because they avoid the overheads associated

Money doesn’t grow on trees

”

medicines in these countries is only a little over 30% and, crucially, these services may actually be paying between 2.5 and 6.5 times the international reference price for essential medicines (largely due to logistical difficulties and chronic under-budgeting for national needs) [3].

with development. We can, for example, expect the price of Herceptin (generically Trastuzumab) to fall enormously once Genentech’s patent expires. Indeed, Roche has already teamed up with Emcure to introduce a far cheaper version to the Indian market.

Pharmaceutical companies are therefore guilty of targeting the most lucrative areas of healthcare: namely, the illnesses and diseases that generate the greatest income. Morbidities affecting predominantly developed countries – where the pockets are deepest – receive a disproportionate amount of attention. The media is filled with news of the latest cancer drugs, many costing tens of thousands of pounds. These may seem superficially desirable, but when analysed using a quality-adjusted life year (or

The pressure of patents and generic drugs was illustrated by two recent scandals involving one of the world’s largest pharmaceutical companies, GlaxoSmithKline (GSK). The company was first accused of market abuse when they were alleged to have given smaller firms pay-outs to delay the release of their generic versions of their anti-depressant Seroxat [5]. Soon after, GSK had to fork out nearly £2 billion when they were found guilty of off-label marketing for several other anti-depressants, as well as bribing physicians

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with lavish kickbacks (including holidays and concert tickets) [6]. So where should the line be? How long should patents last? Should they last forever and curb the short-term pursuit of profit? Or should patents be briefer, increasing market competition and lowering the cost to the health service provider? Whether the pharmaceutical companies wear halos or devil horns is a matter of opinion. Whilst the days of first class flights and endless expense allowances for drug company representatives may be long gone, the continued investment that these companies make in advertising and brand promotion still merits consideration, not least because these enterprises benefit their own bank account far more than the consumer. Why does a customer choose Nurofen over own-brand Ibuprofen? It might be four times the price, but a compelling marketing campaign and a brightly coloured box appear to have us convinced. It is easy to forget that they share the same active ingredients, even having an identical product licence number (as issued by the Medicines and Healthcare Products Regulatory Agency) [7]. So where then is the NHS in all of this? It would be flippant to characterise it as a helpless victim – and perhaps even incorrect. The demands of providing high quality healthcare on a tight budget are well recognised, but poor organisational structure and management leads to inefficiencies in allocation of resources. Money seeping through the cracks is money wasted. But practical solutions exist: for example, many trusts in Scotland have now stopped leasing out onsite premises to external coffee chains. Now replaced by not-for-profit businesses,

their revenue remains within the NHS structure for local reinvestment [8]. A simple and easily reproducible initiative, so why then are more trusts not looking to adopt similar schemes? Perhaps this brings us closer to the root of the problem: mentality. Prevention beats damage limitation: we must avoid setting fires, rather than trying desperately to assuage the flames. Medicine today requires pro-activity, not reactivity. This might sound like empty rhetoric, but it is not. As future doctors, we must take responsibility for initiating and implementing change, working to better the system and deliver better patient care. Clinical directors across the country should not tolerate wastage of money – those funds are better spent on new therapies. Physicians should resist being seduced by the perks of drug companies. And politicians need to reconsider the influence of these drug giants. Mentality remains the secret to success. And as the NHS learns, so too must its patients. In fact, combatting unhealthy lifestyle choices with education may be just as fruitful as battling big pharma. Predictions suggest that, by 2025, one quarter of the NHS budget will go towards obesity-related problems [9] – as such, it may be the mentality of the patient that is most refractory to change. So who will concede first: the greedy corporation or the greedy guy in the street? For the sake of the NHS, I hope both. Full references available at: www.omsg-online.com

Molly Gilmartin is a second year medical student at The Queen’s College The views expressed in this article are the author’s own and do not necessarily reflect those of the Oxford Medical School Gazette

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Empire and

Disease IMAGES/ISTOCK

Emily Duncan considers how plagues shaped the ancient Roman Empire

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edicine and History have always had a symbiotic relationship, with major historical events both shaping and being shaped by the course of Medicine and its advances. As evidence of this interaction, the Romans are of the utmost significance. Public health was a key focus of their policy-making. Along with gladiatorial games and grand spectacles, public works projects were central to the efforts of many aspiring Roman politicians, helping to build popularity among the masses. Wealthy roman patricians would regularly attach their names and funds to aqueducts and sewer systems. In health and sanitation, as in so many other areas, the achievements of the Roman Empire surpassed anything that Europe would see until the Renaissance. Rome's superiority allowed rapid expansion into new territories, with devastating consequences. The immune-naïve population was exposed to new pathogens, facilitating the rapid spread of novel diseases (not least in the Antonine and Justinian Plagues), which would ultimately contribute to the downfall of the Empire.

ing the first occasion of disease transfer from Asia to Europe. Previously, these two regions had seemingly separate disease pools – largely due to formidable geographical barriers. As the Roman Empire expanded towards the east through war and trade, Mediterranean populations gradually came into increasing contact with civilisations east of the Parthian Empire. Primary accounts of the Antonine plague are rare. A key witness to the disease was the prominent Roman physician and philosopher Galen of Pergamon, whose influence on medical practice reverberated until the 1700s. Galen was present in Rome at the plague's onset, and his Methodus Medendi supplies most of our knowledge of its symptoms [2]. He describes in detail the rash, fever, malaena, cough and haemoptysis of the plague. A modern differential diagnosis for these symptoms would include measles, typhus and smallpox. In particular the rash, documented by Galen as a 'black exanthem', has led medical historians to conclude that the outbreak may have been a form of haemorrhagic smallpox.

Faced with an ever more connected world, understanding the epidemiology of contagions in the world's first truly transcontinental civilisation takes on renewed importance.

The most widely accepted theory for the spread of the Antonine Plague is that soldiers travelling back from the Eastern border of the empire, following the Parthian Wars, returned infectious. Trade with each corner of the empire, along with diplomatic missions to the Indian Ocean and South China Sea, may well

The Antonine Plague (164-180 AD) remains a focus of study, be-

"The ancient world never recovered from the blow inflicted on it by the plague which visited it in the reign of M. Aurelius." – Barthold Georg Niebuhr [1] 36

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have expedited this process. Routes such as the Silk Road, which carried caravans between China and Syria (a Roman province), were well used. Perhaps traders travelling from city to city also contributed to its spread. On arrival at the heart of the Empire, the Antonine plague destroyed up to a third of the population. It ravaged the Roman army, particularly affecting its defence of the eastern territories. However, when the disease spread north to the Rhine, it also affected Germanic and Gallic populations beyond the Empire's borders. Lacking in sophisticated public health infrastructures, the deeper impact on Rome's 'barbarian' rivals eased the mounting pressure on the Empire, allowing the Roman armies an opportunity to fight back. The social repercussions of the Antonine Plague were vast. Marcus Aurelius Antonius (Emperor from AD161-180) was one of the plague's last victims, giving both his life and his name to the plague. Philosophical to the end, the Emperor is reputed to have said on his deathbed: "Weep not for me; think rather of the pestilence and the deaths of so many others" [3]. Marcus Aurelius was the last of the 'Five Good Emperors' and his successor, Commodus (villainously portrayed by Joacquin Phoenix in Gladiator),

from bodies in Bavaria, victims of a later outbreak of the Plague of Justinian [6]. Procopius, one of Emperor Justinian's principal archivists gave clear descriptions of the symptoms: fever, vomiting blood and hallucinations [7]. In particular, the description of swellings in the groin, armpit and ears (buboes) lends support to the claims of bubonic and pneumonic plague character. Like the Black Death, infected flea-ridden rats imported by merchant ships probably acted as vectors. The first known cases were reported in 540 AD at Pelusium (Lower Egypt). From Pelusium the plague spread in two directions: to Alexandria and throughout Egypt, and east into Palestine. The plague reached Constantinople (the capital of the Eastern Roman Empire) in AD542. From here it moved east into Asia Minor and Europe, reaching as far as the British Isles. The plague was present in Constantinople for 4 months. Writings by Procopius suggest that (in the capital alone) between 5,000 and 10,000 people died every day at its peak. The number of fatalities exceeded the capacity of those still living to bury them. Roofs were removed from the city's fortified towers so that bodies could be stacked in them - row upon row of rotting

“During these times there was a pestilence, by which the whole human race came near to being annihilated” – Procopius, History of the Wars [4] has been described as a megalomaniac, more interested in proving his gladiatorial skills in the arenas than leading the Empire. He was assassinated in AD192 after alienating the senate and most of the ruling classes of Rome. Following the Antonine Plague the Roman Empire began to crumble. Buckling under the strain from waves of attack, the Roman Empire was split into two regions; a Western Roman Empire and an Eastern Byzantine Empire. Eventually the Western Empire fell in 475, leaving the Byzantine Empire as the remains of Rome. It was at this point in history that Emperor Justinian I came to the throne (in AD527) with the aim of restoring Rome to her former glory. He set out to conquer lost territories and restore the original Empire's boundaries. He appeared to be making good progress, recapturing North Africa, Carthage, Sicily, parts of Hispania, and large swathes of the Italian peninsula [5]. In 540 AD, German resistance was at breaking point: Emperor Justinian was readying for an attack into Gaul, possibly with a view to a future conquest of Britain. But in AD541 his namesake plague struck. The Justinian Plague is thought to have been caused by Yersinia pestis, more famous for its escapades during the 14th century under the moniker 'The Black Death'. The retrospective diagnosis in this case is reasonably robust. DNA evidence has been obtained

corpses. Soon the towers were full, and the stench unbearable [8]. In desperation, rafts were loaded with the dead, rowed out to sea and set adrift in the Sea of Marmora. The plague decimated the population by 35-55%. Those who survived were often left with debilitating neurological deficits. In fact, it has been suggested that the vacuum created by the population crash of the Byzantine Empire paved the way for the rapid expansion of Islam. The Justinian plague might therefore have indirectly precipitated one of the seismic geopolitical shifts of the modern world. Today's cultural and demographic meta-trends may appear less dramatic; yet from SARS to swine flu, we are faced with what many believe are potentially apocalyptic outbreaks of unfamiliar diseases. It may seem like something from a Hollywood blockbuster, but 2000 years ago the world's pre-eminent civilisation was fatally weakened by just such an outbreak, whether it knew it or not. Full references available at: www.omsg-online.com

Emily Duncan is a sixth year medical student at Balliol College The author would like to thank Professor Robert Arnott for his kind help with this article

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The Growing Problem of

Cancer in Africa

CASSIE ALDRICH considers the growing problem of cancer and non-communicable diseases on a continent still battling infectious diseases

he incidence of non-communicable diseases (NCDs),

Africa. Infectious diseases are much bigger players; about a

including cancer, heart disease and diabetes, is grow-

third of cancers in sub-Saharan Africa are considered attrib-

ing rapidly in lower income countries. In September 2011,

utable to infections, compared to 7.4% in developed coun-

these alarming trends prompted the convention of the sec-

tries [2].

ond ever high level meeting of the UN General Assembly to address an impending health crisis - the first, in 2001, was held in response to the AIDS epidemic. The consensus was that ‘the global burden and threat of non-communicable diseases constitutes one of the major challenges for development in the twenty-first century’. While recognizing that infectious, maternal and perinatal conditions are currently still the biggest killers in Africa, concern was expressed over ‘the growing double burden of disease’. In fact, NCDs are expected to become Africa’s biggest killer by 2030 [1].

man papilloma viruses (HPV) and Epstein-Barr virus were estimated to be responsible for 98% of cancers associated with infection [2] (Table 1). The prevalence of HIV/AIDS in this region causes a further devastating impact on cancer incidence rates, with HIV-associated cancers such as Kaposi’s sarcoma, non-Hodgkin lymphoma and cervical cancer making up a large proportion of the total cancer burden. In addition, rates of other, non-AIDS-defining cancers have been increasing in the HIV positive population, likely due to improved life expectancy with the more widespread roll-out

THE NATURE OF THE PROBLEM

Globally, Helicobacter pylori, hepatitis B and C viruses, hu-

of anti-retrovirals [3]. In many regions, more than half of

hile the modifiable risk factors for cancers in the West are largely lifestyle related, these contribute

much less significantly to cancer incidence in sub-Saharan

cancer patients also have HIV [4]. Furthermore, options for cancer treatment may be limited in an already immunosuppressed population [5].

Table 1: Known Carcinogenic infectious agents and their associated cancer types Human Papillomavirus

Cervical, Anogenital, Oropharyngeal

Hepatits B and C viruses

Liver, Non-Hodgkins Lymphoma

Human herpes virus 8

Kaposi’s sarcoma

Helicobacter pylori

Stomach, Non-Hodgkins Lymphoma

Epstein-Barr Virus

Non-Hodgkins and Hodgkins Lymphoma, Nasopharyngeal

Schistosoma haematobium

Bladder

Human T-cell lymphotropic virus 1

Non-Hodgkins Lymphoma

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The West

THE CHALLENGES

Africa

he scarcity of treatment facilities poses a huge challenge, in a region where the population’s access to healthcare is greatly

33%

7.4%

limited by transport and lack of funds. At present, only one dedicated cancer centre, the Uganda Cancer Institute (UCI), serves the whole of the Ugandan population, as well as patients from Rwanda, Burundi,

% of cancers which are due to infections

Eastern Congo and South Sudan. Many African countries don’t have a single Oncologist. Cancer places a heavy socioeconomic burden on sufferers’ families.

cancer

The expense of funding travel and treatment, as well as the inability to tend to farms, homesteads and children while away for the long periods of chemotherapy, often results in significant family hardships. Only

In some African cultures, there is no word for ‘cancer’.

20% of referrals ever present to the UCI. In most African countries, government funding does not cover any cancer-related care. Cancer is expensive and complicated to treat, requiring tertiary referral, while many infectious diseases, including malaria, can be treated in primary care clinics with affordable drugs. For decades, African health systems have been geared towards treating infectious diseases. However, NCD coverage is slowly beginning to improve; at the UCI, chemotherapy is

Just 17 out of 54 countries in Africa have access to oromorph in hospitals

100% government funded (provided the drugs are available) and in 2012 the Kenyan government passed the Cancer Prevention and Control Act which paves the way for free treatment for all cancer patients [6]. In the meantime, faced with patients unable to raise the necessary funds,

0.25

clinicians find themselves having to ration investigations and delay or withhold treatment.

16.7

Dr Fred Okuku, an Oncologist at the UCI, argues that the single greatest challenge facing cancer care in Africa is ‘late presentation’. This is

Number of Oncologists per Million Population (UK vs. Ghana)

fuelled by an array of factors including ‘difficulty accessing hospitals and a lack of awareness about cancer’. Additionally, doctors lack cancer knowledge and there is often little in the way of reliable diagnostic and pathology services [7]. Nearly all patients present with late stage

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9 IMAGES/LARA HIBBS

tended abdomens in a cachectic patient, are all too typical. Advanced

mour, may be offered what is termed ‘toilet mastectomy’. This proce-

disease; fungating tumours, massive pleural effusions and hugely dis-

breast cancer patients, where the whole breast has been eroded by tu-

3 4

8 7

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IMAGE/CASSIE ALDRICH

ing the same antibiotic from a different pharmacy may prove as effective as changing the antibiotic. Patented, targeted anti-cancer drugs are simply too expensive for most hospitals and patients to afford; hence calls for increased access to generic drugs. Whatever the ethical arguments over using drugs that are second line in the West, there is no doubt that any increase in treatment would enable significant improvements in survival rates. Childhood cancer survival rates approach 80% in the West, but the majority of African children

Facial Burkitt’s lymphoma in a seven year old boy dure enables the patient to return home to their family to die, without the unpleasant smell and mass of flies attracted to the necrotic, ulcerated tissue. Late presentation results in a vicious circle where patients die in hospital because there is little that can be offered besides palliation; the belief is then established that cancer is a death sentence and sufferers avoid hospitals until they can no longer stand the pain. In the earlier stages, many will instead put their faith in traditional healers. Indeed, herbal remedies are usually more affordable and easily accessible. The lack of awareness surrounding cancer is exemplified by the fact that many African languages don’t have a word for ‘cancer’. Those cancer patients that find their way to hospital still encounter difficulties accessing drugs. Hospital pharmacies regularly run out of chemotherapy and antibiotics, and fre-

with cancer don’t receive treatment. Burkitt’s lymphoma, the most common paediatric cancer in Eastern Africa, is also one of the most curable. However, the Western politics of drug development continue to severely restrict access to generics globally [9]. A lack of palliative care services, alongside limited morphine supplies across much of the developing world, leads to agonising deaths for cancer patients. Despite its inexpense, only 17 out of 54 African countries have access to oral morphine [10]. Basic palliative care services still do not exist in almost half of Africa’s nations [11]. However, earlier this year, African Union health ministers recommended that memberstates integrate palliative care into national strategies to combat NCDs. Encouragingly, several effective palliative care services have now been set up which can serve as a model – Hospice Africa Uganda is an example of a home-based service providing free access to oral morphine.

quent logistical difficulties in procuring new stock lead to lengthy delays. When government procured, quality-assured drugs run out, family members must purchase the drugs from private pharmacies. Often these are cheap, poor quality products from dubious overseas pharmaceutical companies [8]. If a patient with neutropenic sepsis isn’t improving, buy-

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SO WHAT NOW?

CDs and infectious diseases interact to produce more than a ‘double burden’. Concurrent infectious ill-

nesses are more severe in cancer patients and worsen both response to treatment and outcome. Immunosuppressed HIV

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patients are often too ill for cancer treatment. Anaemia associated with malaria delays chemotherapy. Cancer drugs cause reactivation of latent infections and TB medications interact with them. Where then should efforts be focused? Firstly, the epidemiology must be fully understood. Under-reporting of cancers may mean that their true burden is significantly underestimated; up to 90% of cases in some areas. The development of rational prevention and treatment strategies will depend on more widespread population-based cancer registries. Prevention and early detection will be cheaper than late treatment. Low income countries simply cannot afford to treat advanced cancers where there is a poor prognosis even with the best care. Cancers associated with infections are largely preventable with simple measures. The UN high level summit called for â&#x20AC;&#x2DC;increased access to cost-effective vaccinations to prevent infections associated with cancersâ&#x20AC;&#x2122;. Vaccines such as the hep B vaccine and the new HPV vaccines have an important role in cancer prevention, provided that the international community remains focused on overcoming the logistical and financing difficulties associated with their widespread roll-out. Screening programs, which can be implemented in challenging environments, are needed. Education and advocacy campaigns can spread awareness and reduce the social stigma attached to cancer. The world is waking up to the impending crisis of NCDs in low income countries, but it must act quickly to preserve the gains made in tackling infectious diseases and improving life expectancy. Full references available at: www.omsg-online.com

Cassie Aldrich is a final year graduate entry medical student at Keble College

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IMAGES/ABBIE TAYLOR & GILES NEAL

High impact careers in healthcare We all want to be good doctors, but how much good do doctors really do?

”

I like science and I want to help people.

ost of us wrote something to this effect on our medical school applications. But how much do doctors really ‘help’ people? Medicine is typically regarded as an ethical career, chosen at least in part through altruistic motives - we certainly aren’t in it for the hours! Yet if we step back and try to measure how much good we’re doing as individuals, we may be unpleasantly surprised. The impact of an average doctor added to the NHS has been calculated as around 10 quality-adjusted life years, or QALYs [1]. To those unfamiliar with this con-

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”

cept, that equates to significantly less than one ‘life saved’ per doctor. But surely it is obvious that most doctors save lives on a regular basis? The above estimates can be explained, in part, by considering that most doctors are readily replaceable: working in a competitive field merely prevents someone else of equal competence doing the job. Also, much of our health as a developed nation can be accounted for by sanitation, diet, and vaccination [2]. Hence adding more doctors to the equation has relatively little effect.

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Let’s assume a surgeon operating on 100 patients a year is successful in 80% of cases. That surgeon has saved the lives of 80 people: what a hero! But if another surgeon competing for the same job had an 85% success rate, the second surgeon would have saved 85 lives. So the first surgeon has actually caused the death of five patients by preventing a more skilled surgeon from doing the job. If we then take into account that the actions of the surgeon were only partly responsible for saving the patients’ lives, the surgeon begins to look rather less heroic.

"I can do far more good with my chequebook than I can expect to accomplish with my stethoscope." – Greg Lewis [3]

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the NHS to global problems." – Chris Lavy [6]

to take an interest, to lift their eyes above the problems of

to encourage the middle-aged, grey-haired men in suits

"I've inveigled my way onto the council of the Royal College

Fortunately we can still make a huge difference, but we may need to challenge a few key assumptions. Dette Young is a microbiologist from Melbourne now working in Oxford. Dette is working to save lives both from within and outside the laboratory, donating a large proportion of her income to charities which tackle tropical diseases. Young and her philosopher husband, Toby Ord, will give around £2 million to global health charities over their lifetimes [4]. Giving What We Can, a charity founded by Ord to encourage rational giving, recommends donating 10% of your earnings to the Against Malaria Foundation. With the average salary of a doctor in the UK, this would amount to adding around 19,000 QALYs, or saving over 500 lives [1,5]. Deliberately following the most lucrative career paths in order to donate more could be a powerful way to multiply the number of patients you help.

We have the privilege of working in a National Health Service which, for all its faults, is still the envy of most of the world. However, the boundary between ‘First World problems’ and ‘Third World problems’ is becoming increasingly blurred; geographical proximity no longer determines who we are able to help. As NHS doctors earn more than 99.9% of the world’s population [7] we have a duty of care not only to the patients on our wards, but to those elsewhere in the world. Orthopaedic surgeon Chris Lavy realised this whilst holidaying in Malawi; he then left the comfort of his private practice in London to found a series of children’s hospitals, as well as the first surgical training programme for health workers across East, Central and Southern Africa. Not only has he given countless patients lives free of disabling musculoskeletal conditions, he also believes that his own life has been enhanced in ways he could never have imagined [6]. Another doctor who notoriously lacked a stethoscope [9] was Professor Sir Richard Doll, whose discovery of the link between smoking and lung cancer “has done as much to save lives as the discovery of penicillin or the development of polio vaccine” [10]. Whilst all researchers cannot expect to make such influential breakthroughs, it’s vital that clinical medics help with research and development to discover new ways to improve patient care. Furthermore, real life ‘impact’ is not necessarily measured by the number of publications in highbrow, established journals – we also need to translate that research into practice. Nick Edwards, an Oxford graduate who entered management consultancy after medical school, has achieved this by building collaborations between academic research and the biotech industry. Communicating sound medical advice to the general public is also vital. Carl Heneghan, founder of the Centre for Evidence Based Medicine, uses social media to respond to current issues – from protein shakes to petitioning pharmaceutical companies [12]. Are the most ethical careers for medics in the not-for-profit sector? Former Médecins Sans Frontières (MSF) employee Darryl Stellmach, a man who has led several missions in development and disaster response, believes that this is not necessarily the case. A decade working on the front line led Darryl to conclude that it is possible to have a huge

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"Sir Richard Doll's understanding of epidemiology made him perhaps

the individual who saved more lives than any other

in the 20th century" IMAGE/WIKICOMMONS

– Niall Dickson [8]

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Full references available at: www.omsg-online.com

Abbie Taylor is a fifth year medical student at Green Templeton College

"Solving healthcare challenges is primarily not an issue

So the next time you find yourself wanting to be ‘the best doctor I can be’, think about the less obvious ways to increase your impact factor.

– Darryl Stellmach [6]

As medical students, we are embarking on careers within a system that promotes boxticking, hoop-jumping and early specialisation. Any doctor who does not climb the narrow ladder from foundation doctor to specialist trainee

to consultant might be assumed to have failed, or to lack people skills. These same doctors who entered the profession with aspirations of ‘helping people’ can quickly become cynical, limited by a bureaucratic system where it is easier to criticise than to make positive changes. Those who do tackle unconventional areas (such as policy-making, health advocacy, management and research) play an essential role in delivering better patient care.

of new technologies; it’s an issue of ethics, distribution politics and politcal will.”

impact on global health without leaving the country – in fact, he believes that a backbench MP in Westminster has more power than the head of MSF [12]. We should not underestimate the positive impact made possible by pursuing advocacy or policy-making work, influencing huge budgets and changing the practices of healthcare providers both in the UK and abroad. Shaping the practice of other doctors may mean ‘going over to the dark side’ of medical management. The good that you achieve in these careers may be more indirect than saving lives with your scalpel, but the number of patients you help can be far greater.

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Radiation proctopathy DR BRIAN PHILLIPS examines what is known about this emerging complication of pelvic radiotherapy

o matter how well acquainted we may be with a clinical condition, the urge to further one’s knowledge is all too often irresistible. This was my own response when I was treated recently for prostate carcinoma. I had opted for radiotherapy in preference to surgery, largely due to the threat of urinary incontinence with the latter. Nevertheless I failed to receive adequate advice on the possible side effects of radiation. Indeed, I was one of an apparent minority who succumb to radiation proctopathy; that is, rectal mucosal telangiectasia causing a plethora of symptoms, including change in bowel habit, rectal bleeding and tenesmus. The condition is somewhat intractable, responding problematically to current therapeutic procedures. These include argon plasma coagulation (APC) and formalin instillation via flexible sigmoidoscopy. Although a barium enema suffices for APC preparation, formalin treatment requires induced catharsis. Supplementary treatment is with sucralfate, an aluminium-based product administered by enema once or twice daily for about three weeks. Meanwhile, a trial of hyperbaric oxygen to induce new vessel formation is in progress. Up to 20% of patients treated by radiotherapy for prostate cancer can expect proctopathy. Given that uterine and ovarian malignancies may also receive this attention, it is not surprising that the Royal Marsden Hospital in London, a renowned centre of excellence for the treatment of malignant disease, has set up a dedicated unit to manage the side effects of pelvic radiation (currently headed by Dr J Andreyev, a gastroenterologist with a special interest in this field). As for my story, I responded to the formalin and sucralfate treatment with marked reduction of the profuse rectal bleeding and commensurate decrease in anaemia and resulting dyspnoea. However, the proctopathy tends to peak spontaneously at about three years. Apart from imaging control of the flexible sigmoidoscopy, an additional camera had been used to record high resolution images of the rectal mucosa. One could discern red cells in motion intravascularly, alongside endothelial thickening. From this perspective, the appearance of the rectal mucosa, with the “floret" structure of the glandular crypts, was in fact rather beautiful (though, clearly, this is somewhat ironic given the adverse reputation of this end of the GI tract). The salutary experience of role reversal when we become patients is clearly one that besets many of us, but our reactions are clearly as diverse as the individual personalities concerned. In my view, one’s clinical acumen can only be enhanced by the insight gained. Alas, retirement precluded my proving this!

Full references available at: www.omsg-online.com Dr Brian Phillips was a medical student at Exeter College (1948-52) and qualified at the Royal Free Hospital in 1954

IMAGE/ROSALIE BROOMAN-WHITE

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SOME LIKE IT HOT ANDREW DOOLEY reconsiders our relationship with the radiator…

IMAGE/ISTOCK

limate and ‘Waistline’ Change are two key challenges of our era. But might they be linked? And might they share a common solution? Could, for example, we begin to combat both with the thermostat?

uncoupling protein 1 (UCP1) in the mitochondria.

It was believed that BAT played an important role in small mammals and newborn humans (who lack the ability to shiver), but that the effect of these tissues was negligible by adulthood. This view The prevalence of obesity in the UK has been has now been challenged, largely due to evidence increasing rapidly since the 1970s, roughly in obtained from cancer scans. Radioactive analogues parallel with the introduction of central heating of metabolites were injected prior to PET scans, at home. This could suggest a relationship, at a providing an insight into different activity levels population level, between ambient temperature in different tissues in the body. These repeatedly and obesity [1, 2]. Theoretically then, small demonstrated curious and unexpected signal tweaks to the temperature might have significant patterns: unidentified tissues were exhibiting consequences. high glucose uptake, similar to the tumours being investigated. These tissues were subsequently When in a cold environment, the body uses various shown to contain UCP1, a marker specific for BAT mechanisms to keep warm. These include adaptive [5]. thermogenic responses, in which the body actively produces heat. These mechanisms are divided into Evidence suggests that extended exposure to the shivering thermogenesis (ST) and non-shivering cold leads to changes in BAT behaviour. One thermogenesis (NST) [3]. It has been shown, PET study showed that BAT uptake of a glucose however, that shivering does not continue during analogue is greater during the winter than the extended cold exposure. A rather cruel experiment summer. Though these results were based on 56 in 1961 provided the first evidence for this: young adult subjects of normal BMI only, this suggests men exposed to the cold for 8 hours a day had that BAT activity can be modified by long-term greatly reduced shivering responses by day 10 changes in temperature [6]. However, those who [4]. Interestingly though, energy consumption would most benefit from BAT appear to have the remained high – implicating another thermogenic least. A similar PET study, again measuring glucose process, later coined NST. This raises the question uptake as a marker of BAT activity, was performed as to whether the cold could be used to burn off on 15 morbidly obese subjects. Only three of the excess flab. subjects showed increased BAT activity when exposed to the cold [7]. This could simply be due It is possible that many tissues play a role in NST, to overweight individuals having better insulated but much attention has been focused on brown bodies, and therefore not requiring BAT-mediated adipose tissue (BAT), which produces heat directly. NST. However, an alternative explanation might be BAT uncouples substrate metabolism from ATP more compelling: the subjects were obese precisely synthesis, thereby directly generating heat. This because they lack BAT activity. unusual quirk is thought to be due to the action of

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The relationship between obesity and BAT does warrant further discussion. A recent study showed that mice genetically engineered to exhibit impaired BAT development had a significantly increased risk of obesity [8]. It could be that low BAT activity is a contributor to obesity, though whether this activity could be increased in the cold is another matter. Alternatively, BAT could be targeted pharmacologically – either by regulating its development or control, or by delivering drugs to boost BAT activity directly. It appears that, in rodents at least, BAT thermogenesis is controlled by activation of the seen in humans, these could theoretically be targeted as a treatment for obesity [9]. As yet, there are no drugs

“Could the cold be

subtypes (many of which are involved in other important processes, including regulation of cardiac performance). interesting to measure their potential effect on weight reduction. Will turning the heating down help keep us slim? I do not advocate turning the heating off entirely, but longitudinal studies looking at normal, overweight and obese people living in slightly cooler conditions could be worthwhile. Energy balance is a complicated science, but simply being in a cooler environment does appear to burn more calories. Turning the heating down may not be a substitute for eating properly and exercising, but it might help – and not just with the heating bill.

“Those who would

Full references available at: www.omsg-online.com

Andrew Dooley is a fifth year medical student at St Catherine’s College

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least”

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short tale in the Book of Samuel remains deeply ingrained in the public consciousness after more than two thousand years. Often recounted at major sporting events, particularly those involving England, David and Goliath is a true underdog story; a triumph of good over evil and brains over brawn. But how did a soldier with little more than a sling and stone overcome an undefeated giant? The solution to this intriguing riddle lies i n pathological growth secondary to aberrant activation of an important endocrine axis. The story of David and Goliath is set amidst the backdrop of a long war between the Israelites and t h e Philistines, as the Children of Jacob attempt to reclaim their ancient homeland. The two armies meet near the Valley of Elah, where Goliath, champion of the Philistines, challenges any Israelite soldier to come forward and settle the conflict through single combat. Goliath was a true behemoth; reported to have stood at 9 feet tall, he struck fear into the hearts of men. For forty days he went unchallenged, until the young David finally took up the gauntlet. Goliath taunted, cursed and abused his opponent, backed by raucous cries from the Philistine army. David simply fitted a stone in his sling and hurled the missile at the giant. Goliath, struck in the forehead, fell to the ground and was swiftly beheaded by a victorious David. able defeat may be explained by a likely medical condition. A secretory pituitary adenoma would account for both his gigantism and a visual field defect which would reduce his ability to detect flying missiles and employ evasive behaviours. Gigantism commonly results from aberrant growth hormone (GH) signalling. This peptide hormone is released in a pulsatile fashion, principally at night, by somatotroph cells of the anterior pituitary gland. Through its action at cell surface receptors coupled to intracellular enzymatic cascades, GH stimulates cell growth and proliferation in numerous tissue types. In con-

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junction with nutritional factors and hormones (such as thyroxine and insulin), GH is a crucial determinant of post-natal growth. The pubertal growth spurt is dependent on long bone elongation, mediated by the proliferative actions of GH and other mitogens at the level of epiphyseal plate chondrocytes. As such, an abnormal peri-pubertal rise in GH release will evoke excessive long bone elongation, leading to gigantism. This classically results from abnormal somatotroph proliferation, leading to the development of a tumour which secretes GH in an unregulated fashion, quasi-independent of the dampening influence of hypothalamic hormones. A pituiunusual height - but how does it account for his unexpected defeat?

IMAGE/SIMONE PAULSON

The pituitary gland, located in the pituitary fossa, is encased on three sides by the hard and incompressible sphenoid bone. At the open base of the pituitary fossa lies the optic chiasm, an important junction in the visual system. Retinal ganglion cell axons undergo partial decussation at the optic chiasm to produce binocular vision, which vastly improves depth perception. A hallmark of pituitary enlargement is bitemporal hemianopia - a loss of peripheral vision - which reflects compression of the optic chiasm secondary to downward growth of the enlarged pituitary gland. In the case of Goliath, the narrowing of his visual field would reduce the likelihood of seeing the missile. Giants akin to Goliath are no longer celebrated

knowledge of the complex signalling pathways central to the control of growth. Full references available at: www.omsg-online.com

Charles Coughlan is a third year medical student at Magdalen College

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â&#x20AC;?

grace the pages of the Guinness Book of World Records and star on the basketball court. Regardless, the study of these unusual individuals has

David and Goliath is a true underdog story; a triumph of good over evil and brains over brawn

â&#x20AC;? 49

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LAURA MUNGLANI’s experiences with stroke patients remind us that we have to do more than just ‘Act FAST’... Recently the government launched the Act FAST campaign, aiming to raise awareness of the main symptoms of stroke (FaceArms-Speech-Time to call 999). Although I had seen the advert on TV, it was only when working on the Stroke Rehabilitation ward that I was truly exposed to the sort of severe neurological deficits that may accompany stroke. And while day-to-day improvements in language and movement were heart warming, I

Being able to smile – both in the physical sense and as an expression of joy are defining characteristics of being healthy and happy. One patient, Alice*, described the detrimental impact of her stroke on both of these qualities. She took me back to the day of her admission and how she noticed the smiles of the nurses around her. Though encouraging, each friendly face made her acutely aware of her disability. But as her capacity to smile im-

A patient is much more than the sum of

”

” found that the various examinations were just as much of an ordeal for an onlooker as for the patient. A reminder, perhaps, of how much of their former selves had been lost.

proved, only then did she realise how unhappy she was. The emotional reaction of patients to having a stroke may be overlooked, consciously or otherwise, by many of those around them.

FACE: The face may have dropped on one side, the person may not be able to smile, or their mouth or eye may have dropped.

We may assume that as a patient’s neurological deficits improve, so too should they recover from the stroke at the same pace. However, a patient (as in the case of Alice) is much more than the sum of their measured neurological deficits. We may under-

IMAGE/ROSALIE BROOMAN-WHITE

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I need time to accept what has happened to me

”

estimate how frightening the experience of a stroke might be, and the psychological sequelae it entails. Alice told me “I don’t let my husband know the impact the stroke had on me” - how well does the face mirror a person’s true emotions? In regaining her ability to smile, she found that she no longer had reason to. ARMS: The person with suspected stroke may not be able to lift one or both arms and keep them there because of arm weakness or numbness. Freedom of movement is something the majority of us take for granted. Robert told me that the main impact on his life since his stroke stems from a lack of mobility. Talking to him now, four weeks later in his wheelchair, he says it is a lack of freedom – whether to go shopping or to do the gardening – of which he is most acutely aware. Strokes can be very debilitating in the long term. Patients may never recover their previous baseline activity level, and many of the things they enjoyed prior to the event require a fully functioning body. And though a wheelchair might symbolise relative independence for us, some stroke victims see it both as a prison and as a constant reminder of their illness. Previously, Robert worked as an ecclesiastical wood carver, making furniture for his and friends’ houses; he says this is now impossible. SPEECH: Their speech may be slurred or garbled, or the person may not be able to talk at all despite appearing to be awake. Speech, the way we communicate, is an essential part of our daily interaction. An inability to communicate effectively is something many stroke patients have to cope with. Derek’s son was the first to notice dysarthric speech, with an evolving receptive and responsive aphasia. Speaking to him a little over a month into his recovery, it’s hard to identify any of these features. He is keen to tell me how relieved he was to begin regaining his voice; he had almost abandoned all hope returning to lecture students again. The aphasia lasted only a few days, while the dysarthria persisted longer – even so, he often felt wildly frustrated at being unable to connect to those around him. Derek’s speech is now essentially back to normal, yet he told me “I can’t say how I really feel”. At a time when he feels that he should just be thankful for recovering, he is left unable to

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”

candidly express his fears to those around him: will he have another stroke; how long would it take him to recover; will there be any residual disability? It’s a terrible irony that he has found his voice but not the right words. Though the symptoms of stroke are nearly all negative – the loss of a smile, of happiness, of mobility, of speech – Derek’s story has at least one positive outcome. He told me: “strokes have changed the way I talk”. As his speech improved, so too did his outlook. He is more extrovert, noticing and appreciating the laughter of friends and family. He explains how his sense of empowerment has given him the courage to continue on his road to recovery. TIME: It is time to dial 999 immediately if you see any of these signs or symptoms. Peter’s stroke was sudden, but his recovery was not. Rehabilitation takes time; both to learn to re-use one’s own body as well as come to terms with the trauma. Whilst talking to me, Peter explained that he needs “time to accept what has happened to me.” The emotional consequences of stroke can be equally devastating: not only did Peter tell me about his problems with concentration and tiredness, he also much more aware of his own mortality. Having survived one stroke, he fears that he may not be as lucky next time. We need to consider stroke patients as much more than what we can – or, perhaps more accurately, cannot – see neurologically. We need to have compassion and empathy. We need to recognise the frustration felt by many patients at the suddenness of what has happened and the lengthy recovery process. We must also not forget the psychological effects of stroke; assumptions about a person’s emotional recovery cannot simply be extrapolated from physical findings. Our histories and examinations must probe both sides of the coin. We must Act FAST, then think slow. Full references available at: www.omsg-online.com

Laura Munglani is a fifth year medical student at Balliol College The author would like to thank Bing Tseu for his help in preparing this article.

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in Alzheimer’s A look at the self-medication of nicotine by Alzheimer’s patients Ask someone about the effects of smoking on your health and you may hear about how it increases your risk of throat and lung cancer, increases the risk of cardiovascular disease and increases your chance of getting lung diseases such as emphysema and pneumonia [1]. One syndrome you are unlikely to hear anything about is Alzheimer’s. The relationship between smoking and Alzheimer’s is less widely known and has some unexpected intricacies. In the normal, healthy human brain there are populations of neurons that use acetylcholine as their neurotransmitter. This is released into the synapse where it interacts with post-synaptic receptors, before being degraded by enzymes and taken up by surrounding cells [2]. One of the hallmarks of Alzheimer’s disease is a progressive loss of these acetylcholine-releasing neurons throughout the brain [3]. A global acetylcholine deficit leads to the characteristic deterioration in memory, thinking and ability to perform everyday tasks (beyond that of normal ageing). Current therapies often aim to compensate for the reduction in the amount of synaptic acetylcholine by enzyme blockade. The drugs donepezil, rivastigmine and galantamine are known as acetylcholinesterase inhibitors, stabilising or even improving the cognitive deficits seen in the disease [4]. Nicotine, like acetylcholine, binds to and activates acetylcholine receptors, meaning that less endogenous acetylcholine is required to activate the post-synaptic cell. In Alzheimer’s patients, this allows the nicotine to partially compensate for the reductions of available neurotransmitter. Theoretically then, nicotine could improve cognitive function in these individuals. Studies

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have demonstrated an appreciable effect in vivo, with patients showing improved performance in attentional tasks and reaction times. In a study from Jones and colleagues, 22 patients with Alzheimer’s disease, 24 age-matched healthy controls and 24 young controls were given subcutaneous injections of nicotine and saline boluses over a series of test sessions. When receiving placebo, the Alzheimer’s patients demonstrated marked impairment in tasks of attention and information processing relative to the control group, as expected. However, the administration of nicotine greatly improved the Alzheimer’s group’s performance in these tests [5]. These results were later reproduced by Heidi White and Edward Levin who showed similiar improvements in Alzheimer’s patients given nicotine patches over two 4-week periods [6]. These data suggest that nicotine allows the system to return to a level of function closer to that of the healthy state, potentially encouraging long-term use of the drug. Nicotine in Alzheimer’s patients may thus undergo reinforcement, but not through the typical mechanisms associated with addictive drugs. Usually, drug dependency corrects the symptoms caused by deficits in striatal dopamine during withdrawal periods. However, in Alzheimer’s, the nicotine would act to ameliorate cognitive deficits by acting on the prefrontal cortex to reduce symptomology. Despite the apparent boon to smoking, the benefits of nicotine in Alzheimer’s might be the silver lining of a very dark cloud. One meta-analysis of 19 different studies (covering over 26,000 participants) found that elderly smokers were at far greater risk than never-smokers of developing both Alzheimer’s disease and

We might just be better off without it

”

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The silver lining of a very dark cloud

”

vascular dementia. Current smokers also tended to show greater year-on-year decline throughout the follow up period [7]. When the cognitive improvements seen in the short-term are combined with the long-term damage caused by smoking, a negative reinforcement cycle becomes more apparent. Here, the patient is aware that smoking temporarily increases their attentional and mnemonic ability, driving self-medication. However, the deficits are greater once the drug has left the system, ultimately resulting in increased symptomatology over the timescale of weeks, months and years. As the symptoms grow worse, the patient may feel greater drive to smoke, further perpetuating the vicious cycle. So while self-medicating seems appealing, we might just be better off without it.

John Wilde is a third year physiological sciences student at The Queen’s College

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IMAGES/ROSALIE BROOMAN-WHITE

Full references available at: www.omsg-online.com

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CHEAT GENES S

ince time immemorial – and by fair means or foul – humans have strived to better themselves on the sports field. Over the course of the last century, many athletes have relied upon artificial performanceenhancing methods in variously imaginative ways, a phenomenon that will surely continue into the future. Cheating is now a sophisticated science. Gene doping is defined as the non-therapeutic use of genes, cells, genetic elements and epigenetic modulation to improve athletic performance. Rather than an athlete periodically administering illegal substances, our growing knowledge of gene therapies may be used to augment power, speed or endurance – possibly on a more permanent basis [1,2]. Still highly experimental and far from safe in the therapeutic setting, gene therapy carries a multitude of known and unknown risks [3]. However, the appeal of gene doping is obvious: current detection methods lag far behind the technology itself [4]. Many methods for gene doping exist, but the one most likely to be employed utilises viral vectors. Very simply, a non-harmful virus containing the desired gene is given to the athlete where it is taken up by cells for multiplication. The gene may be integrated into the host genome or remain as an independent episomal element (depending on the type of vector chosen). Transcription of the gene then facilitates expression and function [5]. Candidate genes will depend on the sport. A powerful, muscular physique is required for weightlifting or sprinting, yet endurance events place a far greater emphasis on oxygen carrying capacity. Numerous genes contribute to different athletic phenotypes in complex ways, and future gene dopers will have the challenge of identifying the most effective cocktail for their particular discipline [6].

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Erythropoietin (EPO) – perhaps the most infamous performance-enhancing substance – announced its arrival to top-level sport large during a particularly ugly affair at the 1998 Tour de France [7]. A naturally occurring peptide hormone, EPO acts to increase the number of circulating red blood cells and generate a higher concentration of haemoglobin, thereby improving oxygen delivery to muscle [8,9]. Recombinant human EPO is used to treat the anaemia of various diseases [10], hence its illegal use by professional cyclists to boost aerobic capacity. A putative gene therapy for anaemia (known as Repoxygen) consists of a viral vector containing the gene for EPO and a hypoxia response element [11]. Safety problems with its clinical delivery exist though: in order to avoid either thromboembolic or haemorrhagic events, expression must be tightly controlled. However, a desperate athlete may be willing to gamble with these risks. In many ways then, EPO is both the best and the worst candidate for the gene dopers: an induction protocol already exists, although current (‘conventional’) cheating methods may still be preferred for safety and practical reasons. Vascular endothelial growth factor (VEGF) is another potential target [12]. Physiologically, VEGF is produced by hypoxic cells, acting to stimulate blood vessel growth and branching [13]. It increases ischaemic tissue neovascularization; hence it may help in the clinical rehabilitation of patients after a myocardial or limb infarction [14]. Genetic manipulation of VEGF may benefit endurance athletes looking to combat exhaustion by increasing the perfusion of the heart, muscle and lungs. It has been successfully tested on mice and rats [15], although its raw endurance-promoting effects have yet to be quantified in human trials [14]. 2013 63:2

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Many sports – such as sprinting, rugby and weightlifting – demand muscular size, power and strength. Anti doping agencies are constantly investigating and banning a steady stream of athletes who turn to illegal substances in the pursuit of phenotypic perfection. Genetic manipulation of the muscle growth process is another natural next step for many elite athletes looking to furnish themselves with unfair advantage. For example, myostatin inhibition by such means has already been reported in competitive dog racing [16]. Myostatin is a circulating protein that suppresses muscle growth – indeed, its absence in a newborn German boy in 2004 gave him a remarkably muscular physique [17]. This particular proband had a unique mutation in both copies of the myostatin gene, meaning that his muscles grew excessively at a very young age [18]. Interest in genomic regulation of myostatin has come about due to its potential application to numerous musculoskeletal degenerative diseases, including Duchenne muscular dystrophy [19]. Hypothetical interventions have focussed primarily on insertional disruption of the myostatin propeptide [20]; the disruption of the myostatin gene peptide cleavage sites [17]; and the generation of monoclonal antibodies against myostatin itself [17]. There have been, as yet, no clinical trials in humans. Although the primary literature looks promising, it remains hard to judge whether myostatin inhibition constitutes a viable target for the gene dopers.

a sample could be obtained, leading to false negative results. Furthermore, naturally occurring genetic variation may confound simple interpretation of the data; famously, the cross country skier Eero Mantyranta was found, in 1964, to have congenital polycythaemia arising from a mutation in the EPO receptor gene [23]. Gene doping is an interesting, if dishonest, application of our growing knowledge of gene therapy. Despite being banned in anticipation of its use by the world anti doping agency (WADA), it is surely an increasingly viable option for 21st century sports cheats. The doping technology is streets ahead of currently available detection methods, and identification of such performance-enhancing approaches may become a real problem. If gene doping has yet to have invaded the world of elite sports, we can be sure of one thing: its arrival is only a matter of time. Full references available at: www.omsg-online.com

James Taylor is a third year medical student at St. Catherine’s College

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Gene therapy carries a multitude of known and unknown risks

IMAGE/LARA HIBBS

Cheating is now a sophisticated science

Detection of gene doping poses a significant problem: we know that it it is much more difficult to accurately identify when compared to traditional approaches [21]. Any assay protocol would need to be fast and reliable, with the capacity to be used on a large scale. Testing could, for example, involve the detection of genetic material (or remnants of a viral vector) in blood or biopsy specimens [22]. Alternatively, monitoring immunoreactivity to known viral vectors in vivo has also been suggested. More direct methods of detection might be preferred for legal reasons, although these may lack sensitivity - the agents used in the doping process would likely be metabolised and cleared before

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How to grow a kidney JOHN CASTLE details recent advances in 3D printing 56

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3D printing is a fascinating new technology which uses 3D images, built up layer-by-layer, to ‘map’ a printing protocol

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Developments in regenerative medicine have caused some to boldly proclaim that the organ crisis we’ve been facing for so long may just be about to end. This article will detail how some of these developments have been achieved, and their potential effect on society. Pioneers in regenerative medicine have developed methods that can be used to ‘grow’ new tissues. One such pioneer, Dr. Anthony Atala of the Wake Forest Institute for Regenerative Medicine, has been pivotal in utilising the potential of 3D tissue printing. He has constructed tissues ranging from load-bearing cartilage to kidney prototypes [1]. 3D printing is a fascinating new technology which uses 3D images, built up layer-by-layer, to ‘map’ a printing protocol. The 3D printers have an inkjet cartridge, which contains living cells taken from patients, and a second component that lays down a solid foundation for the cells to adhere to. When I asked Dr. Atala about the potential capabilities of this technique, he answered, “We are currently working on tissues and organs such as cartilage, muscle, bone and kidney. 3D printing is one of several ways to engineer organs and we work to determine the most effective method for each organ type”.

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a charge and projected through an electromagnetic field within which they elongate and are aligned for appropriate positioning. The results of bladder reconstruction are even more promising. They have been successfully transplanted into spina bifida patients, who are likely to suffer from poor bladder control as a consequence of their illness [4]. The method of electrospinning is an example of a process used to acquire scaffolds for tissue grafts. Scaffolds are structures implanted into target graft sites in order to help the new tissue grow. They provide a site for cellular adherence; they can be used to deliver nutrients, and to facilitate the establishment of a healthy milieu. They are diverse in nature, ranging from nanofibres or synthetic polymers to freeze-dried emulsions and gas foam ‘sponges’. Removing pre-existing cultures of cells and encouraging their growth around a scaffold is a major technique under development.

Indeed, the possibilities for this process are virtually endless. In early experiments, load-bearing tissues, such as articular cartilage, were created using chondrocytes and fibroblasts deposited onto a framework of hydrogel fibres taken from rat or bovine plasma. These cells were found to be 80% viable after a week of construction [2].

Dr. Macchiarini of the University of Barcelona has conducted very successful work in this field of scaffolding; he identified the potential of host cell usage in regenerating lost tissues. By taking bone marrow stem cell cultures of a male patient who had suffered severe tracheobronchial carcinoma, Macchiarini and his team were able to grow the cells in vitro, allowing them to mature into chondrocytes, before successfully transplanting them onto a donated decellularised tracheal segment graft. These seeded cells rapidly became vascularised and successfully restored the patient’s lung function over time. They were also well tolerated by the recipient; the cells were his own and thus expressed the same self antigens [6].

From this, Dr. Atala then used a similar technique to print human bladders. The structural components of the bladders are positioned using a 3D printer that utilises a process known as electrospinning. In this process, fibres are given

Dr. Stephen Badylak from the University of Pittsburgh has explored the possibility for human tissue to be used as a scaffold. By isolating extracellular matrix (ECM) from decellularised pig bladders, he is able to produce sheets or

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The possibilities for this process are virtually endless...

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A British Heart Foundation funded group, headed by Dr. Riley at Oxford University, are exploiting the developmental plasticity of epicardium-derived cells (EPDCs). Dr. Riley’s group are seeking to reactivate these plastic properties to produce pluripotent cells for use in the treatment of cardiovascular injury, the world’s biggest killer [11]. But sticking to the original question, how can we grow a kidney? The process begins with CT scanning of the kidney. Computer morphometric imaging techniques are used to produce a layerby-layer map of the kidney from a stack of CT images. The maps are sent to a 3D printer, where previously cultured cells and hydrogels are laid out using the aforementioned printing methods. Within 7 hours, the printer makes a kidney. So to grow a kidney, all you need is a scanner, an expensive printer, a few cells, and some protein for scaffolding – simple! [12]. Given these recent developments in regenerative medicine, it is possible to envisage a future where organ crises are no longer an issue, and where any damaged tissue can be regenerated. When asked his opinion on the role of 3D printing in the future, Dr. Atala said, “It’s hard to predict the future, of course. I believe 3D printing will have a place in future medicine, but it is a complicated, exacting science, and likely isn’t something that every hospital will pursue” [5]. Although the future that Dr. Atala speaks of remains some way off, recent advances have surely boosted our progress by many years.

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powders of ECM, termed ‘Pixie Dust’ [7]. Using this method, Badylak has been able to regrow several kinds of tissues, including muscule tissue after injury [8] and nervous tissue following cerebral trauma [9]. Research into treating oesophageal cancer using ECM is also underway [10]. There is even a case in which a man has reportedly used ECM to regrow parts of his own finger [7]. Lee Spievac lost the distal third of his middle finger in a model aeroplane accident, but with application of ECM, grew back the lost tissues in a little over a month.

So to grow a kidney, all you need is a scanner, an expensive printer, a few cells, and some protein for scaffolding – simple!

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Full references available at: www.omsg-online.com

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John Castle is a third year medical student at Balliol College

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ingewick has been an important part of Oxford Medical School for 73 years. Ask any of the consultants, registrars or junior doctors who trained in Oxford about their Tingewick Pantomime and you’ll bet they can recall it with astonishing detail. They will remember which consultant’s character was spun off for the role of the bad guy, near misses with falling pieces of scenery, wearing outrageous costumes (there seems to have been a lot of cross dressing in Tingewick’s history) and probably even a few lines of the show’s songs.

raising enough money to cover the costs of the show, enabling all the donations on show nights to go directly to charity. The donations seem to rise exponentially each year, adding a certain element of inter-year competition to fundraising. As a result, our firm were busy from the off and we’d like to think we managed to pack a lot into one year…

The TW2012 firm came together one exhausting night in Costa Coffee with Joe, our Treasurer, Aisling, our Producer, and myself, sifting our way through endless, impressive applications. Finally we Having spoken to some, shall we say, more senior selected a bunch of loveable rogues to work with members of Oxford University, it would appear that for the rest of the year. Our first mission, the classic Tingewick has not only morphed itself to fit with Tingewick combo: a bake sale and bop. every generation of which it becomes a part, but it has grown too. And enormously so. Back when there We managed to raise a respectable amount by exwere only thirty students in a medical school year, ploiting both the baking talents of our firm and many a bunch of them would take over Tingewick: writ- members of staff’s susceptibility to emotional blacking, producing and acting in the show, sometimes mail. Massive kudos must go out to Carolyn Cook for for three years in a row. I have it on good author- always making the medical school office buy at least ity, from an ex-Tingewicker who shall not be named, as much cake as they could eat and usually more. We that the running of Tingewick was heavy on alcohol also held several bops throughout the year, including consumption and light on rehearsals. Although some an American-themed Frat Party, complete with red things remain the same, the cringeworthy jokes, the cups and beer pong. We even hosted a bop in which insults aimed at the consultants and, of course, the two blackbirds managed to find their way into Osler ever ubiquitous pink elephant, the show is now run House, only to be found three days later very much each year by a dedicated firm of 27 members, work- worse for wear… That’s one for the grandchildren! ing behind the scenes, alongside 140 or so eager 4th Our first big challenge came with an ambitious idea years on stage. In the run up to the panto, rehearsto host Tingewick’s version of Strictly Come Dancals occur on a daily basis and the new generation of ing. We managed, after many hundreds of emails Tingewickers are foolhardy enough not to depend and several pitiful excuses from senior members of (too heavily) on the booze. Tingewick Society, to recruit a bunch of unsuspectThe fundraising aspect of Tingewick has grown im- ing doctors and paired them up with some of the Unimeasurably, with events held throughout the year versity’s finest Dancesport champions and our very own Tingewick choreographers. Not only did our 60

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choreos have the task of teaching old dogs new dance moves, they also decided to accept the challenge of teaching our firm how to dance. We exploited the talents of our design team to make Strictly training videos and the writers to create witty insults for our panel of esteemed judges to use. Several hours of practice later, some strobe lighting to hide faulty footwork, and much ado about ticket pricing, seating plans and the issues that arise from serving a three course meal, and I think we managed to pull it off!

around Tingewick Foyer, including face painting and free hand massages, courtesy of Lush. Highlights included frozen lasagne taking much longer than intended to cook, the stage being covered with giant cardboard sex toys, victimising one of the senior members in a version of The Night Before Christmas, and re-working Gotye’s classic to insult members of our medical school year who didn’t make it to clinical training.

Before the end of our fourth year, with a slight deAlong came summer, and with it, the annual Tinge- lay due to Strictly, we finally set about writing the wick Weekend away. We were lucky enough in our panto. Original ideas included a version of Robin firm to have access to a 20,000 acre estate, swim- Hood, with reference to the Riots of 2011, but we ming-pool-and-all, and were even blessed with that thought this was probably too heavy on the satire; most unusual occurrence on British shores: good constructing a growing beanstalk to bring to life weather. Between the huge meals and lounging by the story of Jack and said vegetable plant, but that the pool, we spent the weekend learning new dances, would have made our budget quite tight; and finally practising sketches and writing songs for TingeAid. a piece heavy on physical and experimental theatre Alas, with weather so fair, the balance of fun and to enhance the oddities of Alice and Wonderland. productivity was probably slightly skewed. It’s self-explanatory why I was outvoted on that one. Eventually, we settled on remaking the 1980s clasThroughout all this and from the very start of the sic, Footloose, with the perfect excuse to drool exyear, the writing team were busy compiling a se- cessively over Kevin Bacon’s dance moves over the ries of sketches for the TingeAid performance. We coming months. decided to do away with the traditional black tie at TingeAid and, instead, themed our night around a Instead of being set in Middle America, our panto festival. Not only did guests turn up in wellies, but we took place in a terrible, dystopian Oxford, where covered the hall with bunting and had several stalls Tingewick had been banned by the OUH Chairman.

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Tingewick has not only morphed itself to fit with every generation of which it becomes a part, but it has grown too

The students had become boring, lifeless and solely focussed on getting MTAS points. Our protagonist, with the help of a certain Dr Roskell and of course, his sidekick Rita, fights against these dark forces to bring back the cheesy amateur pantomime we all live for. It was a piece of theatre that simultaneously celebrated and poked fun at the history of Tingewick and all those that have been involved. We tried to pack in just about everything, from the sublime to the ridiculous, with street dancing, tangos, rap-offs and 80s pop ballads, and an almost infinite number of difficult-tomove pieces of set!

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including bits of equipment breaking and chairs going missing... but, finally, we made it. We were ready to exhibit our show!

We have had huge amounts of fun creating the pantomime and hosting all the events along the way. Our estimated total for the year is £25,000. The charities we have chosen to donate this to are two charities close to the medical school’s heart: Sobell House Hospice is located on the Churchill site and all students spend time here as part of the 5th year course; Medic to Medic was founded here in Oxford, by medical school alumni, and sponsors medical students in deWith 140 people in the year, we had to create 140 veloping countries. parts, so that everyone could be involved, and held endless rounds of auditions in order to separate the It has been a real privilege to be a part of such a hisstars from the extremely talented. I can’t tell you how toric society and what an exhausting but thoroughly impressed we were! Deciding who was going to play rewarding year we’ve had! We’ve tried to do things our leads, sing the big numbers and lead the dancing a little differently, introducing new shows in to the was a daunting task, with some 4th years having such Tingewick calendar and not sticking strictly to the extraordinary and unusual talents that we simply had panto format. We hope that this different is a good different, one that will breathe fresh air and new life to write extra parts into the show. into a society that is always on the move, and one that We worked the cast hard, with long rehearsals to piece will encourage the years to come to follow in our foottogether the music, acting and dancing. We worked steps. We wish the Tingewick Firm of 2013 the very the design team even harder, with huge backdrops best of luck and hope you all have as much fun as we and an extraordinary number of props to be made. did! The writers were kept busy rewriting song lyrics and Full references available at: www.omsg-online.com inventing parts for guest appearances by consultants, and the choreos always seemed to be rehearsing! We Rebecca Adams is a sixth year medical had late nights ‘tech-ing’ and long days involving, on student at Worcester College my part, lots of shouting, aided by cast members bringing in baked goodies and hindered by various disasters

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Our Necessary Shadow Tom Burns ISBN: 978-1-846-14465-3 Amazon Price: £13.20

What’s Wrong with Fat? Abigail Saguy OUP £18.99

Reviewed by Edward Chesney

Reviewed by Rhys Dore

Oxford's Professor of Social Psychiatry, Tom Burns, has written a fantastic book on the nature and meaning of psychiatry. With Our Necessary Shadow, he addresses psychiatry itself: its history, its controversies and its shortcomings. He provides a well-rounded, thoughtful and personal narrative on psychiatry's achievements and failures, without shying away from its role in wider society. His writing comes across as deeply personal. We are not only given a balanced description and critique of the variety of views that people have on psychiatry, but also an explanation of why, in some cases, his views differ from conventional wisdom. He writes clearly, openly and honestly, avoiding dogmatism with a sharp, self-conscious wit. The first couple of chapters (dealing with the history of psychiatry in broad brush strokes) will be familiar to any 5th or 6th year students who have already completed their rotation. In fact, much of the material overlaps quite significantly with his student lecture series! His attention then turns to the anti-psychiatrists, dismissing their position with great (and perhaps undeserved) courtesy. But covering such vast swathes of material and time comes at a necessary cost; though engaging throughout, the more interested reader may find some of the chapters a little superficial. He deals with arguments about nature vs. nurture (and its influence on politics) with sharp clarity and clear eyes: "[it] clearly involves much more than can be answered by simply calculating a figure for heritability". He also hits the nail on the head in explaining the DSM's main flaw – it has achieved reliability at the expense of validity. Controversial psychiatric diagnosis, such as chronic fatigue syndrome and ADHD, are also attended to with characteristic parsimony, without losing perspective. In explaining his less 'mainstream' views, he pulls no punches. On addiction: "the bewildering range of treatment procedures is a clue to the absence of established knowledge". Again, when drawing comparison between marketing campaigns that associate a broken leg to a broken brain he remarks: "I often feel I must be missing something here. I am unaware of a fundamental philosophical breakthrough... including the existence of free will and the reality of moral choice. Not minor details."

Literature, television, the Internet: all are laden with advertisements for the latest fashionable diet or fitness regime. Be it well renowned campaigns such as Change4Life – or flashy 'Get Fit Quick' pop-ups – one thing is undeniable: tackling obesity is firmly on the agenda. Popular wisdom suggests that fat is an irrevocably bad thing; obesity is the new Western epidemic – but should that be the case? Abigail Saguy questions and refutes many of the detrimental stereotypes associated with being overweight, even discarding the word 'obesity' as a false medicalisation of 'fatness', a term which she preferentially uses throughout. What's Wrong with Fat? explores and challenges such indoctrinated views and their place in society. The backbone of this book concerns the concept of frames – different ways in which fatness can be viewed. These frames feature so heavily that, at times, you may wonder whether you have accidentally stumbled into an art gallery. Nonetheless, the deliberately languid writing style allows extensive description and analysis of the various frames that exist (ranging from the problematic view of fat, to the contrasting Health at Every Size® concept, pausing for thought at everything in between). The unhurried pace can be, admittedly, rather soporific. But, every so often, the reader is forced into a moment of genuine self-reflection; and it is these mind-broadening episodes that prove to be the hidden gems of this text. Support for the many arguments is found in the multitude of studies scattered throughout. These are coupled with a number of bland graphs and arbitrary pictures, the majority of which fail to add appreciably. But if you persevere through the initially slow start, then Saguy's fluid writing style and persuasive manner will have you converted by the end. And what the book might lack in comedy and levity, it makes up for with well-reasoned and worthwhile discussion.

Professor Burns has aimed to tell us what psychiatry is; what it can and cannot do; and where it may be headed in the future. I believe he has succeeded tremendously. On a personal note, I welcome his use of the word 'soul' – something which both the DSM and life as a 5th year student lack – saying, "psychiatry touches directly on that which is most human in us, the central core of our being – our identity or, if you wish, our 'soul'."

Ed Chesney is a 6th year medical student at New College 2013 63:2

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Careers Beyond Clinical Medicine Heidi George Moawad OUP £15.99

Strictly Bipolar Darian Leader ISBN: 978-0-241-14610-1 Amazon Price: £3.75

Reviewed by Giles Neal

Reviewed by Ed Chesney

Finishing first year, this seemed like an interesting and timely book to read. It would either reaffirm a commitment to the construction of a classical medical CV, or shine a light on areas typically beyond the scope of a conventional career. Nevertheless, my intrigue suffered a blow after reading the first page: "I have even known physicians living outside the US who have decided to take their careers in other directions". Not only was it immediately apparent that the book did not cater for non-Americans, it was also strikingly clear that it was largely a self-help book for confused physicians who wanted out. So, perhaps more usefully, I will begin with whom I'd recommend the book to, before dealing with its merits and flaws in turn.

" ...we now live in bipolar times. Mood-stabilising medication is routinely prescribed to adults and children alike, with child prescriptions this decade increasing by 400% and overall diagnoses by 4000%." Darian Leader, a psychoanalyst and mental health activist, has written a short and provocative book, divulging his thoughts on bipolar disorder. The book's cover quotes Hilary Mantel, who states that Strictly Bipolar "could also change lives". Yet – while undoubtedly interesting, well written and accessible – I doubt its capacity to change the world.

If you are a practicing physician, underwhelmed by your career but with little motivation to try something new, then it's well worth a read. You may find some inspiration in the anecdotes accompanying successful career changes. Similarly, if you're a medical student or trainee planning on practicing in the US, it's well worth a skim to see what obstacles you might face should you wish to change career plan. However, if you're practicing or studying outside the US (or you have a firm idea of career trajectory), this book is unlikely to be of benefit. Invest in a pen and pad of paper, and spend an afternoon brainstorming with Google – it will be just as fruitful, and much cheaper. The book follows a rigid, logical structure: Moawad begins by exploring the reasons doctors may want to leave the medical profession, then highlights the necessary financial and personal considerations. He provides well-researched and reliable advice on how to make sensible decisions on what to do next. Crucially, he emphasises the need for a sound escape plan, ending with an explanation as to why the qualities of being an MD never leave you. It's worth noting that the book is designed with the modern reader in mind. One can dip in and out of chapters of particular interest or relevance. Instead of paying £15.99 on Amazon then, a library card might make more financial sense. But credit where credit is due: this book is well researched, thorough on relevant figures, and very accessible. The constant reiteration of 'keeping the qualities of a physician' and how that is of benefit to future careers is reassuring, if not a little tedious by the end. Unfortunately, the editorial process was not quite as thorough – titles such as "Is it too risky" omit question marks, and unnecessary summary diagrams take up entire pages. In fact, had diagrams been removed altogether, the book would be considerably shorter (and easier on the pocket). So while this is a very niche text, it successfully caters to its target audience. However, the title and blurb could be less vague, the book shorter, and the print copy cheaper.

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A founding member of the Centre for Freudian Analysis and Research, Leader's beliefs are rooted in the teachings of the French psychoanalyst Jacques Lacan. It is this theoretical grounding which has led Leader to focus largely on linguistic aspects of bipolar disorder. He elegantly shows how mood elevation may develop from an ability to communicate more effectively. He even suggests that a need to share, to connect and relate to others, should be considered the disorder's defining symptom. His attention to such aspects is a welcome tangent from bland and reductionist biomedical models; tiresome regurgitations of biopsychosocial models and hot cross bun diagrams are mercifully avoided. However, when discussing the role of genetic inheritance, he strays beyond his area of expertise and his argument duly suffers. Leader pours scorn on the extrapolation of diagnostic categories such as bipolar type 2, which he claims has vastly lowered the threshold for diagnosis and prescription. However, he goes overboard in complaint against supposed bipolar types 3, 4, 5 and 6 – at times, one can sense a touch of intellectual arrogance creeping into his writing. But his contention that the current fashion for bipolar diagnoses stems from media and pharmaceutical psycho-propaganda remains genuinely convincing. Many conclusions are drawn from celebrity memoirs (including those of Spike Milligan and Stephen Fry), which, despite being anecdotal, are used appropriately, stylishly, and with insight and humanity. The extracts he uses are overly focused on mania, perhaps since it is a more interesting aspect of the disease. However, he ignores depressive-type symptoms to such an extent that he portrays the disease with somewhat misleading levity. Leader concludes, "However helpful a drug may be, there are questions no drug can answer." This is all well and good, but perhaps a little meaningless, a little hollow. And while his thoughts are academically interesting, they probably fail in clinical practice (a perhaps inevitable consequence of his Lacanian hagiography).

Ed Chesney is a 6th year medical student at New College 2013 63:2

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ORIGINAL RESEARCH

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A Case Report Hetal Acharya

CASE HISTORY AL is an 8-year old girl who presented with a 4-year history of impairments in all aspects of the autistic triad: social interaction, imagination, and social communication. Her teacher noticed a lack of drive to explore environments and decreased ability to parallel play. However, a regression of verbal communication caused the greatest concern. As a result, AL has poor interpersonal relationships, driven by poor verbal and non-verbal comprehension. She experiences delayed echolalia, predominantly associated with a fascination in cartoons. Furthermore, AL’s parents report a sleeplatency problem. An autistic diagnostic assessment observation schedule (ADOS) and an autistic diagnostic interview were conducted. The ADOS is a ‘gold standard’ 30-60 minute semi-structured assessment allowing the examiner to observe social and communication behaviors. Three diagnoses of moderate learning disability, profound global developmental delay, and autism were made:

DEVELOPMENTAL ASSESSMENT AL has a developmental age of approximately 2 ½ years. PAST OBSTETRIC HISTORY AL was born five weeks pre-term weighing 4lbs and 9oz. She spent four weeks in a neonatal unit to gain sufficient weight. FAMILY HISTORY Questions were asked concerning childhood developmental delay and learning disabilities. No relevant history. MANAGEMENT Management of AL’s autism was in accordance with the British Medical Journal Publications of the Scottish Intercollegiate Guidelines Network.[1] This states; ‘Treatment and Education of Autistic and related Communication handicapped Children (TEACCH)’ can be used to reduce symptom frequency and severity, and increase the development of adaptive skills.[2] Pharmacological use of melatonin was introduced to treat the co-morbid sleep-latency problem.[3] Parent-mediated interventions were used to aid AL’s parents through improvement of their knowledge and awareness of autism.[4]

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shifting and has hypnotic properties.[3] Meta-analyses have shown that in many children, administrating Autism is an early-onset neurodevelopmental disormelatonin is effective in increasing the length of ‘total der in which three characteristics prevail: poor social sleep time’ and improving the child’s overall wellbereciprocation, a qualitative impairment in communiing.[3] cation, and idiosyncratic behavior. These characteristics are pervasive, persist over more than one context Whilst we as doctors can do little to control these – e.g. home and school –, and are age inappropriate. external factors, we can have some control over the [4,5] In addition, sense perception differs for a child clinical environment. Medical management of a child with autism. The paradoxical phenomenon of hyper- with autism can be difficult; the unfamiliar, chaotic or hyposensitivity to sound, taste, touch, and smell is environment of a hospital can trigger significant disexperienced as a separate entity. Given this, a child tress.[10] In this instance, AL was treated in the comwith autism may not share the same pattern of human munity with specialist nursing visits at home. There is behavior the way that is ‘neurally’ typical; this differ- limited literature regarding the effectiveness of manence being known as the ‘Culture of Autism’.[4,6] aging autism in a hospital environment vs. communiTherefore autism concerns the whole person, their ty management. Current interventions such as bringing familiar objects from home or reducing noise are relationships, and social circumstances.[6,7] not always feasible and may not suffice.[10] This may Families of a child with autism face many challenges, be an important point to consider when consulting a such as deciding whether to place the child in a mainpatient with autism, in order to provide an effective stream or specialist school. This debate is complicated and appropriate service. by Bandura’s social learning theory that ‘most human behavior is learnt observationally by modeling’, arguCONCLUSION ing that it may not necessarily be in the child’s best interests to be around similar children with autism. Autism is a complex, disabling disorder that is physi[8] Parents may relentlessly worry whether their child cally and emotionally demanding on both the patient will be ‘socially accepted’; self-reports of children with and their family. It has a breadth of psychosocial imautism show that they are more likely to report feel- pacts beginning in childhood and persisting throughings of social isolation at school.[7] There is also an out life. It is only when we can accept and value the increased risk of exploitation, including emotional difference between our culture and the ‘culture of and physical abuse.[8,9] It is unknown whether this autism’ that we can effectively help to ameliorate the increased susceptibility to bullying is due to a limited impact of the disorder. ability to effectively communicate disapproval, or the Full references available at: www.omsg-online.com inability to comprehend the advances of others.[7] DISCUSSION

Lack of sleep is a concern for both teachers and families. Often chronic and disabling, it can result in difficulties in behavior and learning. Melatonin is an endogenous substance that can produce sleep phase

REFERENCES 1. Scottish Intercollegiate Guidelines Network (2007) Assessment, Diagnosis and Clinical Interventions for Children and Young People with Autism Spectrum Disorders (The SIGN Guideline). Edinburgh: Royal College of Physicians. [cited 4 November 2011] Available from URL:http://www.sign.ac.uk 2. Mesibov GB, Shea V. The TEACCH program in the era of evidence-based practice. J Autism Dev Disord 2010;40(5):570-9. 3. Rossignol DA, Frye RE. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev Med Child 2013 63:2

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Hetal Acharya is an F1 and graduate from Southampton University The author would like to thank patient AL and her family for their kind approval

Neurol 2011;53(9):783-92. 4. Sotgiu I, Galati D, Manzano M, Gandione M, Gómez K, Romero Y, et al. Parental attitudes, attachment styles, social networks, and psychological processes in autism spectrum disorders: a cross-cultural perspective. J Genet Psychol 2011;172(4):353-75. 5. Levy E. S, Mandell S. D, Schultz T. R. Autism. Lancet 2009; 374: 1627–3. 6. Lawson W, Jordan R, Simone L. The passionate mind. How people with autism learn. Jessica Kingsley publishers, 2011. 7. Jawaid A, Riby DM, Owens J, White SW,

Tarar T, Schulz PE. ‘Too withdrawn’ or ‘too friendly’: considering social vulnerability in two neuro-developmental disorders. J Intellect Disabil Res 2011. 8. Bandura A. Social learning of moral judgments. J Pers Soc Psychol 1969;11(3):275-9. 9. Wing L. The autistic spectrum. New updated edition. Constable and Company publishers. 2002. 10. Horner RH, Carr EG, Strain PS, Todd AW, Reed HK. Problem behavior interventions for young children with autism: a research synthesis. J Autism Dev Disord 2002;32(5):423-46. 67

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DOWN ACROSS 1 Endless dilutions phooey math - rubbish! (10) 1 Seat of learning : fashionable university takes in Across Down 2 Gets very loud after copper squeezes arm (4) teletubby (11) 1 Seat of learning : fashionable university takes in 1 Endless dilutions phooey math - rubbish! (10) 3 Submitting without right sign causes weak stream 5 Repel! A colomist (5) teletubby (11) 2 Gets very loud after copper squeezes arm (4) (8,6) 6 Shout nothing as a prefix to frosty treatment (4) 5 Repel! A colonist (5) 4 Weighs musically (6) 8 Iron maiden vocal is near3theSubmitting bone (7) without right sign causes weak stream ( 6 Shout nothing as a prefix to frosty treatment (4) 4 Weighs 5 Never this, according to one House doctor! (5) 10 A melting ice-man could be tired (7) musically (6) 8 Iron maiden vocal is near the bone (7) 5 Never 6 Note incline; tightness! (5) 11 Left cure digested in stomach (5) this, according to one House doctor! (5) 10 mess, A melting could be tired (7) 12 Those we care for show6perseverence, Note incline; tightness! (5) 7 Denotes inky leading ice-man to colic (6,5) I hear (8) 11 Left cure digested in stomach (5) 7 Denotes 9 A crash landing is a pain in the arse! (7,6) 13 Fasteners havenâ&#x20AC;&#x2122;t left conductor (6) inky mess, leading to colic (6,5) 12router Those we care for Must showbeperseverance, (8) causes first auction 16 Initially my stopped access? a bug! (4) 14I hear Blockage (4)landing is a pain in the arse! (7,6) 9 Aitem crash Fasteners haven't conductor (6) 15 Sounds like a funny bone? 17 Mentally 13 ill protected from greasy left lumps (6) (7) 16 Initially my router stopped access? Must be a bug! 19 Vector is 14 correct (4) (6) ill protected from greasy lumps (6) Blockage causes first auction item (4)18 Uncomfortable ethics are 17 broken Mentally 20 Why heirs family area left shaking (10)(7) 23 Women going to event19 with daughter experiences 15outside Sounds like funny bone? Vector is correct (4) 21 Medieval18 cleaner is no sucker (6) strong feelings (8) Uncomfortable ethics are broken (6) 20 Why heirs outside family are left shaking (10) 22 To use x-rays on air: plot backed unknown (11) 24 Swelling iron spree losing energy (7) 23 Women going to by event with daughter experiences 21 Medieval cleaner is no sucker (6) 25 Reduces sugarstrong biting iffeelings time and(8) gravity are removed 26 Endemic dysfunction with one cure (8) 22 To use x-rays on air: plot backed by unknown (11) (7) 24 Swelling iron spree losing energy (8) 28 Without quiet paging, the effect of passing time (5) 25 Reduces sugar biting if time and gravity are remov 26 GI airmen26 suffer headache (8) 30 The French pens are creating a superfluous gland (6) Endemic dysfunction with one cure (8) (7) 27 Getting one into a posh sport often causes disability 32 An ape dancing with love? Breath-taking (6) 28 Without quiet paging, the effect of passing time (5) 26 GI airmen suffer headache (8) (5) 33 Lifeless doctor starts rabid, losing character (6) 30 The French pens are creating a superfluous gland (6) one(7) into a posh sport often causes disability 29 6 down is finally included in unwanted meat in your 34 Deliverer inside? Easy,27 ringGetting emergency! 32 An ape dancing with love? Breath-taking (6) 29 6 down is finally included in unwanted meat in you inbox (5) 35 Journal with a cutting edge (6) 33 Lifeless doctor starts rabid, losing character (6) inbox (5) 30 Brain damage first of eight (6) 36 Englishâ&#x20AC;&#x2122;s revolution is rash (6) 34 seamen 30 Brain damage first of eight (6) Deliverer Easy, ring emergency! (7) 31 Are disabled usedinside? to clear out blockages? (6) Crossword created by Alexander Allen, a sixth year

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