A picture is worth a thousand words, that’s why the JSMS have teamed up with the British Medical Association to give you the chance to win our prestigious “Elective Photography Prize” for the best photo taken on elective anywhere in the World.

Your elective will be one of your most memorable experiences. We want you to capture a special moment on your trip and share it with us. We have kept the theme broad and simple, you may take any photo you wish. Perhaps a picture of your time spent with the local people, the beautiful landscape or even one of yourself! Pick up your camera, take a picture and send it in to us.

The competition entries will be judged by Mrs Rosemary Wilman, the Vice President of the Royal Photographic Society. Shortlisted photos will be published in the Journal of Student Medical Sciences.

For further information on applying please click here.

MTAS-fever has passed and the dust has settled. At least until 9th December when final years everywhere will find out the areas they will be working in for the next two years. On the 10th December there will be students’ calling for rereads, remarks and a revamping of the system. When the questions this year came out, there was an audible intake of breath. Everyone was confused and tried to believe faculty staff as they reassured us it was similar to last year with different wording. Despite the initial shock, final-years across the country put their best foot forward, buckled down and produced a form to represent themselves. Having accidently-on-purpose applied to one of the most competitive deaneries in the country, I have thought hard about what it would mean not to get my first choice. In light of the fact that everyone has been guaranteed a job and job satisfaction relies on so much more than your geographical location, where I end up has become less important to me. However, the whole process led me to reflect on what the form valued.

This year the questions were all based on clinical scenarios and your medical training with no room for extra-curricular activities. This took a lot of individuals by surprise. In the past there had always been room to show development outside a medical degree. Despite having chosen to spend my time doing things I loved rather than streamlined to a career, I was still disappointed that it did not merit any points. This got me thinking about the lessons I had learnt from my extra-curricular escapades. All the buzzwords they look for: clear communication, teamwork, prioritisation….the list goes on. I definitely did not pick up those skills on a ward where you wander around trying to clerk patients, watch procedures and get some teaching. Extra-curricular roles such as sport, charity-work or getting hands-on in the community all ask us to be adults, assume responsibility and make things happen. We learn medicine on the wards and learn how to be doctors outside them.

What did get points on the form was having presentations, prizes and publications. More importantly, those items are ones that employers in medicine will always value and will assist in a long term career. Forever, it has been plugged that you will never get published without a supervisor who wants you to get published. Whilst true to an extent, it is possible to get into the academic arena without one. Where there is work that is interesting, there are medics willing to listen. Print journals, web-journals and student journals such as this one are always looking for interesting articles to publish.

Conferences are fantastic for students. They provide an opportunity to present work in a professional environment, meet medical professionals as well as explore your career options. Stalls present a chance to (importantly) grab freebies but also to find out about services you never knew existed and pick up items to help you in clinical practice. I am unlikely to need another highlighter, pen or USB stick for at least another three years. Students are usually offered discounted rates and there can be bursaries available to help students meet the cost. I worked off my fee to one conference, presented at two and found them to be rewarding. The topics chosen for keynote speakers are often interesting and ground-breaking, whilst the themes in small sessions are often thought provoking and promote discussion.

Lots of students in their penultimate year have been asking what to do to get themselves “form-ready” for 2011 entry: chances are you have done it already. Relax, follow your interests and see where they take you.

As an undergraduate student, I enjoyed almost all of the clinical attachments I had during my course. The challenge for me therefore was to decide which kind of doctor I should become? I was fairly confident that I did not want to be a general practitioner because I enjoyed working in teams and thought I would not be temperamentally suited to seeing most of my patients alone. But which branch of hospital medicine to opt for? My ideas really started to gel after my paediatric attachment, at least to the extent of opting to do an increased amount of child psychiatry during my psychiatry attachment and deciding on an elective abroad working with children. The factors that drew me towards paediatrics are listed in box 1. I recognised that whilst many disciplines were attractive to a junior doctor, they were not all equally attractive as a consultant, especially as one spends less than a decade as a trainee but three decades as a consultant, and I was impressed with what consultant paediatricians did. They were still hugely involved in the care of their patients whereas many other specialties seemed to delegate the most interesting parts of their work to registrars. Consultant paediatricians remained involved in emergency care and in the most challenging and difficult cases.

I also liked the patients. As one of a family of five, I had always enjoyed being around children. Children only come into hospital if they are ill – there are no malingerers. Furthermore the vast majority of children get better and that is a hugely rewarding experience. Children are great levellers – they do not respect white coats or grey hair. This means that teams caring for children made up of doctors, nurses and other professionals tend to be less formal and less hierarchical.

There is real drama in paediatrics. I can still remember the first time I was called to the Labour Suite as a Senior House Officer to undertake endotracheal intubation of a newborn baby who was struggling to breathe. As a doctor you only have a few minutes to get it right. It is immensely rewarding as the baby’s heart rate speeds up from perhaps 20 beats per minute to above 100, the baby starts to become pink as oxygen enters the bloodstream and then the baby starts to struggle against the endotracheal tube which you have inserted. I can also remember running all the way from the library to the Accident and Emergency Department when a toddler was admitted blue and unable to breathe and then removing a golf ball from his upper airway with a pair of McGill’s forceps. Seeing children get better and the relief on their faces and those of their parents is a tremendous experience and I have always felt privileged. A life saved from meningitis at the age of one year gives that child potentially 70 years health in the future.

Paediatrics also attracted me in the 1980s because of its breadth. This continues to be the case. When I looked at branches of adult medicine, I could see some consultants doing very specialised areas of work. There was the diabetic clinic, the hypertension clinic, the epilepsy clinic. I could not see myself being satisfied spending all afternoon adjusting a few drugs to maintain someone’s blood pressure within the normal range, when all the patients were pre-selected and there was no element of making a diagnosis. Paediatrics embraces both the extraordinarily rare, such as inborn errors of metabolism due to recessive genetic disorders (for example glycogen storage disease) and the incredibly common such as asthma, gastroenteritis and febrile convulsions.

Irrespective of whether a disease is rare or common, ideally we should practise evidence-based medicine and that needs research. In my own personal paediatric career, I have been very involved in research on children and for the benefit of children. It was easy to see from first-hand experience how a sub-specialty like neonatology would lend itself to research because the Neonatal Intensive Care Unit contains extremely ill children who have invasive procedures and treatments done to them and who have constant vascular access. However, it is also important that we undertake research on children’s medicines, common children’s conditions such as pneumonia and in the area of prevention such as new vaccines. Indeed prevention is a key part of paediatrics. Although I enjoyed the drama and excitement of acute admissions through the Emergency Department, there is no question in my mind that an ounce of prevention is worth a pound of cure. Paediatrics has led the way in providing comprehensive immunisation schemes to protect children against life threatening diseases such as meningitis and polio, and in blood spot testing in newborn babies to detect rare diseases as early as possible. This is an example of secondary prevention.

But paediatrics is not all a bed of roses. What are the downsides to training as a paediatrician?

Sadly children die and others survive but are profoundly handicapped, in pain or have a poor quality of life. This is incredibly distressing. I can certainly say that the hardest thing I have ever done in my whole career is to be the first person to enter a room and tell parents that the previously healthy baby they had a few hours ago has died of cot death. Some students are deterred from paediatrics because young children cannot speak and therefore one cannot have the personal doctor-patient relationship one would have with an adult patient. This was one of my concerns but I learned early on, for example in neonatology, that the parents and the extended family become just as much our patients, and one can have very fulfilling and long-standing personal relationships with the parents of children and, if the child survives, can develop a new doctor-patient relationship with the young person. Recently, a lady waiting in the canteen of my hospital stopped me and asked if I was Professor Stephenson. I said ‘yes’ and she then explained that I had treated her child with asthma and her daughter was now 23. Thankfully, she remembered the consultation in a positive light. This underlines that paediatricians provide care from the newborn up to the transition to adulthood. This also adds to the richness of paediatrics.

Paediatrics is sometimes described as having a fourth dimension, that is the dimension of time. In adult medicine, asthma is not that different whether the patient is aged 30 or 40. However, in paediatrics, asthma is a very different condition when dealing with a 3 year old or a 13 year old. This applies to many children’s diseases where the presentation and the treatment may both differ with age. We try to teach our students that time or age affects the disease and also that the disease itself can affect a child’s own development, both physical and emotional. For example, malabsorption due to coeliac disease can lead to stunting of growth. Profound emotional deprivation can also lead to hyperphagic short stature syndrome where growth is stunted because of the effect of the neglectful environment on the brain’s release of growth hormone.

So there are pros and cons to being a paediatrician and certainly by the time I had graduated I was still not certain. This is reflected in the fact that I spent the first two years after graduation rotating through adult medicine posts. This reinforced the attractions of paediatrics and to some extent reinforced the downside of other specialties. I felt I was seeing many patients who had self-inflicted illnesses, often due to smoking, alcohol or violence, and that only a minority seemed to get better. Even when they did get better, it did not always seem to be due to our intervention and very frequently we would see the same patients re-admitted with the same problem within a few weeks or months. I decided that the only way I would ever make my mind up was to actually do some paediatrics first hand and therefore I applied for my first paediatric Senior House Officer post. However, my continuing indecision was reflected in the fact that in the same week I also had been shortlisted for interviews in neurology and ophthalmology. The paediatric interview came first and I was offered the job, and, as they say, the rest is history. I never regretted the somewhat circuitous way in which I ended up entering paediatrics and, if I had my time again, I would not change a thing. I have found it a tremendously exciting and rewarding career and what I have done has evolved throughout my career, from being a very hands-on paediatric consultant in my thirties to someone now more involved in children’s health nationally.

Most of my experience has been in hospital paediatrics; paediatrics also contains many sub-specialties such as paediatric neurology, paediatric cardiology, neonatology, and about one-third of consultant paediatricians practising in the United Kingdom are community paediatricians who may do some work in the hospital but are principally involved in preventative paediatrics and the care of children in the community.

There is little private practice although that was never an issue for me personally. However, if you want to double your salary in Harley Street, there is very little chance of affording a Bentley in paediatrics. This reflects well on UK paediatrics because one of the reasons there is so little private practice is that there are so few waiting lists and children with serious conditions do get seen very quickly.

During my own professional lifetime in paediatrics over the last quarter of a century, I have seen serious childhood diseases such as haemophilus meningitis and epiglottitis eradicated, I have seen the survival from conditions such as leukaemia and premature births improve tremendously and I have seen the incidence of cot death more than halved. So paediatrics continues to be a very positive specialty – things are getting better. Things are also getting better for paediatricians. In 2000 there were 1600 paediatricians in the United Kingdom and by 2006 there were 2232. Working hours have decreased from over 100 per week when I was a junior doctor to a maximum of 48 per week from this August. The NHS budget has increased from 64 billion to 92 billion pounds per annum in real terms over the life of the present government and consultants have seen a 15% increase in salary in real terms with the New Consultant Contract.

If you would like to find out more, why don’t you visit the College website at www.rcpch.ac.uk where you can read about careers in paediatrics and the pre-application information necessary? We also have a leaflet on the paediatric training pathway which you can obtain from training.enquiries@rcpch.ac.uk. Paediatrics is one of the few specialties in the United Kingdom which, following the MTAS debacle, opted to have ‘run through’ training. This means that after your general broad training in the two foundation years, if you opt to train as a paediatrician and are accepted for one of the specialist training posts, then you do not have to re-apply, as is the case in the so called ‘de-coupled’ specialties. In paediatrics, you enter at ST1 and, provided you fulfil the requirements of a trainee, at the end of seven years will obtain your CCT and be able to apply for a post as a consultant paediatrician.

Good luck!

Introduction – The Tobacco Epidemic

Smoking tobacco is now regarded as the single biggest killer than any other avoidable substance in developed countries [1]. It is estimated to cause around 87,000 deaths in England and costs the NHS £1.5bn a year [2]. In 2006 the General Household Survey reported that the adult smoking prevalence was 22% in the UK [3]. Although the prevalence of smoking has been falling steadily from 1974, with a more recent decline from 2002 onwards (Fig. 1), continued efforts to improve smoking cessation interventions still remain a priority for the Department of Health (DH) since they are among the most cost effective interventions available and have a significant positive impact on the quality of life in all ex-smokers [4].

Attitudes Towards Smoking in the Bangladeshi Community

Few studies have looked into smoking behaviours among black and ethnic minority (BME) backgrounds. The DH recognises that certain BME groups have a very high prevalence of smoking and this is slowly being addressed. Compared to the general adult population as well as other South Asian communities, Bangladeshi men have the highest prevalence of smoking in England (40% in 2004), followed by White Irish (30%) and Pakistani men (29%), compared to 22% in the population as a whole [5].

A detailed analysis of smoking behaviours among Bangladeshi men reveals that there are four inter-related themes that influence smoking behaviour in Bangladeshi adults: gender, age, religion, and culture [6]. Smoking is a widely accepted practise in Bangladesh as a ‘national habit’ among men [7], which is why the prevalence of smoking among men is high due to it being culturally associated with socialising, sharing, and reinforcing male identity. Furthermore, there is evidence to suggest that the prevalence of smoking has not changed significantly following migration to the UK, despite more restrictive tobacco control policies. In fact, a cross-sectional study by Croucher et al [7], in which 81 Bangladeshi men aged 18-64 years, revealed that older participants reported that they continued to smoke because of their migrant experience. They described feeling stressed and ‘not at ease’, because of having to adjust to life in the UK, whilst having to support an extended family in Bangladesh. Thus smoking is seen as a coping strategy for stress [7]. In contrast to the general population, the prevalence of smoking among Bangladeshi women however is low at only 4% [8]. Smoking in women is often hidden from family members as it is associated with stigma and shame6.

Another major factor that influences smoking behaviour in Bangladeshis that differs from the general population is religion. The vast majority of Bangladeshis adhere to the Islamic faith; however, there are varied and sometimes conflicting interpretations of how acceptable smoking is within the religion. While smoking is not explicitly prohibited in the Quran, it is not fully accepted within Islam [9,10]. In a qualitative study of 53 Bangladeshi and Pakistani men and 20 women [8], White et al reported that many smokers had cut down and some had even quit smoking during Ramadan, the month of fasting. The significance of this issue was expressed in all age groups, particularly amongst the older age group. Despite the encouragement to stop smoking during this time, most only succeeded in changing the hours during which they smoked or reducing the number of cigarettes smoked. Moreover, once Ramadan had ended, the majority returned to their usual smoking routine [8].

Effects of National Tobacco Control Policies on Bangladeshi Smokers

The socio-cultural context of the smoking behaviours in Bangladeshi men can arguably be linked to a reported isolation and exclusion from existing tobacco control initiatives [7]. A Cochrane review on mass media interventions also stated that no consistent relationship was observed between the effectiveness of anti-smoking campaigns and ethnicity [11]. The fact that the majority of Bangladeshi migrants did not study at school in this country and possess English as a second, or even a third language may contribute towards this as health warnings on tobacco products could easily be ignored.

Additionally, the restaurant trade is the single biggest source of income for many Bangladeshis in the UK and there is a reported lack of enforcement of Smoke-Free Workplace Environments in such places. This is significant because three in five working Bangladeshi men are employed in the hotel and restaurant trade. Smoking whilst handling and preparing food was not reported to be discouraged by employers. In fact, these workplace social pressures and practices encouraged non-smokers to start smoking. Although these employment opportunities provide social support, they did not support smoking regulations, contrary to practices observed in the general employment market [7].

Experiences of Ethnic Minority Smokers With Smoking Cessation Services

Like all public services, the NHS Stop Smoking Services must be made accessible to a diverse range of people, including those from various ethnic backgrounds. However, current evidence of effectiveness for smoking cessation interventions is not derived from studies involving the UK’s main ethnic minority groups. From the few studies that have been carried out in the Bangladeshi community, a number of factors have been highlighted as to why few Bangladeshi smokers quit and why even fewer take up the NHS Stop Smoking Services.

In the qualitative study by White et al [8], it was reported that both Bangladeshi and Pakistani males had little experience with formal cessation services. In the general population, approximately 40% of smokers seek help advice from health professionals each year [12]; however few community members in this study had sought advice from their GP. Most of the participants did not view the GP as someone they could go to for advice on quitting smoking [8]. In addition to that, many Bangladeshi smokers are unable to speak English. Although interpreters are at hand to translate between doctors and patients, this inevitably means that GP consultations will consume more time and will focus more on the patients presenting complaints as opposed to smoking habits. Moreover, some primary care staff hesitate to raise the topic of quitting smoking as they fear it may cause confrontation. Staff members have also reported that religion is another barrier which may prevent them from offering support as a number of smokers believe that they have less internal control over smoking, citing that Allah (God) has control over their health [7]. Such situations can be particularly difficult to approach unless training is provided for staff members to address these issues sensitively.

Both White et al and Croucher et al also reported that Bangladeshi smokers had a negative view of Nicotine Replacement Therapy (NRT) despite epidemiological evidence proving its efficacy. Common to the wider population, participants felt that they were still putting an addictive substance in the body. Most participants in both studies complained that NRT was too expensive. This is of significance because the Bangladeshi community is known to possess high levels of deprivation and unemployment exceeding 40% in those aged <25 years in some areas [13]. Few participants were aware that NRT was available for free on NHS prescription, further illustrating how Bangladeshis are isolated from current tobacco control initiatives. Moreover, older Bangladeshi smokers stressed that NRT products were only promoted in English with inappropriate imagery, which lead to confusion as some participants may mistakenly perceive them as another cigarette advert [7]. Another important point to consider is that although Ramadan is a good time for health professionals to encourage Bangladeshi smokers to give up smoking, they may discover that clients fail to comply with certain types of NRT (e.g. patches) due to fears of their fast being broken. Thus, in such situations, health professionals need to explain to them NRT can still be used during the times that they are not fasting; however, this can only be achieved if adequate training on Bangladeshi culture and religion is provided by local PCT’s.

The Bangladeshi Stop Tobacco Project

The Bangladeshi Stop Tobacco Project is a project based in the London borough of Tower Hamlets [14]. The Bangladeshi community makes up more than a third of the borough’s population of 65,000. The uniqueness of this project is that the service is sensitive to gender, age, culture and religion – themes which have been shown to significantly influence smoking behaviour in Bangladeshi adults in previous studies [6]. As a result, in the three completed years (2005-2008) of funding from the local PCT, the project has served over 1145 Bangladeshi clients, 66% of whom have successfully stopped tobacco use (either smoked or chewed) as validated by monitoring CO levels at four weeks after having set a quit date [14], which is much higher than the national average of 31% [2].

The project employs workers from within the Bangladeshi community and all aspects of the project are delivered in both English and Bengali, which include advice on how to quit, leaflets, telephone help lines etc. Furthermore, female clients are served by female workers, which is of particular importance as smoking tobacco amongst women is associated with shame and it enables Bangladeshi women to speak to other women without fear of being stigmatised. The project also takes advantage of ‘Islamic seasons’ such as Ramadan and the annual Hajj pilgrimage, in which Bangladeshi smokers are more likely to give up smoking. Moreover, the project has been successful in gaining a strong media profile by advertising in local Bangladeshi TV and Radio channels. Furthermore, the community workers also approach clients who work during unsociable hours especially those within the restaurant trade and mini cab centres. Due to its recognised success, the project receives several referrals from community centres, local mosques, GP surgeries, hospitals, pharmacies, community mental health teams as well as other health care settings.

Once clients are recruited, they follow the normal Four Week Quitter routine and are immediately prescribed NRT once they have set a quite date. Also, clients are asked to abstain from chewing tobacco as some Bangladeshi smokers regard it as an aid to smoking cessation as opposed to an alternative form of tobacco [7]. Community workers also stated that another reason for the higher cessation rate compared to the national average is that they have a longer follow up period of up to 12 weeks for those who fail to quit at four weeks and they offer one-to-one support as opposed to group therapy, which they claim is more effective. Thus the Bangladeshi Stop Tobacco Project has successfully managed to incorporate a detailed understanding of smoking behaviours within the Bangladeshi community into a structure that is able to meet the needs of that community and provide an effective smoking cessation service achieving a cessation rate better than the national average.

Serving Bangladeshi Ethnic Minority Smokers on a National Level

Ethnic minority groups have only recently been defined as a target group in the UK government’s tobacco control strategy [5], which forms the foundation for smoking cessation services. Although examples of ‘good practice’ for smoking cessation services targeting UK South Asian communities have been published [15], there are no published outcome evaluations, and hence there was a need to observe the Bangladeshi Stop Tobacco Project in order to observe its strengths as a leading service to this community. Even in the government’s recent guideline [5] for working with BME smokers, many of the case studies cited in the document were not rigorously evaluated due to difficulties in acquiring formal evidence. Despite this, there is no evidence to suggest that the generic guidance offered in this document will not work in BME communities, although clearly services do need to be adapted for the full range of diversity themes found in various communities.

The current high prevalence of tobacco use and lower levels of successful cessation in the Bangladeshi community can be attributed both external factors, such as exclusion from existing tobacco control initiatives, along with internal factors such as the reported lack of enforcement of any regulatory framework by employers (particularly in the restaurant trade), the pro-smoking expectations within the community as well as the easy access to a wide range of tobacco products (e.g. paan). Restricting access to such sources of tobacco can be achieved by enforcement of current taxation and labelling regulations for the whole range of traditional tobacco products consumed by this community, including paan [16].

In order to curb the prevalence of smoking in one of UK’s largest ethnic minority group, there is a need for the government to address this community’s health inequalities in the broader sense. Firstly, issues such as unemployment, housing and income need to be addressed in the long term because it is known that people in the lowest socio-economic category have the highest prevalence of smoking. Moreover, there needs to be proper enforcement of Smoke-Free Workplace Environments especially in the restaurant trade as this is the most popular sector in which Bangladeshi men are employed and are most likely to be influenced to continue smoking [7]. Language barriers need to be broken with the provision of more translators as well as health care leaflets, which should be made available in all ethnic minority languages and should also be offered routinely in GP consultations.

Local PCT’s should identify factors that influence smoking behaviours in their local ethnic minority group and then approach them in a manner demonstrated by the Bangladeshi Stop Tobacco Project, attending to the sensitivities of gender, age, religion and culture as well as language. It should also be noted that there are still strong similarities between Bangladeshi smokers and the general population, particularly among younger adults. Further training is required for NHS Stop Smoking Staff so that the current generic smoking cessation skills used by them can be expanded to provide a more adaptable response to the range of tobacco use behaviours that are prevalent within the Bangladeshi community.

Although such initiatives require significant pooling of resources and careful planning on the part of local PCT’s, the Bangladeshi Stop Tobacco Project has shown that with some effort, much can be achieved by way of curbing the prevalence of smoking in a community deemed to be difficult to target by existing NHS Stop Smoking Services.

Acknowledgements

Acknowledgements to Professor Ray Croucher and the Bangladeshi Stop Tobacco Project for kindly giving me the opportunity to observe their work and for providing me with data on their services.

References

1. John Britton. ABC of Smoking Cessation. BMJ Books, 2004. Blackwell Publishing

2. NHS Information Centre: Statistics on Smoking: England, 16 Oct 2008.

3. Goddard E. (2008). General Household Survey 2006: Smoking and drinking among adults 2006. Office for National Statistics, Newport.

4. Godfrey C., Parrott S., Coleman T. and Pound, E. (2005). ‘The cost effectiveness of the English smoking treatment services: Evidence from practice’, Addiction, 100(2), pp. 70–83.

5. Communities and Local Government: London. Working with Black and Minority Ethnic Communities. A guide for Stop Smoking Service managers. May 2008

6. Bush J, White M, Kai J, Rankin J, Bhopal R. Understanding influences on smoking in Bangladeshi and Pakistani adults: community based, qualitative study. BMJ. 2003 May 3;326(7396):962.

7. Croucher R, Choudhury SR. Tobacco control policy initiatives and UK resident Bangladeshi male smokers: community-based, qualitative study. Ethn Health. 2007 Sep;12(4):321-37.

8. White M, Bush J, Kai J, Bhopal R, Rankin J. Quitting smoking and experience of smoking cessation interventions among UK Bangladeshi and Pakistani adults: the views of community members and health professionals. J Epidemiol Community Health. 2006 May;60(5):405-11.

9. Al-Qurdawi Y. The Halal and Haram in the private life of the Muslim. The lawful and prohibited in Islam. London: Al Birr Foundation, 2003.

10. Ghouri N, Atcha M and Sheikh A. Influence of Islam on smoking among Muslims. BMJ 2006;332;291-294

11. Bala M, Strzeszynski L, Cahill K. Mass media interventions for smoking cessation in adults. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD004704.

12. Britton J, Lewis S. Trends in the uptake and delivery of smoking cessation services to smokers in Great Britain. J Epidemiol Community Health 2004;58:569–70.

13. Tower Hamlets Primary Care Trust. Tobacco Control Strategy. 2005

14. The Bangladeshi Stop Tobacco Project, under the supervision of Prof Ray Croucher. Barts and the London. Email:r.e.croucher@qmul.ac.uk

15. Brown C. Tobacco and ethnicity: a literature review. Edinburgh: Action on Smoking and Health, Scotland, 2004.

16. McLean, C. A. & Campbell, C. M. (2003) ‘Locating research informants in a multi-ethnic community: ethnic identities, social networks and recruitment methods’, Ethnicity and Health, vol. 8, pp. 4161.

Abstract

Cocaine is a potent drug with a strong addictive effect. Its main actions stem from the blockage of monoamine reuptake such as dopamine, serotonin and noradrenaline thus potentiating their effects. It can be used for anaesthesia as well; the main medical use has been local anaesthesia. In its history it has been used in the eye and also has been administered into the spine.

In recent times, it has been found to have a strong reinforcing effect – the user can suffer physical and psychological effects. Its effects are acute and chronic in nature.

The use of cocaine amongst young individuals has skyrocketed in recent times; the addiction arises from the desire of the “rush” that users get. Some human studies have been done to withdraw conclusions, whilst many animal studies have provided valuable information. Slowly, promising treatments such as pharmacotherapy and psychotherapy are becoming available. They aim to work towards decreasing the addiction.

Introduction

Cocaine has a chequered history. Initially, it was considered a divine gift by the Inca tribe and to this day coca leaves are chewed by the native, mountainous people of Columbia, Bolivia and Peru; it is used to enhance stamina and fight altitude sickness. Koller was the first to use cocaine in a medical setting. He used it as an anaesthetic for eye surgery in 18841 (1)

The physical and psychological effects of cocaine can be both acute and chronic. The early signs of cocaine stimulation include hyperactivity, tachycardia and euphoria – this is by no means an exhaustive list. Its chronic use is notorious associated with addiction. A cocaine overdose can lead to death from respiratory failure, myocardial infarction, stroke or even a cerebral haemorrhage (2).

Nowadays, cocaine is regarded as one of the most destructive narcotics in destroying the fabric of our society. Approximately 12% of adults aged less than 35 years have experimented with cocaine2.Consequently, it has been given the classification of Class A; Table 1 lists the classes and their drugs.

Pharmacological Effects

The most common medical use for cocaine has been as an anaesthetic. Columb et al. (4) outlined the structure of a local anaesthetic in their study. It has a lipophilic aromatic ring, an amine group and ester bond link or an amide bond link. This ester link is susceptible to rapid hydrolysis. Figure 1 shows the structure of a typical local anaesthetic.

Figure 1 shows the three relative parts of lignocaine. The ester link can be replaced by an amide group – the latter maintains the structure for longer because the amide bonds are not as susceptible to rapid hydrolysis as ester links

Local anaesthetics are weak bases and their ionised form blocks the sodium channels during the upstroke of an action potential. Cocaine has a potential for causing cardiovascular problems. Consequently, safer synthetic anaesthetics (for instance prilocaine and lignocaine) have replaced it. Figure 2 shows a typical action potential and the effect of a local anaesthetic.

Figure 2 shows a comparison of action potentials. Graph A shows a typical action potential in a neuronal cells whilst Graph B shows how local anaesthetics, such as cocaine, depress the initial depolarisation.

Dunwiddie et al. (5) demonstrated the anaesthetic effect of cocaine. Coronal slices from the hippocampus of the rat were perfused with 100µm of cocaine. This caused depressed postsynaptic potentials suggesting a mechanism for its anaesthetic effects.

In practice, cocaine was used in the eye because it causes dilatation of the pupil by causing noradrenaline to act on alpha-1 adrenoreceptors(6). Recently, cocaine has been put in a trial for a diagnostic test for Parkinson’s disease because of its mydriatic activity. In this condition, the sympathetic innervation to the papillary dilator muscles is decreased and so the diagnosis would be clearer if cocaine-induced mydriasis occurs(7). The results have shown reasonable accuracy and the authors have called for more research into a promising diagnostic tool.

Cocaine has other pharmacological effects. The theory that it blocks the re-uptake of monoamines (including dopamine, serotonin and noradrenaline) is generally accepted. Chen et al. (8) showed that perfusion of cocaine at low doses (1-10 µM) to the ventral tegmental area increased all three amines similarly in the synapse. However, at 100-1000µM there was a higher dopamine output. This suggests that cocaine blocks the re-uptake of the monoamines and it has a dose-dependent relationship primarily affecting dopamine.

Acute Effects

Cocaine is lipophilic and is able to gain access through the blood-brain barrier with ease. The acute effects can be divided into physical and psychological effects.

The primary psychological effect of cocaine is the ‘rush’ it gives. Breiter et al. (9) conducted a double-blind study in which doses of cocaine (0.6mg/kg) and saline infusions were given to cocaine-dependent individual. The entire brain was imaged byfunctional Magnetic Resonance Imaging (fMRI) 5 minutes before and 13 minutes after whilst being rated for craving. The team concluded that cocaine induced focal signals in the nucleus accumbens and caudate putamen showed a high correlation with the ‘rush’ rating.

An interesting psychological effect is the effects of cocaine on sexuality. Herscovitch(10) found that cocaine ingestion causes uncharacteristic sexual behaviour, which includes multi-partner marathons and sexual abuse of children. Hudgins et al. (11) interviewed each cocaine-user and cocaine-naive individual. One interesting result was that crack cocaine users were more likely to have multiple partners; 49/130 (39%) had more than two partners (P <0.01). Ditton et al. (12) have termed this state ‘hypersexuality’. These studies through the means of cross-sectional analysis and those relying upon a retrospective recall of personal data suggest there is an association between cocaine use and atypical sexual behaviour

Physically, cocaine has major effects on the cardiovascular system. A single blind placebo study (13)was done on 14 healthy volunteers. Doses of 20mg IV cocaine, 40mg IV cocaine and a placebo (with 20mg before 40mg) were administered in a random order. The results showed that the heart rate and vagal tone were mirror opposites as displayed in Figure 3.

Figure 3 shows the changes at the interval of maximal response roughly 10 minutes after an IV injection of saline or cocaine (20mg or 40mg). It shows the heart rate is increasing as vagal inhibition is removed. This is a simplified replica of Figure 1 from the paper of Newlin et al. (13)

The inference made was that tachycardia occurred because of the withdrawal of vagal inhibition. It has been established that cocaine blocks the re-uptake of noradrenaline, serotonin and dopamine – it is the former which acts on the hearts alpha-1 adrenoreceptors to cause this tachycardia.

Chronic Effects

The chronic effects can also be separated into psychological and physical effect. The major psychological effect is the craving it induces; cocaine is widely known to be a ‘reinforcing’ drug. This means that when administered the behaviour of an individual is likely to be orientated towards receiving another dose of the drug. This is illustrated in a study (14) in which 14 detoxified male cocaine users were compared with 6 cocaine naive controls. Using Position Emission Tomography (PET), cerebral blood flow (CBF) was measured whilst a cocaine-induced cue, in this case a video which induced craving, was given. The results showed that limbic blood flow was raised in the right side of the brain. The authors believe that these differences have arisen because the detoxified individuals have been exposed to cocaine previously so their cravings become more intense. The location of the CBF rise is evidence of the limbic system involvement in the craving for drugs – the amygdala is for stimuli (e.g. food, sexual and so on) and the anterior cingulate gyrus shares connections with the amygdala (mood and emotional response). Both the anterior cingulate gyrus and amygdala are linked with the nucleus accumbens.  They conclude that the limbic system is the centre for craving and more specifically, the right side is more active in this process.

A constant exposure to cocaine can cause pharmacological changes. This can be demonstrated by Volkow et al. (15) who performed PET in 10 detoxified cocaine users and 10 normal controls. The binding substance on the PET scans was 18(f) N-methylspiroperidol; this substance measures the changes in the occupancy of dopamine (D2 receptors. The cocaine users had less of an uptake after detoxification after a week but after a month they showed values comparable to the controls. The authors believe this demonstrates that dopamine receptor availability for binding decreases after cocaine use but can recover to the previous normal amount after abstinence.

The current research is promising and calls for more investigation. However, there is a difficulty in doing this because it is completely unethical to do a clinical trials using cocaine given its harmful effects. Nevertheless its effects have been demonstrated by many studies on animals. Similarly, longitudinal studies have their own problems – they are expensive to conduct and not done in a controlled environment. These seem to be the most common but they are done on such small scales it causes difficulty in generalizing the results. However, studies up until now have given plenty of useful information and instigate more progress to be made in the future.

Treatment of dependence syndrome (psychotherapy and pharmacotherapy)

The recovery from cocaine abuse is a long and an arduous process. Carroll et al.16 looked at the recovery process by performing a randomized clinical trial investigating pharmacotherapy and psychotherapy. They assigned 131 patients to four different treatment programmes as shown in Table 2.

Table 2: The different allocations for the study of Carroll et al (16).

All the groups showed improvement but to different extents – for instance higher cocaine-severity patients responded to relapse prevention. In contrast, lower severity patients responded well to desipramine (a tricyclic antidepressant) by demonstrating improved abstinence. It was also shown that desipramine was more effective than a placebo over six weeks in decreasing cocaine use but this result was not consistent with over 12 weeks. It is clear that these findings show the heterogeneity amongst cocaine users when put in a recovery environment.

This study was the first of its kind in this area and the authors noted how there is a need to have specialized treatments and to categorize cocaine users into subgroups. The fact that many of these individuals may be polydrug users makes categorisation difficult. Taking this into account, well demarcated groups would allow tailor made recovery programmes to be constructed that best suit those individuals.

Athletes

Less frequently cocaine is used as an enhancement substance in sports; it increases endurance, delays fatigue and bolsters self-confidence (17). It must be noted that a professional sports career demands high fitness levels and an “athlete’s heart” – this is associated with left ventricular wall thickness and a change in cavity dimensions. It has been established that an exposure to cocaine will not only cause tachycardia; in combination with an “athlete’s heart” hypertrophic cardiomyopathy could arise. This gives rise to morphologic changes that are deleterious (18) potentially leading to death.

In the 19th Century it was common for cocaine to be used by cyclists and other endurance athletes; obviously now it has been prohibited across all sports. The World Anti-Doping Agency (WADA) classifies cocaine as a stimulant (19) because it increases aggression and energy levels. These states are associated with the ‘rush’ cocaine gives.

Conclusion

Cocaine has a vast array of effects. It can be used positively, as seen through its anaesthetic properties. Alternatively, it can be used as a drug of abuse. Its pharmacological effects arise from potentiating the dopamine, serotonin and noradrenaline but it affects this triad slightly differently.

Acutely, it gives the ‘rush’ that makes it so appealing. This can lead to a full-blown addiction and spiral into a plethora of psychological problems. Acute use can cause tachycardia whilst chronic use can lead to pathological changes; both have the potential to cause fatalities.

Plenty has been learned from animal studies but more can still be done. The information provided from human cases has also been extremely useful. Often the small size of the studies or their parameters could be improved; in addition, polydrug use is common and it needs to be factored into all finding. This is specifically relevant to certain treatments, such as pharmacotherapy and psychotherapy; this is because of the variation between cocaine users.

References

1. H Knapp, FH Bosworth, C Koller, RJ Hall. Cocaine and its use in ophthalmic and general surgery. Vienna. Putnam`s Sons. 1886.

2. Galbraith A, Bullock S, Manias E., Hunt B, Richards A. Fundamentals of Pharmacology. 2nd Edition. Essex: Pearson Education Limited. 2004. p194

3. Home Office. Misuse of Drugs Act. [Government report online]. London (cited 2009 Aug 2009). Available from  URL:  http://www.homeoffice.gov.uk/drugs/drugs-law/Class-a-b-c/

4. Columb MO, MacLennan K. Local Anaesthetic Agents. Anaesthesia and Intensive Care Medicine. 2007; 8:4

5. Dunwiddie TV, Proctor WR, Tyma J. Local anaesthetic actions of cocaine effects on excitatory and inhibitory synaptic responses in the hippocampus in vitro. Br. J Pharmacol. 1998; 95: 1117-1124.

6. Foster R., Basic Pharmacology. 4th Edition. Oxford: Butterworth-Heinemann. 1996, p88

7. Sawada, H. Cocaine and Phenylephrine Eye Drop Test for Parkinson Disease. JAMA the Journal of the American Medical Association (Journal of the American Medical Association): 2005; 293: 932.

8. Chen NH, Reith M. Effects of Locally Applied Cocaine, Lidocaine and Various Uptake Blockers on Monoamine Transmission in the Ventral Tegemental Area of Freely Moving Rats: A Microdialysis Study on Monamine Interrelationships. J. Neurochem. 1994; 63 (5): 1701-1713

9. Breiter HC, Gollub RL, Weisskoff RM, Kennedy DN, Makris N, Berke JD, Goodman JM, Kantor HL, Gastfriend DR, Riodern JP, Matthew RT, Rosen BR, Hyman SE. Acute effects of cocaine on human brain activity and emotion. Neuron. 1997; 19 (3): 591-611

10. Herscovitch. Cocaine: The Drug and the Addiction. Florida, USA; Gardner Press: 1996. P31

11. Hudgins R, McCusker J, Stoddard A. Cocaine use and risky injection and sexual behaviours. Drugs and Alcohol Dependence, 1995; 37 7-14

12. Ditton J, Hammersley R, Phiilips S, Forsyth A, Khan F. A Very Greedy Drug. Amsterdam; Harwood Academic Publishers: 1996 (p7)

13. Newlin DB. Effect of cocaine on vagal tone: a common factors approach. Drug and Alcohol Dependence. 1995; 37: 211-216

14. Childress AR, Mozley D, McElgin W, Fitzgerald J, Reivich M, O’ Briend CP. Limbic Activation During Cue-Induced Cocaine Craving. Am J Psychiatry. 1999; 156: 11-18

15. Volkow ND, Wang GJ, Folwer JS, Logan J, Gatley SJ, Wong C, Hitzemann, Pappas NR. Reinforcing Effects of Psychostimulants in Humans are Associated with Increases in Brain Dopamine and Occupancy of D2 receptors. Pharmacology and Experimental Therapeutics. 1999; 291 (1): 409-415

16. Carroll KM, Rounsaville BJ, Gordon LT, Nich C, Jatlow P, Bisighini RM. Psychotherapy and pharmacotherapy for ambulatory cocaine abusers. Arch Gen Psychiatry. 1994 Mar; 51 (3): 177-178

17. Galbraith A, Bullock S, Manias E., Hunt B, Richards A. Fundamentals of Pharmacology. 2nd Edition. Essex: Pearson Education Limited. 2004, p200

18. Barry J. Maron, Antonio Pelliccia, Paolo Spirito. Cardiac Disease in Young Trained Athletes : Insights Into Methods for Distinguishing Athlete’s Heart From Structural Heart Disease, With Particular Emphasis on Hypertrophic Cardiomyopathy. Circulation, Mar 1995; 91: 1596 – 1601

19. World Anti-Doping Agency. The 2009 Prohibited List: World Anti-Doping Code. Valid 1 January 2009 (cited 24 September 2009). Available from URL: http://www.wadaama.org/rtecontent/document/2009_Prohibited_List_ENG_Final_20_Sept_08.pdf

Introduction

Exercise in moderation improves both strength and endurance, and also has a positive effect on cognitive function and neuromuscular coordination. As these health benefits became better known, women of all ages began exercising regularly. However, excessive exercise has several side – effects and many athletes and their coaches are unaware of the special needs of the female athlete [1].

The female reproductive system is very sensitive to physiological stress and several studies have examined the effects of exercise on reproduction. This essay shall aim to review such literature investigating reproductive function in exercising women.

Menstrual Disturbances in Exercise

The female reproductive system is very sensitive to physiological stress and menstrual disturbances have been observed in women who take part in vigorous as well as recreational exercise. One of the earliest studies investigating the relationship between menses and exercise detected delayed menarche in ballet dancers [2]. Further research has shown that luteal phase defect (LPD) is the most prevalent menstrual abnormality in active women, which involves inadequate functioning of the corpus luteum leading to impaired implantation of the fertilised egg. However, the most serious abnormal menstrual profile observed in exercising women is amenorrhoea, which is defined as absence of menstrual cycles for more than three months [3]. Although all athletes are susceptible to such disturbances, those participating in sports that encourage a thin physique, such as long – distance running, are especially at risk [4]. This suggests that exercise alone may not be the main reason for these abnormalities, which may in fact be caused by energy deficiency. The menstrual irregularities are usually inter – related with other exercise associated problems like osteoporosis and disordered eating and the three are collectively referred to as the “female athletic triad”.

Few studies have investigated the effect of resistance exercise on the female reproductive system. Kramer et al. [5] observed raised total testosterone levels after 8 weeks of resistance training in women however longer duration studies need to be conducted to ascertain any such association.

Pathophysiology

Amenorrhoea in athletes is commonly caused by a dysfunctional hypothalamic – pituitary – ovarian axis. The GnRH pulsatile release appears to be blunted, which causes lowered levels of circulating FSH and especially LH. The reduced gonadotrophin release leads to suppressed oestrogen synthesis that occurs as a result of disrupted ovarian function.

Low energy availability has been postulated as a disruptor of GnRH pulsatility since it affects the levels of metabolic hormones, such as leptin, insulin and cortisol. Concentrations of substrates like glucose, and fatty acids may be altered. Similarly, weight loss can also lower leptin levels. One or more of these physiological factors is thought to constitute a metabolic signal to GnRH-secreting neurons in the hypothalamus. However the exact mechanisms and signals interfering with GnRH pulsatility in exercising women have not yet been identified [3].

The menstrual cycle in active women can also undergo mild or irregular suppression. This may occur due to insufficient oestradiol or LH surge in the middle of the cycle. A prolonged follicular phase can also produce a similar outcome. Furthermore, delayed menarche or amenorrhoea in athletes may occur following very low levels of LH [6]. It has also been suggested that exercise stress causes release of endorphins and other inhibitory substances that suppress the HPG axis.

Epidemiology

It is widely acknowledged that menstrual disorders occur more frequently in exercising women and studies investigating prevalence rates have reported wide variations in numbers, ranging from 3 – 66% in athletes to about 2 – 4% in the general population [6].Such large differences are probably due to selection bias, small unnoticed irregularities in the menstrual cycle and disagreements over the definition of amenorrhoea.

Torstveit et al. [7] recently reported a higher percentage of menstrual disturbances in athletes compared to controls. Although the p – value was significant, the limitations of the study can not be ignored. The reliability of the results is questionable as energy intake and expenditure or hormonal profiles were not measured. Hopkinson et al. [8] investigated competitive and recreational female athletes involved in football, running and swimming in a university. Higher incidences of irregular periods, 42.9%, and amenorrhoea, 14.3%, were observed in competitive women compared to recreational athletes, of which 13.4 and 2.9% respectively had the corresponding disorders. De Souza et al. [9] also reported higher frequencies of a wide spectrum of menstrual irregularities in exercising women compared to sedentary subjects. Table 1 summarises the findings of the observational study.

Role of Body Fat and Leptin in Menstrual Abnormalities

Similarities between amenorrhoea in athletes and women with anorexia nervosa lead to the suggestion that body fat may play a role in the onset of menstrual disorders. Miller et al. [10] compared female patients who met all the criteria for an eating disorder, but did not have amenorrhoea, to those with both an eating disorder and amenorrhoea. Although there was a large difference in the number of women in the two study groups, 42 compared to 74, most subject characteristics, including the duration of eating disorder and exercise, were similar in the two groups. The eumenorrhoeic women had higher percent body fat and total mass, as well as greater mean leptin levels as shown in figure 1.

Other recent findings have also suggested a link between low leptin concentrations and menstrual disturbances. Welt et al. [11] administered exogenous leptin in eight amenorrhoeic women to determine if the hormone improves menstrual profile. Despite the limited duration and sample size of the study, the reversal of amenorrhoea in three women suggested that leptin may after all be required to maintain normal reproductive function.

Association between Exercise, Energy Deprivation and Reproductive Function

Considerable controversy exists over whether exercise can disrupt reproductive function on its own or can only do so in the presence of other factors like poor energy balance.

It has been reported that exercise alone can lead to abnormal menstrual profile in athletes with normal energy balance [12]. There is also evidence that regular intensive exercise can shift the oestrogen metabolism from 16α- to C-2 oxidation and lead to synthesis of “catecholoestrogens” [13]. These compounds can interact with noradrenaline in the hypothalamus and lead to menstrual problems by altering the GnRH pulse generator. This mechanism can be stimulated regardless of any changes in energy balance[14]. On the other hand, the carefully controlled study of Loucks et al. [15] showed that energy imbalance is critical in causing menstrual abnormalities and LH suppression. Also, the effects of changes in GnRH pulses in the study by Keizer et al. [12] seem to be limited to alterations in FSH and LH levels, as an anovulatory state has not been observed in such subjects. Furthermore, the altered oestrogen metabolism in exercise [13] can not just be attributed to the stress of physical exertion as it has also been noted in subjects with nutritional deprivation [16]. Many factors further complicate this debate. These include different exercise models used in different experiments, small number of longitudinal studies and genetics [14].

Many studies have suggested an association between amenorrhoea and insufficient caloric intake. In fact caloric deficiency is often reported along with intense exercise. In a study by Kohl et al. [17], over 80% of the women with anorexia undertook excessive exercise during an acute phase of the disorder. Thus, it appears that heavy exercise only causes menstrual disturbances in combination with a compromised energy state.

Conclusion

There is increasing evidence to suggest that excessive exercise in women can have significant effects on the reproductive function. The impact of exercise alone on reproductive function in women is not clear however, excessive exercise can limit the energy availability of the athlete and there is considerable evidence to suggest that intensive training combined with low caloric intake can lead to a wide spectrum of menstrual disturbances. These findings suggest that it may be possible for female athletes to prevent or reverse menstrual disorders by dietary supplementation without changing their exercise regimen.

References

1. Goodman LR, Warren MP. The female athlete and menstrual function. Curr Opin Obstet Gynecol. 2005, Vol. 17, pp. 466-470.

2. MP, Warren. The effects of exercise on pubertal progression and reproductive function in girls. J Clin Endocrinol Metab. 1980, Vol. 51, pp. 1150-1157.

3. Nattiv A, Loucks AB, Manore MM, Sanborn CF, Sundgot-Borgen J, Warren MP and Medicine, American College of Sports. American College of Sports Medicine position stand. The female athlete triad. Med Sci Sports Exerc. 2007, Vol. 39, pp. 1867-1882.

4. MJ, De Souza. Menstrual disturbances in athletes: a focus on luteal phase defects. Med Sci Sports Exerc. 2003, Vol. 35, pp. 1553-1563.

5. Kraemer WJ, Staron RS, Hagerman FC, Hikida RS, Fry AC, Gordon SE, Nindl BC, Gothshalk LA, Volek JS, Marx JO, Newton RU, Häkkinen K. The effects of short-term resistance training on endocrine function in men and women. Eur J Appl Physiol Occup Physiol. 1998, Vol. 78, pp. 69-76.

6. Goodman LR, Warren MP. The female athlete and menstrual function. Curr Opin Obstet Gynecol. 2005, Vol. 17, pp. 466-470.

7. Torstveit MK, Sundgot-Borgen J. The female athlete triad: are elite athletes at increased risk. Med Sci Sports Exerc. 2005, Vol. 37, pp. 184-193.

8. Hopkinson RA, Lock J. Athletics, perfectionism, and disordered eating. Eat Weight Disord. 2004, Vol.9, pp. 99-106.

9. De Souza MJ, Miller BE, Loucks AB, Luciano AA, Pescatello LS, Campbell CG, Lasley BL. High frequency of luteal phase deficiency and anovulation in recreational women runners: blunted elevation in follicle-stimulating hormone observed during luteal-follicular transition. J Clin Endocrinol Metab. 1998, Vol. 83, pp. 4220-4232.

10. Miller KK, Grinspoon S, Gleysteen S, Grieco KA, Ciampa J, Breu J, Herzog DB, Klibanski A. Preservation of neuroendocrine control of reproductive function despite severe undernutrition. J Clin Endocrinol Metab. 2004, Vol. 89, pp. 4434-4438.

11. Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, Karalis A, Mantzoros CS. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med. 2004, Vol. 351, pp. 987-997.

12. Keizer HA, Platen P, Menheere X. The hypothalamic/pituitary axis under exercise stress: the effects of aerobic and anaerobic training. [book auth.] Laron Z, Rogol A. Hormones and Sport. New York : Raven Press, 1989, pp. 101–105.

13. De Crée C, Ball P, Seidlitz B, Van Kranenburg G, Geurten P, Keizer HA. Responses of catecholestrogen metabolism to acute graded exercise in normal menstruating women before and after training. J Clin Endocrinol Metab. 82, 1997, pp. 3342–3348.

14. C, De Crée. Comment on health issues for women athletes: exercise-induced amenorrhea. J Clin Endocrinol Metab. 1999, Vol. 84, pp. 4750-4751.

15. Loucks AB, Verdun M, Heath EM. Low energy availability, not stress of exercise, alters LH pulsatility in exercising women. J Appl Physiol. 1998, Vol. 84, pp. 37– 46.

16. Fishman J, Bradlow HL. Effect of malnutrition on the metabolism of sex hormones in man. Clin Pharmacol Ther. Vol. 22, p. 721.

17. Kohl M, Foulon C, Guelfi GD. Hyperactivity and anorexia nervosa: behavioural and biologic perspective. Encephale. 2004, Vol. 30, pp. 492-499.

Abstract

There has been an increase in research into islet transplantation as a potential therapy to cure type 1 diabetes mellitus (T1DM) in recent years. Initially the aim of islet transplantation was to completely cure T1DM by achieving insulin independence in recipients. However studies have shown that the insulin independence initially achieved decreases over time. Complications of the islet transplantation procedure and side effects of the immunosuppressive regimen also pose problems. These difficulties indicate that, at this stage in its development, islet transplantation is not suitable as a replacement for conventional insulin therapies to treat T1DM.  However, even when insulin independence is lost in islet transplant recipients glycaemic control is maintained. Therefore for the small percentage of T1DM patients who have problems with severe hypoglycaemia and hypoglycaemic unawareness, regardless of intensive insulin therapy, islet transplantation may be an appropriate alternative treatment.

Introduction

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by a decrease in the β-cell mass in the Islets of Langerhans of the pancreas leading to insufficient insulin secretion. The pathogenesis of T1DM involves destruction of the β-cells by autoantigen reactive T lymphocytes [1]. Once 90% of the β-cell mass is destroyed the clinical symptoms of diabetes present [2].

Patients with T1DM need insulin replacement. However even with insulin replacement therapy complications arise in 30% to 50% of T1DM patients, and life expectancy and quality of life are reduced [3].  The main predictor of secondary diabetic complications (microvascular and macrovascular) is the total lifetime exposure to hyperglycaemia therefore it is very important to develop a safe and effective method of maintaining glycaemic control [3].

Currently the main treatment for patients with T1DM is insulin therapy. This either involves intermittent injections of insulin or continuous subcutaneous insulin infusion [4]. In 1993 The Diabetes Control and Complications Trial (DCCT) concluded that glycaemic control could be maintained at a near normal level and secondary complication rates improved with intensive insulin treatment control and a qualified diabetes care team [3]. However there was a three fold increase in the occurrence of severe hypoglycaemic reactions [5]. Although insulin preparations have improved and glucose home monitoring devices have been developed to help patients control their blood glucose, the problem of hypoglycaemia still remains [5].

Alternative potential therapies for T1DM patients include pancreas and islet cell transplantation to restore physiological β-cell function. Pancreas transplantation is often performed with kidney transplantation for T1DM patients with renal failure [6]. Patients with T1DM have destroyed β-cells, which only make up 1-2% of the pancreas, but normal exocrine pancreatic function. In theory, islet cell transplantation is preferable to pancreas transplantation as it is a simpler surgery, involving percutaneous cannulation of the portal vein [7], and requires less immunosuppression [8]. Initially the aim of islet transplantation was to achieve insulin independence but long term results show that insulin independence is lost over time in the majority of patients [9]. There is no evidence that islet transplantation controls recurrent hyperglycaemia or prevents secondary diabetic complications. However it improves glycaemic control indefinitely suggesting that the patients to benefit from such therapy are those who, despite insulin therapy, suffer from severe hypoglycaemia [5].

History of islet transplantation

Pancreatic islet cells were first isolated and transplanted successfully using animal models in the 1970s. Islet cell transplantation in humans was reported in the late 1970s [3]. Successful allogenic islet transplantation from cadavers using conventional immunosuppression for T1DM patients was reported in the 1980s but the international rates of success were less than 10% [8].

Since these early trials islet isolation techniques have improved and more effective and potent immunosuppressants have been developed. In 2000 Shapiro et al. achieved successful islet transplantation in seven patients with T1DM using a glucocorticoid-free immunosuppressive regimen [8]. This breakthrough revived the interest in this potential treatment for T1DM.

The islet transplantation procedure

The procedure begins with the isolation of islets from cadaveric pancreases. The pancreas is removed, the pancreatic duct is cannulated and collagenase is infused to separate the islets from other tissues [6]. The islets are purified by density gradient separation and transferred into the recipient’s hepatic portal vein, usually within 48 hours of isolation, via percutaneous transhepatic infusion. Most recipients need islets from more than one cadaver and the procedure usually requires the patient to stay in hospital for 1-2 days [6].

Islet transplant recipients

The primary indications for islet transplantation are hypoglycaemic unawareness and extreme glycaemic lability in T1DM patients. Long standing T1DM patients typically have hormonal counterregulation impairment which increases their risk of severe hypoglycaemia [10].  The HYPO and Ll scores, measures of hypoglycaemia and glycaemic lability respectively, could be used to select appropriate patients for transplant [11].

Figure 1. A table showing the criteria upon which recipients are currently chosen for islet transplantation.

Recent successes and clinical outcomes

Before 2000 islet transplantation success rates were very low, with world wide achievement of 1 year insulin dependence being less than 12% [6]. However in 2000 Shapiro et al in Edmonton reported 100% success in seven consecutive patients with T1DM and a history of hypoglycaemia. All seven patients achieved sustained insulin independence quickly after transplantation and had normal glycosylated haemoglobin values (HbA1c). No more episodes of hypoglycaemic coma were experienced and there were only minor complications [9].

Figure 2. Graphs to compare 24 hour glucose fluctuation in a patient before (A) and after (B) transplantation. Adapted from; SHAPIRO A.M, LAKEY J.T., RYAN E.A. et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000; 343: 230.

The above graph shows the fluctuations in blood glucose concentrations over a 24 hour period one month before transplantation (A) and after the attainment of insulin independence (B) in a representative patient [9].  The median and range are represented by each bar. The two broken lines represent blood glucose concentrations of 60 and 140mg per decilitre (3.3 and 7.8mmol per litre). This graph clearly shows the improvement in glycaemic control and decrease in glycaemic excursions after transplantation.

This success is probably a result of the modified techniques used. Adequate numbers of viable islets prepared in a xenoprotein-free medium exposed to minimal cold ischaemia were transplanted. The quantity of islets needed to achieve insulin independence was discovered to be double that reported previously, as islets from a single donor did not result in insulin independence [9]. The patients selected were size restricted and C peptide negative, and a steroid free immunosuppression regimen, including sirolimus, low-dose tacrolimus and daclizumab, was adopted. Glucocorticoids have a diabetogenic effect and therefore this new regimen avoided further damage to β-cells. The regimen protected against autoimmune and alloimmune reactivity and there were no episodes of rejection [9].

The Immune Tolerance Network organised an international nine centre trial to assess the reproducibility of these results in 36 patients using a single common protocol (the Edmonton protocol) [12]. 44% of patients achieved the primary end point of insulin independence, 28% had partial graft function but 28% had graft loss. The overall success rate for insulin independence was 52%. There was a progressive loss of insulin independence over time and only 14% of patients remained insulin independent 2 years after islet transplantation. However, the patients who attained the primary end point had no severe hypoglycaemia or hyperglycaemia and those with partial graft function had improved glycaemic control [12]. This trial concluded that successful islet function is beneficial even without insulin independence due to the improvement in glycaemic control and HbA1c levels [12].

Currently the rates of insulin independence achieved vary. Experienced centres have an 80% insulin independence success rate whereas less experienced centres have a 0-63% success rate at short term follow up [5]. Although insulin independence is gradually lost recent Edmonton reports show that 83% of patients still maintain islet function at 5 years according to C-peptide secretion. HbA1c levels were significantly lower in patients maintaining insulin independence (6.4%) and in those requiring exogenous insulin but C-peptide positive (6.7%) than those with total loss of graft function (9%) (p<0.05) [13]. This further shows an improvement in glycaemic lability.

Further effects of islet transplantation

Recent studies show that intrahepatic islets are able to secrete insulin in a pulsatile manner, although release is slower [4].  Pulsatile insulin secretion, as opposed to constant secretion, may have important implications clinically as suppression of hepatic glucose production is greater. It may also have beneficial effects on insulin signalling and insulin extraction by the liver. Furthermore transplanted islets deliver insulin directly to liver sinusoids which is favourable as the physiological route of intraportal insulin delivery is imitated. These observations demonstrate that islet transplantation can re-establish a sequence of insulin secretion similar to that of the β-cells in the pancreas in health [4].

A recent study investigated whether successful islet transplantation improves hypoglycaemic awareness in unstable T1DM patient. The study found that hypoglycaemic awareness was significantly improved after transplantation (P<0.001) even in patients with islet graft failure due to the improved metabolic control [14].  Conversely another recent study comparing hypoglycaemic counterregulation (by glucagon, adrenaline and symptom recognition) found no significant difference between the hormone responses of the transplanted and non-transplanted T1DM patients, although both responses were significantly less than that of the controls.  This study concluded that hypoglycaemic counterregulation and symptom recognition are not improved by islet transplantation [15].

Islet loss and transplant failure

Advances in islet transplantation in recent years have led to an increased success rate of early graft function. Previous early graft failure may have been due to an instant blood mediated inflammatory reaction (IBMIR) when the transplanted islets came into contact with the recipient’s blood. The anticoagulant heparin added to the islet suspension reduces IBMIR and this may have been part of the reason for the success of the Edmonton group [5]. Islet embolism in the portal vein is an important cause of early graft failure and recent studies have shown this may be prevented by liver ischaemia preconditioning [16].

Despite an increase in early graft transplantation success insulin independence is still only relatively short-lived. In a recent study five year islet graft survival was 80% but insulin independence was only 7.5% [17]. It is not known why intrahepatic islets only sustain insulin independence for 3-5 years but various hypotheses have been proposed relating to a loss in β-cell mass. The failure may be due to chronic allograft rejection, immunosuppressive drug toxicity, localised islet ischaemia, failure of islet regeneration, a suboptimal infusion of islets [17] or autoimmune reaction [18].

Adverse effects

A recent review from Edmonton reported a complication rate per procedure as 9%, but as most patients have two islet infusions the complication rate per patient could be as high as 18%.  Complications associated with the initial surgery are potentially serious and include portal vein thrombosis, intra-abdominal haemorrhage and portal hypertension [19].  Long term adverse effects of islet transplantation include hepatic steatosis. This may be due to lipid deposition caused by the high exposure of liver sinusoids to insulin secreted from the intrahepatic islets [4].

Immunosuppression

The immunosuppressive regimen needed causes the majority of reported side effects.  These include mouth ulceration, anaemia, leukopenia, diarrhoea, headaches, neutropenia, nausea and vomiting.  In some patients these side effects lead to a change in therapy (25% in Shapiro et. al 2000 [9]) or even withdrawal from the study [9]. This detrimental impact on the recipients’ quality of life should be weighed up against the positive benefits of the procedure especially when insulin independence is not permanent. Immunosuppression has also been shown to increase the risk for cancer development (relative risk: 3-4) and infection [5].

The steroid-free immunosuppressive regimen introduced by Shapiro et al. [9] avoided the evident diabetogenic effects of glucocorticoids. However all immunosuppressive drugs, including tacrolimus and sirolimus, have been reported to have detrimental effects on the β-cell and its function. Sirolimus has antiproliferative effects which may affect angiogenesis in transplanted islets [8]. In some patients renal decline has been noted which may be due to the toxic effects of tacrolimus and sirolimus on diabetic nephropathy [12]. These observations indicate a need for the development of less toxic immunosuppression without diabetogenic effects [19].

Limited islet supply

Currently islets are harvested from cadaveric donors. However there is a major shortage of donors and demand far exceeds the number of islets available for transplantation. This has fuelled investigation into alternative sources of islet cells including islet cell expansion, xenogenic islets, human islet cell lines, embryonic stem cells [8] and live donation [20].

Initial studies have shown that stem cells can acquire a β-cell like phenotype but to be used for transplant exact β-cell function needs to be reproduced. This is very difficult as the exact molecular mechanisms behind β-cell sensing and secretion of insulin to control blood glucose are not completely understood [6].  Therefore other cellular sources of islet cells such as adult stem cells and transdifferentiation of other adult cells are being investigated. Ductal cells, exocrine tissue and β-cells have all been indicated as possible candidate cells [21]. Researchers are also investigating the use of growth factors, such as hepatocyte growth factor (HGF), to increase islet graft survival and function with the aim of reducing the required number of islets needed for a successful transplantation [22].  Living donor islet transplantation is also being introduced [23] but remains controversial due to possible side effects for the healthy donor, such as diabetes induction.

Although these alternative sources are promising, more research is needed, especially into the mechanisms responsible for insulin synthesis and release by the β-cell, and therefore they are not practical clinically yet.

Future Improvements

Islet transplantation is increasing with the aim of improving early graft function and prolonging insulin independence rates. Newer immunosuppressive drugs are being investigated to prevent primary rejection, such as LEA29Y, shown to be effective in primate trials [24], and FTY720 [25]. The principal objective is to treat the T1DM effectively without needing life long immunosuppression, therefore tolerance induction is a major objective as it could increase graft survival. Currently a combination of anti-thymocyteglobulin and rituximab (anti-CD20) are used [26] but anti-CD3 antibody therapy and cotransfer of CD4+CD25+ Tregs with islet transplantation look to be promising in the future [1].  Furthermore complementary gene therapy strategies are being developed to improve islet graft survival. Such gene therapy could modulate the immune system and introduce a new way to fight β-cell reactive cytotoxic T cells [27].

Comparison with alternative treatments for unstable T1D

There are other treatments already in use to treat patients with unstable T1DM. Continuous subcutaneous insulin infusion (CSII) therapy, insulin pumps, allows for more intensive glycaemic control. Recent improvements in real-time continuous glucose monitoring could lead to the development of closed-loop systems consisting of a continuous glucose monitor, a control algorithm and the insulin pump. This could potentially act as an artificial pancreas. Studies comparing CSII with insulin injection regimens have shown a decrease in HbA1c and a reduction in hypoglycaemic episodes by up to 70% [28]. CSII has the advantages over islet transplantation of minimal side effects and no immunosuppression. However there is a risk of rapid ketoacidosis should the insulin pump fail [28].  Although the majority of patients with refractory hypoglycaemia can be managed by optimal insulin therapy, such as the pump, there are a small number of patients who still suffer from severe hypoglycaemia regardless of such treatment.

Pancreas transplantation has been used clinically since the 1960s [6] and is often carried out with a kidney transplant for T1DM patients with renal failure. Pancreas transplantation generally requires only one operation, whereas islet transplantation usually needs two operations and two pancreases which exacerbates the problem of organ shortage. Although islet transplantation improves HbA1c levels and glycaemic control, pancreas transplantation usually results in complete insulin independence lasting substantially longer than the independence achieved via islet transplant [29]. However pancreas transplant requires major surgery and runs the risk of rejection, intraabdominal infection, peripancreatic abscess and graft pancreatitis [7]. Although islet transplantation is a simpler procedure it is still experimental and so requires a specialised facility, whereas pancreas transplantation can be carried out in almost any hospital with a transplant program and trained surgeons. Patients undergoing islet transplantation also need to maintain some insulin sensitivity, and therefore pancreas transplantation is still indicated for patients with high pretransplant insulin requirements or a pancreatic exocrine deficiency and a combined pancreas and renal transplant is indicated for patients with T1DM and renal failure [3].

Conclusion

The initial aim behind islet transplantation was to effectively cure T1DM by achieving insulin independence in recipients. Although there have been further advances in this therapy, insulin independence is not permanent and the majority of recipients will require exogenous insulin in the future. As of yet there is no evidence that islet transplantation helps with recurrent hyperglycaemia or the progression of secondary complications [5]. Advances in immunosuppressive therapy have increased the success of islet transplantation [9] but such drug treatment is still required for life and the side-effects are intolerable for some patients [12]. Less toxic immunosuppression and tolerance inducing agents need to be developed as a more effective and tolerable treatment to control acute rejection and recurrent autoimmunity [29]. The shortage of donors is also limiting, although research into new sources of islets is expanding.  To conclude, patients on conventional insulin therapy with stable blood glucose and normal renal function should not receive islet transplantation as the potential benefits are not great enough to justify the risks and costs.

Although exogenous insulin may still be required islet transplantation is successful in normalising HbA1c levels and improving glycaemic control, such that hypoglycaemic events are practically eliminated. If complete insulin independence is desired then pancreas transplantation is indicated. However for patients solely wanting to improve their glycaemic control islet transplantation could be the appropriate therapy as it does not involve major surgery and carries less associated risks. It has been estimated that up to 25% of T1DM patients experience severe hypoglycaemia, and 15% of such patients can not achieve glycaemic control or eliminate hypoglycaemia even with optimal insulin therapy [20].  Therefore patients currently indicated to benefit from islet transplantation are insulin sensitive T1DM patients suffering from severe hypoglycaemia and hypoglycaemic unawareness.

References

1. KABELITZ D., GEISSLER E.K., SORIA B., SCHROEDER I.S., FANDRICH F., CHATENOUD L. Toward cell-based therapy of type 1 diabetes. Trends in Immunology 2008. 29(2):68-74.

2. MORRAN M.P., OMENN G.S., PIETROPAOLO M. Immunology and genetics of type 1 diabetes. Mt Sinai J Med 2008. 75(4):314-27. 1

3. SUTHERLAND D., GRUESSNER A., HERING B.J. β-Cell replacement therapy (pancreas and islet transplantation) for treatment of diabetes mellitus: an integrated approach. Transplant Proc 2004. 36(6):1697-9.

4. MEIER J.J., HONG-MCATEE I., GALASSO R., VELDHUIS J.D., MORAN A., HERING B.J., BUTLER P.C. Intrahepatic transplanted islets in humans secrete insulin in a coordinate pulsatile manner directly into the liver. Diabetes 2006. 55(8):2324-32.

5. SRINIVASAN P., HUANG G.C., AMIEL S.A., HEATON N.D. Islet cell transplantation. Postgrad Med J 2007 Apr. 83(978):224-9.

6. REN J., JIN P., WANG E., LIU E., HARLAN D.M., LI X., STRONCEK D.F.  Pancreatic islet cell therapy for type 1 diabetes: understanding the effects of glucose stimulation on islets in order to produce better islets for transplantation. J Transl Med 2007 Jan. 3;5:1.

7. RYAN E.A., BIGAM D., SHAPIRO A.M. Current indications for pancreas or islet transplantation. Diabetes Obes Metab 2006 Jan. 8(1):1-7.

8. ROBERTSON R.P. Islet transplantation as a treatment for diabetes – a work in progress. N Engl J Med. 2004 Feb 12;350(7):694-705.

9. SHAPIRO A.M, LAKEY J.T., RYAN E.A. et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000; 343: 230.

10. LINGENFELSER T., OVERKAMP D., RENN W., HAMSTER W., BOUGHEY J., EGGSTEIN M., JAKOBER B. Cognitive and psychomotor function during severe insulin-induced hypoglycaemia in insulin-dependent diabetic patients. Neuropsychobiology 1992. 25(3):161-5.

11. RYAN E.A., SHANDRO T., GREEN K., PATY B.W., SENIOR P.A., BIGAM D., SHAPIRO A.M., VANTYGHEM M.C. Assessment of the severity of hypoglycaemia and glycaemic lability in type 1 diabetic subjects undergoing islet transplantation. Diabetes 2004. 53:955-962.

12. SHAPIRO A.M., RICORDI C., HERING B.J., AUCHINCLOSS J., LINDBLAD R., ROBERTSON R.P., SECCHI A., BRENDEL M.D., BERNEY T., BRENNAN D.C., CAGLIERO E., ALEJANDRO R., RYAN E.A., DIMERCURIO B., MOREL P., POLONSKY K.S., REEMS J.A., BRETZEL R.G., BERTUZZI F., FROUD T., KANDASWAMY R., SUTHERLAND D.E.R., EISENBARTH G., SEGAL M., PREIKSAITIS J., KORBUTT G.S., BARTON F.B., VIVIANO L., SEYFERT-MARGOLIS V., BLUESTONE J., LAKEY J.R.T. International Trial of the Edmonton Protocol for Islet Transplantation. NEJM 2006 355: 1318-1330.

13. RYAN E.A., PATY B.W., SENIOR P.A. et al. Five-year follow-up after clinical islet transplantation. Diabetes 2005;54:2060–9.

14. LEITAO C.B., THARAVANII T., CURE P., PILEGGI A., BAIDAL D.A., RICORDI C., ALEJANDRO R. Restoration of hypoglycaemia awareness after islet transplantation. Diabetes Care 2008 Aug. 31:2113-2115.

15. PATY B.W., RYAN E.A., SHAPIRO A.M., LAKEY J.R.T., ROBERTSON R.P. Intrahepatic islet transplantation in Type 1 diabetic patients does not restore hypoglycaemic hormonal counterregulation or symptom recognition after insulin independence. Diabetes 2002 51:3428-3434.

16. YIN D., DING J.W., SHEN J., MA L., HARA M., CHONG A.S. Liver Ischemia Contributes to Early Islet Failure Following Intraportal Transplantation: Benefits of Liver Ischemic-Preconditioning. Am J Transplant 2006 Jan;6(1):60-8.

17. SMITH R.N., KENT S.C., NAGLE J., SELIG M., IAFRATE A.J., NAJAFIAN N., HAFLER D.A., AUCHINCLOSS H., ORBAN T., CAGLIERO E. Pathology of an islet transplant 2 years after transplantation: evidence for a nonimmunological loss. Transplantation 2008 Jul. 86(1):54-62.

18. JAEGER C., BRENDEL M.D., HERING B.J., ECKHARD M., BRETZEL R.G. Progressive islet graft failure occurs significantly earlier in autoantibody-positive than in autoantibody-negative IDDM recipients of intrahepatic islet allografts. Diabetes 1997;46:1907-1910.

19. ROTHER K.I, HARLAN D.M. Challenges facing islet transplantation for the treatment of type 1 diabetes mellitus. J Clin Invest 2004 Oct. 114(7):877-883.

20. AMIEL S.A. RELA M. Live organ-donation for islet transplantation. Lancet 2005 Apr 365(9471):1603-4.

21. MEIER J.J et al. The potential for stem cell therapy in diabetes. Pediatr, Res 2006. 59:65-73.

22. FIASCHI-TAESCH N., STEWART A.F., GARCIA-OCANA A. Improving islet transplantation by gene delivery of hepatocyte growth factor (HGF) and its downstream target, protein kinase B (PKB)/Akt. Cell Biochemistry & Biophysics 2007. 48(2-3):191-9.

23. MATSUMOTO S., OKITSU T., IWANAGA Y., NOGUCHI H., NAGATA H., YONEKAWA Y., YAMADA Y., FUKADA K., TSUKIYAMA K., SUZUKI H., KAWASAKI Y., SHIMODAIRA M., MATSUOKA K., SHIBATA T., KASAI Y., MAEKAWA T., SHAPIRO J., TANAKA K. Insulin independence after living-donor distal pancreatectomy and islet allotransplantation. Lancet 2005 May 365(9471):1642-4.

24. RYAN E.A. PATY B.W., SENIOR P.A. et al. Beta-score: An assessment of beta-cell function after islet transplantation. Diabetes Care 2005;28:343–8.

25. SHAPIRO A.M., LAKEY J.R., PATY B.W. et al. Strategic opportunities in clinical islet transplantation. Transplantation 2005;79:1304–7.

26. MATTHEWS J.B., RAMOS E., BLUESTONE J.A. Clinical trials of transplant tolerance: slow but steady progress. Am J Transplant 2003. 3:794:803.

27. CHUANG Y.P., CHU C.H., SYTWU H.K. Genetic manipulation of islet cells in autoimmune diabetes: from bench to bedside. Frontiers in Bioscience 2008. 13:6155-69.

28. COHEN N.D., SHAW J.E. Diabetes: advances in treatment. Intern Med J 2007 Jun. 37(6):383-8.

29. TRUONG W., LAKEY J.R., RYAN E.A., SHAPRO A.M. Clinical islet transplantation at the University of Alberta–the Edmonton experience. Clinical Transplants 2005. 153-72.

The Foundation Programme Application process commences at the beginning of a medical student’s 5^th year of study. The process begins with completion of an application form, scored out of a possible 100 points. Up to 40 of these are awarded for academic ranking, whilst the remaining 60 are based on application questions, with a possible 8 of these for additional academic achievement. The remaining 52 points are allocated based on answers to 7 questions involving Care Pathways, Professional Behaviour, Team Work, Challenge & Pressure, and Non-academic achievement. The UKFPO calls upon 5-10% of applicants to verify their answers, and electronic plagiarism software is used to identify duplicate responses.

The process contains 2 phases, the first involving allocation to a Foundation School, with the first choice school scoring the application. Acceptance to a foundation school is based on the application score and the student’s preferences. The second phase concerns matching to a programme within the foundation school, and the process varies locally.

If interviews were to be introduced, when in the process would they take place? Would they be part of the initial phase involving allocation to a foundation school, or be held for specific jobs once foundation schools have been allocated?

The 2008 programme was regarded as a success. All 6902 UK graduates were allocated a post, with 92.4% of applicants receiving their first choice foundation school. Whilst 100% satisfaction is impossible, it is difficult to argue with these statistics, and it is difficult to see how an interview process regarding foundation schools would improve this phase.

A particular criticism among students is the lack of opportunity to show interest in a particular programme with the current application questions. Job allocation in the 2^nd phase is based on the ranking decile awarded, itself based on application score. For example, the South Thames Foundation School manages 814 programmes for 814 successful applicants. The highest scoring applicant in the foundation school receives their 1^st choice programme; the 2^nd highest scoring is then awarded their highest available programme and so on. This system has caused some contention with medical students. Amber Appleton and Caroline Morley, 4^th and 5^th year medical students at King’s College, London, state that:

“Medical students should definitely be interviewed when applying for their foundation year jobs. The current application scheme does not adequately reflect individual personalities and allow for true representation of key interpersonal skills, which patients hope to find in their future doctor. Interviews would be a much fairer and simpler method to discriminate the highly motivated, hard working and deserving candidates, and allocate the jobs appropriately.”

It is true that interviews for individual posts would allow interviewees to discern an applicant’s interest and suitability to a speciality more accurately than a points system. Ideally clinicians involved with that programme would directly interview candidates applying for it, although whether they would be willing to accept the additional workload is uncertain.

An example of this is the current system allocating Academic Posts, which are advertised locally by individual deaneries, in June and July of a student’s 4^th year. Taking place several months before the FY1 process, applicants are interviewed for a specific post at a specific hospital rather than a foundation school. Competition for these placements is high, and interview is a tool used to select to the correct candidate for the job. The relatively small number of posts enables the interview of all candidates applying for them.

Conversely, there are valid arguments against interviews. The logistical requirement to annually organise nearly 7,000 interviews, and their effect on NHS productivity, is likely to be considerable. Also, foundation training is pre-specialisation, and although the programmes can vary considerably, the core training of doctors should not vary. All Foundation Doctors are required to meet the contents and standards of core training set out by the GMC in FY1 and the PMETB in FY2. Why interview for foundation programmes when all Doctors theoretically have the same clinical skills at the end of it?

In the current system where jobs are allocated based on ranking there is no place for interviews. Only if the system were to change incorporating interview as part of the allocation process would they be of any use. The review of the Foundation Programme application system is due in 2010. An informed and unbiased debate is required on the topic, which is beyond the word limit of this article.

The author would like to thank Laura Mackenzie of King’s College London Careers Service, and Dr James Pattison of Guys Hospital.

Introduction

Tennis elbow, clinically known as lateral epicondylitis (LE), is a tendinopathy that affects the extensor tendons of the wrist slightly distal to the origin at the lateral epicondyle. Clinically, LE presents itself as a painful forearm between one and three days after repeated use of the wrist extensors that improves with rest. Athletes affected by LE are usually racquet sport players or fencers whose careers depend upon having a pain-free forearm; it is therefore essential that these athletes upon correct diagnosis are rehabilitated as soon as possible.

The treatment options that exist for LE are diverse and broadly include conservative, medical and surgical options, as well as sport-specific biomechanical adjustments to prevent reoccurrence. Currently, cellular therapies are being added to the treatment arsenal at tertiary referral centres with promising results.

How does tennis elbow develop?

It is generally agreed that LE is an ‘overuse syndrome’. The origin of the extensor carpi radialis brevis (ECRB) is the most common pathological site in LE, although occasionally the origin of the extensor digitorum communis (EDC) shows pathological involvement [1].

Applying the term ‘LE’ to tennis elbow is up for semantic debate, as the pathophysiological mechanism shows degeneration, rather than histopathological markers shown in inflammation. This is represented by a loss of linear collagen integrity, a dense fibroblast population, and highly vascularised tissue, and normal cell densities of neutrophils, macrophages and lymphocytes infiltrating the affected tissue. The degenerative changes are thought to arise from tendon tissue exceeding its yield stress points leading to microtears in the tissue. Repairing these microtears involves fibroblasts producing more collagen cross-links as well as releasing cytokines that upregulates fibroblast differentiation and angiogenesis. This pathological situation is referred to as angiofibroblastic tendinosis(1). Clinically it is not possible to undertake a histological assessment of each patient that comes in, so it cannot be assumed that each case of tennis elbow is LE, so Stasinopoulos et al. have proposed the term ‘lateral elbow tendinopathy’ to replace LE [2].

Recently, a pathophysiological model of LE has been proposed which unites changes in tendon tissue composition, pain pathways and motor impairment. The hyperalgesia in LE is thought to be caused by an increase in concentrations of the neurotransmitter glutamate, as well as an increase in nerve fibres around the hypervascular regions such as substance P and calcitonin gene-related peptide reactive nerve fibres. The rationale behind this pathological triad of alterations in tendon tissue composition, pain pathway and motor impairment was that its multifactorial aetiology differed between patients, and that a possible sub-classification of LE could take place which could aid clinicians in choosing management plans [3].

Risk factors and prevention in tennis players

Gruchow et al. conducted a study that looked at risk factors in developing LE in over 500 adult tennis players. They found that LE had a prevalence of around 14%, and that about 40% of the entire study group were affected by LE at some point. Two very strong risk factors were increasing age and increasing the playing time. Playing ability was also a significant risk factor, with players of higher ability more likely to develop LE, but this has been attributed to longer training hours. It was shown that there is no significant association with developing LE and the material or weight of racquet, but there was an association in the over 40’s with increasing grip size and developing LE [4].

Kelley et al. have looked at the electromyography and kinematics of tennis strokes to see how it varies between affected and unaffected individuals. In this study, affected individuals showed greater activity of extensor muscles during ball impact. These affected individuals also showed on kinematic analysis to have ‘leading elbow’ stroke mechanics [5]. Giangarra et al. conducted a similar study, but compared muscle activity between single- and double-handed backstroke shots. They concluded that a double-handed stroke reduced the incidence of LE because it improved the kinematics of the stroke, but did not necessarily reduce muscle-firing from the extensors [6].

Recognising tennis elbow in athletes

Whilst racquet sport players are at risk of developing LE, other clinical pathologies should be considered. A differential diagnosis for LE would include nerve root compression of C6 or C7, posterior interosseus nerve (PIN) syndrome or arthritis of the radial head. Upon taking a history, an examination should involve assessing the range of motion of the elbow and wrist, motor strength of the ECRB and EDC and observing any tenderness of the radial head. Eliciting pain by extending the middle finger (a positive Maudsley test) is a common finding in LE [7]. Another common finding in LE is a positive chair test, in which the patient is asked to lift a chair with the arm extended and forearm pronated; pain around the lateral epicondyle gives a positive chair test and indicates LE. To rule out PIN syndrome, a lidocaine injection can be administered distal to the lateral epicondyle giving palsy of the PIN, and in the case of PIN syndrome, there is temporary relief of pain. Magnetic resonance imaging (MRI) and Doppler ultrasound can be used to diagnose LE, and rule out arthritis [8].

A pain scale exists that is broadly split into four categories: benign pain (stiffness and soreness after exercise), semi-benign pain (stiffness and soreness before exercise, relieved through warm-up exercises), semi-harmful pain (pain before exercise that alters the way in which the athlete undertakes activity), and harmful pain (severe pain) [1].

Management principles for tennis elbow

Each pain category can act as a clinical compass for directing treatment. It is recommended to take precautions and modify kinematics for benign pain, use non-operative pharmacological and physical therapies for semi-benign and semi-harmful pain, and to reserve operative treatment for harmful pain [1].

As mentioned earlier, poor stroke kinematics can act as a cause of degeneration. Although not all athletes have poor stroke kinematics, the elimination of this risk factor leads to improvements in nearly all cases, and can even cure LE [9]. Changing to a double-handed backhand shot can also be beneficial.

Changing equipment to minimise forces going to the lateral epicondyle has been cited as another conservative option. Slowing the ball down by playing on clay courts, using a graphite racquet that reduces vibrations, increasing the string count and loosening the strings on the racquet are just a few examples of improving force distribution to the extensors [10].

From a physical therapy perspective, standard acute anti-inflammatory precautions such as protection, rest and ice are all recommended. Compression can be achieved by a counter-force brace which straps over the wrist extensors. This brace dissipates the forces that are imposed upon the origins of the extensors over a larger area and also reduces the extent of muscle expansion during activity which can reduce pain and increase function. Whilst these braces can be used as a conservative treatment, some evidence suggests that they have no significant benefits when compared with no orthotic bracing [11].

Various physiotherapy exercises can be given to patients with LE. Two common types of this therapy are stretching and eccentric exercises (eccentric exercises being where forces generated by the muscle are less than the opposing force leading to muscle elongation after tension). A cohort study looked at comparing stretching and eccentric exercises in which two groups were given either stretching or eccentric exercises as treatment. Whilst no control group was used in this study, the eccentric exercise group were shown more improved outcomes compared with the stretching group: 71% of the eccentric exercise group reported to be cured compared with only 39% of the stretching exercise group, suggesting that eccentric exercises are much more beneficial compared with stretching exercises [12]. Other forms of physical therapy available are pulsed ultrasound and deep friction massage [13].

Common medical treatments for LE can include using non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroid injections. One randomised controlled trial with high statistical power exists that compares corticosteroid injection with physical therapy and ‘wait-and-see’. Numerous outcome measures were used, with corticosteroid injection proving the most effective treatment option at six weeks, with what was deemed successful treatment in 92% of the corticosteroid injection group, compared with 47% success in physical therapy and 32% with no treatment. However, in the long term, it was shown that physical therapy was the most beneficial treatment, as many corticosteroid subjects relapsed over time [14]. One study looked at using the NSAID diclofenac to treat LE compared with a placebo. The results in this study showed a significant reduction in pain with the diclofenac group compared with the placebo group, although no significant improvement with functional outcomes such as grip strength [15].

Moving to the slightly more invasive end of the spectrum exists extracorporeal shockwave therapy (ESWT). ESWT is a more recent treatment for LE that has been in use for treating non-union of fractures and lithotripsy of renal calculi for a long time. This involves the guidance of pressure pulse that lasts for one microsecond per pulse. The theory is that calcification is reduced, whilst tissue healing is encouraged over degeneration. Additionally, ESWT is thought to inhibit pain receptors. One double-blind randomised controlled study has shown that compared with the control; there is no significant difference, with 50% improvement of functional outcomes in 35% of the ESWT, compared with 34% in the control. The authors concluded that ESWT showed improvement through the placebo effect, as opposed to the hypothesised physiological mechanism [16].

Botulinum toxin is another more recent treatment for LE. The actions of botulinum toxin cause paralysis of the nerves which is why it can act as an analgesic. In one double-blind randomised controlled trial, botulinum toxin was shown to significantly reduce pain when compared with a placebo at three months; however it did cause slight muscle weakness, suggesting that this may not be an appropriate treatment for athletes [17]. The advantages of this treatment are that its effects last for a few months and are temporary.

Low-level laser therapy (LLLT) has been around for a few decades now as a treatment for LE. Its effects are thought to be similar in promoting tissue repair and reducing pain through similar mechanisms such as those used hypothesised in ESWT. A study by Lam et al. compared LLLT with a placebo for treating LE in a randomised controlled trial. This study showed that there was a statistically significant improvement in pain, grip strength and function with LLLT compared with a placebo. As well as its efficacy, LLLT has been shown to be safe [18].

Glyceryl trinitrate (GTN), used to treat angina pectoris, has been shown to be effective in treating LE. It is thought to affect the way fibroblasts modulate collagen synthesis by affecting fibroblast stimulation linked with factors such as nitrogen oxygen synthase. GTN in LE can be administered as a skin patch. It has been shown that there is a significant improvement in pain with a topical GTN patch when compared with a placebo [19].

In common clinical practice, surgical intervention is indicated in cases where all conservative interventions have failed, although it may be thought of as an earlier intervention in the ‘harmful’ pain category of LE. These include the release of the common extensor origin, débriding damaged tissue around the ECRB origin, PIN release and denervation of the lateral epicondyle. All of these surgical options are generally very successful in curing LE [20]. Whilst this is the case, it should be remembered that there are many risks involved in surgery, from like severe adverse reactions from for example anaesthesia. Even athletes are at risk during surgery, demonstrated recently by rugby league player Jamie Rooney’s heart stopping during a knee operation [21].

Cell therapies and tennis elbow

LE is a clinical manifestation of degeneration. Whilst the body can repair itself, it cannot regenerate. Cell therapies have the potential for regeneration, making LE a good candidate for its application.

One type of cell therapy does not induce regeneration, but promotes the healing cascade. This treatment is autologous blood injection around the lateral epicondyle. This is thought to increase the concentration of transforming growth factor-β, and fibroblast growth factor. Under guidance of ultrasound, this technique has been shown to work as a treatment for LE [22]. In a recent study, dermal fibroblasts were seeded into a medium and injected under ultrasound guidance around the lateral epicondyle. Eleven out of twelve subjects in this study responded positively to this treatment [23]. These two pilot studies demonstrate the safety and efficacy of cell therapies to treat LE. In the future, these can be expanded to compare these treatments with more orthodox therapies.

Conclusions

LE is prevalent in many tennis players, and can be categorised according to different levels of pain. Upon successful diagnosis, different management strategies can be decided, depending on the pain category. Correcting stroke kinematics and altering equipment to limit forces going to the lateral epicondyle are two first-line precautions that can be used in benign and semi-benign cases of LE. Acute sports injury physiotherapy management such as protection, rest and ice are all recommended to aid the healing response. Counter-force braces are available to apply compression, but the evidence suggests that in practice, these are not significantly effective. Exercises are available to improve strength, without exerting excessive forces on the extensors; eccentric exercises have been shown to be more effective at treating LE compared with standard stretching exercises. Progressing to medical management, corticosteroid therapy has shown to be effective in the short-term compared with physical therapy, and NSAIDs are effective at relieving pain compared with no treatment. Surgery is a final option and is very successful, but carries the risks associated with invasive intervention such as infection and adverse effects. The efficacy and safety of cell therapy injections has been demonstrated, and future trials will determine whether or not these are effective at treating LE compared with current clinical practice, along with other treatments such as GTN, botulinum toxin and LLLT.

When given the diagnosis of LE, the athlete must decide after initial precautions and alterations are made, whether or not to have surgery to give a long-term solution as a first-line treatment, but to take a period of time out of training for surgery and rehabilitation can affect an athlete’s career, especially if the surgery goes wrong. A cell therapy injection that could quickly, non-invasively cure LE offers a promising future, and would be ideal for athletes. More studies are needed, but hopefully a quick and effective injection could cure harmful pain LE quicker than the duration of the clay court season.

References

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2. Stasinopoulos D, Johnson MI. ‘Lateral elbow tendinopathy’ is the most appropriate diagnostic term for the condition commonly referred-to as lateral epicondylitis. Medical Hypotheses 2006;67(6):1400-2.

3. Coombes BK, Bisset L, Vicenzino B. A new integrative model of lateral epicondylalgia. British Journal of Sports Medicine 2009 Apr;43(4):252-8.

4. Gruchow HW, Pelletier D. An epidemiologic study of tennis elbow: Incidence, recurrence, and effectiveness of prevention strategies. The American Journal of Sports Medicine 2009;7(4):234-8.

5. Kelley JD, Lombardo SJ, Pink M, Perry J, Giangarra CE. Electromyographic and Cinematographic Analysis of Elbow Function in Tennis Players with Lateral Epicondylitis. American Journal of Sports Medicine 1994 May;22(3):359-63.

6. Giangarra CE, Conroy B, Jobe FW, Pink M, Perry J. Electromyographic and Cinematographic Analysis of Elbow Function in Tennis Players Using Single-Handed and Double-Handed Backhand Strokes. American Journal of Sports Medicine 1993 May;21(3):394-9.

7. Fairbank SM, Corlett RJ. The role of the extensor digitorum communis muscle in lateral epicondylitis. Journal of Hand Surgery-British and European Volume 2002 Oct;27B(5):405-9.

8. Wheeless CR. Tennis Elbow – Lateral Epicondylitis. Wheeless’ Textbook of Orthopaedics. 2009.

9. Ilfeld FW. Can Stroke Modification Relieve Tennis Elbow. Clinical Orthopaedics and Related Research 1992 Mar;(276):182-6.

10. Jobe FW, Ciccotti MG. Lateral and Medial Epicondylitis of the Elbow. J Am Acad Orthop Surg 1994 Jan 1;2(1):1-8.

11. Wuori JL, Overend TJ, Kramer JF, MacDermid J. Strength and pain measures associated with lateral epicondylitis bracing. Archives of Physical Medicine and Rehabilitation 1998 Jul;79(7):832-7.

12. Svernlov B, Adolfsson L. Non-operative treatment regime including eccentric training for lateral humeral epicondylalgia. Scandinavian Journal of Medicine & Science in Sports 2001 Dec;11(6):328-34.

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