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lsjm 15 june 2009 volume 01
EDITORIAL
A very warm welcome to the Medicine section in this landmark edition of the London Student Journal of Medicine. The Medicine section aims to challenge the limits of current understanding, and refine clinical practice across the allied health professions. A wide and diverse section, we select articles conveying an insightful, novel approach reflecting pertinent issues in healthcare today. In the light of the revised GMC and Medical Schools Council guidelines released earlier this year1, defining professional values and fitness to practise have become hot topics of discussion. Jaimie Henry explores how our actions now impact upon our practice as healthcare professionals tomorrow. Also under the microscope are our attitudes towards our own health, we take a look at one upshot of binge drinking in a case report on alcohol induced peripheral neuropathy. The latest WHO estimates suggest , 1.6 billion adults are overweight worldwide with another 400 million clinically obese2; society’s expanding waistline is getting harder to tuck away. The war on BMI reached new heights as popular obesity treatment ‘Orlistat’ (brand name ‘Alli’) became available over the counter for the first time in the UK. In this issue we look at origins of obesity therapy, as Daniel Hammersley reopens the story of Leptin. This review highlights ongoing research dedicated to further unlocking Leptin’s potential; showing far from being a footnote relegated to the past, Leptin may still aid our fight against a fat future. A fundamental aim of the medicine section is to inform without regurgitating information easily available in a textbook. With this in mind we kick off our ongoing series into chronic conditions with an educational and engaging review of anti-TNF therapy. To complement this review is a piece from the patients view as a student shares their experience with RA treatment. Visit our section online to read these articles. With the promise of potential new treatments, mitochondrial medicine is an area rapidly gaining in recognition as top clinicians and experts worldwide compile a letter to President Barack Obama urging him to include the field amongst his top research priorities3. As we investigate current doors being opened by mitochondrial medicine, Professors Vamsi Mootha and Richard Haas, signatories of the letter and leading experts in the field, provide us with their thoughts on the incredible potential mitochondrial medicine offers and where it may take us in the future. With a bright future in view we take a fascinating look into the past in a topical tour of humankind’s evolution; in a whirlwind journey combining genetics, language and culture, Kartik Logishetty looks at the direction our species is taking, asking how will we continue to evolve? This is your journal, dedicated to help you in developing your ideas for publication. Whether you have an article for submission, an idea or simply want to write, get in touch by emailing medicine@thelsjm.co.uk. We welcome your input and also encourage you to help us improve by writing in with any comments, feedback and suggestions. Finally, an enormous thank you to all involved in putting this issue together. From the talented authors, peer and expert reviewers to Laura Vincent co-editor and the superb medicine panel, for their commitment, consistent hard work and continuous support. I hope you enjoy reading this issue, as much as we have enjoyed putting it together.
Maham Khan Section Editor of Medicine References 1. Illustration: Robert de Niet
2. 3.
Medical Students: Fitness to practise and behaviour guidelines document. General Medical Council [online]http:// www.medschools.ac.uk/documents/FitnesstopractiseguidanceSep2007.pdf (last accessed 21st April 2009) The WHO media centre, 2006. Fact sheet no 311. http://www.who.int/mediacentre/factsheets/fs311/en/index.html (last accessed 21st April 2009) Letter to President Obama, downloaded from United Mitochondrial Disease Foundation [online].http://www. umdf.org/atf/cf/%7B28038C4C-02EE-4AD0-9DB5-D23E9D9F4D45%7D/Mitochondrial%20Research%20 Letter%20to%20the%20President-Elect%20-%20rev04%200122.pdf (Last accessed April 21st 2009)
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PERSPECTIVE
Risky business: are fast-living healthcare students endangering the lives of their future patients? Jaimie Henry Year 2 Medicine, Imperial College jaimie.henry07@imperial.ac.uk It is something many healthcare students will have heard countless times just as they are about to tuck into their family sized bucket of deep fried chicken: “You’re going to be a doctor/nurse and you’re eating that rubbish!” That scenario is usually taken in a light hearted manner and such a rebuke is normally shrugged off and ignored. However, it does raise a very important question: how does this type of potentially damaging health behaviour impact upon the public’s perception of healthcare students and the profession in general? For a long time it has been a cliché of medical education and indeed the profession in general that doctors, and in particular student doctors, have the inalienable right to abuse their health, often in a way that far exceeds the misdemeanours of their patients. Studies have shown that medical students not only drink more than their counterparts in the arts, but suffer more adverse effects, including liver cirrhosis and alcohol-related vehicular deaths or violence1. This not only presents the obvious issues of poor performance at work and the direct endangerment of patients as a result of acting under the influence, but also presents indirect consequences: those students who are excessive drinkers omit to routinely counsel patients with excessive alcohol intake2. In itself, this could mean failing to advise a patient about a potentially fatal yet manageable condition.
Such behaviour has been shown to put at risk the inherent trust which forms the basis of the doctor patient relationship. With the move away from paternalism, patients no longer accept medical advice without remark but frequently question both the advice and the doctor. It is not surprising that evidence indicate that patients put poor confidence in any health advice given to them by an obese doctor.5 The overriding responsibility placed upon all healthcare professionals is to “make the care of the patient your first concern.” Perhaps now the GMC should consider whether it is not simply the conduct or health of student doctors that calls into question their fitness to practise, but whether it is also these risky health behaviours. Whilst there is currently little in the way of explicit or acute embarrassment of the profession as a result of binge drinking or smoking more insidious embarrassment is becoming plain to see and could even go so far as to jeopardise the long-term care of patients. On the whole, the behaviour of healthcare students is substantially underappreciated especially when one considers the effect such behaviour has on a future health professional’s ability to effectively treat or counsel their patients. Whilst patients would generally avoid consultation with an incompetent doctor/nurse or one with a criminal record, the overall outcome is equally ineffective if they disregard the advice given by a competent physician because of their apparent medical hypocrisy. References:
This is a problem that continues all the way through to qualified doctors and other healthcare professionals, where as few as 13% of all healthcare staff in one hospital (including respiratory registrars) believed all cigarettes were harmful3. It would appear that the only way to effectively deal with such a gaping lack of knowledge is at a grass roots level. Unfortunately, surveys have consistently found that teaching on smoking has not been sufficient enough to inform students themselves about the risks; they are then unable to effectively counsel patients in smoking cessation4.
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McCarron P, Okasha M, McEwan J, Davey Smith G. Association between course of study at university and causespecific mortality. J R Soc Med 2003;96: pp. 384-388 Frank E, Elon L, Naimi T, Brewer R. Alcohol Consumption and alcohol counselling behaviour among US medical students: Cohort Study. BMJ 2008;337: a2155 Bowen EF, Rayner CFJ. Medical students’ knowledge of smoking Thorax 1999;54: p.655 Richmond R. Teaching Medical Students about Tobacco Thorax 1999;54: pp. 70-78 Hash RB, Munna RK, Vogel RL, Bason J. Does Physician weight affect perception of health advice? Preventative Medicine 2003;36(1): pp. 41-44
lsjm 15 june 2009 volume 01
NEWS Image: Change4Life
Obesity: The Next Generation Laura Vincent Change4Life is a government survey which was launched in January to tackle increasing rates of obesity by promoting healthy eating and exercise. Based on 260,000 responders in England it showed that 72% of children do not participate in the recommended hour of daily activity outside school and therefore do not do enough physical activity to keep them healthy and prevent obesity. The survey reported that 45% of children either watched TV or played videogames before school, and only 22% did physical activity after their evening meal. The current exercise recommendations for children and young people state that they should achieve at least one hour of moderate intensity physical exercise every day. Also at least twice a week they should include additional activities which should improve strength, flexibility and bone health. The survey highlights the huge challenge that the government and the department of health face in the on-going battle with the nation’s obesity crisis. Marni Craze from World Cancer Research Fund said “The survey is a concern because it is important children get into the habit of being regularly physically active as early as possible. This is because habit formed as children often last into adulthood and there is convincing evidence that being physically active reduces risk of cancer and other chronic diseases.” Change4Life has launched a new marketing campaign which aims to motivate families to work together to improve their lifestyles. This highlights the consequences of inactivity, including cancer, heart disease and type-II diabetes. www.nhs.uk/Change4Life
The LSJM is a partner of the Change4Life initiative
Problems with the internet Laura Vincent
Laura Vincent is the associate editor of LSJM Medicine
A recent survey conducted by GP magazine has found that at least a quarter of doctors have treated adverse reactions caused by medicines brought on the internet. Along with treating adverse reactions, 85% of responders felt that online pharmacies need tighter regulations. Dr Sarah Jarvis from the Royal College of General Practitioners told GP “Surveys looking at many online medications suggest that the proportion of counterfeits is enormously high and the many of them contain very worrying ingredients”. The Royal Pharmaceutical Society of Great Britain (RPSGB) have recently issued a warning relating to the dangers of internet pharmacies. They are concerned that the general public are not fully aware of the risks of purchasing medicines online, as they may not be suitable for the patient and could lead to serious health risks. Although controls are in place, counterfeit drugs are still available in large volumes. To try and combat this problem the RPSGB have launched an Internet Pharmacy Logo, which identifies legitimate pharmacy websites where patients can be sure they are buying safe products. The Medicine and Healthcare products Regulatory Agency (MHRA) is working with the RPSGB to highlight the dangers of counterfeit drugs and help patients become more aware of the problems. This includes information leaflets which will be handed out with the dispensed products from all pharmacies which will provide advice on how to purchase medicines safely.
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PERSPECTIVE
Another pint? Go on, it’s not going to affect anyone ... Mitul Palan Year 3 Medicine, Imperial College Mitul.palan06@imperial.ac.uk A healthy lifestyle - something we emphasise to patients seen on wards or in clinics. I say this whilst wolfing down my scrumptious Indian takeaway. Have we as medical students forgotten to practise what we preach? The first topic to surface in this discussion is undoubtedly alcohol. A strong drinking ethic is prevalent in many medical schools, both in the USA and UK; gallons of alcohol are shovelled down first-year throats in the first few weeks. Is this the right mindset to impose on budding physicians? Recent studies in the USA 1 and in European 2 medical student populations have highlighted this binge-drinking culture, marking men as more likely to partake in such conduct than women. Binge drinkers also seemed to see more positives from drinking than others – does this suggest that our viewpoint on alcohol intake is completely wrong? Although compared to the overall population medical students drink less on average,1 we are the role-models of the future, and we should set an example. Illustration: Elaine Parker
Smoking does not seem to be as prominent in medical student population as excessive alcohol intake, but poor nutrition is very apparent. 3, 4 Current studies show students to have a very high saturated fat intake, and to be deficient in vegetables, fruit, dietary fibre and vitamins.4 Our grasp of the UK and US obesity problem has been found to be fairly poor. Studies suggest that the hectic schedules we are subjected to, along with the increased stress over years may be to blame for our poor nutritional intake.5 Once again, it is a lifestyle we must endeavour to change, both for our sakes and that of our patients. After all, is it ethical for a clinically obese physician to advise an obese patient on their diet? Perhaps we are unaware of what constitutes healthy behaviour, or perhaps we choose to ignore it: the latter seems more plausible. However, as a country with a rapidly increasing obese population, renowned for a smoking and drinking culture, the future of the nation’s health falls to us – and before changing their health behaviour, we have to first change ours.
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References 1.
2.
3.
4.
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Frank E, Elon L, Naimi T, Brewer R. Alcohol consumption and alcohol counselling behaviour among US medical students: cohort study. BMJ (Clinical research ed.) 2008 Nov 7;337: pp. a2155. Keller S, Maddock JE, Laforge RG, Velicer WF, Basler HD. Binge drinking and health behaviour in medical students. Addictive Behaviors 2007 Mar;32(3): pp. 505-515. Frank E, Carrera JS, Elon L, Hertzberg VS. Basic demographics, health practices, and health status of U.S. medical students. American Journal of Preventive Medicine 2006 Dec;31(6): pp. 499-505. Skemiene L, Ustinaviciene R, Piesine L, Radisauskas R. Peculiarities of medical students’ nutrition. Medicina (Kaunas, Lithuania) 2007;43(2): pp. 145-152. Swift JA, Sheard C, Rutherford M. Trainee health care professionals’ knowledge of the health risks associated with obesity. Journal of human nutrition and dietetics : the official journal of the British Dietetic Association 2007 Dec;20(6): pp. 599-604.
lsjm 15 june 2009 volume 01
SHORT CASE
Alcoholic Peripheral Neuropathy in a 24 Year Old Ronit Das Year 3 Medicine, Kings College London ronit.das@kcl.ac.uk doi:10.4201.lsjm/med.002 The extended abuse of alcohol leads to a myriad of health issues, and in up to 50% of cases results in a peripheral neuropathy.1 The corrosive effect of ethanol produces a primary axonal degeneration that characteristically takes several years to develop and manifest as symptoms. Sensory features often dominate the typical neuropathy, with minor motor compromise. It is therefore unusual to see an alcoholic neuropathy, with major motor and sensory features, manifest in a young abuser.
cally light touch, was diminished distally in the hands The lower limbs were the most obviously compromised. The patellar and ankle were absent with equivocal plantar reflexes. Power was preserved at the hip though diminished at each level distally, such that the power of the extensor hallucis longis was rated at MRC 1 bilaterally. The sense of light touch, vibration and pain were absent along with proprioception, below the level of the patella. The distal weakening of the upper limb and the stocking distribution of lower motor neuron signs in the lower limb clearly indicated a peripheral neuropathy. The patient’s report of “burning” and “tingling” pains in the absence of pain perception was also typical of peripheral neuropathies. Figure 1: Findings on examination
The patient, JD, was a 24-year-old female who chronically abused alcohol in the four years up to admission. She presented to A&E unable to walk, complaining of a burning pain over her shins and feet. Initial clinical suspicion was that a primary pathology was being compounded by alcohol abuse. This diagnostically challenging case provided an atypical perspective into alcoholic neuropathy. Miss JD presented to emergency services with numbness, pain and weakness in the hands and legs. The symptoms arose progressively over several weeks, prior to attendance at A&E. Tingling in the feet and fingertips was the initial sensation the patient became aware of. Within two weeks the “slightly odd” discomfort was replaced by intense burning pain over the feet and shins, and was accompanied by an inability to walk normally. On the day of admission the patient awoke “in agony”, unable to mobilize or stand. Prior to this event, JD had been treated for depression, opiate dependence and had a single hospital stay for a delivery at age twenty. Heroin use was initiated at age 17, and non-intravenous abuse continued for 3 years. JD was managed on methadone for the duration of her pregnancy, leading to sustained heroin-abstinence. At JD’s request methadone treatment was stopped after18 months of addiction management. Opiate withdrawal was not well tolerated and alcohol use escalated to alleviate symptoms. The patient reported drinking 4-5 bottles of wine per day, supplemented with other beverages – daily consuming approximately 60-85 units of alcohol. This 4-year period of binge drinking was associated with a nutritionally limited diet. Clinical Evaluation On admission JD was not distressed, though in severe pain. Immediate observations of blood pressure and temperature were normal. General inspection revealed no loss of muscle bulk or obvious lesions. A neurological examination found no tremors or involuntary movements in upper or lower limbs. Tone was also normal throughout. Testing did not reveal signs of an upper motor neuron lesion. Reflexes in the upper limb were normal. Power was bilaterally maintained at a MRC 5 rating except at the interossei, at which it was weakened to MRC 3 bilaterally. Similarly sensation, specifi-
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Differentials & Investigations The initial pre-investigative thinking was that JD’s neuropathy was aggravated by excessive alcohol consumption, though not produced by it. A primary aetiology was sought. Vasculitis was suspected following a DVT two hours into admission. A blood test revealed normal inflammatory markers and a sedimentation rate within range. Most small or medium artery inflammation syndromes, capable of producing neuropathic change, would distinctively affect such indicators. Paraneoplastic syndromes could cause autonomic and peripheral disturbances, but are rarely confined to motor and sensory deficits in pattern distributions. Though no primary lesion suggestive of neoplasm was found, paraneoplastic antibodies could present anomalously and had to be excluded. The paraneoplastic antineuronal antibodies “Hu” and “Yo” were absent on CSF sampling. Multiple myeloma, which is associated with anti-neuronal immune activation, was also excluded with a negative urine screen for Bence-Jones proteins. JD’s HIV status was questioned. The virus could appear as a neural lesion reflecting a CD4 drop or opportunistic invasion. The patient’s HIV status was negative.
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SHORT CASE References The symmetrical distribution of neurological deficits and symptoms meanwhile strongly suggested Guillain Barre. Protein concentration in CSF samples though did not meet the diagnostic criteria of greater than 10g/L.
1.
This meticulous process of exclusion left only alcohol-abuse as the potential cause. A sural nerve biopsy was conducted, and the subsequent nerve conduction study showed patterns consistent with axonal damage– characteristic of alcohol related neuropathy. A head CT also revealed significant brain volume loss, a feature of long-term alcohol abuse. Additionally, late into investigation, it came to light that JD’s father had abused alcohol and suffered a peripheral neuropathy. The positive family history along with the nerve study results strongly suggested alcoholic neuropathy.
3.
The principal treatment was alcohol cessation and dietary vitamin supplementation. Neuropathic pain was managed on Amitryptilline, Gabapentin, Paracetamol and Ibuprofen. Muscular pain was managed on Tramadol. Physiotherapy to rehabilitate lower limb functionality remains on going. Discussion This syndrome most commonly presents after years of alcohol abuse. How is it possible that a young person, with a relatively short period of abuse, presented with such fulminant signs? It is difficult to establish a reason for early onset, as the exact cause of alcohol related neuropathy is disputed. The syndrome is clinically distinct from the thiamine deficiency etiology of Wernicke’s encephalopathy and Korsakoff’s syndrome; though low vitamin B levels certainly are a factor.1 Animal models indicate that ethanol distorts cytoskeletal elements and neuronal organelles.2 Acetaldehyde, a metabolite of ethanol, is also directly neurodegenerative. A study by Monforte et al suggested that the severity of polyneuropathy is primarily dose dependent, implicating excessive alcohol use.3 What is clear is that female alcohol abusers suffer higher rates of peripheral neuropathy with a high incidence often seen amongst women with affected family members.4 A growing body of evidence suggests that alcoholic peripheral neuropathy is related to genetic susceptibility to ethanol toxicity and damage. Results from a Japanese study showed a correlation between an alcohol dehydrogenase gene mutation which results in decreased ethanol metabolism to diminished peripheral nerve conduction.5
2.
4.
5.
Koike H, Iijima M, et al. Alcoholic neuropathy is clinicopathologically distinct from thiamine-deficiency neuropathy. Annals of Neurology. July 2003 – Vol 54: p. 19-29. Corsetti G, Rezzani R, et al. Ultrastructural study of the alterations in spinal ganglion cells of rats chronically fed on ethanol. Ustructural Pathology. August 1998 – Vol. 22: p.309-19. Monforte R, Estruch R, et al. Autonomic and peripheral neuropathies in patients with chronic alcoholism. A dose-related toxic effect of alcohol. Archives of Neurology. January 1995 – Vol. 52: p. 45-51. Pessione F, Gerchstein JL, et al. Parental history of alcoholism: a risk factor for alcohol-related peripheral neuropathies. Alcohol. November 1995 – Vol. 30: p. 749-54. Masaki T, Mochizuki H, et al. Association of aldehyde dehydrogenase-2 polymorphism with alcoholic polyneuropathy in humans. Neuroscience Letters. June 2004 – Vol. 363: p. 288-90.
How much is too much? The most recent Government recommendations are up to 2-3 units per day for women and up to 3-4 units for men. 1 unit is equivalent to 8g of alcohol, which is approximately half a pint of 4% beer or a 25ml measure of spirits (40%). Statistics show over 40% of men and 33% of women drink more than this, with over half drinking double their recommended intake at least one day in the last week. Young people were found to be more likely to exceed daily guidelines and were also more likely to drink heavily, with 19% of 16-24 year old men drinking more than 8 units on a particular day and 8% of 16-24 year old women drinking more than 6 units. While the proportion of young women (age 16-24) drinking heavily was increasing rapidly reaching 28% in 2002, this figure has been falling in recent years and went down to 22% in 2005. Between 2006-2007 there were nearly 60,000 NHS admissions where the main diagnosis was related to alcohol, which is an increase of 50% over the last decade. Sources: NHS Information Centre, Statistics on Alcohol: England 2008, The General Household Survey 2005 and the National Statistics Omnibus Survey 2006.
JD, fell into a surprising number of these risk categories, implying a greater susceptibility. A cumulative effect of familial vulnerability, poor diet, and considerable alcoholic insult lead to her presentation. Whether a genetic mutation or trait was present is speculative although highly intriguing when considered as the root abnormality. Such cases are unique, though no longer rare due to soaring rates of youth alcohol misuse. Should this trend continue similar presentations could become familiar.
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lsjm 15 june 2009 volume 01
EXPERT COMMENTS Source: Wellcome Images
Mitochondrial medicine: What the experts say This is a field of growing importance as the role of mitochondria in common diseases such as diabetes, heart disease and the neurodegenerative disorders is becoming better understood. There is currently a NIH funded trial of Coenzyme Q10 in Parkinson disease underway in the US and Canada recruiting 600 patients at over 50 centres – a therapeutic opportunity which stems from the recognition of the mitochondrial role in Parkinson’s disease. An estimated 1% of young diabetics have a mitochondrial DNA cause and worldwide research on the mitochondrial role in Type 2 diabetes is underway. There is good evidence that the study of primary (genetic) mitochondrial diseases and their treatment provides valuable insights into mitochondrial function with important implications for more common diseases – this is the focus of mitochondrial medicine.’ Richard Haas, MD Professor of Neurosciences and Paediatrics Director UCSD Mitochondrial Disease Laboratory
Mitochondrial medicine is an exciting new field that focuses on human disorders that stem from inherited or acquired defects in mitochondria. There are a large number of inborn errors that are due to mutations in the mitochondrial genome or mtDNA - these are often termed the primary mitochondrial disorders, and we know with certainty that mitochondrial dysfunction causes the disease. What’s important to remember is that for the majority of the more common disorders [such as diabetes and obesity], it is unclear at present whether the mitochondrial dysfunction is a cause or consequence of the disease. Human genetics studies of common disease will help answer this question. Regardless, the important lessons we are learning from the primary mitochondrial disorders will impact our approach to even the common disorders. The mitochondrion is a remarkable organelle, and scientists from a variety of disciplines are helping to understand how it functions as an integrated system. I think the mitochondrion will prove to be a valuable model for systems biology - and that the lessons we learn from mitochondrial medicine can be extended to virtually all other human diseases.’ Vamsi Mootha, MD Associate Professor, Department of Systems Biology Harvard Medical School
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REVIEW
Mitochondria … more than meets the eye Stuart Potter
Year 1 Medicine, St. George’s University of London m0701759@sgul.ac.uk doi:10.4201.lsjm/med.005
For the full article and references see thelsjm.co.uk
Introduction Mitochondria play a significant role in one of the most important processes in the human body: aerobic (or cellular) respiration. Mitochondria are double-membrane organelles that primarily provide energy for the cell. Utilizing the products of glycolysis in a series of reactions called the citric acid cycle, mitochondria generate Adenosine Tri-Phosphate (ATP), the hydrolysis of which releases a substantial amount of energy. This is a very efficient process, where as many as 36-38 molecules of ATP can be converted from a single glucose molecule1. It is in this capacity as an energy supplier that mitochondria are often referred to as the ‘powerhouse’ of a cell, however this is not the only function they provide. Mitochondria also have the ability to synthesise hormones, such as oestrogen and testosterone2, store calcium, and are associated in the processes of cell signalling3. Another function that if not correctly regulated could have devastating effects on the body, is in apoptosis. Apoptosis Apoptosis is the controlled and regulated series of events which results in cell death. These events can be initiated by an immune response to stop an infection spreading or induced through extracellular (extrinsic) signals such as hormones and developmentalmediated signals. Apoptosis can also be induced when intrinsic (intracellular) signals are produced as a result of cellular stress; injury, oxidative stress caused by free radicals and exposure to radiation, chemicals or a viral infection. This programmed cell death (PCD) or ‘cell suicide’ is favourable to the other form of cell death, necrosis, which is uncontrolled and can result in potentially serious health problems. Cell death plays a vital role in many mechanisms and is important in the normal development of any multi-cellular organism. During development PCD causes superfluous tissue to disappear, effectively sculpting the developing tissue4. An example of this is the induction of apoptosis in inter-digital tissue, which prevents human hands being web-like. Apoptosis can also be induced to defend an organism against unwanted or potentially dangerous cells, such as tumour cells5 or cells infected by viruses6. This mechanism is drastic, but also the most effective at halting viral proliferation. PCD also serves to regulate the number of cells in an organism, keeping the number relatively constant to maintain homeostasis7. This is essential for the normal function of an organism, as without
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Figure 1: Diagram showing the role of mitochondria in apoptosis (Reproductive and Cardiovascular Research Group)
proper regulation the consequences can prove fatal. Mitochondria contain many pro-apoptotic proteins and therefore have a very important role in the regulation of intrinsic PCD. The role of mitochondria in apoptosis Apoptotic signals such as cellular damage or stress trigger apoptosis by activating the bcl-2 family of proteins found in the cytoplasm. Pro-apoptotic proteins, in this family such as Bax and Bid, relocate to the surface membrane of mitochondria where they disrupt the functioning of apoptosis inhibitors. The anti-apoptotic protein Bcl-2, works to maintain the membrane potential of the mitochondrion8 ; disruption of this function leads to the formation of permeability transition (PT) pores 9which release pro-apoptotic molecules, including cytochrome C. The release of cytochrome C initiates a caspase (Cysteine Aspartate Specific ProteASE) cascade, which is one of the main executors PCD. Upon release, cytochrome C binds to Apaf-1 (apoptosis proteaseactivating factor 1), a cytosolic protein that normally exists as an inactive monomer, this institutes a conformational change that allows it to bind with ATP 10forming apoptosome. Apoptosome then recruits multiple pro-caspase 9 molecules, facilitating their activation to caspase 9, which in turn activate caspase 3 (the executioner caspase) and the induction of apoptosis (Fig. 1)
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REVIEW Consequences of Unregulated Apoptosis Unregulated apoptosis, where more cells are induced to die than can be replaced by mitosis, can exacerbate or even cause diseases. These include neurodegenerative diseases like Alzheimer’s and ischemic strokes (a result of restricted blood supply to the brain) 11,12 as well as immunodeficiency disease such as AIDS.13 Dysfunctional or damaged mitochondria can affect the balance between cell death and cell division (mitosis), the effect being unregulated mitosis. Without the balance provided by apoptosis, the cell effectively becomes ‘immortal’ with its unrestrained mitosis resulting in the development of a tumour. Recent research into the role of mitochondria in the propagation of tumours has lead to some promising developments in combating cancer.
Conclusion With many important functions vital for normal cell processes, mitochondria are an essential component of a cell. The current research into the application of mitochondrial-stimulated apoptosis in combating cancer is particularly promising. This development, when considered in conjunction with other mitochondria-associated functions, demonstrates that mitochondria are more than just the cells’ powerhouse. References 1.
2. 3.
Medical Application of Apoptosis Researchers in Edmonton, Canada believe they have found a cheap, effective and relatively safe treatment for many forms of cancer. Dr. Evangelos Michelakis, a professor of the Department of Medicine at the University of Alberta, has shown that the drug dichloroacetate (DCA) attacks cancer cells while leaving surrounding healthy tissue intact. The drug has been used for years to treat metabolic conditions due to mitochondrial disease, but when introduced to cultures of lung, breast and brain tumours, the drug caused regression of the cancer cells.
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Researchers originally thought that cancer resulted in the irreparable damage of mitochondria; however Dr Michelakis and his colleagues found that DCA revived cancer-affected mitochondria, showing that the cancer only suppressed their function. Dr Michelakis believed that DCA could be selective for cancer cells whilst leaving normal cells as “it attacks a fundamental process in cancer development that is unique to cancer cells”14
8.
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It was believed that cancer cells use glycolysis because their mitochondria were damaged, but Dr Michelakis’ study suggests that these cells ‘switch off’ their mitochondria as a survival mechanism. When the cells don’t receive enough oxygen for their mitochondria to function properly they ‘switch off’ the mitochondria so they can produce energy through glycolysis. Incidentally, a product of glycolysis is pyruvate, which in anaerobic conditions generates lactic acid. It is thought that lactic acid can work to propagate the spread of cancerous cells, spreading tumours throughout the body.15 As the normal function of mitochondria is the apoptosis of abnormal cells, switching it off confers immortality on the cell. DCA reactivates mitochondria, shifting metabolism from glycolysis to glucose oxidation16. This reduces lactic acid production and restores the normal function of the organelle. With normal function restored, the mitochondria initiate PCD in the abnormal cancer cells; leaving non-cancer cells unaffected. Side effects Results for clinical trials using DCA to treat cancer in humans are unavailable presently; the drug has been used to treat other conditions with some of its side-effects known. These include pain, fatigue, gastrointestinal distress, numbness and gait disturbance.17, 18 Dichloroacetate can also cause toxic neuropathy in certain individuals.19 Such problems would be considered minor if clinical trials substantiate its effectiveness as an anti-cancer treatment.
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Cooper, G. M. Metabolic energy. [Internet]. The Cell: A Molecular Approach 2000. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?indexed =google&rid=cooper.section.294 [Accessed October 25th 2007] Widmaier, Eric P., Raff, Hershel and Strang, Kevin T. Vander’s Human Physiology.10th edition 2006 New York: McGraw-Hill Smaili, S. S. Mitochondria in Ca2+ signaling and apoptosis. 2000 Caspases.org. <http://www.caspases.org/showinfo. php?pmid=11768760>[Accessed October 15th 2007] Clarke, P. G. & Clarke, S. Nineteenth century research on naturally occuring cell death and related phenomena. 1996 Anat. Embryol. [Internet]. (193). 81-99. In:Mignotte, B. V. (1998). Mitochondria and Apoptosis. Eur. J. Biochem. 252. 1-15. <http:// www.blackwell-synergy.com/> [Accessed 25th October 2007] Williams, G. T. Programmed cell Death: apoptosis and oncogenesis. 1991 Cell [Internet]. (65). In: Mignotte, B. V. (1998). Mitochondria and Apoptosis. Eur. J. Biochem. 252. 1-15. <http://www.blackwell-synergy.com/> Vaux, D. L.. An evolutionary perspective on apoptosis 1994 Cell [Internet]. (76). In: Mignotte, B. V. (1998). Mitochondria and Apoptosis. Eur. J. Biochem. 252. 1-15. <http://www.blackwell-synergy.com/> Raff, M. Social control on cell survival and cell death 1996 Nature [Internet]. (356). In: Mignotte, B. V. (1998). Mitochondria and Apoptosis. Eur. J. Biochem. 252. 1-15. <http://www.blackwell-synergy.com/> Zamzami, N. S.-M. Mitochondrial control of nuclear apoptosis. 1996J. Exp. Med. [Internet]. (183). In: Mignotte, B. V. (1998). Mitochondria and Apoptosis. Eur. J. Biochem. 252. 1-15. <http://www.blackwell-synergy.com/> Antonsson, B. C.. Inhibition of Bax channel-forming activity by Bcl-2. Science 1997 [Internet]. (277), 370-372. In: Mignotte, B. V. (1998). Mitochondria and Apoptosis. Eur. J. Biochem. 252. 1-15. <http://www.blackwell-synergy.com/> Wang, X. The expanding role of mitochondria in apoptosis. Genes and Development 2001 [Internet]. 15 (22), 2922-2933. <http://www. genesdev.org/cgi/reprint/15/22/2922.pdf> [Accessed October 2007]
Mitochondrial Medicine Research in the UK has demonstrated that mitochondrial diseases are not rare. A study carried out at Newcastle University shows that 1 in every 200 people have a DNA mutation that could potentially cause a mitochondrial disease.1 Symptoms of Mitochondrial Disease Mitochondrial diseases are extremely complex. The affected individual may present with the following symptoms: • Seizures • Muscle weakness • Severe vomiting and diarrhoea/constipation • Feeding problems • Poor immune system • Failure to thrive • Delayed achievement of key milestones • Heat/cold intolerance • Diabetes and lactic acidosis A “red flag” would be where a patient has more than three systems affected, or when a disease exhibits atypical signs and symptoms. Further Reading http://www.ncl.ac.uk/biomedicine/research/groups/mitochondrial.htm References 1. Turnbull, D and Chinnery, P. How Common are Mitochondrial Disorders? s.l. : United Mitochondrial Disease Foundation, 2001.
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The successes and failures of Leptin in the fight against obesity Daniel Hammersley BA Hons(Oxon) Year 4 Medicine, Imperial College djhammersley@googlemail.com doi:10.4201.lsjm/med.001
For the full article and references see thelsjm.co.uk
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The world obesity problem is now reaching pandemic proportions. Using criteria drawn up by the World Health Organisation (WHO) defining ‘overweight’ as a Body Mass Index (BMI) of over 25 and ‘obese’ as a BMI of over 30, worldwide estimates in 2005 were of the order of 1.6 billion overweight and 400 million obese. The WHO predicts that by 2015, an estimated 2.3 billion will be overweight and more than 700 million obese.1 The considerable morbidity and mortality associated with obesity mean that the condition now presents one of the leading world health burdens. Despite the overwhelming proportions of the obesity problem, obesity is a poorly understood condition for which therapeutic intervention and clinical management strategies are clearly inadequate. In 1994, the discovery of the hormone Leptin3 was heralded as a major breakthrough in the field of appetite control and obesity. Initial hopes that the hormone would yield a ‘magic bullet’ treatment for obesity were met with disappointment; however the implications of the discovery of Leptin reach far beyond these initial hopes. The discovery of Leptin has opened up a whole new area of biology relating to appetite and energy homeostasis and provided a scientific framework for approaching obesity and developing novel therapeutic approaches.
Leptin and its role in energy homeostasis Leptin is a single-chain protein hormone with a molecular mass of 16kDa .4 Leptin is the cleaved transcript of the ob gene, produced predominantly by adipocytes in white adipose tissue.5 It functions as an afferent signalling molecule responsible for feeding back the body’s energy status from peripheral adipose tissue to the hypothalamus. Leptin signalling results in the modulation of feeding and energy expenditure, and thus is involved in energy homeostasis and weight maintenance. Circulating basal Leptin levels reflect the total fat stored in adipose tissue. Fluctuations from this level occur during times of energy imbalance, especially during times of energy deficiency, when circulating Leptin levels are rapidly reduced.6
Historical background Understanding the physiological control of appetite and energy homeostasis has long been an elusive goal for scientists. Fundamental to the understanding of energy homeostasis was an initial appreciation that humans obey the first law of thermodynamics; meaning that in order to maintain body weight, energy input must balance energy expenditure. 6 Such is the stability of body weight that it was assumed that this balance was maintained by extensive regulatory mechanisms; the identification of which remained unknown to scientists for many years. 6 Hypothalamic lesion studies indicated that the hypothalamus plays a key role in
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REVIEW the regulation of energy balance and body weight. 7 The concept of a peripheral factor responsible for relaying energy status to the hypothalamus was later introduced. 8 It was suggested that this factor was responsible for matching changes in body energy status with compensatory changes in food intake and energy expenditure, so as to maintain energy stores. Evidence for this being a bloodborne factor came from Hervey’s parabiosis experiments. 9 Hervey showed that parabiosis between a rat that was obese due to a lesion of the ventromedial hypothalamus (VMH) and wild-type rat, caused profound weight loss in the latter; this was assumed to be a result of an unidentified circulating factor produced in the lesioned rat acting on the wild-type rat. It was not until 1994 that Friedman’s group identified the ob gene by positional cloning, identifying also its gene product Leptin.3 This discovery was soon followed by the identification of the Leptin receptor.10 Such high hopes were held for Leptin, that the commercial rights to the hormone were bought by Amgen for US$20 million in 1995. 11
Knowledge acquired from the discovery of Leptin The discovery of Leptin has opened up an entirely novel area of research which has given energy homeostasis a biological context, whilst offering a new perspective from which to consider obesity.21 Human understanding of the biology of energy homeostasis has increased exponentially since its discovery, and this knowledge is crucial in understanding how this system may malfunction in obesity. It is through understanding the pathophysiology of obesity that effective novel therapies will be developed. The discovery of Leptin has facilitated the precise unravelling of many molecular pathways and the hypothalamic neurocircuitry involved in energy homeostasis, and in particular in appetite control. Crucial to this, is the ability of Leptin to manipulate anorexigenic (inhibiting appetite) and orexigenic (stimulating appetite) neuropeptides in the hypothalamus. This is illustrated in Figure 1.
Hy pothalam us
Early work following the discovery of Leptin If we consider the early experiments published following the discovery of Leptin, one can begin to understand the scale of the initial ‘scientific hype’ that surrounded its discovery. Early experiments involved the morbidly obese ob/ob mouse, which is homozygous for mutation of the ob gene. Following administration of recombinant Leptin, the ob/ob mouse showed marked weight loss characterized by a reduction in the percentage body fat. 12 This finding lead to hopes that the pathophysiology of common human obesity related to low levels of Leptin, and therefore that recombinant Leptin therapy could act as a novel and revolutionary treatment. However, only in a very small number of cases has recombinant Leptin therapy proved effective; 13 this is limited to individuals with absolute congenital Leptin deficiency caused by homozygous mutation of the human ob gene. 14 Congenital Leptin deficiency is exceedingly rare, and in the years following the discovery of Leptin, evidence accumulated to suggest that the direct use of recombinant Leptin alone was of little therapeutic value to the vast majority of obese patients. The initial evidence for this came from the observation that subjects suffering from common obesity had raised plasma Leptin concentrations.15 This inferred that in common obesity there is a state of ‘Leptin resistance’. Subsequent evidence from a number of clinical trials showed that subcutaneous recombinant Leptin administration did not induce a significant reduction in body weight in obese patients.16, 17 These findings accompanied a shift in opinion concerning the major physiological role of Leptin from a prevailing view that it acted as an anti-obesity hormone to a belief that Leptin was in fact more important as an anti-starvation hormone, and that in low concentrations, Leptin signalling initiates some of the adaptive physiological responses to starvation.18 Why was the discovery of Leptin a major scientific breakthrough? The failure of Leptin to provide a therapy for obesity coupled with its suggested primary role in signalling during starvation, initially lead some to question whether Leptin has lived up to its early promise as a major breakthrough in the field of obesity and appetite control. However, the significance of its discovery is justified by first considering the scientific knowledge that has been acquired as a result, and second by considering the future implications of its discovery.
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ARC W hit e A di pose T issue
L epti n
-
NPY A gR P
+
PO M C CA R T
L HA F ood int ak e
En er gy expendi t ure
PVN
BBB
Figure 1: Simplified schematic diagram illustrating the major effects of Leptin on hypothalamic neurocircuitry. Leptin is transported across the bloodbrain barrier (BBB). Leptin binding in the hypothalamic arcuate nucleus (ARC) results in the inhibition of orexigenic neuropeptide Y (NPY) and agouti-related protein (AgRP) neurons and the stimulation of anorexigenic pro-opiomelanocortin (POMC) and cocaine- and amphetamine- related transcript (CART) neurons. AgRP is an endogenous antagonist of receptors downstream of the POMC neurons (melanocortin – 3 and – 4 receptors [MC-3R, MC-4R]). First-order neurons project primarily to the lateral hypothalamus (LHA) and the paraventricular nucleus (PVN). The action of Leptin on the hypothalamic neurocircuitry results in reduced food intake and increased energy expenditure. Conversely, low levels of Leptin, as occurs during starvation, stimulates NYP and AgRP and inhibits POMC and CART.
Leptin signalling undoubtedly affects a number of other neuropeptides such as corticotrophin-releasing hormone (CRH), orexin, galanin and neurotensin, also involved in energy homeostasis signalling.23 Leptin is therefore important in integrating the many different hypothalamic neuropeptides involved in energy homeostasis.
A further integrative role for Leptin As well as integrating hypothalamic neuropeptides, Leptin signalling is known to mediate some of its effects on energy balance via the regulation of other parallel systems involved with communicating peripheral energy status to the CNS. Leptin is known to regulate the responsiveness of the Nucleus of the Solitary Tract (NTS) to short-acting gut-derived satiety signals such as cholecystokinin.24 Leptin has also been found to directly modulate reward pathways associated with feeding. 25 Beyond the homeostatic control imposed by the hypothalamus, feeding is known to also be influenced by the reward value and pleasure associated with particular food,
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REVIEW mediated via the mesolimbic pathway.26 Leptin receptors are expressed on dopaminergic neurons in the ventral tegmental area and Leptin binding has an inhibitory effect on this circuit, reducing the reward value of food.27 Conversely, decreased Leptin signalling increases the reward value of food, accounting for the increased palatability of food during starvation.25 Therefore, there is increasing evidence for Leptin being a ‘kingpin’ hormone with a number of integrative roles linking different systems that influence food intake and energy balance. The future implications of the discovery of Leptin Much research is ongoing in the field of Leptin resistance. Leptin is undoubtedly an effective signalling molecule in low concentrations; however what remains to be seen is whether overcoming Leptin resistance will result in Leptin acting at higher concentrations to reduce body weight. It is likely that Leptin resistance is a remnant from our evolutionary past which once conferred a selective advantage.18 This probably evolved in response to ‘feast-famine’ feeding habits, when the Leptin resistance allowed the development of ‘latent obesity’ during times of plenty, and that this storage of excess fat was advantageous during subsequent times of food scarcity. 6 Thus Leptin resistance may have been a component of the so-called ‘thrifty genotype’. However, in modern society where food is generally unlimited and a sedentary lifestyle the norm, the existence of such ‘thrifty genes’ is associated with the widespread development of obesity. If Leptin resistance is indeed involved in the pathophysiology of obesity then understanding and overcoming this resistance could provide the key to novel therapies. Two main hypotheses have been put forward to explain Leptin resistance; the first relates to a failure in the BBB Leptin transport system and the second to impairment of Leptin signal transduction pathways. Considering the former, rodent studies revealed that the transport system responsible for transporting Leptin across the BBB is saturable28 and that diet-induced obesity is associated with a reduction in the ability to transport Leptin across the BBB,29 this proposed mechanism is termed ‘peripheral resistance’. The second hypothesis, relates to the finding that Leptin signal transduction is inhibited by regulatory molecules such as suppressor of cytokine signalling 3 (SOCS3). The activity of such molecules has been shown to be increased in obese rats compared with wild-type,30 termed ‘central resistance’. Although presently the manipulation of downstream Leptin pathways has not yielded novel therapies for obesity, it is hoped that given the current level of research this approach will soon result in a breakthrough. That said, critics question the existence of Leptin resistance, believing that the hormone only functions at low concentrations and that high Leptin levels in obesity are purely a consequence of the increased adipocyte fat mass, rather than a cause of the condition.35 Further research will reveal whether this theory holds true.
life-style alterations. Consistent with this hypothesis, it was found that weight loss caused by Sibutramine (a centrally-acting appetite suppressant that can be prescribed to promote weight loss in obese patients) was enhanced by the serendipitous administrations of low doses of Leptin in rats.2 Summary The discovery of Leptin has greatly expanded human understanding of appetite control and energy homeostasis and it is for this reason that this discovery has been a scientific advance of major significance. Leptin itself has not provided an instantaneous cure for obesity, but its discovery has unveiled a whole new area of biology which has opened up a ‘Pandora’s box’ of possible therapeutic targets for the future. One cannot expect to find an effective treatment for obesity without first having a sound understanding of the physiology of energy homeostasis and the pathogenesis of obesity. The discovery of Leptin has resulted in major advances human understanding of both these areas. An understanding of Leptin biology is likely to underpin future developments in appetite control and obesity. References 1.
2.
3.
4.
5. 6. 7. 8. 9. 10.
WHO media centre. WHO Fact Sheet No. 311. 2006. Available from http://www.who.int/mediacentre/ factsheets/fs311/en/, accessed on 05/03/09. Boozer CN, Leibel RL, Love RJ, Cha MC, Aronne LJ. Synergy of sibutramine and low-dose Leptin in treatment of dietinduced obesity in rats. Metabolism. 2001; 50:889-93. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994; 372:425-32. Meier U & Gressner AM. Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of Leptin, ghrelin, adiponectin, and resistin. Clin Chem. 2004; 50:1511-25. Trayhurn P & Bing C. Appetite and energy balance signals from adipocytes. Philos Trans R Soc Lond B Biol Sci. 2006; 361:1237-49. Friedman JM. Modern science versus the stigma of obesity. Nat Med. 2004; 10:563-9. Anand BK & Brobeck JR. Hypothalamic control of food intake in rats and cats. Yale J Biol Med. 1951; 24:123-40. Kennedy GC. The role of depot fat in the hypothalamic control of food intake in the rat. Proc R Soc Lond B Biol Sci. 1953; 140:578-96. Hervey GR. The effects of lesions in the hypothalamus in parabiotic rats. J Physiol. 1959; 145:336-52. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI. Identification and expression cloning of a Leptin receptor, OB-R. Cell. 1995; 83:1263-71.
Another potential future role for Leptin is to prevent the re-gaining of weight following weight loss. The reduction in Leptin levels following weight loss and the physiological response to this is thought to be a major contributing factor to the subsequent re-gain of weight. Therefore it has been hypothesized that exogenous Leptin therapy, in order to maintain high Leptin levels, may help to maintain weight loss. Leptin therapy could be used in this way in combination with other anti-obesity therapies or simply with
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Rheumatoid arthritis and the anti-TNF revolution Bernard Freudenthal BA (Hons)
Year 5 Medicine, University College London bfreud@gmail.com For the full article and references see thelsjm.co.uk
Introduction Advances in biotechnology have given rise to ‘biotherapeutics’ synthetic proteins that mimic antibodies or large-molecule inhibitors to directly modulate specific disease pathways. The development of anti-TNF cytokine inhibition in rheumatoid arthritis (RA) is a great success story of recent medical science. Background RA is a systemic inflammatory disease marked by a symmetrical peripheral polyarthritis 1. It affects approximately 1% of people worldwide, with a highly variable clinical course. Features include joint swelling, pain, stiffness, fatigue and fever. RA can be highly debilitating with significant morbidity, loss of productivity and shortened life expectancy. Articular involvement is characterised by erythema, effusion and synovitis that can lead to progressive joint destruction and deformity especially of the proximal interphalangeal, metacarpaland metatarsal-phalangeal joints, and of the wrist and ankle. Common extra-articular manifestations include subcutaneous ‘rheumatoid’ nodules, anaemia, pulmonary fibrosis, and Sjögren’s syndrome .2 Before recombinant biotherapeutics, treatment was restricted to non-steroidal anti-inflammatory drugs (NSAIDs), smallmolecule disease-modifying anti-rheumatic drugs (DMARDs), and corticosteroids. Though DMARDs such as methotrexate can allow sparing of corticosteroids, they often have toxicity and limited efficacy .3 Cytokines in RA RA is commonly regarded as an autoimmune disease with 80% of patients having serum rheumatoid factor (RF) (anti-IgG autoantibodies). Deranged antigen presentation or T-cell recognition have also been implicated, given RA’s correlation with HLA-DR4/DR1 alleles (MHC class II) and since T-cells are found in the synovial infiltrate.1 With increasing knowledge of the role of cytokines in inflammation, RA disease mechanisms are better understood, though what triggers its onset remains unclear. Cytokines are extracellular short-range paracrine or autocrine signalling proteins that regulate inflammation, tissue repair, immunity, and cell division . 4 There are over 100 known cytokines,
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which function via complex network-like interactions. Though they must also drive pathogenic inflammatory processes, it is difficult to demonstrate an aetiological role for specific cytokines in a given disease .5 For a given cytokine to become a potential therapeutic target, it must be shown to have a key rate-controlling function. Qualified deductions can be made from animal models by cytokine over expression or total abrogation in transgenic mice, or by infusion of neutralising antibodies5. Alternatively, human in vitro models using cultures or explants can be used. However, transient and variable cytokine expression, and synergy and antagonism between cytokines and physiological inhibitors, can frequently cause negative results .6 To discover which of the many cytokines identified are upstream and rate-limiting, anti-TNF antibodies were added to rheumatoid synovial cell cultures, which caused a decrease in IL-1 production.11 Furthermore, TNF induced the synthesis of IL-1 in endothelial cell cultures12, while an IL-1 receptor antagonist did not reduce TNF expression in rheumatoid synovial cell cultures.13 IL-1 was already known to be a crucial stimulator of fibroblast proliferation and prostaglandin synthesis in cell cultures, bone resorption and proteolysis in tissue explants, and release of systemic acute phase proteins.10,14 TNF - the key RA cytokine? Tumour necrosis factor (TNF) was first identified in 1975 as a serum extract from mice inoculated with bacterial endotoxin, which induced haemorrhagic necrosis of tumours .15 By 1985, the molecular identity of human TNF was characterised and cDNA clones were synthesised .16 A structurally homologous cytotoxic factor was named TNFβ to differentiate from the original ‘TNFα’.17 TNFβ was subsequently renamed ‘lymphotoxin’ and is mainly produced by stimulated T-cells. TNF is synonymous with TNFα, and is produced in disease by macrophages. Physiological functions of TNF include protection against bacterial infection, and also modulation of cell growth, viral replication, tumour genesis and immune regulation.17
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PERSPECTIVE Animal models further demonstrated TNF’s role in RA. Collageninduced arthritis (CIA) arises in genetically susceptible mice injected with collagen type-II and an adjuvant, and has many similarities with RA. Administration of anti-TNF antibodies in CIA mice reduced both active inflammation and joint damage.18 In addition, over expression of TNF in transgenic mice caused an erosive polyarthritis, which anti-TNF antibodies could prevent.19 Therapeutic anti-TNF Sufficient evidence had been accumulated to move onto clinical trial of TNF blockade in RA. Fortuitously, anti-TNF antibodies and TNF-receptor (TNFR)-IgG-Fc fusion proteins were already in development as experimental treatment of TNF-mediated sepsis.18 The first anti-TNF agent tested was a chimeric antibody, later named ‘infliximab’, with a mouse variable region grafted to a human constant region. In 1992, an open trial was performed at Charing Cross Hospital, London. Infliximab infusion was given to twenty longstanding RA patients who were unresponsive to DMARDs.20 All the patients responded, many with dramatic symptomatic improvement, and at 6 weeks there was a 70% reduction of swollen joints. By 26 weeks, all the patients had relapsed, showing that TNF blockade only brings temporary relief, but the therapy appeared efficacious and safe, warranting further trials. A phase-2 double-blind randomised placebo-controlled trial was performed in 1993 with two doses to demonstrate dose response, with 79% response to the high dose.18 Many questions remained concerning the feasibility of long-term TNF blockade. Might the infused antibodies, even if completely humanised, still prove to be immunogenic on the long-term and so elicit a neutralising host antibody response? Even if TNF could be successively inhibited, might another cytokine replace TNF’s function, given the dynamic cross-communication of cytokine pathways? An additional concern was that permanent disruption of TNF’s physiological functions might increase susceptibility to infection and malignancy.18
including ankylosing spondylitis, psoriasis and Crohn’s disease.17 However, results have been more mixed in other diseases such as systemic lupus erythematosus and multiple sclerosis, and anti-TNF proved to be ineffective in treating septic shock, for which it was first developed.25 Even in RA, anti-TNF treatment is not without its problems, with concerns that anti-TNF could cause infection and malignancy. UK National Institute for Clinical Excellence (NICE) guidelines require all patients to be enrolled in the Biologics Registry of the British Society of Rheumatology to monitor the long-term safety of anti-TNF. Rates of serious infection are so far unchanged, though there is an increase in skin and soft tissue infections, in particular with intracellular pathogens such as salmonella, listeria and legionella, and as of March 2005, there were 11 cases of tuberculosis.26 A recent meta-analysis of adverse effects in antiTNF trials (excluding soluble TNFR) showed a dose-dependent increase in malignancies and serious infections, suggesting that a minimum required dose should be used, and that patients should be screened for subclinical malignancies before initiating anti-TNF therapy.27 Conclusion Anti-TNF is a remarkable clinical success and continues to be the predominant biological therapy for RA over a decade after being licensed. It has transformed the lives of many thousands of sufferers of a severely debilitating progressive illness. However, the use of biotherapeutics will always be affected by their prohibitive expense – a year’s treatment of infliximab costs nearly £10,000. Treatment by cytokine inhibition requires that continuous blockade will always be required, and the requirement for parenteral administration is an important practical consideration. With advancing understanding of disease mechanisms, future goals for biological treatment of RA should be to induce long-term remission by targeting the underlying pathogenic causes. References
A subsequent study with five doses over three months showed that immunogenicity could be managed either by using larger doses or by co-administering methotrexate, which is known to deplete T-cells.18 This suggests a synergistic effect similar to the successful co-administration of anti-CD4 (a T-cell marker) and anti-TNF antibodies in the CIA model.21 A two-year phase-3 study with six months’ treatment showed that cartilage and bone damage was arrested, with sustained benefit in over half the patients.22 In some patients there was even evidence of repair to damaged joints. Trials of a TNFR fusion protein, etanercept, followed soon after, and both drugs were subsequently licensed for use in RA. Current UK guidelines advocate their use in patients who have failed to respond to at least two DMARDs including methotrexate.23 With response rates of 60-80% in trial subjects who were resistant to all other treatments, anti-TNF was a huge success.18 Nonresponders might have raised a neutralising human anti-chimeric antibody (HACA) response, they might have TNF or other cytokine polymorphisms, or they could require higher dosing. Synovial biopsy has shown that patients with low TNF in their synovial fluid are less likely to respond,24 suggesting heterogeneous pathogenic mechanisms.
1. 2. 3. 4.
5. 6. 7.
8.
9.
10.
Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet. 2001; 358(9285):903-11. Young A, Koduri G. Extra-articular manifestations and complications of rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2007; 21(5):907 Smolen JS, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov. 2003; 2(6):473-88. Oppenheim JJ, Feldman M. Introduction to the Role of Cytokines in Innate Host Defense and Adaptive Immunity, In: Cytokine Reference, Vol 1: Ligands. London: Academic Press, 2001. Feldmann M, Brennan FM. Cytokines and Disease, In: Cytokine Reference, Vol 1: Ligands. London: Academic Press, 2001. Feldmann M, Saklatvala J. Proinflammatory cytokines, In: Cytokine Reference, Vol 1: Ligands. London: Academic Press, 2001. Brennan FM, Chantry D, Jackson A, et al. Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet. 1989; 2(8657):244-7. Nawroth PP, Bank I, Handley D, et al. Tumor necrosis factor/ cachectin interacts with endothelial cell receptors to induce release of interleukin 1. J Exp Med. 1986; 163(6):1363-75. Butler DM, Maini RN, Feldmann M, et al. Modulation of proinflammatory cytokine release in rheumatoid synovial membrane cell cultures. Comparison of monoclonal anti TNF-alpha antibody with the interleukin-1 receptor antagonist. Eur Cytokine Netw. 1995; 6(4):225-30. Saklatvala J, Sarsfield SJ, Townsend Y. Pig interleukin 1. Purification of two immunologically different leukocyte proteins that cause cartilage resorption, lymphocyte activation, and fever. J Exp Med. 1985; 162(4):1208-22.
Anti-TNF treatment has since been successfully tested and licensed for use in other autoimmune inflammatory diseases
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Rheumatoid Arthritis – A Medical Student’s Perspective Sarah Hewett Year 3 Medicine, Imperial College Sarah.hewett06@imperial.ac.uk Ironically, I was sitting in a rheumatology lecture when I first realised that I had arthritis. I had had a few random joint pains for a month or so, but assumed I’d just bumped my hand, or twisted my ankle. I was probably in denial for a while - four or five years previously, I got a virus, which lead to arthritis, and I did not want to admit that it was back. Eventually though, the arthritis was interfering with daily activities like walking and writing, so I knew I had to get some help. At the beginning of the summer 2008, I went to see the GP. Unfortunately, he could see no signs of active inflammation and so, despite the pain I was in, he was unable to give me a referral. Shortly afterwards, I had the first of many flare ups. My left hip was excruciatingly painful on any movement and to the touch. I went to my local A&E, and was given co-codamol, which helped hugely, and a referral to an excellent rheumatologist in London. My rheumatologist has been wonderful. He suspected rheumatoid arthritis from the start, and ordered bloods (including rheumatoid factor and anti-CCP antibody, both of which were positive). He also gave me an IM injection of depo-medrone, a corticosteroid, which calmed the arthritis for about a month, and allowed me to enjoy the rest of the summer. I was formally diagnosed at the next appointment in September 2008. I do not have the typical symmetrical rheumatoid arthritis. Different joints are involved at different times. My shoulders, elbows, wrists, hands, hips, knees, ankles and feet have all been affected. The arthritis jumps at random between the joints, affecting varying numbers of joints at any one time. I was started on a low dose of methotrexate (7.5mg once weekly). Methotrexate is a disease modifying anti-rheumatic drug (DMARD). The dose was slowly increased as I didn’t seem to have any benefit from the methotrexate, up to the maximum dose for rheumatoid arthritis (20 mg once weekly). Luckily, I didn’t have any side effects either! However, the methotrexate didn’t seem to do the trick so, a few months later, hydroxychloroquine (another DMARD) was added, along with a regular NSAID (diclofenac). The next step in the treatment of rheumatoid arthritis is anti-TNF. Anti-TNF is currently the best treatment for rheumatoid arthritis, but patients have to jump through many hoops to get it. Current NICE guidelines state that a patient has to have tried at least two DMARDs for six months each, partly because anti-TNF is a very expensive medication. Of course, this means up to twelve months of failed therapy before getting the medication which works, which can cause unnecessary suffering and irreversible joint damage. The addition of hydroxychloroquine was done with future anti-TNF treatment in mind, so that I would meet these criteria as soon as possible. I was hugely lucky, because my rheumatologist and the rheumatology specialist nurse did so much to help me. One month ago, I started taking Etanercept 50mg once weekly.
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The first hurdle there was learning how to inject myself. The first time was terrifying, and it took about ten minutes before I worked up the courage to do it! But after that, it became much easier. The benefit of being on the anti-TNF quickly became apparent, so that gave me some incentive. Of course, anti-TNF disrupts the immune system, making me more prone to infections. I developed a chest infection a couple of weeks ago, so had to miss my dose of anti-TNF to give myself a chance to recover, and wound up having two flare ups in as many weeks. Back on the anti-TNF now, I’m feeling a hundred times better again. The flare ups, when I have them, are really tough. The pain is often excruciating, and can be in just a few joints or all over. Pain killers don’t do much for the pain on the first day of the flare up, but do help after that. Flare ups usually last for a few days. Since being on the anti-TNF, I have found that the flare ups I have don’t seem to last as long as they did before I started treatment, which is a definite bonus. One of the hardest things to cope with has been the tiredness. The arthritis means that everything is a huge effort, so I’m always exhausted by the end of the day, and I usually don’t sleep very well because of discomfort. But, by going to bed very early, and giving up my extra-curricular activities, I have been able to continue with my studies. Something else that has been quite difficult is the fact that physically I look quite well. This means that the people around me, who do not know about my condition don’t understand why, for example, it takes me a few moments to get off the bus, or longer to walk up the stairs. I often get unpleasant looks from people who simply don’t realise what is wrong with me. I have been extremely lucky with the support that I have been given. My rheumatologist and the rheumatology specialist nurse are always happy to talk to me, and I am extremely grateful for this, as there have been times when I have needed advice quickly on how to manage pain during flare ups, or information about my medication. My mum lives fairly close to me, and has always been there to drop everything and take me home whenever I need her. She has made it possible for me to continue studying medicine and I owe her so much. My wonderful boyfriend puts up with my whinging, and is always there for me when I need him. My friends have all stuck by me, giving me both moral support and helping me to complete tasks that I physically can’t do, like changing my sheets, or brushing my hair. All of these people have made this so much easier for me, and I am eternally grateful to them all. I am now in the middle of a ten week clinical attachment, and, despite everything, really enjoying it. My team are really understanding of my condition, and do everything they can to help me. Medicine is what I’ve always wanted to do, and, although I do have times when I feel down, usually I can look to the future, when the arthritis should be under much better control, with great enthusiasm.
lsjm 15 june 2009 volume 01
PERSPECTIVE
Will Homo sapiens Continue to Evolve? If so, how? Kartik Logishetty BSc (Hons) Year 4 Medicine, Kings College London karlog43@googlemail.com In the shadow of the 200th anniversary of the birth of Charles Darwin, biologists continue to furiously debate the continuation or, indeed, the end of human evolution. The increased average life-span of the homo sapien means that a greater proportion of the population reach reproductive potential than ever before, leading to decreased deletions of unique genes.1 Simultaneously, the inter-breeding of ever more distant and distinct populations has produced a colourful blending of genes. In the ‘Western’ world, the unchallenging availability of food, provision of healthcare and dominance of hygiene, has dampened the environmental conditions that Darwin, Mendel, Huxley and their contemporaries deemed necessarily for evolution through natural selection. Most humans, especially the male of the species whose reproductive potential is not limited by child-bearing mechanics or timing, are able to propagate their genotype to the next offspring, irrespective of the extent of their adaptability to the prevailing environment. More so, with fewer older fathers there are fewer spermline mutations potentially passed on, and therefore decreased individual variation. This homogeneity suggests that evolution has ground to a standstill, and that without a sensational change in climate or an epidemic proliferation of cloning and gene therapy, the future is as we see it today. Inversely, a large body of scientists argue that evolution is as unstoppable as it is unpredictable, particularly in the developing world. The slow phenotypic changes, produced by today’s larger gene pools, serve to mask the unremitting dialogue between the species and environment. The capricious advent of new diseases will force natural selection of Homo sapiens – for example, incidence of haemoglobin ‘C’, which confers a resistance to malaria without anaemia, is increasing exponentially in West African populations. Some even predict the emergence of an AIDS-resistant population in areas currently epidemically ravaged by HIV. The clash of these two opposing perspectives could in fact exist concurrently. It may well be that evolution has stopped in certain populations, and is continuing in others. However, a new conflict arises when one attempts to define evolution, and whether in a more fluid sense, it continues as strongly and ubiquitously as ever. Evolution, in its most literal sense, means change over time – changing species, changing populations, or changing characteristics. Evolution is not only a genetic mechanism, and perhaps natural selection and culture are the motors of change.2 The continuing development of the human race, spurred by technology, creativity, and money, itself engenders competition – the foundation of natural selection.
lsjm 15 june 2009 volume 01
Homo sapiens are considered uniquely capable of representational communication. Language is one of our greatest commodities and has developed in tandem with another almost exclusively human trait: culture. Language allows for ‘productivity’ i.e. the capacity to say things that have never been said or heard before, yet still be understood, and ‘cultural transmission’ i.e. our genes have a strong capacity to acquire language, which can be transmitted extragenetically by learning and teaching. Darwin claimed that the human brain is selected for sociability, which would explain the origin and strength of culture, as well as its variability.3 As argued by Pinker, 1990, human language is the product of Darwinian natural selection, arising from the reproductive advantages that linguistic compositionality affords. Furthermore, cultural transmission (e.g. seen in the recent proliferation of the ‘SMS’ language) combined with biological transmission, influence the evolution of language, and indirectly, the evolution of homo sapiens.4 As well as the transmission of language, culture has spawned materialism. The evolution of human behaviour is seen in three dynamic processes termed ‘first nature’ (matter originating from the Big Bang), ‘second nature’ (the evolution of life forms, from bacteria), and ‘third nature’ (the dawn of ideology, symbolic thought, and agrarianism). ‘Third nature’ has infused the human mind with the idea of progress, which has itself fueled the evolution of complex institutional order and technology, and their unfortunate symbiosis with war and environmental degradation.5 A concerted effort by neuroscientists and archeologists has demonstrated that the rapid encephalization seen in early homo sapiens was intimately related to social relationships, later extended by an increasing engagement with material culture. The ability today to manipulate social networks using a variety of material resources continues to reflect the evolution of culture.6 The craft with which homo sapiens can now apply material devices is under the constant scrutiny of morals and ethics. The recent manifestation of international and local standards of ethical ‘acceptability’ has demonstrated a new form of evolution in culture.7 The argument on the prevalence of evolution can therefore only be settled based on the fluidity of its definition. Using the broader brush, it is clear that our species is still evolving on a genetic, linguistic, and cultural plane, albeit in more subtle ways. The future will almost inevitably be one of a uniform brown skin phenotype, but where our verbal, social, and moral compasses direct us is altogether unknown. References 1. 2. 3. 4. 5. 6. 7.
Hockett, C. F. (1960). “The origin of speech.” Sci Am 203: 89-96. Aoki, K. (2001). “Theoretical and empirical aspects of geneculture coevolution.” Theor Popul Biol 59(4): 253-61. Hayflick, L. (2000). “The future of ageing.” Nature 408(6809): 267-9. Johnston, W. A. (2005). “Third nature: the co-evolution of human behavior, culture, and technology.” Nonlinear Dynamics Psychol Life Sci 9(3): 235-80. Kirby, S., M. Dowman, et al. (2007). “Innateness and culture in the evolution of language.” Proc Natl Acad Sci U S A 104(12): 5241-5. Phillips, C. S. (2001). “Culture, social minds, and governance in evolution.” Politics Life Sci 20(2): 189-202. Mesoudi, A. and P. Danielson (2008). “Ethics, evolution and culture.” Theory Biosci 127(3): 229-40.
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