Journal of European Medical Students' Association on Medical and Scientific Affairs Volume: 6 Issue: 1 2011
Responcibility Ethics & Public Health
Breakthrough European Integration
Journal of European Medical Students' Association on Medical and Scientific Affairs Volume 6 Issue 1 2011
Student Editorial Board Editor in Chiefs Ilyas Sahin, Hacettepe University Faculty of Medicine,TURKEY Elshad Hasanov, Hacettepe University Faculty of Medicine,TURKEY
Editors Abas Hashimov, Hacettepe University Faculty of Medicine, TURKEY Ahmed Aber, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UNITED KINGDOM Amra Nadarevic, University of Tuzla, Faculty of Medicine, BOSNIA AND HERZEGOVINA Andre Madaleno, Trinity College Dublin , IRELAND Annakan Navaratnam, Imperial College School of Medicine, UNITED KINGDOM Atanas Banchev, Medical University of Plovdiv, BULGARIA Bernardo Barata, Faculty of Medical Sciences, New University of Lisbon, PORTUGAL Caziuc Alexandra, Iuliu Hatieganu University of Medicine and Pharmacy,ROMANIA Erhan Ararat, Hacettepe University Faculty of Medicine, TURKEY Evgenia Katsoni, University of Southampton School of Medicine, UNITED KINGDOM Fleur Janmaat, Maastricht University Medical Centre, The NETHERLANDS Kavita Aggarwal, Imperial College School of Medicine ,UNITED KINGDOM Necati Enver, Otolaryngology Department, Istanbul University Faculty of Medicine TURKEY Paul Brennan, University of Dundee, IRELAND Pinar Haznedar, Ankara University Faculty of Medicine, TURKEY Rohan Shotton, University of St Andrews Bute Medical School, UNITED KINGDOM Sajjad Muhammad, Pharmacological Institute, University of Heidelberg, GERMANY Tomuleasa Ciprian, Ion Chiricuta Comprehensive Cancer Center Cluj Napoca, ROMANIA Zehra Ordulu, Hacettepe University Faculty of Medicine, TURKEY
EMSA (European Medical Students’ Association) and the editor do not hold themselves responsible for the statements made, or the views put forward in the various articles and papers. Medical knowledge is constantly changing. The authors and the editor, as far as it is possible, have taken care to ensure that the information given in this text is accurate and up-to-date. However, readers are strongly advised to confirm that the information is correct. Despite judicious efforts errors may have crept in and EMSA, the editor and the publisher do not accept responsibility for this.
This journal, including all individual contributions and illustrations published therein, is legally protected by copyright for the duration of the copyright period. Any use, exploitation or commercialisation outside narrow limits set by copyright legislation, without the publishers’ consent, is illegal and liable to criminal prosecution. This applies in particular to photostat reproduction, copying, cyclostyling, mimeographing or duplication of any kind, translating, preparation of microfilms, and electronic data processing or storage. Apart from any fair dealing for the purposes of research or private study, or criticism or review as permitted under the European copyright, design and patent laws, no part of this publication may be reproduced, stored, or transmitted, in any form or by any means, without the prior permission in writing of the editor, the article writers and the EEB (EMSA European Board).
Senior Editorial Board Akira Matsumori, MD, PhD, FACC, FAHA, FESC,
Department of Cardiovascular Medicine, Kyoto University Graduate
School of Medicine, JAPAN
Bogdan Petrunov , MD, PhD, DSc,
Academician of Bulgarian Academy of Sciences, BULGARIA
Barbara A. Miller, MD, Division of Pediatric Hematology / Oncology, Penn State Milton S. Hershey Medical Center, USA Can Ince , PhD,
Department of Translational Physiology, Academic Medical Centre, University of Amsterdam, NETHERLANDS
Constantinos Deltas, PhD , Department of Biological Sciences, University of Cyprus, CYPRUS Craig Hillemeier , MD,
Department of Pediatrics, Penn State Milton S. Hershey Medical Center, USA
Donna M. Wilcock, PhD,
Department of Medicine/Division of Neurology, Duke University , USA
Dennis Scolnik, MSc, MB, ChB, DCH, FRCP Eero Vasar MD, PhD, Elio Roti, MD,
Department of Paediatrics, University of Toronto, CANADA
Department of Physiology , University of Tartu, ESTONIA
Institute of Endocrinology, University of Milan, ITALY
Emmanuelle Wollman, DR, CNRS(Centre National de la Recherche Scientifique)–Département des Sciences de la Vie, Member of ANAES scientific council, FRANCE Emin Maltepe, MD, PhD, Department of Pediatrics Division of Neonatology, University of California San Francisco, USA Esen K. Akpek, MD,
Department of Ophthalmology , The Wilmer Eye Institute, Johns Hopkins Hospital,USA
Frank V. Brozovich, MD, PhD, Department of Medicine/Physiology, Mayo Clinic ,USA Ibrahim Halil Gullu , MD, Jordi Pales, Phd,
Department of Medical Oncology, Hacettepe University Institute of Oncology, TURKEY
Spanish Society for Medical Education, Medical Education Foundation and Faculty of Medicine of the University
of Barcelona, SPAIN
J. Lennert Veerman, MD, PhD,
School of Population Health, University of Queesnland, AUSTRALIA
Kalervo Vaananen, MD, PhD , Institute of Biomedicine , University of Turku, FINLAND Kenneth Offit, MD, MPH, Klaus A. Kuhn, MD,
Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, USA
Institute of Medical Statistics and Epidemiology, Technische Universität München , GERMANY
Lau Wan Yee Joseph, MD,
Department of Surgery, Chinese University of Hong Kong, HONG KONG
Linda Sofie Lindström, MSc, PhD, Jonas Bergh group Cancer Center Karolinska, Karolinska Institute and University Hospital Stockholm, SWEDEN
M. Kadri Altundag , MD ,
Department of Medical Oncology, Hacettepe University Institute of Oncology, TURKEY
Markus Müller, MD, Deptartment of Clinical Pharmacology, Medical University Vienna, Vienna General Hospital (AKH), AUSTRIA Mary Jane Platt ,
MBBS MPH MD FRCPCH FFPH, Division of Public Health , The University of Liverpool, UNITED KINGDOM
Mark H. Cohen, MD ,
Division of Pediatric Cardiology, Penn State Milton S. Hershey Medical Center, USA
Michael Symonds , PhD, Centre for Reproduction and Early Life, the Institute of Clinical Research, the University of Nottingham, UNITED KINGDOM
Neslihan Dikmenoglu, MD, PhD ,Department of Physiology, Hacettepe University,TURKEY Ozgur Ogut, PhD,
Department of Biochemistry/Molecular Biology , Mayo Clinic, USA
Robert Jan M van Geuns, MD, PhD,
Department of Cardiology, Erasmus University Medical Center, NETHERLANDS
Subhra Mohapatra, PhD, Departments of Medicine, Molecular Medicine and Oncologic Sciences ,University of South Florida– College of Medicine, USA
Sule Cataltepe, MD, Division of Newborn Medicine, Brigham and Women’s Hospital, Harvard Medical School, USA Werner Zimmerli, MD, Unit of Infectious Diseases, Basel University Medical Clinic, SWITZERLAND
Contents Letter from Editor-in-Chiefs
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Ilyas Sahin, Elshad Hasanov Hacettepe University Faculty of Medicine, Turkey
Letter from President
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Tin Knezevic University of Zagreb School of Medicine, Croatia
An Investigation into the Prevalence of Depression Symptoms in Students
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Amy M Whiteford: MBChB (pending), Faculty of Medicine, University of Dundee
Paraneoplastic syndromes as key elements for differential diagnosis. “It’s not always lupus”
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Tanase Timis, Doru Tomesc, Bobe Petrushev, Claudiu Sas, Mihaela Aldea, Ciprian Tomuleasa Department of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
Is it ethical to incentivise sterilisation?
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Edwin Selvaratnam DPMSA Kings College London, Faculty of Medicine, England
Borderline Personality Disorder: an overview on the aetiology and treatment
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Fotios Tsanakalis Department of Psychiatry, Faculty of Medicine, University of Cambridge, Cambridge, United Kingdom
An Overview of Cancer Stem Cells and Chemo-Resistance In Breast, Colon and Prostate Cancer
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Hardip Singh Gendeh1, Susan Anne Watson2, Rajendra Kumari3, Manvin Kaur Gendeh4, Balwant Singh Gendeh5 Faculty of Medicine and Health Science, Medical School, The University of Nottingham, United Kingdom. Division of Pre-Clinical Oncology, University Of Nottingham, United Kingdom. 3 Division of Pre-Clinical Oncology, University of Nottingham, United Kingdom. 4 University Hospital of North Durham, United Kingdom. 5 Department of Otorhinolaryngology Head and Neck Surgery, Medical Faculty, The National University of Malaysia Medical Centre, Malaysia. 1
Letter from Editor-in-Chiefs Dear readers, Since timeliness of publication and the quality of articles were of greatest importance to move forwards toward our goals, we are proud to publish the first issue of this leading student journal for 2011. Thank you to all members of team JEMSA.
to emphasize that giving constructive feedback and encouragement to students is critical in developing an appreciation of their own behaviors and achievements.
Modern medicine is increasingly intertwined with science. Therefore, writing and submission for publication is a great opportunities for students and may pave the way for their future career goals by exposing them to medical research and scientific inquiry early in their training. In addition, it is worth
We always welcome new ideas. Thanks and wish the best for this New Year.
Letter from President Dear Readers, It is my great pleasure to open yet another edition of JEMSA, the Journal of EMSA on Medical and Scientific Affairs! Let us start off with the words of one William Lawrence Bragg: „The important thing in science is not so much to obtain new facts as to discover new ways of thinking about them.“ Several years back, EMSA dared to do what was not done before... To create a students’ medical journal! Today we have a growing tradition and our lasting dedication to contribute to the world of science. The journey we are on may not be an easy one, but it is an exciting one. No one knows the thrill of research until that one moment of clarity when all the pieces of the puzzle start adding up. Since we live in a world where puzzles have become more and more complex it is vital to cooperate, to share and to dedicate onself to growth. This is why EMSA not only fosters the spirit of research, but also one
of cooperation and multidisciplinary thinking. If two heads are better then one, then surely they are even brighter if they think differently. And so, in the spirit of European integration, believeing that diversity is what unites us, we stand determined to reach new horizonts... Together! On behalf of the international board of the European Medical Students’ Association,
Tin Kneževi President of EMSA Europe 2009/2010
Role Models in Medical Education Perspective Andre Madaleno (JEMSA Editor) Trinity College Dublin , IRELAND email:
eaching ethics is a difficult challenge for medical schools. When the urge to produce more doctors at lower costs, rushed curricula and a multicultural student body meets the need for personal reflection, small group learning and a wide variety of personal belief systems it is not surprising that some loose ends remain. This becomes more and more evident as what needs to be taught becomes less and less clear: Values? Attitudes? Communication skills? Character?1 Solving such a complex jigsaw implies finding the best methods to teach medical ethics. Inherent to any curriculum is the need to formalize, rationalize, and assess it: lectures, problem-based learning and written assignments are probably complementary but certainly incomplete ways of education 2 . As Aristotle wrote in the Nicomachean Ethics: “With regard to excellence, it is not enough to know, but we must try to have and use it” 3 . In contrast, the need of students for role models is usually acknowledged but in practice neglected by most medical schools and therefore left to the roulette game of rotations and consultants’ moods and teaching skills. However, a recent Swedish study has suggested that the attitude of medical students to the medical ethics programs themselves is highly related to their experience of role models: good example is linked to an increased interest in ethics and (sadly) vice-versa 4 . This apparently surprising result was really confirmed not discovered. Most people can relate some of their core beliefs and attitudes to a “relevant someo-
ne”: family, friends, etc5. An insight recognized in the original Hippocratic Oath though phrased in a strange and impractical way to our modern ears: “I swear...to consider dear to me, as my parents, him who taught me this art; to live in common with him and, if necessary, to share my goods with him”. However, what makes a physician a role model? It seems straightforward that a talent for teaching, which comes also with experience, and a social savoir-être are some of the factors. Less obvious are other “traits” like the stressing of aspects of the doctor-patient relationship and the psychosocial aspects of medicine in one’s teaching, sometimes linked to an interest in the medical humanities6. Sir William Osler’s statement that “The wider and freer a man’s general education, the better practioner he is likely to be”7 has until now stood the test of association studies but it is erroneous to assume this as a simple fancy for polite conversation rather than a need for students to develop crucial interpersonal skills and a practical mastery of key health psychology concepts8. In a world of deontological demands that seem often daunting, abstract, and contrasting with fastpassed clinical practice and learning, medical ethics is often regarded as too aerial to be meaningful or practical. Example from experienced and able clinicians is often the answer to the question “How should I do this?” and provides the encouragement and reassurance so often needed by medical students and junior doctors alike. Revaluing apprenticeship seems therefore a promising challenge for the future of medical education.
References 1. Mattick K, Bligh J. Teaching and assessing medical ethics: where are we now? J Med Ethics. 2006; 32:181-5 2. Bryan CS, Babelay AM. Building a character: a model for reflective practice. Theor. Med. 1995; 16:281-9 3. Pakaluk M. Aristotle’s Nichomachean Ethics: an Introduction. Chicago University Press. 2001 4. Lynoe N, Löfmark R, Thulesius HO. Teaching medical ethics: what is the impact of role models? Some experiences from Swedish medical schools. J Med Ethics. 2008; 34:315-6 5. Paice E, Heard S, Moss F. How important are role models in making good doctors? BMJ. 2002; 325:707-10
6. Wright SM, Kern DE, Kolodner K, Howard DM, Brancadi FL. Attributes of excellent attending-physician role models. N Eng J Med. 1998; 339:1986-93 7. Osler W, Hirohara S, Niki H. Osler’s “A way of life” and other addresses, with commentary and annotations. Duke University Press. 2001 8. Wershof Schwartz A, Abramson JS, Wojnowich I, Accordino R, Ronan EJ, Rifkin MR. Evaluating the impact of the humanities in medical education. Mt Sinai J Med. 2009; 76: 372-80
A New Opportunity for Scientific Research: EMSA Research Centers Project Erhan Ararat Coordinator of Research Training Fellowships for European Medical Students Onur Arpat Assistant Coordinator of Research Training Fellowships for European Medical Students Hacettepe University Faculty of Medicine, Turkey
Herein, we would like to give some information about Research Centers Project under medical science pillar of EMSA. The goal of our program is to support medical students for improving their research skills during their medical education. Basic science and clinical research are very vital to our decision making in today’s medicine. In order to become a better doctor and keep ourselves updated, as medical students it is necessary to involve in research projects in our areas of interest starting from medical school years. Research Centers Project is quite new with a history of 9 months. We communicate with research group leaders in Europe via email or face to face meetings to find research positions for medical students. It is sometimes boring to find each group leader’s email address and to send e-mails; nevertheless we patiently send e-mails explaining the aim of our effort and request them for lending a hand. Many research centers are interested and we feel great whenever we have a positive response. When a research group leader accepts to support us, we discuss the details about research position such as research project name, beginning time and duration etc.
We announce the research positions in our website with all the details and ask students to apply with their curriculum vitae and a cover letter. The students are chosen according to research group leader’s requirements such as being an MD-PhD student, having an experience with a specific lab technique and being in a certain year of medical school. Also, the timing and duration of student’s stay are important. We really believe that this kind of research opportunity could be a milestone in the scientific career of medical students and important step towards bigger goals. Students are going to be able to work with people who are authors in their areas and will have a chance to get a reference letter from their supervisors if they spend their time efficiently in the lab. For future goals, collaboration list for research centers should be prolonged firstly; new connections with in different countries are needed. We try to figure out the issue of financial support for students. Financial problem shouldn’t be a barrier in front of those future scientists. Now it’s your turn: Visit JEMSA’s web site and apply for the position that you want to involve. This may be a
Women in Surgery: The Beginning of the New Age Caziuc Alexandra (JEMSA Editor) Iuliu Hatieganu University of Medicine and Pharmacy, ROMANIA email:
Women have practiced medicine for many centuries. In the last years their number increased in specialties like internal medicine, pediatrics, family practice or obstetric and gynecology, in contrast with the lack of interest for surgical careers. It is clear that the field of surgery is male dominated, although in medical schools girls are prevailing.
This feeling is charged also by stiffness of the surgical team composed in majority by males and patients’ distrust. Social studies showed that in generally men don’t want to be operated by women, situation demonstrated by the small number of women urologists and the preference for fields like obstetric and gynecology or pediatric surgery.
They are many reasons for this imbalance. Systematizing, we can recognize three main causes for which women avoid this field. 1. The conflict between career and personal life – classically women must bid the stability of home, provide child care and support the career of their husbands. Nowadays this concept is overfulfilled because the society offers so many alternatives for women that desire to build a career and the choices aren’t mutually exclusive. 2. Sexual harassment – unfortunately being a woman in a world dominated by men can bring unsavory scenes. This aspect can’t be blot out, but it is possible to eschew it by adopting a hard-bitten attitude and self-confidence. 3. Prejudice by patients and staff – this is the most important item that discourages women in choosing a surgical career. Surgery is described to be an aggressive, stress-generating and physically exhausting, in total contrariety with the delicacy and gentleness of females. With such ideas, many women might have trouble seeing themselves as surgeons.
The problem of attracting women in surgical careers is multifactorial and it represents the concern of several associations and institutions. For women to bend to surgery it is necessary to assure a friendly, amenable and tolerable environment. Changing mentality of human beings had never been easy but this evolution of concepts is required. A modern view and assuring equal opportunity for both women and men are the keys for providing accuracy in the training of young medical students and residents. Raising the profile of women in surgery and gaining more and more leaderships in the field will serve to highlight the many ways in which women can succeed in the profession and the many benefits they bring to the surgical workforce. Being a woman at this intersection of conflicting ideas can be overwhelming. However the many examples of women that managed to demonstrate that it is possible to reach the top dispel all myths and should encourage us to consider careers in surgery. On my opinion the age of women in surgery is only at the beginning and the next years will bring significant developments.
An Investigation into the Prevalence of Depression Symptoms in Students Review Amy M Whiteford: MBChB (pending), Faculty of Medicine, University of Dundee. email: firstname.lastname@example.org
ABSTR AC T Aims: To determine if the college a student belongs to is associated with variation in the prevalence of depression symptoms and if students showing signs of depression feel adequately supported at university. Methods: An anonymous online questionnaire, composed of the Zung Self Rated Depression Scale (ZDS) and questions on student support, was offered to all students enrolled in the College of Medicine, Dentistry and Nursing (CMDN); or the College of Arts and Social Sciences (CASS) at the University of Dundee in September 2008. Results: 571 students (10.2%) responded. 24.2% of participants from the College of Arts and Social Sciences (24 students) scored over 50 in the ZDS, compared to 13.9% (48 students) from the College of Medicine, Dentistry and Nursing. 18.9% of participants (108 students) made use of student support facilities. This percentage increased in those scoring over 50 in the questionnaire – 25% of these participants (22 students) made use of student support. 34.7% of participants (198 students) said that they would like to see more student support facilities. This increased in those who had scored over 50, with 47.7% (42 students) requesting more support. Conclusion: The college a student belongs to is associated with variation in the prevalence of depression symptoms. The majority of students, even those at high risk of depression, do not make use of student support facilities. Most students feel that current student support is adequate, however many at high risk of depression would like to see more support available. Key Words Depression, students
number of studies have demonstrated a high prevalence of anxiety and depression in medical professionals, including one American study1 which concluded that: “the prevalence of depression among medical students and resident physicians has been shown to be as high as fifteen to thirty percent”, whilst prevalence in the general population was “ten to twenty percent” (2,3). There have also been studies investigating the prevalence of depression in medical students compared to those on other courses (4). One limitation of these studies is that very little information is published on the ‘control group’ i.e. the group of “nonmedical” students, who could be doing medical-allied courses. It would be useful to have a study specifically targeted at students in the College of Medicine, Dentistry and Nursing and at those in a completely different college,
as opposed to a randomly selected group of “non-medical students”, in order to better highlight any differences associated with the type of course studied. It has also been demonstrated that medical professionals are less likely to access support facilities for mental health than their non-medical counterparts (2). The use and availability of student support is not always assessed within studies looking at the prevalence of depression (2,3) so the inclusion of questions on this area would be very informative. The aims of this research are therefore to determine: · If the college is associated with variation in the prevalence of depression symptoms. · If students, particularly those showing symptoms of depression, make use of student support faciliti-
2 JEMSA (Journal of European Medical Students' Association on Medical and Scientific Affairs)
from the College of Arts and Social Sciences (4.2%) and 437 from the College of Medicine, Dentistry and Nursing (17.6%). The breakdown of responses for the College of Medicine, Dentistry and Nursing is shown in Table 1.
Table 1 . Responses for College of M, D
es and if they feel the provision of these facilities is adequate.
An anonymous online questionnaire was selected as the best study design, as this could be completed at the participant’s own convenience and would ensure confidentiality. This meant a self-assessment scale had to be used, which limits the validity of the study, as it cannot diagnose depression. The study therefore aimed only to identify those showing depression symptoms. The study was based upon the Zung Self Rating Depression Scale (ZDS). The final questionnaire (see Appendix 1) incorporated the ZDS5 with questions on the use of student support facilities. There were also a number of questions on student demographics at the start of the questionnaire, to aid assessment of response bias. Participants completed the questionnaire online at their own convenience. Ethics approval from the University Research Ethics Committee was applied for and obtained. Permission was also obtained from the School of Nursing and Midwifery.
Medicine Dentistry and Nursing
Analysis The questionnaires were analysed by converting each response into a value 1-4, with 1 corresponding to ‘A little of the time’, 2 to ‘Some of the time’, 3 to ‘A good part of the Time’ and 4 to ‘Most of the Time’. The total ZDS score for each participant was then calculated by adding together the values for all the questions on depression. Prevalence of depression symptoms was then assessed based upon the number of students on each course scoring 50 or over in either questionnaire, this being the accepted cut-off6 used to detect those at risk of mild depression. SPSS was then used to perform cross-tabulation and Chi-square analysis to determine the significance of the association between the course studied and the score on ZDS. This same analysis was also used to assess the significance between the ZDS score and the use or requirement of student support facilities.
RESULTS Section 1–Variation in the prevalence of depression symptoms. 571 students responded (10.2%), but 4 were excluded for failing to provide all the necessary information. 130
Response Rate (%)
Nursing and Midwifery
There were also differences in the response rates of males and females, as shown in Table 2. Table 2. Response Rates by College and Gender:
Recruitment of Participants In order to compare students in two different colleges, the questionnaire was emailed to all students enrolled in the College of Medicine, Dentistry and Nursing (2482 students); or the College of Arts and Social Sciences (3101 students) at the University of Dundee in September 2008. It was sent out at the beginning of the academic year (September).
Response (no of students)
Arts and Social Sciences No of Male Participants
No of Female Participants
Medicine, Dentistry, Nursing Fisher’s and Exact P Midwifery value Value 77 0.012
Significantly more females compared to males responded from the College of Medicine, Dentistry, Nursing and Midwifery than from the College of Arts and Social Sciences. Eighty-eight students scored 50 or above in the ZDS, this was 15.5% of participants. Table 3 shows the difference in results between the two faculties. Table 3. Participants scoring over 50 in ZDS,
Number of students scoring 50 or above in ZDS
Arts and Social Sciences
Medicine, Dentistry and Nursing
Percentage scoring 50 P or above in Value ZDS (%)
Fisher’s Exact Value
Role Models in Medical Education 3
There was no significant difference between the number of males and females in each college scoring over 50 in the ZDS, as shown in Table 4. Table 4. Comparison of Gender and College in those Scoring over 50 in ZDS:
College Arts and Social Sciences No of Males scoring over 50
No of Females scoring over 50
Medicine, Dentistry, Fisher’s Nursing and Exact Midwifery P value Value
and N: (Endnotes)
Section 2–Use of student support facilities A total of 108 students who responded received some form of student support (18.9%). There was no significant difference in the receipt of student support between students in different faculties – 16% used student support in the College of Medicine, Dentistry and Nursing (70 participants) compared to 23.1% (30 participants) in the College of Arts and Social Sciences (p value 0.1, Fisher’s 0.114). There were, however, differences in the percentage of students receiving student support who scored over 50 in the ZDS and the percentage receiving student support that scored under 50. 25% of participants (22 students) who scored over 50 in the ZDS made use of student support facilities, compared to 17.8% (86 students) that scored over 50 (p value 0.044, Fisher’s 0.048).
Section 3–Adequate provision of student support facilities 34.7% (198 students) of participants felt there was a need for more student support. 35.5% (155 students) of those in the College of Medicine, Dentistry and Nursing wanted more support, compared to 30% (39 students) of those in the College of Arts and Social Sciences. There was no relation between the wish for further student support and the college a student belonged to (p value 0.097, Fisher’s 0.114). Perception of the need for further student support did, however, vary with score in the ZDS. 47.7% of participants (42 students) who scored over 50 in the ZDS expressed a need for more support, compared to 32.3% (156 students) that scored under 50 (p value 0.001, Fisher’s 0.001).
Dıscussion Study Strengths and Limitations The main strength of this study was that it included questions on student support as well as a screening tool for depression. This combination has not always been used in previous studies, but it was key in highlighting that participants most at risk of depression were those least satisfied with the provision of student support. It is also a strength of this project that there was complete anonymity of participants, which should have encouraged responses even in healthcare students, who are known to be reluctant to admit to psychiatric illness (2). This study was also well designed in that the group of ‘non-medical’ students was precisely defined, ensuring that those doing medical-allied courses were not included in the ‘non-medical’ group. This ensured a more accurate comparison to better demonstrate differences associated with the type of course studied. The main limitation of this study is the poor response rate, particularly from students in the College of Arts and Social Sciences. This limits the validity of results, as it is likely that bias will have significantly impacted the results and the particularly low response rate from the college of arts and social sciences may have caused an artificially high prevalence of depression, due to response bias. The response rate was initially poor in both colleges, however it substantially rose in the College of Medicine, Dentistry and Nursing after a reminder email was sent out halfway through the investigation. Unfortunately this strategy could not be used to improve the response rate in the other college. This was because three of the School Secretaries did not agree to distribute the questionnaire at all and because the College Secretary declined to send a reminder email, after having received complaints from students that they should not be expected to complete questionnaires sent out by medical students. This might have been avoided if each individual school secretary had been contacted for permission to send out the questionnaire, rather than just the College Secretary. There should also have been better explanation of the importance of this research to all students in the Participant Information Sheet, so that those in the College of Arts and Social Sciences would not feel it was irrelevant to them. Similar studies have had higher response rates (4862%) when surveys were completed by hand after lectures or exams (1,2). This method was not felt to be appropriate in this case due to the need to maintain confidentiality. The intensely personal nature of the study meant that it was important students completed it willingly and were not intimidated by being asked to complete it in the company of their peers. It would also have been useful to include more questions on the participant, particularly: age, socioeconomic status, past history of psychiatric illness, use
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of medication, drug or alcohol use and social support. An attempt was made to keep the questionnaire short so it could be completed within 15-20 minutes as it was felt that students would be reluctant to complete a more time-consuming questionnaire, and it was considered important to encourage a high response rate. However, in retrospect the above important questions could have been included without a significant increase in time commitment and this would be rectified if the study were repeated.
Variation in the prevalence of depression symptoms There was a significant difference between the percentage of students scoring 50 or over in ZDS from the College of Arts and Social Sciences, and those scoring 50 or over from the College of Medicine, Dentistry and Nursing. This demonstrated that those in the College of Arts and Social Sciences were at greater risk of depression symptoms than medical professionals. This is in contrast to other studies, including a recent systematic review in Canada, which showed medical students to have a higher prevalence of depression symptoms (4,3) One possible explanation of this would be the relationship between stress and depression. It is very difficult to find evidence on the relative stress and workloads of specific courses, making accurate comparison difficult. However, one measure is the entrance requirements for courses, which are based partially on the difficulty of the course. Medicine has an entrance requirement at Dundee of AAABB at SQA Higher; compared to psychology (BBBB), law (AABB or ABBBB) and dentistry (AAAAA). This would suggest that the healthcare-based courses are in general more stressful, which would imply that there should have been a higher prevalence of depressive symptoms in students from the college of medicine, dentistry and nursing. However, it is important to note that this questionnaire was completed at the start of the year. Most students in the College of Medicine, Dentistry and Nursing have no formal assessment until Christmas, so stress levels should be lower at this time. In contrast, the majority of students in the College of Arts and Social Sciences are assessed continually, by coursework and tests, throughout the year on a weekly or monthly basis. This may have given them higher stress levels than their medical counterparts. Stress is associated with depression, which may account for the difference in prevalence. The other likely explanation for the higher prevalence in the College of Arts and Social Sciences is response bias. The response rate for this college was so low; it may be that those who suspected themselves of suffering from depression were more likely to complete the questionnaire. This is less of a factor in the medical, dentistry and nursing students, who probably replied due to a sense
of solidarity with a fellow student researcher. The low response rate from the Arts and Social Science College makes bias very likely as an explanation for the results. It would have been useful to complete this study looking at every college in the university, to better highlight any changes in the prevalence of depressive symptoms that are associated with the college a student attends.
Use of student support facilities There was no real difference between the two colleges in the percentage of students who used support facilities. This is in contrast to previous studies showing that medical professionals are less likely to access support.2 3 This was not shown in this survey of students, suggesting that these attitudes are learnt later in professional life, or that the university has been successful in removing the barriers to healthcare students accessing support. It is also important to note that significantly more students with a ZDS score of 50 or over accessed support than those with a score under 50. This demonstrates that the support system is working effectively, with students accessing it more if they are suffering from symptoms of depression than if they are healthy. However, it is also evident that the vast majority of students scoring highly in the questionnaire did not use student support facilities. This shows that many students in need of support are still not able to access the facilities on offer. This may be due to a need for better advertising of the support available or more opportunities for students to access services and a separate study looking at why students do not access support would be useful.
Adequate provision of student support facilities The majority of students felt that the support facilities currently offered were adequate and did not express a wish for any further help. However, this was not maintained in those who had scored highly in the questionnaire. Those scoring over 50 were significantly more likely to express a belief in the need for more student support than those who had scored less than 50. This is a crucial finding, as it indicates that the students who most need support facilities do not feel there is adequate provision. This would be a strong indicator for universities to extend the provision of student support, so that those in a vulnerable position will feel more satisfied with the help available to them.
Implications In summary, the college a student belongs to is associated with variation in the prevalence of depression symptoms. The vast majority of students, even those at high risk of depression, do not make use of student support facilities. The majority of students feel that current student support services are adequate. However, this is not true of those students at high risk of depression, where many would
Role Models in Medical Education 5
like to see more student support facilities available. A significant number of students who responded were still at high risk of having depression and the type of course they take does seem to have an impact on this. It is important for universities to be aware of this link and to put in place strategies to recognise those suffering from depression. This will allow them to educate students on the symptoms to look out for, so that this condition can be identified and treated early. It is increasingly being recognised that mental health has a significant impact on the wellbeing and performance of students and that medical students are unlikely to access support if distressed.4 Universities both in the UK and abroad5 have begun to recognise the need for student support, however this study demonstrates that most students at risk of mental illness are not accessing support and do not feel the support on offer is adequate. Students place themselves under increased pressure when they try to overcome illness alone and this behaviour may carry over into their working lives, causing problems for the professionals of the future.2 It is therefore crucial that universities recognise the prevalence of mental illness demonstrated in this and other studies9 and take steps to help their students identify and gain help for depression early on.
ACKNOWLEDGEMENTS Thanks are due to Dr Richard K Day (Clinical Senior Lecturer & Honorary Consultant Psychiatrist, Ninewells Hospital, University of Dundee) for the encouragement, advice and substantial help he provided during this research project.
Appendix 1–Questionnaire Each question had a pull-down box beside it to allow easy selection of one of the answers shown in blue. 1) Your Gender Possible answers: Male/Female 2) College Possible answers: College of Medicine, Dentistry and Nursing/ College of Arts and Social Sciences 3) School (if answers College of Arts and Social Sciences) Possible answers: School of Accountancy and Finance/ School of Education, Social Work and Community Education/ School of Humanities/ School of Law/ Postgraduate School of Management and Policy/ School of Psychology/ School of Social and Environmental Sciences/ Other (please specify) 4) School (if answers College of Medicine, Dentistry and Nursing): Possible answers: School of Dentistry/ School of Medicine/ School of Nursing and Midwifery/ Other (please specify) 5) Age Range:
Possible answers: 17-20, 21-25, 26-30, 30+ 6) Year of Study: Possible answers: First/ Second/ Third/ Fourth/ Fourth Intercalated/ Fifth 7) Are you: Possible answers: Postgraduate/ Undergraduate • Possible responses for questions 8-46: None or a little of the time/ Some of the time/ A good part of the time/ Most or all of the time/ Not applicable 8) I feel more nervous and anxious than usual. 9) I feel down-hearted and blue. 10) I feel afraid for no reason at all. 11) Morning is when I feel the best. 12) I get upset easily or feel panicky. 13) I have crying spells or feel like it. 14) I feel like I'm falling apart and going to pieces. 15) I have trouble sleeping at night. 16) I feel that everything is all right and nothing bad will happen. 17) I eat as much as I used to. 18) My arms and legs shake and tremble. 19) I still enjoy sex. 20) I am bothered by headaches, neck and back pains. 21) I notice that I am losing weight. 22) I feel weak and get tired easily. 23) I have trouble with constipation. 24) I feel calm and can sit still easily. 25) My heart beats faster than usual. 26) I get tired for no reason. 27) I am bothered by dizzy spells. 28) My mind is as clear as it used to be. 29) I have fainting spells or feel faint. 30) I find it easy to do the things I used to. 31) I can breathe in and out easily. 32) I am restless and can’t keep still. 33) I get feelings of numbness and tingling in my fingers and toes. 34) I feel hopeful about the future. 35) I am bothered by stomach-aches or indigestion. 36) I am more irritable than usual. 37) I have to empty my bladder often. 38) I find it easy to make decisions. 39) My hands are usually dry and warm. 40) I feel that I am useful and needed. 41) My face gets hot and blushes. 42) My life is pretty full. 43) I fall asleep easily and get a good night's rest. 44) I feel that others would be better off if I were not here. 45) I have nightmares. 46) I still enjoy the things I used to. 47) Do you currently receive any student support? Possible answers: Yes/ No 48) Where do you receive student support from? Possible answers (please tick all that apply): N/A, Per-
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sonal Tutor, Course Tutor, Student Services Counselling Service, Peer Connections, Student Services Health Service, Student Advisory Service, Other – please specify (free text for additional response)
49) Would you like to see more student support? Possible answers: Yes/No 50) What additional student support would you like to see? (Free text box for responses)
References 1. Center C, Davis M, Detre T, Ford D, et al. Confronting depression and suicide in physicians: A consensus statement. JAMA. 2003; 289:3161-3166. 2. Schwenk TL, Leja DW, Gorenflo LM. A survey on the impact of being depressed on the professional status and mental health care of physicians. J Clin Psychiatry. 2008 Apr;69(4):617-20. 3. Tyssen R, Vaglum P, Gronvold NT, Ekeberg O. Suicidal ideation among medical students and young physicians: a nationwide and prospective study of prevalence and predictors. J Affective Disorders. 2001;64:69-79. 4. Vitaliano PP, Maiuro RD, Russo J, Mitchell ES. Medical student distress: a longitudinal study. J Nerv Ment Dis. 1989;177:70-76. 5. Zung WWK. A Self-rating Depression Scale. Arch Gen Psychiatry. 1865;12:63-70. 6. World Health Organisation. Zung depression scale [homepage on the Internet]. No date [cited 2009 Feburary 20]. Available from: http://www.who.int/substance_abuse/ research_tools/zungdepressionscale/en/index.html
7. Singh G, Hankins M, Weinman JA. Does medical school cause health anxiety and worry in medical students? Medical Education. 2004;38:479-481. 8. Kernan WD, Wheat ME, Lerner BA. Linking learning and health: a pilot study of medical students’ perceptions of the academic impact of various health issues. Journal of the Association for Academic Psychiatry. 2008;32:61-64. 9. Dyrbye LN, Thomas MR, Shanafelt TD. Systematic review of depression, anxiety and other indicators of psychological distress among US and Canadian medical students. Academic Medicine. 2006:81(4); 354-373. 10. Plaut SM, Maxwell SA, Seng L, O’Brien JJ, Fairclough GF Jr. Mental health services for medical students: Perceptions of students, student affairs deans and mental health providers. Academic Medicine. 1993;68:260-65. 11. Wong JG, Patil NG, Beh SL, Cheung EP, Wong V, Chan LC, Lieh Mak F. Cultivating psychological well-being in Hong Kong’s future doctors. Med Teach. 2005:27(8);715-9.
Paraneoplastic syndromes as key elements for differential diagnosis. “It’s not always lupus” Review Tanase Timis, Doru Tomesc, Bobe Petrushev, Claudiu Sas, Mihaela Aldea, Ciprian Tomuleasa Department of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania email: email@example.com
ABSTR AC T Paraneoplastic syndromes are remote effects of cancer that are, by definition, caused neither by invasion of the tumor or its metastases nor by infection, ischemia, metabolic and nutritional deficits, surgery or other forms of tumor treatment. The purpose of the current review is to present these challenging elements of differential diagnosis in oncology, as they may represent the main clinical problem in a patient diagnosed with cancer, even though the complete knowledge of both their clinical aspects and pathogenesis remains quite poor. This review focuses on the paraneoplastic syndromes related to dermatology and rheumatology, as these are the most frequent manifestations that might determine a patient to ask for a consult by a general practitioner. Key Words Paraneoplastic syndromes, Differential diagnosis, Cancer
Introduction Paraneoplastic syndromes (PNS) are defined as a group of symptoms and clinical signs that occur in cancer patients and involve system effects that take place remotely from the tumor. These signs are not caused by invasion of the initial tumoral mass or its metastases. Nor by infection, ischemia, metabolic and nutritional deficits, surgery, radiotherapy or any other forms of oncology treatments (1). A paraneoplastic phenomenon usually arises from biologically active substances such as hormones, hormone precursors or hormone-like substances. Also, another mechanisms is the modulation of the immune system via autoimmunity, immune complexes production or immune suppression, or even by still unknown mechanisms (2,3). To recognize a PNS may be clinically crucial for many different reasons, the most important of which being that it can lead to the early diagnosis of a previously undetected neoplasia. It may also dominate the clinical presentation and lead to errors regarding the origin and type of primary cancer, or even follow the clinical course of the underlying tumor. In this way, such symptoms may be useful in monitoring the patient’s evolution, similar
to a neoplastic marker just as prostate specific antigen (PSA) level in prostate adenocarcinoma. An increasing number of reports of paraneoplastic phenomena can be found in the international medical literature over the past few years, as explained by the availability of better diagnostic tools and more effective therapies that by prolonging the survival of patients diagnosed with cancer, may promote the occurrence of neoplastic hormonogensesis. The purpose of the current review is to present some of the main paraneoplastic clinical manifestations, useful to know not only by oncologists but also by general practitioners, because the rapid detection and immediate treatment of the underlying neoplasia may offer the best chance to stabilizing a patients and prevent further deterioration, if not even the chance for a cure.
Dermatology Numerous cutaneous disorders have been associated with an underlying malignancy. In some cases the skin can be directly infiltrated by cancer cells that represent
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a metastatic spread from a internal tumor, such as the Sister Mary Joseph nodule (4). In other cases, skin lessions are related to the underlying presence of neoplasia, but don’t contain malignant cells and are reffered to as paraneoplastic dermatological syndromes. Some of them, such as Muir-Torre, Peutz-Jeghers or CronkhiteCanada syndromes, are inherited and are caused by genetic factors. But others have unknown etiologies and unpredictable expression and prognosis (5). Dermatologists have the advantage of recognizing certain cutaneous signs which may hint at a previously unknown malignancy and from a practical perspective such a skin manifestation has a very important diagnostic value if it is the sole expression of an otherwise asymptomatic carcinoma, leading to prompt diagnosis and treatment. Many familial cancer syndromes have prominent dermatological features and very often the potential for a visceral malignancy is suspected after the skin disease is recognized. One such case is Gardner syndrome, an autonomic dominant disorder characterized by extensive adenomatous polyps of the colon and rectum. These polyps have a very high incidence of oncogenesis and are accompanied by extra colonic cancers, such as thyroid cancer, and also large epidemoid cysts, fibromas, lipomas, leiomyomas, trichoepitheliomas or neurofibromas. This condition, associated with adenomatous polyposis coli tumor suppressor gene, also include clinical features such as osteomas or congenital hypertrophy of the retinal pigment epithelium (6). Peutz-Jeghers syndrome, found to be related to mutations in the STK11/LKB1 gene on chromosome 19q13.3, is characterized by extensive hamartomatous polyps and carcinomas of the gastrointestinal tract, but also pigmented macules found on the lips, nose, buccal mucosa, fingertips and under the nails. But unlike the Gardner syndrome, malignant transformation of the polyps is rare. Cowden disease, also known as multiple hamartoma syndrome, is associated with trichilemmomas on the head, neck or even on the tongue and gingival. These cutaneous signs appear together with fibrocystic disease of the breast, thyroid tumors or endometrial cancer (7,8). The association of visceral carcinoma and numerous both malignant and benign sebaceous gland tumors cand be found in the case of Muir-Torre syndrome (Image 1), considered to be a subset of the hereditary nonpolyposis colon cancer syndrome. In the case of BirtHogg-Dube syndrome, physicians associate skin tags and benign hair follicle tumors that most often appear on the head and neck with a high incidence of chromofobe and oncocytic types of renal or lung carcinoma, as well as spontaneous pneumothorax [ref]. Just like Birt-HoggDube’s disease, a mutation of chromosome 17 also lead to another interesting malignancy: Howel-Evans syndrome (9).
Image 1. Muir-Torre clinical dermatological manifestation
Howel-Evans syndrome, first reported in two English families, describes benign tylosis and a high incidence of esophageal cancer, as well as oral leukoplakia. The thickened skin of the palms and soles develops during childhood, unlike the esophageal tumor that is delayed until middle age, a feature that makes upper digestive endoscopy a very effective screening method. Last, but certainly not least and a very well-known dermatological condition is Neurofibromatosis type 1, known as von Recklinghausen disease. It includes axillary and inguinal freckling, cutaneous neurofibromas, plexiform neuromas and café-au-lait macules. This clinical features are complicated by malignant degeneration of the neurofibromas, multiple Schwann cell tumors, gastrointestinal stromas tumors and even bilateral pheochromocytomas (Images 2,3). Genetic conditions may also include less frequent diseases, as poikiloderma congenitale, ataxia-teleangiectasia syndrome, Wiskott-Aldrich syndrome or Bloom syndrome, known for their inherited immunodeficiency (10,11). Acanthosis nigricans is defined as a local, hyperkeratotic symmetric discoloration and verrucous lesions rarely involving the oral mucosa. These lesions are most often located on the face, albows, axilla, knees and intermammary area, but also around the anus and two forms are distinguisehd (Image 4). These forms may be benign, congenital or acquired as a result of endocronopathies, erythema nodosum or nicotinic urogastrone, or maligant, associated with cancer of various organs. Such cancers inlcude adenocarcinomas of the abdominal cavity, thiroid, breast, esophagus or even sarcomas (12,13). Acanthosis nigricans is also associated with other pareneoplastic conditions, such as Leser-Trelat symptom, paraneoplastic pemfigus or necrolytic migratory erythema. Ulysse Trelat was the first to propose that multiple seborrheic keratoses are associated with visceral malignancies (14,15).
Paraneoplastic syndromes as key elements for differential diagnosis. “It’s not always lupus” 9
Appart from less common PNS, such as CronkhiteCanada syndrome or paraneoplastic hypertrichosis lanuginosa acquisita, a special attential must be given to Bazex syndrome. This disease, also known as acrokeratosis paraneoplastica, is actually a dermatosis characterized by acral psoriasiform lesions, characteritically seen in men and most commonly associated with squamous cell carcinoma of the upper aerodigestive tract or metastases to the cervical region (16).
Images 2, 3. von Recklinghausen’s disease, a syndrome known for over one hundred years.
Image 4. Acanthosis nigricans, on the neck of a patient diagnosed with small-cell lung cancer.
It describes a sudden increase in the sumber or size of these multiple seborrheic keratoses, while no evidence of dermatitis or erythroderma procede the features with pruritus as a leading symptoms in most cases.
The musculoskeletal system can be affected by direct invasion of the primary tumor, metastasis, synovial reaction to juxtaarticular masses and also indirectly, by the effects of a distant tumor. This later reffered to as a paraneoplastic syndrome in rheumatology, is thought to be the result of humoral mechanisms, the diagnosis of which being challenging in the absence of known malignancy. Finger clubbing, a sign that involves distal phalanx thickening and nail convexity frequently allows the identification of a severe organic disease. Hypertrophic osteoarthropathy is a clinical syndrome that clubbing of both fingers and toes, joint pain and swelling and also extremity enlargement. Primary hypertrophy osteoarthropathy, also known as pachydermoperiostosis, is a rare genetic disease but secondary pachydermoperiostosis is cited as hypertrophy pulmonary osteoarthropathy and is associated with lung disease, such as lung adenocarcinoma (17,18). Carcinomatous polyarthritis is another PNS frequently associated with pulmonary cancers. The differential diagnosis is broad and includes infectious diseases (i.e. Lyme disease or chlamydia), crystal-induced arthropathy, reactive arthritis, autoimmune diseases (i.e. systemic lupus erythematosus or rheumatic fever), or even connective tissue dissorders or spondyloarthridies (19,20). As carcinomatous polyarthritis is a diagnosis of exclusion, it lacks the other systemic manifestations that characterize these disorders, such as neurological involvement, mucocutaneous lesions, claudicating, Raynaud’s phenomenum, renal involvement or gastrointestinal complains. It also laks the association with antibodies such as anti-nuclear antibody (ANA), antidouble stranded DNA (anti-dsDNA), anti-Smith or anticentromere (21). Determiningwhether musculoskeletal symptoms are caused by a rheumatic disease or a malignancy is complex and intriguing. A special attention must be given to polymyalgia rheumatica. This is a clinical syndrome characterized by pain and stiffness in the neck, shoulders and hips, fatigue, wight loss and low-grade fewer (22). Nevertheless, is rarely presented as a PNS manifestation, unlike the asociation of cancer and vasculitis. Just like other paraneoplastic syndromes, cutaneous vasculitis can be the consequence of infections,
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The mechanism involved is linked to autoimmunity, that may arise in the setting of a result of immune responses to mutated forms of self-antigens generated in nascent cancer cells. This will subsequently lead to the targeting of wild-type forms of the proteins in non-transformed cells (27). Athogh tantalizing, to prove this theory of paraneoplasia is difficult and requires the identification of myositis-specific antigens (MSA)-specific T cells capable of lysing tumor targets both in patients with myositis and in those with related neoplasia who do not develop myositis. It is also important to determine whether anti-MSA immunity develops over time in the setting of tumorigenesis in large prospective population-based studies (28). Image 5. Henoch-Schönlein’s purpura
Conclusion hypersensitivity, rheumatic and autoimmune diseases. Vasculitides associated with malignancy are mainly cutaneous leukocytoclastic vasculitis, polyarteritis nodosa, Churg-Strauss syndrome, microscopic polyangiitis, Wegener’s granulomatosis and HenochSchönlein purpura (23) (Image 5). Cutaneous manifestations of paraneoplastic vasculitis are polymorphic and non-specific, involving papules, nodules, bullae, purpura, ulcerations and necrotic lesions, unlike articular or other systemic manifestations that are more rarely observed. Usually, paraneoplastic vasculitis fails to respond to treatment with prednisone and improves with effective treatment of canecr. In addition, recurrence of such signs often occur with progression or metastases of cancer. A interesting systemic vasculitis is HonechSchonlein purpura, involving the small vessels of the skin, gastrointestinal tract and glomeration, as well as arthralgia or arthritis. Its main histopathology features are leukocytoclastic vasculitis mainly in pappilar dermis with haematoxylin-eosin staining. It also includes vascular deposits of immunoglobulin A and complement 3 with direct immunofluorescence (24). It should be said that hematological malignancies are three to five times more common than solid tumors when talking about paraneoplastic vasculitis (25), with path physiology mechanisms including decreased immune complex clearance or abnormal production of antibodies and tumor neoantigens leading to the formation of immune complexes that deposit within the blood complexes. It also includes similarities between tumor antigens and endothelial cell antigens, deregulated lymphocytes that cause a switch from IgM to IgA isotypes and aberrant inflammatory cytokines produced either by malignant tumor cells or through the tumor microenvironment (26). Cancer is detected in approximately one third of dermatomyositis in 15% of poliomyelitis, with over half of tumors diagnosed after the initial diagnsosis of sympathy, out of which the majority within one year time difference.
At the time of presentation of the skin or joint symptoms, most patients have not yet been diagnosed with cancer and the detection of paraneoplastic signs can help diagnose the obvious syndrome and may direct the search for an underlying neoplasm. On the other hand, in a patient known to have cancer, the presentation of a PNS may herald recurrence of the tumor or of second tumor, after metastatic complications have already been ruled out. The rapid detection and immediate treatment of the cancer so often appears to offer the ebst chance of stabilizing the patient and prevent further deterioration. Thus, as the American College of Rheumatology suggests, a skin or musculoskeletal manifestation does not always direct to the most obvious diagnosis such as systemic lupus erythematosus. Sometimes a more thorough analysis is required, a analysis that might represent the difference between life and death in some cases.
Ackbowledgements All authors contributed equally to the present manuscript. The authors also acknowledge the insightfull and critical reviews of Assistant Professor Gabriel Kacso, MD, PhD (Department of Medical Oncology at the Iuliu Hatieganu University of Medicine and Pharmacy in Cluj Napoca, Romania) and of Ali Garcia, MD (Department of Internal Medicine/Rheumatology at the Johns Hopkins University School of Medicine in Baltimore, MD, United States of America).
Paraneoplastic syndromes as key elements for differential diagnosis. “It’s not always lupus” 11
References 1. Toro C, Rinaldo A, Silver CE, Politi M, Ferlito A. Paraneoplastic syndromes in patients with nasopharyngeal cancer. Auris Nasus Larynx 2009; 36(5):5130520. 2. Vinet E, Tangri N, Pineau CA. Not arthritis. Lancet 2007; 370(9600):1736. 3. Kurzrock R, Cohen PR. Erythema gyratum repens. JAMA 1995; 273(7):594. 4. Liu CY, Yong CC, Wu SC, Lin CY, Chen CL, Wang CC. Sister Mary Joseph’s nodule associated with hepatocellular carcinoma. Surgery 2010; 147(1):167-168. 5. Lee A. Skin manifestations of systemic disease. Aust Fam Physician 2009; 38(7):498-505. 6. Garder’s syndrome (familial adenomatous polyposis): a ciliarelated disorder. Lancet Oncol 2009; 10(7):727-735. 7. Jasperson KW, Tuohy TM, Neklason DW, Burt RW. Hereditary and familial colon. Gastroenterology 2010; 138(6):2044-2058. 8. Oliveira MA, Medina JB, Xavier FC, Magalhaes M, Ortega KL. Cowden syndrome. Dermatol Online J 2010; 16(1):7. 9. Shalin SC, Lyle S, Calonje E, Lazar AJ. Sebaceous neoplasia and the Muir-Torre syndrome: important connections with clinical implications. Histopathology 2010; 56(1):133-147. 10. Zografos GN, Vasiliadis GK, Zagouri F, et al. Pheochromocytoma associated with neurofibromatosis type 1: concepts and current trends. World J Surg Oncol 2010; 8:14. 11. German J. Bloom’s syndrome. Dermatol Clin 1995; 13(1):7-18. 12. Dourmishev LA, Draganov PV. Paraneoplastic dermatological manifestations of gastrointestinal malignancies. World J Gastroenterol 2009; 15(35):4372-4379. 13. Yoshino N, Yamagishi S, Kubokura H, et al. Mediastinal lymph node metastasis of lung cancer with an unknown primary lesion having concurrent endocrine abnormality and acanthosis nigricans: report of a case. Ann Thorac Cardiovasc Surg 2009; 15:397-400. 14. Denuce M. A symptom of malignancy (symptom of Trelat’s noevi) applicable to the deep tumours of the abdomen and pelvis. Revue des maladies cancereuses (Paris) 1899; 5:146-156. 15. Bolke E, Gerber PA, Peiper M, et al. Leser-Trelat sign presenting in a patient with ovarian cancer: a case report. J Med Case Reports 2009; 3:8583. 16. Torrelo A, Sprecher E, Mediero IG, Bergman R, Zambrano A. What syndrome is this? Bazex-Dupre-Christol syndrome. Pediatr Dermatol 2006; 23(3):286-290. 17. Kittisupamongkol W. Digital clubbing. Eur J Intern Med 2009; 20(1):e20.
18. Makis W, Abikhzer G, Rush C. Hypertrophic pulmonary osteoarthropathy diagnosed by FDG PET-CT in a patient with lung adenocarcinoma. Clin Nucl Med 2009; 34(9):625-627. 19. Stummvoll GH, Aringer M, Machold KP, et al. Cancer polyarthritis resembling rheumatoid arthritis as a first sign of hidden neoplasm. Scand J Rheumatol 2001; 30:40-44. 20. Hatem SF, Petersilge CA, Park JK. Musculoskeletal case of the day. Metastatic carcinomatous arthritis from mutinous adenocarcinoma of the colon. AJR Am J Roentgenol 1997; 169(1):286. 21. Farhey Y, Luggen M. Seropositive, symmetric polyarthritis in a patient with poorly differentiated lung carcinoma: carcinomatous polyarthritis, hypertrophic osteoarthropathy, or rheumatoid arthritis? Arthritis Care Res 1998; 11(2):146-149. 22. Sahin M, Alanoglu G, Aksu O, Tunc SE, Kapuguoglu N, Yener M. Hodgkin’s lymphoma initially presenting with polymialgic symptoms: a case report. Mod Rheumatol 2007; 17:160-162. 23. Solans-Laque R, Bosch-Gil JA, Perez-Bocanegra C, SelvaO’Callaghan A, Simeon-Aznar CP, Vilardell-Tarres M. Paraneoplastic vasculitis in patients with solid tumors: report of 15 cases. J Rheumatol 2008; 35:294-304. 24. Pertuiset E, Liote F, Launay-Russ E, Kemiche F, CerfPayrastre I, Checneau AM. Adult Henoch-Schonlein purpura associated with malignancy. Semin Arthritis Rheum 2000; 29:360-367. 25. Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med 1997; 337:1512-1523. 26. Birchmore D, Sweeney C, Choudhury D, Konwinski MF, Carnevale K, D’Agati V. IgA multiple myeloma presenting as Henoch-Schonlein purpura/polyarteritis nodosa overlap syndrome. Arthritis Rheum 1996; 39:698-703. 27. Dourmishev LA, Popov JM, Rusinova D. Paraneoplastic dermatomyositis associated with testicular cancer: a case report and literature review. Acta Dermatoven 2010; 19(1):3943. 28. Engelhorn ME, Guevara-Patino JA, Noffz G, et al. Autoimmunity and tumor immunity induced by immune responses to mutations in self. Nat Med 2006; 12:198-206.
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Is it ethical to incentivise sterilisation? Review Edwin Selvaratnam DPMSA Kings College London, Faculty of Medicine, England
ABSTR AC T Project Prevention is an organisation founded in 1997 with the express purpose of “offering cash incentives to women and men addicted to drugs and/or alcohol to use long term or permanent birth control.” (1) To date it has paid money out to 3,388 ‘clients’ who have agreed to a range of contraception’s. This discussion will focus on the 1307 individuals who have had permanent sterilisation, it aims to focus on the act of incentivising people to have the intervention as oppose to consequences of the intervention itself. The framework for Project Prevention is to give selected women the option of having some form of contraception (long-term or permanent) with an incentive of $300 to undergo the procedure. The women are selected based on how many pregnancies they have had before, how many miscarriages they have had and how long they are considered to be drug addicts. One of the core issues in our discussion is whether the individuals being sterilised have had the opportunity for a fair and honest decision? How, if at all, has the monetary incentives affected this process and to what end can this effect be considered ethical? Personal financial incentives are increasingly being used to motivate patients and general populations to change their behaviour, most often as part of schemes aimed at reducing rates of obesity, smoking, and other addictive behaviours (7). For drug addicts can autonomy exist and be utilised on a decision based on the procurement of drugs? Is it ethical to incentivise sterilisation? The decision making process that participants of incentivised sterilisation have to make is fraught with conflict and dilemmas. How at a glance it appears Project Prevention is simply making an alternative available, in reality the influence exercised by the offer is manipulative, coercive and exploitative, exerted on vulnerable, easily motivated individuals with relatively little to gain other than an opportunity to satiate their drug addiction. The activities of the organisation Project Prevention whilst altruistic in intent leaves many questions unanswered. It crosses a very tangible threshold and could very well be the distinct line that moves us towards a less tolerant society. Key Words Incentivise, sterilisations, Project Prevention, capacity, autonomy, coercion, consent
Is it ethical to incentivise sterilisations? Project Prevention is an organisation founded in 1997 with the express purpose of “offering cash incentives to women and men addicted to drugs and/or alcohol to use long term or permanent birth control.” (1) To date it has paid money out to 3,388 ‘clients’ who have agreed to a range of contraception’s. 1,059 have chosen DepoProvera, 1,260 Tubal Ligation, 873 IUD, 111 Implanon, 38 Norplant, and 47 Vasectomies. The organisation offers $300 with the aim of reducing unwanted pregnancies, miscarriages, children born with addictions and what it
defines as a dramatic effect on the foster care system. In the last two years the organisation has grown both in size and influence and has begun activity in Maui, Hawaii and the UK. The framework for Project Prevention is to give selected women the option of having some form of contraception (long-term or permanent) with an incentive of $300 to undergo the procedure. The women are selected based on how many pregnancies they have had before, how many miscarriages they have had and
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how long they are considered to be drug addicts. Project Prevention is quick to declare that all of the women who have had permanent sterilisation have had children before. Sterilisation is an increasingly popular method of contraception, it is considered quick and easy to perform, permanent and relatively free of undesirable side-effects, very reliable and unobtrusive during sexual activity. The activity of Project Prevention raises a number of philosophical and ethical dilemmas. We will attempt to explore the fragile decision making process that the selfdescribed drug addicts have at their disposable. How it responds to outside influence and whether that can be considered ethical despite any perceived altruistic intent. This discussion will focus on the 1307 individuals who have had permanent sterilisation, it aims to focus on the act of incentivising people to have the intervention as oppose to consequences of the intervention itself. Some of this discussion will focus on quotes and statements from Barbara Harris [Founder of Project Prevention]; this is not an attack on her personal ideology. It should be noted that Project Prevention has paid women to have sterilisation in all 50 states in America and has markedly increased activity in Maui, Hawaii and the UK. Since its inception it has not needed to raise money, funds have come via private donations and some openly from the political far right. Her influence is not trivial and her opinions have been treated accordingly.
The decision making process One of the core issues in our discussion is whether the individuals being sterilised have had the opportunity for a fair and honest decision? Have they gone through a process of weighing up the alternatives and chosen the option that best reflects their wishes? How, if at all, has the monetary incentives affected this process and to what end can this effect be considered ethical? A decision making process is loaded with hurdles and conditions and require many stipulations before it can be considered as independent and based on his or her preferences, desires, values and ideals. The diagram below is an interpretation of the decisionmaking process. In reality the steps are often more fluid and dynamic; some decisions need not require all the processes whilst others would stop at a point before a decision can be made. Capacity
Capacity & individuals with a drug addiction The individuals who fit the criteria for entry into Project Prevention are men and women who are known drug addicts. The vast majority of participants are women who
are typically of the lowest socio-economic class. They have had multiple pregnancies some of which end in miscarriage, children born with disability and the majority going into the foster care system. Project Prevention does not propose a structured guideline for participant criteria, there is no screening process. Do the individual have the capacity to make an autonomous decision? The 1307 people who have been sterilised as part of their involvement with Project Prevention are all drug users who have either had multiple pregnancies or fathered numerous children. These children -some of whom do not survive infancy- go into the foster care system. Do the participants have the capacity to make the significant decision to be sterilised? Capacity can be defined as “…the ability to understand treatment-related information, to appreciate the significance of this information, to exercise reasoning in comparing the treatment in question with other alternatives or no treatment, and finally to express a choice coming out of this process” (4). Can the label of possessing capacity be a blanket statement and refer to all aspects of an individual’s life? An alcoholic certainly does not possess the capacity when deciding if he should accept another drink from a generous bartender. However few would argue that this label of lack of capacity can be extended to the rest of the individuals’ life. It is acknowledged that an autonomous individual can (and often do) make irrational decisions. For example, there are people who risk their lives in the pursuit of an ‘adrenaline rush’, many would consider this behaviour irrational but some could quite easily rationalise it. In practice we often respect a person’s autonomy even though they are not utilising their decision-making capacity. “A person is not to be treated as unable to make a decision merely because s/he makes an unwise decision” (Mental Capacity Act 2005). What is clear is that “…the capacity to decide autonomously, rather than the actual content of any decision, should form the basis of any respect for individuality” (9). Having said this there are occasions where autonomy is rescinded. “The mental Capacity Act (2005) provides a legal framework for decision-making on behalf of an adult who lack the capacity to make specific decisions for themselves” (Department of health). One could argue that the decision making capacity of the 1307 that have been sterilised are clearly reduced in relation to the drug taking practices. They have a physiological and psychological addiction that overrides any other rationale and leaves them dictated by their drive to satiate their addiction. We find ourselves asking the question, if someone can so effortlessly change their decision or action based on one additional facet; do they have the capacity to make that decision? For example an individual has a
Paraneoplastic syndromes as key elements for differential diagnosis. “It’s not always lupus” 15
career defining presentation to give. They incidentally find alcohol in their home on the day of the presentation and proceed to drink heavily despite the consequences. As a result they perform badly in the presentation and their career suffers as a consequence. Does this situation constitute the suggestion that they lack capacity? And perhaps more importantly does this perceived limitation in the individual make them vulnerable to external influence? One could argue that these individuals are susceptible to influence, regardless of its altruistic nature, or otherwise.
Autonomy & individuals with a drug addiction Proponents of voluntary sterilisation often use autonomy as a defence. The individual has made an autonomous decision and given consent, we are merely facilitating this; “…making the option available”. Autonomy is a philosophical view about morality that is shared by moral philosophers as divergent as Kant, Kierkegaard, Nietzsche, Royce, Hare, Popper, Sartre and Wolff. Autonomy also plays a key role in current normative philosophical work. John Rawls makes clear that a central feature in the notion of autonomy is that a certain ideal of a person is the cornerstone of his moral edifice. As Kant argues, moral autonomy is a combination of freedom and responsibility; it is a submission to laws that one has made for oneself. “The autonomous man, insofar as he is autonomous, is not subject to the will of another” (13). Personal financial incentives are increasingly being used to motivate patients and general populations to change their behaviour, most often as part of schemes aimed at reducing rates of obesity, smoking, and other addictive behaviours (7). What needs to be addressed is the relationship between remuneration and desire to undertake an objective. [Within the confines of this discussion, desirability is defined as the drive to do something in light of the all the consequences, including any external influence or remuneration]. We would expect, for most cases, there to be a linear relationship between the extent of remuneration and the desirability for an individual to complete a task. This is
all that can be said with any confidence. The gradient of the graph; the sum of remuneration required to move from undesirable to desirable would vary from person to person. This would depend on the individuals; personality, life experiences, current situation and numerous others. We would also expect people to be more ‘pliable’ to external influence dependant on what type remuneration was involved. Naturally many decisions require no external remuneration. What is the relationship between successfully incentivising an action in relation to how desirable it was without any incentive? At what point is the disparity no longer morally justifiable? In practice there are occasions where patients do not want to take a drug or undergo a procedure. This alone cannot be an argument against incentives in medicine. Much of what health professionals do is about convincing and persuading people having all kinds of illness to do something. Persuasion, based on the consequences of an individual’s actions is an integral tool for a clinician and aids in reaching a critical threshold to where an active decision is made. Remuneration is crucially different from persuasion, they can be considered as points on a spectrum but a tangible line has been crossed. We have moved from using consequences to external positives to influence a decision.
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A number of terms have been used to describe the process with which patients receive remuneration or the remuneration itself. For the benefit of clarity the terms are defined below. Reward: To repay, requite, or recompense (a person) for some service, merit, etc. Incentive: Having the quality of inciting or arousing to feeling or action; provocative, exciting. Leverage: Advantage for accomplishing a purpose; increased power of action. Inducement: The action of inducing or moving by persuasion or influence. Bribery: Paying people to act against their wishes Exploitation: The action of turning to account for selfish purposes, using for one’s own profit. Coercion: Constraint, restraint, compulsion; the application of force to control the action of a voluntary agent. Whilst the specific order of the terms on the spectrum can be debated, the general trend down would not be considered welcome. Perhaps the terms ‘spectrum of influence’ is appropriate at this point. It could be reasoned that; · The larger the disparity between ‘desirability without external remuneration’ and ‘successfully incentivising an action’. The further along the spectrum the external influence can be characterised as. (In a situation where all persuasion has been exhausted). · The smaller the gradient (i.e. little remuneration for a relatively larger change in desirability) the more manipulative the external influence can be characterised as having. · If the external influence gleams more or the same benefit from the decision than the incentivised, one could claim there was a component of exploitation. It is worth at this point, to attempt to differentiate autonomy with freedom (liberty). Freedom can be defined as “the ability of a person to do what he wishes and to have significant options that are not closed or made less eligible by the actions of other agents”. “If for example, a doctor forces a Jehovah’s Witness to have a blood transfusion against his will, this is a direct interference with the liberty of the patient. But because this is also clearly a denial of the patient’s autonomy, understood as a power if self-determination, the thought arises that autonomy at liberty are not the same” (5). Some have suggested that “…inducing offers and threats are simply interventions that change what a person wants to do and hence these do not diminish one’s freedom” (11). Whilst others maintain; successful systems of rewards and coercion already exist in healthcare (4). Although people may be free to deny such tactics, they still incur the consequences if they reject the offer. It can be considered that incentives [regardless at which
point on the spectrum they are on] reduce one’s ‘internal freedom’, which is described as the ability to control one’s destiny by using internal decision-making machinery (9). Inducements make choosing to be sterilised increasingly more likely than without the aid of external influences. Many would argue, at this point, that our lives are strewn with eternal pressures that influence our morals and decisions and any belief to the contrary is naïve at best, they propose that an individual does not create his own moral law. “We are born into a given environment with a given set of biological endowments. We mature more slowly than other animals and are deeply influenced by parents, siblings, peers, culture, class, climate, schools, accident, genes and the accumulated history of the species it makes no more sense to suppose we invent the moral law for ourselves than to suppose that we invent the language we speak for ourselves” (5). Receiving a salary for example, can be construed as an incentive. In fact using the definitions above one could argue that a salary could be a line placed anywhere on the graph. Perhaps it is not the disparity between ‘desirability without external remuneration’ and ‘successfully incentivising an action’ that should be our concern, but if the individual’s decision remains a reflection of their morals.
Consent & individuals with a drug addiction There exists opportunities to influence the decision making process; both in terms of capacity and autonomy. We have discussed whether individuals with an addiction have areas where either capacity does not exist or it is not being utilised. Does this varying degree of capacity constitute a label of ‘lack of capacity’ which would be perceived globally for the individual? For drug addicts can autonomy exist and be utilised on a decision based on the procurement of drugs? In an interview Barbara Harris [Founder of Project Prevention] was asked what the money given to participants were used for. Her reply was “Drugs, they all use them to get on their next high.” With this in mind we can tentatively say that whilst the headlines about Project Prevention are “Money for drug users to be sterilised” it could be suggested as ‘Drugs for drug users to be sterilised’. In Switzerland there are researchers who carry out studies into the effectiveness of heroin prescription as a way of treating long-term addicts who are not responding to other forms of treatment (10). The researchers need to recruit heroin addicts with the intent of giving them free heroin over a period of several months. The recruits in turn need to give consent to take part in the study. This study has caused huge controversy and sparked debate; some suggest we should assume that such addicts are incompetent to consent to such trials unless proven otherwise (3). While others suggest that participants of the trial, whilst having a strong desires for drugs, still
Paraneoplastic syndromes as key elements for differential diagnosis. “It’s not always lupus” 17
retain their ability to make decisions and can competently give consent. A study was tasked with interviewing participants of study in Switzerland and similar research studies, it’s objective was to understand the offer in terms of the participants and explore their decision making process. “Cynthia (one of the participants in the study), who when asked if someone addicted to heroin could voluntarily consent to take part in research where free heroin would be on offer replied, ‘That’s crazy, if you’re addicted to heroin, then by definition you can’t say ‘No’ to the stuff’” (3). This statement gives us insight into a number of issues. How influential is the offer to participants? She suggests that she and others would say yes regardless of any perceived benefit to herself or others. So we find ourselves asking the question; can we as external agents judge what is ethical to offer people? Shows a hypothetical situation where the benefits of an action (A) are balanced by the risks and negative consequences (B). (A) Can be split into in component parts; any personal benefits obtained by participation (Ai), any benefit obtained to society as a whole (may not necessarily be a component of the individuals decision making process) (Aii), and procurement of drugs (X). (B) Can be split into in its component parts, involvement of study as a risk to the individual (Bi) and procurement of drugs as a risk to the individual (Bii). If the participant (like Cynthia) has no option but to give consent to the study then; no other benefits have a component in the decision making process. And arguable more importantly is that no foreseeable risks would be considered a factor either. Does the situation described in, where the drive for a specific outcome takes precedent on any and perhaps all other consequences, demand intervention? Can this individual give competent consent? “For a decision to be voluntary it looks as if the decision has to be made by the person themselves; but if the addict really is compelled to act by his/her addiction then it is hard to see his/her action as being really her own” (12). Some have characterised this type involvement as undue influence. It is defined as “occurring through an
offer of an excessive, unwarranted, inappropriate or improper reward or other overture in order to obtain compliance. Also, inducements that would ordinarily be acceptable may become undue influences if the subject is especially vulnerable” (2). What does not show is the participants desire to not receive drugs. There are no doubt certain individuals have this desire, how moral can the offer be if this is a component in their decision making process? It should be noted that the study in Switzerland does not include those who are currently in withdrawal or under the immediate influence of drugs. Whether this in itself qualifies their actions is beyond the scope of the discussion. But it does beg the question; what is the state of the participants in Project Prevention? Does the varying degree of addiction swing the incentive along the spectrum? If $300; equates to a certain amount of drugs (Y). It would be sensible to expect the intrinsic value of Y to vary with the addiction. Is there a particular point in their addiction process where the remuneration goes from being an incentive to bribery and exploitation? Or is this a moot point and the mere fact that an external influence is introduced make this action immoral? The candidates for exceptions to informed consent can be grouped under the headings of emergency, incompetence, waiver and therapeutic privilege. (8) Can the participants be characterised as being incompetent in relation to giving consent in this matter? If they fall into the category of an exception to informed consent, how then can their consent be valid?
Decisions & individuals with a drug addiction Project Prevention is unusual in that it does not attempt to rationalise its actions solely for the benefit of the participants. In fact very little of effort has been made to promote it in this way. “Her [Project Prevention participant] life would be better because she wouldn’t have to go through any more heartache” (Project Prevention). If an ‘incentive’ can guarantee consent, is any term on the ‘spectrum of influence’ appropriate? Could it be argued that no real decision has taken place at all? Can we suggest that a participant in Project Prevention has gone through the decision making process, or has the
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offer of money, (which has been implied as wholly to procure drugs) simply forced the decision in favour of the external agent. Is it ethical to incentivise sterilisation? This discussion is unable to provide an answer but has explored a number of dilemmas. The introduction of an incentive influences the decision making process at every stage. The offer made by Project Prevention to drug user’s calls into question their capacity; I would find it difficult to expect them to retain it. Particularly bearing in mind the very direct relationship between the money they are awarded and their drug use. The participants have an addiction, both physiologically and psychologically, which overrides any other intention and leaves them dictated to by their drive to satiate their addiction. Regardless of the ‘altruistic’ intent of the organisation the offer highlights their vulnerability to external influences. There is little doubt in my mind that the participant’s autonomy is influenced by the incentive. The disparity between ‘desirability without external remuneration’ and ‘successfully incentivising an action’ calls into question how ethical the incentive is. In fact I would perhaps go further and suggest; even if the participant is indifferent regarding the sterilisation itself the fact remain that the surgery carries with it an innate risk of harm. Not only does an incentive reduce ones freedom in this case it also increases their risk to harm.
Can we judge what is ethical to offer people? That quite naturally depends on the situation of the individual; an offer of a chocolate after a child has studied would be different then offering a diabetic insulin in exchange for a task. The latter would be exploitative not just because the external agent achieves more out of the exchange, but the diabetic has little alternative but to accept. If the participant has no option but to give consent then no other benefits or risks have a component in the decision making process. It should be considered that involvement or lack thereof, in the preceding events that lead the drug users into their current state of affairs has little bearing on what constitutes coercion in the situation now. The decision making process that participants of incentivised sterilisation have to make is fraught with conflict and dilemmas. How at a glance it appears Project Prevention is simply making an alternative available, in reality the influence exercised by the offer is manipulative, coercive and exploitative, exerted on vulnerable, easily motivated individuals with relatively little to gain other than an opportunity to satiate their drug addiction. The activities of the organisation Project Prevention whilst altruistic in intent leaves many questions unanswered. It crosses a very tangible threshold and could very well be the distinct line that moves us towards a less tolerant society
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Borderline Personality Disorder: an overview on the aetiology and treatment Review Fotios Tsanakalis Department of Psychiatry, Faculty of Medicine, University of Cambridge, Cambridge, United Kingdom email: firstname.lastname@example.org
ABSTR AC T Borderline Personality Disorder (BPD) is one of the most controversial psychiatric conditions, historically considered to be on the border between neuroses and psychoses. Affected individuals are characterized by instability of mood and interpersonal relationships, marked impulsivity and self-destructive behaviour. Borderline Personality Disorder is associated with poor response to pharmaceutical and psychotherapeutic treatments and unfavorable prognosis and thus it constitutes a therapeutic challenge for mental health workers. Its aetiology is multifactorial, including neurobiological, early developmental and psychosocial factors. The contribution of biological factors has been gaining ground, as sophisticated neuroimaging methods make the study of the neuronal brain circuits and neurotransmitters more approachable. Reduced serotoninergic activity in orbital prefrontal and cingulate cortex, along with hyperactivity of hypothalamic pituitary adrenal axis, and genetic variations in genes related with neurotransmission are suggested to be of significant importance. Genetic effects explain 35 to 45% of the variance in borderline personality disorder and borderline personality features. Disturbed interpersonal relationships, sexual or physical abuse during childhood, deranged family environment and neglect are present in the majority of borderline patients. The normal attachment processes are disturbed and the borderline patients appear to be fixated at Mahlerâ€™s separation-individuation phase, constantly reexperiencing the anxiety caused by their separation from their caregivers. The understanding of gene-gene and gene-environment interactions constitutes the most promising new field in the study of BPD. The treatment of Borderline Personality Disorder consists of psychopharmacological and psychotherapeutic approaches. Psychodynamic, cognitive-behavioural and supportive therapies along with selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics and mood stabilizers, constitute potential therapeutic approaches. Abbreviations: BPD, borderline personality disorder; HPA, hypothalamic pituitary adrenal axis; 5-HT1A, serotonin 1A receptor; 5-HT1B, serotonin 1B receptor; 5-HT2A, serotonin 2A receptor; 5-HT2C, serotonin 2C receptor; MAOA, monoamine oxidase A; OR, odds ratio; TPH2, tryptophan hydroxylase 2; 5-HTT, serotonin transporter gene; COMT, Catechol-O-methyltransferase; 5-HTTLPR, serotonintransporter-linked promoter region. Key Words Borderline Personality Disorder, aetiology, treatment, neurobiology, theories
Introduction Personality Disorders are defined as â€œenduring patterns of inner experience and behaviour that deviate markedly from the expectations of the culture of the individual who exhibits themâ€?. They are characterized by persistent patterns of behaviour that are rigid and pervasive and that emerge in late adolescence or early adulthood (1).
Borderline Personality Disorder (BPD) is one of the most severe, pervasive and perplexing behavioural disturbances with high rates of morbidity and mortality. The diagnosis of BPD is based on criteria established by the American Psychiatric Association (Table 1). BPD affects from 1.2% to almost 6% of the general population in the US, approximately 10% of those who
Borderline Personality Disorder: an overview on the aetiology and treatment 21
Table 1. Diagnostic Criteria for Borderline Personality Disorder
A pervasive pattern of instability of interpersonal relationships, self-image, and affects and marked impulsivity beginning by early adulthood and present in a variety of contexts as indicated by five (or more) of the following: •
Frantic efforts to avoid real or imagined abandonment
A pattern of unstable and intense interpersonal relationships characterized by alternating between extremes of idealization and devaluation
Identity disturbance markedly and persistently unstable self-image or sense of self
Impulsivity in at least two areas that are potentially self-damaging (e.g., spending, sex, substance abuse, reckless driving, binge eating)
Recurrent suicidal behaviour, gestures, or threats, or self-mutilating behaviour
Affective instability due to a marked reactivity of mood (e.g., intense episodic dysphoria, irritability, or anxiety usually lasting a few hours and only rarely more than a few days)
Chronic feelings of emptiness
Inappropriate, intense anger or difficulty controlling anger (e.g., frequent displays of temper, constant anger, recurrent physical fights)
Transient, stress-related paranoid ideation or severe dissociative symptoms
seek outpatient services, and as many as 20% of those who undergo inpatient treatment (2). In addition, up to 10% of those who meet criteria for BPD commit suicide, 50 times that observed in the general population (1). Moreover, 69% to 75% of borderline patients engage in self-harming behaviours while the frequency of selfinjury is higher than any other psychiatric diagnosis (3). Borderline Personality Disorder is associated with considerable social disability, stigma and family burden. Therefore, a better understanding of its precursors in the general population is necessary, in order to identify the prone individuals and prevent the development of illness early in childhood, through appropriate parenting and prompt interventions by medical professionals. The aim of this work is to summarize the prevalent theories regarding the aetiology of Borderline Personality Disorder, with focus on the therapeutic approaches for disease prevention and symptom control.
Neurobiological Factors Certain cardinal characteristics of the Borderline Personality Disorder, such as impulsivity, irritability, hypersensitivity to stimulation, emotional instability, reactivity, and intensity, have all been associated with a biological foundation (4). Studies indicate that several neurotransmitter systems, including serotonin-, dopamine-, vasopressin-, acetylcholine-, noradrenaline-, and GABA-ergic systems may be involved (5). Studies with twin adopted children have demonstrated that impulsive aggression, one of the main features of BPD, is heritable and it has been correlated with biological indices associated with serotoninergic
activity. Neuroimaging studies in patients with BPD revealed reduced serotoninergic responsiveness of key cortical areas associated with inhibition of aggression. These areas are mainly located in orbital frontal cortex, ventral medial prefrontal cortex and cingulate cortex, which control the limbic release of aggression (5). The observed dysfunctions in the neurotransmitter systems are in parallel with structural changes in certain regions of the brain. Voxel-based morphometry (VBM) studies have demonstrated decreased gray matter volume in BPD, compared with healthy controls, in ventral cingulate gyrus and several regions of the medial temportal cortex, including hippocampus, amygdala, parahippocampal gyrus and uncus (Figure 1 and 2). A matter of significant interest is that a difference has been shown between the male and female patients with Borderline Personality Disorder; decreased gray matter volume in medial temporal cortex was mostly observed to female patients especially those with a history of childhood abuse, while male, but not female, patients were found to have diminished gray matter volume in anterior cingulate compared to controls (6). Research on other neurotransmitter systems is still at an early stage. A significant association was found between genetic variations of the dopamine receptor transporter (DAT1) gene and certain traits of borderline patients. DAT1 participates in the reuptake of dopamine from the synaptic cleft. Abnormalities resulting in hyperdopaminergic functioning have been related to the psychotic features of BPD, while abnormalities causing hypodopaminergic states were associated with impulsivity. Nevertheless, the exact mechanism of
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dopamine dysfunction (hypo versus hyperfunctioning) remains unresolved and the results from different research groups are contradictory (5). In addition to the abnormalities in the key cortical regions mentioned above, the hypothalamic pituitary adrenal axis (HPA) also seems to be disturbed in BPD patients (7, 8). In fact, patients with BPD who have had a history of recurrent trauma in childhood tend to have hyperactive HPA axis, which underlies a very rapid transition from inhibition and planning to the reflex of fight-or-flight. Neurologically, this transition is explained by a switch from prefrontal inhibitory to posterior-limbic affective processing (8). In practice, the main impact of this transition in borderline patients is that their executive neurocognitive abilities might be severely affected, as relatively low levels of emotional stress can lead them into a fight-or-flight physiological and emotional state. In addition to the compromise in the executive neurocognitive capacities, chronic HPA hyperactivity affects the episodic and semantic memory encoding, possibly because of dendritic cell atrophy in the hippocampus (9). Cognitive inhibition impairment in borderline patients may be a strong predictor of suicidal or parasuicidal behaviour, as suicidal tendency has been significantly associated with deficits in neurocognitive functions (10).
Genetic Transmıssıon, Gene-Gene And GeneEnvironment Interactions Genetic research is currently being undertaken in order to determine the extent to which the genetic background of the individual and the cultural and environmental influences each participate in the development of BPD. Family studies and classical twin studies indicate that genetic effects account for 35 to 45% of the variance in borderline personality disorder and borderline personality features (11). BPD features have been found to be genetic in origin but only partially transmitted from parents to offspring because dominant genetic effects influence borderline personality only in combination with other genes which are not shared by parents and children. This means that there is an additive genetic effect that can explain 0 to 34% of variance in borderline traits. The respective percentage for dominant genetic effects is 11 to 35% (11) A number of serotonin-related genes, such as the genes of tryptophan hydroxylase, serotonin transporter, 5-HT1a receptor, 5-HT1b receptor and 5-HT2a receptor, have been studied to explain the reduced serotoninergic activity in the key cortical regions associated with BPD. The results were promising and certain alleles such as the “S” allele of the gene encoding the serotonin transporter and the “L” allele of the gene encoding the enzyme tryptophan hydroxylase have been associated with certain features of borderline patients, like impulsivity,
aggression and suicidal behaviour (12). Research on gene-gene and gene-environment interactions seems to be the most challenging field in the study of BPD. Analysis of gene-gene interactions is a promising area of particular significance for elucidating the molecular mechanisms of complex human diseases. Recent studies have revealed significant gene-gene interactions within the serotonin system in susceptibility to BPD. In particular, gene interactions between 5-HT2C and TPH2 and among 5-HT2C, 5-HTT, MAOA and TPH2 have been discovered (13). Moreover, a significant association between the COMT Met158 and the 5-HTTLPR S allele might play a role in the susceptibility to the disease. Borderline patients carrying the 5-HTTLPR S allele displayed an over-representation of the low-activity COMT Met158 allele compared to healthy controls, resulting in ORs (Odds ratios) of 1.84 and 3.63 (one or two COMTMet158 alleles, respectively). COMT (Catechol-O-methyl-transferase) is the enzyme which metabolizes epinephrine, norepinephrine and dopamine. The COMT gene contains a functional Val158Met single nucleotide polymorphism (SNP) in exon 4 with a codominant effect (14). The Met158 allele has only 25–33% of the activity of the enzyme containing the Val158 allele. The Val158Met polymorphism appears to have pleiotropic effects (it influences multiple phenotypic traits) on human behaviour and various mental functions (15). The Met158 allele has been found associated with higher aggression in schizophrenic patients, violence of suicide attempts and outwardly directed anger in suicide attempters (16). Regarding the gene-environment interactions, it has been shown that 54.9% of variance in borderline personality was explained by unique environmental influences such as sexual and physical abuse, parental divorce and parental psychopathology. The genes determine the extent to which an individual is prone to a specific environment. In the presence of geneenvironment interaction, individuals with a predisposed genotype will be more susceptible to develop BPD if an undesirable environment is present, than individuals with non-predisposed genotype. (11) Moreover, in a research aiming to identify specific environmental influences that moderate the genetic and environmental influences on BPD features, it was found that sexual assault is the only factor that has such a major effect that even in less genetically predisposed individuals, it is associated with more BPD features. (17)
Early Developmental Factors Disrupted interpersonal relationships in childhood have been described as a significant risk factor for the development of Borderline Personality (18). Disturbed attachments in an early stage of development have been suggested to be the core of BPD’s psychopathology (19).
Borderline Personality Disorder: an overview on the aetiology and treatment 23
According to the seminal developmental theory of John Bowlby, infants develop behavioural patterns such as proximity seeking, smiling and clinging, which result in caretaking behaviour by the adults, and this constitutes the basis of attachment, that is an affective bond between the infant and the caregiver. The aim of attachment is the development of an external environment through which the infant develops an internal image of the self and others (20-22). These primary attachment models are reflected in any other relationship in the future. When the normal process of attachment is not disturbed, the child develops a positive, stable self-image and a sense of deserving to be loved, along with the general premise that the people surrounding him/her accept him/her and respond to his/ hers needs. It has been proposed that the infant develops a secure attachment if his/hers caregivers have a good ability to think about their own minds and those of others. In that case, the child is also able to consider what lies in the mind of his/hers caregivers. However, borderline individuals have generally great difficulty in recognizing their caregivers’ thoughts and emotions, and this acts as a defense mechanism which protects them from facing hostility or malevolent thoughts towards them. This mechanism could explain many of the central symptoms of BPD, including instability of self-image, impulsivity and chronic feelings of emptiness (23, 24). It has also been suggested that the intolerance of aloneness of the patients with BPD reflects unstable and insecure attachments in an early stage of their development, which hinder their ability to perform a “soothing introjection” in periods of distress and agony. In Freudian terms, introjection is the aspect of the ego’s system of relational mechanisms which handles checks and balances from a perspective external to what one normally considers ‘oneself’, infolding these inputs into the internal world of the self-definitions, where they can be weighed and balanced against one’s various senses of externality. A common pathological type of attachment in patients with BPD is the preoccupied attachment, in which individuals pursue close, intimate relationships but are very reactive to their perceived dependency or undervaluation (19). This type of attachment has also been described by Meyer as the prototypic borderline form of attachment which is characterized by ambivalent and erratic feelings in close relationships. According to Kernberg, patients with BPD are fixated at Mahler’s separation-individuation phase, specifically in the rapprochement sub-phase, which happens in children between 16 to 30 months old. In this phase, the children start to realize the limits of their omnipotence and develop a new awareness of their separation from the caregiver. They exhibit in the same time a need for autonomy and a need for support from the caregiver which is reflected by behaviors such as pushing away while whining and
clinging. Throughout their lives, the patients with BPD are constantly reexperiencing the overwhelming separation anxiety, which might explain why they cannot tolerate to be alone for long (4).
Psychosocial Factors and Sexual Trauma Adverse events related to a deranged family environment during childhood, such as separation from parents, growing up in foster homes, adoption, domestic violence, lack of care, neglect, physical, emotional and sexual abuse have been significantly associated to the development of Borderline Personality Disorder (25). The most common of them in patients with BPD is sexual abuse which is present in 4071% of inpatients (25). The severity of the sexual abuse has been linked to the severity of the borderline manifestations. Ongoing sexual abuse during childhood was related to more severe borderline symptoms, including parasuicidal behaviour, chronic hopelessness, paranoia and regression in therapy. It has been suggested that continuous sexual abuse hinders the child’s ability to develop safe attachments. Children therefore believe that the people around them are not safe and that they are only interested in gratifying themselves, and this leads them to believe in “a malevolent object world” (4).The high rates of sexual abuse have led some researchers to believe that BPD could be a form of chronic Post-Traumatic Stress Disorder (26). Nevertheless, although sexual trauma is common among borderline patients, there is no evidence that it is either necessary or sufficient factor for the development of this disorder (25). In addition, it should be taken into account that false abuse memories may arise during psychotherapy or that abuse histories of borderline patients may be products of confabulation (27). The socio-cultural environment, in terms of social integration has also been recognized by some authors as an indirect influence to the development of BPD. According to Paris, individuals who are raised in an integrated society are protected from developing borderline traits, whereas those who grow up in a disintegrated society are more prone to develop such traits (28). The social disintegration, the prevalence of extended family and the diminution of the role of traditional institutions such as church and school may also form part of the aetiology of BPD (4).
Psychopharmacological Approach The treatment of patients with borderline personality disorder should focus on four different dimensions of symptoms: affective dysregulation, impulsive-behavioural dyscontrol, cognitive-perceptual symptoms and anxietyinhibition symptoms (29,30). A wide range of agents have so far been used to alleviate these multi-dimensional symptoms, including antidepressants, atypical antipsychotics and mood stabilizers.
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Benzodiazepines are not very useful in BPD and carry some danger of abuse (31). Selective serotonin reuptake inhibitors (SSRIs) constitute the anti-depressant treatment of choice, as they are effective in the management of impulsivity, and at the same time they have a high therapeutic index, which is essential in the case of an attempted suicide caused by overdose. Fluoxetine has been associated with an early response and improvement of impulsive symptoms, while sertraline has been found to decrease the parasuicidal and self-harm behaviour after treatment for a year. Paroxetine seems to cause a more significant decrease in self-injury. Fluvoxamine and citalopram have also been found to be effective in some individuals. It should be underlined that the potential inefficacy of one SSRI does not preclude the efficacy of another (32). Atypical antipsychotic treatment in lower doses than those used in psychoses was found to reduce self-harm and impulsive behaviours, aggressiveness and hostility towards the family environment. Olanzapine, risperidone, and in very serious cases clozapine have been associated with an improvement of psychosocial functioning (3335). Quetiapine has been found to improve executive functioning and it is also effective in the treatment of impulsivity and affective symptoms in patients with BPD (36,37). Aripiprazole, another atypical antipsychotic drug, was found to strengthen anger management in borderline patients. Aripiprazole is a safe and well-tolerated agent, which dramatically decreases the propensity to direct anger outward and inward, and at the same time treats the aggression component of borderline personality disorder (38,39). Concerning the adverse effects of atypical antipsychotics, clozapine presents a serious risk of blood dyscrasia and particularly neutropenia and agranulocytosis. The incidence of extrapyramidal symptoms differs among the different drugs, with risperidone being associated with the highest incidence and clozapine with the lowest incidence. Aripirazole has been related to headaches, insomnia and anxiety (30). Mood stabilizers have been used to control the emotional instability of borderline patients and to strengthen the antidepressant effect of SSRIs. Lithium is not a first choice treatment because of its toxicity profile, although it is effective in treating the affective dysregulation. Anti-convulsive drugs, including primarily valproic acid but also topiramate, oxcarbamazepine and lamotrigine, have demonstrated great efficacy in the treatment of irritability, anxiety, anger and emotional instability. Valproic acid is especially recommended in the case of co-morbidity with bipolar I disorder, while topiramate is recommended in co-morbid bulimia nervosa (32, 40). Valproic acid causes dose-related adverse effects, such as gastrointestinal dysfunction (nausea), mild transaminase elevations, tremor, sedation and weight gain (30).
Psychotherapeutic Approach Three main psychotherapeutic approaches are used for the management of patients with BPD: psychodynamic, cognitive-behavioural and supportive therapies. Psychodynamic therapies are based on the theory that unconscious conflicts which are troubling the patient are responsible for the borderline symptoms (41, 42). The cognitive-behavioural therapies attempt to detect maladaptive patterns of behaviour and help the patient control his emotions and strengthen his identity (43, 44). Supportive therapies include education, sympathetic listening, encouragement, advice and validation (45, 46). There is no particularly strong evidence that one treatment is better than the other and patients with BPD can be responsive at a variety of treatments. The main areas to which psychotherapeutic treatments have proven to be consistently effective are self-mutilation and suicide attempts (42). The major limitations of such treatments are that they are intensive, long in duration and that they require special training for the therapist (42). In general, psychotherapy, individual and in group, becomes the dominant intervention for BPD, with such goals as psychic integration, skills training, and the fostering of long-range ambitions relating to friendships, partner choice, and work (41).
Conclusion Although the exact aetiology of Borderline Personality Disorder still remains unknown, research has so far identified a multitude of factors that appear to be implicated in its aetiology. Pharmacological treatment and psychotherapy seem to be effective in alleviating symptoms. More studies on BPD are definitely required for the development of evidence-based approaches, regarding treatment, early identification and prevention of this debilitating and enigmatic disorder.
Acknowledgements I would like to thank Dr. Arnob Chakraborti for his invaluable support and guidance during my rotation in the early intervention for psychosis unit (CAMEO) in Ida Darwin Site, Fulbourn, Cambridge during August 2009.
Borderline Personality Disorder: an overview on the aetiology and treatment 25
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polymorphism on the cognitive stability and aggression in the first-onset schizophrenic patients. Neuroreport 2006; 17: 95–99. 17. Distel MA, Middeldorp CM, Trull TJ, Derom CA, Willemsen G, Boomsma DI. Life events and borderline personality features: the influence of gene-environment interaction and geneenvironment correlation. Psychol Med 2010 (ahead of print). 18. Gunderson JG. The borderline patient’s intolerance of aloneness: Insecure attachments and therapist availability. A J Psychiatry 1996; 153: 752–758. 19. Agrawal HR, Gunderson J, Holmes BM, Lyons-Ruth K. Attachment studies with borderline patients: A review. Harv Rev Psychiatry 2004; 12: 94–104. 20. Bowlby J. Attachment and loss. Vol. I: Attachment. New York: Basic Books, 1969. 21. Bowlby J. Attachment and loss. Vol. II: Separation: anxiety and anger. New York: Basic Books, 1973. 22. Bowlby J. Attachment and loss. Vol. III: Sadness and depression. New York: Basic Books, 1980. 23. Fonagy P, Steele M, Steele H, Leigh T, Kennedy R, Matoon G et al. Attachment, the reflective self, and borderline states: the predictive specificity of the Adult Attachment Interview and pathological emotional development. In: Goldberg S, Muir R, Kerr J (eds). Attachment theory: social, developmental, and clinical perspectives.New York: Analytic, 1995: 233–278. Hillsdale, NJ: Analytic Press 24. Fonagy P, Leigh T, Steele M, Steele H, Kennedy R, Mattoon G et al. The relation of attachment status, psychiatric classification, and response to psychotherapy. J Consult Clin Psychol 1996; 64: 22–31. 25. Lieb K, Zanarini MC, Schmahl C, Linehan MM, Bohus M. Borderline Personality Disorder. Lancet 2004; 364: 453–61. 26. Gunderson JG, Sabo AN. The phenomenological and conceptual interface between borderline personality disorder and PTSD. Am J Psychiatry 1993; 150: 19– 27. 27. Frankel FH. Adult reconstruction of childhood events in the multiple personality literature. Am J Psychiatry 1993; 150: 954–958. 28. Paris J. The etiology of borderline personality disorder: A biopsychosocial approach. Psychiatry 1994; 57: 316–325. 29. Siever LJ, Davis KL. A psychobiological perspective on the personality disorders. Am J Psychiatry 1991; 148: 1647-58. 30. Bellino S, Paradiso E, Bogetto F. Efficacy and tolerability of pharmacotherapies for borderline personality disorder. CNS drugs 2008; 22(8): 671-92. 31. Soloff P. Psychopharmacological treatment of borderline personality disorder. Psychiatr Clin North Am 2000; 23:16992. 32. Díaz-Marsá M, González Bardanca S, Tajima K, GarcíaAlbea J, Navas M, Carrasco JL. Psychopharmacological treatment in borderline personality disorder. Actas Esp Psiquiatr 2008; 36: 39-49.
26â€ƒ JEMSA (Journal of European Medical Students' Association on Medical and Scientific Affairs) 33. Bogenschutz MP, Nurnberg GH. Olanzapine versus placebo in the treatment of BPD. J Clin Psychiatry 2004; 65: 104-9. 34. Chengappa KNR, Ebeling T, Kang JS. Clozapine reduces severe self-mutilation and aggression in psychotic patients with BPD. J Clin Psychiatry 1999; 60: 477-84. 35. Rocca P, Marchiaro L, Cocuzza E. Treatment of BPD with risperidone. J Clin Psychiatry 2002; 63: 241-4. 36. Van den Eynde F, De Saedeleer S, Naudts K, Day J, Vogels C, van Heeringen C, Audenaert K. Quetiapine treatment and improved cognitive functioning in borderline personality disorder. Hum Psychopharmacol 2009;24(8):646-9. 37. Van den Eynde F, Senturk V, Naudts K, Vogels C, Bernagie K, Thas O, van Heeringen C, Audenaert K. Efficacy of quetiapine for impulsivity and affective symptoms in borderline personality disorder. J Clin Psychopharmacol. 2008; 28(2): 147-55. 38. Mobascher A, Mobascher J, Schlemper V, Winterer G, Malevani J. Aripiprazole pharmacotherapy of borderline personality disorder. Pharmacopsychiatry 2006; 39(3): 111-2. 39. Nickel MK, Muehlbacher M, Nickel C, Kettler C, Pedrosa Gil F, Bachler E, Buschmann W, Rother N, Fartacek R, Egger C, Anvar J, Rother WK, Loew TH, Kaplan P. Aripiprazole in the treatment of patients with borderline personality disorder: a double-blind, placebo-controlled study. Am J Psychiatry. 2006; 163: 833-8. 40. Zanarini MC. Update on pharmacotherapy of BPD. Curr Psychiatry Rep 2004; 6: 66-70. 41. Stone MH. Management of borderline personality disorder: a review of psychotherapeutic approaches. World Psychiatry 2006; 5: 15-20. 42. Zanarini MC. Psychotherapy of borderline personality disorder. Acta Psychiatr Scand. 2009; 120(5): 373-7. 43. Linehan MM, Armstrong HE, Suarez A. Cognitive-behavioral treatment of chronically parasuicidal borderline patients. Arch Gen Psychiatry 1991; 48: 1060-4. 44. Clarkin JF, Yeomans FE, Kernberg OF. Psychotherapy for borderline personality. New York: Wiley, 1999. 45. Rockland LH. Supportive therapy: a psychodynamic approach. New York: Basic Books, 1989. 46. Aviram RB, Hellerstein DJ, Gerson J, Stanley B. Adapting supportive psychotherapy for individuals with Borderline personality disorder who self-injure or attempt suicide. J Psychiatr Prac 2004; 10(3): 145-55.
An Overview of Cancer Stem Cells and ChemoResistance In Breast, Colon And Prostate Cancer Review Hardip Singh Gendeh1, Susan Anne Watson2, Rajendra Kumari3, Manvin Kaur Gendeh4, Balwant Singh Gendeh5 Faculty of Medicine and Health Science, Medical School, The University of Nottingham, United Kingdom. Division of Pre-Clinical Oncology, University Of Nottingham, United Kingdom. 3 Division of Pre-Clinical Oncology, University of Nottingham, United Kingdom. 4 University Hospital of North Durham, United Kingdom. 5 Department of Otorhinolaryngology Head and Neck Surgery, Medical Faculty, The National University of Malaysia Medical Centre, Malaysia. 1
ABSTR AC T In 2007, prostate cancer and breast cancer had the highest incidence for males and females respectively, and colon cancer the most commonly diagnosed after lung cancer. Recently, these common cancers have been associated with the presence of Cancer Stem Cells (CSC). Based on the CSC theory, tumours consist of a small population of highly tumorigenic cancer cells surrounded by a larger proportion of non-tumorigenic proliferative cancer cells. These highly tumorigenic cancer cells share similar properties to normal human stem cells and termed CSCs. They have shown to express specific cell surface markers (i.e. CD 44 and CD24 for breast cancer, CD133 for colon cancer and CD44 for prostate cancer) and are associated with the initiation, progression, metastasis and chemo-resistance of breast, prostate and colon cancer. CSCs are resistant to conventional chemotherapy. Hence, CSCs could be targeted specifically via the expression of a panel of cell surface markers, besides improving the treatment outcome and prognosis for cancer patients.
Key Words Cancer Stem Cells, chemo-resistance, breast, colon, prostrate
Introduction Breast, prostate and colorectal cancers are prevailing cancers in the United Kingdom, where 38 048, 30 201 and 30 727 new cases were discovered respectively in the year 2007 (1) . Breast, prostate and colorectal cancers contributed a significant 8%, 6% and 10% mortality respectively, of the 156 723 total deaths due to cancer in the year 2008 (1).
The discovery of CSCs has brought a paradigm shift to cancer research and it has been the core of many international laboratories and clinical based cancer research. It has earned its position in cancer research as CSCs may have provided many answers to unknown questions in the past. The contribution of progressing research in its field does provide good promises for the future.
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It has been widely hypothesized that CSCs that are present in breast prostate and colon cancers are highly tumorigenic and are involved in the development of chemoresistance and metastasis to secondary sites. The aim of this article is to provide an update about the recent advances of breast, prostate and colon cancers in relation to CSCs, further understand the patho-physiology of CSCs and discover new treatment modalities that specifically target these killer cells. Before we deluge into the details, it is essential that we understand the relationship between the functional properties of normal and malignant human stem cells.
Stem Cells The first stem cell discovered was the human embryonic stem cell, well known for its existence in an undifferentiated form, its ability to undergo mitosis to form clone daughter cells and its pluripotency to form highly differentiated and/ or specialized cells of different organs. Progenitors, transit cells or transit amplifying cells are the intermediate states prior to forming a highly differentiated daughter cell (2). Stem cells and transit amplifying cells differ in their ability to proliferate and remain undifferentiated for a given period of time (3). Stem cells often undergo asymmetrical differentiation producing one daughter cell, that is genetically and functionally similar to itself and another daughter cell that forms the transit amplifying cell (4). This enables the maintenance of the stem cell population and its function, besides ensuring that the genetic properties of the stem cells are retained. Transit amplifying cells on the other hand form a highly specialized population, important in cell proliferation during growth and cell replacement. This is supported by studies on haematopoietic stem cells
(HSC) with subsequent discovery of two subgroups of primitive haematopoietic cells. The first being progenitor cells that are capable of short term reconstitution, while the later are HSC with the ability of self renewal. Besides, stem cells may be more susceptible to genetic mutations due to their longer life span and self renewing properties (3,5). Therefore, it should be logically be true that stem cells tend to accumulate mutations over time as compared to normal somatic cells.
Cancer Stem Cell Theory Tumours contain a heterogeneous population of cells, which was initially reported in liquid tumours. The cancer stem cell theory is supported by studies on leukemic patients as they possess a highly clonigenic subpopulation of leukemic cells in acute myelogenous leukemia as shown when grown in non-obese diabetic/severe combined immunodeficient (NOD/SCID) immunocompromised mice (3). This cancer stem cell theory is believed also to be applicable to solid tumours (6). It was shown that breast cancer cells consist of heterogeneous cells that expressed different cell surface markers with different tumour initiating abilities. This is supported by recent studies indicating that tumours mainly consist of a small proportion of highly tumorigenic cancer cells known as cancer-initiating cells (3), surrounded by a larger proportion of non-tumorigenic proliferative cancer cells. These tumorigenic cells have the capacity to divide and form more similar tumorigenic cells as well as nontumorigenic cells (6) that form cancer proliferative cells (Figure 1 and 2). Thus, the tumorigenic cells have similar characteristics to normal stem cells in terms of the ability to undergo extensive proliferation, produce a reduced nonproliferative heterogeneous cell population, capable of self-
Figure 1. Highly tumorigenic CSC undergoing asymmetrical cell division to give rise to more cells of its own kind and cancer proliferating cells, ultimately increasing the heterogeneity of the tumour. (Adapted from Ricci-Vitiani et al., 20085)
Borderline Personality Disorder: an overview on the aetiology and treatmentâ€ƒ 29
Figure 3. a) A schematic diagram of CD44 receptor molecule whereby the extracellular distal domain is involved in the binding with hyaluronan; b) alternative splicing of CD44 exons (Adapted from Coradini et al., 200440)
renewal via regenerating to maintain their population and ultimately ensure their continued survival (4). Therefore, these highly tumorigenic cells share the same properties as normal human stem cells, awarding them with the name cancer stem cells (CSC). In summary, there are two main activities that have lead to the formation of CSC. Firstly, normal stem cells lying dormant for a period of time could have accumulated oncogenic mutations, altering the mechanisms of cell expansion giving rise to a tumour. Alternatively, oncogenic mutations occuring in transit amplifying cells stimulate their proliferation to form tomurigenic cells without entering the post-mitotic differentiated states (3). These situations are highly plausible as cancer cells would have to arise from a dividing cell population. Therefore, CSC could be derived directly or indirectly from a human stem cell via transit amplifying cells.
Tumour Development Two models of cancer development have been suggested (5). In the stochastic model, it is assumed that every cell contributing to the tumour bulk has the capacity
to regenerate and proliferate. Hence, various cells with different functional and/or phenotypic characteristics will have the same tumour initiating capacity. On the contrary, the CSC model suggests that only a small population of tumour cells have the ability to initiate growth, regenerate and proliferate as described extensively in the CSC theory above. Therefore, it may be possible to isolate a small population of tumour initiating cells by exploiting the presence of cell surface markers.
Experimental Evidence of Cscs In Breast Cancer The term human cell differentiating (CD) molecule was introduced based on the observation of the clustering of antibodies that showed similar patterns of binding to leucocytes (7) and has been widely used for other cellsurface markers. CD44 is a hyaluronate cell surface receptor involved in cellular attachment to ligands and the extracellular matrix (8) and is expressed by lymphocytes (Figure 3). CD24 is a glycosyl phosphatidylinositol linked membranous siaglycoprotein mainly expressed by
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B cells and granulocytes (9). Breast cancer cells are heterogeneous in terms of the expression of a number of cell surface markers i.e. CD44, CD24 and B38.1 (6). AlHajj et al., 2003 discovered that NOD/SCID mice injected with CD44+ cell and CD24-/low breast cancer cells (Figure 4), suggested to represent the CSC phenotype, resulted in visible and palpable tumours after 12 weeks with a 10 to 50 fold increase in likelihood to form a tumour, unlike the CD44+ and CD24+ cells (6). The highly tumorigenic role of CSCs makes them susceptible to metastasis and the development of tumours at secondary sites. Balic
et al., 2006 showed for the first time that disseminated breast tumour cells at secondary tumour sites expressed the CD44+/CD24-/low phenotype, the same as that found among breast CSC at primary tumour sites (10). Besides, breast cancer cells with CD44+/CD24- phenotype have increased expression of genes involved in invasion into epithelial surfaces resulting in the cells having enhanced invasive ability (11) providing evidence that CSCs are involved in the metastasis of cancer. Ginestier et al., 2007 demonstrated that increased expression of aldehyde dehydrogenase (ALDH1) enzyme is a common marker
Figure 4. Flow Cytometry of human breast cancer cells tested for tumorigenicity in NOD/SCID mice. T1 (b) and T3 (c) had been passaged (P) once in NOD/SCID mice, whereas the rest of the cells were frozen or unfrozen samples obtained directly after removal from a patient (UP). Each plot depicts the CD24 and CD44 staining patterns of live human Lineageâˆ’ cancer cells, and the frequency of the boxed tumorigenic cancer population as a percentage of cancer cells in each specimen is shown. (Adapted from Al-Hajj et al., 20036)
Borderline Personality Disorder: an overview on the aetiology and treatmentâ€ƒ 31
for both normal and malignant breast cancer stem cells and is associated with the highly tumourigenic CD44+/ CD24-/lin- phenotype and poorer prognosis (12). Moreover a recent study by Ginestier et al., 2010 discovered that cells expressing ALDH1 also had an over-expression of CXCR1, an interleukin-8 (IL8) receptor (13). Hence, CXCR1 blockade resulted in the apoptosis of the breast tumour and reduction in metastasis. It was suggested that the blockade of CXCR1 in CXCR1+ cells that only contributed to 1% of the tumour population, resulted in CXCR1- cell death via a bystander effect.
Experimental Evidence of CSCs in COLON CANCER CD133 or Prominin-1 is another putative cancer stem cell marker which was expressed on mouse neuro-epithelial stem cells (14). Its surface antigen is now established as a human hematopoietic (15) and neural (16), plus colon cancer stem cell marker. Ricci-Vitiani et al., 2007 reported that colon cancer initiating cells consist of CD133+ cell surface markers that are present on a small population of normal colon cells (17). In contrast, cells with no CD133 expression have shown to be non-tumorgenic (14). Recently it was also discovered that colon cancer cells, also expressing CD44 surface markers have enhanced stem cells properties and are able to generate tumours (18). CD44+ cells from colon tumour cells had enhanced tumorigenicity unlike CD133+ cells (19). However, CD133+ colonic tumour initiating cells that are involved in tumorigenesis are believed to undergo down regulation to form CD133- cells (20). Instead, these CD133- cells are metastasized and initiate tumour growth at secondary metastatic sites (20). CD44 down regulation in colon cancer cell lines affected tumorigenicity to a greater extent than the down regulation of CD133 (21). In addition, CD44 down regulation in the Apc Min/+ mouse resulted in attenuation of intestinal tumorigenesis (22). ALD1/CD44 co-expression was shown to further select for cells with tumorigenic potential (19). Besides, Haegebarth et al., 2009 has also highlighted the possibility of a new colon CSC marker Lgr5 (also known as Gpr49) (23). Lgr5 is a gene which was first known to be a human colon stem cell marker encodes a G-protein coupled receptor with a large leucine-rich extracellular domain and seven transmembrane domains. This gene is a target for Wnt gene expression and was expressed in a small number of colonic adenoma cells believed to be tumour initiating cells (23,24). The different CSC marker discovered shows that this is a rapidly progressing field of research and warrants more study in the future.
Experimental Evidence of Cscs In Prostate Cancer Intermediate prostate cancer cells have also shown to express basal cell surface markers (25). In the prostate
cancer setting, Patrawala et al., 2006 showed that human androgen negative prostate cancer cell expressing CD44+ cell surface markers had enhanced in vitro proliferation and increased in vivo metastasis (26). Hence, they exhibit CSC properties as they are 10 to 100 times more tumorigenic than prostate cancer cell expressing CD44- cell surface marker. It was reported that 0.1% of cells in prostate tumour expressed CD44+/Îą2Î˛1hi/ CD133+ CSC phenotype (27). Therefore, prostatic cancer may be derived from a small population of prostatic CSC originating from normal stem cells found at the basal lamina of the prostate gland (25). CD44+ phenotype markers have also been shown to be more proliferative, tumorigenic and metastatic than prostatic cancer cells with CD24- phenotype (26). Moreover, Patrawala et al., 2006 also suggested that CD44- prostate cancer cells are capable of initiating tumours and CD44- may be derived from CD44+ and vice versa.
Cancer Stem Cells and Chemo-Resistance It is believed that CSCs play a pivotal role in tumour relapse from chemo-radiotherapy, especially in solid tumours, where conventional therapies do not target the CSCs (28). Ravdin et al., 1997 described that all cancer cells are sensitized to chemotherapy but upon repetitive exposure, these cells will acquire resistance (29). On the other hand there are some cancer cells that are intrinsically chemo-resistant which may not respond to chemotherapy. The development of chemo-resistance among cancers cells has been an issue for impeding the clinical efficacy of chemotherapy. Although Paclitaxel and Adriamycin (doxorubicin) used in neo-adjuvant therapy have significantly improved clinical response in patients with breast cancer (30), resistance in vitro has been identified (31) (Figure 5). Moreover, 5-fluorouracil and oxaliplatin (Cisplatin) have been used in the treatment of colorectal cancer for more than a decade (32) and chemo-resistance to these agents has also been shown in vitro (33,34). Leukemic stem cells are resistant to standard chemotherapeutic agents due to its quiescent nature (35). Likewise, CSCs are also shown to be highly resistant to standard care treatments such as chemotherapy and radiotherapy. Colon cancer CD133+ cell lines were nonresponsive to chemotherapy induced cell apoptosis even at high drug concentrations (36) and that chemo-resistance in colonic CSC was due to the increased autocrine production of interleukin-4 (IL4) and the expression of IL4 receptors among CSC as compared to normal colonic cell population (36). IL4 prevents CSC from undergoing apoptosis by up-regulating anti apoptotic proteins since the inhibition of IL4 via anti-IL4 treatment resulting in the down regulation of anti apoptotic proteins i.e. Cflip, Bcl-xL and PED (36). Breast CSC chemo-resistance was shown to be caused by the increase in expression of
32 JEMSA (Journal of European Medical Students' Association on Medical and Scientific Affairs)
Figure 5. Immunofluorescence of MCF-7 Adriamycin resistant breast cancer cell expressing significant CD44 CSC surface markers (green) and nuclei (blue). (Adapted from Gendeh et al., 201041)
thymosin β4 (TB4) protein (37). Moreover, the presence of oncogenes and mutations occurring to p53 and pRB tumor suppressor genes may also contribute to the ability of a cancer cell to avoid apoptosis, but their role in chemoresistance among CSC does require more evidence. Although all cancer cells are sensitized to chemotherapy, eventually these cells will acquire resistance (29), while some cancer cells that are
intrinsically chemo-resistant which may not respond to chemotherapy at all. Anti-cancer chemotherapeutics target rapidly dividing and differentiating cells. Therefore, current selection of general chemotherapeutic agents is based on broad non-selective cytotoxic effects which may result in the widespread killing of proliferating tumour cells and ultimately tumour de-bulking. Thus, if the CSC hypothesis is true, only the non-tumorigenic proliferative cancer cells forming the bulk of the tumour will be eliminated whilst the highly tumorigenic CSC will remain unaffected5 and are capable of undergoing further cell division to form more CSCs and cancer proliferating cells. Hence, it is hypothesized that CSCs are spared, resulting in the re-emergence of the cancer, contributing to the poor prognosis and high incidence of reoccurrence and metastasis especially in solid tumours, such as breast, prostate and colon cancers, where conventional therapies do not target the CSCs (28). A hypothetical model proposes that CSC targeting by more specific treatments would not de-bulk but reduce metastatic potential and chemo/radio-resistance (Figure 6) (38). Therefore the tumour would not be able to be sustained. CSCs have also been shown to exclude cellular dyes such as the Hoechst dye, and can be isolated by flow cytometry as a ‘side’ population. This exclusion property is believed to be facilitated by ABC drug transporters, therefore leading to the formation of a
Figure 6. Tumour debulking does not eradicate CSC; specifically targeting CSCs results in tumour cessation. (Adapted from Dalerba et al., 200838)v
Borderline Personality Disorder: an overview on the aetiology and treatmentâ€ƒ 33
multi-drug resistant phenotype. ABC-enriched CSCs exist in a number of cancer types including glioblastomas and gastro-intestinal cancer such as colon (28). Together, this highlights the importance of targeting CSC specifically. The main characteristics that identify CSCs are that it represent a minority of total cancer cells and have tumorigenic potential in vivo models, have a distinct profile of associated cell markers, develop into a heterogeneous population from a CSC clone and are chemo-resistant.
Clinical Relevance CSCs play an important role in key aspects of cancer biology and treatment. More effort is needed in identifying optimal panels consisting of not only one but several of CSC intracellular and extracellular markers for all cancer types. These panels of CSC markers can be used to provide prognostic indicators as seen for prostate (38) and colorectal cancer patients (39), act as biomarkers of chemo-resistance to standard chemo/radio-therapy and act as biomarkers to guide new treatments targeted at these cells. However, this solution may have its limitation. Since an optimal panel may consist of a combination of several different markers, but it may be a while before we are able to identify an optimal panel as new CSC markers are being and still needed to be discovered. Ishii et al., 2008 proposed the presence of both dormant and proliferative CSC (28), therefore it will be important to find accurate markers of each of these sub-populations. Moreover, they proposed that dormant
CSCs are protected within a niche regulated by a number of signaling pathways including Notch and Hedgehog. A summary of the 6 therapeutic regulatory signaling pathways protecting dormant CSCs that can be targeted is shown in Table 1 and 2.
Conclusion With increasing evidence, the CSCs theory is emerging to be a promising feature in cancer pathology. CSCs have been shown to be responsible for the initiation, progression, metastasis and chemo-resistance of breast, prostate and colon cancers. These cancers have shown to express specific CSC markers. It is essential to focus on new treatment modalities to specifically target CSCs, as the reduction and removal of the primary tumour will not necessary eradicate cancers and allow for relapse. As a start, a panel of various markers associated with breast, prostate and colon CSCs provide an opportunity to specifically target CSCs and providing new opportunities for the development of new treatment that would have an improved outcome from cancer modalities and ultimately enhancing patient survival.
ACKNOWLEDGEMENTS My sincere thanks to the staff of the Division of PreClinical Oncology, The University of Nottingham for their resourcefulness which contributed towards this academic article.
Table 1. Various Cancer Stem Cells and their associated cell surfa-
Table 2. The 6 therapeutic regulatory signaling pathways involved
ce marker(s) (Adapted from Ricci-Vitiani et al., 20085)
in the protection of dormant CSCs that can be targeted28
Targeting niche regulation through inhibition of Hedgehog (hh), Notch, Wnt and chemokine signaling pathways
Type of Cancer
Cell Surface Marker(s)
Acute Myeloid Leukemia
Targeting molecular markers such as CD133
Control of checkpoints such as Chk1 and Chk2
Induction of differentiation through use of e.g. retinoic acid
Head and Neck
CD44+, CD24+, ESA+
Inhibition of ABC transporters
34 JEMSA (Journal of European Medical Students' Association on Medical and Scientific Affairs)
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ZIMS - Zagreb International Medical Summit
ZIMS - Zagreb International Medical Summit is a medical congress that brings together medical students and young doctors, worldwide, but mostly from Europe. In accordance with EMSA spirit, this medical summit is organized for medical students from medical students; ZIMS OC members are students from School of Medicine at University of Zagreb, members of EMSA Zagreb and Students Section of Croatian Medical Association. For 10 times in a row, looking forward to 11th, ZIMS is a place of constant exchange of experience, presentation of scientific papers and acquisition of new knowledge from colleagues and invited professors in medical science. Further on, additional message is to promote city of Zagreb as a cultural and youth centre, and therefore field trip, workshops and evening gatherings are important part of the agenda. It is important to mention that ZIMS is the only conference where young students and not yet affirmed scientists have access to the world of publishing, thus becoming the only conference in Europe where the book of abstracts is published as a supplement to a prestigious medical journal, ‘Lijecnicki Vjesnik’, which is indexed in EMBASE / Index Medicus. Moreover, the best works are published as full texts. Consequently, the highest quality of an abstract, which goes through strict criteria process, is
mandatory. As we know how important presentation of a project is, we expect you to represent your work either orally or as a poster. ZIMS 10 took place from November 11-14th 2010. 120 students and young doctors from 16 countries participated. More than 200 abstracts were submitted and 53 of them accepted and presented, 33 orally and 20 as posters. One scientific paper is published as full text. ZIMS 10 organizing committe had 25 members. 8 distinguished doctors, scientists and professors formed Scientific Jury. After exceptionally succesful ZIMS 10 we are very proud to invite you to participate in ZIMS 11 which will take place in Zagreb, Croatia from November 09-12th 2011. You can participate either as presenting or non-presenting participant. The registration form will be available on our website from April. Allow us to be a part of your new, plentiful, life experience; to help you to acquire medical knowledge, bound with colleagues from all over the world, enjoy Croatian beauty and hospitality. Come to Zagreb and experience science! For all the other information about congress feel free to visit www.zims.hr and contact us via e-mail: email@example.com We are looking forward seeing you in Zagreb at ZIMS11!
ZIMS 11 OC
International Student Congress Of (bio)Medical Sciences Call for Abstracts
The International Student Congress Of (bio)Medical Sciences is approaching soon! The Abstracts submission period is now officially open, and you can send in your abstract until the 18th of February 2011. Why submit your abstract?
• To present your research in a poster session, oral session or plenary session • To come into contact with students from all over the world and from different cultures and exchange experience • To listen to a lecture of a Nobel prize winner, sir Tim Hunt! • To participate in different kinds of (hands-on)workshops • To experience a masterclass, with courses like ‘How to present your abstract?’ • To enjoy the elaborate and fun social programme • To join the selection of the ISCOMS Research Fellowships, a two week long internship under supervision of researchers in the UMCG • And many more reasons! So send in your research soon!
ISCOMS Facts Date: 7-10 June 2011 Location: University Medical Center Groningen Country: The Netherlands Topic: All fields of (bio)medical and dentistry research Who: undergraduate students, graduate students and post doctoral scientists Deadline for abstract submission: February 18th 2011
For more information you can visit our website www.iscoms.com or you can contact us by email: firstname.lastname@example.org Kind regards, The Committee of International Contacts 2011
The NEMSC The Network of European Medical Students' Conferences (NEMSC) is a collaboration between EMSA and two (bio)medical student congresses: ISCOMS and ESC-Berlin. The NEMSC is founded to facilitate interfaculty exchange of high-potential (bio)medical, to enhance Medical Science Student Congresses in Europe, to promote Science in Europe by informing students about research events and to establish a joint website and to enhance integration of medical science researchers. The three NEMSC members are: ISCOMS The International Students Congress Of Medical Sciences (ISCOMS) is one of the world leading student congresses on (bio)medical sciences. Each year young researchers from all around the world will be able to exchange their work and share new ideas and views. By offering such a meeting place, the congress pursues to stimulate international co-operation between research groups that actively stimulate student participation in their research. Thereby the congress provides a starting point for interested and talented students to pursue a career in medical research. Unique about the ISCOMS is that students can apply for an ISCOMS research fellowship (IRF). With an IRF, students can participate in a challenging two week research oriented programme in the University Medical Center Groningen (UMCG). Participating in an IRF could act as a stepping stone towards a PhD in the UMCG. For more information about ISCOMS and the IRF’s you can visit our website www.iscoms.nl. ESC European Students’ Conference (ESC) is one of the largest biomedical conferences worldwide and has been one of the main events of the Charité for many years. Addressing young scientists, graduate students, post-graduate students, PhD students, post-docs, and everyone interested in biomedical research from all around the world, the ESC represents an interdisciplinary platform for international scientific exchange between numerous countries, students, clinicians, and professors from different fields of research and various cultures. For more information visit: http://www.esc-berlin.com. EMSA The European Medical Students' Association (EMSA) seeks to improve the health and quality of care of the citizens of Europe, by acting as a conduit for increased interaction and sharing of knowledge between European medical students in the fields of medical education, medical ethics, medical science and European integration. The EMSA forms a network between European medical students to facilitate European integration and develop a sense of European identity. They promote training, activities and projects related to health in Europe to the benefit of medical students and society. EMSA has two statutory meetings per year: the EMSA General Assembly & European Medical Students' Congress and the EMSA National Coordinators and Enthusiasts Meeting (NCM). For more information visit our website www.emsa-europe.org.
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