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Transcript of Module Book Clinical Immunology - med.unhas.ac.id · Clinical Immunology Module coordinators: Dr....
Clinical Immunology
M O D U L E B O O K
Bachelor Medicine, Third year
Course year 2014-2015
© 2014 Alle rechten voorbehouden
LUMC
Behoudens de in of krachtens de Auteurswet van 1912 gestelde uitzonderingen, mag niets uit deze
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Voor vragen of informatie kunt u contact opnemen met:
Directoraat Onderwijs en Opleidingen, PB 9600, 2300 RC Leiden
Clinical Immunology
Module coordinators:
Dr. M. Bax
LUMC, Department of Rheumatology
Email: [email protected]
Dr. R.G.M. Bredius
LUMC, Department of Paediatrics
Email: [email protected]
Dr. A. Lankester
LUMC, Department of Paediatrics
Email: [email protected]
M O D U L E B O O K
Bachelor Medicine, third year
Course year 2014-2015
Contents
Module committee and teachers 1
Preface 5
Introduction and general information 7
Themes 17
Introduction in immune‐mediated disease 18
Diagnostics in immunological disorders 32
Neuro‐immunology 40
Rheumatology 45
Pulmonology 49
Nephrology 52
Final report patient case 56
Innovative Therapies 58
Appendices 70
Instructions for final report week 8 70
Assessment criteria grant proposal poster presentation 71
Assessment form 73
Guidelines diagnosis report 74
Oral presentation lab visit 75
Oral presentation patient casus 76
Report neuro‐immunology 77
Oral presentation rheumatic disease 78
Oral presentation pulmonology 79
Report nephrology 80
1
Module committee and teachers
Module coordinators
Dr. M. Bax
LUMC, Dept. of Rheumatology
Email: [email protected]
Dr. K.L.L. Habets
LUMC, Dept. of Rheumatology
Email: [email protected]
Dr. R.G.M. Bredius
LUMC, Dept. of Paediatrics
Email: [email protected]
Dr. A. Lankester
LUMC, Dept. of Paediatrics
Email: [email protected]
Logistical support
Module committee
Dr. H.H. Smits Dept. of Parasitology Email:[email protected] Dr. J.J.C. de Vries Dept. of Medical Microbiology Email: [email protected] Dr. J.A. Bakker Dept. of Clinical chemistry Email: [email protected] Dr. B.E.P.B. Ballieux Dept. of Clinical chemistry Email: [email protected] Prof. dr. J.J.G.M. Verschuuren Dept. of Neurology Email: [email protected] Dr. J.J. Plomp Dept. of Neurology Email: [email protected] Dr. J.K. de Vries‐BouwstraDept. of Rheumatology Email: J.K.de_Vries‐[email protected]
Prof. dr. R.E.M. ToesDept. of Rheumatology Email: [email protected] Prof. dr. C. TaubeDept. of Pulmonology Email: [email protected] Prof. dr. P.S. HiemstraDept. of Pulmonology Email: [email protected] Dr. A.P.J. de VriesDept. of Nephrology Email: [email protected] Prof. dr. C. van KootenDept. of Nephrology Email: [email protected] Dr. B.G.A. GuigasDept. of Parasitology Email: [email protected]
2
Secretariat
Mw. N.E. Schenk‐Lagendijk
LUMC, Dept. of Rheumatology
Phone: 071‐5263423
Email: N.E.Schenk‐[email protected]
Teachers
LT = lecture, PR = practical, PD = patient demonstration, WG = work group
Dr. A. Aartsma‐Rus Dept. of human genetics
LT
Drs. G.D. Amatngalim Dept. Pulmonology, LUMC
LT
Dr. U.A. Badrising Dept. of Neurology, LUMC
LT, WG, PD
Dr. J.A. Bakker Dept. of Clinical Chemistry, LUMC
LT, PR
Dr. B.E.P.B. Ballieux Dept. of Clinical Chemistry, LUMC
LT, PR
Dr. M. Bax Dept. of Rheumatology, LUMC
PR
Dr. V. Bekker Dept. of Paediatrics
LT
Dr. M. de Boer Dept. of Infectious diseases
LT
Dr. E.L.E.M. Bollen Dept. of Neurology, LUMC
LT, WG, PD
Mw. B.C.M. Bos‐van NoortDept. Pulmonology, LUMC
LT
Drs. H. Bouwsma Dept. of Nephrology, LUMC
PD
Dr. R.G.M. Bredius Dept. of Paediatrics, LUMC
LT, WG
Dr. C.M. Cobbaert Dept. of Clinical Chemistry, LUMC
LT
Prof. dr. A.F. Cohen Dept. of Nephrology, LUMC
LT
Prof dr. D.P. Engberts Dept. Ethics & Law
LT
Prof. dr. J.W. de Fijter Dept. of Nephrology, LUMC
LT
Dr. F.A. van Gaalen Dept. of Rheumatology, LUMC
LT, WG
Prof dr. H.J. Guchelaar Dept. KFT
LT
Dr. B.G.A. Guigas Dept. of Parasitology
LT
Dr. K.L.L. Habets Dept. of Rheumatology, LUMC
PR
Dr. T. van Hall Dept. of Clinical oncology)
LT
Dr. L.M. ‘t Hart (MCB) WG
Dept. Of Molecular cell biology Prof. dr. P.S. HiemstraDept. of Pulmonology, LUMC
LT, PR, WG
Drs. P.C.E. Hissink MullerDept. of Paediatrics, LUMC
LT
Dr. C.H. HokkeDept. of Parasitology
LT
Dr. S. KleijnDept. Pulmonology, LUMC
LT
Prof. dr. F. KoningDept. of Immunohematology and Blood bank, LUMC
LT
Drs. P. KhedoeDept. Pulmonology, LUMC
LT
Prof. dr. C. van KootenDept. of Nephrology,LUMC
LT
Dr. F. KroonDept. of Infectious diseases
LT
Dr. A. LankesterDept. of Paediatrics, LUMC
LT, WG
Dr. A.F. LipkaDept. of Rheumatology
LT, WG, PD
Dr. E. LoprioreDept. of Paediatrics, LUMC
LT
Prof. dr. R.M. MaizelsEdinburgh, UK
LT
Dr. M.L. Mearin Manrique Dept. of Paediatrics, LUMC
LT
Drs. D.J.A.R. MoesDept. of Clinical Pharmacy and Toxicology
LT
Mr. I. de NooijerLURIS
LT
Dr. F.A. OssendorpDept. of Immunohematology and Blood bank, LUMC
LT
Dr. J.J. PlompDept. of Neurology, LUMC
PR, LT
Prof. Dr. T. RabelinkDept. of Nephrology, LUMC
LT
Drs. S.R.S. RamaiDept. Pulmonology, LUMC
LT
Dr. M.E.J. Reijnders LT
3
Dept. of Nephrology, LUMCDr. D.L. Roelen Dept. of Immunohematology and Blood bank, LUMC
LT
Dr. J.N. Samsom Dept of Paediatric Gastroenterology, Erasmus MC
LT
Mw. A. van Schadewijk Dept. Pulmonology, LUMC
PD
Dr. K. Schimmel Dept. KFT
LT
Ir. R. Schot Dept. Pulmonology, LUMC
PR
Dr. A.M. Slats Dept. Pulmonology, LUMC
LT
Dr. J.J. Schweizer Dept. of Paediatrics)
LT
Prof dr. F.J. Staal Dept. of Immunohematology and Blood bank, LUMC
LT
Dr. B.C. Stoel Dept. Pulmonology, LUMC
PR
Dr. Y.K.O. Teng Dept. of Nephrology, LUMC
LT
Prof. dr. R.E.M. Toes Dept. of Rheumatology, LUMC
LT, WG
Prof. dr. C. Taube Dept. Pulmonology, LUMC
LT, PD
Dr. M.D.J. van Tol Dept. of Paediatrics, LUMC
LT, PR
Dr. L.A. Trouw Dept. of Rheumatology, LUMC
LT, PR
Dr. J. Vellinga Crucell
LT
Drs. E.P.M. van der Vlugt Dept. Pulmonology, LUMC
LT
Dr. E. van de Vosse Dept. of Infectious diseases, LUMC
LT
Dr. A.P.J. de Vries Dept. of Nephrology, LUMC
LT, PR
Dr. J.J.C. de Vries Dept. of Medical Microbiology, LUMC
LT
Dr. J.K. de Vries‐BouwstraDept. of Rheumatology, LUMC
LT, PR, PD, WG
Dr. M. de Vries Dept. of Paediatrics
LT
Prof. dr. J.J.G.M. Verschuuren Dept. of Neurology, LUMC
LT, WG, PD
Drs. Y. van Wijck Dept. Pulmonology, LUMC
LT
Dr. L.N.A. Willems Dept. Pulmonology, LUMC
LT, PD
Dr. D. van der Woude Dept. of Rheumatology, LUMC
LT, PR, PD, WG
Drs. M. Zarcone Dept. Pulmonology, LUMC
LT
Dr. M.C. van ZelmDept. of Molecular Immunology, Erasmus MC
LT
5
Preface
The human immune system is intended to recognize non‐self, harmful entities in order to eliminate
them to avoid damage. Upon re‐exposure to the same pathogenic entity, a faster and stronger
immune response occurs, known as memory. The memory response has been used throughout
history to confer immunity, even before our understanding of the physiological basis of the immune
response. Already more than 2000 years ago, Thucydides wrote in his History of the Peloponnesian
War that persons who had been exposed to plague previously were protected against disease. Much
later, in the 18th century, Edward Jenner postulated that the pus in the blisters from cowpox
protected milkmaids from smallpox. He tested this hypothesis by inoculating an eight‐year‐old boy
with pus from cowpox blisters in both arms. The boy developed fever and some uneasiness, but not a
full‐blown infection. A few months later, Jenner challenged this boy with live smallpox and found
that the boy was protected against this infection.
In the next years, basic knowledge on the immune system improved, and especially genetically
inherited primarily immunodeficiency’s has provided valuable insights into the functioning of the
immune system. The study of immunology provides the opportunity in medicine to relate the
findings of basic scientific investigations to clinical problems. Currently we know that the immune
system has the important task to maintain a delicate balance between the potency to destroy foreign
cells and viruses, while refraining from destruction of the host's own tissue. When the immune
system is not able to mount a sufficient defense of the host, this is considered as an immune
deficiency (e.g. HIV infection and SCID), whereas if the immune system acts too vigorously, allergy
might be induced or the immune system might start to attack the host, initiating autoimmune
diseases (e.g. Rheumatoid arthritis and Myasthenia gravis).
During this 10‐weeks course, many different disciplines involved in immune‐mediated diseases are
offered, including Parasitology, Medical Microbiology, Neurology, Rheumatology, Pulmonology, and
Nephrology. In the first two weeks of this half minor, case studies describing real events from records
of different hospitals are presented, illustrating in a clinical context essential points about the
fundamental mechanisms of immunity. Subsequently, clinicians, basic researchers, and patients of
different departments involved in immune mediated diseases will be introduced. At the end of this
module, the student is able to understand immune‐mediated mechanisms leading to disease, and is
prepared to present a research proposal with state‐of‐art laboratory techniques to investigate
specific components of the immune system related to disease, based on recent literature (Scholar
competence). By attending patient demonstrations, taking a patient’s history, and investigate
diagnostic profiles, the student is able to diagnose a patient with an immune mediated disease
correctly. The student is also capable to set up a diagnostic and therapeutic plan for a patient
suspected to suffer from an immune mediated disorder, making the first steps to become a Medical
expert. In collaboration with other students, a Grant proposal for an innovative therapy will be
designed. The last day of the half minor, this Grant proposal poster will be presented clearly to an
audience showing Communicator and Collaborator competences, and might be selected for the best
poster award.
7
Introduction and general information
Description Immune mechanisms underlying immune deficient patients are explained to understand the consequences of a defective immune system. Based on specific patients cases, the students will take a patient’s history, attend patient demonstrations, and investigate the diagnostic profile to diagnose the patient correctly. By independent search of recent literature, the students are able to find out the pathogenic mechanisms underlying a specific immune related disorder and tools to investigate these mechanisms with state‐of‐art laboratory techniques. By knowledge tolerance inducing agents, the students are able to design a therapeutic plan. The last day of the half minor, the students present a Grant proposal poster for an innovative therapy, that might be selected for the best poster award.
Subjects
1. Immune deficiencies 2. Diagnostics in immune mediated disorders 3. Autoimmune diseases 4. Allergy 5. Transplantation 6. Innovative treatments 7. State‐of‐art laboratory techniques 8. Grant proposal Schematic overview 10 weeks:
Diagnostics in immunological
disorders
Neuro‐immunology
Rheumatology
Innovative therapies
Nephrology
Introduction in immune mediated
diseases
Pulmonology
Assessment case
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Week 7
Week 8
Week 9
Week 10
8
Study goals of the module:
General learning objectives for Academic and Scientific competences:
The student is able to:
• professionally implement his knowledge, insight, and competences to function well within the health system and in medical sciences related situations
• collect and interpret relevant information in the area of medical sciences to make a decision based on relevant social, scientific, and ethical aspects
• communicate information, ideas, and solutions to an audience with or without medical experts • possess the capacity to perform autonomously a high level follow‐up study
Specific learning objectives of this half minor:
The student is able to:
take a patients’ history in order to examine whether (s)he suffers from an immunological disorder (Medical expert)
perform independently literature research based on a specific patient casus and select three relevant papers to analyse and report the immunological background of the patient casus in detail (Academic)
explain and determine by knowledge obtained from lectures and literature the pathogenic mechanism(s) underlying the symptoms of a patient diagnosed with an immunological disorder
relate the mechanism of disease of a systemic auto‐immune disease to organ specific involvement by understanding the defect immune components related to the disorder
create a diagnostic plan by evaluation of immunological laboratory techniques based on a differential diagnosis and motivate why these techniques are appropriate to be able to diagnose the patient correctly (Academic)
interpret results from diagnostic tests and subsequently translate these results to potentially underlying immunological diseases
develop a therapeutic plan based on results from diagnostic tests and corresponding diagnosis and describe the method to check the effect of the intervention (Medical expert)
formulate and communicate clearly in collaboration with other students following another ½ minor the disbalance between the ‘good’ and ‘bad’ immune system in a specific patient casus and develop a therapeutic plan with groups of therapeutics to manipulate the immune system in order to reach a balance again (Communicator, Collaborator)
Under the different Themes, specific learning objectives for each module are described.
Competency lines Medical expert and Professional
Learning objectives:
take a patients’ history in order to examine whether (s)he suffers from an immunological disorder
develop a therapeutic plan based on results from diagnostic tests and corresponding diagnosis and describe the method to check the effect of the intervention
9
Academic
Learning objectives:
perform independently literature research based on a specific patient casus and select three relevant papers to analyse and report the immunological background of the patient casus in detail
create a diagnostic plan by evaluation of immunological laboratory techniques based on a differential diagnosis and motivate why these techniques are appropriate to be able to diagnose the patient correctly
Collaborator and Communicator
Learning objectives:
formulate and communicate clearly in collaboration with other students following another ½ minor the disbalance between the ‘good’ and ‘bad’ immune system in a specific patient casus and develop a therapeutic plan with groups of therapeutics to manipulate the immune system in order to reach a balance again
Prerequisites
‐Mechanisms of disease I, theme I, III, IV, and VI (2nd year Medicine)
‐Knowledge of the English language
Place in the curriculum
This module will follow‐up on the immunological basis the students obtained in G2MD1, and gives
students with an interest in the broad field of immunology the change to intensify their
immunological knowledge in a specific clinical setting. This module prepares the students for the
subsequent modules regarding patient interactions and diagnostic potential.
10
Assessment matrix
Assessment: Knowledge Final report Grant proposal poster
Exam type: Open question exam Written report of ~2000 words Oral presentation
Area: Knowledge Knowledge and ability Knowledge, ability, and communication
Time: Week 2 Week 8 Week 10
Duration: 1,5 hrs 36 hrs 20 hrs preparation
Weight: 10% 60% 30%
Collaboration: Individual Individual Couple
Assessed by: Minor teacher One minor teacher and one Specialist (evaluation form available)
Average of one minor teacher and one Specialist
Number of questions: 10 1800‐2200 words N/A
Assessment matrix related to learning objectives
Assessment: Knowledge Final report Grant proposal poster
General academic and scientific learning objectives X X
1 diagnose a patient with an immunological disorder by
performing taking a patient’s history (Medical expert) X
2 perform literature research on a patient casus and select
papers to report the immunological background in detail.
(Academic)
X X
3 determine the pathogenic mechanism(s) of a patient casus X X X
4 relate the mechanism of disease of a systemic auto‐immune
disease to organ specific involvement X X X
5 create a diagnostic plan by evaluation of state of the art
laboratory techniques on a differential diagnosis (Academic) X X
6 interpret results from diagnostic tests and subsequently
translate which immunological defects might underlie the results X X X
7 develop a state of the art therapeutic plan from diagnostic
tests and the method to check the effect of the intervention X
8 formulate and communicate disbalance between ‘good’ and
‘bad’ immune system in a specific patient casus and develop a
therapeutic plan with groups of therapeutics (Communicator,
Collaborator)
X X
11
Assessment information
Summative assessment plan consists of:
• Knowledge exam • Final written report • Grant proposal poster presentation
• Additional requirements (Passed/Failed)
o Diagnosis report (1x) o Oral presentations (4x) o Written reports (2x)
I) Knowledge exam
The knowledge exam consists of 10 open questions Rating: Mark 1‐10 Assessment form: Mark fixed depending on the number of right answered questions. Assessed by: Workgroup docent week 1‐2 Assessment criteria: N/A
II) Final report
In Week 8, the students should combine all knowledge obtained in Week 3‐7 by writing individually a
report (approximately 2000 words) on a specific immunological disease (MG, SLE, aHUS, Allergy;
received in Week 3).
Assessment: Mark 1‐10 Assessment form: See Appendix A. Assessed by: Medical specialists of the corresponding casus. Assessment criteria: See Appendix A.
III) Grant proposal poster presentation
Students are grouped in pairs (one from Clinical Immunology (CI) and one from Infections, Vaccines
and Immune modulation (IVIM)) and get a personal tutor assigned for 2 weeks. Together they will
develop a grant proposal on an innovative therapeutic strategy for a specific immunological or
infectious disease. The students will have at least 4 feedback moments on their grant proposal with
their personal tutor. At the last day, the idea for the grant proposal is presented by a poster at a
symposium. Clear guidelines are provided to the students for both the grant proposal idea and the
poster presentation (See Appendix B).
Rating: mark 1‐10 Assessed by: Tutors Week 9‐10 Assessment: The grant proposal will be evaluated based on a E‐poster presentation (7 min) during the final symposium and a 15 min discussion. The mark for the poster presentation will be an average of the evaluation of all tutors present plus the mark from the assigned personal tutor (1:1 ratio). The students will also evaluate and rank all the posters using a written anonymous form. The poster with the highest rank will receive a poster award. Assessment criteria: use of immunological knowledge into novel concepts, innovation, creativity, collaboration, communication, writing skills, presentation. The topic should be different from the final report (Week 8).
12
Calculation overall mark
The final report and the final mark has to be >5.5, to pass the half minor.
‐ Open question exam = 10% of the final mark
‐ Final report = 60% of the final mark
‐ Grant proposal poster presentation = 30%
See Appendix C.
Additional requirements
1. Diagnosis report in Week 2 Assessment: Passed/Failed Assessed by: Minor teacher Week 1/2. Assessment criteria: Individual report to show understanding of immunology and diagnosis for selected case studies according to strict guidelines (Appendix D). This assignment is a preparative assignment for the report of week 8.
2. Oral presentation Laboratory Assessment: Passed/Failed Assessed by: Diagnostic test teacher Week 1/2. Assessment criteria: Short oral presentation to show understanding of the application and principle of a dedicated set of clinical tests (Appendix E).
3. Oral presentation patient casus Week 3 Assessment: Passed/Failed Assessed by: Medical specialist of the casus Assessment criteria: Being able to prepare a clear presentation in a group of max. 5 students about the immunological mechanisms and diagnostic tools at the end of Week 3 (Appendix F).
4. Written report Neuro‐immunology Assessment: Passed/Failed Assessed by: Neurologist Assessment criteria: Being able to collaborate, prepare in a group of max 5 students a written review report about one neuro‐immunological disease (Appendix G). Students with the case MG for the written report of Week 8 should choose another disease this week.
5. Oral presentation Rheumatology Assessment: Passed/Failed Assessed by: Medical specialist of the corresponding week. Assessment criteria: Being able to collaborate, prepare a clear presentation with literature and knowledge obtained previously, present clear, answer questions (Appendix H). Students with the case SLE case for the written report of Week 8 should choose another disease this week.
6. Oral presentation Pulmonology Assessment: Passed/Failed Assessed by: Medical specialist of the corresponding week. Assessment criteria: Being able to collaborate, prepare a clear presentation with literature and knowledge obtained previously, present clear, answer questions (Appendix I). Students with the case Allergy case for the written report of Week 8 should choose another disease this week.
7. Written report Nephrology Assessment: Passed/Failed Assessed by: Medical specialist of the corresponding week. Assessment criteria: Prepare individually a clear written report about one biological with literature and knowledge obtained previously (Appendix J).
13
A minimal number 5/7 of the additional tasks have to be passed. A maximal number of two failed additional task might be repeated. In case of an oral exam, a written report should be handed in.
Presence
Presence during the complete program will be recorded and at least 90% of the contact hours should
be attended. If not, additional tasks should be performed to compensate for the missed hours.
Re‐examination
One exam; the multiple choice exam, the final report, or the Grant proposal (report instead of
poster) can be repeated in case the final report or the final mark is <5.5.
A maximal number of two failed additional task might be repeated to pass 5/7 additional requirements. In case of an oral exam, a written report should be handed in.
FORMATIVE examination and FEEDBACK
Diagnosis report (Week 2) – Exercise for final report (Week 8).
Short oral presentation (Week 3) – Feedback will be provided directly after the presentation and it will be checked in the final report if the feedback is used
Oral presentations (Week 2, 5, 6) – After all presentations feedback will be provided, to be used for Grant proposal poster presentation (Week 10)
Small written report (Week 4, 7) – Exercise for written report (Week 8), Feedback on small reports will be provided within one week.
Study books
• The immune system (Peter Parham)
• Other study material are placed on Blackboard
Relevant websites
• Links of relevant websites and other required study material are placed on Blackboard
14
Module schedule overview
Week 1 Monday Tuesday Wednesday Thursday Friday
Introduction 1‐sep‐14 2‐sep‐14 3‐sep‐14 4‐sep‐14 5‐sep‐14 hours
1 self study self study self study prepare lab visit 08:30 ‐ 09:30
2 Clinical case adaptive immune disorders Clinical case heamolytic disease *Lab visit 09:30 ‐ 10:30
3 Free: Clinical case innate immune disorders Role of B cells in infections DCs in Ag pres. and T cell activation clinical immunology 10:30 ‐ 11:30
4 Opening of the Role of innate immunity and PRR self study self study Instructions Diagnosis Report 11:30 ‐ 12:30
Academic Year
5 Self study: Self study: Self study: Free: 13:30 ‐ 14:30
6 parham parham prepare work group Inauguration of 14:30 ‐ 15:30
7 written case studies written case studies work group student societies 15:30‐16:30
8 case reports & questions 16:30‐17:30
*No room needed
Week 2 Monday Tuesday Wednesday Thursday Friday
Introduction 08‐sep‐14 9‐sep‐14 10‐sep‐14 11‐sep‐14 12‐sep‐14 hours
1 self study self study self study Self study: 08:30 ‐ 09:30
2 Clin case: juvenile RA, hyper IgE Clin case:X‐linked lymphoprolif syndr Clin case: Crohn's dis, Celiac Dis prepare 09:30 ‐ 10:30
3 destructive inflammation & T cells Mendellian suscept. for mycobacterial infections Celiac disease: adaptive vs innate immunity written exam 10:30 ‐ 11:30
4 self study self study self study Self‐study 11:30 ‐ 12:30
prepare
5 oral presentations Self study: Self study: written exam Written exam 13:30 ‐ 14:30
6 on lab visits write prepare work group (summative) 14:30 ‐ 15:30
7 Self study: prepare diagnosis report diagnosis report work group Free 15:30‐16:30
8 (formative) (formative) case reports & questions 16:30‐17:30
Week 3 Monday Tuesday Wednesday Thursday Friday
CKCL 15‐sep‐14 16‐sep‐14 17‐sep‐14 18‐sep‐14 19‐sep‐14 hours
1 distribution patient casus Laboratory diagnostics I Laboratory diagnostics II Lymphocyte characterization in diagnostics preparation of presentatio case studies 09:00‐10:00
2 Intro in laboratory diagnostics 10:00‐11:00
3 self study 11:00‐12:00
4
5 Group 1: Group 2: Group 3: Group 4: 13:30‐14:00
6 laboratory visit laboratory visit laboratory visit laboratory visit Student presentations 14:00‐15:00
7 self study self study self study self study case studies 15:00‐16:00
8 work on patient casus work on patient casus work on patient casus work on patient casus 16:00‐17:30
Week 4 Monday Tuesday Wednesday Thursday Friday
Neurology 22‐sep‐14 23‐sep‐14 24‐sep‐14 25‐sep‐14 26‐sep‐14 hours
1 Self study: Self study: Self study: Self study: 09:00‐10:00
2 Prepare today's topic Prepare today's topic Voortgangstoets Prepare today's topic Report 10:00‐11:00
3 Lecture MS Lecture MG & LEMS Lecture GBS & CIDP 11:00‐11:45
4 Patient demonstration MS Patient demonstration MG & LEMS Patient demonstration GBS & CIDP 11:45‐12:15
12:15‐13:15
5 Workgroup MS Workgroup MG & LEMS Lecture IBM Workgroup GBS & CIDP 13:15‐14:30
6 Patient demonstrationIBM 14:30‐15:00
7 *Laboratory visit Group 1 *Laboratory visit Group 2 Workgroup IBM *Laboratory visit Group 4 15:00‐16:30
8 Self study: Report Self study: Report *Laboratory visit Group 3 Self study: Report 16:30‐17:30
*No room needed *No room needed *No room needed *No room needed
Week 5 Monday Tuesday Wednesday Thursday Friday
Rheumatology 29‐sep‐14 30‐sep‐14 1‐okt‐14 2‐okt‐14 3‐okt‐14 hours
Lectures Patient demonstrations *Clinical rounds: Self study: Free day: 09:00‐10:00
Rheumatic diseases Multidisciplinary day care, Read literature and Leids ontzet 10:00‐11:00
Self study: Laboratory visit part I joint puncture, nailfold capillaroscopy prepare presentation 11:00‐12:00
Immunology 12:00‐13:00
of Rheumatic diseases Self study: *Laboratory visit part II Student presentations 13:00‐14:00
Read literature and Self study: 14:00‐15:00
prepare presentation Read literature and 15:00‐16:00
prepare presentation 16:00‐17:00
Introduction of immune system
Lecture
Practical
Patient demonstration
Workgroup
Self study
15
Week 6 Monday Tuesday Wednesday Thursday Friday
Pulmonology 06‐okt‐14 7‐okt‐14 8‐okt‐14 9‐okt‐14 10‐okt‐14 hours
Lectures: 9:00‐9:30 questions self study 9:00‐12:00 Lectures: Interactive mini‐symposium Question hour presentation 09:00‐10:00
Anatomy and Physiology of the lung 9:30‐11:00 Patient demonstrations In vivo and cell culture models 10:00‐11:30 Self study 10:00‐11:00
Cell biology and host defense of the lung 11:15‐13:00 Diagnostic procedures Clinical research 11:30‐13:00 Presentations 11:00‐12:00
COPD and asthma 12:00‐13:00
Self study: Self study 12:30‐13:30 *Lunch meeting PulmoScience Self study: 13:00‐13:30 Break 13:00‐14:00
Immunology Literature 13:30‐14:15 **Microscopy Read literature and 13:30‐15:00 Presentations 14:00‐15:00
of COPD and asthma 14:15‐17:00 Self study prepare presentation 15:00‐16:00
Read literature 16:00‐17:00
*Lecture hall for 50 attendants required
**Lecture room at Pathology Department with microscope and projection
Week 7 Monday Tuesday Wednesday Thursday Friday
Nephrology 13‐okt‐14 14‐okt‐14 15‐okt‐14 16‐okt‐14 17‐okt‐14 hours
Lectures: Lectures: Lectures: Self study Self study: write report 09:00‐10:00
Introduction to Clinical Nephrology, SLE Immunogenetics and HLA, Acute rejection, Viral infection immunosuppressive drugs 10:00‐11:00
nephritis, Complement‐rel. renal disease Allo‐immunity, Belatacept Self study 11:00‐12:00
12:00‐13:00
ANCA‐vasculitis Immunosuppressive drugs 13:30‐14:00 *Histopathology rounds Lecture: HIV and renal transplantation 13:00‐14:00
handing out assignment target therapy Therapeutic drug monitoring Self study *Clinical rounds 14:00‐15:00
Self study Self study 15:30‐16:30 Lecture PCP and fungal inf Self study 15:00‐16:00
Self study 16:00‐17:30
hand in written report 16:30‐17:30
*No room needed *No room needed
Week 8 Monday Tuesday Wednesday Thursday Friday
Assessment 20‐okt‐14 21‐okt‐14 22‐okt‐14 23‐okt‐14 24‐okt‐14 hours
Self study: write report Self study: write report Self study: write report Self study: write report Self study: write report 09:00‐10:00
10:00‐11:00
11:00‐12:00
12:00‐13:00
13:00‐14:00
14:00‐15:00
15:00‐16:00
16:00‐17:30
16:30‐17:30
Week 9 Monday Tuesday Wednesday Thursday Friday
Innovative thera 27‐okt‐14 28‐okt‐14 29‐okt‐14 30‐okt‐14 31‐okt‐14 hours
1 Self study:symposium/grant proposal Self study:symposium/grant proposal Innovative therapies & IT Self study: 08:30
2 Introduction Innovative therapies How to develop a clinical trial for IT preparing Round table discussion *Site Visit Leiden BiosciencePark
3 Philosophy and ethics of IT Exon Skipping therapy for DMD Stem cell‐based gene therapy for SCID Towards personalized medicine:
4 Meet the mentors Self study:symposium/grant proposal EU FP7 approach on helminth vaccines Pros and Cons (formative) Meet the mentors 12:30
5 Self study: Symposium Rick Maizels Meet the mentors Self study: Self study: 13:30
6 Preparing Symposium/Grant proposal Self study: preparing Symposium/Grant proposal preparing Symposium/Grant proposal
7 preparing Symposium/Grant proposal
8 17:30
*No room needed
Week 10 Monday Tuesday Wednesday Thursday Friday
Innovative thera 03‐nov‐14 04‐nov‐14 05‐nov‐14 06‐nov‐14 07‐nov‐14 hours
1 Self study: *Site Visit LUMC pharmacy manufacture Self study: preparing JC lecture Self study: 08:30
2 preparing Symposium/Grant proposal Hot topics in innovative therapies: preparing Symposium/Grant proposal Poster Symposium: Study group 1‐10
3 Pre‐ and probiotics for immune diseases Meet the mentors highlights from high‐ranking journals summative
4 IT: new approaches for vaccination Self study: Dealing with minor age for IT 12:30
5 Self study: Self study: Self study: Self study: 13:30
6 preparing Symposium/Grant proposal preparing Symposium/Grant proposal preparing Symposium/Grant proposal PRINTING POSTER Poster Symposium: Study group 11‐20
7 Deadline 1.30am summative
8 17:30
Lecture
Practical
Patient demonstration
Workgroup
Self study
16
Line schedule
17
Themes
1. Introduction in Immune‐mediated diseases
2. Diagnostics in immunological disorders
3. Neuro‐immunology
4. Rheumatology
5. Pulmonology
6. Nephrology
7. Write report patient case
8. Innovative therapies
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1. Introduction in Immune‐mediated diseases
Clinical coordinators: Dr. R.G.M. Bredius (Paediatrics), Dr. A.C. Lankester (Paediatrics) Scientific coordinators: Dr. M. Bax (Rheumatology), Dr. H.H. Smits (Parasitology) Other teachers involved: Dr. V. Bekker (Paediatrics), Dr. T. van Hall (Clinical oncology), Prof Dr.
P.S. Hiemstra (Pulmonology), Dr. Hissink Muller (Paediatrics), Prof. Dr. F. Koning (IHB), Dr. E. Loprione (Paediatrics), Dr. L. Mearin (Paediatrics), Dr. P. Nibbering (Infectious diseases), Dr. J.J. Schweizer (Paediatrics) , Prof dr. R. Toes (Rheumatology), Dr. E. van de Vosse (Infectious diseases), Dr. J.J.C. de Vries (Medical microbiology), Dr. M. van Zelm (Erasmus MC)
Background
The immune system is a sophisticated system designed to protect us against invading pathogens, which try to exploit us for their own survival. The immune system consists of different intertwined layers, such as innate and adaptive elements. Innate immunity is germline‐encoded and will react immediately by e.g. circulating complement molecules and/or soluble mediators secreted by various innate cell types in responds to danger signals. In contrast, adaptive immunity only slowly develops but results in effective tailor‐made high affinity T and B cells and immunoglobulins. Importantly, the immune system is not only capable of distinguishing between self and non‐self but also between harmful and harmless. As such, the immune system has developed the capacity to dampen or prevent immune responses in the case of non‐self, but ubiquitous molecules to protect against unnecessary tissue damage as a result of otherwise exaggerated inflammatory responses. Clinical presentations
The concepts of immunology are illustrated by medical problems in patients with (inheritable) immune deficiencies of either the innate or the adaptive immune system. Study goals
The student can
Describe medical conditions when the innate immune system does not properly recognize pathogens.
Describe medical consequences when cell subset(s) of the adaptive immune system are lacking
Explain the dichotomy of the immune system towards ‘self/non‐self’ and ‘harmful/harmless’ and describe medical consequences when these systems fail
In patients with (genetic) immune deficiencies, describe the medical problems due to specific infections and explain the immunological mechanism
Contact hours (~14 hr), divided over 8½ days: Lectures/ demonstrations of patients with genetic immune deficiencies to explain the following aspects of the immune system:
‐ Broad overview of the different elements of the immune system (2 hours) ‐ The innate immune system (3 hours) ‐ Dendritic cells in antigen presentation and recognition of self vs non‐self (2 hours) ‐ B cells and immunoglobulins (2 hours) ‐ The role of T cells and cytokines in inflammation (3 hours) ‐ Distinction between harmful or harmless (2 hours)
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Self‐study hours:
Read indicated book chapters of Parham plus relevant review articles
Write diagnosis report
Prepare workgroups
Prepare oral presentation (laboratory visit) Study materials Book: The immune system (Peter Parham) Other materials are posted on Blackboard Evaluation:
Oral presentation (laboratory visit) (p/f)
Workgroups (p/f)
Diagnosis report (p/f)
Multiple‐choice exam (summative) Detailed program and study material:
Tuesday 2 September Theme: Innate immunity Self‐study 8.30‐9.30 hour
Prepare case studies and lectures of this morning
Lecture 8.30 – 8.45 hour Title Introduction to the module immune‐mediated diseases Instructor Dr. R. Bredius MD (Dept of Paediatrics) Goals Explain the content, the learning objectives and the assignments for this module Lecture 8.45 – 10.30 hour Title General overview of the immune system Instructor Prof dr. P.S. Hiemstra (Dept. of Pulmonology) Goals The aim of this first lecture is to refresh your memory! If you know it all you may sit
back and relax, but also consider asking questions about the immune system that were left unanswered from your second year courses in immunology and mechanisms of disease. More likely, your memory will welcome some refreshment. The aim of this lecture is therefore to lay a solid foundation for the two minors on immune‐mediated disease: “Infections, Vaccines, Immune Modulation” and “Clinical Immunology”. We will review the innate and adaptive immune systems with the various cell types, mediators and effector molecules involved. We will discuss the apparently complicated way that the immune system uses MHC/HLA molecules and dendritic cells to present antigens, and how this system offers intriguing opportunities to prevent infections and tune the immune system. We will also explore the way the
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immune system controls its own activity as an essential opportunity to prevent hypersensitivity reactions, including autoimmune diseases and allergies.
Literature Parham: Hst. 1: 1.4‐1.6, 1.7 Fig. 1.7‐1.12. Hst. 3: Complete, including all figures. Case study 11.00 – 11.45 hour Title Deficiencies in innate immunity Instructor Dr. V. Bekker MD (Dept. of Paediatrics) Goals Case presentation of patient with defects in innate immunity. These patients lack
important components of the innate defence, i.e. complement, phagocytes. Due to this immune defect these patients have a specific susceptibility spectrum, some infectious agents will be problematic while others are not. Phagocyte dysfunctions such as seen in Chronic Granulomatous Disease and absolute deficiencies in number of phagocytes (Congenital Neutropenia) will be discussed.
Literature Parham Hst. 2: 2.2, 2.4. 2.5, 2.13, 2.14 Fig: 2.5, 2.9, 2.10, 2.27, 2.33 Preparation See case studies at Blackboard Lecture 11.45 – 12.30 hour Title Host pathogen interactions: it takes two to tango Instructor Dr. P. Nibbering (Dept. of Infectious Diseases) Goals Using examples from patients this presentation is dedicated to barriers (both
chemical and microbiological), the inflammatory response, defences against viral infections, defences against bacterial infections, and some emphasis on immune evasion. The focus will be on both cells and molecules involved.
Literature Parham Hst. 2: 2.10, 2.11, 2.12 Fig 2.19, 2.24 Self‐study 12.30‐17.00 hour
See case studies and quizzes on Blackboard.
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Wednesday 3 September Theme: Adaptive Immunity and the role of T and B cells Self‐study 8.30‐9.30 hour
Prepare case studies and lectures of this morning Case study 8.30‐9.30 hour Title Deficiencies of the adaptive immune system Instructor Dr. A. Lankester MD/ Dr. R. Bredius MD (Dept. of Paediatrics) Goals Cases with severe genetic defects in the adaptive immunity will be demonstrated.
Both T and B cellular defects are adaptive immune system disorders. T cellular defects such as seen in SCID (absent or dysfunctional T/B cells) are the most severe defects and usually these patients need urgent treatment at young age. B cellular, humoral defects such as seen in X‐linked Agammaglobulinemia (no B cells) or class switch defects (Activation‐induced Cytidine Deaminase Deficiencies) lead to infection proneness when maternal trans‐placental transferred antibodies fade away.
Literature Parham Hst. 5: 5.2‐5.4, Fig. 5.1, 5.5. Hst. 8: Fig. 8.37 Preparation Case studies at blackboard Lecture 9.30‐10.30 hour Title Critical steps in B‐cell development revealed in patients with primary
immunodeficiencies Instructor Dr. M.C. van Zelm (Dept. of Imunology, ErasmusMC) Goals In the past 2 decades, many new genetic defects have been found to underlie
immunodeficiencies with impaired antibody production. These single gene defects have revealed critical steps in B‐cell differentiation and antibody responses. In this lecture, immunobiological processes will be discussed that have been found impaired in antibody‐deficient individuals. Specifically, the importance of V(D)J recombination, antibody receptor signaling, somatic hypermutation (SHM) and Ig class switch recombination will be explained.
Literature Parham Hst. 4: 4.8‐4.16 Fig. 4.2, 4.5, 4.17, 4.20, 4.30, 4.32 Self‐study 10.30‐17.00 hour
See case studies at Blackboard.
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Thursday 4 September Theme: Recognition of self/non‐self Self‐study 8.30‐9.30 hour
Prepare case studies and lectures of this morning Case study 9.30 – 10.30 hour Title Auto‐ and alloimmune cytopenias in neonates and other immunoglobulin mediated
problems in neonates Instructor Dr. E. Loprione MD (Dept. of Neonatology) Goals Maternal antibodies can severely disturb intrauterine and neonatal life. A case study
on hemolytic disease of the newborn and allo and auto‐immune thrombocytopenia will be presented.
Literature Parham Hst. 5: 5.7‐5.15 5.17 Fig. 5.13‐5.14, 5.20, 5.23, 5.25. Hst. 8: 8.13‐8.18 Fig. 8.1, 8.27, 8.34, 8.37; Hst. 13: 13.24 Fig.13.35
Preparation See case studies at Blackboard. Lecture 10.30‐11.30 hour Title Recognition between self and non‐self: the start of a T cell response Instructor Dr. T. van Hall (Dept. of Oncology) Goals At the moment a pathogen enters our body, they are detected by ‘antigen‐
presenting cells’ (APC) that are spread around in all our tissues. These cells of the innate immune system try to eradicate the micro‐organisms. In addition, the dendritic cells, as specialized APC, generate fragments of the proteins derived from the intruders en present these partial proteins on HLA class I and II molecules at their cell surface. This is the start of a T cell response
Literature Parham Hst. 5: 5.7‐5.15 5.17 Fig. 5.13‐5.14, 5.20, 5.23, 5.25. Hst. 8: 8.13‐8.18 Fig. 8.1, 8.27, 8.34, 8.37; Hst. 13: 13.24 Fig.13.35
Self‐study 11.30 – 15.30 hour Prepare case studies and questions for the workgroup, posted on Blackboard.
Work group 15.30 – 17.30 hour Instructors Dr. V. Bekker MD; Dr. R. Bredius MD (Dept. of Paediatrics); Dr. H.H. Smits (Dept. of
Parasitology) Test element Formative (pass/fail)
23
Information Workgroup In the workgroup primary immunodeficiencies (PID) cases will be discussed with clinicians. The case histories and the immunological introduction can be found on blackboard. Preparation of the workgroup is essential. Use sources such as Up to Date and Parham for preparation of the workgroup. For each case the following questions need to be addressed:
1. Immunological background Which immunodeficiency is present in this patient? Explain what part of the immune system is causing this disease?
2. Clinical picture
What kind of problems can be encountered in patients with this deficiency and why is that? What is the typical disease presentation and what complications can be expected?
3. Diagnosis
How is the disease diagnosed and what is the differential diagnosis?
4. Management How is the disease managed and treated, and what preventive measures are helpful?
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Friday 5 September Theme: Introduction to diagnosis of immune disorders Self‐study 8.30‐10.00 hour
Prepare laboratory visit
Laboratories visit 10.00 – 11.30 hour Goals The students will be split into 6 groups of max. 6 students. Each group will get an
introduction to a dedicated set of laboratory techniques which form a central element to diagnose patients with various immune disorders. These include immunoglobulin and complement analysis, blood group typing, immune cell numbers and phenotyping and cytokine production. The technique will be demonstrated and the principle of the test system will be explained. The expected range of a normal test result will be detailed and what deviations can be expected with respective immune disorders. The laboratory visit will be ended by an introduction lecture on diagnosis reports.
Preparation Details on the respective labs, lab protocols and range of normal values can be found on Blackboard.
Lecture 11.30 – 12.30 hour Title Clinical immunology diagnosis reports Instructor Dr. M. van Tol (Dept. of Paediatrics) Goals Introduction to clinical immunology diagnosis reports. The instructions and
guidelines for the diagnosis report are explained by some examples from the daily practise.
Free 12.30‐17.00 hour
Inauguration of the student societies.
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Monday 8 September Theme: T cell‐mediated (auto‐immune) inflammation Self‐study 8.30‐9.30 hour
Prepare case studies and lectures of this morning
Case study 9.30 – 10.30 hour Title Auto‐immune and auto‐inflammatory diseases Instructor Dr. P. Hissink Muller MD (Dept. of Paediatrics) Goals Case report on (juvenile) RA patient and anti‐TNF therapy and auto inflammatory
diseases will be presented Preparation See case studies at Blackboard. Lecture 10.30‐11.30 hour Title Adaptive immunity and RA: how do they connect? Instructor Prof dr. R. Toes (Dept. of Rheumatology) Goals Many targeted therapies employing biologicals used in the treatment of patients
with rheumatic disease are directed against molecules that play a dedicated role in the induction or propagation of immune responses. In the context of this presentation, the function of‐ and place in the immune system of several of the molecules targeted by different biologicals will be discussed in relation to their role in the immune response against invading pathogens as well as in relation to auto‐immunity.
Self‐study 11.30 – 13.30 hour Prepare oral presentation on the lab visits according to the following guidelines: 1. Prepare a presentation of 10‐15 min and include appropriate images 2. Explain the application of the diagnostic test (medical conditions) 3. Explain the principle of the diagnostic test 4. Show a typical test result (including the range of a ‘normal’ response) 5. Explain how these results should be interpreted Oral presentations on lab visits 13.30 – 15.00 hour Instructor Dr. R. Bredius MD, Dr. M. van Tol (Dept. of Paediatrics), Dr. H.H. Smits (Dept. of
Parasitology) Goals Students explain each other on the different techniques they have been introduced
to during the lab visit (5 September 2014) and the application of this technique to diagnose various immune disorders.
Test element Formative (pass/fail) Self‐study 15.00 – 17.00 hour
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Informatio Diagnosis report: Case information and aim of laboratory test When seeing a patient for the first time in the (outpatient)clinic, a physician will make an inventory of the clinical history of the patient in particular and his/her family in general, and perform physical examination. Also utilizing information from the refering centre, which may include results of previously performed laboratory tests, the physician will make a differential diagnosis and a work plan based on professional knowledge, experience and “some gut feeling”. Part of this plan will usually be to send patient material to a general and/or a more specialized laboratory in order to document the actual clinical status and to explore the likelihood of presence of a clinical disorder that is high on the list of differential diagnosis. Delivery of the patient material to the laboratory will be accompanied by a specified question, e.g., perform test A or B, which are usually tests routinely performed in the laboratory. In an ideal setting, the physician is posing an additional question or is indicating some key observations leading to the work plan. For an optimal interpretations of laboratory findings, the laboratory specialist should take notice of the question(s) and indications formulated. Diagnosis report: Step 1: Shortly summarize the issues arising from previous clinical and laboratory investigations that are considered most relevant to interprete the data obtained from the laboratory tests to be performed. Laboratory tests Tests asked for by the physician will be executed in the laboratory. It is always important to check whether the material sent in for analysis has been witdrawn and delivered in a proper way, related to the techniques that have te be performed. If not, investigation might be useless, because results can not be trusted. The physician should be informed immediately when this situation occurs. Tests will be performed under GLP conditions, implying amongst others that the used apparatus and other lab devices have been validated and that applied reagents are used under validated conditions. The numerical results of the tests are, especially in the pediatric setting, compared with ranges of normal values obtained by performing the same tests on material obtained from healthy age‐matched controls. Quantitative data measured below the sensitivity threshold of the test are reported as being below that threshold (which not neccesarily means that the value is zero). The tests and resulting data are controlled, results are compared with the age‐dependent range of normal values and interpreted by experienced lab technicians/staff. Finally, the data are authorized by a person familiar with the tests before officially reporting to the physican, who will have an overview of all data generated by different labs in EZIS (Electronisch Ziekenhuis Informatie Systeem). Qualitative data are usually described pointing to the characteristics that are addressed by applying a particular qualitative test. Diagnosis report: Step 2: Make a list of data generated by the laboratory tests, put these data in perspective by also listing the corresponding range of age‐matched normal values (if applicable), and indicate which values are outside this range (increased or decreased) If applicable, shortly describe the resuls of a qualitative test. Interpretation and conclusions The most difficult, but also most challenging and certainly most relevant, task is to interprete the new data resulting from the tests in the context of the questions posed by the physician and the already known findings from previous laboratory investigations and clinical observations and examinations. To this end, it is essential to have some knowledge of the area of immune related disorders possibly involved.
27
Diagnosis report: Step 3: Interprete the results of the tests in a way relevant to the physician. This means that you will point to parts of the data supporting or dismissing the questions/suggestions raised by the physician and shortly give arguments for your conclusion. In addtion, it is important to address unexpected results because these may lead to new insights and contribute to reach a diagnosis. And next? The conclusions from the tests, may give rise to a change of insights leading to explore an alternative from the differential diagnosis list constructed by the physician. Alternatively, the conclusions may lead to a proposal to perform additional tests to investigate more in depth the clues arising from the results of the performed tests. Also, you may conclude that the test results are (in)conclusive. Diagnosis report: Step 4: Based on your interpretation and conclusions, you decide whether additional investigations are required. Motivate your decision and, if you consider further diagnostic tests or research useful or essential, put forward your suggestion regarding the test(s) to be performed and the reason why. Indicate the nature of the material (blood, plasma,serum, urine, saliva, bone marrow, biopsy, others) that is required to execute the investigations. If you consider the results of the performed test (s) conclusive, and if relevant, advise an appropriate therapy to the physician. If you consider the results inconclusive, give an advice how to proceed. Diagnosis report instructions: Prepare Diagnosis report on clinical cases provided on Blackboard according to the instructions above which are summarized as follows: 1. Summarize the most important laboratory results (raw data) of the requested tests. Point out
both remarkable, unexpected data and the results relevant for specific clinical question. 2. Summarize the clinical information (relevant history taking/ physical examination and/or other
diagnostic test results) in no more than two sentences. Make up your differential diagnosis and estimate the pre‐test probability (highly suspected, suspected, not suspected) for the specific disease tested for.
3. Combine the clinical information with the laboratory data and estimate the post‐test probability. Use estimates of the test sensitivity and the specificity in order to estimate the risk of false positive and false negative test results. Take into account the type of specimen, timing of sampling, and if appropriate, sample handling/transport conditions that may have affected the test result.
4. Clearly formulate your conclusion / interpretation of the data relevant for the clinician. 5. If relevant, add a suggestion for additional diagnostic testing (if appropriate, list your updated
differential diagnosis, and/or follow‐up samples). If relevant, advise the optimal specimen (e.g. serology, biopsy, etc) and/or timing of sampling.
6. Advise an appropriate therapy, if relevant.
Test element Formative (pass/fail)
28
Tuesday 9 September Theme: Macrophage activation and cytotoxicity Self‐study 8.30‐9.30 hour
Prepare case studies and lectures of this morning
Case study 9.30 – 10.30 hour Title Case report of patient with hemophagocytosis Instructor Dr. A. Lankester MD / Dr. R. Bredius MD (Dept. of Paediatrics) Goals Various immune defects lead to susceptibility of patients to a syndrome called
hemophagocytosis (HLH). HLH is a severe inflammatory response to a trigger, often an infection leading to macrophage activation and cytopenias due to hemophagocytosis. A defect in cytotoxicity and clearance of infections causes this inflammatory response. Examples of these defects will be presented, i.e. X‐linked lymphoproliferative syndrome, Hemophagocytic lymphohistiocytosis, Chediak‐Higashi Syndrome.
Literature Parham Hst 2: 2.21, Fig 2.47. 2.4 Preparation See case studies at Blackboard. Lecture 10.30‐11.30 hour Title Mendellian susceptibility for mycobacterial infections Instructor Dr. E. van de Vosse (Dept. Of Infectious Disease) Goals Non‐tuberculous, environmental mycobacteria do not cause disease in
immunocompetent individuals, while these can cause severe, life‐threatening infections in people with Mendelian susceptibility to mycobacterial disease (MSMD). In contrast to susceptibility to M. tuberculosis, which is due to a combination of many genetic and environmental factors, MSMD is a primary immunodeficiency caused by heritable monogenic mutations. Several MSMD cases will be presented as well as the genes and pathways involved.
Preparation See case studies at Blackboard. Self‐study 11.30 – 17.00 hour
Continue on Diagnosis report on clinical cases provided on Blackboard.
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Wednesday 10 September 09.30 DEADLINE Diagnosis report (formative test)
Theme: Inflammation and tolerance in the gut Self‐study 8.30‐9.30 hour
Prepare case studies and lectures of this morning
Case study 9.30 – 10.30 hour Title Inflammatory bowel disease Instructor Dr. L. Mearin MD/ Dr. J. Schweizer MD (Dept. of Paediatrics) Goals Case presentation on colitis ulcerosa and Crohn's disease. Literature Parham Hst. 12: 12.1, Fig. 12.2; Hst. 9: 9.4, 9.9, 9.11‐9.16, 9.20 Fig. 9.9, 9.22‐9.25 Preparation See case studies at Blackboard. Lecture 10.30‐11.30 hour Title Celiac disease: sandwiched between adaptive and innate immunity Instructor Prof. dr. F. Koning (Dept. of Immunohematology) Goals Celiac disease is caused by an uncontrolled immune reaction against the dietary
gluten proteins present in wheat, barley and rye. The disease has a strong HLA‐association, virtually all patients are either HLA‐DQ2 and/or HLA‐DQ8 positive, which is explained by the observation that these HLA‐molecules can bind (modified) gluten‐derived peptides and trigger adaptive CD4 T cell responses in the lamina propria. Concomitantly, innate immune responses in the epithelium contribute to the tissue remodelling and cause epithelia cell damage. During the seminar I will discuss the nature and molecular basis for the induction of the deleterious immune responses and how cross‐talk between the lamina propria and epithelial compartment results in disease pathogenesis.
Literature Parham Hst. 12: 12.1, Fig. 12.2; Dariusz Stepniak and Frits Koning. Celiac Disease: sandwiched between innate and adaptive immunity. Human Immunology 67: 460‐468 (2006)
Self‐study 11.30 – 15.30 hour
Prepare case studies and questions for the workgroup, posted on Blackboard. Work group 15.30 – 17.30 hour Instructors Dr. J. Schweizer MD; Dr. R. Bredius MD (Dept. of Paediatrics); Dr. H.H. Smits (Dept.
of Parasitology) Test element Formative (pass/fail)
30
Information Workgroup In the workgroup primary immunodeficiencies (PID) cases will be discussed with clinicians. The case histories and the immunological introduction can be found on blackboard. Preparation of the workgroup is essential. Use sources such as Up to Date and Parham for preparation of the workgroup. For each case the following questions need to be addressed:
1. Immunological background Which immunodeficiency is present in this patient? Explain what part of the immune system is causing this disease?
2. Clinical picture
What kind of problems can be encountered in patients with this deficiency and why is that? What is the typical disease presentation and what complications can be expected?
3. Diagnosis
How is the disease diagnosed and what is the differential diagnosis?
4. Management How is the disease managed and treated, and what preventive measures are helpful?
Thursday 11 September Self‐study 8.30‐17.00 hour
Prepare written exam; Example questions are posted at Blackboard.
Friday 12 September Self‐study 8.30‐17.00 hour
Prepare written exam; Example questions are posted at Blackboard. Written exam 13.30 ‐15.30 hour Test element Summative (10% of final mark)
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Time Activity Title Teacher Material
8.30 – 8.45 LectureIntroduction to the module
immune‐mediated diseasesDr. H.H. Smits
8.45 – 10.30 LectureGeneral overview of the immune
systemProf dr. P.S. Hiemstra
Parham: Hst. 1: 1.4‐
1.6, 1.7 Fig. 1.7‐
1.12. Hst. 3:
Complete,
including all
figures
Parham Hst. 2: 2.2,
2.4. 2.5, 2.13, 2.14
Fig: 2.5, 2.9, 2.10,
2.27, 2.33
Case studies: see
blackboard
11.30 – 12.30 Lecture Innate immunity and PRR Dr. P. Nibbering
Parham Hst. 2:
2.10, 2.11, 2.12 Fig
2.19, 2.24
13:30‐17:30 Self studySee case studies and quizzes at
Blackboard
8:30‐9:30 Self studyPrepare case studies and lectures
of this morning
Parham Hst. 5: 5.2‐
5.4, Fig. 5.1, 5.5.
Hst. 8: Fig. 8.37
Case studies: see
blackboard
10.30‐11.30 Lecture Role of B cells in infections Dr. M.C. van Zelm
Parham Hst. 4: 4.8‐
4.16 Fig. 4.2, 4.5,
4.17, 4.20, 4.30,
4.32
11.30‐12.30 Self study Written case studies
13:30‐17:0 Self studySee case studies and quizzes at
Blackboard
8:30‐9:30 Self studyPrepare case studies and lectures
of this morning
Parham Hst. 5: 5.7‐
5.15 5.17 Fig. 5.13‐
5.14, 5.20, 5.23,
5.25. Hst. 8: 8.13‐
8.18 Fig. 8.1, 8.27,
8.34, 8.37; Hst. 13:
13.24 Fig.13.35
Case studies: see
blackboard
10.30‐11.30 LectureDCs in Ag presentation/T cell
activationDr. T. van Hall
Parham Hst. 5: 5.7‐
5.15 5.17 Fig. 5.13‐
5.14, 5.20, 5.23,
5.25. Hst. 8: 8.13‐
8.18 Fig. 8.1, 8.27,
8.34, 8.37; Hst. 13:
13.24 Fig.13.35
11:30‐12:30 Self‐study Written case studies
13:30‐15:30 self study Prepare work group
15.30 – 17.30 Work group Case reports and questionsDr. V. Bekker, Dr. R. Bredius,
Dr. H.H. Smits
Prepare case
studies and
questions, posted
on Blackboard
8:30‐9:30 Self study Prepare laboratory visit
10:00‐11:30 LaboratoriesIntroduction to a dedicated set of
laboratory techniquesSee Blackboard
11.30–12.30 LectureClinical immunology diagnosis
reportsDr. M. van Tol
12:30‐17:30 FreeInauguration of the student
societies
Monday
01‐sep‐14
Free: Opening of the academic year
Tuesday
Wednesday
02‐sep‐14
10.30‐11.30 Case study Deficiencies in innate immunity
03‐sep‐14
Dr. V. Bekker
9.30‐10.30 Case studyDeficiencies of the adaptive
immune system
Dr. A. Lankester / Dr. R.
Bredius
Friday
05‐sep‐14
Thursday
04‐sep‐14
9.30‐10.30 Case study heamolytic disease Dr. E. Loprione
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Time Activity Title Teacher Material
8:30‐9:30 Self studyPrepare case studies and lectures
of this morning
9.30 – 10.30 Case studyAuto‐immune and auto‐
inflammatory diseasesDr. P. Hissink Muller
Case studies: see
blackboard
10.30‐11.30 LectureAdaptive immunity and RA: how do
they connect?Prof dr. R. Toes
11.30‐12:30 Self studyPrepare oral presentation on the
lab visits
13.30 – 15.30 Oral presentations Oral presentations on lab visitsGuidelines on
Blackboard
15:30‐17:30 Self study Prepare Diagnosis report
8:30‐9:30 Self studyPrepare case studies and lectures
of this morning
Parham Hst 2:
2.21, Fig 2.47. 2.4
Case studies: see
blackboard
10.30‐11.30 LectureMendelian susceptibility for
mycobacterial infectionsDr. E. van de Vosse
Case studies: see
blackboard
11:30‐17:30 Self‐study Prepare Diagnosis report
8:30‐9:30 Self study Finalize Diagnosis report
Parham Hst. 12:
12.1, Fig. 12.2; Hst.
9: 9.4, 9.9, 9.11‐
9.16, 9.20 Fig. 9.9,
9.22‐9.25
Case studies: see
blackboard
Parham Hst. 12:
12.1, Fig. 12.2
Dariusz Stepniak
and Frits Koning.
Celiac Disease:
sandwiched
between innate
and adaptive
immunity. Human
Immunology 67:
460‐468 (2006)
11:30‐15:30 Self‐studyPrepare case studies and
questions for the workgroup
15.30 – 17.30 Work group Case reports and questionsDr. V. Bekker, Dr. R. Bredius,
Dr. H.H. Smits
Prepare case
studies and
questions, posted
on Blackboard
Prepare written exam
Example questions are posted at
Blackboard
Prepare written exam
Example questions are posted at
Blackboard
13:30‐15:30 Written exam
Monday
08‐sep‐14
Tuesday
09‐sep‐14
9.30 – 10.30 Case study Patient with hemophagocytosisDr. A. Lankester / Dr. R.
Bredius
Wednesday
10‐sep‐14
9.30 – 10.30 Case study Inflammatory bowel disease Dr. L. Mearin / Dr. J. Schweizer
10.30‐11.30 Lecture
Celiac disease: sandwiched
between adaptive and innate
immunity
Prof. dr. F. Koning
Thursday
11‐sep‐14
8:30‐17:30 Self study
Friday
12‐sep‐14
8:30‐13:30 Self study
33
Diagnostics in immunological disorders
Coordinator(s): Dr. J.A. Bakker (AKCL), Dr. B.E.P.B Ballieux (AKCL) Other teachers involved: Dr. C.M. Cobbaert (AKCL), Dr. M.D.J. van Tol (Paediatrics)
Background
The clinical laboratory plays an essential role in the diagnostics and follow‐up of immunological diseases. An expanding number of (validated) laboratory test and techniques provide results and interpretative comments to the clinicians demanding these tests. The aim of this week is to get insight in the role of the laboratory scientist in the chain of clinical decision making. First a general overview of laboratory diagnostics will be presented, with emphasis on aspects of quality, methodology and traceability of the methods and the analytes. Specific aspects of laboratory methods in immunology will be the topic of a second lecture, where remaining lectures will focus on laboratory diagnostics of immunologic diseases, both cellular and humoral immunity will be highlighted in this respect. Laboratory diagnostics for rheumatology, allergic disease, vasculitis, neuro‐immunological disease, haematological diseases and others will be presented. In this week, we will start with the preparation of the written report, which will be finalized in week 8. From four clinical disciplines, a casus will be presented to the students (MG, SLE, Allergy, a‐Hus). Each student will receive a specific student case and during week 3‐7, the knowledge on the specific case will be intensified on a diverse range of aspects including taking a patient’s history, performing literature search, knowledge of diagnostic methods, treatment options etc. During this week, students will learn more about diagnostic tests from their specific casus during the laboratory visits. Week 8 is completely dedicated to write this individual report.
After receiving the patient case in this week, groups of students with the same case prepare a short oral presentation about the symptoms of the disease, the underlying immunological mechanisms that cause the symptoms, and the diagnostics tools used to establish the disorder. Feedback will be provided by the corresponding clinician and will be used to prepare the final report.
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Case reports: Monday 15 September 9.00‐10
Instructor: All mentors involved in guiding students in this assignment
Goal: During this presentation the mentors/tutors will present the patient case. Students will be divided into groups ( 4 groups of 3) and by the end of the week the group will give a first overview of the case. The final INDIVIDUAL report must be handed in at Friday 17th of October.
Lecture Monday 15 September 10:15‐12:15 Instructor: Dr. C.M. Cobbaert, Clinical chemist Title: Evidence based use of medical tests in laboratory medicine
Goal: Understanding the selection, utilization and interpretation of medical (diagnostic) tests and the role of laboratory medicine
In order to justify the use of medical tests in clinical practice, regulators and healthcare payers are increasingly demanding evidence that medical tests improve patient outcome. Young medical doctors should be aware about the movement towards evidence based test utilization of medical tests in this era of high demand and decreasing healthcare budgets. Medical tests should only be used if knowing the test result relates to better patient outcome (consequentialism). To that end, medical doctors and medical students should be aware of the drivers behind proper medical test selection, utilization and interpretation.
Frameworks have been developed encompassing all essential elements for evaluating added value and clinical usefulness of medical tests, such as the one of Horvath AR et al. [1]. Firstly, the analytical performance of medical tests (specificity, analytical sensitivity, linearity, reproducibility, …) has to be aligned with the purpose (diagnosis, follow up, prognosis or risk classification) and role of the medical test in the specific clinical pathway. Secondly, the clinical performance of medical tests needs to be established in terms of sensitivity, specificity, predictive value, reference values or medical decision limits, gender‐, race‐ or age‐dependence, …., taking into account the intended use. Thirdly, the clinical utility and incremental added value of the medical test for patient care should be clarified. Fourthly, if introduced in clinical practice, the medical test should be cost‐effective, i.e. it should be able to reduce expensive or invasive testing. If relevant, consideration should also be given to the fact whether the increase in quality adjusted life years (QALY) justifies the increased cost related to the medical test. Finally, the general impact of introducing a medical test should be regarded. The mere availability of a medical test may put individuals under psychological pressure to do this test, individually or by peer.
The cyclical framework for test evaluation [1] emphasizes the central role of the medical test in the clinical pathway, the interdependency of the different components, and that clinical effectiveness data should be fed back to refine analytical and clinical performance of tests to achieve improved outcomes.
Preparation: To extend your knowledge in order to understand and appreciate this lecture, the
following educational papers from the literature are advised for reading. Horvath AR, Lord SJ, StJohn A, Sandberg S, Cobbaert CM, Lorenz S, Monaghan PJ, Verhagen‐Kamerbeek WD, Ebert C, Bossuyt PM. Test Evaluation Working Group of the European Federation of Clinical Chemistry Laboratory Medicine. From biomarkers to medical tests: the changing landscape of test evaluation. Clin Chim Acta. 2014 PMID: 24076255.
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Lecture Tuesday 16 September 09:00‐11:00 Instructor: Dr. B.E.P. Ballieux Title: Immunoassays beyond immunology. Assay characteristics and quality issues
Goal: From the publication of the first radioimmunoassay in 1960 the use of immunoassays has rapidly expanded in clinical immunology and clinical chemistry. These techniques enabled specific analysis of proteins and low molecular weight hormones in the nano‐ and pico‐molar range. Further improvements, non‐radioactive techniques, the introduction of monoclonal antibodies in the 80’s and automation have resulted in robust assays with analytical variations close to those of conventional clinical chemistry assays. Despite their overall sensitivity and specificity, antigen polymorphism, antigen degradation and cross‐reactivity due to structural similarity with the analyte have hampered the use of immunoassays in certain applications. Furthermore circulating immune complexes, heterophilic antibodies and antigen excess create challenges in assay development and laboratory professionals have an educating role is clarifying these caveats to their clinical staff. Comparability of assays between assay developers is one of the current challenges in clinical chemistry and immunology. Worldwide standardisation of immunoassays is guided by working groups of the international societies for clinical chemistry, immunology and endocrinology. For this purpose new chromatography‐mass spectrometry reference methods are being developed in combination with international reference preparations. Where those are not available harmonisation of assays is being pursued.
Preparation: To refresh and/or extend you knowledge in order to understand and appreciate this
lecture, the following educational papers from the literature are advised for reading.
Zegers I and Schimmel H. Clinical Chemistry 2014. To Harmonize and Standardize: Making Measurement Results Comparable
Miller WG et al. Clinical Chemistry 2011. Roadmap for Harmonization of Clinical Laboratory Measurement Procedures
Spencer C1, Petrovic I, Fatemi S. JCEM 2011. Current thyroglobulin autoantibody (TgAb) assays often fail to detect interfering TgAb that can result in the reporting of falsely low/undetectable serum Tg IMA values for patients with differentiated thyroid cancer.
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Lecture Wednesday 17 September 09:00‐11:00 Instructor: Dr. J.A. Bakker Title: Laboratory diagnostics in immunological disease
Goal: Diseases in which the immune system is involved are clinically heterogeneous, presenting as a systemic disease, affecting several organs, or restricted to a specific site. Laboratory diagnostics are often required to support a clinical diagnosis.
The scope of the immunological laboratory is the detection and classification of diseases with involvement of the immune system: detection of autoantibodies in the case of systemic diseases like rheumatoid arthritis (RA), scleroderma , systemic lupus erythematosus (SLE) and vasculitis. Antibodies against tissue antigens are responsible for coeliac disease, a disease which is aggravated by the consumption of gluten from the diet. Classification and quantification of M‐proteins in serum is used to detect patients with multiple myeloma . Complement activation is often the case in immunological disease, measurement of complement factors and functionality of the complement activation pathways are laboratory tools to detect aberrant complement consumption. Allergic disease is classified by the detection of antibodies against (classes of) allergens, present in our environment or in food.
Clinical cases will be used to illustrate the use of the different laboratory techniques for the detection and classification of immunological diseases.
Preparation: To refresh and/or extend you knowledge in order to understand and appreciate this
lecture, the following educational papers from the literature are advised for reading.
Vavricka S, R, Burri E, Beglinger C, Degen L, Manz M, Serum Protein Electrophoresis: An Underused but Very Useful Test. Digestion 2009;79:203‐210
Elio Tonutti, Nicola Bizzaro, Diagnosis and classification of celiac disease and gluten sensitivity, Autoimmunity Reviews, Volume 13, Issues 4–5, Pages 472‐476
Robert G. Hamilton, Clinical laboratory assessment of immediate‐type hypersensitivity, Journal of Allergy and Clinical Immunology, Volume 125, Issue 2, Supplement 2, Pages S284‐S296
Mahler M, Meroni PL, Bossuyt X, Fritzler MJ. Current concepts and future directions for the assessment of autoantibodies to cellular antigens referred to as anti‐nuclear antibodies.J Immunol Res. 2014;2014:315179. doi: 10.1155/2014/315179. Epub 2014 Apr 27.
Nilsson B, Ekdahl KN. Complement diagnostics: concepts, indications, and practical guidelines. Clin Dev Immunol. 2012;2012:962702. doi: 10.1155/2012/962702. Epub 2012 Nov12
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Lecture Thursday 18 September 9.00‐11.00 Instructor: Dr. M.J.D. van Tol, Dept. of Pediatrics Title: Lymphocyte characterisation in immunological diagnostics
Goal: Not surprisingly, phenotypic and functional characterisation of lymphocytes is a central part in the diagnosis of patients suspected of disorders affecting the immune system. In addition, investigation of lymphocytes (and other cells involved in immune defence) contributes to the understanding of the aetiology of immune diseases and the monitoring of the effect of therapy.
Techniques applied to study lymphocyte phenotype and function will be presented and their application in the diagnosis of primary immunodeficiencies (PID) will be illustrated in this lecture. Emphasis will be laid on flow cytometry (also called fluorescence activated cell sorting, FACS) enabling characterisation of lymphocytes with respect to their lineage, differentiation stage and activation state, based on the cell surface expression of certain proteins. After stimulation of cells in culture followed by intra‐ or extracellular staining, FACS is instrumental in investigation of the function of cells, e.g., their capability to produce and secrete soluble proteins such as cytokines, to express activation markers, and to proliferate. Also, the principle of lymphocyte proliferation tests as measured by 3H‐thymidine incorporation will shortly be addressed.
Next, the strategy applied to diagnose primary immunodeficiencies (PID) will be discussed. Signs and symptoms pointing towards PID will be addressed with a focus on infectious problems, because the type of agent(s) causing severe, recurrent or atypical infections may give a clue of the distinct pathway of the immune system that is impaired due to a possible genetic defect in a component relevant to that pathway. The role of laboratory techniques like FACS and in vitro lymphocyte proliferation will be illustrated in the diagnosis of three PID cases, i.e., X‐linked agammaglobulinemia (XLA), severe combined immunodeficiency (SCID) and hyper‐IgM syndrome (HIGM).
Preparation: To refresh and/or extend you knowledge in order to understand and appreciate this lecture, the following parts of the Parham textbook and educational papers from the literature are advised for reading.
Parham, The immune system, 3rd edition. Chapter 6: B cell development: Fig. 6.25 (p. 183) and summary section (p. 182); Chapter 8: T cell subsets and function: Fig. 8.27 (p. 234) and Th2‐B cell interaction: Fig. 8.37 (p. 241); Chapter 9: Th2‐B cell interaction: Fig. 9.9 (p. 255), Production Ig classes during life: Fig. 9.24 (p. 268); Chapter 10: T‐cell differentiation: Fig. 10.29 (p. 314). Read as an introduction to inherited immunodeficiency diseases: Chapter 11, sections 11‐8 (Fig. 11.9), 11‐9, 11‐11 XLA, Fig. 11.11) , 11‐12 (X‐linked hyper IgM) and 11‐15 (only part about SCID).
Driessen and van der Burg. Primary antibody deficiencies. Eur J Pediatrics, 2011; 170: 693‐702.
Van der Burg and Gennery. The expanding clinical and immunological spectrum of severe combined immunodeficiency. Eur J Pediatrics, 2011; 170: 561‐571.
De Vries and Driessen. Primary immunodeficiencies in children: a diagnostic challenge. Eur J Pediatrics, 2011; 170: 169‐177.
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Presentation case Thursday 19 September 14‐00‐17.00 Instructor: Dr. M.J.D. van Tol, Dept. of Pediatrics Goal: Students will present a first draft/overview of their clinical case
During this presentation students present the set‐up for their casus to see if they understand which topics must be addressed in the final written report regarding the casus. Students will prepare and present this presentation per group (not individually). Students will gain more information of the specific disease during the upcoming weeks. The final INDIVIDUAL report must be handed in at Friday 17th of October.
Essential components of the case:
Introduction of the disease: o Symptoms o Questions for taking patients history o Immunological mechanism behind the disease (needs extra focus!) o Relation between defective immune system and complaints o Differential diagnosis (which symptoms/elements could also be presented in other
diseases; which tests to use to exclude differential diagnosis)
Diagnostic tests: o What kind of test(s) is appropriate o What is the principle of the test o Show typical test result (including a “normal response”) o Explain how these results should be interpreted
Therapeutic plan o What kind of therapy o What is the underlying immunological principle of this therapy o How can you check if the therapy is effective?
IMPORTANT: The idea behind this presentation is that the mentors can give feedback on the set‐
up of the casus which the students present. The emphasis must be on the underlying immunological mechanisms and that the students show that they understand how the diagnostic tests work. However, detailed information about the disease will be provided in the weeks hereafter.
Study goals The student can • use basic knowledge on clinical laboratory diagnostics • show familiarity with the issues on quality, methodology and traceability in laboratory
diagnostics • explain the techniques used in immunology and the (dis)advantages of these methods, i.e.
flowcytometry, ELISA, protein assays, immunohistological techniques (Scholar) • use laboratory diagnostics in the clinical practice of Rheumatology, Allergy, Haematology,
Neurology, Nephrology, Paediatrics, and Pulmonology (Medical expert) • understand the limitations of laboratory diagnostics in resolving complex disease patterns.
create a diagnostic plan by evaluation of laboratory techniques that could be applied based on a differential diagnosis and motivate why this technique is appropriate to be able to diagnose correctly (Medical expert)
interpret results from diagnostic tests and subsequently translate which immunological defects might underlie the results
perform independently literature research based on a specific patient case and select three relevant papers to report the immunological defects and corresponding diagnostic tests and results of the patient case in detail (Scholar)
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Study materials Articles will be provided on Blackboard. • Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 5th edition by Carl A. Burtis PhD,
Edward R. Ashwood MD, David E. Bruns MD. (2011) Saunders ISBN: 978‐1‐4160‐6164‐9 • Roitt's Essential Immunology, Includes Desktop Edition, 12th edition Peter J. Delves, Seamus J.
Martin, Dennis R. Burton, Ivan M. Roitt (2011) Wiley‐Blackwell ISBN: 978‐1‐118‐23287‐3 • Essentials of Clinical Immunology, 6th Edition Helen Chapel, Mansel Haeney, Siraj Misbah, Neil
Snowden (2014) Wiley‐Blackwell ISBN : 978‐1‐118‐48785‐3 • Zegers, I., et al. (2013). "The Importance of Commutability of Reference Materials Used as
Calibrators: The Example of Ceruloplasmin." Clinical Chemistry 59(9): 1322‐1329 • C.G. Fraser Biological Variation: From Principle to Practice (2001) AACC Press • Ichihara, K. "Statistical considerations for harmonization of the global multicenter study on
reference values." Clinica Chimica Acta(2014) http://dx.doi.org/10.1016/j.cca.2014.01.025 • Senolt, L., et al. (2014). "Laboratory biomarkers or imaging in the diagnostics of rheumatoid
arthritis?" BMC Medicine 12(1): 49 • Steinman, L. (2013). Weighing In On Autoimmune Disease: 'Hub‐and‐spoke' T cell traffic in
autoimmunity. Nature Medicine, 19(2), 139‐141. doi:10.1038/nm.3088 • Anaya, J.‐M. (2012). "Common mechanisms of autoimmune diseases (the autoimmune
tautology)." Autoimmunity Reviews 11(11): 781‐784 Contact hours:
Clinicians of the respective discipline (4x) will provide the students with a patient casus
Lectures Introduction laboratory medicine
Lectures Laboratory testing in immunological disease
Laboratory visit
Short presentations (4x) by groups of maximal 5 students about their specific patient case Self‐study hours:
Prepare oral presentation
Start with the final written report Evaluation: Short oral presentation in a group about specific patient case, explaining immunological mechanisms
and diagnostics (p/f), see guidelines below program
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Laboratory visit related to clinical cases:
Group 1 Laboratory techniques involved in SLE diagnostics and follow‐up
Indirect immune fluorescence tests and immunoassays are the cornerstones for the detection of
autoantibodies involved in SLE. These techniques will be demonstrated and the students have to
perform the analyses (in part) and give an interpretation of the results in relation to the clinical case.
Group 2 Laboratory techniques in the diagnosis of Myasthenia gravis
Laboratory diagnosis of MG is based on the detection of certain antibodies. RIA methods will be
demonstrated and ELISA techniques performed.
Group 3 Atypical HUS and complement
Laboratory techniques for complement analyses will be demonstrated and (in part) the students will
perform the analyses. Interpretation of laboratory results in complement disorders in general and
aHUS particularly will be discussed.
Group 4 Allergy: laboratory techniques and pitfalls
Allergy diagnostics will be performed, both screening assays and detection of specific allergens. The
interpretation of the results will be discussed in relation to clinical symptoms.
REMARK: Standard operating procedures for the different laboratory techniques will be available
(electronically) at the start of week 3.
Guidelines Assignments:
Oral presentation casus • Prepare a presentation of ~20 min and include appropriate images • Explain symptoms of the disease (differential diagnosis?) • Explain immune mechanism behind the disease • Explain the application of the diagnostic test (medical conditions) • Explain the principle of the diagnostic test • Show a typical test result (including the range of a ‘normal’ response) • Explain how these results should be interpreted • Therapeutic plan Detailed program and study material: Week 3:
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Time Activity Title Teacher
9:00‐10:00 Distribution patient case
Distribution and small (10 min)
presentation of MG, SLE, aHUS, and
Allergy)
Dr. D. van der Woude / Dr. J.
de Vries‐Bouwstra, Dr. J.J.
Plomp, prof. Dr. J.J.
Verschuuren, Dr. J.G.
Koopmans, Dr. A. Slats, Dr. O.
Teng, Dr. A. de Vries
10:15 – 12:15 LectureEvidence bases use of medical
tests in laboratory scienceDr. C.M. Cobbaert
13:30 – 15:00Group 1: Laboratory visit
SLE
Clinical Chemistry Laboratory /
Immunology unitDr. J.A.. Bakker
15:00 – 17:30 Self‐study Work on patient case
9:00 – 11:00 Lecture
Immunoassays beyond
immunology: Assay characteristics
and quality issues
Dr. B.E.P. Ballieux
13:30 – 15:00Group I1: Laboratory visit:
aHUS
Clinical Chemistry Laboratory /
Immunology unitDr. J.A.. Bakker
15:00 – 17:30 Self‐study Work on patient case
9:00 – 11:00 LectureLaboratory diagnostics in
immunological disease IIDr. J.A, Bakker
13:30 – 15:00Group II1: Laboratory visit:
Allergy
Clinical Chemistry Laboratory /
Immunology unitDr. J.A.. Bakker
15:00 – 17:30 Self‐study Work on patient case
9:00‐11:00 Lecture Lymphocyte characterisation in
immunological diagnostics Dr. M.J.D. van Tol
13:30 – 15:00Group IV: Laboratory visit:
MG
Clinical Chemistry Laboratory /
Immunology unitDr. J.A.. Bakker
15:00 – 17:30 Self‐study Work on patient case
9:00‐12:00 Self studyPreparation of presentation case
studies
14:00‐14:45 MGProf. dr. J.J.G.M. Verschuuren,
Dr. J.J. Plomp
14:45‐15:30 SLEDr. D. van der Woude
Dr. J. de Vries‐Bouwstra
15:30‐16:15 aHUS Dr. O. Teng, Dr. A. de Vries
16:15‐17:00 AllergyDr. J.G. Koopmans,
Dr. A. Slats
Monday
15‐sep‐14
Tuesday
16‐sep‐14
Wednesday
17‐sep‐14
Thursday
18‐sep‐14
Friday
19‐sep‐14
Student presentations
42
Neuro‐immunology
Clinical coordinator: Prof. Dr. J.J.G.M. Verschuuren (Neurology) Scientific coordinator: Dr. J.J. Plomp (Neurology) Other teachers involved: Dr. U.A. Badrising (Neurology) Drs. A.F. Lipka (Neurology)
Dr. E.L.E.M. Bollen (Neurology)
Background
Neuroimmunology is concerned with interactions between the immune system and the nervous system. Disturbances in these mechanisms can lead to neurological disease. The field is relatively young; immune system involvement in many of the neuroimmunological disorders has only been recognized for the last few decades. It is also a rapidly developing field; many aspects of the pathogenic mechanisms are nowadays being discovered with the aid of modern genetic and immunological research methods. As a result, specific drug therapies are currently beginning to emerge. However, in many neuroimmunological disorders the underlying (auto)immune and neuropathogenic disease mechanisms are still poorly understood and therapies are insufficient or accompanied by considerable side effects. For long it was thought that the central nervous system (CNS) was completely protected from entry of immune cells, immune mediator molecules and antibodies by the blood‐brain barrier (BBB). Similarly, nerves in the peripheral nervous system (PNS) were thought to be protected by a blood‐nerve barrier (BNB). Both barriers are mainly formed by the microvascular endothelial cells which are strongly attached to each other through tight junction molecules, preventing passage of cells and large molecules from the blood into the neuronal tissue. However, recent findings have changed this view as it seems that many of the neuroimmunological disorders have an initial phase in which the BBB or BNB becomes injured and allows for leakage of immune factors into the nervous system. Subsequently neuropathogenic effects take place which lead to the neurological symptoms. The neuromuscular junction, forming the synaptic contact between a motor axon and a skeletal muscle fibre, is extra vulnerable for autoimmune attack as it lacks a BNB. The resulting damage will block neurotransmission and thus lead to muscle weakness. Myasthenia Gravis (MG) and Lambert‐Eaton myasthenic syndrome (LEMS) (Prof. Dr. J.J.G.M. Verschuuren) MG is an acquired autoimmune disorder in which autoantibodies attack crucial membrane components of the neuromuscular junction (NMJ), the synapse which transmit impulses from the motor nerve onto the muscle fibre. The resulting transmission block causes fatigable muscle weakness. As for most autoimmune disorders, the immuno‐etiology leading to the loss of self‐tolerance in MG is poorly understood and likely involves interplay of (immuno)genetic, epigenetic and environmental factors. Most MG patient have antibodies against postsynaptic acetylcholine receptors at the NMJ. Administration of immunosuppressants and cholinesterase‐inhibitors are the main drug treatments. About 15% of the MG patients have no acetylcholine receptor antibodies. In recent years, antibodies to other NMJ membrane proteins have been shown for an increasing part of these patients.
LEMS is a rare disorder, clinically distinct from MG. There are antibodies against presynaptic calcium channels at the NMJ, causing block of acetylcholine release. About 50% of LEMS patients has an underlying small‐cell lung cancer. Treatment options are limited.
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Inclusion‐body myositis (IBM) (Dr. UA Badrising) IBM is the most common acquired muscle disease in people aged >45 years. There is progressive muscle weakness causing serious disability. Together with dermatomyositis and polymyositis, IBM belongs to a group of idiopathic inflammatory myopathies, with inflammatory infiltrates in skeletal muscle. Diagnosis is made upon the clinical features in combination with typical muscle biopsy features, including invasion of non‐necrotic fibres by mononuclear cells, vacuolated muscle fibres and intracellular amyloid deposits. Treatment options are very limited. Although IBM is less responsive to immunomodulatory therapy as compared to the other forms of myositis there are several indications that the immune system plays an important pathogenic role. Very recently, specific autoantibodies have been found associated, but it is still unknown whether these are causing the disease. Guillain‐Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) (Drs. AF Lipka) GBS is an acute and potentially severe neurological disorder, hallmarked by paralysis and sensory disturbances. Often the disease is preceded by an microbial infection, which most likely triggers the production of anti‐microbial antibodies that have the ability to cross‐react with antigens of motor and sensory peripheral nerves. Several types of auto‐antibodies have been discovered, including antibodies against gangliosides, which are neuronal membrane components. The disease is mostly self‐limiting with rather good recovery, but a large part of patients needs to be ventilated for some period. Often there is demyelinization of nerves. Main treatments are the removal of IgG through plasma‐exchange and intravenous administration of large amounts of human immunoglobulins, believed to neutralize the pathogenic antibodies. There is also a chronic variant of the disease, CIDP, which is treated more or less similarly. Multiple sclerosis (MS) (Dr. E.L.E.M. Bollen) MS is an autoimmune disease characterized by chronic inflammation and demyelination of axons in the CNS and occasionally also the PNS. Clinical presentation and course of the disease are highly variable. Common symptoms include numbness, weakness, visual disturbances, diplopia, coordination and gait disturbances, etc. The majority of patients has a relapsing and remitting course but in a smaller part the symptoms progress. Diagnosis is mainly clinical with the aid of MRI; there is no laboratory test. There is no definite cure for MS, but immunomodulatory drugs are often used, including beta‐interferons in certain cases. Neuromuscular junction (NMJ) laboratory demonstration (Dr. J.J. Plomp) You will visit in small groups of students our laboratory in which function and morphology of NMJs are studied. In this demonstration we will explain to you how we can experimentally analyze NMJs in muscle preparations of experimental animals and muscle biopsies of human patients. The visit will include hands‐on practice with micro‐electrode study of the synaptic electrophysiological signals which underlie neurotransmission in the NMJ. Furthermore, you will get the opportunity to observe NMJs under a fluorescence microscope. Summary program Neuro‐immunology week: In this Neuro‐immunology course week we will focus on the symptoms, diagnosis, (immuno‐)etiology, epidemiology, pathophysiology and current and emerging treatments of several prototypical neuro‐immunological disorders. The topics cover the most important areas of the nervous system: 1) multiple sclerosis (MS), a chronic autoimmune disease of (mainly) the CNS, 2) Guillain‐Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) which are an acute and a chronic variant of PNS autoimmunity, respectively, and 3) myasthenia gravis (MG)
44
and Lambert‐Eaton myasthenic syndrome (LEMS), autoimmune disorders of the neuromuscular junction. Besides the CNS and PNS, also skeletal muscle can be the target of autoimmunity. Patients with these types of disease are suffering from muscle weakness and are also diagnosed and treated by the neurologist. In this course week we will also teach you on an example of such a muscle disorder, inclusion body myositis (IBM). The study program for each disorder encompasses self‐study of relevant literature, a patient demonstration, a lecture and a workgroup. There will be visit to the neuromuscular synapse research laboratory. Groups of maximal 5 students will together produce a review‐like report on one of the neuro‐immunological disorder topics. This has to be handed in at the end of the week and will be evaluated.
Study goals
The student can
diagnose a patient by taking a patient’s history with a patient suspected to suffer from an neurological immunological disorder
determine the defects of the immune system that might underlie the complaints of a patient diagnosed with an neuro‐immunological disorder
relate the mechanism of disease of a systemic auto‐immune disease to neuronal involvement by understanding the defect immune components related to the disorder
develop a therapeutic plan based on results from diagnostic tests from week 3 and neurological laboratory tests to confirm a neurological disorder and describe a laboratory test to check the effect of the intervention.
perform independently literature research based on a specific patient casus and select relevant review articles to report the immunological background of the patient casus in detail for the report in this week and in week 8
Study materials Book: The immune system (Peter Parham) Suggested review article reading (pdf's will be put on Blackboard):
Diamond et al. Losing your nerves? Maybe it’s the antibodies. Nat Rev Immunol 2009;9: 449.
Kamm and Zettl. Autoimmune disorders affecting both the central and peripheral nervous system. Autoimmun Rev 2012;11:196.
Kanda. Biology of the blood–nerve barrier and its alteration in immune mediated neuropathies. J Neurol Neurosurg Psychiatry 2013;84:208.
Kieseier et al. Autoimmune diseases of the peripheral nervous system. Autoimmun Rev 2012;11:191.
Machado et al. Update in inclusion body myositis. Curr Opin Rheumatol 2013;25:763.
Muldoon et al. Immunologic privilege in the central nervous system and the blood–brain barrier. J Cereb Blood Flow Metab 2013;33:13.
Peltier and Donofrio. Chronic inflammatory demyelinating polyradiculoneuropathy: from bench to bedside. Semin Neurol 2012;32:187.
Selmi et al. A clear look at the neuroimmunology of multiple sclerosis and beyond. Autoimmun Rev 2012;11:159.
Titulaer et al. Lancet Neurol 2011;10:1098. Lambert‐Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies.
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Verschuuren et al. Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle‐specific kinase and low‐density lipoprotein receptor‐related protein 4. Autoimmun Rev 2013;12:918. Contact hours:
Patient demonstration followed by a lecture: 1) MG, LEMS: Prof. dr. J.J.G.M. Verschuuren 2) IBM: Dr. U.A. Badrising 3) MS: Dr. E.L.E.M. Bollen 4) GBS/CIDP: Dr. A.F. Lipka
Work group 1) MG, LEMS: Prof. dr. J.J.G.M. Verschuuren 2) IBM: Dr. U.A. Badrising 3) MS: Dr. E.L.E.M. Bollen
4) GBS/CIDP: Dr. A.F. Lipka
Laboratory visit to the neuromuscular synapse research laboratory: Dr. J.J. Plomp Self‐study hours:
Prepare for patient demonstration and workgroups by reading about neuro‐immunological disorders and suggested review articles
Prepare a review report in groups of maximal 5 students about one neuro‐immunological disease Evaluation:
Written report (Passed/Failed), see guidelines below program Guidelines written report:
Review report
Students with MG casus for the report of week 8 should choose this week another neuro‐immunological disorder
In groups of max 5 students, one report (900‐1100 words) will be prepared consisting of: o Background disease and symptoms (~200 words) o Diagnosis (~200 words) o Pathophysiology (~200 words) o State of art laboratory research (~200 words) o Treatment (~200 words) o Every student will prepare one chapter and each part is evaluated (passed/failed)
separately
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Detailed program and study material: Week 4:
Time Activity Title Teacher
9:00‐11:00 Self‐study Prepare topic today (MS)
11:00 ‐11:45 Lecture MS Bollen
11:45 ‐ 12:15 Patient demonstration MS Bollen
12:15 ‐ 13:15 Break
13:15 ‐ 14:30 Workgroup MS Bollen
14:30 ‐ 15:00 Break
15:00 ‐ 16:30 Group 1: Laboratory visit NMJ research laboratory visit Plomp
15:00 ‐ 17:30 Self‐study Work on report/prepare
tomorrow's topic
9:00‐11:00 Self‐study Prepare topic today (MG and LEMS)
11:00 ‐11:45 Lecture MG and LEMS Verschuuren
11:45 ‐ 12:15 Patient demonstration MG and LEMS Verschuuren
12:15 ‐ 13:15 Break
13:15 ‐ 14:30 Workgroup MG and LEMS Verschuuren
14:30 ‐ 15:00 Break
15:00 ‐ 16:30 Group 2: Laboratory visit NMJ research laboratory visit Plomp
15:00 ‐ 17:30 Self‐study Work on report/prepare
tomorrow's topic
13:30 ‐ 14:15 Lecture IBM Badrising
14:30 ‐ 15:00 Patient demonstration IBM Badrising
15:00‐16:15 Workgroup IBM Badrising
16:30‐17:00 Group 3: Laboratory visit Plomp
9:00‐11:00 Self‐study Prepare topic today (GBS and CIDP)
11:00 ‐11:45 Lecture GBS and CIDP Lipka
11:45 ‐ 12:15 Patient demonstration GBS and CIDP Lipka
12:15 ‐ 13:15 Break
13:15 ‐ 14:30 Workgroup GBS and CIDP Lipka
14:30 ‐ 15:00 Break
15:00 ‐ 16:30 Group 4: Laboratory visit NMJ research laboratory visit Plomp
15:00 ‐ 17:30 Self‐study Work on report/prepare
tomorrow's topic
9:00‐17:30 Self‐study Prepare report
Thursday
25‐sep‐14
Friday
26‐sep‐14
Monday
22‐sep‐14
Tuesday
23‐sep‐14
Wednesday
24‐sep‐14
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2. Rheumatology
Clinical coordinator: Dr. J.K. de Vries‐Bouwstra (Rheumatology) Scientific coordinator: Dr. M. Bax (Rheumatology)/Dr. K.L.L. Habets (Rheumatology) Other teachers involved: Dr. D. van der Woude (Rheumatology) Prof dr. R.E.M. Toes (Rheumatology) Dr. F.A. van Gaalen (Rheumatology)
Prof. dr. T.W.J. Huizinga (Rheumatology))
Background
The field of rheumatology concerns the care of patients with immune‐mediated chronic inflammatory diseases. As such, clinical rheumatology composes an essential part of the ½ minor clinical immunology. The development of new targeted, biologic therapies, like TNFα‐ blockers, during the past decades resulted in enormous improvement of patients suffering from rheumatic diseases. Development of these drugs is a direct result from increasing knowledge on the cellular and molecular basis of immune responses, perfectly demonstrating the relevance of knowledge on the pathophysiologic background of immune mediated diseases. Summary program Rheumatology week: During the week that you will visit the department of Rheumatology, four chronic immune mediated diseases with different immunological backgrounds will be demonstrated and discussed in detail:1. Rheumatoid arthritis, 2. Systemic Lupus Erythematosus, 3. Spondyloarthritis and 4. Systemic Sclerosis. Four groups of students will be formed; each group will focus on one of the four diseases during the rest of the week. At the end of the week, you will give a presentation on novel insights in the pathogenetic background of the specific disease and propose a possible novel drug targets based on your knowledge of pathophysiology. As all lectures and presentations will be scheduled with the whole group, you will assemble knowledge on all of the four diseases. On the first day lectures are scheduled providing an introduction on each of these diseases by experts in the field. Following these presentations, you will be provided with literature on basic pathophysiology of the different diseases, as well as a clinical case study describing the specific clinical features in relation to the immunologic background. The second day 4 patients suffering from these disease will participate in a clinical case demonstration. Students will get the opportunity to perform medical history taking and limited physical examination (skin, joints). Following these case demonstrations each group of students will receive a recent article on new insights in the immunological background of the specific disease. These articles will form the cornerstone for the final presentation. In addition, students will visit the rheumatology laboratory and participate in incubation of the anti‐cyclic citrullinated peptide (ACPA) ELISA. The third day comprises a clinical round in rheumatology: students will visit the day care department where patients with active disease and/ or limitations in everyday activities are treated by a multidisciplinary team consisting of a rheumatologist, a specialised nurse, a physical therapist, an occupational therapist and a social worker. Also, students will get the opportunity to perform a joint puncture on joint models, and nailfold capillaroscopy will be demonstrated (a diagnostic tool in Raynaud’s phenomenon). After the clinical round, students will visit the laboratory again to read‐out the ACPA test.
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On the fourth day, in the afternoon, all students will give a presentation on novel insights on the immunologic background of specific disease they focussed on, concluding with a proposal for development of innovative therapy. Study goals The student can
diagnose a patient by performing an anamnesis with a patient suffering from joint pain (Medical expert)
perform independently literature research based on a specific patient casus and select three relevant papers to report the immunological background of the patient casus in detail. (Academic)
determine the pathogenic mechanism(s) based on literature research that might underlie the complaints of a patient diagnosed with a rheumatic disease
relate the mechanism of disease of a systemic auto‐immune disease to joint involvement by understanding the defect immune components related to the disorder
develop a therapeutic plan based on results from diagnostic tests of week 3 and describe the method to check the effect of the intervention
Study materials
The immune system (Peter Parham)
Case studies from immunology – clinical case studies and disease pathophysiology (Strober and Gottesman, 2009 (Blackboard)
RA, SLE, Scleroderma, and SpA; specific chapters from EULAR compendium on rheumatic diseases (Blackboard)
Case studies in immunology (Geha 2011): RA and SLE (Blackboard)
Recent published articles (Blackboard) Contact hours:
Lectures and distribution recent literature on immunological background of rheumatic diseases 1) RA
2) SLE 3) SpA 4) Scleroderma
Consult demonstration with four patients suffering from four different rheumatic diseases, final diagnosis after discussion by students with help from clinicians
Clinical rounds RAZ (Reumatologie ambulante zorg)
Joint puncture (on joint models)
Nailfold capillaroscopy
Laboratory visit detection of auto‐antibodies
Presentations of groups of max 5 students about one rheumatic disease (RA, SLE, SpA, Scleroderma) and new drug targets prepared with recent literature and knowledge obtained in previous days
Self‐study hours: • Read Immunological background of all demonstrated rheumatic disorders (RA, SLE, SpA,
Scleroderma) • Read recent literature break through articles • Prepare a presentation about possible new drug targets for specific rheumatic diseases
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Evaluation:
Oral presentation about one rheumatic disease and drug targets in groups of maximal 5 students (p/f), see guidelines below program
Guidelines oral presentation:
Oral presentation rheumatic disease:
Students with SLE casus for the report of week 8 should choose this week another rheumatic disease
In groups of max 5 students, one presentation of ~20 minutes will be prepared consisting of:
Background disease and symptoms
Diagnosis
Immunological background of disease
State of art laboratory research
Treatment
Every student will prepare one part of the presentation and three persons will present while the
two others will answer the questions in the discussion. Each student is evaluated separately
(passed/failed)
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Detailed program: Week 5:
Time Activity Title Teacher
9:00‐9:30 Lecture Lecture RA Prof. dr R.E.M. Toes
9:30‐10:00 Lecture Lecture SLE Dr. D. van der Woude
10:00‐10:30 Lecture Lecture SpA Dr. F.A. van Gaalen
10:30‐11:00 Lecture Lecture Scleroderma Dr. J.K. de Vries‐Bouwstra
11:00‐11:15 Distribution review articles
11:00‐17:00 Self‐studySelf‐study immunology behind
arthritic diseases
9:00:11.00 Patient demonstrations
Interactive Consult
demonstrations 4 patients with
different diseases
Dr. D. van der Woude and dr.
J.K. de Vries‐Bouwstra
11:00‐11:15 Distribution article for case study
11:00‐13:00 Laboratory visit part I
Introduction on commonly used
tests for autoantibodies +
incubation CCP ELISA
dr. L.A. Trouw
13:00‐17:00 Self‐study Read literature and prepare
presentation
9:00‐12:00 Clinical roundMultidisciplinary day care, joint
puncture, nailfold capillaroscopy
Dr. D. Van der Woude/
Dr J. de Vries‐Bouwstra
12:00‐13:00 Break
13:00‐14:00 Laboratory visit part II Read‐out and analyse CCP ELISA Dr. L.A. Trouw
14:00‐17:00 Self‐study Read literature and prepare
presentation
9:00‐13:00 Self‐study Read literature and prepare
presentation
13:00‐13:30 Student presentation RA Prof dr. R.E.M. Toes
13:30‐14:00 Student presentation SLE Dr. D. van der Woude
14:00‐14:30 Break
14:30‐15:00 Student presentation SpA Dr. F.A. van Gaalen
15:00‐15:30 Student presentation Scleroderma Dr. J.K. de Vries‐Bouwstra
15:30‐16:00 Evaluation of the presentations all mentors
Thursday
02‐Oct‐2014
Student presentations
Friday
03‐Oct‐2014
Free day: Leids ontzet
Monday
29‐sep‐14
Tuesday
30‐sep‐14
Wednesday
01‐Oct‐2014
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3. Pulmonology
Clinical coordinator: Prof. dr. C. Taube Scientific coordinator: Prof. dr. P.S. Hiemstra Other teachers involved: Dr. S. de Kleijn, Dr. J. Stolk, Ir. R. Schot, Dr. B.C. Stoel, Dr. L.N.A. Willems,
Drs. P. Khedoe, Drs. G.D. Amatngalim, Drs. Y. van Wijck, Mw. B.C.M. Bos‐van Noort, Dr. A.M. Slats, Mw. A. van Schadewijk, Drs. E.P.M. van der Vlugt, Drs. M. Zarcone, Dr. J.G Koopmans
Background The immune system is critically involved in a large numbers of diseases, including infectious diseases, chronic inflammatory diseases such as allergies and auto‐immune diseases, and cancer. Therefore detailed knowledge of the immune system is essential for optimal diagnosis and patient care, and crucial for the development of new insights and treatment options based on basic, translational as well as clinical research. The availability of new biologicals such as monoclonal antibodies to modulate the immune system (in addition to more traditional anti‐inflammatory treatment and vaccination strategies for infectious diseases) offers novel strategies for treatment of patients with diseases associated with substantial morbidity and mortality. Inhibition of the pro‐inflammatory cytokine TNF‐α with the afore mentioned biologicals has been successfully introduced as an important treatment for large numbers of patients with rheumatoid arthritis. Importantly, treatment options based on modulation of e.g. IgE and cytokine activity are now also introduced for the treatment of chronic inflammatory lung diseases. Summary program Pulmonology week: In this week we will largely focus on asthma and chronic obstructive lung disease (COPD). We will start by covering the basics: anatomy, physiology, cell biology and immunology of the lung. Following an introduction into asthma and COPD, patient demonstrations and discussions of diagnostic procedures will be used to link theory to clinical practice. Next we will discuss the pros and cons of in vitro cell culture models, and in vivo human and animal models, to explore how these can help us provide new insight and define novel drug targets for asthma and COPD. Finally we will discuss the impact of the environment, life style and genetics on development of asthma and COPD.
Study goals The student can
diagnose a patient suffering from oppression by taking a patient’s history. (Medical expert)
determine the pathogenic mechanism(s) that might underlie the complaints of a patient diagnosed with an airway disorder and define immunological differences between asthma, COPD and allergy
create a diagnostic plan by evaluation of laboratory techniques that could be applied to be able to diagnose airway inflammations correctly, and motivate why this technique is appropriate. (Medical expert)
develop a diagnostic and therapeutic plan for an allergy, asthma, and COPD patient and describe the method to check the effect of the intervention.
present convincingly the immunological disorders underlying lung diseases and novel research directions and immunological therapeutics based on a literature
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Study materials
The immune system (Peter Parham)
Allergy handbook (Dept of Pulmonology)
Pathophysiology of disease by Mc Phee: Chapter Pulmonary disease (except pulmonary edema and lung embolism)
Recent published articles (Blackboard) (1) Barnes PJ. Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev
Immunol 2008 Mar;8(3):183‐92. (2) Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat
Med 2012 May 4;18(5):716‐25. (3) Heederik D, von Mutius E. Does diversity of environmental microbial exposure matter for the
occurrence of allergy and asthma? Journal of Allergy and Clinical Immunology 2012 Jul;130(1):44‐50.
(4) Brusselle GG, Joos GF, Bracke KR. New insights into the immunology of chronic obstructive pulmonary disease. The Lancet 2011 Sep 10;378(9795):1015‐26.
Contact hours:
Lectures and distribution of (review) papers about immunological mechanisms and pathophysiology in different airway diseases and current concepts in novel therapeutics as well as novel research directions
Interactive consult demonstrations with patient suffering from airway disease
Practical demonstration of diagnostic and research tools
Microscopic analysis of lung tissue
Interactive mini‐symposium
Student presentations
Self‐study hours: • Study recent research articles and review articles about the immunological mechanism behind
asthma, COPD and allergic airway disease, and novel immunological therapeutics in asthma, COPD, and allergic airway disease
• Divide the students over three groups and they have to prepare a presentation about immunological mechanisms, novel research directions, and novel immunological therapeutics in Asthma, Allergic disease, COPD.
Evaluation: Oral presentation about one airway disease in groups of maximal 5 students (p/f), see guideline below program Guidelines oral presentation: Oral presentation Pulmonology:
Students with Allergy case for the report of week 8 should choose this week another airway disease
In groups of students, one presentation of ~30 minutes will be prepared based on mini
symposium
Each student is evaluated separately (passed/failed)
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Detailed program: Week 6:
Time Activity Title Teacher
9:00‐10:30Anatomy and Physiology of the
lungDr. L.N.A. Willems
10:30‐11:00 Questions and break
11:00‐12:00Cell biology and host defense of
the lungProf. dr. P.S. Hiemstra
12:00‐13:00
Introduction COPD and asthma
and distribution of self‐study
material
Prof. dr. C. Taube
13:00‐17:00 Self‐study Immunology of asthma and COPD
9:00‐9:30 Questions self‐study Prof. dr. P.S. Hiemstra and
Prof. dr. C. Taube
9:30‐11:00 Patient demonstration
Interactive consult
demonstrations of patients with
asthma and COPD
Dr. J. Stolk, Prof. dr. C. Taube,
Dr. L.N.A. Willems
11:00‐11:15 Break
11:15‐13:00 Diagnostics
Diagnostic procedures: allergy,
lung function, and imaging and
distribution self‐study literature
Prof. dr. P.S. Hiemstra, Dr. J.
Stolk, Ir. R. Schot, Dr. B.C.
Stoel
13:00‐17:00 Self‐study Read literature and prepare
presentation
9:00‐9:45In vivo models for allergic airways
diseaseDr. S. de Kleijn
9:45‐10:30 In vivo models for COPD Drs. P. Khedoe
10:30‐11:15Cell culture models in asthma and
COPD
Drs. G.D. Amatngalim and
Drs. Y. van Wijck
11:15‐12:00
Clinical research in asthma and
COPD: pitfalls and practical
aspects
B.C.M. Bos‐van Noort, Dr. A.M.
Slats, Dr. J. Stolk
12:00‐12:30 Break
12:30‐13:30 Lunch meeting Lunch meeting: PulmoScience
13:30‐14:15 Laboratory Microscopic analysis of lung tissue Mw. A. van Schadewijk
14:15‐17:00 Self‐study Read literature
9:00‐13:00 Symposium
Interactive mini‐symposium: Life
style, genetics and inflammatory
lung diseases.
Prof. dr. P.S. Hiemstra, Prof.
dr. C. Taube, Drs. E.P.M. van
der Vlugt, Drs. M. Zarcone
13:00‐13:30 Break
13:30‐17:00 Self‐study
Reading literature and
preparation of presentations
based on mini‐symposium
9:00‐10:00 Question hour for presentations Prof. dr. P.S. Hiemstra
10:00‐11:30 Self‐study Preparation of presentations
11:30‐13:00 Students presentations
13:00‐13:30 Break
13:30‐15:00 Student presentations
Prof. dr. P.S. Hiemstra, Dr. S.
de Kleijn, Prof. dr. C. Taube,
Dr. L.N.A. Willems
Lectures
Thursday 09‐Oct‐2014
Friday 10‐Oct‐2014
Monday 06‐Oct‐2014
Lectures
Tuesday 07‐Oct‐2014
Wednesday 08‐Oct‐2014
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4. Nephrology
Clinical coordinator: Dr. A.P.J. de Vries (Nephrology) Scientific coordinator: Prof. dr. C. van Kooten (Nephrology) Other teachers involved: Prof. dr. J.W. de Fijter (Nephrology), Prof. Dr. T. Rabelink (Nephrology),
Prof. dr. A.F. Cohen (Nephrology), Dr. M.E.J. Reinders (Nephrology), Dr. D.L. Roelen (Immunohematology and blood transfusion), Dr. Y.K.O. Teng (Nephrology), Drs. H. Bouwsma (Nephrology), Dr. M. de Boer (Infectious diseases), Dr. F. Kroon (Infectious diseases), Drs. D.J.A.R. Moes (KFT)
Background
The primary glomerulopathies are often auto‐immune diseases with an immunologic response to self in the kidney. Activation of the innate (complement) and/or acquired immune systems (B‐cells, T‐cells) play an important role in glomerular pathology. In the past century, lack of understanding of the involved pathophysiological pathways lead to induction treatments that consisted largely of non‐targeted therapy with corticosteroids (prednisolone) or chemotherapy (cyclophosphamide). These non‐directed treatments resulted in serious side‐effects and toxicity, such as opportunistic infection, metabolic complications, and increased risk of malignancy. Steroid‐sparing maintenance strategies were developed with the advent of novel oral immunosuppressants from the transplant setting such as azathioprine and mycophenolate. These steroid‐sparing alternatives have often a less toxic profile and were a significant improvement of the nephrologist’s therapeutic armamentarium. Over recent decades, growing insight in the biomolecular pathways of the immune system and kidney disease has resulted in novel therapeutic antibodies (“biologicals”) that often target more specific pathways with less unwanted side‐effects. Still, it remains a challenge for the nephrologist to navigate between over‐ and under‐immunosuppression as biomarkers to precisely monitor immune status and disease activity are often lacking. Since immunosuppression merely suppresses and not cures disease, a large portion of patients will still progress to end‐stage renal disease. Kidney transplantation has become a successful renal replacement therapy for patients with end‐stage renal disease, and is a model of allo‐immunity. Over the past three decades, advances in histocompatibility testing and immunosuppressive drug therapy have led to dramatic declines in the incidence of acute rejection in the first few months after transplantation. As a result, 1‐year graft survival has increased substantially, and attention has shifted towards reducing the incidence of late allograft failure. Increased and better immunosuppressive drugs take their toll as viral and malignant complications. Death with a functioning allograft and chronic rejection cause the majority of late allograft failures nowadays. Because much of the mortality in the late post‐transplantation period can be directly or indirectly linked to complications of immunosuppression, a number of studies have examined whether one or more agents can be safely withdrawn. This strategy is designed to capture the early benefit of acute rejection without paying the price of long‐term toxicity but still avoiding chronic rejection. It would seem that more specific therapeutic regimens might require better therapeutic drug monitoring or even more targeted therapy or tailor‐made to individual patients. Alternatively, more detailed knowledge of allo‐immunity may reveal non‐variant points that can be more universally targeted. Thus, donor‐specific tolerance, defined as a state of systemic non‐responsiveness to allograft without the need for immunosuppressive drugs, is still the “holy grail” of transplantation.
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Summary program Nephrology week: In this week you will get general understanding of auto‐immunity, allo‐immunity, immunosuppression, and associated complications from a clinical nephrology perspective.
Study goals The student can
understand the immunological mechanism(s) that underlie a selection of immune‐mediated kidney diseases
describe medical presentation, serology and histopathology to clinically diagnose a selection of immune‐mediated kidney diseases (Medical expert)
describe the biology of the immune system and understand the concepts of auto‐immunity and allo‐immunity
understand the immunological mechanism(s) that underlie transplant tolerance or rejection and describe the relevance of immunogenetics and tissue typing
determine the pathogenic mechanism(s) that might underlie transplant rejection or acceptation and predict the change of acceptation of a donor organ in a specific patient casus
define selected auto‐immune nephritic disorders and explain if a kidney transplantation would be beneficial for the specific patient (Medical expert)
describe various classes of immunosuppressive drugs to treat kidney disease and prevent rejection after transplantation, including the role of therapeutic drug monitoring and the role of targeted therapy with biologicals (Medical expert)
describe side‐effects of immunosuppression such as opportunistic infections.
develop a therapeutic plan based on results from diagnostic tests and corresponding diagnosis (complement disorder (a‐Hus) and SLE casus received in week 3) (Medical expert, Academic)
explain and report the mechanism of action and clinical evidence, effectiveness, and safety based on recent literature of an immunomodulatory agent used in transplantation or clinical nephrology (Academic and Medical expert)
understand the patient perspective of chronic immunosuppressive therapy (Medical expert) Preparation Medical students: It is expected that students will recapitulate relevant subthemes on:
- Year 1: from Basis to Homeostasis: construction and function of kidneys, glomerular and tubular functions
- Year 2: Mechanism of disease: immunity, pathology, transplantation - Year 2: Chest and Kidney: primary glomerulonephritis
Biomedical sciences students:
- Year 2: Immunology. - Year 2: Human pathology: nephropathology and clinical nephrology
Study materials (see Blackboard) Core Books (relevant chapters from): The immune system (Peter Parham) Kumar, Clinical Medicine, 8th Edition,
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Advised Books (relevant chapters from) Feehally, Comprehensive Clinical Nephrology, 4th Edition Hricik, Primer on Transplantation, 3rd Edition Roitt, Essential Immunology, 12th Edition References that might be used to study specific topics or prepare the report: 1) Noris M et al. Atypical haemolytic uremic syndrome. N Engl J Med 2009; 361(17): 1676‐87. 2) Legendre CM et al. Terminal complement inhibitor eculizumab in atypical haemolytic uremic syndrome. N Engl J Med 2013; 368(23): 2169‐81. 3) Ardissino G et al. Discontinuation of eculizumab maintenance treatment for atypical haemolytic uremic syndrome: a report of 10 cases. Am J Kidn Disease 2014; doi: 10.1053/j.ajkd.2014.01.434 4) Nishimura J et al. Genetic variants in C5 and poor response to eculizumab. N Engl J Med 2014; 270(7): 632‐9. 5) Rovin BH et al. Lupus nephritis: the evolving role of novel therapeutics. Am J Kidn Dis 2014;63(4):677‐90. 6) Borchers AT et al. Lupus nephritis: a critical review. Autoimmun Rev 2012; 12:174‐194 7) Jones et al. Rituximab vs. Cyclophosphamide in ANCA‐associated renal vasculitis. N Engl J Med. 2010; 363:211‐220. 8) Stone et al. Rituximab vs. Cyclophosphamide for ANCA‐associated vasculitis. N Engl J Med 2010; 363: 221‐232. 9) Nankivell BJ et al. Rejection of the kidney allograft. N Engl J Med 2010; 363: 1451‐62. 10) Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004; 351: 2715‐29. 11) Susal C et al. Current role of human leukocyte antigen matching in kidney transplantation. Curr Opin Organ Transplant 2013; 18(4): 438‐44. 12) Becker LE et al. Kidney transplantation across HLA and ABO antibody barriers. Curr Opin Organ Transplant 2013; 18(4): 445‐54. 13) Hanaway et al. Alemtuzumab induction in renal transplantation. N Engl J Med 2011; 364: 1909‐19. 14) Garnock‐Jones KP. Belatacept: in adult kidney transplant recipients. BioDrugs 2012; 26(6):413‐24. 15) Vincenti F et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med 2005; 353‐770‐781 16) Loupy et al. Complement binding anti‐HLA antibodies and kidney allograft survival. N Engl J Med 2013; 369:1215‐1226 17) Fishman JA. Infection in solid‐organ transplant recipients. N Engl J Med 2007; 357: 2601‐14 18) Stock P et al. Outcomes of kidney transplantation in HIV‐infected recipients. N Engl J Med 2010; 363: 2004‐2014. 19) Moes DJ et al. Effect op CYP3A4*22, CYP3A5*3, CYP3A combined genotypes on cyclosporine, everolimus, and tacrolimus pharmacokinetics in renal transplantation. CPT Pharmacometrics Syst Pharmacol 2014; 12.; e100 doi: 10.1038/psp.2013.78
Contact hours:
Lectures
Histopathology rounds
Clinical Rounds on the Nephrology or Transplant ward
Self‐study hours: • Read about nephritic disorders and transplantation • Focus on one immune modulatory agent (belatacept, belimumab, eculizumab, alemtuzumab,
rituximab, or ATG) to prepare an individual report about the working mechanism and clinical evidence, effectiveness, and safety with recent literature and other information sources
Evaluation: Individually written report on one immune modulatory agent (belatacept, belimumab, eculizumab, alemtuzumab, rituximab, or ATG) about the working mechanism, clinical evidence, effectiveness, and safety (p/f), see guidelines below program. Guidelines written report (Passed/Failed): All students will write individually a small report (900‐1100 words) about one target therapy
(belatacept, belimumab, eculizumab, alemtuzumab, rituximab, or ATG). Topics to be included in the
report:
• working mechanism
• clinical evidence
• effectiveness
• safety
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Detailed program: Week 7:
Time Activity Title Teacher Literature
9:00‐10:00 Introduction to Clinical Nephrology Dr. A.P.J. de VriesKumar,
Feehally
10:00‐11:00 SLE nephritis dr. Y.K.O TengFeehally,
refs 5+6
11:00‐12:00 Complement‐related renal disease Dr. A.P.J. de VriesFeehally,
refs 1‐4
12:00‐13:00 Break
13:00‐14:00 Lecture ANCA‐vasculitis Prof. dr. T. RabelinkFeehally,
refs 7+8
14:00‐14:30Handing out assignment on target
therapyDr. A.P.J. de Vries
14:00‐17:30 Self‐study
9:00‐10:00 Immunogenetics and HLA Dr. D. RoelenHricik, refs
11, 12, 16
10:00‐11:00Allo‐immunity and tolerance in
solid organ transplantationProf. dr. C. van Kooten
Hricik, refs
9, 10,11
11:00‐12:00Belatacept in kidney
transplantationDrs. H. Bouwsma refs 14,15
12:00‐13:00 Break
13:00‐14:00Immunosuppressive drugs in
nephrology/transplantationProf. dr. A.F. Cohen
Refs 5, 6, 7,
8,10, 13, 14,
15
14:00‐15:00 Therapeutic drug monitoring Drs. D.J. Moes Hricik, ref 19
14:00‐17:30 Self‐study
9:00‐10:00Rejection and cell therapy in renal
transplantationDr. M. Reinders
Hricik, refs
9, 10, 13, 16
10:00‐11:00Viral infection (CMV/BK) in organ
transplantationDrs. D. Soonawala Hricik, ref 17
11:00‐13:30 Self study
13:30‐14:00 Histopathology roundsHistopathology rounds; renal
pathologist, all nephrologists
14:00‐15:30 Self study
15:30‐16:30 LecturePCP and fungal infections after
solid organ transplantationDr. M. de Boer Hricik, ref 17
16:30‐17:30 Self‐study
9:00‐13:00 Self study
13:00‐14:00 Lectures HIV and Renal Transplantation Dr. F. Kroon refs 17, 18
14:00‐15:00 Clinical roundsClinical Rounds on the Nephrology
or Transplant ward
Drs. H. Bouwsma
Dr. A.P.J. de Vries
14:30‐17:30 Self study
9:00‐17:30 Self study
17:30 Hand in written report
Friday 17‐Oct‐2014
Lecture
Wednesday 15‐Oct‐2014
Lectures
Thursday 16‐Oct‐2014
Monday 13‐Oct‐2014
Lectures
Tuesday 14‐Oct‐2014
Lectures
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5. Write final report patient case
Clinical coordinators: Dr. R.G.M. Bredius (Paediatrics), Dr. A.C. Lankester (Paediatrics) Scientific coordinators: Dr. M. Bax (Rheumatology) Other teachers involved: Dr. J.J. Plomp (Neurology), Prof Dr. J.J.G.M. Verschuuren (Neurology), Dr.
D. van der Woude (Rheumatology), Dr. J.K. de Vries (Rheumatology), Dr. O. Teng (Nephrology), Dr. A. de Vries ((Nephrology), Dr. J.G. Koopmans (Pulmonology), Dr. A. Slats (Pulmonology)
Summary of this week:
At the beginning of week 3, the students have chosen one immunological disease out of four different diseases (MG, SLE, aHUS, Allergy). At the end of week 3, in groups of students, a short presentation has been given to obtain feedback from the corresponding clinicians to prepare the final report. In weeks 3‐7, information on the specific disease has been collected, and this week is completely dedicated to write the final report. Study goals
The student can
perform independently literature research based on a specific immunological disease and select relevant papers to analyse and report the immunological background of the patient casus in detail (Academic).
relate the mechanism of disease of a systemic auto‐immune disease to organ specific involvement by understanding the defect immune components related to the disorder.
create a diagnostic plan by evaluation of laboratory techniques based on a differential diagnosis and motivate why these techniques are appropriate to be able to diagnose correctly in this particular patient case.
interpret results from diagnostic tests and subsequently translate which immunological defects might underlie the results, and relate them to symptoms and complaints as gathered via patients’ history.
develop a therapeutic plan for the specific casus based on results from diagnostic tests and corresponding diagnosis and describe the method to check the effect of the intervention.
Study materials Book: The immune system (Peter Parham) Other materials that are posted on Blackboard of the previous weeks Literature obtained by independent literature research Contact hours: If necessary, the student can contact the corresponding clinician in case of questions.
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Self‐study hours: This whole week is dedicated to write the final report. Evaluation: The final report will be evaluated by the two corresponding clinicians (1:1) and the mark (0‐10) counts for 60% of the final mark. Guidelines for the final written report:
Instruction for students:
Disease: MG/SLE/Allergy/aHus
1. Introduction disease: 100‐150 words 2. Immunological mechanism behind disease (+ figure and implementation of at least three
relevant research papers found by independent literature search) and relation to involved organ: 600‐800 words
3. Relation defective immune mechanisms and complaints patient: 200‐250 words 4. Questions for taking the patients history: 250‐300 words 5. Diagnostic plan and predicted results: 300‐400 words 6. Therapeutic plan and method to check the effect: 300‐400 words
Instruction for teachers:
1. Introduction disease (100‐150 words): 0‐0.5 pnt 2. Immunological mechanism behind disease (600‐800 words):
In‐depth explanation of pathogenic immunological components of disease 0‐2.0 pnt
clear summary picture of involved immune mechanisms 0‐1.0 pnt
collection and implementation of relevant research papers 0‐1.0 ptn 3. Relation defective immune mechanisms and complaints patient (200‐250 words): 0‐0.5 4. Questions for taking the patients history: 250‐300 words 0‐1.0 pnt 5. Diagnostic plan and predicted results: 300‐400 words 0‐2.0 pnt 6. Therapeutic plan and method to check the effect: 300‐400 words 0‐2.0 pnt
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6. Innovative therapies
Clinical coordinators: Dr. R.G.M. Bredius MD (Paediatrics); Dr. A.C. Lankester MD (Paediatrics) Scientific coordinators: Dr. B.G.A. Guigas (Parasitology) Other teachers involved: Dr. I. de Nooijer (LURIS), Dr. A. Aartsma‐Rus (HG), Prof dr. F.J. Staal (IHB),
Prof dr. Guchelaar H.‐K. (KFT), Dr. K. Schimmel (KFT), Prof dr. D.P. Engberts (Dept. Ethics & Law), Dr. M. de Vries (KJC), Prof. dr. R.M. Maizels (Edinburgh, UK), Dr. J. Vellinga (Crucell), and all teachers from the combined half minor as tutors to guide the grant proposals
Background: In the past modules of the half minor ‘Infections, Immunity and Immune modulation’ the students got an introduction to the complexity of the immune system and the delicacy of the fine‐tuned balance between inflammation and tolerance based on symptoms and problems faced by patients with (inherited) immunodeficiencies. Host‐pathogen interactions with the immune system have been explained, the concepts of vaccinology and the consequences of dysfunctional and pathogen‐driven modulation of the immune system have also been extensively discussed. At the same time, the concept of bad and good microbes has been introduced, discussing the potential health effect of certain commensals, such as the microbiota and/or helminths. During the modules of the half minor ‘clinical immunology’ clinical symptoms and the inflammatory responses of various non‐communicable diseases have been discussed as well as current therapeutic strategies. Now the moment has come to integrate the gained knowledge of the two half minors in this last module where innovative therapies will be discussed. Examples will be provided of bright new ideas and novel treatment opportunities In addition, the various steps for setting up clinical trials will be explained, including ethical considerations, law legislations and intellectual property. The students will be introduced to bench‐to‐bedside examples of translational researches and will visit the LUMC pharmacy manufacture and a biotech company of the Leiden Bioscience Park. Finally, students will set‐up their own grant proposal in their immune disease area of choice and defend this during a symposium on the last day of the module. Learning objectives: The student can:
Transfer immunological knowledge gained during the previous modules (in the ‘Infections, Vaccines and Immune Modulation’ minor) to the students of the ‘Clinical Immunology’ minor
Describe the crucial ethical and regulatory steps necessary in developing innovative therapies for immunological and/or infectious diseases.
Perform self‐directed literature searches to obtain relevant information on immunological and/or microbiological diseases
Analyse the current therapeutic options for treating an immunological and/or infectious disease and present the pros/cons of treatment
Propose an innovative therapeutic strategy that may be developed, for targeting a specific immunological and/or infectious disease.
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Contact hours (10 hours over 2 weeks): ‐Lectures on bring Innovative therapies (IT) into the clinic: 1) Philosophy and ethics 2) How to develop a clinical trial 3) Intellectual property & IT
4) From bench to bedside: examples of translational IT 5) New approaches for vaccination 6) Pre‐ and probiotics for immune diseases ‐ Interaction hours (10 hours over 2 weeks): ‐ Site visit
1) One company involved in IT from the Leiden Bioscience Park 2) LUMC pharmacy manufacture ‐ Scientific symposium on “Communicable and non‐communicable diseases” ‐ Presentations of the students about their grant proposal (they work in couples; one from IIP and one from CI) Self‐study hours (~40 hours): Hours of self‐study devoted to preparation of grant proposal and final oral presentation Prepare Round Table discussion: “Towards personalized medicine for IT: pro and cons” Evaluation:
‐ Work groups (p/f) ‐ Poster presentation of the grant proposal (summative)
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Day to Day program Monday 27 October Lecture 9.30 – 10.30 hour Title Introduction to the module immune‐mediated diseases Instructor Dr. B. Guigas (Dept. of Parasitology) Goals Explain the content, the learning objectives and the assignments for this module Assign tutors: The students are grouped in pairs (one from Clinical Immunology and one from
Infections, Vaccines and Immune modulation) and assigned to a specific tutor. Together they will develop a grant proposal on an innovative therapeutic strategy for a specific immunological or infectious disease. At the last day of this module, the idea for the grant proposal is presented by a poster during a common symposium. The student pairs will be mentored by their dedicated tutor and will have at least 4 feed‐back moments on their grant proposal. Guidelines for the grant proposal and the poster presentation and the final list of tutors are provided below and/or on Blackboard. Topics include Type 1 diabetes, Metabolic syndrome, Systemic lupus erythematosus, Kidney Transplantation, Asthma, COPD, respiratory allergy, Myasthenia gravis, X‐linked agammaglobulinemia, SCID, Rheumatoid arthritis, Inflammatory Bowel disease, Crohn's disease, Recurrent diarrhea, Celiac disease (Gluten syndrome), HIV, Malaria, Bacterial infections, Schistosomiasis, Paediatric orphan diseases
Test summative (30% of final mark): grant proposal idea + poster +poster presentation Feedback 10.30 – 12.00 hour Instructor Assigned tutors (see list on Blackboard)
Meet the tutors for guidance on the research grant proposal and poster presentation
Guidelines for the Grant Proposal Description Each group (two students) will build an original research grant proposal in which a gene/protein/signalling module/cell/tissue/… is proposed as a target for innovative therapeutic development in a immune disease‐orientated specific context. Students should formulate their research proposal based on current literature, new data, tempting viewpoints, and will be helped through recurrent interaction with their respective tutors. In the symposium at the end of the course each group will give a poster presentation of the proposal they intend to develop. General aim Imagine that you have discovered a target/method/process and now try to obtain a research contract from an institute, a funding/charity organization or a company for therapeutic development. Thus, try to first present an as attractive/innovative project as possible, and next give an as positive enthusiastic in‐depth presentation as you can that would convince a sceptical scientific board from these organizations. Advices Try to answer (some of) the following questions: What is the (basic) science behind the idea? How was this target/process/approach discovered/developed/validated? What will be the therapeutic indication? Is there already proof of principle in animal models or how would you go about it to obtain such knowledge? What is the approach that you envision for drug discovery, therapeutic and clinical development? Why is it a good target/process/method? Are there anticipated side effects? How is this target/process/method better than the products that are already on the market? Is there
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a market/will the drug/method/process make money? Also discuss potential opportunities and strategies for personalized treatment.
Guidelines for the poster creation and presentation General aim The poster is aimed for presenting your research grant proposal and generating active discussion with the audience. You will also be encouraged to participate in the discussions from other presenters. Format Prepare the poster in landscape Powerpoint format (an empty template will be provided on Blackboard). The poster may be structured, possibly but not mandatorily, as follows: title, introduction, aim/objectives, experimental approaches, expected results/outcomes and potential translation to human disease. Pay extra attention to the visibility, readability and originality of your poster in general and the figures in particular. Design and layout advices • Less is more. Be clear and concise with poster design and content. • Make it obvious to the viewer how to progressively view the poster. The poster generally should read from left to right, and top to bottom. Numbering the individuals panels, or connecting them with arrows might be an option for a "guidance system". • Keep the text brief (no more than one‐fourth of the poster space) and readable from couple of meters away. Use "visuals" (graphs, photographs, schematics, maps, etc.) to tell your "story". • Cite and reference any sources of information other than your own. Presentation All the posters should be ready from printing (on a USB stick or uploaded on Blackboard) before Thursday Nov 6th 1pm. During the symposium, the posters will be mounted and presented using both Powerpoint and a poster walk. For the Powerpoint presentation, 15 minutes will be allocated for each couple of students: 5 min to present their poster, followed by a ~ 10 min discussion. Following the presentations, there will be a poster walk in which 1 student will be answering questions at his/her poster while the other student will walk around and ask questions/grade the posters of the other grant proposals. Halfway the poster walk, students will switch places so all students had individual time to a) answer questions at their poster and b) walk around and ask questions/evaluate. Assessment criteria • Structure and feasibility of the grant idea outline • Presence of a contingency plan • Clarity and grammar of the writing • Quality/originality of supportive graphical elements • Presentation skills (concision, structured talk and capacity to bring forward the idea in limited time; eagerness/enthusiasm 'to sell' your idea) • Discussion (capacity to answer scientific questions and coping with 'criticism')
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Tuesday 28 October Lecture 08.30 – 09.30 hour Title Organizing Clinical Research, a Routemap Instructor Dr. L. Duits‐Veltrop (Dept. of Clinical Pharmacy and Toxicology)
Goals After research on new therapies or procedures in the laboratory, the most promising experimental treatments are moved into clinical trials. In these trials new ways will be studied to prevent, detect or treat disease or to improvement a standard therapy. But what do you have to do before you can include your first volunteer? It is more than sending 15 forms to the ethical committee, but where to start in the labyrinth of clinical research.
Literature To be announced on Blackboard Lecture 9.30 – 10.30 hour Title Gene therapy, a risky business? Instructor Dr. G. van Willigen (Dept. of Safety and the Environment)
Goals In the presentation / discussion session a few recent gene therapy protocols will be shortly introduced. The students should identify the risks of the studies (for the patient and the environment) a suggest measures to mitigate the identified risks.
Literature To be announced on Blackboard Lecture 10.30 – 11.30 hour Title Antisense‐mediated exon skipping: An approach with therapeutic potential for
Duchenne muscular dystrophy and other diseases Instructor Dr. A. Aartsma‐Rus (Dept. of Human Genetics)
Goals Mistakes and alterations in the pre‐mRNA splicing process underlie many genetic and acquired diseases. Antisense oligonucleotides (small pieces of modified DNA) can be used to manipulate splicing. This approach has advanced into the clinical trial phase for Duchenne muscular dystrophy, but also has therapeutic potential for many other diseases.
Literatures Spitali P & Aartsma‐Rus A. Splice modulating therapies for human disease. Cell. 148(6):1085‐8, 2012 Aartsma‐Rus A. Antisense‐mediated modulation of splicing: therapeutic implications for Duchenne muscular dystrophy. RNA Biol. 7(4):453‐61, 2010
Self‐study 11.30 – 12.30 hour Prepare research grant proposal/poster presentation
Symposium 13.00 – 17.00 hour Lectures from national and international speakers on communicable and non‐communicable diseases, including a keynote lecture from Prof. dr. Rick Maizels (Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom) Program “At the Intersection of our major challenges: from communicable to non‐communicable diseases” 13.00: Prof. dr. Rudi Westendorp (LAVA) ‐ The epidemiologic transition 13.45: Prof. dr. Tari Haahtela (Helsinki University Hospital) ‐ The biodiversity hypothesis 14.30: Prof. dr. Maria Yazdanbakhsh (LUMC) ‐ Changing immune responses along the rural‐urban gradient 15.00: Dr. Bruno Guigas (LUMC) ‐ Helminth infections and metabolic disorders 15.45: Prof. dr. Rick Maizels (Edinburgh University) ‐ Parasites and Immunity: Evolutionary Insights into the Diseases of Modernity 16.30: Eurolife Medal and Drinks
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Wednesday 29 October Lecture 8.30 – 10.00 hour Title Intellectual property & Innovative therapies Instructor Dr. I. de Nooijer (LURIS) Goals The lecture will provide a general introduction to Intellectual Property Law. What
does it do, why and how does it achieve its aim? In addition it will explain the way patent law works in a more detailed manner, emphasizing the specific elements in patent law.
Literature Annette Kur & Thomas Dreier. Book European Intellectual Property Law. Edward Elgar 2013 http://www.wipo.int/export/sites/www/freepublications/en/intproperty/489/wipo_pub_489.pdf
Break 10.00‐10.30 hour Lecture 10.30 – 11.30 hour Title From bench to benchside: Stem cell‐based gene therapy for SCID Instructor Prof. dr. F. Staal (Dept. of Immunohematology and Blood Transfusion) Goals The Mesenchymal Stem Cell therapy program has shown that MSC’s may be able to
modulate in‐vivo immune responses in the setting of allogeneic stem cell transplantation or autoimmune disorders. This program is close to translation to clinical application and currently been studied in (randomized) clinical trials, notably for children suffering from severe combined immunodeficiency (SCID).
Literature Mikkers H, …, Staal FJ. Induced pluripotent stem cells and severe combined immunodeficiency: merely disease modeling or potentially a novel cure? Pediatr Res. 71(4 Pt 2):427‐32, 2012 Pike‐Overzet K, …, Staal FJ. Correction of murine Rag1 deficiency by self‐inactivating lentiviral vector‐mediated gene transfer. Leukemia. 25(9):1471‐83, 2011
Lecture 11.30 – 12.30 hour Title An EU FP7 project towards the development of novel helminth vaccines Instructor Dr. C.H. Hokke (Dept. of Parasitology) Goals To date no effective vaccines for helminth infections exist. Classical approaches
where an abundant antigen expressed as a recombinant protein is used for immunisation to induce protective antibodies so far fail. Some reasons for this may be that a) helminths apply sophisticated strategies to modulate and regulate the immune system of the host, rendering vaccination in an infected population ineffective b) the vaccine targets and the life stages in which they are expressed have not been chosen correctly c) the recombinant expression systems used do not take into account the proper glycosylation of the protein d) the protective mechanisms against helminths are insufficiently understood. Presented and discussed will be the outline and template of the EU‐FP7 project TheSchistoVac in which a pipeline of vaccine target discovery and in vitro/in vivo pre‐clinical testing is applied to address the above questions and develop novel vaccine candidates and strategies for schistosomiasis and related helminth infections.
Literature 1) Hewitson JP, Maizels RM. Vaccination against helminth parasite infections. Expert Rev Vaccines. 2014 Mar 7. PubMed PMID: 24606541. 2) Mo AX, Agosti JM, Walson JL, Hall BF, Gordon L. Schistosomiasis elimination strategies and potential role of a vaccine in achieving global health goals. Am J Trop Med Hyg. 2014 Jan;90(1):54‐60. 3) www.theschistova.eu
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Feedback 13.30 – 14.30 hour Instructor Assigned tutors (see list on Blackboard)
Meet the tutors for guidance on the research grant proposal Self‐study 14.30 – 17.00 hour Prepare research grant proposal/poster presentation
Thursday 30 October Self‐study 8.30 – 10.30 hour
Prepare Pros and Cons statements for Round table discussion Round table 10.30 – 12.30 hour Title Towards personalized medicine for IT: pro and cons Instructors Dr. B. Guigas (Dept of Parasitology); Dr. R. Bredius MD (Dept of Paediatrics); Dr.
Leen ‘t Hart (Dept of Molecular Epidemiology and Molecular Cell Biology) Goals Each half of the student group will have to defend a pro or con statement,
respectively Pros: “Personalized medicine is the future of health care” Cons: “Personalized medicine is ethically borderline and reflects the lack of innovative therapies from the industry”
Test formative (pass/fail) Self‐study 13.30 – 17.30 hour
Prepare research grant proposal/poster presentation
Friday 31 October Site visit 8.30 – 11.30 hour
Site visit and discussion with CEO and/or R&D head of an innovative start‐up from the Leiden BiosciencePark
Feedback 11.30 – 12.30 hour Instructor Assigned tutors (see list on Blackboard)
Meet the tutors for guidance on the research grant proposal
Self‐study 13.30 – 17.30 hour Prepare research grant proposal/poster presentation
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Monday 3 November Self‐study 8.30 – 10.30 hour
Prepare research grant proposal/poster presentation Lecture 10.30 – 11.30 hour Title Pre‐ and probiotics for immune diseases Instructor Prof dr. H. Savelkoul (Dept. of Cell Biology & Immunology, Wageningen) (speaker to
be confirmed) Goals Probiotics have formed a vital part of Mediterranean and Middle Eastern diets for
thousands of years, in the form of fermented milk and vegetable products such as yogurt and pickles. They are credited, in part, for the relatively low rates of chronic, age‐related diseases that prevail in those regions. Now, research is catching up with this traditional wisdom in the form of accelerated scientific investigations into the broad spectrum health benefits of probiotics. Probiotics are beneficial organisms, most of which are normally found in the healthy human gastrointestinal tract. Probiotics can restore and rebalance your gut microbiome, strengthening its ability to interact with your immune system in many ways. These friendly bacteria stimulate healthy immune surveillance, boosting populations of cells that seek out and destroy infecting organisms and cancers. They upregulate inflammatory cytokines during the acute stage of an infection, cancer, or other threat to your body’s integrity, but they also contribute to suppression of the inflammatory response as the threat fades. The use of probiotics holds great promise for treatment of many immune‐related disorders, but what is truly effective and where do we stand?
Literature TA Oelschlaeger, Mechanisms of probiotic actions – A review, Int J Med Microbiol, (2010); 300 (1): 57–62 Quigley EMM, Prebiotics and probiotics; modifying and mining the microbiota, Pharmacological Research, 2010, 61(3): 213–218 Aureli et al, Probiotics and health: An evidence‐based review, PharmacologicalResearch, 2011, 63(5): 366‐376
Lecture 11.30 – 12.30 hour Title Innovative therapies: new approaches for vaccination Instructor Dr. J. Vellinga (Crucell) Goals Crucell are developing prophylactic and therapeutic vaccines against a number of
infectious diseases. Several of the vaccines in development in Crucell are based on replication deficient adenoviral vectors but we are also focusing on vaccines based on live‐attenuated viruses and whole inactivated viruses. The research involves antigen discovery and design, technology development, manufacturing and characterization of prototype vaccines.
Literature NA Self‐study 13.30 – 17.30 hour
Prepare research grant proposal/poster presentation
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Tuesday 4 November Site visit 8.30 – 10.30 hour Instructor Prof. dr. Henk‐Jan Guchelaar & Dr. Kirsten Schimmel (Dept. of Clinical Pharmacy
and Toxicology) Goals Each half of the student group will visit the pharmacy drug manufacture and will get
an introduction on how this important LUMC facility is currently involved in the development of IT
Feedback 10.30 – 11.30 hour Instructor Assigned tutors (see list on Blackboard)
Meet the tutors for guidance on the research grant proposal Self‐study 11.30 – 17.30 hour
Prepare research grant proposal/poster presentation
Wednesday 5 November Self‐study 8.30 – 10.00 hour
Prepare ‘Journal Club’ lecture: read abstract and result section of the 3‐4 articles Lecture 10.00 – 11.30 hour Title Hot topics in innovative therapies: recent highlights from high‐ranking journals Instructor Postdocs from various groups involved in the ½ minor Goals 3‐4 cutting‐edge publications on IT for immune diseases published in high‐ranking
journals in 2014 will be presented and discussed with the students Literature To be announced on Blackboard Lecture 11.30 – 12.30 hour Title Dealing with minor age for IT Instructor Dr. M. de Vries (Dept. of Pediatrics) Goals Dealing with minors in experimental studies give rise to considerable ethical issues.
Minors deserve well designed drugs, dosing regimens suitable for children and good research. On the other hand regulators have to take care of the protection of this group against non‐ethical studies. The Dutch law for scientific research in minors (WMO) is currently under debate. These and other ethical issues of studies in minors will be discussed in this lecture.
Literature To be announced on Blackboard Self‐study 13.30 – 17.30 hour
Prepare research grant proposal/poster presentation
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Thursday 6 November Self‐study 8.30 – 17.30 hour
Prepare research grant proposal/poster presentation DEADLINE poster printing: 1.30am; see on Blackboard
Friday 7 November Final symposium 8.30 – 16.00 hour Instructor All the tutors involved in students guidance Goals The mark for the poster presentation will be an average of the evaluation of
all tutors present plus the mark from the assigned personal tutor (1:1 ratio). The students will also evaluate and rank all the posters using a written anonymous form. The poster with the highest rank will receive a poster award.
Program Symposium (either in Burumazaal or in the Foyer):
8.30‐9.00 Poster hanging group 1 and 2 (in the foyer)
9.00‐11.00 Poster presentation group 1 (PowerPoint presentation)
(15 min per group; 5 min presentation + 10 min discussion)
11.00‐12.00 Poster viewing and discussion at the poster group 1:
1 student will stay at the poster while the other one is doing a poster walk. Halfway
the poster viewing, students will switch.
12.00‐13.00 Break
13.00‐15.00 Poster presentation group 2 (PowerPoint presentation)
(15 min per group; 5 min presentation + 10 min discussion)
15.00‐16.00 Poster viewing and discussion at the poster group 1:
1 student will stay at the poster while the other one is doing a poster walk. Halfway
the poster viewing, students will switch.
16.00 Poster prize, Awards, Drinks
Test Summative (30%): Grant proposal idea + poster + oral presentation
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Week 9:
Time Activity Title Teacher
9.30‐10.30 LectureIntroduction to Module innovative
therapiesDr. B.G.A. Guigas
10.30‐12.00 Tutorial Meet the Mentors All tutors
12:30‐17:30 Self‐studyPrepare symposium/Grant
proposal
8.30‐9.30 LectureOrganizing Clinical Research, a
routemapDr. L. Duits‐Veltrop
9.30‐10.30Lecture gen therapy, a risky business? Dr. G. van Willigen
10.30‐11.30 Lecture
Antisense‐mediated exon
skipping: An approach with
therapeutic potential for
Duchenne muscular dystrophy and
other diseases
Dr. A. Aartsma‐Rus
11.30‐13.00 Self studyPrepare Symposium/Grant
proposal
13.00‐13.45 Symposium The epidemiologic transition Prof. dr. R. Westendorp
13.45‐14.30 The biodiversity hypothesis Prof. DRr. T. Haahtela
14.30‐15.00changing immune responses along
the rural‐urban gradientProf. Dr. Yazdanbakhsh
15.00‐15.45Helminth infections and metabolic
disordersDr. B. Guigas
15.45‐16.30 Parasites and immunity Prof. Dr/ R. Maizels
16.30 Eurolife Medal and drinkls
8.30‐10.00 LectureInnovative therapies: intellectual
property & EU/US regulationsMr. I. de Nooijer
10.00‐10.30 Break
10.30‐11.30 LectureFrom bench to benchside: Stem
cell‐based gene therapy for SCIDProf dr. F.J. Staal
11.30‐12.30 Lecture
An EU FP7 project towards the
development of novel helminth
vaccines
Dr. C.H. Hokke
13.30‐14.30 Tutorial Meet the Mentors All tutors
14:30‐17:30 Self studyPrepare Symposium/Grant
proposal
8:30‐10:30 Self‐study Prepare round table discussion
10.30‐12.30 WorkgroupTowards personalized medicine for
IT: pro and cons
Dr. B. Guigas, Dr. R. Bredius,
Dr. L.M. ‘t Hart
13:30‐17:30 Self studyPrepare Symposium/Grant
proposal
8.30‐11.30 Site visitSite Visit Leiden BiosciencePark:
Innovative Startup
11.30‐12.30 Tutorial Meet the Mentors All tutors
13:30‐17:30 Self studyPrepare Symposium/Grant
proposal
Tuesday
28‐Oct‐2014
Monday
27‐Oct‐2014
Friday
31‐Oct‐2014
Thursday
30‐Oct‐2014
Wednesday
29‐Oct‐2014
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Week 10:
Time Activity Title Teacher
8.30‐10.30 Self studyPrepare Symposium/Grant
proposal
10.30‐11.30 LecturePre‐ and probiotics for immune
diseasesProf dr. H. Savelkoul
11.30‐12.30 LectureInnovative therapies: new
approaches for vaccinationDr. J. Vellinga
13.30‐17.30 Self studyPrepare Symposium/Grant
proposal
8.30‐10.30 Site visitSite Visit: Pharmacy manufacture
at LUMC
Prof dr. H.J. Guchelaar (KFT),
Dr. K. Schimmel (KFT)
10.30‐11.30 Tutorial Meet the Mentors All tutors
11.30‐17.30 Self study
8.30‐10.00 Self study
Prepare ‘Journal Club’ lecture:
read abstract and result section of
the 3‐4 articles
10.00‐11.30 WorkgroupHot topics in innovative therapies:
4 high‐ranking papersPost‐docs various groups
11.30‐12.30 Lecture Dealing with minor age for IT Dr. M. de Vries
13.30‐17.30 Self studyPrepare Symposium/Grant
proposal
8.30‐17.30 Self studyPrepare Symposium/Grant
proposal
8.30‐12.00 Symposium study group 1‐10 all tutors
13.00‐17.00 Symposium study group 11‐20 All tutors
Thursday
06‐nov‐14
Friday
07‐nov‐14
Monday
03‐nov‐14
Tuesday
04‐nov‐14
Wednesday
05‐nov‐14
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Appendix A – Instructions for Final report week 8
Instruction for students:
Disease: MG/SLE/Allergy/aHus
1. Introduction disease: 100‐150 words 2. Immunological mechanism behind disease (+ figure and implementation of at least three
relevant research papers found by independent literature search) and relation to involved organ: 600‐800 words
3. Relation defective immune mechanisms and complaints patient: 200‐250 words 4. Questions for taking the patients history: 250‐300 words 5. Differential diagnosis: 250‐300 words 6. Diagnostic plan and predicted results: 300‐400 words 7. Therapeutic plan and method to check the effect: 300‐400 words
Instruction for teachers:
1. Introduction disease (100‐150 words): 0‐0.5 pnt 2. Immunological mechanism behind disease (600‐800 words):
In‐depth explanation of pathogenic immunological components of disease 0‐2.0 pnt
clear summary picture of involved immune mechanisms 0‐1.0 pnt
collection and implementation of relevant research papers 0‐1.0 ptn 3. Relation defective immune mechanisms and complaints patient (200‐250 words): 0‐0.5 4. Questions for taking the patients history: 250‐300 words 0‐1.0 pnt 5. Differential diagnosis:
a. Which elements of the presented case could also be presented in other diseases: 0‐0.5 pnt
b. Which additional diagnostics test would you order to discriminate to exclude the differential diagnosis: 0‐0.5 pnt
6. Diagnostic plan and predicted results: 300‐400 words 0‐1.5 pnt 7. Therapeutic plan and method to check the effect: 300‐400 words 0‐1.5 pnt
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Appendix B – Guidelines grant proposal poster presentation
Description Each group (two students) will build an original research grant proposal in which a gene/protein/signalling module/cell/tissue/… is proposed as a target for innovative therapeutic development in a immune disease‐orientated specific context. Students should formulate their research proposal based on current literature, new data, tempting viewpoints, and will be helped through recurrent interaction with their respective tutors. In the symposium at the end of the course each group will give a poster presentation of the proposal they intend to develop. General aim Imagine that you have discovered a target/method/process and now try to obtain a research contract from an institute, a funding/charity organization or a company for therapeutic development. Thus, try to first present an as attractive/innovative project as possible, and next give an as positive enthusiastic in‐depth presentation as you can that would convince a sceptical scientific board from these organizations. Advices Try to answer (some of) the following questions: What is the (basic) science behind the idea? How was this target/process/approach discovered/developed/validated? What will be the therapeutic indication? Is there already proof of principle in animal models or how would you go about it to obtain such knowledge? What is the approach that you envision for drug discovery, therapeutic and clinical development? Why is it a good target/process/method? Are there anticipated side effects? How is this target/process/method better than the products that are already on the market? Is there a market/will the drug/method/process make money? Also discuss potential opportunities and strategies for personalized treatment.
Guidelines for the poster creation and presentation General aim The poster is aimed for presenting your research grant proposal and generating active discussion with the audience. You will also be encouraged to participate in the discussions from other presenters. Format Prepare the poster in landscape Powerpoint format (an empty template will be provided on Blackboard). The poster may be structured, possibly but not mandatorily, as follows: title, introduction, aim/objectives, experimental approaches, expected results/outcomes and potential translation to human disease. Pay extra attention to the visibility, readability and originality of your poster in general and the figures in particular. Design and layout advices • Less is more. Be clear and concise with poster design and content. • Make it obvious to the viewer how to progressively view the poster. The poster generally should read from left to right, and top to bottom. Numbering the individuals panels, or connecting them with arrows might be an option for a "guidance system". • Keep the text brief (no more than one‐fourth of the poster space) and readable from couple of meters away. Use "visuals" (graphs, photographs, schematics, maps, etc.) to tell your "story". • Cite and reference any sources of information other than your own.
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Presentation All the posters should be ready from printing (on a USB stick or uploaded on Blackboard) before Thursday Nov 6th 1pm. During the symposium, the posters will be mounted and presented using both Powerpoint and a poster walk. For the Powerpoint presentation, 15 minutes will be allocated for each couple of students: 5 min to present their poster, followed by a ~ 10 min discussion. Following the presentations, there will be a poster walk in which 1 student will be answering questions at his/her poster while the other student will walk around and ask questions/grade the posters of the other grant proposals. Halfway the poster walk, students will switch places so all students had individual time to a) answer questions at their poster and b) walk around and ask questions/evaluate. Assessment criteria • Structure and feasibility of the grant idea outline • Presence of a contingency plan • Clarity and grammar of the writing • Quality/originality of supportive graphical elements • Presentation skills (concision, structured talk and capacity to bring forward the idea in limited time; eagerness/enthusiasm 'to sell' your idea) • Discussion (capacity to answer scientific questions and coping with 'criticism')
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Appendix C ‐ Assessment form
Half minor:
Name student:
Exam Mark Weight Passed/Failed* Final**
Week 1+2
Open question exam 0.1
*Diagnosis report
*Oral presentation laboratory
Week 3‐8
*Oral presentation patient casus
*Report Neuro‐immunology
*Oral presentation Rheumatology
*Oral presentation Pulmonology
*Report Nephrology
**Final report (Week 8) 0.6
Week 9+10
Grant proposal poster topic teacher
Grant proposal poster Week 9/10
teacher
Average two teachers 0.3
Total
**Final
*At least 5/7 have to be Passed
**To pass this half minor, both final report and final mark should be >5,5.
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Appendix D – Guideline diagnosis report (Passed/Failed)
1. Summarize the most important laboratory results (raw data) of the requested tests. Point out both
remarkable, unexpected data and the results relevant for the specific clinical question. (1 point)
2. Summarize the clinical information (relevant history taking/ physical examination and/or other
diagnostic test results) in no more than two sentences. Make up your differential diagnosis and
estimate the pre‐test probability (highly suspected, suspected, not suspected) for the specific disease
tested for. (1 point)
3. Combine the clinical information with the laboratory data and estimate the post‐test probability.
Use estimates of the test sensitivity and the specificity in order to estimate the risk of false positive
and false negative test results. Take into account the type of specimen, timing of sampling, and if
appropriate, sample handling/transport conditions that may have affected the test result. (3 points)
4. Clearly formulate your conclusion / interpretation of the data relevant for the clinician. (3 points)
5. If relevant, add a suggestion for additional diagnostic testing (if appropriate, list your updated
differential diagnosis, and/or follow‐up samples). If relevant, advise the optimal specimen (e.g.
serology, biopsy, etc.) and/or timing of sampling. (1 point)
6. Advise an appropriate therapy, if relevant. (1 point)
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Appendix E – Oral presentation lab visit (Passed/Failed)
6. Prepare a presentation of 10‐15 min and include appropriate images 7. Explain the application of the diagnostic test (medical conditions) 8. Explain the principle of the diagnostic test 9. Show a typical test result (including the range of a ‘normal’ response) 10. Explain how these results should be interpreted
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Appendix F – Oral presentation patient casus (Passed/Failed)
1. Prepare a presentation in groups of maximal 5 students of ~20 min and include appropriate images
2. Explain symptoms of the disease 3. Explain immune mechanism behind the disease 4. Explain the application of the diagnostic test (medical conditions) 5. Explain the principle of the diagnostic test 6. Show a typical test result (including the range of a ‘normal’ response) 7. Explain how these results should be interpreted
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Appendix G – Report neuro‐immunology (Passed/Failed)
Review report
Students with MG casus for the report of week 8 should choose this week another neuro‐immunological disorder
In groups of max 5 students, one report (900‐1100 words) will be prepared consisting of:
Background disease and symptoms (~200 words)
Diagnosis (~200 words)
Pathophysiology ((~200 words)
State of art laboratory research (~200 words)
Treatment (~200 words)
Every student will prepare one chapter and each part is evaluated (passed/failed) separately
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Appendix H – Guidelines Oral presentation rheumatic disease
(Passed/Failed):
Students with SLE casus for the report of week 8 should choose this week another rheumatic disease
In groups of max 5 students, one presentation of ~20 minutes will be prepared consisting of:
Background disease and symptoms
Diagnosis
Immunological background of disease
State of art laboratory research
Treatment
Every student will prepare one part of the presentation and three persons will present while the two
others will answer the questions in the discussion. Each student is evaluated separately
(passed/failed)
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Appendix I – Oral presentation Pulmonology (Passed/Failed)
Oral presentation Pulmonology:
Students with Allergy case for the report of week 8 should choose this week another airway disease
In groups of students, one presentation of ~30 minutes will be prepared based on mini
symposium
Each student is evaluated separately
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Appendix J – Report nephrology (Passed/Failed)
All students will write individually a small report (900‐1100 words) about one target therapy
(belatacept, belimumab, eculizumab, alemtuzumab, rituximab, or ATG). Topics to be included in the
report:
• working mechanism
• clinical evidence
• effectiveness
• safety