The University Of Sydney

School of Medical Sciences

Discipline of Physiology

Heart and Circulation: Normal and Applied Function

(PHSI 3007/PHSI 3907)

&

Heart and Circulation: Dysfunction

(PHSI 3008/PHSI 3908)

SEMESTER 2 2010

This document can be downloaded as a pdf from the H&C WebCT site or purchased as a bound hardcopy from the copy centre.

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Contents PAGE

Units of study description 3

Units of study aims 3

PHSI3007/3907

Learning outcomes 5

Learner preparation 5

commitments and contact times 6

Learning MODES 6

Unit of study program 7

assessment schedule 9

PHSI3008/3908

Learning outcomes 10

Learner preparation 10

commitments and contact times 11

Learning MODES 11

Unit of study program 12

assessment schedule 13

Units of study references 14

general learning resources 14

illness and misadventure 14

ESSAY AND REPORT WRITING: Plagiarism 14

staff contact information 16

administration 16

prizes 16

Advanced Units of Study (PHSI3907/3908) 17

Introduction to problem based learning 19

PBL1PBL2PBL3

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WELCOME AND UNITS OF STUDY DESCRIPTIONWelcome to the Department of Physiology’s “Heart and Circulation: Normal and Applied Function (PHSI 3007; Advanced PHSI 3907)” and “Heart and Circulation: Dysfunction (PHSI 3008; Advanced PHSI 3908)”. These units are the second semester senior level units of study offered by the Discipline of Physiology. If you complete 24 credit points of senior level units of study offered by the Discipline of Physiology (see Table1, pg 82 of the Faculty of Science Handbook 2008) then you will have completed a major in Physiology. A description of the Units of Study can be found in the “Faculty of Science Handbook 2008” at the following website:

http://www.scifac.usyd.edu.au/about/handbook.html

The specific knowledge and generic skills that you will develop in these units of study will prepare you for more independent study and research in the Honours program offered by the Discipline of Physiology. The department is research intensive with expertise in many areas of cardiovascular function. Research within the discipline falls under the auspices of the Bosch Institute. Information regarding activities of the Institute can be accessed via the Physiology website (under research). For further information about the Honours program and the research interests of the Discipline of Physiology browse the Physiology website at the following address:

www.physiol.usyd.edu.au

At this site you can also access the contact details of the Honours year co-coordinator and the administrative staff who can assist you with further inquires.

PHSI 3007/3907 UNIT OF STUDY AIMS

The aim of this unit of study is to examine in depth the structure and function of the cardiovascular system at the organ, cellular and molecular levels. There is a particular focus on exercise physiology and the way in which the heart, circulation and skeletal muscles contribute to the limits of sporting achievement. The excitability, contractility and energetics of the heart and blood vessels are studied and the regulation of these organs by local (physical and chemical) factors, hormones and the nervous system are discussed, with emphasis on cellular and molecular mechanisms. At the systemic level, short term (neural) mechanisms controlling the blood pressure and how the system behaves during exercise and other stresses are dealt with. Long term (hormonal) mechanisms regulating blood pressure via the renal control of extracellular fluid volume are also discussed. Lectures will be complemented by practical classes and tutorials that reinforce the theory and emphasize experimental design, data interpretation and presentation.

PHSI 3008/3908 UNIT OF STUDY AIMS

This unit of study complements PHSI3007/3907 and it is strongly recommended that the two units are studied together. This unit of study focuses on cardiovascular disease, which is a major cause of death in western society, and on diseases associated with the skeletal muscular system. Lectures provide the background to understanding (a) the disruption of normal physiological processes, (b) recent advances in cellular and molecular aspects, and (c) the physiological basis of modern approaches to treatment. Examples of diseases covered include: heart failure, heart attack, cardiac hypertrophy, atheroma and hypertension, muscular dystrophy and malignant hyperemia. In the problem-based-learning (PBL)

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sessions, students will work in small groups under the guidance of a non-expert tutor, in self directed learning exercises that further extend the understanding of cellular and molecular mechanisms underpinning cardiovascular disease. Problems that relate to a particular disease are supported by a reading list. Through analysis and discussion of the readings students develop skills necessary for interpreting and communicating science.

Whilst gaining an understanding of the cardiovascular system you will be developing skills that will prepare you for success in any career, whether it is in biomedical research, medicine or in the business field. These generic skills are developed through engagement with the following learning activities:

Generic skills (University Policy Number 102: Generic attributes of Graduates of the University of Sydney)

Through the preparation of essays and seminar presentations you will develop• the ability to identify, access, organize and communicate knowledge in both

written and oral form appropriate to the discipline of Physiology• the ability to critically evaluate and synthesize information from a wide range of

sources in the scientific literature• an appreciation of the requirements and characteristics of scholarship and

research in the area of Physiology

Through the participation in practical classes and the preparation of reports you will• develop expertise in the use of the Maclab data acquisition system, used in the

physiology laboratory, and Excel, used for data display and analysis• generate and test hypotheses related to physiological problems• adopt a problem solving approach to experimental design• be able to collect, correlate, display and analyze data• be able to report observations clearly and logically and identify discrepancies

between predictions and observations• consider the reliability of methods • be creative and critical when discussing observations with reference to current

theories and models

Through group work in practical classes and PBLs you will• develop the ability to work with others • strive for tolerance, acceptance and integrity• acknowledge your responsibility for your own behaviour and your ethical

behaviour towards others

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Heart and Circulation: Normal and Applied Function

(PHSI 3007/PHSI 3907)

LEARNING OUTCOMES

By the end of this unit of study you will able to• understand the cellular and molecular function of the heart and blood vessels in

light of recent advances • explain how local factors, hormones and autonomic nerves affect the function of

these cells, and the whole organ• apply your understanding of normal cellular and molecular function and control to

explain practical class data• understand and identify the neural pathways associated with changes in

cardiorespiratory function during exercise• explain the importance of exercise in promoting physical fitness and health and

the factors that limit physical performance• critically analyze current and pioneering research papers and gain an

appreciation of the conflicts and uncertainties in the scientific literature• present logical arguments, in written and oral format, to support current scientific

theories and models • design experiments, collect, present and analyze scientific data in light of theory

and current research• generate hypotheses to explain scientific data discussed in research papers or

collected in the laboratory • confidently use a wide range of data acquisition and data manipulation software • think like physiologists

SPECIFIC LEARNING OBJECTIVES ARE AVAILABLE ON WEBCT UNDER

LECTURE SYNOPSES AND OBJECTIVES

LEARNER PREPARATIONThe prerequisite units of study for BSc and BSc combined degrees are Intermediate Physiology PHSI(2005 or 2905) and PHSI(2006 or 2906) plus at least 12 credit points of Intermediate Science units of Study. For BMedSc the prerequisites are BMED (2801 and 2803). If you have gained permission to enroll in Heart and Circulation without these units of study then you are advised to read the cardiovascular chapter of the Intermediate Physiology recommended textbook (Sherwood, L. (2004), Human Physiology). Assumed knowledge includes 6 credit points of MBLG and a basic understanding of metabolism as discussed in any intermediate level biochemistry textbook.

It is recommended that you take PHSI3007 (or PHSI3907) in combination withPHSI3008 (or PHSI3908) as together they will provide a deeper understanding of normal function and the pathophysiology of the heart, circulation and associated systems.

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LEARNING COMMITMENTS AND CONTACT TIMES

LecturesIt is expected that you attend two lectures per week at the following times and in the following venues:

Monday 11 am General Lecture Theatre

Wednesday 10 am Carslaw 275

.Practical and seminar session times and locationsThere are several practical sessions in the semester, each related to a specific theme that is defined in the “Unit of Study Program”. You will be allocated to one of three practical groups, A, B or C, and within these classes you will work in small groups comprised of 3-4 students. GROUP ALLOCATIONS ARE GENERATED AUTOMATICALLY ON YOUR PERSONAL TIMETABLE. The schedule for the practical can be found in the “Unit of Study Program”. Practical notes are available on the PHSI3007 WebCT site under “course content” link. Download the notes and bring along to the lab sessions. Reading the lab notes prior to each session will result in a better, more fulfilling learning experience.

Monday practical Group A 2-5pm Anderson Stuart Building

Tuesday practical Group B 2-5pm Anderson Stuart Building

Wednesday practical Group C 2-5pm Anderson Stuart Building

IT IS EXPECTED THAT YOU ATTEND ALL SCHEDULED PRACTICAL AND SEMINAR SESSIONS. ATTENDENCE IS COMPULSORY AND WILL BE RECORDED. FAILURE TO ATTEND WITHOUT THE GRANTING OF SPECIAL CONSIDERATION COULD JEPORDISE YOUR MARK ALLOCATION FOR THE UNIT INVOLVED.

LEARNING MODES

LecturesThe topic areas studied in this unit are organized into several themes. Each theme has an associated series of lectures and, for some themes, a practical class. The aim of the lectures is to help you to place new material in a broader knowledge base, introduce and illustrate important concepts, explain difficult mechanisms, stimulate your interest and clarify misconceptions helping you to engage fully with the practical classes and practical reports. It is expected that you will integrate your learning in lectures with the other learning situations offered in this unit.

Practical classesStructure of the practical streamThere are 3 practical classes. Practicals will be assessed either by an individual report, a group practical report, a group oral presentation. In the first session of the 2-day practicals you will familiarize yourselves with the available equipment and methods, design a protocol, predict outcomes, generate and test hypotheses and collect preliminary data. In the second session there will be an opportunity to refine protocols, collect more data, manipulate and present data using excel, discuss outcomes with your peers and demonstrators. A discussion tutorial will be held at the end of the second practical session, or in the following week. The tutorial will provide

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an opportunity to further discuss the outcomes of the practical session. The submission of the final report or delivery of the oral presentation will take place one or two weeks after the discussion tutorial.

Record keepingDuring the practical you will record information in a separate record book. The record book will include results, analysis and interpretation of results from practical sessions.It is expected that the protocols are summarized in a flow diagram and that any changes are recorded. Accurate record keeping will help you to explain your data fully, especially if your observations are not as predicted. Your demonstrators will give you feedback during the practical class on how clearly you have recorded your data and how logically it is presented. You may also record any interpretations of the data.

AssessmentsThe group work in practical classes allows you the opportunity to engage in scientific inquiry and develop deeper understanding through discussion with your peers. It is an opportunity to work collaboratively and learn to be a supportive and responsible group member. Your reports (individual or group) and your oral presentation will be assessed on how well you

• justify the methods used (where these have been developed by your group) • describe and present the data, (including legends, titles, labels)• support the conclusions with the collected data • integrate appropriate literature

In addition there will be specific criteria that you must address. This will be found at the end of your practical notes or on WebCT. To achieve a high grade you will make appropriate reference to the experimental data and show how it supports the underlying mechanisms described in the literature. You will also need to generate hypotheses to explain any results that are not explained by current theories. The report structure will be outlined in each case by the academic in charge.

UNIT OF STUDY PROGRAM

A detailed timetable is linked to the WebCT site.It is expected that you check this site regularly for any alterations to the timetable.The following table highlights the relationship between the lectures and practical classes in this unit of study.

LECTURE THEMES PRACTICAL CLASSES

Physiology of the heart Contractility of the myocardium

Neurotransmission and CV regulationVascular biology Regulation of the circulation and respiratory function

Respiration videoCardiorespiratory regulation during dynamic exercise

Cardiovascular endocrinology Sports physiology Human nerve and muscle

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function

LECTURERS AND LECTURE TOPICS

Prof Dampney:Overview of cardiovascular regulationCardiac output and venous return - Guyton modelCardiac output and venous return - Guyton modelNeural effector mechanismsShort term reflex control

Prof Morris:Cardiovascular Endocrinology 1Cardiovascular Endocrinology 2

Prof Bennett:Neurotransmission and CV regulation 1Neurotransmission and CV regulation 2

Prof Allen:Cardiac muscle structureExcitation-contraction couplingPumps and exchangers and channelsThe ventricular action potentialPacemaker activityStarling's Law of the HeartHuman Performance during exerciseLimitations imposed by the heartLimitations imposed by the lungsMetabolic limits on muscle performanceExcitation-contraction coupling and fatigue

Dr FraserDevelopment of CV 1&2Foetal blood cell developmentAdult blood cell development

SPECIFIC LECTURE SYNOPSES AND OBJECTIVES CAN BE FOUND ON WEBCT

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ASSESSMENT SCHEDULE

Assessment type Assessment topic Due dates Weight of whole semester

Group report:Data collection, presentation, analysis1000 words

Cardiorespiratory regulation during dynamic exercise

Friday 27 August 15%

Quizes: on-line MCQs

Various During Lab, weeks 4, 8 & 12

5%

Individual report:Data collection, presentation, analysis1000 words

Contractility of the myocardium

Friday 24 September 15%

Group oral presentation:Data collection, presentation, analysis (10-12min presentation)

Human nerve and muscle function

To be held in tutorial session in week 11/12

10%

PHSI3907Advanced Essay/reportMax 2000 wrds

Monday 25 October 30% replaces Individual and group reports (2x15%).

Final Exam (SAQs)*assessing understanding and integration of lecture material

Structured answer questions of all course material and labs

Exam period 55%

*Structured Answer Questions

On-line QuizzesIn response to student feedback, we have introduced a series of on-line MCQ quizzes. These quizzes are designed to be formative. That is, on completing each question, immediate feedback is available to you to monitor and inform you as to the correct reasoning of the answer. Marks awarded for all quizzes are combined for a total of 5% of your overall mark. These are to be completed by both 3007 and 3907 students. Quizzes will be open from noon on Monday to 5pm on Wednesday of the timetabled week. They must be completed in this time. There is no exception to this. You will only be allowed one attempt of each quiz. It is therefore vital that once you start a quiz, you complete it before leaving the system.

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Heart and Circulation: Dysfunction(PHSI3008/PHSI3908)

LEARNING OUTCOMES

By the end of this unit of study you will able to• understand the disruption to normal cellular and molecular processes of the heart,

blood vessels and skeletal muscles that lead to diseases such as heart failure, atherosclerosis and muscular dystrophy

• explain how changes in local factors, hormones and autonomic nerves affect the function of these cells, and the whole organ

• apply your understanding of normal cellular and molecular function to explain current treatments for disease

• understand and identify the neural pathways associated with changes in cardiorespiratory function during stress

• critically analyze current and pioneering research papers and gain an appreciation of the conflicts and uncertainties in the scientific literature

• present logical arguments, in written and oral format, to support current scientific theories and models

• think like physiologists

SPECIFIC LEARNING OBJECTIVES ARE AVAILABLE ON WEBCT UNDER

LECTURE SYNOPSES AND OBJECTIVES

LEARNER PREPARATION

As for 3007, the prerequisite units of study for BSc and BSc combined degrees are Intermediate Physiology PHSI(2005 or 2905) and PHSI(2006 or 2906) plus at least 12 credit points of Intermediate Science units of Study. For BMedSc the prerequisites are BMED (2801 and 2803).It is strongly recommended that you take PHSI3007 (or PHSI3907) in combination with PHSI3008 (or PHSI3908) as together they will provide a deeper understanding of normal function and the pathophysiology of the heart, circulation and associated systems. In PHSI3008/3908 we will go beyond the broad theory and delve deeply into the physiological basis of common ailments of the cardiovascular system. Without a sound knowledge of normal physiology of the CV as studied in PHSI300793907) students will find it extremely difficult to understand the basis of cardiovascular disease.

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LEARNING COMMITMENTS AND CONTACT TIMES

LecturesIt is expected that you attend two lectures per week at the following times and in the following venues:

Friday 12-1pm Eastern Avenue Lecture Theatre

Friday 2-3pm Eastern Avenue Lecture Theatre

PBL session timesYou will be allocated to a PBL group consisting of 10-12 students. There are two PBL session per week scheduled at the times indicated below. You must attend both sessions.

Tuesday 9-10 or 12-1pm

Friday 9-10 or 3-4pm

PBL SESSION ATTENDENCE IS COMPULSORY AND WILL BE RECORDED. YOU MUST GO TO YOUR ALLOTED PBL GROUP. CHANGES CAN ONLY BE MADE IN EXCEPTIONAL CIRCUMSTANCES.

LEARNING MODES

LecturesThe topic areas studied in this unit are organized into several themes. Each theme has associated with it a series of lectures. Some themes include a PBL scenario. The aim of the lectures is to help you to place new material in a broader knowledge base, introduce and illustrate important concepts, explain difficult mechanisms, stimulate your interest and clarify misconceptions, helping you to engage fully with the PBL sessions and essays. It is expected that you will integrate your learning in lectures with the learning in the PBL sessions.

LECTURERS AND LECTURE TOPICS

Prof Dampney:Stress and CV regulation (and intro to PBL 3)Local control of blood flowMaintenance of sympathetic vasomotor toneLong term control of blood pressure and sympathetic activityCirculatory regulation during heart failure

Prof Mason:Lipid MetabolismAtherosclerosisRisk Factors and their modification

Prof Morris:Hypertension

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Reactive Oxygen SpeciesAgeing: Is it tractable?

Prof Allen:Malignant hyperemiaCardiac ischaemiaHeart failureStem cell research

Dr FraserAngiogenesis and targeted therapyDevelopmental abnormalities in CV formationSickle cell anaemia and leukaemia

SPECIFIC LECTURE SYNOPSES AND OBJECTIVES CAN BE FOUND ON WEBCT

PBLsThere are three PBL scenarios, each related to a lecture theme. Each problem scenario runs for 4 weeks and the learning is assessed by a formal group oral presentation, a written summary, an individual oral presentation and participation in group discussion. The aim of the PBL is to develop a deeper understanding of the pathophysiology of the heart and circulation in the context of normal function, in addition to developing skills in discussing, integrating, explaining and presenting current research and ideas in the field.

UNIT OF STUDY PROGRAMA detailed timetable is linked to the WebCT site. It is expected that you check this site regularly for any alterations to the timetable.The following table highlights the relationship between the lectures and practical classes in this unit of study.

LECTURE THEMES Lecturers PBL topics

Dysfunction of the blood vessels

Rebecca Mason Ageing and Hypertension

Hypertension and aging Brian Morris Ageing and Hypertension

CV regulation and stress

Roger Dampney Stress and the nervous system

Pathophysiology of the heart

David Allen

Pathophysiology of skeletal muscles

David Allen

Developmental pathologies of the CV system

Stuart Fraser Angiogenesis

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SUMMARY OF ASSESSMENT

Assessment Components of the assessment Due dates % of total

PBL 3 problems each including an• oral presentation(~6% per

problem)• individual contribution

inclusing individual

presentation & summary

overhead (~6% per problem)

Problem 1: 27 AugProblem 2: 24 SepProblem 3: 29 Oct

35%

Final Exam

(SAQs*)

• Theory lectures (50%)2 Qs from each of 3 sections

Exam period 65%

TOTAL 100%PHSI3908

PBL 2 problems• oral presentation (~6% per

problem)• individual contribution

inclusing individual

presentation & summary

overhead (~6% per problem)

Problem 1: 28 AugProblem 2: 25 Sep

25%

Final Exam

(SAQs*)

• Theory lectures (50%)2 Qs from each of 3 sections

Exam period 50%

Advanced project

Development of PBL problem based on 3007 topic

29 Oct 25%

TOTAL 100%

*Structured Answer Questions

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UNIT OF STUDY REFERENCES (3007/3008)

The course incorporates very recent information, and no single textbook is deemed sufficiently advanced or up-to-date. Students are recommended to make extensive use of monographs and reviews in the Burkitt-Ford (A27) Library or the Medical Library (D06).

Textbooks

The textbooks below are in special reserve in the Burkitt Ford and Medical libraries and can also be purchased from the Medical Society Bookshop in Bosch:

Opie, L.H. (2004) The heart: physiology, from cell to circulation, 4th edn, Lippincott Williams and Wilkins, Philadelphia, covers most aspects of the unit of study but particularly the physiology of the heart and endocrine function. Regulation of the circulation is covered at an elementary level. The text is not recommended for the Neurotransmission and CV regulation section of the UoS.

Aaronson, P.I. et al. (1999). The Cardiovascular System at a Glance, Blackwell Science Ltd., gives a comprehensive and concise description of the cardiovascular system. It is useful if you need to revise material but does not cover all aspects of the unit equally well.

The following textbooks are also relevant and have been placed in Special Reserve:Katz, AM (2006) Physiology of the Heart, Lippincott Williams and Wilkins, Philadelphia.

A list of eBooks available is listed on WebCT. You may find these useful.

GENERAL LEARNING RESOURCESInformation on essay writing, report writing and referencing can be found in WebCT.It is extremely important that you read these instructions as marks will be deducted if the guidelines are not followed.

ILLNESS AND MISADVENTUREThe departmental policy on assessment submissions, extensions, late submissions, illness and misadventure can be found in WebCT.

ESSAY AND REPORT WRITING: PLAGIARISM

In the Heart and Circulation unit of study you are asked to submit essays and reports, which are expected to be your own work. If you do use the work of others then this must be clearly acknowledged through appropriate referencing. Failure to appropriately reference the Work of others may be seen as a deliberate act of plagiarism which brings with it severe penalties. For this reason, when preparing your essays and reports you should be aware of issues surrounding plagiarism, as outlined by the University of Sydney Student Plagiarism: Coursework Policy and Procedure, April 2005. (http://www.usyd.edu.au/senate/policies/Plagiarism.pdf). The following are extracts from the policy document.

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The policy defines Plagiarism as:

"presenting another person's Work as one’s own Work by presenting, copying or reproducing it without Acknowledgement of the Source. It includes presenting Work for assessment, publication, or otherwise, that includes

a) sentences, paragraphs or longer extracts from published or unpublished Work (including from the Internet) without Acknowledgement of the Source; or

b) the Work of another person, without Acknowledgement of the Source and presented in such a way that exceeds the boundaries of Legitimate cooperation. ”

Legitimate Co-operation can be defined as “any constructive educational and intellectual practice that aims to facilitate optimal learning outcomes through interaction between students.” Typical examples of these practices may include “researching, writing and/or presenting joint work; discussion of general themes and concepts; interpretation of assessment criteria; informal study/discussion groups; strengthening and development of academic writing skills through peer assistance.”

A Compliance statement must be submitted with all assessments to ensure that you are familiar with the plagiarism policy. The Compliance Statement (available on WebCT) certifies that no part of the assessment breaches the University of Sydney plagiarism policy. In addition, practical reports, that involve group work with other students, must be submitted with a cover sheet acknowledging the contribution of each group member.

The penalties for cases of plagiarism, as outlined in the policy document, may range from a request to resubmit the assessment to a fail grade being awarded for the assessment. All cases of plagiarism will be placed on a central file with the university Registrar.

Sometimes a lack of understanding of how to acknowledge information obtained from published or unpublished work (including the internet) may inadvertently lead to plagiarism. More details on the basics of citations and reference lists can be found in the Dept of Physiology Document "Essay writing and reference lists" on WebCT.

For any material to be assessed, the most important principles which you should bearin mind are:

1) Express what you have read in your OWN words.2) Do not quote from sources verbatim, even if using quote marks and citing

your source, UNLESS the wording is so perfect that you feel that it must under no circumstances be omitted (Shakespeare falls into this category, if he’s relevant!)

Remember that the person who suffers most from plagiarism is the plagiarizer. If you are found out, you are liable to be expelled from the course, or from the University. If you escape detection, you still will suffer, because you will not have learned or produced anything new if you simply copy down what others have written.

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STAFF CONTACT INFORMATION

Academic staffIf you need help with a specific area of study please e-mail your lecturer.

AcademicE-mail address

Steve Assinder (course coordinator) stephena@physiol.usyd.edu.au

David Allen. davida@physiol.usyd.edu.auMax Bennett maxb@physiol.usyd.edu.au

Roger Dampney rogerd@physiol.usyd.edu.auRebecca Mason rebeccam@physiol.usyd.edu.au

Brian Morris brianm@physiol.usyd.edu.auStuart Fraser stuart.fraser@sydney.edu.au

A number of other academics, PhD students and postdoctoral fellows will also be teaching in this unit of study and can be contacted through the student liaison office.The e-mail addresses of all academics in the department can be found on our web site at www.physiol.usyd.edu.au.

ADMINISTRATION

InquiriesAll student inquiries should be directed to the Student Liaison Office or to Louise Harrison at louisejh@physiol.usyd.edu.au.

Submission of assessmentsAll assessments must be submitted to the Student Liaison Office by 4.30pm on the due date. You must attach a compliance statement and coversheet to your assessments and you will receive a signed and stamped receipt. DO NOT SUBMIT ESSAYS DIRECTLY TO LECTURERS OR SLIP THEM UNDER DOORS.

PRIZES

The Claude Bernard Prize will be awarded to the student enrolled in both PHSI3007 (or PHSI3907) and PHSI3008 (or PHSI3908) who has the best final average marks in the two units of study, provided that the candidate’s work is of sufficient merit. The award will be made on the recommendation of the Head of the Discipline of Physiology after consulting with the unit of study co-ordinator and is valued at $150.

Claude Bernard (1813-1878) was a renowned French physiologist, involved in the study of the sympathetic nervous system in relation to vasoconstriction and vasodilation. He also introduced the idea that the body maintains a constant internal environment in the face of a dynamic external environment, a concept that later led to the term homeostasis.

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HEART AND CIRCULATION: NORMAL AND APPLIED FUNCTION (ADVANCED-PHSI3907)

The lecture and practical component for the advanced stream is the same as for PHSI3007 described above, however, students will be required to prepare an alternate assessment task. This will take the form of an essay or report constituting 30% of the total semester mark. The style of the report will be negotiated with your supervisor and may take the form of a journal article. Note that the advanced project replaces some of the continuous assessments prepared by students enrolled in PHSI3007.

The project allows students to extend their knowledge and understanding of a specific area of cardiovascular physiology, under the guidance of an academic teaching in the unit of study. The students will be involved in the research activities of the laboratories of choice in a capacity negotiated with the academic.

A list of projects and supervisors is available on the PHSI 3007/3008 WebCT site.

What you need to do to set up your Advanced research projects.1. Contact the Unit of study coordinator, Steve Assinder (contact details above)

to get permission to enroll. You will need to bring a form from the Faculty Office and your academic transcript.

2. Choose one or more preferred topics posted on WebCT3. Contact the lecturer/s leading those projects to learn more of what is involved,

check whether the project is still available and, if so, organize regular (fortnightly is recommended as minimum) mentorship/progress meetings. In the case of lab based projects, organize a timetable that will allow timely completion of the work.

4. Turn up to the meetings on time, with papers and summaries of the reading you have done, and a list of questions that you would like advice/guidance on.

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HEART AND CIRCULATION: DYSFUNCTION (ADVANCED-PHSI3908)

The lecture and PBL stream for the advanced unit of study is the same as for PHSI3008 described above, however, the final exam will exclude the PBL component and will only be worth 50% (instead of 65%) of the total semester’s mark. In addition, advanced students will participate only in two of the three PBL problems. The PBL component is replaced by an alternate assessment that will be the development of an original PBL worth 25% of the total mark. This will be modeled on the existing PBL format and will be developed under the supervision of an academic mentor teaching in the unit of study. The topics to be developed will be in the research area of the academic mentor and related to the PHSI3907 advanced essay topic.

The project allows students to extend their knowledge and understanding of a specific area of cardiovascular physiology, under the guidance of an academic teaching in the unit of study. In addition, it allows students the opportunity to engage in curriculum design and development.

Brief summary of the project requirements:• Develop a scenario for third year H&C students enrolled in PHSI3008 (assumed

knowledge PHSI3007 or 3907).• Create a reading list to support the problem scenario.• Develop a tutor guide which includes key points that should arise out of the

scenario, a summary of each of the papers in the reading list, highlighting important points.

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Introduction to the Problem Based Learning Topics (PBLs)

Structure of the PBL There are 3 PBL topics. Each topic lasts for 4 weeks. In the week prior to each PBL you are expected to read the introductory papers and answer the introductory questions. These questions will relate to the general reference/s to be read by all students. Answers to the questions should be prepared by each student for discussion in the first PBL. The aim is to ensure everyone is engaged in the background to the scenario prior to formal sessions. There will be an introductory lecture to introduce each PBL topic prior to commencement of PBLs. In the remaining three weeks there will be a total of six sessions, each of 1 hour duration, on Tuesdays and Fridays (see timetable). In session 1, the problem scenario will be discussed and the specific references will be allocated to students. These papers will be presented to the whole group by individual students in a 3 minute oral presentation in sessions 2 and 3. Sessions 4 and 5 will be used to discuss and integrate the ideas arising from the references and to begin preparation of the final presentation. In session 6 a subset of students will present the outcomes of the whole group’s research on the topic. For each PBL topic a different subset of students will present the research findings. A tutor will be present to facilitate the discussion and to assist in the organization of the presentation. A different tutor will assess the final presentation.

Each topic scenario and associated references are posted on WebCT and attached at the end of the course guide.

How to get started 1. Engage with the discussion questions and with your PBL group. This is a

compulsory activity and participation will be recorded. The contribution must be of a good quality and the mark will contribute to the overall participation mark.

2. Allocate at least one paper to each student. The student will become an expert on the paper and will produce an overhead that summarises the key findings that are relevant to the topic. The presentation of the paper must be made in session 2 or 3.

3. All students must read the recommended general reference before session 1.

Reading list (general and specific references)The general reference must be read by all students before session 1 so that a discussion of important issues can begin in this session. The specific references will be allocated to all group members. Each student will engage deeply with at least one of the specific references and produce a summary overhead wich can be posted on WebCT for the PBL group.

Criteria for assessment of PBL contributions

Criteria for marking individual contributions to the PBL (Contributes 50% of mark awarded to you in each PBL)This will be assessed by tutors with the aid of written summaries and overheads prepared by students for each PBL. The following criteria (mark out of 5)

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Mark awarded 0 absent without excuse or apology; or severely disruptive 1 present but not useful contribution (totally unprepared, no evidence of reading

done); or somewhat disruptive 2 present but minimal contribution, not well-prepared 3 average expectation: well prepared, offers some contribution, perhaps misconceptions 4 evidence of good understanding, thorough reading 5 exceptional contribution, real insight into the problem

Criteria for assessing group presentations (50% of the mark awarded to you in PBL)These marks are awarded to the group on the basis of the quality of the group presentation at the end of each topic. This will be assessed in session 6 of each problem by a tutor other than the one who normally has the group. In session 5, the group's own tutor will provide feedback to the group on their rehearsal talk. The talks should run for not more than 45 minutes. The quality of the presentation will be assessed with regard to information content, critical development of ideas, and effective communication (each of these three counting equally to the final assessment mark).

Information content • Clear and thorough description of the normal physiology of the system in question.• Succinct description of the abnormalities focusing on the ways in which normal

physiology is known to be disturbed.• Clear explanation of well established cellular and molecular pathways involved in

the normal physiology, pointing out steps that have been proposed to be disrupted in the disorder.

Critical development of ideas• Clear delineation of the boundaries between what has been well established

(through experimental and other evidence) and hypotheses that have been put forward in the literature.

• Explicit description of relevant current hypotheses. This should explain what the hypothesis proposes about the cellular and molecular mechanisms behind thenormal physiology and about how these might be disrupted in the disorder.

• A rational line of argument explaining how specific types of experimental and other evidence provide support for a particular hypothesis.

Raise any evidence that may argue against a particular hypothesis explaining why it does.

Effective Communication• Clear, easy to follow speech.• Effective use of overheads and drawings.• Speakers coordinated amongst themselves such that the sequential development

of the key ideas is obvious to the listener.

How can you do well in the presentations? The key to this is that as a group you work to gain a deep understanding of the issues. It will then be necessary for the people who are assigned by the group to do the presentation to work together to plan the talk. Everyone in the group should be a presenter for one of the 3 problems as this is an important generic skill for all graduates.

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PBL 1

Stress and cardiovascular disorders

Prof R Dampney

Preliminary questions

(1) What are the main features of the physiological response to acute stress?(2) What is the hypothalamus-pituitary-adrenal axis?(3) What are the physiological effects of cortisol?(4) Compare and contrast the peripheral sympathetic and somatomotor nerves with respect

to their target organs, anatomical organization and neurotransmitters.

Scenario

You are a general practitioner. A middle-aged patient comes to see you, because he has been feeling stressed over a long period of time, for at least several months. Occasionally,he experiences a very strong emotional and physiological reaction, triggered by difficult events at work or at home. At these times he feels extremely anxious and he notices that his heart is racing and that he is breathing very rapidly. You measure his blood pressure, and find that it is 150/95 mmHg, which is above the normal healthy range. You are concerned about two things: (1) whether the acute episodes of extreme anxiety could trigger an acute cardiac event, and (2) whether the chronic stress that he is experiencing may be a cause of, or increase the risk of, a heart attack or other cardiovascular disorder.

Questions

1) What is the definition of stress? What is a stressor? How does the normal physiological response to a stressor help to maintain homeostasis? (See Vanitallie, 2002; Dayas et al., 2001).

2) One characteristic feature of stress is that it is associated with the release of the hormone adrenocorticotropin (ACTH). What are the main pathways in the brain that subserve the release of ACTH in response to stressors? (See Benarroch, 2005).

3) In experimental animals, much has been learned about the organization of the brain pathways that regulate the physiological responses to stressors, particularly by using the method of c-fos immunohistochemistry. Explain the principles of the method of c-fos immunohistochemistry for labeling activated neurons in the brain. (See Dampney & Horiuchi, 2006). What are the different types of stress, and how do they differ with respect to the brain pathways that trigger the release of ACTH? (See Dayas et al., 2001).

4) The paraventricular nucleus (PVN) is a crucial component of the hypothalamus-pituitary-adrenal axis that is activated during stress. It also contains neurons that project to the sympathetic outflow, both indirectly and indirectly. Briefly describe the organization of these descending pathways, and discuss what is thought to be their functional role. (See Benarroch, 2005; Blair et al., 1996; Dampney et al., 2002).

5) With regard to acute psychological stimuli, what are (a) the main physiological responses to this stressor? (b) the central pathways and central relay nuclei that mediate these effects? (See DiMicco, 2002; Dampney et al., 2002).

6) The increase in heart rate and blood pressure associated with stress in your patient suggests that there may be overactivity of his sympathetic nervous system. What are the methods that are used to measure sympathetic activity in conscious humans? (See Esler, 1998).

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a) What is the evidence that acute psychological stress causes increased sympathetic activity in humans? (See Esler, 1998; Esler et al., 2004).

b) What is the evidence that acute psychological stress may trigger an acute myocardial infraction or cardiac arryhythmia? (See Esler, 1998; Wilbert-Lampen et al., 2008; Zipes, 1991).

c) What is the evidence that chronic psychological stress increases the risk of cardiovascular disease? (See Marmot et al., 1997).

7) Patients with anxiety or mood disorders are sometimes treated with drugs that alter the level of serotonin in the brain. It is known that there are several different subtypes of serotonin receptors, but two subtypes, 5-HT1a and 5-HT2a receptors, are thought to influence affect the level of anxiety experienced in stressful situations. Very recent evidence also indicates that these receptors can also modulate the cardiovascular response during acute psychological stress.

a) What effects do activation of serotonin 5-HT1a receptors have on the cardiovascular response during psychological stress? Do these effects also occur in other types of stress? At what sites in the brain could these effects occur? What possible relevance could these observations have for cardiovascular medicine? (See Ngampramuan et al., 2008).

b) What effect does activation of serotonin 5-HT1a receptors in the hypothalamus have on the hormonal and behavioural response to psychological stress? (See Li et al., 2004).

c) What role do 5-HT2a receptors in the brain have on the cardiovascular response to stress? (see Ferreria et al., 2005).

General references:

Benarroch EE. Paraventricular nucleus, stress response, and cardiovascular disease. Clinical Autonomic Research 2005; 15:254-63.

Vanitallie TB. Stress: a risk factor for serious illness. Metabolism: Clinical & Experimental2002; 51(6 Suppl 1):40-5.

Specific references:

Blair ML, Piekut D, Want A, Olschowka JA. Role of the hypothalamic paraventricular nucleus in cardiovascular regulation. Clinical & Experimental Pharmacology & Physiology1996; 23:161-5.

Dampney RAL, Coleman MJ, Fontes MAP, Hirooka Y, Horiuchi J, Li YW, Polson JW, Potts PD, Tagawa T. Central mechanisms underlying short- and long-term regulation of the cardiovascular system. Clinical & Experimental Pharmacology & Physiology 2002; 29:261-8.

Dampney RAL, Horiuchi, J. Functional organisation of central cardiovascular pathways: studies using c-fos gene expression. Progress in Neurobiology 2003; 71: 359-84. (special abridged version).

Dayas CV, Buller KM, Crane JW, Xu Y, Day TA. Stressor categorization: acute physical and psychological stressors elicit distinctive recruitment patterns in the amygdala and in medullary noradrenergic cell groups. European Journal of Neuroscience 2001; 14:1143-52.

DiMicco JA, Samuels BC, Zaretskaia MV, Zaretsky DV. The dorsomedial hypothalamus and the response to stress: part renaissance, part revolution. Pharmacology, Biochemistry & Behavior 2002; 71:469-80.

Esler MD. Mental stress, panic disorder and the heart. Stress Medicine 1998; 14: 237-243.

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Esler M, Alvarenga M, Lambert G, Kaye D, Hastings J, Jennings G, Morris M, Schwarz R, Richards J. Cardiac sympathetic nerve biology and brain monoamine turnover in panic disorder. Annals of the New York Academy of Sciences 2004; 1018:505-14.

Ferreira HS, Oliveira E, Faustino TN, Silva Ede C, Fregoneze JB. Effect of the activation of central 5-HT2C receptors by the 5-HT2C agonist mCPP on blood pressure and heart rate in rats. Brain Research 2005; 1040:64-72.

Li Q, Holmes A, Ma L, Van de Kar LD, Garcia F, Murphy DL. Medial hypothalamic 5-hydroxytryptamine (5-HT)1A receptors regulate neuroendocrine responses to stress and exploratory locomotor activity: application of recombinant adenovirus containing 5-HT1A sequences. Journal of Neuroscience 2004; 24:10868-77.

Marmot MG, Bosma H, Hemingway H, Brunner E, Stansfeld S, Contribution of job control and other risk factors to social variations in coronary heart disease incidence. Lancet 1997; 350:235-9.

Ngampramuan S, Baumert M, Beig MI, Kotchabhakdi N, Nalivaiko E. Activation of 5-HT(1A) receptors attenuates tachycardia induced by restraint stress in rats. American Journal of Physiology - Regulatory Integrative & Comparative Physiology 2008; 294:R132-41.

Wilbert-Lampen U, Leistner D, Greven S et al. Cardiovascular events during World Cup soccer. New England Journal of Medicine 2008; 358:475-83.

Zipes DP. The long QT interval syndrome. A Rosetta stone for sympathetic related ventricular tachyarrhythmias. Circulation 1991; 84:1414-9.

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PBL 2

Pathophysiological Role of ROS with Ageing on the Cardiovascular System

Prof Brian Morris

Scenario

Mr Harry Hardman, aged 65, has recently experienced a mild heart attack. A diagnosis of ‘metabolic syndrome’ is made. His clinical features include being overweight (body mass index 29 kg/m2), systolic/diastolic blood pressure of 170/106 mmHg, total cholesterol of 5.5 mmol/L, and triglycerides 2.0 mmol/L. A test reveals he has mild insulin resistance but he does not have type 2 diabetes.

His diet and lifestyle are at odds with health messages. He has a low intake of fruit and vegetables, he drinks on average 3 units of alcoholic beverages per day, he has been a regular smoker from his late teens, and he says his exercise is restricted to an occasional walk to his corner store to buy bread, milk, cigarettes and the newspaper. He becomes very worried when told by his doctor that his symptoms may shorten his life and that he is likely to suffer years of progressively worsening illness. Even though he will need to be treated, his doctor also explains that treatments are on average only partly effective, but nevertheless important in trying to address his condition.

Preliminary Questions:1. What is the metabolic syndrome? (see Finkel 2005, pp 972-3) 2. Outline the main clinical features of the metabolic syndrome briefly in order to set the

scene. 3. What risk factors for metabolic syndrome and cardiovascular disease does Mr

Hardman exhibit?

In the next set of questions you will be asked to build up a picture of certain general underlying defects responsible for Mr Hardman’s metabolic syndrome – from the molecular abnormalities right through to how these manifest at the whole body level in the symptoms seen. In doing so, rather than attempt to cover all of the myriad of factors, concentrate on the following:

There are a number of ways of approaching these sorts of problems, but in this activity you will be asked to concentrate on one. Please note that the focus of this topic is reactive oxygen species (ROS) in blood vessels. The aim in particular is to obtain a picture of

what is happening in the vessel wall – vascular smooth muscle, endothelium, and

lumen at the local level.

1.. Accumulating research has pointed to a common theme in people with the metabolic syndrome, namely an increase in production of ROS. Explain what ROS are, how they are produced, changes in ROS production with age, the effect of unhealthy diet and lifestyle factors on ROS levels. (See Finkel (2005) and Förstermann (2008) for reviews)

3. How might ROS be involved in hypertension, atherosclerosis and insulin resistance associated with the metabolic syndrome? In particular, focus on the molecular mechanisms involved inside the cell and how these lead to changes at the tissue and whole body level (Förstermann, 2008).

Some of the following questions may help steer you and focus your presentation:

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(a). What role do cardio-regulatory hormones such as angiotensin II play in ROS formation leading to vascular pathology? (See Editorial Commentary by Morris (2005) and references cited therein, as well Imanashi et al. (2005).)

(b). What is the role of local paracrine factors such as nitric oxide on shear stress and atherogenic mechanisms? And how is its production influenced by NOS (Haendeler et al., 2006; Sánchez et al., 2005).

(c). How can cell culture and animal models be used to assess the role of ROS in insulin resistance? (Houstis et al., 2006).

4. What dietary and lifestyle advice should the doctor give Mr Hardman, and what might be the molecular effects of such a change? You should concentrate on two (Everitt et al., 2005; Finkel, 2005; Houston, 2005; Morris, 2008; Porcu, 2005; Sánchez et al., 2005; Baur & Sinclair 2006; Cifuentes and Pagano 2006; van Zonneveld & Rabelink 2006, Förstermann, 2008).

REFERENCES

General

Finkel T. Radical medicine: treating ageing to cure disease. Nat Rev Mol Cell Biol 2005; 6: 971-6.

More specific

Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5:493-506

Cifuentes ME, Pagano PJ. Targeting reactive oxygen species in hypertension. Curr Opin Hypertens 2006; 15: 179-186

Evans JL, Youngren JF, Goldfine ID. Effective treatments for insulin resistance: trim the fat and douse the fire. Trends Endocrinol Metab 2005; 15: 425-31.

Everitt AV, Hilmer SN, Brand-Miller JC, Jamieson HA, Truswell AS, Sharma AP, Mason RS, Morris BJ, et al. Dietary approaches that delay age-related diseases. Clin Intervent Aging 2005; 1: 11-31.

Förstermann U. Oxidative stress in vascular disease: causes, defense mechanisms and potential therapies. Nature Clin Pract Cardiovasc Med 2008; 5: 338-49

Haendeler J. Nitric oxide and endothelial cell aging. Eur J Clin Pharmacol 2006; 62 (Suppl 13): 137-40.

Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multipleforms of insulin resistance. Nature 2006; 440: 944-8.

Houston MC. Nutraceuticals, vitamins, antioxidants, and minerals in the prevention and treatment of hypertension. Prog Cardiovasc Dis 2005; 47: 396-449.

Imanashi T, Hano T, Nisho I. Angiotensin II accelerates endothelial progenitor cell senescence through induction of oxidative stress. J Hypertens 2004; 23: 97-104.

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Morris BJ. How xenohormetic compounds confer health benefits. In: Le Bourg E, Rattan SIS (eds). Mild Stress: Applying Hormesis in Aging Research and Interventions. Springer, Netherlands. 2008: pp 115–138. [a pdf of this chapter supplied on request]

Morris BJ. The scorching breath of angiotensin. [Editorial Commentary] J Hypertens 2005; 23: 33-5.

Porcu M, Chiarugi A. The emerging therapeutic potential of sirtuin-interacting drugs: from cell death to lifespan extension. Trends Pharmacol Sci 2005; 26: 94-103.

Sánchez M, Galisteo M, Vera R, Villar IC, Zarzuelo A, Tamargo J, Perez-Vizcaino F, Duarte J. Quercetin downregulates NADPH oxidase, increases eNOS activity and prevents endothelial dysfunction in spontaneously hypertensive rats. J Hypertens 2006; 24: 75-84.

van Zonneveld A-J, Rabelink TJ. Endothelial progenitor cells: biology and therapeutic potential in hypertension. Curr Opin Nephrol Hypertens 2006; 15: 167-172

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PBL 3

Tumour angiogenesis

Dr. Stuart Fraser

The vascular system transports oxygen, nutrients, electrolytes, hormones and growth factors throughout the body. This system also carries metabolic waste products and CO2 out of the tissues. The development of the vasculature is a critical phase in embryogenesis. Knockout mice that exhibit defects in vascular formation typically die in utero illustrating the importance of this system maintaining homeostasis.

A tumour is limited in its ability to grow by its capability to obtain nutrients and dispose of waste products. Tumours have unique metabolic properties and have, therefore, expensive requirements for nutrients and oxygen.

The focus of this PBL is to understand how tumours obtain the necessary requirements for growth and how they develop a vascular network to do so. To do this, you will discuss the basic necessities of tumours and how they re-start genetic programmes typically seen in the developing embryo.

With cancer being the greatest cause of death for humans in both developed and developing nations, finding novel targets for the development of therapeutic agents is need now more than ever. Weʼll discuss how tumour angiogenesis may offer novel targets for a range of cancers.

Before the first session:Each group member should read the following review articles as an introduction to the field.

Carmeliet, P. (2005) Angiogenesis in life, disease and medicine. Nature. Dec 15;438(7070):932-6.

Red-Horse, K., et al. (2007) Endothelium-Microenvironment Interactions in the Developing Embryo and in the Adult. Developmental Cell Feb;12(2):181-94.

Introductory Questions: to be discussed as a group in Session 1.

Understanding the different forms of vessel development are important as these vessels are regulated in distinct manners.

1. What are the distinctions between the following processes?

a. Vasculogenesisb. Angiogenesisc. Lymphangiogenesisd. Tumour angiogenesise. Sprouting

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2. What growth factors and growth factor receptors are needed in the formation and development of the vasculature?

Your Task:At the end of session 1, papers from the list below should be assigned to each group member to be read and summarised before session 2.

Sessions 2, 3 and 4: It is your responsibility to read, interpret and present an oral and written summary to the group, together with a figure and legend. The 1 page summary, figure and legend should be self explanatory. Each student should discuss the paper they have been assigned and explicitly relate their assigned paper to those topics raised in the PBL discussion below.

Your Goal:A 45 min (max) group presentation that explains the process of normal vessel

formation, mechanisms by which tumours re-activate programmes of vesseldevelopment. You should consider how tumour cells attract endothelial cells to form blood vessels; which cell types, other than endothelial cells, play important roles in tumour angiogenesis; examples of molecules that serve as potentially useful anti-angiogenic therapies describing the underlying rationale. Where appropriate you should support your claims using available experimental evidence. Discuss any inconsistencies in the literature and how these might be explained, bearing in mind one of the criteria for assessment is “critical development of ideas”.

Specific References

Asahara T, (1997). Isolation of putative progenitor endothelial cells for angiogenesis.Science. Feb 14;275(5302):964-7.

Benny O, et al.,(2008). An orally delivered small-molecule formulation with antiangiogenic and anticancer activity. Nat Biotechnol. Jul;26(7):799-807.

Corada M., et al., (2002). A monoclonal antibody to vascular endothelial-cadherin inhibits tumor angiogenesis without side effects on endothelial permeability. Blood.Aug 1;100(3):905-11.

Dong et al., (2004) VEGF-null cells require PDGFR alpha signaling-mediated stromal fibroblast recruitment for tumorigenesis, EMBO J. 23 (2004), pp. 2800–2810.

He et al., (2005) Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer Res. 65, pp. 4739–4746.

Maione, F. et al., (2009). Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models. J Clin Invest. 2009; Volume 119, Issue 11 119(11):3356

Plate, C.H., et al., (1992) Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359, 845 - 848

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Sato TN, et al., (1995) Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2in blood vessel formation. Nature. Jul 6;376(6535):70-4

Shalaby F. et al., (1995). Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. Jul 6;376(6535):62-6.

Shojaei F, et al., (2007) Bv8 regulates myeloid-cell-dependent tumour angiogenesis.Nature. Dec 6;450(7171):825-31.

Tammela T, et al., (2008). Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature. 2008 Jul 31;454(7204):656-60.

Wang HU, Chen ZF, Anderson DJ. (1998). Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell. May 29;93(5):741-53.

Yamashita J, et al., (2000) Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature. Nov 2;408(6808):92-6.