Nurturing Clinical Research Issues and Examples David de Kretser

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Nurturing Clinical ResearchIssues and
ExamplesDavid de Kretser
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Nurturing Clinical Research

• Is clinical research important?
• Who carries it out?
• What can the medical graduate provide?
• How can we recruit the medical graduate?
• What is the ideal person?
• Are there issues that slow clinical research?
• Are there new frontiers where clinical research
  is invaluable?
• What are some example?

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Nurturing Clinical Research Is clinical research
important?

• Provides the route for basic science into the
  clinic both for therapeutics and diagnostics
• Can define new clinical disorders and identify
  solutions or seek more basic knowledge
• Can define the place of new investigations
• Is critical for the post-marketing surveillance
• Enables study of patient populations both within
  and outside the hospital setting
• Encompasses the study of population health

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Nurturing Clinical Research Who performs it?

• All branches of medical specialization but in
  differing settings
• All paramedical specialties such as nursing,
  physiotherapy, psychologists, occupational
  therapy, sociology, geneticists etc.
• Population studies involve epidemiologists and
  other disciplines with key questions and
  definitions involve the medical practitioner
• Often the best studies involve teams of the above
  people

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Nurturing Clinical Research What can the medical
graduate provide?

• A person with an understanding of the whole
  organism combined with an understanding of the
  basic sciences underpinning the practice of
  medicine
• The capacity to provide clinical information
  crucial to many studies such as
  genotype-phenotype studies
• The ability to critically appraise clinical,
  diagnostic and basic science data related to
  clinical research

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Nurturing Clinical Research How can we recruit
the medical graduate?

• There are competing opportunities for a medical
  graduate so a recruiting strategy is essential
• Expose them during the medical course to the
  excitement of research but this requires good
  teachers
• Recognise their value and maintain flexibility in
  remuneration and conditions of employment in the
  university and hospital sectors
• Do not burden them with teaching, patient care
  and administration to the exclusion of research

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Nurturing Clinical Research How can we recruit
the medical graduate?

• Convince the hospital sector of the value of
  appointing research active clinicians who can
  evaluate advances and assist in their translation
  to clinical care the importance of the
  university teaching hospital
• Define and enhance career paths in research for
  medical graduates and ensure that there is
  funding for clinically related projects that are
  in balance with basic science
• Provide examples of innovation and
  commercialisation

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Nurturing Clinical Research Is there an ideal
person for clinical research?

• The easy answer is that it depends on the project
• A medical graduate who has specialised and
  experienced clinical practice and who has
  experienced and has a continuing interest in
  basic science who can build and manage a team.
  These qualifications enhance the likelihood of an
  understanding of the new developments in the
  biological sciences that can be applied to
  clinical research and patient care

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Nurturing Clinical Research Are there issues that
slow clinical research?

• Privacy issues
• The myriad of forms and the time taken for
  ethical approvals especially for multicentre
  trials
• Funding especially at the interface of basic
  research and commercial possibilities

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Nurturing Clinical Research Are there new
frontiers where clinical research is very
valuable?

• Recruitment of patients and definition of
  phenotype
• Provision of quality clinical data collection
• Phenotype genotype studies critical for exploring
  the identification of new mutations causing
  disease The Human Variome Project
• Pharmacogenomics
• New medical devices including stem cell research
  and applications

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Studies of Inflammatory MechanismsBench to
Bedside
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Activins

• Activins are disulphide-linked dimers with a
  molecular weight of 24-28kDa
• Activin A ßAßA
• Activin B ßBßB
• Activin AB ßAßB
• Activin C ßCßC dimers of the ßC subunit with
  the other subunits probably occur but to date
  these are inactive

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Follistatin

• Follistatin is a monomeric variably glycosylated
  protein structurally unrelated to the inhibins or
  activins and can bind activin with Kd 198pM
• Follistatin can bind and neutralise essentially
  all the actions of activin A and B

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Species homology for activin
100
99
97
87
58
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Species homology for follistatin
100
99
98
97
90
83
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Response to Lipopolysaccharide in sheep
Activin
IN CONFIDENCE
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Activin response in the mouse
Activin
Follistatin
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Activin response to purified LPS
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Response to blocking activin
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Effect of follistatin in acute inflammation
100
Controls (n26)
Follistatin (n16)
90
80
Percent survival
70
60
50
0
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12
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15
16
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23
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Time (hours)
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Clinical septicaemia profiles
From Michel et al. (2003) Eur J Endocrinol 148,
559-64.
IN CONFIDENCE
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Clinical septicaemia profiles
From Michel et al. (2003) Eur J Endocrinol 148,
559-64.
IN CONFIDENCE
IN CONFIDENCE
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Serum activin/follistatin and Burns
IN CONFIDENCE
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Burns Blister Fluid
IN CONFIDENCE
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V
F
M
bA Neg
bA
HE
FS Neg
FS
IN CONFIDENCE
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Andrology Australia Longitudinal Study Group.
Andrology Australia, c/o Monash Institute of
Medical Research, Melbourne, Australia
Men in Australia, Telephone Survey (MATeS)
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Longitudinal Study Working Group
Dr Carol Holden Prof. Rob McLachlan
Prof. Marian Pitts Prof. Bob Cumming
Prof. Gary Wittert Prof. David
Handelsman Prof. David de Kretser
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Methods

• Men in Australia, Telephone Survey (MATeS)
• Commissioned by Andrology Australia
• 5990 men (78.5) participated, from a total of
  7636 randomly selected households.
• Unbiased sampling stratified by age and across
  the 7 states
• Age groups 40-49, 50-59, 60-69 and 70 years
• Findings are census-standardised to the national
  population
• 20 minute telephone interview on broad aspects of
  mens health and well-being, including
  reproductive health
• Survey conducted between Sept - Dec 2003

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MATeS
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MATeS Socio-demographic
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MATeS General Health
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MATeS General health
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MATeS General health
87 of all men had visited a doctor in the past
12 months, Over 80 of men reported having good
health status
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MATeS Reproductive health
Reproductive health declined with age
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A NATIONAL DNA REPOSITORYA TOOL TO INVESTIGATE
GENETIC CAUSES OF MALE INFERTILITY
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Why Set up a DNA Repository?

• In approx. 40 of men with spermatogenic
  disruption, no cause can be found
• In some men, there is a significant family
  history of infertility
• There is increasing evidence that genetic causes
  of infertility exist
• Numerous gene knock-outs in mice have resulted
  in an infertility phenotype

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What Are the Essential Features of the Repository?

• DNA of high quality extracted from peripheral
  blood leucocytes
• Detailed clinical information is crucial to
  enable phenotype-genotype correlations to be
  determined
• Computerisation of the data
• A large number of patients with diverse semen
  patterns and normal controls are necessary to
  identify rarer genetic causes of infertility

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What Is the Clinical Information in the Database?

• Age
• Family history of infertility
• Identifiable causes of infertility
• Testicular size
• Abnormal features on clinical examination

• Diagnosis
• Semen data
• FSH, LH, T
• Karyotype, Y chrom. deletion analysis
• Testicular biopsy data

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What Is the Current State of Our Database?

• DNA from approx. 2000 men with infertility,
  together with their clinical information and DNA
  from 500 normal men
• Because of a specific focus on motility
  disorders, specific information on electron
  microscopic analysis of semen in 35 men is
  available
• A separate database holds 520 samples of DNA from
  male children and their fathers, together with
  their clinical information

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Karyotype
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Yq deletion analysis in men entering ART
(May 1998 October 2001)
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Demonstrated That Yq Deletions Could Be
Transmitted to Sons by ICSI

• Provided samples from 99 ICSI born sons and their
  86 fathers that showed vertical transmission of
  Yq deletions
• 2 / 29 (6.9) azoospermic or severely
  oligozoospermic men had Yq deletions and
  identical deletions were found in their sons
• The remaining 97 sons showed no de novo
  deletion (Cram et al, 2000)

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Clinical importance ofY chromosome testing

• Explanation for infertility
• Risk assessment for male offspring
• Prognostic value
• Option of sex selection for female embryos in the
  case of a severe Yq deletion

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How we got into the inflammation area

• Original hypothesis
• Follistatin is a feedback factor predominantly
  produced by the gonad to regulate FSH
• Removal of the testis results in almost
  undetectable levels of follistatin in the
  circulation
• 3 groups of rams in study
• Blood sampling only
• Surgical castration
• Sham castration

IN CONFIDENCE
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Testing the original hypothesis
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Genetic map of the Y chromosome
Non-recombining region
Yp
Yq
Hetero - chromatin
4
1
2
3
7
5
6
qter
pter
RBM1
CDY
PRY
PRY
CDY
SRY
DAZ
PRY
TTY1
BPY2
BPY1
TTY2
TTY1
TSPY
TTY2
Testis genes
XKRY
TSPY
AZF regions
A
B
C