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Fetal Origins of Adult Disease=
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------=_NextPart_01C6420B.51CD2470 Content-Location: file:///C:/1E09C636/Fetal_origins_Brune_Rossel_2006_files/master08.xml Content-Transfer-Encoding: quoted-printable Content-Type: text/xml; charset="utf-8" ------=_NextPart_01C6420B.51CD2470 Content-Location: file:///C:/1E09C636/Fetal_origins_Brune_Rossel_2006_files/master02.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="windows-1252" ------=_NextPart_01C6420B.51CD2470 Content-Location: file:///C:/1E09C636/Fetal_origins_Brune_Rossel_2006_files/pres.xml Content-Transfer-Encoding: quoted-printable Content-Type: text/xml; charset="utf-8" ------=_NextPart_01C6420B.51CD2470 Content-Location: file:///C:/1E09C636/Fetal_origins_Brune_Rossel_2006_files/slide0382.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="windows-1252" Fetal origins of adult diseases - Marie-Noël Bruné Rossel
3= /7/2006
1
Children's Heal= th and the Environment
WHO Training Package for the Health Sector
World Health Organization
www.who.int/ceh
pFETAL ORIGINS
pOF ADULT DISEASE
pMarie-Noël Bruné Rossel
TRAINING FOR THE HEALTH SECTOR
Training Course in Reproductive Health / Sexual Health Research
 7 March 2006, WHO HQ=
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3= /7/2006
2
Fetal Origins of Adult Disease
FETAL= ENVIRONMENT
Intra= uterine Env
U-Pla= cental Unit
+
GENOME
MATERNAL
ENVIRONMENT
+
MATERNAL
& PLACENTAL
PHYSIOLOGY
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3= /7/2006
3
Fetal Origins of Adult Disease
FETAL= ENVIRONMENT
Intra= uterine Env
U-Pla= cental Unity
+
GENOME
MATERNAL
ENVIRONMENT
+
MATERNAL
& PLACENTAL
PHYSIOLOGY
ALTERATIONS:
• FETAL GROWTH =
• INTERACTI= ON PRE-AND POST-NATAL ENVIRONMENTS =
 
 
FETAL OR= IGIN OF DISEASE
RESPONSE= S TO ADVERSE ENVIRONMENTS: =
<= span style=3D'mso-special-format:"numbullet3\,1";position:absolute;left:-11.81%= '>1.Accelera= ted maturation (   G-corticoid level)
<= span style=3D'mso-special-format:"numbullet3\,1";position:absolute;left:-11.55%= '>2.Keeps nutrients     (    growth & nutrition)
<= span style=3D'mso-special-format:"numbullet3\,1";position:absolute;left:-12.62%= '>3.Pregnancy termination (abortion, prematurity)
------=_NextPart_01C6420B.51CD2470 Content-Location: file:///C:/1E09C636/Fetal_origins_Brune_Rossel_2006_files/slide0411.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="windows-1252" Fetal origins of adult diseases - Marie-Noël Bruné Rossel
3= /7/2006
4
Fetal Origins of Adult Disease
v
vHow does the fetus respond to an
vadverse environment – e.g.: nutritional?
vBy making irreversible changes in its development <= /span>
v
vAb= normal insulin Type II diabet= es
v sec= retion/action
v
<= span style=3D'font-size:108%;color:black;mso-color-index:1;font-weight:normal; text-shadow:none'>vRe= duced vascularity Hypertensi= on
<= span style=3D'font-size:42%;color:black;mso-color-index:1;font-weight:normal; text-shadow:none;visibility:hidden'>v
<= span style=3D'font-size:108%;color:black;mso-color-index:1;font-weight:normal; text-shadow:none'>vRe= duced nephron number CV disease
v
v
 EHP
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Fetal origins of adult diseases - Marie-Noël Bruné Rossel
3= /7/2006
5
Fetal Origins of Adult Disease
PREDICTIVE ADAPTIVE RESPONSES (PARs)
vThe developing organism predicts its future environment
= v
vEmbryo/fetus depend on the information transmitted by t= he mother/placenta to evaluate/predict the present and fut= ure environments.
§
vPAR= s: decisions to change the course of development for future advantages
§Appropriate PARs
§Inappropriate PARs
v
------=_NextPart_01C6420B.51CD2470 Content-Location: file:///C:/1E09C636/Fetal_origins_Brune_Rossel_2006_files/slide0407.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="windows-1252" Fetal origins of adult diseases - Marie-Noël Bruné Rossel
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Fetal Origins of Adult Disease
DEVELOPM= ENTAL PLASTICITY
vPlasticity #  Disruption
v = ;
v= Developmental plasticity: normal processes that allow a range of phenotypes to develop from a single genotype
<= span style=3D'mso-special-format:bullet;color:#006600;position:absolute;left:-4= .28%; font-family:Wingdings'>v <= /span>
= v Disruption: alteration of the developmental program =
v <= /span>
= vSometimes, the difference is not evident
------=_NextPart_01C6420B.51CD2470 Content-Location: file:///C:/1E09C636/Fetal_origins_Brune_Rossel_2006_files/slide0403.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="windows-1252" Fetal origins of adult diseases - Marie-Noël Bruné Rossel
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Fetal Origins of Adult Disease
 Moore, Elsevier Inc, 1973
WINDOWS OF DEVELOPMENT
DYNAMIC DEVELOPMENTAL PHYSIOLOGY
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quoted-printable Content-Type: text/html; charset="windows-1252" Fetal origins of adult diseases - Marie-Noël Bruné Rossel
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Fetal Origins of Adult Disease
vKey concept: match/mismatch PARs
v Relationship between real and predicted postnatal environments determines disease risk
v
üMatch: low risk of disease
üNo match: higher risk of disease
v
vNutritional signals: low food availability:
v insulin resistance
v
------=_NextPart_01C6420B.51CD2470 Content-Location: file:///C:/1E09C636/Fetal_origins_Brune_Rossel_2006_files/slide0424.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="windows-1252" Fetal origins of adult diseases - Marie-Noël Bruné Rossel
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Fetal Origins of Adult Disease
WHO
Very adverse environment<= span style=3D'mso-tab-count:3;width:22.99%'> Death
Less adverse environment<= span style=3D'mso-tab-count:3;width:21.85%'> Alterations of =
- Maturity
- Size
- Growth
=
Small newborn
(Prematurity)
Other factors:
- Infections&#= 13;
- Genetics
Long-term <= span style=3D'position:absolute;top:75.25%;left:11.98%;width:34.64%;height:5.25= %'>consequences
Compensatory growth
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3= /7/2006
10<= /span>
Fetal Origins of Adult Disease
vPer= i-conception period
vCrucial nutrients: vitamin B12, folate, choline, methionine, glicine
v
vBir= th: environmental transition in human development
v <= /div>
vNeo= nate is in a phase of plasticity
= v
vThe neonate perceives as his/her environment what the hea= lth care provider/mother presents
FETAL AND INFANT PROGRAMMING
------=_NextPart_01C6420B.51CD2470 Content-Location: file:///C:/1E09C636/Fetal_origins_Brune_Rossel_2006_files/slide0427.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="windows-1252" Fetal origins of adult diseases - Marie-Noël Bruné Rossel
3= /7/2006
11<= /span>
Fetal Origins of Adult Disease
v= Suspected fetal/environmental origins of disease:
v
vHerbicides Parkinson disease
vInsecticides
vMan= ganese
vPb, Hg, PCBs Dementia
vDifferent chemicals Cancer
vUnd= ernutrition Osteoporosis
vPoor early growth Ageing&#= 13;
vUndernutrition COPD
vAnxiety disorders Stress
p? Alzheimer disease
------=_NextPart_01C6420B.51CD2470 Content-Location: file:///C:/1E09C636/Fetal_origins_Brune_Rossel_2006_files/slide0426.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="windows-1252" Fetal origins of adult diseases - Marie-Noël Bruné Rossel
3= /7/2006
12<= /span>
Fetal Origins of Adult Disease
IMPLICAT= IONS OF THESE MODELS
<= span style=3D'font-size:86%;color:black;mso-color-index:1;font-weight:normal; text-shadow:none'>v&qu= ot;Lifestyle" disease
v
<= span style=3D'font-size:86%;color:black;mso-color-index:1;font-weight:normal; text-shadow:none'>vImp= rove maternal and child health
v and= their environments
<= span style=3D'font-size:86%;color:black;mso-color-index:1;font-weight:normal; text-shadow:none;visibility:hidden'>v
<= span style=3D'font-size:86%;color:black;mso-color-index:1;font-weight:normal; text-shadow:none'>vMore research needed in:
v - Genetic changes
v - Peri-conception period
v - Women's nutrition
v - Metabolic, cardiovascular,
v    skeletal & other systems <= /div>
WHO
WHO
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3= /7/2006
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Fetal Origins of Adult Disease
pFir= st draft prepared by Marie-Noel Bruné, M. Sc.(WH= O)
pWit= h the advice of the Working Group on Training Package for Hea= lth Care Providers:  Cristina Alonzo MD (Uruguay); Yona Amitai MD, MPH (Israel); Stephan Boese-O’Reilly MD MPH (Germany); Irena Buka MD (Canada); Lil= ian Corra MD (Argentina); PhD (USA); Ruth A. Etzel, MD, = PhD (USA); Amalia Laborde MD (Uruguay); Ligia Fruchtenga= rten MD (Brazil); Leda Nemer, TO (WHO/EURO); R. Romizzi MD (I= SDE, Italy); S. Borgo MD (ISDE, Italy).
p <= /div>
pReviewers:
p
p= WHO CEH Training Project Coordination:  Jenny Pronczuk, MD
p= Medical Consultant:  Katherine M. Shea, MD= , MPH, USA
p= Technical Assistance:  Marie-Noel Bruné, M. = Sc.
ACKNOWLEDGEMENTS

WHO is grateful to the US EPA Office of Children’s Health Protection for financial support that m= ade this project possible and for the data, graphics and = t= ext used in preparing these materials for a broad audience.
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Fetal Origins of Adult Disease
 
pDISCLAIMER
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<<NOTE TO USER:  Please add details of the date, time, = place and sponsorship of the meeting for which you are using this presentation in the space indicated.>>
<<NOTE TO USER:  Both emb= ryonic and fetal origins of adult disease will be considered in this presentation. The end of the eighth week of gestation marks the end= of the "embryonic period" and the beginning of the "fetal period">>
•Fetal growth: interaction between fetal environment and genome  (G y E).
•Fetal environment determined by maternal environment and maternal placental = physiology^.
•Interaction between fetal environment and genome determines the ris= k of postnatal = disease.
•Studies between size at birth and long-term disease: hypothesis of "fetal origins of disease"
•Fetal growth: interaction between environment and fetal genome. Fet= al environment is determin= ed by maternal environment and by maternal and placental physiology. Fetal nutrition and mate= rnal nutrition are different. Fetal nutrition is the end of a long line of distribution  that begins in the maternal macroenvironment, goes on to the maternal gastrointestinal and metabolic systems and end in the <= /span>utero-placental system.= The fetal environment does not reflect the external environment but it is affected by it= .
•Interaction between fetal environment and genome can determine risk= of postnatal = disease. And individual capacity to cope with postnatal environment.
•Studies between measures of birth size and long-term disease risk appeared. They led to the so-called "fetal origins of disease" hypothesis: events <= /span>in utero = which reduce fetal growth, permanently alt= er the structure and physiology of the offspring, such that the risk of heart disease = and diabetes later in life was increased. The word "programming" describes the unknown linkages between fetal life and long-term consequences.
-
Ref:
Gluckman, Developmental origins of disease paradigm: a mechanist= ic and evolutionary perspective. Pediatric Research (2004) 56: 311
•
•3 types of adverse resp= onses to an adverse environment::
- Accelerati= on of maturation (e.g. by elevating glucocorticoid levels)
- Conservati= on of nutrients (reducing growth and activity)
- Termination of pregnancy (abortion/premature delivery). In evolutionary terms, this means another fetus can= be conceived but loss of the mother means loss of her genome, therefore most circumstances= will favor the mother.
-
Ref: =
Gluckman, Developmental origins of disease paradigm: a mechanistic and evolutionary perspec= tive. Pediatric Research (2004) 56: 311
Thrifty phenotype hypoth= esis: according to it, the fetus responds to adverse environment by making ir= reversible changes in its development. Specially by reducing its growth to keep the energy for cardiac function and neurodevelopment. Possible problem: the ma= ture organism was adapted to a nutritionally deprived environment. This carried abnormalities of insulin secretion and action, reduced vascularity in orga= ns and reduced nephron number. Particularly, if the person is obese at middle age, cardiovascular and metabolic diseases would appear. This model has its limitations: it can explain consequences of extreme intrauterine growth retardation but not how mild shifts in normal development or how exposure = at a critical moment can lead to long-term consequences. This model (proposed by Barker and Hales) evolved then into the models of the fol= lowing slides.
Ref:
•Gluckman, The fetal, neonatal and infant environments – the long-term consequences for disease risk, = Early Human Development (2005) 81:51.
Picture: Extramurally speaking, Fetal basis of child= hood and adult disease: Role of the environment (2002) EHP 110 (6): ehp.niehs.nih.gov/docs/2002/110-6/extram-speaking.html
There are adaptive responses that may be made by the developing organ= ism in response to the envir= onment. These have no obvious adaptive value but are made in expectation of the fu= ture environment. (In locusts, larvas, responding to pheromones, have to commit to a wing shape and metabolism for either the migratory o= r the solitary form. There is no advantage to the larva, whatever it chooses, but if the adult should deve= lop as migratory in an overcrowded environment the consequences might be disadvantageous and vice ver= sa.)
•<= /span>PARs (Predictive Adaptive Responses): decisions made by the developing organism to change the course of development might be made f= or future advantages. PARs can be appropriate or inappropriate, this depending on whether the physiological responses the mature organism can have are adapted to the environment it is exposed to.&#= 13;
- The appropriate PARS are those where the physiological responses the mature organism can have are adapted to the environment it is exposed to.
- When this is not the case, in the inappropriate PARs, the risk of disease in later life is greater.
PARs only happen during critical windows of development when developmental plasticity operates. The windows of potential induction differ for different organs.
•<= /span>The key idea in the PARs model is tha= t the developing organism has to predict its future environment quite accurately. The embryo and the = fetus depend on the mother and placenta to transmit them information and therefore evaluate the current and future environment. These metabolic, nutrient and hormonal signals can suffer from interference by maternal or placental dysfunction. In the case of the human, the only information the neonate receives o= f its nutritional environment is the feeding it receives from the mother or health care provider. They are = the ones translating the information about the environment, so a risk of misinformation exists ag= ain. This is the idea of maternal constraint. Another example of this occurs when small women have small babies, the growth of babies is limited by the size of their mothers. When ovum donation occurs, even = if the donor is large, the size of the receiver is the one that counts for the baby’s size (in addition t= o the nutrients for growth). The baby’s size in utero depends on the sit= uation the mother can supply regarding food and accommodation.
•<= /span>Finally, adaptive responses are dicho= tomous in that they can be immediately adaptive or predictively adaptive. For example, insulin resist= ance can be advantageous before and after birth in poor nutritional environments but it also creates a di= sease risk in the future according to the environment the child/adult will be living in.
Refs:
•<= /span>Barker, Fetal origins of adult dis= ease: strengths of effects and biological basis, International Journal of Epidemiology(2002) 31:1235.
•<= /span>Gluckman, The fetal, neonatal and = infant environments – the long-term consequences for disease risk, Early Human Development (2005) 81:= 51.
To understand the previous slide better, it is important to introduce the con= cept of developmental plasticity. •Developmental plasticity involves normal processes that enables a range of phenotypes to= develop from a single genotype. Also known as phen= otypic plasticity, it allows one phenotype to develop different physiological or morphological states in answer to environmental conditions during development. The benefit is that in a changing environment, these gene-environment interactions can produce phenotypes be= tter adapted to their environment than if = the same phenotype occurred in all environments The evolutionary idea of adapt= ive advantage refers to a change on phenotype that all= ows for better reproductive fitness (capa= city to preserve the organism's genome). Adaptive responses need an environment= al stimulus. •<= /span>Disruption means an alteration of the developmental program in response to environmental = signals. Some environmental signals disrupt development. The consequences are a bur= den for the organism and not an adaptive advantage. &#= 13;•The fetus can also respond in a adaptive way to the environment, like in the case of <= span style=3D'font-size:90%'>homeostatic responses. For example, the fetus resp= onds to transient asphyxia by changes in h= is blood flows to conserve oxygen for the brain, placenta and heart. Developmental trajectories can be cha= nneled by changes in the environment: this is called homeorrhesis. These responses are usually transient, but if they became permanent, the fetus and the adult must cope with the consequences. If the long-term channel is not appropriate for the channel of development, then the organism is at risk.
Reminder:
Genotype: the genetic m= akeup of an individual
Phenotype: the physical and physiological traits of an individual resulting from genotype and environment The genotype is the complete set o= f alleles (maternal and paternal) of all the genes in an= individual. The phenotype is the distinctive expression of a genotype in a given environment. An individual’s phenotype depends = on the proteins manufactured during the course on his or her life, starting in the embryo and extending throughout adulthoo= d. Although genes control these proteins (either or both alleles), phenotype is not dictated strictly by genotype: the env= ironment greatly influences the regulation and expression of genes, or, in other wo= rds, their translation= into proteins at a given moment and in a given cell<= /i> . Consequently, a gene that predisposes a person to a cer= tain form of cancer might forever remain silent, depe= nding on the person’s lifestyle. Definit= ion from:  www.lexicon-biology.com/biology/definition2_58= .html
Refs: <= /div> •Barker, Fetal origins of adult disease: strengths of effects and biological basis, International Jou= rnal of Epidemiology(2002) 31:1235. <= span style=3D'mso-special-format:bullet;position:absolute;left:-.68%'>•<= /span>Gluckman, The fetal, neonatal and = infant environments – the long-term consequences for disease risk, Early Human Development (2005) 81:51.
<= /div>
Physiological differences manifest in more ways than immature metabolic pathways. Because important systems are still different= iating and growing, the fetus and then the child, has unique susceptibilities compared to adults — and critical time windows in = those susceptibilities.
•<= /span>Preconception
•<= /span>Gestation
– thalidomide, DES
– ionizing radiation
– methylmercury
– second-hand tobacco smoke
– lead.
There has been an explosion of knowledge about development in past decade or so,= and it is hard to remember that it was on= ly about 50 years ago that the discovery was made that the fetus is vulnerabl= e to exposures. The phocomelia epidemic resulting fr= om use of thalidomide in pregnancy was an early and dramatic example of the ability of chemicals to cross the placenta and dam= age the fetus.  Additionally, thalidomide administered during a sm= all, 4-day window between gestational days 20 and 24, may increase the risk of autism (Stromland, 1994).  More than one system can be susceptible and different pathology may occur depending upon the d= ose and timing of exposure.
Now we know that other exposures during gestation can harm systems, and some a= re listed here. We also know that preconception exposure of both parents can cause harm to children, as well= as postnatal exposures.
<<NOTES TO USER:  It is important to point= out the different responses to insults shown on the bottom bar of the figure.  Significant insult during the embryonic phase will result in pregnancy loss (first 2 weeks) or major organ malformation. During the fetal stage, damag= e is more subtle and related to sys= tem dysfunction.>>
Ref:
•<= /span>Stromland, Autism in thalidomide embryopathy: a population study, Developmental Medic= ine & Child Neurology (1994) 36(4):351.
Of a population of 100 Swedish thalidomide embryopathy cases, at least four met full criteria for DSM-III-R autistic disorder and ICD-10 childhood au= tism. Thalidomide embryopathy of the kind encountered in these cases affects fetal development early = in pregnancy, probably on days 20 to 24 after conception. It is argued that the possible association of thalidom= ide embryopathy with autism may shed = some light on the issue of which neural circuitries may be involved in autism pathogenesis.
Figure: Reprinted from The developing human, Moore, Elsevier Inc., 1973. Used with copyright permission (2004) fr= om Elsevier.
•The model to expl= ain the “developmental origins of child disease” suggests that the relationship between the predicted and actual mature environm= ents determines disease risk. If the environments mat= ch, the risk of disease is low. If they don’t the ri= sk of disease is greater. The physiological settings established during the plas= tic and predictive phases (that occur before birth and after birt= h in the case of some organs) are not appropriate for= the environment of the non-plastic mature phase. •<= span lang=3DEN-GB>Considering the example of insulin: during the plastic phases= , if nutritional signals show limited food availabili= ty, the fetus sets its physiology to have a degree of insulin resistance. The changes become irreversible once the plastic phase is over= . But if the non-plastic environment is too rich, the risk of g= lucose intolerance increases. As nutritional intakes in childhood and adulthood increase rapidly in many societies, the risk of mismatch rises and the ri= sk of diabetes increases.
Ref:
•Gluckman, The fetal, neonatal and infant environments – the long-term consequences for disease risk, = Early Human Development (2005) 81:51.
The thrifty phenotype hypothesis and the epidemiological observations focused on impaired fetal nutrition and therefore a reduction in fetal growth as a central concept to their hypothesis. Size at birth serves as a marker of fetal nutrition. Growth is only one manifestation of the im= pact of the environment on the developing organism. There may be also responses of altered maturation and= /or altered timing of fetal development. The fetus in an impaired environment has fewer options. These options can even include= death. In evolutionary terms, the fetus’ sacrifice will allow the mother to repro= duce her genes again. In less dramatic situations, the fetus can change its maturation, gestational leng= th and growth rate and be b= orn smaller.
•<= /span>Prematurity itself is a marker of an = adverse uterine environment, PARs can be induced in utero by the same stimul= i that induces premature delivery.
•<= /span>Studies in sheep have shown that gest= ational length can depend on periconceptual undernutrition. This has been linked to changes in placent= al and fetal endocrine functions, including premature activation of HPA (hypothalamic-pituitary-adrenal) = axis.
•The long-term effects of prematurity = may also be a consequence of being born premature.
All these aspects play a role in inducing long-term consequences for those being born small.
The fact is that prematurity is not a problem exclusive of the poor. Despite current levels of nutrition in developed countries, the nutrition of the fetus (a= nd the infant) is often unbalanced because of tobacco smoke, unbalanced diets or because of the long and vulnerable fetal supply line.
•<= /span>Since the plastic period extends into= the neonatal period, altered nutrition in this period has long-term consequences. Rapid growth in childho= od compensates for low birth weight. It is not known yet whether the catch-up phase is an independent = risk factor or whether it is the biological/sociological (parental overfeeding) consequence of being a growth-impaired infant. However, compensatory growth can have high costs. In animals, their life-sp= an is reduced. Barker’s suggestion is that “a higher rate of cell division causes more rapid shortening= of the protective ends of the chromosomes (telomeres) and hastens cell death and degradation. There are a nu= mber of other possible processes by which, in humans, undernutrition and small size at birth fol= lowed by rapid childhood growth could lead to cardiovascular disease, type 2 diabetes and hypert= ension in later life.”
We must remember that nutrition is only one of the many factors that affect f= etal maturation and growth. T= here are environmental factors that have adverse consequences and last for long on = the organism but have no eff= ect on size at birth. For example, during the Dutch winter famine (1944), women w= ho ate less than 800 calore= s per day had babies with normal birth weight but that became obese later on in life.
Refs:
•<= /span>Barker, Fetal origins of adult dis= ease: strengths of effects and biological basis, International Journal of Epidemiology(2002) 31:1235.
•<= /span>Gluckman, The fetal, neonatal and = infant environments – the long-term consequences for disease risk, Early Human Development (2005) 81:= 51.
&#= 13;
•<= /span>The term "fetal origins" of= disease can be replaced by "developmental origins". Environmental cues c= an occur very early in pregnancy: during= the conceptual period and also during the preimplantation period and still program the fetus. There is= still little known about the elements that signal the nutritional cues for the induction of PARs. Macronutri= ents are amplification factors but micronutrients may be present in the induction of programming. During = the periconceptual period, nutrients that affect the methyl group supply are particularly critical: vit= amin B12, folate, choline, methionine, glycine.
•<= /span>Birth is an environmental transition = in human development as the fetus changes from being in utero to the outside wor= ld.
•<= /span>The premature neonate is still in a p= hase of plasticity.
•<= /span>Care by the mother or health care pro= vider will limit what the neonate sees as its environment even though this has little relationship t= o the actual mature environment.
The biology of the embryo/fetus/newborn still needs to be better understood. In developed countries, even though prevention is always better, interventions can start at t= he postplastic phase. The PARs prediction can help in planning preventive strategies in the developing world to redu= ce the  burden of disease. This would imply focusing on the plastic = phase, that is how to improve the health of girls and women prior to and during pregnancy.
Ref:
•<= /span>Barker, Fetal origins of adult dis= ease: strengths of effects and biological basis, International Journal of Epidemiology(2002) 31:1235.
•<= /span>Gluckman, The fetal, neonatal and = infant environments – the long-term consequences for disease risk, Early Human Development (2005) 81:= 51.
•The models we hav= e seen change our perspective about how to intervene in the epidemic "lifestyle" disease. Interventions on lifestyle only are just partially effective in those affected by inappro= priate PARs. Improving maternal and fetal health will h= elp us deal better with postnatal nutritional conditions.. •<= span lang=3DEN-GB>If the main programming mechanism is epigenetic change, then = we must learn more about the changes that happen, t= heir causes, the key nutrients involved and whether t= here are windows of opportunity during which the effects can be reverted. Regarding certain changes, like the reduction of the number of nephrons, only preventive measures can be taken.= •<= span lang=3DEN-GB>As we mentioned, the periconceptual period is having each tim= e more importance, that is why we should concentrate on women's nutrition during conception and during e= arly pregnancy. However, we don't know yet what is the best diet for women during the different stages of their life and during pregnancy. •In these slides, we have focused on= the metabolic system, but similar arguments are begi= nning to be studied about cardiovascular and skeletal changes, necessary = for reproduction and survival. The adaptive responses model i= s also applicable to other programmed physiological sys= tems.
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Start=3Dhref.indexOf('!')+1=20 End=3Dhref.lastIndexOf('/')+1=20 if (End < Start)=20 return href.substring(0, Start)=20 else=20 return href.substring(0, End)=20 } return ''; } function GetTags(base,tag) { if(g_supportsPPTHTML) return base.all.tags(tag); else return base.getElementsByTagName(tag); } function UpdNtsPane(){ if(frames["PPTNts"]) PPTNts.location.replace( MHTMLP= refix+GetHrefObj( gCurSld ).mNtsHref ) } function UpdNavPane( sldIndex ){ if(gNavLoaded) PPTNav.UpdNav() } function UpdOtNavPane(){ if(gOtlNavLoaded) PPTOtlNav.UpdOtlNav() } function UpdOtlPane(){ if(gOtlLoaded) PPTOtl.UpdOtl() } function SetHasNts( fVal ) { if( gHasNts !=3D fVal ) { gHasNts=3DfVal UpdNavPane() } } function ToggleOtlText() { gOtlTxtExp=3D!gOtlTxtExp UpdOtlPane() } function ClearMedia() { // Clear any sounds playing before launching another browser window. Other= wise, // in fullscreen mode, you'll continue to hear the sound in the frames mod= e. if (PPTSld.pptSound) PPTSld.pptSound.loop =3D 0; } function FullScreen() {=20 if ( PPTSld.g_animUseRuntime ) PPTSld.document.body.pause(); ClearMedia(); var href =3D ( document.location.protocol =3D=3D 'mhtml:') ? FULLSCR_HREF = : FULLSCR_HREF+"#"+GetHrefObj(gCurSld).mSldHref; if(PPTNav.event.ctrlKey) { var w =3D (window.screen.availWidth * 1.0) / 2.0 var h =3D w * (PPTSld.g_origH * 1.0) / PPTSld.g_origW win =3D window.open( MHTMLPrefix+href,null,"toolbar=3D0,resizable=3D1,top= =3D0,left=3D0," + "width=3D"+ w + ",height=3D" + h ); if( win.document.body && PPTSld.g_animUseRuntime ) win.document.body.PPTSldFrameset=3Dwindow; } else { win =3D window.open( MHTMLPrefix+href,null,"fullscreen=3Dyes" ); if( win.document.body && PPTSld.g_animUseRuntime ) win.document.body.PPTSldFrameset=3Dwindow; } } function ToggleVNarration() { rObj=3DPPTSld.document.all("NSPlay") if( rObj && !PPTSld.g_animUseRuntime ) { if( (rObj.playState =3D=3D 1)||(rObj.playState =3D=3D 0) ) rObj.Play() else if( rObj.playState =3D=3D 2 ) rObj.Pause() else return; } else if( PPTSld.g_animUseRuntime ) { narObj =3D PPTSld.document.all("narrationID") if( narObj ) narObj.togglePause() } } function GetCurSldNum() { =20 obj=3DGetHrefObj(gCurSld) if( obj.mOrigVis =3D=3D 1 ) return obj.mSldIdx else =20 return gCurSld } function GetNumSlds() { =20 if( GetHrefObj(gCurSld).mOrigVis =3D=3D 1 ) return GetSldList().mNumVisSlds; else return GetSldList().mList.length } function GetSldNum( href ) { for(ii=3D0; ii 1 ) PopSldList(); else if( !IsFramesMode() ) { if( gLoopCont ) GoToFirst() else EndShow() } } function GoToPrevSld() { ii=3DgCurSld-1 if( ii > 0 ) { obj=3DGetHrefObj(ii) while ( obj && ( obj.mVis =3D=3D 0 ) && ( ii>0 ) ) obj=3DGetHrefObj(--ii) if( ii =3D=3D 0 ) ii=3D1 GoToSldNum(ii) } } function GoToFirst(){ GoToSld( GetHrefObj(1).mSldHref ) } function GoToLast() { ii=3DGetSldList().mList.length if( ii !=3D gCurSld ) GoToSld( GetHrefObj(ii).mSldHref ) } function GoToSldNum( num ) { if( PPTSld.event ) PPTSld.event.cancelBubble=3Dtrue obj =3D GetHrefObj( num ) obj.mVis=3D1 gPrevSld=3DgCurSld gCurSld =3D num; PPTSld.location.replace(MHTMLPrefix+obj.mSldHref) if( IsFramesMode() ) { UpdNavPane(); UpdOtlPane(); UpdNtsPane() } } function GoToSld( href ) { if( PPTSld.event ) PPTSld.event.cancelBubble=3Dtrue GetHrefObj( GetSldNum(href) ).mVis=3D1 PPTSld.location.replace(MHTMLPrefix+href) } function SldUpdated( id ) { if( id =3D=3D GetHrefObj(gCurSld).mSldHref ) return gPrevSld=3DgCurSld gCurSld=3DGetSldNum(id) if( IsFramesMode() ) { UpdNavPane(); UpdOtlPane(); UpdNtsPane() } } function PrevSldViewed(){ GoToSld( GetHrefObj(gPrevSld).mSldHref ) } function HasPrevSld() { return ( gIsEndShow || ( gCurSld !=3D 1 && GetHrefO= bj( gCurSld-1 ).mVis =3D=3D 1 )||( GetCurSldNum() > 1 ) ) } function HasNextSld() { return (GetCurSldNum() !=3D GetNumSlds()) } function CloseWindow() { if( HideMenu() ) return; =09 var event =3D PPTSld.event; if( !IsFramesMode() && event && (event.keyCode=3D=3D27 || event.keyCode=3D= =3D32 || event.type=3D=3D"click" ) ) window.close( self ); CatchNumKeys( self, event ); } function Unload() { gIsEndShow=3D0; } function SetupEndShow() { gIsEndShow=3D1; PPTSld.document.body.scroll=3D"no"; PPTSld.document.onkeypress=3DCloseWindow; PPTSld.document.onclick=3DCloseWindow; PPTSld.document.oncontextmenu=3D_CM; } function EndShow() { if( IsFramesMode() ) return if( PPTSld.event ) PPTSld.event.cancelBubble=3Dtrue doc=3DPPTSld.document var dir =3D doc.body.dir if( dir !=3D "rtl" ) dir =3D "ltr"; doc.open() doc.writeln('


' + ENDSHOW_MESG + '

') doc.close() } function SetSldVisited(){ GetSldList().mList[gCurSld-1].mVisited=3Dtrue } function IsSldVisited(){ return GetSldList().mList[gCurSld-1].mVisited } function hrefList( sldHref, visible, advDelay, advClk ) { this.mSldHref=3D this.mNtsHref =3D sldHref this.mOrigVis=3D this.mVis =3D visible this.mVisited=3D false this.mAdvDelay=3D advDelay this.mAdvOnClk=3D advClk } function SldList(arr,curSld,fEnd) { this.mCurSld =3D curSld; this.mList =3D new Array(); var idx =3D 1; for(ii=3D0;ii 0) { PushSldList(sldList,fEnd); gCurSld =3D 1; } else if( PPTSld.event ) PPTSld.event.cancelBubble=3Dtrue } function PushSldList(arr,fEnd) { var ii =3D gSldStack.length; gSldStack[ii] =3D new SldList(arr,gCurSld,fEnd); GoToSld( gSldStack[ii].mList[0].mSldHref ); } function PopSldList() { if (gSldStack[gSldStack.length-1].fEndShow) EndShow() else { gCurSld =3D gSldStack[gSldStack.length-1].mCurSld; gSldStack[gSldStack.length-1] =3D null; gSldStack.length--; var sldList =3D gSldStack[gSldStack.length-1]; GoToSld( sldList.mList[gCurSld - 1].mSldHref ); } } var custShowList=3Dnew Array(); /********************************************* Navigation button implementation There are 2 types of buttons: ImgBtn, TxtBtn implemented as function objects. They share a similiar interface so the event handlers can call SetActive, for example, on a button=20 object without needing to know exactly=20 what type of button it is. **********************************************/ //---------------------------------- function ImgBtn( oId,bId,w,action ) //---------------------------------- { var t=3Dthis t.Perform =3D _IBP t.SetActive =3D _IBSetA t.SetInactive=3D _IBSetI t.SetPressed =3D _IBSetP t.SetDisabled=3D _IBSetD t.Enabled =3D _IBSetE t.ChangeIcon =3D null t.UserAction =3D action t.ChgState =3D _IBUI t.mObjId =3D oId t.mBorderId=3D bId t.mWidth =3D w t.mIsOn =3D t.mCurState =3D 0 } function _IBSetA() { if( this.mIsOn ) { obj=3Dthis.ChgState( gHiliteClr,gShadowClr,2 ) obj.style.posTop=3D0 } } function _IBSetI() { if( this.mIsOn ) { obj=3Dthis.ChgState( gFaceClr,gFaceClr,1 ) obj.style.posTop=3D0=20 } } function _IBSetP() { if( this.mIsOn ) { obj=3Dthis.ChgState( gShadowClr,gHiliteClr,2 ) obj.style.posLeft+=3D1; obj.style.posTop+=3D1 } } function _IBSetD() { =20 obj=3Dthis.ChgState( gFaceClr,gFaceClr,0 ) obj.style.posTop=3D0=20 } function _IBSetE( state ) { var t=3Dthis GetObj( t.mBorderId ).style.visibility=3D"visible" if( state !=3D t.mIsOn ) { t.mIsOn=3Dstate if( state ) t.SetInactive() else t.SetDisabled() } } function _IBP() { var t=3Dthis if( t.mIsOn ) { if( t.UserAction !=3D null ) t.UserAction() if( t.ChangeIcon ) { obj=3DGetObj(t.mObjId) if( t.ChangeIcon() ) obj.style.posLeft=3Dobj.style.posLeft+(t.mCurState-4)*t.mWidth else obj.style.posLeft=3Dobj.style.posLeft+(t.mCurState-0)*t.mWidth } t.SetActive() } =20 } function _IBUI( clr1,clr2,nextState ) { var t=3Dthis SetBorder( GetObj( t.mBorderId ),clr1,clr2 ) obj=3DGetObj( t.mObjId ) obj.style.posLeft=3Dobj.style.posLeft+(t.mCurState-nextState)*t.mWidth-obj= .style.posTop t.mCurState=3DnextState return obj } //----------------------------------------- function TxtBtn( oId,oeId,action,chkState ) //----------------------------------------- { var t=3Dthis t.Perform =3D _TBP t.SetActive =3D _TBSetA t.SetInactive=3D _TBSetI t.SetPressed =3D _TBSetP t.SetDisabled=3D _TBSetD t.SetEnabled =3D _TBSetE t.GetState =3D chkState t.UserAction =3D action t.ChgState =3D _TBUI t.mObjId =3D oId t.m_elementsId=3D oeId t.mIsOn =3D 1 } function _TBSetA() { var t=3Dthis if( t.mIsOn && !t.GetState() ) t.ChgState( gHiliteClr,gShadowClr,0,0 ) } function _TBSetI() { var t=3Dthis if( t.mIsOn && !t.GetState() ) t.ChgState( gFaceClr,gFaceClr,0,0 ) } function _TBSetP() { if( this.mIsOn ) this.ChgState( gShadowClr,gHiliteClr,1,1 ) } function _TBSetD() { =20 this.ChgState( gFaceClr,gFaceClr,0,0 ) this.mIsOn =3D 0 } function _TBSetE() { var t=3Dthis if( !t.GetState() ) t.ChgState( gFaceClr,gFaceClr,0,0 ) else t.ChgState( gShadowClr,gHiliteClr,1,1 ) t.mIsOn =3D 1 } function _TBP() { var t=3Dthis if( t.mIsOn ) {=20 if( t.UserAction !=3D null ) t.UserAction() if( !t.GetState ) return if( t.GetState() ) t.SetPressed() else t.SetActive() } =20 } function _TBUI( clr1,clr2,lOffset,tOffset ) { SetBorder( GetObj( this.mObjId ),clr1,clr2 ) Offset( GetObj( this.m_elementsId ),lOffset,tOffset ) } function Offset( obj, top, left ){ obj.style.top=3Dtop; obj.style.left=3Dle= ft } function SetBorder( obj, upperLeft, lowerRight ) { s=3Dobj.style; s.borderStyle =3D "solid" s.borderWidth =3D 1=20 s.borderLeftColor =3D s.borderTopColor =3D upperLeft s.borderBottomColor=3D s.borderRightColor =3D lowerRight } function GetBtnObj(){ return gBtnArr[window.event.srcElement.id] } function BtnOnOver(){ b=3DGetBtnObj(); if( b !=3D null ) b.SetActive() } function BtnOnDown(){ b=3DGetBtnObj(); if( b !=3D null ) b.SetPressed() } function BtnOnOut(){ b=3DGetBtnObj(); if( b !=3D null ) b.SetInactive() } function BtnOnUp() { b=3DGetBtnObj() if( b !=3D null ) b.Perform() else Upd() } function GetNtsState(){ return parent.gNtsOpen } function GetOtlState(){ return parent.gOtlOpen } function GetOtlTxtState(){ return parent.gOtlTxtExp } function NtsBtnSetFlag( fVal ) { s=3Ddocument.all.item( this.m_flagId ).style s.display=3D"none" if( fVal ) s.display=3D"" else s.display=3D"none" } function _BSetA_Border(){ b =3D gBtnArr[this.mObjId]; if( b !=3D null ) b.S= etActive() } function _BSetI_Border(){ b =3D gBtnArr[this.mObjId]; if( b !=3D null ) b.S= etInactive() } function _BSetP_Border(){ b =3D gBtnArr[this.mObjId]; if( b !=3D null ) b.S= etPressed() } function _BSetA_BorderImg() {=20 b =3D gBtnArr[this.mBorderId]=20 if( b !=3D null && this.mIsOn && !b.GetState() ) { obj=3Dthis.ChgState( gHiliteClr,gShadowClr,2 ) obj.style.posTop=3D0 } } function _BSetI_BorderImg() {=20 b =3D gBtnArr[this.mBorderId] if( b !=3D null && this.mIsOn && !b.GetState() ) { obj=3Dthis.ChgState( gFaceClr,gFaceClr,1 ) obj.style.posTop=3D0 } } var gHiliteClr=3D"THREEDHIGHLIGHT",gShadowClr=3D"THREEDSHADOW",gFaceClr=3D"= THREEDFACE" var gBtnArr =3D new Array() gBtnArr["nb_otl"] =3D new TxtBtn( "nb_otl","nb_otlElem",parent.ToggleOtlPan= e,GetOtlState ) gBtnArr["nb_otlElem"] =3D new TxtBtn( "nb_otl","nb_otlElem",parent.ToggleOt= lPane,GetOtlState ) gBtnArr["nb_nts"] =3D new ImgBtn( "nb_nts","nb_ntsBorder",10,parent.ToggleN= tsPane ) gBtnArr["nb_nts"].SetActive =3D _BSetA_BorderImg; gBtnArr["nb_nts"].SetInactive =3D _BSetI_BorderImg; gBtnArr["nb_ntsBorder"] =3D new TxtBtn( "nb_ntsBorder","nb_ntsElem",parent.= ToggleNtsPane,GetNtsState ) gBtnArr["nb_ntsElem"] =3D new TxtBtn( "nb_ntsBorder","nb_ntsElem",parent.To= ggleNtsPane,GetNtsState ) gBtnArr["nb_prevBorder"] =3D gBtnArr["nb_prev"]=3D new ImgBtn( "nb_prev","n= b_prevBorder",30,parent.GoToPrevSld ) gBtnArr["nb_nextBorder"] =3D gBtnArr["nb_next"]=3D new ImgBtn( "nb_next","n= b_nextBorder",30,parent.GoToNextSld ) gBtnArr["nb_sldshw"]=3D new ImgBtn( "nb_sldshw","nb_sldshwBorder",18,parent= .FullScreen ) gBtnArr["nb_sldshwBorder"] =3D new TxtBtn( "nb_sldshw","nb_sldshwBorder",pa= rent.FullScreen,null ) gBtnArr["nb_sldshwBorder"].SetActive =3D _BSetA_Border; gBtnArr["nb_sldshwBorder"].SetInactive =3D _BSetI_Border; gBtnArr["nb_sldshwText"] =3D new TxtBtn( "nb_sldshw","nb_sldshwText",parent= .FullScreen,null ) gBtnArr["nb_sldshwText"].SetActive =3D _BSetA_Border; gBtnArr["nb_sldshwText"].SetInactive =3D _BSetI_Border; gBtnArr["nb_voice"] =3D gBtnArr["nb_voiceBorder"] =3D new ImgBtn( "nb_voice= ","nb_voiceBorder",18,parent.ToggleVNarration ) gBtnArr["nb_otlTxtBorder"] =3D gBtnArr["nb_otlTxt"]=3D new ImgBtn( "nb_otlT= xt","nb_otlTxtBorder",23,parent.ToggleOtlText ) gBtnArr["nb_ntsBorder"].m_flagId=3D "nb_nts" gBtnArr["nb_ntsBorder"].SetFlag =3D NtsBtnSetFlag gBtnArr["nb_otlTxt"].ChangeIcon=3D GetOtlTxtState /********************************************* Context menu implementation _CM() is the function that's hooked up to the oncontextmenu event. Once we're asked to show the menu, we first build it by creating DIVs on-the-fly. Then we position it=20 within the screen area so it doesn't get clipped. Creating the DIVs using createElement() means we don't have to write out any extra HTML into the slide HTML files. **********************************************/ var sNext=3D"Next",sPrev=3D"Previous",sEnd=3D"End Show",sFont=3D"Arial",sAr= row=3D"Arrow",sFreeform=3D"Freeform",sRect=3D"Rectangle",sOval=3D"Oval" function ShowMenu() { BuildMenu(); var doc=3DPPTSld.document.body,x=3DPPTSld.event.clientX+doc.scrollLeft,y= =3DPPTSld.event.clientY+doc.scrollTop m =3D PPTSld.document.all.item("ctxtmenu") m.style.pixelLeft=3Dx if( (x+m.scrollWidth > doc.clientWidth)&&(x-m.scrollWidth > 0) ) m.style.pixelLeft=3Dx-m.scrollWidth m.style.pixelTop=3Dy if( (y+m.scrollHeight > doc.clientHeight)&&(y-m.scrollHeight > 0) ) m.style.pixelTop=3Dy-m.scrollHeight m.style.display=3D"" } function _CM() { if( !parent.IsFullScrMode() ) return; if(!PPTSld.event.ctrlKey) { ShowMenu() return false } else HideMenu() } function BuildMenu() { if( PPTSld.document.all.item("ctxtmenu") ) return var mObj=3DCreateItem( PPTSld.document.body ) mObj.id=3D"ctxtmenu" mObj.style.visibility=3D"hidden" var s=3DmObj.style s.position=3D"absolute" s.cursor=3D"default" s.width=3D"120px" SetCMBorder(mObj,"menu","black") var iObj=3DCreateItem( mObj ) SetCMBorder( iObj, "threedhighlight","threedshadow" ) iObj.style.padding=3D2 CreateMenuItem( iObj,sNext,M_GoNextSld,M_True ) CreateMenuItem( iObj,sPrev,M_GoPrevSld,M_HasPrevSld ) =09 CreateSeparator( iObj ) CreateMenuItem( iObj,sEnd,M_End,M_True ) mObj.style.visibility=3D"visible" } function Cancel() { window.event.cancelBubble=3Dtrue; window.event.returnVa= lue=3Dfalse } function Highlight() { ChangeClr("activecaption","threedhighlight") } function Deselect() { ChangeClr("threedface","menutext") } function Perform() { e=3DPPTSld.event.srcElement if( e.type=3D=3D"menuitem" && e.IsActive() ) e.Action() else PPTSld.event.cancelBubble=3Dtrue } function ChangeClr( bg,clr ) { e=3DPPTSld.event.srcElement if( e.type=3D=3D"menuitem" && e.IsActive() ) { e.style.backgroundColor=3Dbg e.style.color=3Dclr } } function M_HasPrevSld() { return( parent.HasPrevSld() ) } function M_GoNextSld() { if( gIsEndShow ) M_End(); else GoToNextSld() } function M_GoPrevSld() { if( gIsEndShow ) { gIsEndShow=3D0; history.back();= PPTSld.event.cancelBubble=3Dtrue; } else GoToPrevSld() } function M_True() { return true } function M_End() { window.close( self ) } function CreateMenuItem( node,text,action,eval ) { var e=3DCreateItem( node ) e.type=3D"menuitem" e.Action=3Daction e.IsActive=3Deval e.innerHTML=3Dtext if( !e.IsActive() ) e.style.color=3D"threedshadow" e.onclick=3DPerform e.onmouseover=3DHighlight e.onmouseout=3DDeselect s=3De.style; s.fontFamily=3DsFont s.fontSize=3D"9pt" s.paddingLeft=3D2 } function CreateSeparator( node ) { var sObj=3DCreateItem( node ) SetCMBorder(sObj,"menu","menu") var s=3DsObj.style s.borderTopColor=3D"threedshadow" s.borderBottomColor=3D"threedhighlight" s.height=3D1 s.fontSize=3D"0px" } function CreateItem( node ) { var elem=3DPPTSld.document.createElement("DIV") node.insertBefore( elem ) return elem } function SetCMBorder( o,ltClr,rbClr ) { var s=3Do.style s.backgroundColor=3D"menu" s.borderStyle=3D"solid" s.borderWidth=3D1 s.borderColor=3DltClr+" "+rbClr+" "+rbClr+" "+ltClr } ------=_NextPart_01C6420B.51CD2470 Content-Location: file:///C:/1E09C636/Fetal_origins_Brune_Rossel_2006_files/fullscreen.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="windows-1252" ------=_NextPart_01C6420B.51CD2470 Content-Location: file:///C:/1E09C636/Fetal_origins_Brune_Rossel_2006_files/buttons.gif Content-Transfer-Encoding: base64 Content-Type: image/gif R0lGODlhWAESAPf4AAAAAIAAAACAAICAAAAAgIAAgACAgICAgAQEBISEBASEBISEhAQEhMTExAQE /KTM9Pz8/ERERPz8BAT8/KSkpGRkhMTcxCRkxAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAMDAwP8AAAD/AP//AAAA//8A/wD//////yH5BAEAAPgALAAAAABYARIA QAj/APEJHEiwoMGDCBMqXMiwocOHECNKnEixosWLGCEiQKCRo8YDIEHig2DxAD4LKD1avDDhgUuV GUOGbHBR5QGYFBG4fHAB58EKECJEwCfUYAWPFGAygLCRKQIIUKM6WAohKUGgCikcFWh1INWoYKVS 7SrQ41GbIhGYLAuVQVOoC+IyXUuUAkG1HE3KFDhAwkgJc5/qDZmxsOHDiBMrXsy4sePDGyP7lChT 5MULmDPnlDw5YmW6FTNrfgi0aNGEZPEtbfo2bNTUpYeeRph69dPWrqvCNFuBIGG1A59CYPAVQtwF cw0OxWdTIOiBCQAjaAB17fOFII8voGmRc+eOkilm/z9OvTtnjN4hYk1YoT3H2rnBOphPAB9skgq3 2lcaX/5YnJVt9BloAar12UEIRGCZdQghMABI1Tn32IQUVthYexhmqGGGMBHAgIfEhSiiiATAtOGJ GnYI4ogsEldicAYOGNJGZaml3Y0L3NTZUBz1xlB0PUoUI0jlVWRSVN89xBKSGB1YU1TMoRfVBEle hR9HQs1GEHxQ3RZZbveZthxt/LEmXHyp5XWABSCpaRJwbM13gAACPHVccgJFgF+NEhqUAEkQSCfc ddhVhh5dVTaEAEsTUNlkZUWKN9BNGDE6QU8OrSdbllzpxyVTTrU21Uj3scfhp7nNpyoDaTIEJ3P9 If8J2kbLNYegg9JRBwGhFvbq66+ZUiDssMQWK2yHxiZLrInKNotss8l+B5yBrr5p2UIJvortANoC 6+234IbLla/elRtZjeamh5CC3Sb0YLvixivvYkDFGlZqBNh7r4n6goVvv6/ZlCicN+kL71ALTnpQ dCIZp7CihkLA3UQmoWRBogyxtBPGCTnZncVR1rSTo5nuydC/Eo8kUH+lOoTyyvjoCuZu+PjYIKLD rZybtrM1d10C0QXKEVz48GrQkEeWdFJKlbb0UmEeV0SzyC6RvNB646LWIVjUNeC1zAFb+RDKXksM 9r531bwmpQW9+hQDDsx5pqwDRWBXcFES2hc+gEn/wJGdEEWdE6LoWcoxQweaTNmkhydkKaYMYY2Q p1unbLl/pPKbn3v7EZRvrKvqlja2ONvrtoIw9tn2g32/tQBlhtYkU+MNikZ7QYlPDPuMldpOmuJX nVo5VF3HjI+q89mteX5IDd/fVFClma5kiE4f2XUJhlz09gj2NbTDRifkmu7zXjR++RVJ/lPznuvr QH2iD6S+UewP9Dnon6d2NLwN8n90BB6hC68cFMCHoe+ACASP9c4DowUyEF0OPFcDI0ij/VXPaAKC UfhS95AKGoQ7IBRICI1HwhGaUIQoLGEKT6jCFrLwhSuMoQtlCMMZ2rCGOKShDm+4wxzy8Ic+DGIP B4cIRCKGMCAAOy== ------=_NextPart_01C6420B.51CD2470 Content-Location: file:///C:/1E09C636/Fetal_origins_Brune_Rossel_2006_files/frame.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="windows-1252" Fetal origins of adult diseases - Marie-Noël Bruné Rossel ------=_NextPart_01C6420B.51CD2470 Content-Location: file:///C:/1E09C636/Fetal_origins_Brune_Rossel_2006_files/outline.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="windows-1252"
 No= tes
Slide Show
Outline
------=_NextPart_01C6420B.51CD2470 Content-Location: file:///C:/1E09C636/Fetal_origins_Brune_Rossel_2006_files/filelist.xml Content-Transfer-Encoding: quoted-printable Content-Type: text/xml; charset="utf-8" ------=_NextPart_01C6420B.51CD2470--