Transcript Epigenetic mechanism and Regulation of Transcription

Child Health And Development
Opportunities And Challenges In
Next Decade
• Leadership is about imagining the future
and preparing for it.
• Characteristics of Sustained Program and
Institutional excellence
-Core values
-Adaptability
-Collaborative culture
Challenges In Health Care Delivery
• Loss in translation from policy to programs.
• We must learn to deliver better what we know.
• The coverage of child survival interventions is still an
issue.
Policy
Strategy
Plans
- Quantitative measures of process and outcome
- Continuing innovation in design and delivery of programs
- Effective use of technology
- Simple innovation in useful product design for easier
delivery
Underused life securing commodities for
maternal Child health; UN Commission, 2012
• Oxytocin for prevention of PPH
• Misoprostol for prevention of PPH
• Injectable antibiotics for neonatal sepsis
• Antenatal steroids for fetal living development
• Chlorhexidine for cord care
• Resuscitation devices for new born care
• Amoxicillin for pneumonia
• ORS, Zinc
• Female condoms
• Contraceptives implants
• Emergency contraceptives
Innovation in delivering services
• Neonatal Home care, District Neonatal units
• Conditional Cash transfer
• ICT in health system
• Novel Human resource strategies
• Decentralization and local ownership
• Affordable product innovation and diffusion
• Outsourcing services by Government in a competitive
framework
• Public-Private partnership
Challenges In Next Decade
Sustaining Survival, Moving to Child
Development
Issues In Child Development
Early Nutrition Origin of Disease
• Nutrition insults during fetal life have surprising, long
lasting ramifications for health and development
Cohort Studies in Brazil, Ghana, India, P,
South Africa show-
• Size and birth and accelerated weight gain after
48 months of life is related to Insulin resistance
• Greater weight gain during first five years of life is
associated with elevated blood pressure
Disturbed energy balance; a combination of
Genetics, Epigenetics and Environmental
Factors
Epigenetic Mechanism and Regulation of Transcription
• Heritable changes in gene expression without altering
gene sequence.
DNA Methylation
Histone Modification
Micro RNA
Hypo
Transcriptional activation
Hypo
Transcriptional suppression
Maternal Diet And Altered Genetic
Regulation
• A nutritional challenge in early pregnancy or early post
natal life can result in DNA methylation which is
detectable 60 years later.
• Overfeeding in post natal life can alter methylation of
genes critical for appetite control.
Reversibility of Altered Phenotype And
Epigenotype
Nutrition, Stress
Pre and Peri-conceptual
Later Pregnancy
Postnatal Life
Design of Complementary feeding; Child feeding
Physical activity
Pharmacology
Depression in Pregnancy, Low Birth Weight and
DNA methylation of Imprinted Regulatory Genes
Methylation at MEG3 for infants of women with
severe and no depressed mood
An impoverished environment and early
brain development
Functional magnetic resonance Imaging reveals
important impact of• Cognitive Nurturing
• Toxic stress operating through lack of engagement and
through hormonal and Neural responses.
• Prefrontal cortex; Most affected language, problem
solving, self regulation and social bonding
INCREASING LINEAR GROWTH WITHOUT
EXCESSIVE WEIGHT GAIN
Wasting is an individual disorder
Stunting reflects population Inequalities
Linear growth faltering -9months to 24 months
age
Timing of Nutritional Insults a key issue
Data from a birth cohort from Faridabad, Haryana
PROPORTION STUNTED, WASTED, UNDER WEIGHT AT VARIOUS AGES
6 weeks
6 months
9 months
12 months
n
3866
3546
3488
2987
Stunted
28.5%
36.2%
43.5%
51.2%
Wasted
15.6%
14.3%
15.2%
18.0%
Under weight
39.4%
38.5%
40.7%
40.5%
Severely Stunted
10.0%
11.2%
14.9%
19.8%
Severely Wasted
4.5%
3.8%
3.3%
3.9%
Severely Under weight
15.2%
13.9%
14.7%
13.7%
Data from a birth cohort from Faridabad, Haryana
CONTRIBUTION OF LBW TO MALNUTRITION AT 6 MONTHS
LBW
Normal Birth Weight
Stunted
38.7%
61.3%
Wasted
38%
62%
Under weight
41.3%
58.7%
GUT HEALTH AND LINEAR GROWTH
• Microbial Population that triggers inflammation and or gut
dysfunction
• Persistent Gastroenteropathy associated with an active
inflammatory response than immune suppression
•
Stunted not underweight children have higher anti-endotoxin
levels
• Children spend roughly 10 times more days with subclinical
inflammation than with diarrhea itself.
Reduction in stunting
• Brazil
37% to 7% in 33 years
• Mexico
27% to 16% in 18 years
• Ghana
35% to 29% in 20 years
• India
54% to 45% in 13 years (1993-2006)
SUCCESS FACTORS IN STUNTING
REDUCTION
• Increase income through conditional cash transfer(B,M)
• Maternal schooling(B)
• Increased use of health care(B,M)
• Improved water and sanitation services(B)
Behavior Change Is Key Challenge
• Scientific evidence must drive policy for
Individual, family and community behaviors in
21st century.
• Current strategies lack research basis.
Preventing Preterm Birth Is A Key Challenge
WHO 1997
Regional causes of U5 deaths in 2010
Southeast Asia (N=2.096m)
Injury
4%
Other childhood
disorders
13%
Neonatal infectious
diseases
16%
Childhood infectious diseases
31%
Congenital
abnormalities
5%
Adapted from Liu et al., 2012
Preterm birth
complications
19%
Other neonatal
disorders
2%
Intrapartum-related
complicaations
10%
Clinical types of preterm birth in LMIC and
Developed Countries
LMIC
Developed
Countries
Spontaneous PTB
(with intact
membranes)
70%,
40-45%
pPROM
Spontaneous with
premature rupture
of membranes
Provider initiated
16-21%
20-40%
11-15%
30-35%
Possible causes of preterm birth
Intra uterine infections
Almost 90% mid-trimester spontaneous PTB have intrauterine
infection vs 15% at 34–36 w;
Culture positive amniotic fluid associated with almost 50% PTB
at 23-26 w, 16% at 27-30 w & 11% at 31-34 w
Implantation
Extreme & very
premature/
Still birth
Phase 0
Phase 1
Phase 2
Quiescence
Activation
Stimulation
Uterine over distension, stress
Phase 3
Involution
Preterm births
from 32- 36 weeks
Adapted from Gravett et al, BMC Pregnancy and Childbirth 2010
Preterm Birth
Long term translational research goals
• Appropriate risk stratification of women
• Better prediction tools
• Optimal time of prediction & clinical intervention
• Unusual/novel microbes that could serve as biomarkers;
Gut, Reproductive tract, blood ,urine
• Identify focused remedies targeting one or more
mechanistic pathways –infection, inflammation
• Application of currently available interventions (tocolytic
agents) based on better understanding of biological
mechanisms
Exploring Our Microbiome Through Metagenomics
(DNA, RNA, Protein, Metabolites)
• New concept aboutPost natal development
Systems physiology
Individuality
• DISEASE ASSOCIATION OF GUT MICROBIOME
Prematurity, low birth weight, resistance to
infection/Immunity and inflammation
Asthma, Auto immune disease, risk of obesity/chronic
disease
Metagenome of Human Microbiome
No. of people participated: 9
No. of sites screened: 27
Total no. of bacterial
phyla identified: 22
Elizabeth et al., 2009, Science
Human Gut Microbiota
Where Do They Come From?
Urogenital tract
How Are They Selected?
GI tract
Dietary source
Envn. sources
Skin, GI tract
Vaginal birth canal
Envn. sources
Oronasopharyngeal cavity
Dietary sources
Skin
Envn. sources
Skin
Vaginal birth canal
Envn. sources
Reid et al., 2011, Nat. Revw. Microb.
Who Are They?
Where Are They?
O’Hara and Shanahan, 2006, EMBO rep.
Backhed et al.,2005, Science
Bad digestion is the root of all evil
Nicholson et al, Science, 2012,
INNOVATION LANDSCAPING FOR
AFFORDABLE TECHNOLGY
• Physicians are conceptual innovators
• Physicians must define technology and product needs and
product profiles
Medical Innovation
Stanford-India Biodesign (Alumni Fellows)
• Focus: Pedatrics (2011-2012)
Avijit Bansal
Mridusmita Choudhury
Ayesha Chaudhary
Chinmay Deodhar
Stanford-India Biodesign Program : Projects
Device
5.
Project NeoBreathe
6.
7.
Status
Neonatal Resuscitation Device
 Working prototype developed and benchtested
 Positive feedback from physicians during
preliminary mannequin trial
Patient Transfer System
 Working prototype developed and tested
 Positive reviews from local med-tech firms
Surgical Sharps Management
 Working prototype developed and tested
 Talks in progress to identify
commercialization partners
8.
Trans-illumination device
 Working prototype developed and tested
 Positive feedback from physicians
Stanford-India Biodesign Program : Projects from
Clinical Immersion
Device
Status
1. Fecal Incontinence Device
 First-in-man safety trial completed
 Start-up launched
 Series A funding obtained, 2012
2.
Limb Immobilization Device
 Field-tested in Trauma Center at A.I.I. M.S
 Talks in progress with industry partners for
commercialization
3.
Emergency Intra-osseous Access Device
 Cadaveric trials successfully completed
 Talks in progress with industry partners for
commercialization
4.
Screening for all
Newborn Hearing Screening Device
 Safety and efficacy trials completed
 Seed funding obtained for further development
and commercialization
Point of Care Diagnostics
Physicians to design the strategy
Diversity of target product profiles, users, and selling of POC testing
The Riddle of Protein Biomarkers
FUTURE BRIGHT OR BLEAK
• <1.5 near test per year cleared by FDA
• 53% of tests cleared by the FDA since 1993 used in <10%
labs, 60% in <25%
• FDA clearance does not translate into clinical acceptance
Challenges and Opportunities
Culture change – Gender perception
Promote a culture were a female fetus, infant, child,
adolescent and adult women are perceived as critical to
development process and their inate abilities are nurtured.
• Pediatrics education, training and
carrier paths in future
• Pediatrics Institutional design
Pediatricians should show the path to
others