Introductory Lecture Flashcards
Where are embryonic stem cells derived from?
Inner cell mass of trophoblasts; are a pluripotent stem cell population.
How are stem cells induced to form different cell types?
Inducing signals causes differentiation into different cell types.
Cells grow into tissues/organs for transplantation.
What is the benefit of using the patients own stems cells?
Genetically identical to patient.
Reduces risk of rejection and the use of immunosuppressant drugs.
What disease did the first human stem cell trial treat?
Macular degeneration. By using stem cells from spare embryos leftover from IVF treatment.
Benefit: Eye has less of an immune response.
Why was the first human transplant of stem cell successful?
The patients old trachea was damaged by TB.
Her own bone marrow stem cells were seeded onto a dead donor trachea (stripped of living cells, leaving only a collagenous frame), grown in vitro.
What % of live births present with significant malformations and where is it more common?
5%.
Higher frequency in spontaneously aborted embryos.
Common defects seen in the heart, followed musculoskeletal and then urogenital.
What is the % of human birth defects with no known cause?
60%.
What is the major consequence of kidney defects?
Hypertension.
What % of live births will have some defects, and what are the short-term and long-term consequences?
20%.
25% are both major and minor defects.
Short-term: 1 in 5 of infant deaths are caused by birth defects = hence it is the leading cause of infant mortality.
Long-term: 5th leading cause of years of potential life lost and long-term disability and childhood morbidity.
What % of birth defects could be prevented?
50%.
By taking folate and avoiding alcohol, drugs and smoking.
What is the commonest birth defects in the USA?
Heart defects - due to obese/diabetic mothers
What is the commonest birth defects in Australia?
Musculoskeletal - genetic cause.
What are examples of infectious agent teratogens?
Toxoplasma parasite. Parvovirus. Rubella virus. Cytomegalovirus. Herpes simplex. HIV. Syphilis.
What are examples of medical treatment teratogens?
Vitamin A and analogues. Anticoagulant: Warfarin. Anticonvulsant: Valproic acid & phenytoin. Chemotherapy. Trimethoprim (folate antagonist).
What are examples of recreational drug teratogens?
Alcohol.
Tobacco.
Cocaine.
What was Thalidomide previously used for, and what illness is it used to treat now?
Previously used to treat nausea in pregnancy. Babies were born with phocomelia (shortening of limbs).
Led to FDA setting up new guidelines on drug testing (drugs tested on 2 species).
Now used for: leprosy, AIDS and some cancers.
N.B. Women taking thalidomide, need to be on 2 types of contraception.
What are the 9 features of foetal alcohol syndrome?
Microcephaly (small head). Short palpebral features (eye openings). Epicanthal folds (folds over eyelids). Low nasal bridge. Short nose. Smooth philtrum. Flat mid face. Thin upper lip. Micrognathia (small jaw).
During which period is the foetus most susceptible to birth defects?
In the embryonic period (3-8 weeks), in particular week 5.
Between weeks 0-3: foetus miscarries.
Between weeks 8-38 (foetal period): less pronounced defects.
In which period is the CNS affected?
It can be affected throughout gestation, since it continuous to develop until full term.
Which birth defect is decreasing in incidences?
Spina bifida - following introduction of folate supplements.
Which birth defects are increasing in incidences?
Gastroschisis, cleft lip/palate and hypospadias (abnormal genitalia).
Why was the infant mortality high before the harvest, but low after the harvest?
Before harvest: Mother were not fed well, led to thymic defects in babies.
After harvest: Mothers were fed well and their offsprings had a higher chance of survival.
Thymic and lymphoid tissue are very sensitive to lack of nutrition than other tissue types. Poor nutrition leads to heart disease and type 2 diabetes.
Does maternal obesity and diabetes increase the risk of birth defects?
Yes.
What can we do to decrease birth defects and the consequences of birth defects?
- Avoid teratogens: E.g. Alcohol, drugs.
- Take preventative supplements: Folic acid, dexamethasone for lupus and congenital adrenal hyperplasia.
- Better screening/diagnostics tests: Amniocentesis, chorionic villus sampling, ultrasonography.
- Foetal surgery (embryos don’t scar): E.g. For Potter’s sequence.
- Gene therapy?
Why is folic acid important during pregnancy?
Required for synthesis of DNA bases (especially thymine) and hence DNA replication and cell division.
Required for amino acid metabolism (methionine) for methylation.
Reduces neural tube defects by 70%.
What are the daily dietary requirements of folic acid when a) trying to conceive and b) for women who have had a previous child with NTD?
Conceiving: 0.4mg.
Previous child: 4mg.
How does congenital adrenal hyperplasia (CAH) develop?
Reduction in enzyme 21-hydroxylase –> decreases cortisol, increases ACTH –> supraadrenal hyperplasia –> excess supraadrenal androgens (testosterone).
Increases masculisation in females.
What is the treatment for CAH?
Corticosteroid, dexamethasone.
What does the breakthrough research on Down’s Syndrome involve?
Injecting NAP and SAL into pregnant mice with trisomic pups.
= improved cognition.
What is a key feature to look out for in babies born with Down’s Syndrome?
Single palmar crease.
What is evident on an ultrasonography in order to diagnose Down’s Syndrome?
Nuchal transparency at 12 weeks.
Causes accumulation of fluids, since lymphatics are not developed to drain into veins.
What % of babies are born with polydactyl or other congenital defects?
15%.
In which syndromes are radial ray abnormality seen in?
Holt-Oram syndrome. Thrombocytopenia-absent radius. VATER/VACTERL. Fanconi's anaemia. Trisomy 13/18.
In which syndromes are clenched hand deformity seen in?
Trisomy 18. Amniotic band syndrome. Pena Shokeir syndrome. Arthrogryposis. Multiple pterygium syndrome.
In which syndromes are sandal gap deformity seen in?
Down’s syndrome (45%).
Normal variant.
How does diagnostic tests for genetic disorders work?
The defective gene is removed and the remaining cells of the embryo are transplanted in the mother.
Used in Tay Sachs (prevalent in Jewish community), muscular dystrophy and X-linked disorder like haemophilia.
What does autosomal dominant mean?
One copy of mutation = Have the syndrome.
What does autosomal recessive mean?
One copy of mutation = Fine.
Two copy up mutation = Syndrome.
What is piebaldism?
Pigmentation defect in EMT –> As derived from neural crest.
A mutation in endothelin 3.
Has enteric ganglion defect.
What is Potter’s sequence?
Kidney/bladder obstruction –> hydronephrosis (dilated ureters & kidney) –> megacystis (dilated bladder) –> Oligohydramnios (too little amniotic fluid) –> Lung damage & craniofacial and limb defects.
What is craniosynostosis?
Sutures close too early –> abnormal head growth.
Linked to limb defects.
Required for FGF and Hh (gain of function mutation).
