Phase 2 KPH - Week 2 (Spina Bifida) Flashcards
Organogenesis
Weeks 4-8 of gestation, also called embryogenesis - the process by which the endoderm, mesoderm and ectoderm differentiate to give rise to major tissues, organs and organ systems in the body
List the events which occur at the end of week 3 of gestation
- Neurulation
- Somitogenesis
- Development of the intraembryonic coelom
Neurulation
Neural plate forms neural tube, leading to formation of the CNS
Describe the formation of the neural plate
19 days gestation - notochord (mesoderm) induces ectodermal cells cranial to primitive node to differentiate into columnar neuroepithelial cells - process called neural induction
Give examples of important signals involved with the process of neural induction
- Noggin - inactivates BMP4 - absence of BMP4 causes patterning of neural tube and somites
- Chordin - BMP antagonist
Describe the development of the neural plate after neural induction
- Neural plate forms at cranial end, grows cranial to caudal
- Cranial end of neural plate = region of eventual brain
- Narrower caudal end of neural plate = eventual region of spinal cord
Describe the folding of the neural plate to form the neural tube
- By end of week 3, lateral edges of neural plate become elevated, fold to form neural fold, depressed mid-region forms neural groove
- By approx. day 25 - neural folds approach the midline where they fuse forming the neural tube (precursor to CNS)
What physical changes to the neural plate is bending of the neural plate controlled by?
- Cell wedging - microtubules + microfilaments changing cell shape
- Hinge points - median hinge point and dorsolateral hinge points
- Extrinsic forces - pushing of surface ectoderm, adhesion point with notochord
Where does folding of the neural plate begin?
At the level of the 4th somite
Describe fusion of the neural tube
- Fusion begins in cervical region, extends in cranial and caudal directions
- Openings formed at cranial and caudal ends = cranial and caudal neuropores
- During closure, cells on lateral sides of neural plate detach forming new cell population - neural crest
Explain the development and role of the neural crest cells
- During closure of neural tube, cells on lateral sides of neural plate detach forming new cell population = neural crest
- Neural crest cells migrate + displace the cells of the ectoderm to enter underlying mesoderm
- Contribute to the formation of the PNS, including formation of neurones and glial cells of sympathetic, parasympathetic and sensory nervous systems
Describe the process of somitogenesis
- During 3rd week - lateral strips of mesoderm beside notochord thicken to form paraxial mesoderm
- As neural tube forms, paraxial mesoderm becomes organised into segments - somitomeres, first in cranial region, develops cranial -> caudal
- In eventual trunk region, somitomeres further differentiate into paired somites - block-like condensations of mesoderm
- Remains unsegmented in head region
- Each somite differentiates into 3 regions, which eventually give rise to different structures and tissues
When and where do the first pair of somites develop?
Day 20, border of head and trunk
How many pairs of somites form in total?
42-44 in total - addition correlates with approximate age of embryo
Why does the paraxial mesoderm remain unsegmented in the head region?
- Head region dissipates during development
- Supplemented with ectodermal neural crest cells, formed during neurulation
- Mesoderm in head region eventually differentiates to form connective tissue + muscles of face
Describe the differentiation of somites
- Myotome = major body muscles of neck, trunk and limbs
- Dermatome = major connective tissues of body, including bones, cartilage + dermis of skin
- Sclerotome = forms vertebrae and ribs
Describe the development of the intraembryonic coelom
- During week 3, spaces appear within lateral plate mesoderm (region of mesoderm most lateral to neural tube)
- Spaces fuse to form large cavity - intraembryonic coelom - splits the lateral plate mesoderm into two distinct parts:
1. Splanchnic mesoderm
2. Somatic mesoderm
Splanchnic mesoderm
- Layer of lateral plate mesoderm adjacent to ectoderm
- Gives rise to:
1. Bones of limbs
2. Ligaments of limbs
3. Dermis of limbs
4. Parietal layer of the serous membrane of the pericardium
Embryonic folding
Process of converting the embryo from a flat disc into a cylinder
Describe the process of embryonic folding
- Consists of 3 main layers derived from trilaminar disc - endoderm in centre, ectoderm on outside, mesoderm between
- During week 4
- Occurs as a result of differential rates of growth of embryonic structures - embryonic disc and amnion grow rapidly, growth of the yolk sac is slower
- Horizontal plane - development of the two lateral body folds
- Median sagittal plane - longitudinal cranial (head fold) and caudal (tail fold)
Which germ layer is the GI tract derived from?
Epithelial lining + glands mostly formed by endoderm
Describe the process of the formation of the primitive gut tube
- As lateral, cranial and caudal folds of endoderm fold towards the midline, they fuse, incorporating the dorsal part of the yolk sac to create primitive gut tube
Describe the structure of the primitive gut tube
- Split into foregut, midgut and hindgut
- Foregut seen at cranial end, temporarily closed by oropharyngeal membrane
- At end of week 4, oropharyngeal membrane ruptures to connect future oral cavity w/ pharynx
- Until week 5, midgut connected to yolk sac, narrows into stalk called vitelline duct- eventually yolk sac constricts and detaches from midgut, midgut seals
- Caudal end of hindgut is temporarily closed by cloacal membrane, separates upper + lower anal canal - ruptures during week 7 to form urogenital and anal openings
Describe the formation of the skin
- Ectoderm covers outer surface of embryo, except for umbilical region
- Ecotderm + dermatomes + lateral plate mesoderm + neural crest cells formed during neurulation go on to form skin and other structures including CNS and PNS
- Mesoderm layers organise into somites which go on to form muscle tissue, cartilage, bone and subcutaneous tissue of the skin
Pharyngeal arches
Paired structures that produce swellings in the region of the developing pharynx, neck and head of embryo. Tissue forming arches contributes to formation of structures of head + neck e.g. tongue, thyroid, pharynx, larynx, maxilla and mandible
Describe the formation of the pharyngeal arches
- Migration of neural crest cells into mesoderm of head + neck results in formation of 5 pairs of arches - develop cranial to caudal
- First arch - beginning of week 4
- All arches developed by end of week 5
- Consist of core of mesenchymal cells with outer covering of ectodermal cells, inner layer of endodermal epithelial cells. On lateral ectodermal surface, separated by pharyngeal clefts, on endodermal, internal surface separated by pharyngeal pouch
What is needed after week 8 to ensure successful organogenesis
Sufficient blood supply is required to provide nutrients + oxygen to developing organs/systems
Give a timeline of the major developments during organogenesis
Day 15 = Central nervous system + spinal cord Day 18 = Heart Day 22 = Eye and ear Day 28 = Digestive system Day 35 = Respiratory tract Day 35 = skeletal system Day 38 = Muscular system
Describe the development of the heart
- Begins as pair of elongated strands called cardiogenic cords
- Cords become hollow + fold to form single primitive heart tube
- Primitive heart tube divides into 5 distinct regions
- Undergoes elongation and folding, orientates the atria and ventricles into their final position
Describe the development of the eyes
- Eyes develop from ectoderm - bulges to form optic grooves in walls of prosencephalon
- Optic grooves enlarge and thicken to form lens placodes - invaginates + develops into lens vesicles, which develop into the lenses
Describe the development of the ears
- Ear forms from thickening of surface ectoderm - otic placodes
- Otic placodes invaginate to form otic pits, pits pinch off to form otic vesicles which go on to form the structures of the internal ear
- Middle ear formed from 1st pharyngeal pouch
- Ossicles develop from 1st and 2nd pharyngeal arches
- External ear forms from 1st pharyngeal cleft
Which structures are derived from the foregut?
Pharynx, oesophagus, stomach and parts of duodenum, liver, gallbladder, pancreas and salivary
Which structures are derived from the midgut?
Remaining duodenum, jejunum, ileum and large intestine
Which structures are derived from the hindgut?
Remaining parts of the large intestine
Describe the development of the respiratory tract
- Pulmonary groove forms at level of last pharyngeal arch
- Groove deepens, forms tube = trachea
- End of tube branch to form 2 lung buds - elongate and branch off to form numerous terminal branches
- Bronchioles develop the alveoli of the lungs
Describe the development of the skeletal system
- Vertebral column formed from sclerotome
- Complete model of vertebrae formed by week 8 - cartilage of vertebral centra form around spinal cord
- Appendicular skeleton - formed within limb buds, develop around week 5
- Cartilage precursors form within pelvic + pectoral limb buds, eventually ossify to form bones of appendicular system
- Clavicle ossifies week 6 - first to start last to finish
Describe the development of the muscular system
- Muscular system develops from mesoderm, arranged in segmented pairs of somites
- Myotomes form skeletal muscle of head, neck and limbs
- Cardiac muscle develops from mesodermal cells - migrate to heart during its development
- Smooth muscle develops from mesodermal cells - migrate to GI tract during development
List the maternal physical changes which occur during pregnancy
- Uterine expansion
- Weight gain
- Increased blood volume
- Increased oxygen demand
Describe the uterine expansion which occurs during pregnancy
- Increases in size, pushes up into abdominal cavity
- From fist sized to fill pelvic cavity by week 16
Why does uterine expansion occur in pregnancy?
Increased vascularisation, to accommodate foetus, placenta and amniotic fluid
Describe the side effects associated with uterine expansion in pregnancy
- Oedema of lower limbs, due to compression of inferior vena cava - can cause varicose veins
- Heat burn because of shift in position of oesophagus and pressure placed on stomach
- Compression of bladder requiring more urination, can also lead to stress incontinence
- Constipation
Why does weight gain occur during pregnancy?
- Increased appetite - need to consume 300 extra calories per day to support growing foetus
- 11-15kg is normal, due to increase in size of foetus, amniotic fluid, placenta, changes to maternal body e.g. lactation
Describe the side effects associated with weight gain in pregnancy
Shift in centre of gravity causing compensatory lordosis of spine + subsequent back pain
Why does an increase in blood volume occur during pregnancy?
- To meet demands of growing foetus for oxygen + nutrients
Increased by up to 50% in last trimester - Cardiac output can increase by 20-30%
- Heart rate increases by 15%
- Amount of blood flowing to placenta reduces volume of blood in systemic circulation, production of renin + erythropoietin are stimulated as a result of low PO2, leads to increase in blood volume
Describe the side effects associated with the increase in blood volume which occurs during pregnancy
- Pre-eclampsia - pregnancy induced hypertension occurs in conjunction with proteinuria. Results in diminished oxygen supply to foetus as there is insufficient blood supply to the placenta
- Proteinuria - excess serum protein in urine
- Nose bleeds
Describe how the increased oxygen demand during pregnancy is met
- Airway resistance in bronchial tree declines, allowing more oxygen to enter blood serum
- Ribs expand causing thorax to increase in width
Why is there an increased oxygen demand during pregnancy?
To cope with demands of the foetus and compensate for organs being forced against the diaphragm as uterus increases in size
List the side effects associated with the increased oxygen demand during pregnancy
- Dyspnoea (shortness of breath)
List the hormones secreted at increased levels during pregnancy
- Progesterone
- Oestrogen
- Human chorionic gonadotrophin
- Relaxin
- Human placental lactogen
- Human chorionic thyrotropin
- Corticotrophin-releasing hormone
- Cortisol
- Human chorionic somatomammotropin
Describe the production of progesterone and oestrogen during pregnancy
- Secreted by corpus luteum in ovary up to 4th month
- After 4th month, chorion of placenta maintains the levels of progesterone/oestrogen throughout rest of gestation
Describe the function of progesterone and oestrogen during pregnancy
- Maintenance of the uterine lining to prevent detachment of embryo
- Preparation of the mammary glands to produce milk
Describe the production of human chorionic gonadotrophin during pregnancy
- Secreted by chorion
- Secretion peaks at week 9
- Decreases rapidly in 4th + 5th month of pregnancy
Describe the function of human chorionic gonadotrophin during pregnancy
- Stimulates corpus luteum to produce progesterone + oestrogen
- High levels after 5th month can indicate Down syndrome
- Fluctuating levels of hCG could be cause of morning sickness by stimulating ovaries to secrete oestrogen
- Decrease in levels of hCG later in pregnancy may explain reduction in morning sickness at this time
Describe the role of relaxin in pregnancy
- Secreted by corpus luteum and towards end of pregnancy by placenta
- Function = promotes flexibility of pubic symphysis + ligaments of pelvis
- Helps to dilate the cervix
Describe the role of human placental lactogen during pregnancy
- Secreted by chorion of placenta
- Maximum secretion reached at week 32
- Function =
1. Prepares mammary glands for lactation
2. Regulates parts of maternal metabolism, ensures the foetus receives the nutrients it needs
3. Proportional increase in human placental lactogen with increase in placental weight
Describe the role of human chorionic thyrotropin during pregnancy
- Secreted by placenta
- Function =
1. Increase the rate of maternal metabolism
2. Elevates level of vitamin D to allow developing foetus sufficient calcium to promote healthy bone development
Describe the role of corticotrophin-releasing hormone during pregnancy
- Secreted by placenta
- Secretion starts around week 12, increases dramatically towards end of pregnancy
- Function = important in maturation of foetus
- Related to timing of parturition and delivery
- Responsible for determining length of gestation of pregnancy
Describe the role of cortisol in pregnancy
- Secreted towards end of pregnancy
- Triggers the production of surfactant in alveoli
Describe the role of human chorionic somatomammotropin in pregnancy
- Stimulates the development of the mammary glands
Define teratogen
Chemicals or environmental agents that may induce/increase the incidence of abnormalities to physiological development of the embryo/foetus - can induce harmful or fatal consequences
What factors influence the effect of teratogens?
- Level of damage dependent on dosage + length of exposure
- Degree of damage also depends on stage at which exposure occurs
- More susceptible to damage during embryonic period - esp. when major body systems are beginning to form
Give examples of teratogens
- Nicotine
- Alcohol
- Drugs
- Radiation
- Infectious agents
Describe the effect of nicotine exposure during pregnancy
- Prevents oxygen delivery to foetus resulting in stunted growth and low birth weight, can cause congenital cardiac problems + anancephaly
- Sudden infant death
- Increases risk of ectopic pregnancy
- Cleft lips/palates
- Secondary smoking also harmful in utero and to nursing infants - increases chances of developing respiratory problems
Describe the effect of alcohol in pregnancy
Foetal alcohol syndrome:
- Physical and/or behavioural symptoms, sometimes not evident until foetus is older
- Stunted growth
- Microcephaly
- Malformed limbs/organs
- Damage to CNS
- Characteristic facial features e.g. short palpebral fissures, thin upper lip, sunken nasal bridge
- Behavioural problems - hypersensitivity, extreme nervousness, decreased attention span
Give examples of prescription drugs which are teratogens
- Sodium valproate (used to treat epilepsy)
- Methotrexate (rheumatoid arthritis)
- ACE inhibitors (hypertension)
- Warfarin (blood thinner)
- Selective serotonin reuptake inhibitors (depression)
- Isotretinoin (acne)
- Some antibiotics
- Thalidomide
Give examples of recreational drugs which are teratogens
- Cocaine
- Heroin
- Alcohol
- Methampheamine
Describe the effect of cocaine exposure during pregnancy
- Spontaneous abortion
- Premature birth
- Stillbirths
- Low birth weight
Describe the effect of heroin exposure during pregnancy
- Foetus develops dependency - withdrawal at birth
- Premature birth
- Low birth weight
- Increased risk of sudden infant death syndrome
Describe the effect of radiation exposure during pregnancy
- Any form is teratogenic, including X-rays used in diagnostic procedures
- During embryonic stage, exposure can cause cell death or uncontrollable division, leading to malformations in organ development
- During foetal stage - exposure most often leads to malformation of the skeletal and nervous systems
- Microcephaly
- Mental retardation
- Skeletal malformations e.g. spina bifida, dwarfism
List the types of infectious agents which can have teratogenic effects
- Viruses e.g. HIV, herpes simplex, measles + rubella
- Bacteria e.g. gonorrhoea, syphilis, chlamydia
Describe the effects of infectious agents during pregnancy
- Cardiac defects
- Cataracts
- Deafness
- HIV - retarded growth, microcephaly + mental deficiency
Describe the role of sonic hedgehog
- Potent inductive signal during neurulation
- Part of sequence of master genes
- Critical role in development, patterning of brain and spinal cord (+ limb development and somite patterning)
- Causes cells in ventral somite - sclerotome - to undergo epithelia-mesenchymal transformation
- They can then migrate - move towards signal source (from vertebral column around the notochord)
- Also effects dermomyotome - induces competence to respond to signals from surface ectoderm
What is the cause of neural tube defects?
- Result of failure or incomplete closure of the neural tube
- Failure in anterior neuropore - anencephaly
- Failure in posterior neuropore - spina bifida
List the types of spina bifida
- Spina bifida occulta
- Spina bifida cystica - meningocoel
- Spina bifida cystica - myelomeningocoele
Spina bifida occulta
- Spinal cord is fully formed
- Vertebral column not completely fused
- Dimple on back
- Patch of hair on back
Spina bifida cystica meningocoel
- Lump at bottom of spine
- Cyst of fluid
- Spinal cord is still inside spinal column
Spina bifida cystica myelomeningocoel
- More nervous tissue in cyst
- Loss of sensation/mobility
- Bladder/bowel control in lower limbs
What complication is found in 80-90% of cases of spina bifida?
Hydrocephalus:
- Difference in pressure between head and spinal cord means collection of CSF in skull
How are neural tube defects diagnosed?
- Standard ultrasound scans
- Indicated by raised levels of alpha-fetoprotein
Describe the closure of the neural tube in the lower spine
- Dorsolateral hinge points not needed - only medial
- Inhibition by BMP2 allows dorsolateral hinge points to form
Describe the development of a neural tube defect in the low spinal region
Increased sonic hedgehog pathway activity in the neural tube leads to neural tube defects in low spinal region - at low spine levels, where a medial hinge point doesn’t form, suppression of dorsolateral hinge points inhibits closure and leads to neural tube defects
Describe sonic hedgehog signalling
- Cascade - requires patched and smoothened genes to encode transmembrane proteins
- Triggers cascade which leads to activation or repression of targer genes by transcription factors in Gli family
- Patched is negative regulator - inhibits smoothened by blocking downstream signalling via Gli which will transduce sonic hedgehog signal
- If sonic hedgehog binds to patched, patched can’t inhibit smoothened
- Activation of smoothened upregulates downstream pathways - bind to DNA and controls effector genes in sonic hedgehog pathway
How is sonic hedgehog activated?
Synthesised as inactive precursor - needs cholesterol to become active, released from plasma membrane via protein dispatched allowing it to establish the concentration gradient characteristic of its action as a morphogen
List the risk factors associated with neural tube defects
- Previous NTD-affected pregnancy - increases chance of having another NTD-affected pregnancy by approx. 20 times
- Maternal insulin-dependent diabetes
- Anti-seizure medication
- Medically diagnosed obesity
- Exposure to high temperatures in early pregnancy e.g. high fevers + hot tub use
- Race/ethnicity - more common in white + hispanic women
- Lower socio-economic status
Describe the use of folic acid to prevent neural tube defects
- Taken as vitamin supplement, when taken one month before conception + throughout first trimester, reduces risk of NTD-affected pregnancy by 50-70%
- Needed in body before and during pregnancy
- Folate found naturally in food sources, folic acid is synthetic in vitamin supplements and added to fortified foods - synthetic folic acid is better absorbed than natural folate
- Must take folic acid at least one month before conception and continue taking throughout first trimester
- Need 0.4 milligrams every day to reduce risk of NTD-affected pregnancy
Describe the role of folic acid in pregnancty
- Necessary for proper cell growth and development of the embryo - role in tissue formation
- Required for production of DNA, necessary for rapid cell growth needed to make foetal tissues + organs early in pregnancy
Why is the growth of children measured?
- Growth is an index of health and wellbeing in individuals and populations
- Abnormalities of growth and weight gain associated with illness, syndromes, under- and over-nutrition
How is children’s growth measured?
- Weight
- Length/height
- Body mass index
- Proper equipments and techniques essential
- Shoes taken off
How do we tell if a child’s growth is normal?
- Compare to other children
- Use growth charts
How is a growth chart constructed?
- Group of children of same age and gender have growth measured
- Distribution curve seen
- Can compare to average
- Made from series of cross sectional samples of measurements from children at different ages
- Standard centile lines - lines are evenly spaces (2/3 standard deviations) and include extreme outer centiles
What does a height on the 25th centile of a growth chart mean?
Out of a hundred healthy children of the same age and gender lined up in height order, there should be around 25 children shorted and 75 children taller
- The child is within normal range, but below average height
List some potential limitations of growth charts
- Average heights in a population will change over time - could become out-dated
- Depends on whether infants were breast or bottle fed (gain weight differently)
- Average height etc. depends on ethnicity
How were the WHO growth charts constructed?
- Needed a growth chart based on healthy, breast fed infants as the physiological norm to demonstrate how healthy children should grow
- 2006 - WHO published growth charts
