Reproduction, Development and Ageing Flashcards
1
Q
What are the male reproductive hormones?
A
- gonadotrophin releasing hormone (GnRH) - hypothalamus
- luteinising hormone (LH) - anterior pituitary
- follicle stimulating hormone (FSH) - anterior pituitary
- testosterone - testis
2
Q
What are the reproductive hormone names based off?
A
o there action in FEMALES
- in the testes there are no follicles -> LH and FSH names have nothing to do with their action biologically or physiologically in males
3
Q
What is the course of ejaculate?
A
- sperm are released from the testis and stored within the epididymis within the scrotum prior to ejaculation
- at ejaculation sperm pass through the two Vas Deferens (which are contractile), and is mixed with fluid from the seminal vesicles -> the fluid then leaves the ejaculatory duct, and passes into the urethra where it mixes with secretions from the prostate gland
- then is contiunally propelled out of the urethra
4
Q
Describe Leydig cells.
A
- lie outside of the seminiferous tubules
- the primary source of androgens in ALL male mammals -> prodominantly testosterone
- site of LH action
5
Q
Describe Sertoli cells.
A
- cells in the seminiferous tubules support the process of spermatogenesis
- produce inhibin
- function of Sertoli cells is driven by FSH and testosterone together
6
Q
Describe the production of testosterone.
A
- produced in the testis by Leydig cells
- inhibin negatively feeds back on the hypothalamus to constrain the production of GnRH
- testosterone also feeds back from the Leydig cells to the hypothalamus and pituitary gland -> therefore constrains the production of gonadotrophins (LH/FSH)
- androgen binding protein mediates the effects of testosterone on Sertoli cells by binding to testosterone
- is a pulsatile manner to the regulation of the productive system
7
Q
Where are sperm produced?
A
- seminiferous tubules
8
Q
Describe spermatogenesis.
A
- primordial sperm cells undergo mitosis to produce prmary spermatocytes
- primary spermatocytes undergo the first stage of meiosis to produce secondary spermatocytes -> the second meiotic division produces spermatids
- spermatids then mature into spermatozoa
9
Q
Do men go produce sperm throughout their lives?
A
o yes, after puberty
- quantity and quality does generally decrease with increasing age
10
Q
What are the females reproductive hormones?
A
- gonadotrophin releasing hormone (GnRH) - hypothalamus
- luteinising hormone (LH) - anterior pituitary
- follicle stimulating hormone (FSH) - anterior pituitary
- oestrogen - ovaries
- progesterone - ovaries
11
Q
Describe the reproductive axis in women in the follicular phase.
A
- hypothalamus prodcued GnRH which stimulates the anterior pituitary to prodcue and secrete FSH and LH
- this causes the ovary to produce estradiol and progesterone -> oestradiol is dominant
- oestradiol then has a negative feedback on the hypothalamus and the pituitary
- around 10 days in oestradiol switches to positive feedback on the hyothalamus and pituitary which causes a LH surge which further drives the positive feedback -> oestradiol is still dominant
12
Q
Describe the reproductive axis in women in the luteal phase.
A
- after ovulation the cycle switches back to negative feedback on the hypothalamus and pituitary
- progesterone aslo becomes dominant to maintain the uterine wall
13
Q
What occurs to the female hypothalamus-pituitary axis in pregnancy?
A
- progesterone levels RISE, and continues to do so for the whole length of pregnancy -> switches off the whole hypothalamic-pituitary axis
- menstrual cycle completely comes to a halt during pregnancy due to progesterone –ve feedback
14
Q
Which phase of the ovarian cycle will change its length if the cycle becomes shorter or longer due to environmental factors?
A
- the luteal phase -> stress can make this phase several days longer
15
Q
What physiological change occurs at ovulation?
A
- a womens body temperature will rise by around 0.5 degrees celcius
16
Q
Describe the endometrial cycle.
A
17
Q
Describe oogenesis.
A
o the first polar body is essentially a nucleus -> takes half of the chromosomes away -> process comes to a halt at the point of the development of the secondary oocyte -> eggs are metaphase II
- meiosis resumes at the point of puberty, and after that point -> individual eggs resume the process as they go through the final stages of folliculogenesis
- the longer the eggs are held, the poorer the organisation of the DNA -> why developmental problems are associated with increasing maternal age
o start with a primary oocyte, living inside a primordial follicle -> follicle starts growing independent of the sex hormones
o eventually, one follicle becomes dominant -> grows more quickly than the others -> dominant follicle enters the secondary part of the development, to become the antral follicle
o antral follicle gives rise to the egg that is released -> other follicles enter the process of atresia and break down -> normally, one ovary produces one dominant follicle per cycle (not always the case)
18
Q
How long does the process of producting a mature oocyte take?
A
- around 3 months
- will be multiple occytesmaturing in each ovary
19
Q
How long can oocytes and spermatozoa last in the femlae reproductive tract?
A
- oocyte = 24 hours
- spermatozoa = 3 days
20
Q
Describe fertilsation.
A
- sperm swims to where the egg is in the fallopian tube -> once close enough are attracted by chemo-attraction
- binds to the zona pellucida on the outside of the egg -> sperm produce digestive enzymes to digest their way through the zona pellucida -> eventually, one sperm will RELEASE its nucleus into the cytoplasm of the egg
- meiosis of maternal chromosomes resumes, forming female pro-nucleus (23 chromatids), and the second polar body
- sperm chromosomes de-condense to form male pro-nucleus (23 chromatids)
- BOTH pro-nuclei are duplicated and then align on the mitotic spindle, and are separated into 2 identical ‘daughter’ cells -> done at the 1st cleavage division of the embryo
21
Q
What cause penile and clitoral erection?
A
- partly under the control of the brain, via the spinal cord and efferent nervous system
- tactile stimulus of the organ can activate the afferent system (pudendal nerve) -> is a more direct interaction
22
Q
What changes occur during erection?
A
- initiated by increased parasympathetic activity to smooth muscle of pudendal artery
- is an increases in the activity of Nitric Oxide Synthase (NOS), and hence nitric oxide (NO) -> increased production of cyclic GMP which induces dilatation of arterial smooth muscle -> increases blood flow in corpus cavernosum
- in turn this compresses the dorsal vein, restricting the outflow of blood
- urethra is protected from increased pressure by surrounding corpus spongiosum (less turgid)
- same mechanims are in play in the clitoris
23
Q
When is the absolutel limit of survival outside of the womb?
A
- without the intensive care unit, the absolute limit of survival outside the womb is 27 weeks (defines the end of the second trimester)
- modern intensive care cots have increased this limit to 23 weeks -> is extremely dangerous -> survival rates are quite low when premature births take place
24
Q
What are the maternal changes that occur during pregnancy and what trimester do they prodominantly occur in?
A
- increased weight [3rd]
- increased blood volume [2nd & later]
- increased blood clotting tendency [2nd & later]
- decreased blood pressure [2nd]
- altered brain function [throughout] – function of the brain changes
- altered hormones [throughout] – can be largely different to normal physiology
- altered appetite (quantity and quality of what the mother eats changes) [throughout]
- GI imbalance (morning sickness)
- altered fluid balance [2nd & later]
- altered emotional state [throughout]
- altered joints - e.g. more flexible knees [3rd]
- altered immune system [throughout]
25
What hormonal changes occur in a women during pregnancy?
- human chorionic gonadotrophin is the key hormone in early pregnancy -\> is a functional homologue of LH, driving the production of oestrogens and progesterones from the corpus luteum
- corpus luteum usually degenerates towards the end of the last week of the menstrual cycle -\> fall in progesterone results in the breakdown of endometrium -\> to keep the pregnancy going, we need progesterone -\> hCG drives the progesterone production from the corpus luteum -\> peaks and falls in the first trimester
- placental lactogen is produced, and levels increase as the size of the placenta increases, same pattern of production is seen in progesterone and oestrogens
- by 10 weeks gestation, the placenta is the source of all progesterone -\> up to then, mainly corpus luteum
- levels of progesterone and oestrogens greatly exceed the levels seen during the normal menstrual cycle, so they may have potent effects on the maternal system in pregnancy -\> are well above required because low progesterone levels lead to loss of the pregnancy at all gestational ages.
- high levels of steroids suppressing the HPG, leads to very low levels of LH and FSH throughout pregnancy, and hence no cyclic ovarian or uterine functions
26
What is meant by the term conceptus?
- everything resulting from fertilised egg -\> baby, placenta, fetal membranes, umbilical cord
27
What are the timing issues in pregnancy?
- menstrual cycle is not precisely 28 days, and ovulation is not precisely on day 14
o first day of the last menstrual period is taken as the start of pregnancy -\> a clearly established day -\> from this, we can work out when the women ovulated (2 weeks after that)
o embryologists, however, will take the first day as being the point of fertilisation
- these timings differ by 2 weeks -\> doesn’t make a huge difference in the scheme of ‘term dates’ but does at the beginning of pregnancy
28
What are the lumps in a placenta called?
- cotyledons
29
Describe the structure of the placenta.
- placental villus is extensively branched, which provides a very large surface area
- maternal vascular system is set up over this surface area
- umbilical vein carries the oxygenated blood (is flowing away from the foetal heart) and the 2 umbilical arteies carry the deoxygenated blood -\> same as in the lungs
30
What are the functions of the placenta?
- separation of blood supplies of mother and baby
- exchange of nutrients (maternal to foetal) and waste products (foetal to maternal)
- connection (or anchorage)
- immunoregulation -\> allows the maternal immune system to switch off
- biosynthesis -\> e.g. progesterone, oestrogens and hCG
31
Describe the development of a placenta.
- starts as a layer of single cells in the blastocyst
- day 9 post-fertilisation, the conceptus is almost completely implanted within the endometrium -\> At this stage, the outer layer of the conceptus is multi-nucleated syncytiotrophoblasts containing fluid-filled lacunae
- underlying layer of cytotrophoblast is proliferating adjacent to the embryo -\> where the placenta will develop -\> following implantation, the cytotrophoblast proliferate into the syncytium
- a columnar structure forms (cytotrophoblast column), which undergoes branching (villous sprouts) -\> at the centre of each villus are mesenchymal (extra-embryonic mesoderm) cells -\> from these cells, the villus vascular system develops
- branching continues throughout pregnancy -\> gives rise to the complex branched villi
32
Why do cytotrophoblast shells limit blood supply to an embryo in early development?
- keeps the number of free radicals from oxygen low -\> less likely to cause damage
- allows for remodelling of spiral arteries to allow high volume of blood in second and third trimesters
33
What does mal-development of the placenta lead to?
- miscarriage (late first trimester) – if the placenta doesn’t anchor properly
- miscarriage (second trimester)
- pre-eclampsia (early delivery)
- fetal growth restriction (small infant)
34
What is the cut off point for a delivery to be considered term?
- term = 37-41 weeks
- pre-term = 23-37 weeks -\> mostly due to pre-term labour but some are due to C-sections due to a significant risk to the baby and/or mother
35
Define labour.
- fundally dominant contractions, coupled with cervical ripening (softening) and effacement (thinning of the cervix as well as expanding sideays)
36
Describe the process of labour is independent of gestational age.
- cervical ripening and effacement (increasing)
- co-ordinated myometrial contractions (increasing)
- rupture of fetal membranes
- delivery of infant
- delivery of placenta
- contraction of uterus
37
What are Braxton Hicks contractions?
- a latent stage, around 8 weeks before labour, in which the myometrium undergoes changes
- rather than being completely relaxed (to allow for foetal growth), a part of it contracts briefly, and relaxes
- occurs intermittently but regularly
38
Describe phase I of labour?
- involves contractions and cervical/uterine changes
- \> contractions become more powerful and more co-ordinated
- \> cervix begins to soften (ripening) and gets thinner (effacement)
- length of phase I is incredibly variable (12 to 48 hours) -\> gets shorter with subsequent pregnancies
39
Describe phase II of labour.
- baby is delivered
- \> contractions continually get stronger and more frequent
- can last hours but is never as long as phase one
40
Describe phase III of labour.
- the placenta is delivered
- around half an hour long
41
What initiates term labour?
- no-one really knows
- might be driven by oestrogens, low progesterones, CRH and oxytocin etc
42
What initiates pre-term labour?
- intrauterine infection
- infection elsewhere in mother’s body
- intrauterine bleeding
- multiple pregnancy
- maternal stress
- many other factors
43
Describe cervical ripening and effacement.
- change from rigid to flexible structure
- remodelling (loss) of extracellular matrix
- recruitment of leukocytes (neutrophils)
o is an inflammatory process -\> leads to the production of:
- \> prostaglandin E2, interleukin-8
- \> local (paracrine) change in IL-8
44
Describe co-ordinated myometrial contractions.
- fundal dominance
- increased co-ordination and power of contractions
- mediated by:
- \> prostaglandin F2a (E2) levels increased from fetal membranes
- \> oxytocin receptor increases -\> more oxytocin receptors (not oxytocin) means the uterus in more responsive to it
- \> contraction associated proteins
45
Describe rupture of the foetal membranes.
- loss of strength due to changes in amnion basement component
o is what is happening when a woman’s ‘water breaks’
- involves inflammatory changes and leukocyte recruitment -\> is modest in normal labour, exacerbated in pre-term labour
- \> increased levels and activity of MMPs
46
Which pro-inflammatory transcription factor is most important in labour?
o NF-Kappa-B
- enters the nucleus and upregulates lots of porteins which are key in labour -\> e.g. COX-2 (prostaglandins), IL-8, IL-1b, MMPs, oxytocin receptor, PG receptors, contraction-associated proteins
47
Name the current top 2 factors for initiating normal labour.
- corticotrophin releasing hormone
- platelet activating factor
48
Why does CRH make sense to be an initiator of labour?
- its maternal blood circulation levels rise dramatically in the last 3-4 weeks of pregnancy due to the loss of its binding protein
- it increases the production of prostaglandins (COX-2, E2) which are known to be important in labour
49
Why does platelt activating factor make sense to be an initiator of labour?
- PAF is part of lung surfactant
- babies don't have surfactant in utero however surfactant proteins and complexes are produced in the last couple of months of pregnancy by the maturing lungs -\> more mature the lung is = the higher the levels of surfactant get
- levels of surfactant in amniotic fluid increase near term -\> a foetal signal of maturity -\> baby can now be delivered safely, because it can breathe air
50
What is the current hypothesis on parturition?
- high levels of CRH will start to switch UP IL and prostaglandin production in the foetal membranes
- cortisol from the adrenal gland is acts on the foetal lung -\> stimulates the foetal lungs to produce surfactant (including PAF)
o high levels of cortisol production = more surfactant produced = more PAF
- lungs are in intimate contact with amniotic fluid (baby takes amniotic fluid into lungs, and expels it) -\> allows PAF to enter the amniotic fluid, and PAF upregulates the same factors in the membranes
51
What is DHEAS?
- a steroid produced in the adrenal glands
- can move to the placenta and can be converted to oestrogens
- oestrogens upregulate PGs, OT and OT receptors -\> all required for increased myometrial contractility
52
How does pregnancy occur despite progesterone levels remaining high?
- progesterone is NEEDED to sustain pregnancy -\> one of the ways of causing pregnancy loss is giving a progesterone antagonist
- progesterone levels remain very high until after delivery of the placenta (unlike sheep) but the effect of progesterone is lost in normal term labour -\> thought to be because there is an interaction between the progesterone receptor and NFkB
- throughout pregnancy progesterone receptors are present in large quantities (unlike NFkB) therefore, NFkB cannot do its normal job of upregulation inflammatory cascades
- at the end of pregnancy, NFkB levels rise (driven by CRH/PAF) and progesterone levels fall
- switching off of progesterone may act as an initiator of labour
53
Define foetal growth.
- increase in mass that occurs between the end of embryonic peoid and birth
54
What 2 factors is foetal growth dependent on?
o genetic potential -\> derived from both parents and mediated through growth factors e.g. insulin like growth factors
o substrate supply -\> essential to achieve genetic potential
-\> derived from placenta which is dependent upon both uterine and placental vascularity
55
What are the 3 phases of normla foetal growth?
1. cellular hyperplasia (happens rapidly in the first few weeks)
2. hyperplasia and hypertrophy
3. hypertrophy alone
56
What techniques are used to ante-natally asses the size of a foetus?
- palpation of the maternal abdomen
- measure the uterus with a tape measure -\> measure their symphysis fundal height = pubic symphysis to the fundus of the uterus - SFH
57
Why might a foetus be measured to be smaller than expected?
- we have the wrong dates
- baby is small for gestational age -\> could be pathological or just a small baby
- oligohydramnios - amniotic fluid deficiency
- the foetus is lying transversely
58
Why might a foetus by measured to be larger than expected?
- we have the dates wrong
- molar pregnancy
- multiple gestation
- large for gestational age
- polyhydramnios - excess amniotic fluid
- maternal obesity
- fibroids - non-cancerous growth of the uterus
59
What are the pros and cons of SFH?
o pros of SFH = SIMPLE and INEXPENSIVE
o cons of SFH = low detection rate, great inter-operator variability, influenced by a number of factors (BMI, foetal lie, amniotic fluid, fibroids)
- nowadays, in modern obstetric practice, we use ultrasound machines to measure the baby more objectively
60
How are pregnancies dated?
- dating can be done by asking the mother for the first day of her last menstrual cycle (LMP) -\> fairly inaccurate method (irregular periods, abnormal bleeding, contraceptives, breast feeding)
- nowadays all pregnancies are dated using the crown rump length (CRL) -\> exception being IVF (know exactly when the embryos were made)
61
What 4 measuremenst are taken to asses foetal growth?
- bi-parietal diameter
- head circumference
- abdominal circumference
- femur length
62
What are the factors that influence foetal growth?
o maternal factors -\> poverty, age, drug use, weight (low BMI can result in a small baby), disease (hypertension, diabetes, coagulopathy), smoking, alcohol, diet, prenatal depression, environmental toxins
- foeto-placental factors -\> genotype -\> genetic potential, gender (B\>G), hormones -\> previous pregnancy (if a mother has had a previously affected pregnancy with intra-uterine growth restriction, she is at a higher risk of having it again in subsequent pregnancy)
63
What are the major foetal hormones?
- GH
- prolactin
- FSH
- LH
- insulin
- androgens
- iodothyronines
64
Describe customised growth charts.
- adjusted to reflect maternal constitutional variation (maternal height, weight, ethnicity, parity)
- optimised by presenting a standard free from pathological factors such as diabetes and smoking
- based on foetal weight curves derived from normal pregnancies
65
What is the difference between small for gestational age (SGA) and foetal growth restricted (FGR)?
- SGA = estimated birth weight that is \<10th centile
- FGR = failure of foetus to achieve its pre-determined potential which is backed up with definitive evidence
66
How is foetal growth restriction assessed?
- the term FGR should only be used for foetuses with definite evidence that growth has altered
- growth is a dynamic process of a change of size over time -\> so it can only be assessed by serial observation -\> the gap between measurements is at least 2 weeks
- allows doctors to truly see what the projectile is on a centile biometry
67
What are the short-term problems associated with low birth weight, FGP and pre-maturity?
- respiratory distress -\> particularly if developed before 34 weeks (minimised by giving steroid injections)
- intraventricular haemorrhage -\> produces a risk of cerebral palsy later on
- sepsis -\> due to an immature immune system
- hypoglycaemia -\> if the liver is less developed, you see metabolic problems
- necrotising enterocolitis
- jaundice
- electrolyte imbalance
68
What are the medium-term problems associated with low birth weight, FGP and pre-maturity?
- respiratory problems
- developmental delay -\> special needs schooling maybe required
69
What are the long-term problems associated with low birth weight, FGP and pre-maturity?
- foetal programming -\> ischaemic heart disease, congenital heart disease and diabetes are more common, due to compensatory pathways (influenced by initiation by poor growth at the beginning of life)
70
What are the causes of small for gestational age babies?
- dating problems and normal /simply a small baby make up 75%
- foetal problem -\> abnormality or infection etc
- placental insufficiency -\> placental cysts, infarction, placenta praevia etc
- maternal factors -\> medical (chronic hypertension, diabetes etc) or behavouiral (smoking, alcohol, drugs etc)
71
What is pre-eclampsia?
- a failure in the trophoblastic invasion of the placenta -\> spiral arteries remain narrow -\> requires high shearing force to maintain a=enough blood supply tp the foetus
- defined as: pregnant women who have hypertension, oedoma and proteinuria
- high bp occurs in 10% of pregnancies and is associated with small babies
72
Which foetuses have their growth monitored closely?
o mother has a bad obstetric history -\> previous maternal hypertension, previous FGR, previous stillbirth, placental abruption
o concerns in index pregnancy -\> abnormal serum biochemistry, reduced symphysis fundal height, antepartum haemorrhage, maternal systemic disease e.g. hypertension, renal, coagulation
73
How are pregnancies screened for 'at risk' FGR foetuses?
- uterine artery doppler at 24 weeks -\> blood flow through uterine arteries -\> allows us to identify high resistance flow -\> have high resistant flow = higher increase in resistance in the maternal circulation
74
What factors are used to predict if a foetuses may become growth- restricted?
- mother has a poor obstetric history
- primips
- obese
- Afro-Caribbean/African
- family history
- diabetes
- systemic vascular disease
- renal disease
- thrombophilias
75
What is the consequences of impedence of the umbilical veins?
- foetus moves less to reserve energy
76
How FGR pregnancies dealt with?
- if it is confirmed to due to impedence of the umbilical vein -\> immediate delivery of the bay is offered it is over 28 weeks of 500g or larger
- will need corticosteroids to improve neonatal wellbeing
77
What complicates delivery in pregnancies with FGR?
- timing delivery in these pregnancies depends on balancing the risks to the foetus if it remains in utero and the hazards from the prematurity, which decrease as the gestation advances
- evidence of foetal compromise on CTGs or abnormal Dopplers/ultrasound finding/maternal compromise
78
If delivery is required as a treatment, how is the mode of delivery decided?
o dependent on:
- gestation of the pregnancy
- condition of the pregnancy
- state of the cervix
- presentation of the foetus
- other factors: oligohydramnios -\> labour may be poorly tolerated due to cord compression
79
Fetal growth restriction is not associated with:
A) High resistance umbilical artery Doppler readings
B) Preterm delivery
C) Increased risk of delivery by Caesarean section
D) Neonatal hyperglycaemia
E) Neonatal necrotising enterocolitis
- D -\> is associated with hypoglycaemia but not hyperglycaemia
80
What are the causes of mal-development?
- genetics = 30%
- environmental = 15%
- multifactorial = 55%
81
What is chimerism?
- 2 genetically distinct conceptuses that fuse to form one individual early on in development
82
What chromosome distribution mal-developments exsist?
- mosaicism
- chimerism
83
Which 3 chromosomes can a human have 3 of and still be compatible with life?
- 13 = Patau's syndrome -\> most die before birth and 80% die within a year
- 18 = Edward's syndrome -\> most die before birth, the few who don't are unlikely to for more than 2 weeks
- 21 = Down's syndrome -\> heart problems determine survival
- all other trisomies have been detected in pregnancy but don't make it to birth -\> exception is chromosome 1 -\> never been found -\> though to be because it carries the most DNA so a problem with it is fatal before implantation can occur
84
Which chromosome is viable with life there is only one copy?
- X0 = Turner's syndrome
- partial chromosome losses can be compatible -\> increased chance of cancers/tumours -\> only a single hit is required in TSG
- translocations can also occur and lead to XX boys etc
85
Describe Holt-Oram syndrome.
o range of heart and hand defects
- chambers in the heart don't develop properly due to septal defects
- thumbs will develop as fingers -\> sometimes only on one hand
o phenotype is due toa mutation in TBX5 (a TF)
86
Describe achondroplasia.
- gain of function mutation in FGFR3 causes a defect is in conversion of cartilage to bone -\> a lack of bone growth occurs
- gives rise to achondroplastic dwarfism
- long bones of the legs in particularly haven’t developed as they should -\> very short
87
Define teratogen.
- any agent that can disturb the development of an embryo or foetus
88
Name the 3 categories of teratogens and give some examples.
- infectious agents -\> rubella virus , herpes simplex virus, HIV, syphilis, zika virus etc
- physical agents -\> X-rays and other ionising radiation
- chemical agents -\> thalidomide, lithium, amphetamines, cocaine, alcohol etc
89
When is a foetus most vunerable to teratogens?
- first trimester -\> although the first couple of weeks aren't affected in terms of mal-development -\> the foetus imple wouldn't be able to survive so would die
- some systems (CNS) are vunerable throughout
90
What is polydactly?
- a minor defect in which a hand (or both) has an extra finger
- is usually still fully functional
91
Summarise limb development.
- fore limb bud appears at day 27/28 and the hind limb bud at day 29
- buds grow out from lateral plate mesoderm rapidly under the control of special signalling regions
- digits are fully formed and patterned by day 56
92
How does sonic hedehog gene influence growth of the limbs?
- expressed in the control centre of the limbs -\> co-ordinated the development of the limbs
- if it is also expressed on the corresponding mirror image you will get the formation of a limb which is symmetrical -\> 2 thumbs and 2 fingers (in a chicken a wing with two end bones)
93
What is a cleft lip and/or palate?
- a major mal-development of the lip and/or palate
94
Describe development of the face and what goes wrong when a cleft lip and/or palate forms.
- faces start developing with the eyes either side of the head (near to the ears), the nose also starts off developing relatively laterally
- movement of structures medially requires that clefting occurs in the middle of the face -\> this gap is then filled in with cells -\> if this filling in process fails a cleft lip and/or palate will form
95
Why must a cleft palate be treated?
- to prevent food entering the nasal cavity and then potentially the lungs
96
Why is it important to treat a cleft lip?
- the cosemetics and psychology of the patient
97
What is the treatment for cleft lips and/or palates, plus state the results?
- surgery
- outcomes are very good as cells are proliferating very fast in a young infant (surgery must be done soon) so very little scarring occurs
98
What is spina bifida?
- defect where there is incomplete closing of the backbone and membranes around the spinal cord
99
What are the 3 types of spina bifida?
- spina bifida occulta -\> CNS is okay but the spine isn't correctly formed -\> characterised by a small patch of hair over the lesion -\> is hidden and often doesnt cause any major problems
- meningocele -\> a swelling/lesion containing CSF pokes out of the spinal column
- myelomeningocele -\> swelling/lesion containing nervous tissue pokes out of the spinal column -\> all nerves below the lesion will be damaged and many will not function at all
100
Describe the development of the spinal column and what goes wrong in spina bifida?
- development of the bony part of the spine is driven and controlled by neural tissue (CNS tissue)
- spina bifida development takes place within the first 4 weeks post-fertilisation
- formation of the CNS is the formation of a tubular structure
- in spina bifida, the tube does not completely seal up (in one or more places) -\> this process is called neuralation -\> in spina bifida, neuralation is of the posterior neuropore is faulty
101
Which vitamin is very important in preventing spina bifida? When should this vitamin be taken?
o folic acid
- folic acid should be given 3 months prior to conception -\> egg does most of its development before it is selected as the main follicle within these 3 months -\> at this point, the egg is taking up nutrients and building its reserves for development -\> why folic acid must be given 3 months before fertilisation
102
What is anencephaly?
- defect in skull and brain development due to a faulty closure of the anterior neuropore
- the more complicated areas of the brain don't develop but the parts essential for life (brainstem etc) do
- more common in females
103
How can anencephaly be prevented?
- folic acid 3 months before conception
104
What defects occur when thalidomide is taken during pregnancy?
- predominantly the limbs (upper limbs more common, but lower limbs can also be affected)
- deformed eyes and hearts, deformed alimentary and urinary tracts, blindness and deafness
105
What was thalidomide used to treat and what is it now used to treat?
- was = hyperemia gravidarum - severe morning sickness
- now = some cancers and leprosy
106
How does thalidomide induce limb defects?
- one of the thalidomide isoforms STOPS blood vessel development by inhibiting FGF and snic hedgehog in some way -\> if it stops vessel development, cell death results -\> growing limb cannot grow
- is devoid of nutrients and truncates prematurely -\> if the exposure is short, it is PARTIAL limb loss that results, longer exposure can result in complete limb loss
107
What is respiratory distress syndrome?
- lung surfactant disorder/deficiency
- occurs in premature babies as lung development occurs slowly throughout pregnancy and after birth -\> affects 100% at GA 24 weeks, 50% at GA 26-28 weeks and 25% at GA 30-31 weeks
- symptoms can be lessened with a glucocorticoid injection into the mother 2-3 days before birth -\> wil still require support
108
Why do doctors measure growth?
- poor growth in infancy is associated with high childhood morbidity and mortality.
- growth is the best indicator of health – a child who is growing well will be healthy
- demonstration of normality of growth by age and stage of puberty
- measurement allows us to identify disorders of growth
- assess obesity
109
What is the height velocity calculation?
110
Describe the endocrine control of growth.
- hypothalamus produces GHRH, which stimulates the pituitary gland to make and release GH -\> GH binds to proteins and travels to the GH receptor
- initiates the production of IGF-1 -\> IGF-1 travels around the body with binding proteins -\> IGF-1 receptors are located within the growth plates of bones (IGF-1 has an autocrine AND paracrine effect)
- growth plate is cartilage which within are osteoblasts -\> IGF-1 interacts with the osteoblasts and activates them -\> begin to proliferate, and the bone becomes longer and longer
- is some negative control by GH from the hypothalamus
111
Where is most IGF-1 produced?
- liver = 70%
112
What kind of effecst does IGF-1 have?
- autocrine and paracrine
113
In what phase of growth is growth fastest?
- ante-natal followed by the first year of life
114
Describe growth in infancy/under 1 year old.
- rapid initial growth -\> 23-25 cm in first year -\> continuation of foetal growth, but a decrease in the velocity
- baby is nutritionally dependant for a year -\> nutrition controls growth in the first year of life -\> when the baby reaches 1 year of age, GH is vital in baby growth -\> 9-12 months growth starts to be influenced by GH
- in GH deficiency, the height of a baby plateaus very low down on a growth chart around 9-12 months
115
Describe growth in childhood (1-adolescence).
- post infancy to adolescence
- growth rates in boys and girls similar -\> same growth velocity = 5-6cm/year
- is where the GH/IGF-1 axis drives growth -\> nutrition has less impact her
- after this sex steroid drive growth along with GH
116
Whay happens when a person stops growing?
- bones mature and epiphyses fuse -\> sex steroids fuse the growth plates
- final growth occurs in the spine
- final epiphyses to fuse are in the pelvis
117
Name some causes of short stature.
- genetics -\> if you have short parents, you will be short
- pubertal and growth delay
- IUGR/SGA -\> 10-20% of babies who are small at birth
- dysmorphic syndromes -\> chromosome abnormalities often result in short stature
- endocrine disorders
- chronic paediatric disease
- psychosocial depravation -\> stressors can affect the pulsatility of GH
118
How can mid-parental centiles be used to estimate maximum potential height of a child?
- male = ((mothers' height + fathers' height)/2) + 7
- females = ((mothers' height + fathers' height)/2) - 7
119
If growth is abnormally patterned but hormones are normal what causes could be at play?
o may be due to syndromes
- Turner syndrome XO – females who don’t go through puberty, and are short
- Down’s syndrome (trisomy 21)
- skeletal dysplasias
o significant illnesses can interfere with growth -\> inflammation, poor nutrition and the effects of drugs such as steroids -\> blocks the intracellular signalling processes of GH – so IGF-1 will be much lower
o achondroplasia -\> actually have a normal sitting height but an abnormal standing height, because of their shorter legs
120
Name some chronic paediatric diseases known to affect growth.
- badly controlled asthma
- sickle cell
- juvenile chronic arthritis
- inflammatory bowel disease -\> Crohn’s disease or coeliac disease
- cystic fibrosis
- renal failure
- congenital heart disease
121
Name some causes of tall stature.
- parents are tall, the child will be tall
- early puberty – makes a child tall at first
- Marfans syndrome or Klinefelter's syndrome -\> really long arm span and really tall
- growth hormone excess
122
Name 3 syndromes associated with obesity.
- Prader-Willi
- Cushing's
- Lawrence-Moon-Biedl
123
Describe the genetics of weight gain?
o polygenic inheritance - \> many genes affect how much we will weight -\> monogenic obesity syndromes (PWS etc are very rare)
o weight is a highly heritable trait (40-70%)
- leptin deficiency or leptin receptor deficiency
- POMC deficiency
- PC-1 deficiency
- MC4R deficiency
124
Define puberty.
- process of physical changes through which a child’s body matures into an adult body that is capable of sexual reproduction
125
Define adrenarche.
o increase in adrenal androgen production
- occurs prior to onset of puberty (between the ages of 6 and 10)
- during adrenarche the adrenal cortex secretes increased levels of androgens (DHEA, DHEAS) but without increased cortisol levels
126
Define menarche.
- onset of the first menstraul cycle
- although the definition is a singular event you can't really define menstraul cycle as began before 3 complete cycles
127
Describe the 5 stages of puberty.
- stage 1 = hormone production begins/increases but there aren't any physical signs
- stage 2 = change in body shape (breast begins to form, more triangular in boys and curvy in girls) and pubic hair begins to appear -\> girls begine to grow in height and weight
- stage 3 = contiuation of growth and change in body shape (boys also begin to grow) as well as changes in siza and shape of genitals -\> boys shoulders and muscle mass increases dramatically and voice begins to deepen
- stage 4 -\> girls = breasts and aureolas develop, pubic hair has a more triangular adult appearance, menarche will begin if it hasn't already
- \> boys = penis starts to grow in width (texture more adult like too) , testicles and scrotum also continue to grow, hair may begin to grow on the anus, armpits and face, the voice continues to deepen
- stage 5 = final height is reached/approached, genital and hair is like that of an adults = fully developed -\> some boys will continue to grow into their 20s
128
What are the main psychological changes in adolescence?
- cogntition -\> abstract thinking
- identity
- increased self-awareness
- expression and regulation affected
129
What is anorexia nervosa?
- persistent restriction of energy intake leading to significantly low body weight (in context of what is minimally expected for age, sex, developmental trajectory, and physical health -\> used to defined as a body weight at least 15% below expected or BMI\<17.5
- linked with a psychopathology-morbid dread of fatness -\> aim for lower weight than premorbid or healthy -\> hence particularly avoid fattening food
- causes endocrine disturbance -\> secondary amenorrhoea or loss of sexual interest/potency in men/boys
130
Describe conduct disorder.
o conduct disorder is the child equivalent of anti-social personality disorder -\> a persistent failure to control behaviour appropriately within socially defined rules
- are 3 overlapping domains of behaviours -\> defiance against authority, aggressiveness and antisocial behaviours
- becomes a disorder when it becomes an impairment in every day functioning
131
How is conduct disorder treated/intervented?
- child focused -\> behaviour modification, problem-solving skills training
- family-focused -\> family counseling and social work, family therapy, parent management training -\> ARE MORE EFFECTIVE
132
What are some causes of conduct disroders?
- genes are NOT strongly linked
- “difficult” temperament
- immediate environment -\> parental psychiatric disorder, parental criminality, sexual abuse
- wider environment -\> school factors (ways in which schools deal with these children), wider social influences
133
How is depression treated?
- mild depression -\> support and stress reduction with non-specific counseling
- moderate depression -\> 3-step plan -\> support and stress reduction first, cognitive behavioural therapy and anti-depressants
- severe depression -\> combination from the start
134
What are the 2 main theory branches on why we age?
- programmed ageing
- damage or error theory
135
Describe programmed ageing theory.
- revolve around genetics -\> is evidence that cells in culture have a limit for the number of times they can divide -\> this is the Hayflick limit - after this limit is reached, cells cannot continue to divide
- theoretical benefit of limiting replication is prevention of cancer
- EVIDENCE TO SUGGEST THAT HUMANS WITH MORE ACTIVE TELOMERASE LIVE LONGER
136
Describe damage or error theories on ageing.
- revolve around free radicals (oxygen, hydrogen peroxide and nitrous oxide)
- free radicals are generated in the body, particularly by mitochondria and damage the mitochondria, and mitochondrial DNA -\> mitochondrial DNA doesn’t have very good repair mechanisms -\> as mitochondria become damaged they die which leads to cell death
137
What challenges does society face as a result of population ageing?
- working life/retirement balance -\> won’t be able to fund pensions for everyone
- caring for older people, the sandwich generation (people with young children and elderly parents)
- extending healthy old age not just life expectancy
- iInadequate or absent services
- outdated and ageist beliefs/assumptions
- medical system designed for single acute diseases
- limited accessibility for those with disabilities
138
Define frailty.
- a physiologic syndrome characterized by decreased reserve and resistance to stressors, resulting from cumulative decline across multiple physiologic systems, and causing vulnerability to adverse outcomes
139
How does frailty develop?
**- genetic factors -\> s**ome people age faster than other people -\> if your parents live to old age, you are much more likely to live to old age
- **environmental factors** (e.g. smoking and alcohol consumption) -\> combine to cause cellular and molecular damage -\> reduced physiological reserves in all the organ systems -\> FRAILTY
- a minor stressor event pushes people beyond their functional reserve -\> cannot cope anymore -\> this often becomes cyclical
140
How can frailty be treated?
- exercise, nutrition and drugs -\> **prevention** is better than cure
- ACE inhibitors may be beneficial in preventing frailty
141
What are the non-specific presentations of frailty?
- falls
- reduced mobility
- recurrent infections
- confusion
- weight loss
- “not coping” at home
- iatrogenic harm
142
How might elderly peoples symptoms change?
o older people are less likely to have “textbook” symptoms of disease:
**- acute coronary syndrome:** less likely to have chest pain - more likely to have SOB
**- PE:** less likely to have pleuritic chest pain, and haemoptysis - more likely to have syncope (fainting)
143
What are the negative impacts of multimorbidity?
- worse quality of life -\> more likely to be depressed
- increased functional impairment
- burden of treatment
- polypharmacy
144
Why do older people take more drugs?
- multimorbidity
- guidelines/QOF/NICE
- undetected non-adherence
- infrequent review
- poor communication
145
What is a comprehensive geriatric assessment?
- a multidisciplinary assessment that leads to an individual, goal based plan
- assesses physical and mental health, functional ability, social situation and environment
146
What physical changes occur to the brain as you get older?
- sulciand ventricles become much more prominent in the older brain
- as we age, we lose both grey and white matter -\> numbers of connections between the neurones are reduced, and the neurones themselves begin to shrink in size slightly -\> see an **atrophic appearance** -\> is completely normal
147
Name some normal cognitive changes in older people.
- processing speed slows
- working memory slightly reduced (e.g. digit spans)
- simple attention ability preserved, but reduction in divided attention
- executive functions generally reduced
- no change in non-declarative memory (e.g. how to do things)
- no change in visuo-spatial abilities
- no overall change in language -\> some reduction in verbal fluency
148
What is dementia?
- progressive, degenerative and irreversible decline in all cognitive functions -\> not just memory but that is often how it presents
- causes loss of memory, impairment of function, loss of executive function, behavioural and psychological changes and lack of insight
149
Can dementia be prevented?
- yes
- exercise, low alcohol consumption, not smoking, healthy diet
150
What are the types of dementia?
- Alzheimer's = MOST COMMON
- vascular dementia = just under a 1/4 of dementia
151
What is delirium?
- an acute, global failure of higher brain function -\> affects level and content of consciousness -\> i.e. alertness and cognition
152
What are the differences between dementia and delirium?
153
What cognitive screening tests exist?
- AMT, clock drawing test, 4AT, GP COG, 6CIT…
- mini Mental State Examination (MMSE)
- Montreal Cognitive Assessment (MOCA)
154
What cognitive diagnostic tests exist?
- Addenbrooke’s Cognitive Examination (ACE)
- detailed neuropsychometric testing
155
What are the general problems with cognitive assessments?
- hearing and visual impairment may limit testing
- physical problems may limit testing (e.g. holding a pencil to draw)
- most assume numeracy and literacy
- most assume some basic cultural knowledge
- depression can masquerade as dementia
- not valid in acute illness
- normal cognitive changes (slower processing speed, slower reaction times) may affect administration
