BCS Flashcards
1
Q
What hormone do sertoli cells produce?
A
Anti-mullerian hormone
2
Q
What hormone do leydig cells produce?
A
Testosterone
3
Q
What is the key part of sex differentiation?
A
Y chromosome, SRY gene
4
Q
What do the primoridal germ cells become?
A
Sperm in men, oocytes in women
5
Q
What do the primitive sex cords become?
A
Sertoli cells (AMH) in men, Granulosa (estradiol) in women
6
Q
What do the mesonephric cells become?
A
Leydig cells in men (testosterone), Theca cells in women (androsteriedione = substrate for estradiol)
7
Q
What are the three ‘waves’ of cells that invade the genital ridge?
A
Primordial germ cells, primitive sex cords, mesonephric cells
8
Q
Outline primordial germ cell migration
A
9
Q
Outline primitve sex cord development - men and women
A
10
Q
Outline roles and future development of mullerian and wolffian ducts
A
Men - wolffian - seminal vesicles and vas deferens Women - mullerian - uterine tubes, uterus, upper 1/3 of vagina
11
Q
Outline the differentiation of the gonad in men and women, cells and hormones involved
A
12
Q
What is the role of DHT in men?
A
Fusion of labial scrotal fold, growth of phallus and prostate
13
Q
What does the lack of androgen in utero do in female development?
A
Leads to vagina, labia and clitoris
14
Q
Define gonadal dysgenesis
A
Sex differentiation is incomplete or gonad development is abnormal
15
Q
Describe partial and complete AIS - Int and external genitalia, role of hormones, effect at puberty
A
Puberty delayed in partial, absent if complete
16
Q
What happens if XY,, makes testosterone, but it doesn’t work?
A
Androgen insensitivity syndrome
17
Q
Whast happens if XY, testosterone is made but not DHT?
A
5 alpha reductase deficiency
18
Q
Describe 5 alpha reductase deficiency - Int and external genitalia, role of hormones, effect at puberty
A
19
Q
What happens if only 45 chromosomes XO
A
Turner syndrome (1:3000)
20
Q
Describe Turner syndrome - Int and external genitalia, role of hormones, effect at puberty
A
21
Q
What happens if XX exposed to high levels of androgens in utero?
A
Congenital adrenal hyperplasia (1:15,000)
22
Q
Describe Congenital adrenal hyperplasia - Int and external genitalia, role of hormones, effect at puberty, difference between XX and XY
A
Pathway block so aldosterone and cortisol are not produced in sufficient quantities, more androgens produced - impact on XX genitalia
23
Q
REVIEW events in sex differentiation with foetal ages
A
24
Q
What is kisspeptin and how does it stimulate GnRH production? How many amino acids?
A
25
How many amino acids does GnRH have?
10
26
Describe the journey made by Kisspeptin and GnRH
27
Describe the importance of pulsaltile GnRH secretion - what is the significance of slow vs rapid frequency pulses?
28
What are the gonadotrophins and what are their structures?
29
What are the three sex steriods?
Estradiol (E2), Progesterone (P4), and Testosterone
30
Describe puberty changes in men and women
31
Describe process of adrenarche - what is happening? What is secreted? At what age is this occurring? Which adrenal steriods are involved? What triggers it?
32
What happens to DHEAS in the body?
Can be converted to testosterone / DHT
33
Describe pubarche - what is it? at what age is it considered early? What other changes are associated?
34
Review relationship between androgens and pilosebaceous units
35
Describe gonadarche - what is it? what is the relationship between gonadarche and foetal development? What triggers its start?
36
Describe epiphyseal fusion
37
What stimulates the onset of puberty? (3 theories)
38
Describe the biphasic effect of eastrogen on epiphyseal growth
39
Define consonance and outline normal progression for boys and girls
40
Review Tanner scale of pubertal development - outline stages 1-5 for boys and girls
41
What are the psychological changes that occur during puberty? (3)
1. increasing need for independence 2. increasing sexual awareness / interest 3. development of sexual personality
42
How do you define a delay in puberty (what age in boys and girls?)
Absence of secondary signs in boys by 14yo and in girls at 13yo (or absence of menarche by 18)
43
Outline causes of pubertal delay
44
Describe McCune Albright syndrome - symptoms
45
Central precocious puberty - what causes it? is consonance maintained? How do you manage it?
46
What causes 33% of cases of central precocious puberty?
47
Peripheral precocious puberty - what causes it? is consonance maintained? How do you manage it?
48
What kind of cells become the egg and sperm?
Primordial germ cells
49
Describe the journey of germ cells to the gonad
First identifiable in yolk sac at 3 weeks, undergo many cycles of mitosis, migrate to genital ridge which becomes the gonads
50
What do germ cells become in the ovary? What are they called once mitosis stops?
Oogenia when in the ovary Primary oocytes once mitosis stops
51
How long does the primary oocyte remain in first phase of meiosis?
Until ovulated or it dies - so maybe 52 years
52
REVIEW mitosis
53
REVIEW meiosis
54
Describe the process of oogenisis and folliculogenesis
55
Where are the primary oocytes in the ovary?
Outer layer, cortex
56
What cells make up the primordial follicle?
57
What is the definition of folliculogenesis?
Growth and development of follicles from the early resting stages in foetus through ovulation
58
What layers are formed around the follicle as it grows? (2 more)
Zona pellucida (acellular) Theca cells
59
What stimulates the follicle growth process?
60
How are follicles generally classified?
Pre-antral (or primary), antral (or secondary), preovulatory / Graafian follicle, ovulatory
61
Are all follicles visible on ultrasound?
No, pre-antral follicles are not
62
Describe the processes of follicle initiation and recruitment
63
Outline the stages of follicle growth - how long does each phase take? how big are they? Is the process gonadotrophin-dependent?
64
Describe role of LH and FSH - what cells do they work on and what is the impact?
65
What is the feedback process of folliculogenesis? What hormones are involved?
66
REVIEW summary of follicle formation and growth
67
What should you consider if some is trying to get pregnant?
HIV / Hep B/STIs Haemoglobinopathy Folic acid - 400 mcg or 5mg Alcohol, smoking, drus Chronic disease management
68
REVIEW reliability stats on various contraceptives
69
Condoms - advantages and disadvantages
70
Caps - types, advantages and disadvantages
71
Fertility awareness - factors used, advantages and disadvantages
72
Combined oral contraception - types
73
Combined oral contraception - basic principles, roles of estrogen and progesterone
74
COCP - benefits
BENEFITS Reliable Safe Unrelated to coitus Woman in control Rapidly reversible Halve ca ovary Halve ca endometrium Helps endometriosis, premenstrual syndrome, dysmenorrhoea, menorrhagia Can stop periods if taken continuously
75
COCP - risks
Cardiovascular - Arterial – Progestogen , HBP, smoking (\>15 and \>35), Venous – Oestrogen-VTE-clotting disorders (DVT, PE, Migraine) Neoplastic - Breast, Cervix, Liver Gastrointestinal – COH/insulin metabolism, Weight gain, Crohn’s disease Hepatic – hormone metabolisms, congenital non-haemolytic jaundices, gall stones Dermatological – Chloasma, acne, erythema multiforme Psychological – Mood swings, depression, Libido
76
COCP contraindications - absolute (13) and relative (5)
Breast cancer; undiagnosed genital bleeding; pregnancy; \<3 weeks post partum; breast feeding; hypertension; PH thrombosis; migraine with aura; active liver disease; thrombophilia; systemic lupus erythematosus; thrombotic thrombocytopenic purpura; smoking \>15 and age \>35 Relative contraindications: BMI\>35;migraine without aura; hypertension; diabetes; hyperprolactinoma;
77
REVIEW COCP interactions and drug which reduce hormone levels
REDUCE Barbiturates Lamogitrine Topiramate Carbamazepine Oxcarbazepine Phenytoin Primidone Rifampicin Griseofulvin Certain antiretrovirals Modafinil INTERACTIONS Lamogitrine (levels reduced by cocp) Ciclosporin (levels reduced by cocp) Potassium sparing diuretics (in drosperidone containing cocp)
78
Monitoring for COCP
Annual BMI and BP
79
Combined vaginal contraceptive ring
Same as COCP except vaginal delivery (ring) for 21 days Remove for 7 days Adv – don’t have to take every day Disadv - don’t have to take every day!!
80
What are the progesterone only methods?
81
What are the principles of the progrogesterone only methods?
82
Describe copper IUD, benefits, disadvantages (not risks)
83
Copper IUD - Risks, absolute contraindications, relative contraindications
84
What is the best option for emergency contraception? How does it work? How far after sex can it be used?
Copper IUD Up to 120 hours after presumed ovulation or 120 hours after one single episode of UPSI at any time of the cycle Failure extremely rare Copper kills sperm in 1st part of the cycle Device prevents implantation in 2nd part of the cycle
85
What pills are available for emergency contraception? How do they differ?
86
Describe the symptoms (7) of the menstrual transition and relate them to the physiology of the menopause.
Reduced cycle length - due to reduced length of follicular phase
Reduced fertility - fewer eggs, cycles may become anovulatory
Heavier periods and breast tenderness - due to high oestrogen
Hot flashes, dry vagina and disturbed sleep - due to decling oestrogen levels
87
Describe treatment options for menopausal symptoms - hot flashes, vaginal dryness, irregular menstrual cycle
Can give low dose HRT (needs to be oestrogen with opposition from prospesterone unless the woman has had a hysterectomy
Can give combo of progesterone and estrogen in form of mirena IUS (or oral) and estrogen patch
SSRIs are sometimes indicated
Topical for vaginal dryness
88
Outline the changes in the hypothalmic axis leading up to menopause
89
What are the physiological (or pathological) changes observed in the lead up to menopause? (4)
Reduced number of follicles
Reduced number of granulosa cells
Loss of granulosa cell function
Increased chromosomal abnormalities of oocytes
90
At age do you have the most eggs in the ovary? How many do you have in menstrual transition?
20-24 weeks - 6-7 million
Puberty - 300,000-400,000
Menstrual transition - 100s
91
What factors contribute to follicular depletion?
Increased apoptosis (which can be increased by smoking)
Accleratied follicular loss (because AMH declines, FSH increases, more follicular recruitment)
Decline in graulosa cell numbers (by about 30%)
Loss of granulosa cell function
Decline in oocyte function and development
92
What is the role of the granulosa cell in menstrual transition?
The produce less inhibin B in follicular phase which allows higher FSH
Anovulatory cycles lead to drop in inhibin A (as no luteal phase) which allows higher FSH
Decrease in FSH receptors prevents recruitment of dominant follicle
Less secretion - GFs, signalling, oestrogen and progesterone
93
What are the symptoms of granulosa cell dysfunction?
94
What is the first hormonal sign of declining ovarian function? What are the other hormonal changes and when do they occur?
95
What factors can affect the age of menopause?
Smoking, ethnicity, geography, mother's age of menopause, several candidate genes, surgery / chemotherapy
96
Describe considerations when prescribing HRT - dosage, risks, contraception, progesterone
Hyperplasia found in 56% of women who take unopposed estrogen, 3% will develop carcinoma (so give 10-13 days progesterone)
97
Describe the different modes of prescribing estrogen and progesterone - risks and benefits of each
98
Discuss the long term risks and possible benefits of HRT in terms of other illnesses
More than 5 years, BC risk goes up (but not as bad as alcohol, obesity\_
May have benefits in alzheimer's - unknown
Improves osteoporosis BUT not if only on for 5 years (give bisphosphonates instead)
No benefits in incontinence
May help with sleep disturbance (by addressing hot flashes)
99
What is menopause?
What is peri-menopause / transition?
Menopause - 1 year without menstruation (retrospective diagnosis) - if woman are under 40, its 'premature ovarian failure'
Perimenopause - 2-8 years pre-menopause
100
101
Outline the HPG axis in terms of the control of the mnstrual cycle
102
What does GnRh have to be pulsaltile? What happens if it's continous? What do slow or fast pulses do?
If continuous, production of LH/FSH stops
Slow - FSH
Fast LH
103
What is happening on day 1 of the menstrual cycle?
Bleeding
104
What is happening in day 1-14 of menstrual cycle? Which hormone is key?
Follicular phase, growth of follicles to prepare for ovulation
Dominated by estrogen (which is produced by follicles)
105
What is happening in day 14-18 of menstrual cycle? Which hormone is key?
Luteal phase, formation of corpus luteum from empty follicle which produces progesterone
106
Outline the HPG feedback through the menstrual cycle - at late luteral/early follicular, mid follicular, mid cycle and mid luteal
When does it change from negative to positive feedback?
At end of follicular phase, E2 levels are raised for long enough (48hr) and at high enough levels (more than 300pM) to switch feedback from negative to positive
107
What is important about the inter-cycle rise and fall of FSH?
Selection of a single follicle - the early rise (during menses) allows one follicle to be selected to grow. The fall in FSH prevents other follicles from growing unnecessarily (fall caused by rise in oestrogen levels which reinstated negative feedback)
108
Once selected, how is the dominant follicle maintained despite the drop in FSH levels?
The dominant follicle gains LH receptors on the granulosa cells - as the LH levels rise, this keeps this dominant follicle stimulated
109
REVIEW cells nad receptors of dominant follicle
110
Outline which steroids are produced by theca and granulosa cells (1 each) and which ones are created by both (3)
111
Describe what triggers the LH surge - what triggers it and what does it cause?
112
Describe process of ovulation - what are the 'cascade of events' occurring?
113
When / why does the follicle complete the first meiotic division? What does it become?
114
Describe corpus luteum formation and its hormone production - how does it differ during pregnancy?
115
Role of corpus luteum secretions, what is its lifespan?
Progesterione supports oocyte in journey, maintains CL, prepares endometrium, controls cells in fallopian tubes, alters cervical secretions
Estrogen - for endometrium
Life span is 14 days (fixed)
116
Potential treatments if issues with mentstrual irregularity
117
What is 'normal' in terms of length of menstrual cycle?
menses - 3-8 days
cycle can vary in length (27-32) but there should not be 4+ day variability month to month
118
What are clinical signs of ovulation?
119
In what part of your cycle are you fertile?
Generally 6 day span - egg lives from 24 hr post ovulation, sperm can live up to 5 days (median is 1.5 days)
120
REVIEW basic anatomy of uterus
121
REVIEW anatomy of uterus, cervix, ovary
122
Why is a newborn uterus larger than 4 year old?
Because newborn female has been effected by maternal steroids
123
Where does fertilisation occur?
Ampulla of uterine tubes
124
What makes the myometrium grow?
Estradiol
125
What layer of the myometrium grows during childhood?
Outer layer
126
What are the layers of the myometrium (3)? and what shape are their fibres?
What are the other layers of the uterine wall (2)?
Inner - circular
Middle - Figure 8 / spiral
Outer - longitudinal
Other layers are endometrium and perimetrium
127
REVIEW layers of endometrium, blood supply
128
What is the amount of endometrium a good indicator for?
Good 'bioassay' of estradiol levels
129
Which endometrial cells are changing throughout the menstrual cycle?
Changes in glandular and epithelial cells through cycle.
130
What does the endometrium look like after menstruation - cell type, thickness
After menstruation - stromal matrix with small columnar cells with glandular extensions 2-3mm thick
glands are simple and straight.
131
Describe the endometrial proliferative phase - what is it stimulated by (and where is this made?)
What occurs to the cells / glands / blood supply (and when are these changes at max levels)
Proliferative phase Stimulated by estradiol from the dominant follicle.
Stromal cell division, ciliated surface. Glands expand and become tortuous, increased vascularity, neoangiogenesis
maximal cell division by days 12-14.
132
At what thickness of endometrium do progesterone receptors develop? And what other process starts?
When endometrium \>4mm induction of progesterone receptors and small muscular contractions of the myometrium.
133
REVIEW overview of follicular and endometrial phases - what are the phases called, which hormones are peaking when?
134
When does the secretory phase of the endometrium start? What stimulates it? What happens to the glands, blood supply, muscle cells?
Secretory phase (luteal phase of ovary) 2-3 days after ovulation, the gradual rise in progesterone (secreted by CL) causes a reduction in cell division.
Glands increase in tortuosity and distend…secretion of glycoproteins and lipids commences.
Oedema, increased vascular permeability arterioles contract and grow tightly wound.
Myometrial cells enlarge and movement is suppressed
blood supply increases.
135
Describe regression of corpus luteum? What keeps it alive? What is its lifespan?
What saves it during pregnancy? What happens if it isn't saved?
Corpus luteum stimulated by LH from pituitary during luteal phase.
The fertilised oocyte becomes a blastocyst and produces human chorionic gonadotrophin (hCG) which acts like LH ie on LH receptor, and ‘rescues’ the CL.
In the absence of this, falling levels of steroid from the CL results in menstruation.
136
Describe menstruation - what day of cycle? What stimulates prostaglandins? What do the prostaglandins do?
How long does bleeding last? How much? What layers remain? What start the next cycle?
Prostaglandin release (caused by drop in progesterone, as CL has died) causes constriction of spiral arterioles. Hypoxia causes necrosis.
Vessels then dilate and bleeding ensues.
Proteolytic enzymes released from the dying tissue.
Outer layer of endometrium shed, 50% lost in 24hrs, up to 80ml is considered normal. Bleeding normally lasts 4+ days.
Basal layer remains and is then covered by extension of glandular epithelium.
Estrogen from follicle in next follicular phase starts cycle off again.
137
What are the sections (4) and cellular levels of the uterine tubes (3)?
138
What changes do the cells in the uterine tubes undergo during the cycle? (2 types of cells)
When in cycle are changes occurring? Role of hormones
Estrodiol before
Progesterone after
139
How long does the fertilied embryo remain in uterine tube?
5-6 days
140
What can cause damage to the uterine tubes? And resulting symptoms?
Damage to lining of the tube by infection, endometriosis, surgery or adhesions may cause blockage or damage to ciliated epithelia, resulting in…
pain
infertility
ectopic pregnancy
141
Describe investiagetions to determine if uterine tube blockage?
Laparoscopy better if you suspect endometriosis or PID as you have view inside
142
What are the parts of the cervix? What is its role? What cells are present (and their role?)?
143
What is happening to the cervix in the follicular phase? What causes this?
Estrogen in the follicular phase causes…
change in vascularity of cervix and oedema
144
What happens to the cervix mid cycle? Why?
Mid-cycle estrogen levels cause change in mucous to become less viscous.
change in mucous composition, contains glycoproteins which become aligned and form microscopic channels and sperm swim up the channels!
145
What happens to the cervix in the luteal phase? Which hormone causes it? What happens to mucus?
Progesterone in luteal phase causes…
Reduced secretion and viscous mucous (reduced water content)
Glycoproteins now form mesh like structure: acts as barrier
One mechanism of action of oral contraceptives.
146
Describe vagina - length / cell types?
Thick-walled tube approx 10cm
Lined by specialised ‘squamous epithelial’ cells
147
Vagina - why is it susceptible to infection AND how does it prevent infection (3)?
Warm damp environment containing glycoprotein…
Susceptible to infection, which is prevented by…
layers of epithelial cells shed constantly and ‘flow’ downwards with the secretions
secretions are from cervix and transudation from vaginal epithelium
secretions change with cycle and are generally acidic providing anti-microbial protection
148
Vagina - Which glands are present - where? and what do they do? what is the equivalent in men?
Bartholins glands located slightly posterior and to the left and right of the opening of the vagina secrete mucus to lubricate the vagina and are homologous to bulbourethral glands in males.
149
What are the layers of the endometrium? (4) Which are shed during menstruation? (2)
* Compactum (SHED)
* Spongiosum (SHED)
* Basalis
* Junctional zone
And then muscle
150
Ouline the stages of menstruation - what initiates it? What are the local mediators involved?
* Initiated by withdrawal of E and P
* Local mediators PG’s (F2a and Tx), PAF (platelet activating factor)
1. Vasoconstriction
2. Ischaemia and tissue damage
3. Relaxation
4. Shedding of functional endometrium
5. And then fibrinolysis / coagulation balance
Menstruation occurs as a consequence of intense vasoconstriction and coagulation in the spiral arteries leading to intense inflammation and partial necrosis, after which the functionalis layer of the endometrium separates from the underlying basalis and is shed with blood
151
What are the different types of prostaglandins? Which is most involved in menstruation?
Pro-bleeding (E+I) - anti-platelet, dilate blood vessels
Anti - bleeding (Tx and F2a) - pro-platelet, constrict blood vessels (this one is most involved)
152
What interleukins are most involved in menstruation? (3)
8, 13, 16
153
What cause the issues with menstruation? Three factors that can be thrown out of balance
Inflammation, coagulation, fibrinolysis
154
What are the most cimmon causes of abnormal vaginal bleeding?
**‘Pathological causes’**
* Fibroids – submucous
* Adenomyosis
* Endometrial pathology – benign adenomas or polyps
- hyperplasia
- carcinoma
•Cervical pathology – polyps
- carcinoma
* Cervical Infection - Chlamydia
* Pregnancy
**DUB - diagnosis of exclusion**
155
How much do submucosal fibroids increase the risk of abnormal peri-menopausal bleeding?
threefold increased risk
156
What are the aims for investigations of abnromal uterine bleeding - what do we need to EXCLUDE first? (4) which methods should be used?
* Exclude pregnancy
* Exclude cervical pathology
* Exclude focal intracavity pathology (polyps, submucous fibroids)
* Consider endometrial pathology (\> 40)
* Use the least invasive method to achieve this
157
Key points in abnormal bleeding history (4) and exam (4)?
HISTORY
* –LMP - was it normal?
* –Regular or irregular periods
* •with bleeding between?
* •heavy- clots, flooding?
* •post coital bleeding?
* •Pain
* –Medication, smoker, smear, operations
* –Contraception - is family complete?
EXAM
* –BMI
* –Abdomen
* •Distension, scars, pain, masses
* –Bimanual
* •Uterine size, adnexal masses, pain
* –Cervix
* •polyps, suspect lesions
158
159
Potential investigations for abnormal bleeding (7) - what do you do, what are you looking for?
* Pregnancy test where appropriate
* Hb if heavy bleeding
* Swabs – endocervical (Chlamydia)
* Cervical smear – only if due
* Transvaginal ultrasound
* Endometrial sampling
* Hysteroscopy - in-patient or OPD
160
Transvaginal ultrasound - what is it good for seeing?
What do you do next if it's abnormal?
* Can assess the relationship of fibroids to the cavity
* Has a high detection rate for polyps
* Assess function – anovulatory cycles
* Can reliably assess structures outside the uterus (tubal and ovarian pathology)
161
What are the 'cut-off' values for endometrial thickness? pre / post menopausal
•Cut-off values for ET are arbitrary in premenopausal women - @ 6 mm post menstrual or 12 mm anytime in cycle
162
Why would you do a hysteroscopy? (3)
* If TVS abnormal
* Non-response to medical therapy
* Multiple risk factors for endometrial pathology
163
What are the types of endometrial hyperplasia? What is the most common cause?
Simple and atypical, usually caused by unopposed estrogen
If atypical, need to investigate further
If simple, give progesterone
164
Treating polyps - 1
Surgery -transcervical resection / polypectomy
165
Treating fibroids - 3
* –Medical Mirena IUS (if only symptom is heavy bleeding)
* –Surgery TCRF/Myomectomy (if many fibroids)
* –Hysterectomy
* •total/subtotal abdominal
* •vaginal
166
Treating DUB - do you need to? what are the options (hormonal 4, non-hormonal 2, surgery 3)
* •Nothing
* •Medical
* –Non Hormonal
* •Anti fibrinolytics 40-50% reduction in blood loss
* •Mefenamic acid 30% reduction in blood loss
* –Hormonal
* •COCP – 20 - 30% reduction in blood loss
* •Progestagens NOT beneficial for loss
* •Use to control cycle length in anovulatory DUB
* •Mirena IUS – 90% reduction
* Surgery
* Endometrial resection / ablation - with radiofrequency
* Hysterectomy
* Remove ovaries?
167
REVIEW treatment algorithm for menorrhagia
168
What is the defition of labour? How can it be diagnosed?
DEFINITION: The process of _uterine contraction_s and _cervical dilatation_ that enables the uterus to deliver the viable fetus (\>24 weeks), placenta and membranes.
DIAGNOSIS: When there are _regular_ & increasing _painful_ uterine contractions that brings about progressive _cervical effacement and/or dilatation_
169
What are the theories regarding the iniation of labour?
PROGESTERONE WITHDRAWAL?
NEURONAL STIMULATION FROM CERVICAL PRESSURE
CRH (corticotrophin releasing hormone) PLACENTAL CLOCK
INFLAMMATORY PROCESS IN CERVIX
170
What are the stages of labour?
FIRST STAGE - THE PERIOD BETWEEN ONSET OF REGULAR PAINFUL UTERINE CONTRACTIONS TO FULL CERVICAL DILATATION (this is difficult to quantify and scientific studies are based on observed first stage of labour)
SECOND STAGE - FROM FULL CERVICAL DILATATION TO DELIVERY OF THE FETUS (usually one hour in the nulliparous & half an hour in the multiparous woman)
THIRD STAGE - FROM DELIVERY OF THE FETUS TO DELIVERY OF THE PLACENTA & MEMBRANES (usually \<15 mins with active management of the third stage of labour)
171
What are the two phases of the 1st stage of labour? Cervical signs, how fast does it usually progress?
**LATENT PHASE** - THE DURATION FOR THE CERVIX TO BECOME EFFACED (FROM 3 CM LONG TO \<0.5 CM) AND DILATED TO 3 CM. WITH REGULAR UTERINE CONTRACTIONS IT COULD TAKE 6-8 HRS IN A NULLIPARA AND 4-6 HRS IN A MULTIPARA
**ACTIVE PHASE** - THE DURATION FOR THE CERVIX TO DILATE FROM 3 TO 10 CM (FULLY DILATED). THE RATE OF CERVICAL DILATATION IS ON THE AVERAGE ABOUT 1 CM/HR
172
What does a partogram do? What factors does it look at?
A graphic representation of the process of labour
* Rate of cervical dilatation
* Descent of head
* Contraction frequency / duration
* FHR
* Liquor colour and quantity
* Caput and moulding fetal head
* Maternal parameters (T, P BP, UO, Urine dip)
173
What is the sinciput and occiput? How to measure descent of head?
Sinciput - front
Occiput - back
174
What are the alert and action lines?
Using partogram to determine if labour is progressing at normal speed
ALERT LINE - A LINE DRAWN AT A RATE OF 1CM/HR FROM ADMISSION CERVICAL DILATATION IN THE ACTIVE PHASE
ACTION LINE - A LINE DRAWN 2 OR 3 CM TO THE RIGHT AND PARALLEL TO THE ALERT LINE
LABOUR PROGRESS TO THE RIGHT OF THE ACTION LINE IS DEEMED TO BE SLOW NEEDING SOME INTERVENTION
175
What are the 3 factors that can slow down labour? Which is commonest?
Passage - is the space big enough?
Passenger - too big? wrong position?
Power - COMMONEST - issue with contractions
176
What issues can slow labour in first stage lead to?
Dehydration / exhaustion
Infection
Fetal distress
Instrumental delivery
Uterine rupture
Postpartum haemorrhage
Maternal / fetal morbitity
Fistula
177
What are the key things in the first stage of labour?
GET THE DIAGNOSIS OF LABOUR CORRECT!
PROVIDE SUPPORT, PAIN RELIEF & HYDRATION
EMOTIONAL SUPPORT IS ESSENTIAL
MIDWIFERY-LED CARE IF NORMAL
BE PREPARED FOR ANY EMERGENCY
CONSULT WHEN REQUIRED
178
What factors may cause a prolonged second stage of labour?
–Nullip vs multip
–Epidural vs no epidural
–Active pushing vs not
–Maternal exhaustion vs distress
–Failure to descend / rotate
179
Management in third stage of labour (6)
IM Syntometrine given to mum with delivery of baby’s anterior shoulder.
Left hand placed above symphysis pubis to guard anterior wall of uterus
Controlled cord traction until placenta is delivered
Placenta and membranes checked for completeness
Estimate blood loss
Check for tears and suture under local anaesthetic if required
180
Issues with third stage of labour (5)
Retained placenta
Postpartum haemorrhage
Perineal trauma: 2nd / 3rd / 4th degree tear
Perineal / pelvic haematoma
Uterine inversion
181
Descirbe the mechanism of labour - what position is the head in?
1. occipito-transverse as it enters pelvis
2. descent with head flexion (looking down)
3. internal rotation to occipito-anterior
4. Extension back (looking up)
5. Restitution - external rotation to align head with the shoulders)
6. shoulders delivered AP
182
What is the ideal number of contractions per 10 mns? How can you speed up or slow down?
4-5 every 10 mins, lasting over 40seconds
If too often, give turbutiline (because cord compressed during contraction, need breaks for nutrients)
If not progressing, can give oxytocin to increase contractions (start with 2-4 and increase in units of 2-4)
183
What time perod is the puerperium? Which systems are changing?
Delivery to Day 42 post-natal
Changes are multifactorial
* –Physical
* –Endocrine
* –Immunological
* –Psychological
* –Social
184
What is the biggest cause of maternal death in the UK?
Thrombo-embolism (others are Pre-eclampsia / eclampsia, Haemorrhage, Sepsis - GAS)
Highest INDIRECT cause of death is CVD
WORLDWIDE 600,000 deaths per year- Haemorrhage by far biggest cause (and then others above)
185
What is the purpose of post-natal care? (5)
- Facilitate and reassure normality for mother and baby including bonding and establishing feeding
- Identify, investigate and manage abnormality
- Consideration during lactation e.g. prescribing
- Provide contraceptive advice
- Make plans for next time!
186
Outline the physical and endocrine shifts post birth? Which hormones are key (4) and what are 4 of the changes?
Involution means pregnant uterus returning to normal
187
Outline the changes to the uterus, CVS, coagulation and metabolism post pregnancy
Uterine involution - autolysis
- pelvis by D10
- bleeding stops (lochia)
- resumption menstruation (HPO axis)
CV changes - CO / TPR / BP
- normal by 2 weeks
Coagulation - fibrinolysis normal within 30 minutes!
- pro-coagulant state remains
(clotting factors increased)
Metabolic - insulin resistance goes immediately
188
What inhibits prolactin pre-delivery?
High estrogen
189
What are the factors involved in lactation post-delivery?
190
What are the components of colostrum (3)? When does the normal milk come in and what are its components (3)?
First 48 hours = colostrum
Major source IgA (mucosal type Ig)
Lysosyme / macrophages
Moderate CHO / FAT (protein)
Day 3-4 = milk
Increased CHO / FAT (protein)
Lactose (glu/galactose)
Lactalbumin / Casein
191
REVIEW pros and cons of breast feeding
192
Outline some issues invovled with lactation - what most commonly causes mastitis? what happens if mastitis goes untreated?
* Failure of lactation - rare
* Cracked nipples and pain - common
* Acute Mastitis
* •usually following cracked nipple
* •Key pathogen = Staph. Aureus
* •Presentation - pain / red, hot breast / fever
* •Mx - maintain feeding or expressing + antibiotics (flucloxacillin)
* Breast abscess
* •sequelae of ignored / untreated mastitis
* •Mx - as above BUT also needs I+D
193
Outline the types of PPH (3) and definition
Blood loss \> 500ml from genital tract
5% - subjective and underestimated
Primary - first 24 hours
Secondary - \>24 hours to 42 days
Tertiary - \> 42 days
Causes significant maternal morbidity (anaemia / Tx)
and mortality
194
Outline the causes (4) and management plans for primary PPH
4Ts and 4Rs
**Causes Management**
* Tone Remedy the cause
* Tissue Replace volume
* Trauma Replace O2 carry cap.
* Thrombin Replace clotting factors
195
What are the risk factors for secondary PPH, how does it present, how do you manage it?
Secondary PPH - endometritis +/- RPOC
Presentation - Excessive lochia / pain / fever
Mx Antibiotics
Analgesia
If no improvement 48 hrs ERPC (evacuation of retained products of conception)
196
When are women at thehighest risk of VTE / PE
Pro-coagulant state continues throughout the puerperium
Highest risk - 10-14 days
Majority - post-partum
Majority - multiple risk factors
VTE BIGGEST CAUSE OF MATERNAL MORTALITY
197
Risk factors for VTE (8)
Prophylaxis options (5)
And management option
RISK
* Obesity
* Older
* Intercurrent illness e.g. infection / PET
* Immobility
* Operative delivery - CS
* Previous TED
* FH TED
* Known thrombophilia
PROPHYLAXIS
Stocking
S/C heparin
Early mobilisation
Adequate hydration
Education
MANAGEMENT
LMWH
198
What is the most common cause of purperal pyrexia?
Infection - but need to find out where
Can be physiological within first 24-48 hrs
BUT if any fever, check for sepsis
ALWAYS CHECK LEGS AND CHEST
199
Outline the three things you give, three things you take out in suspected sepsis
GIVE O2, fluids, broad spectrum antibiotics
TAKE bloods, lactate, urine
200
201
Outline the difference between baby blues, PND, puerperal psychosis
Baby Blues - very common (60 - 70%)
- first 3-4 days
- weepy, labile, helpless
- support and reassurance only needed for most
- short lived and self-limiting
PND - 10% (underestimated!)
- from 4 weeks onwards (“after the event!”)
- spectrum: mild mood disorder to severe clinical depression
- most have risk factors - most common is previous PND or psych history
Puerperal psychosis - rare BUT severe
- usually first 2 weeks
- severe psychotic episodes
- delusions and hallucinations
- serious suicide / infanticide risk
Mx - URGENT PSYCHIATRIC HELP
- Mother-baby units (try + keep together)
- usually self limiting with good outcome
202
What is a 'trophoblast'? What do they secrete?
cells of blastocyst that invade endometrium and myometrium (D 5-6)
secrete ßHCG (Human Chorionic Gonadotrophin)
203
What is the 'chorion'? What is the 'amnion'?
Chorion - becomes placenta
Amnion - becomes amniotic sac
204
Describe the first 5-6 days for a fertilised egg
205
REVIEW hormones of menstrual cycle
206
Which two layers does the trophoblast invade?
Decidua and myometrium
207
When is the 'window of implantation'? When must the trophoblast start producing hCG?
Day 5-6, Day 10
208
What is the significance of βHCG. When does it peak?
* “maternal recognition of pregnancy”
* Maintenance of the corpus luteum – Progesterone production
* Decidualisation under progesterone
* Vital until placental steroidogenesis established
* Maximal by 9 – 11 weeks
209
Difference between urine and serum pregnancy tests
Both BhCG - urine is just qualititative - it is either there or it's not
Serum is quantitative to see if the preganancy is progressing normally
210
What are the functions of the placenta? (4)
* Steroidogenesis – oestrogens, Progesterone, HPL, cortisol
* Provision of maternal O2, CHO, Fats, AA’s, Vitamins, Minerals, Antibodies
* Removal of CO2, urea, NH4, Minerals
* Barrier - e.g. bacteria, viruses, drugs, etc
211
What makes the placenta so effective? (4)
* Huge maternal uterine blood supply - low pressure
* Huge reserve in function
* Huge surface area in contact with maternal blood
* Highly adapted + efficient transfer system
212
Describe the layers of trophoblast that invade wall - which layer is first, second, third?
Syn first, then cyto, then extraembryonic mesoderm
213
Describe the structure of the placenta. What is the functional unit?
Functional unit - cotyledon
214
What is the function of the amniotic cavity? (3)
* Homeostasis - temp, fluid, ions,
* Vital for development of certain structures e.g. limbs, lungs
* Protection - physical and barrier e.g. ascending infection
215
Describe how the amniotic sac develops
216
What are some disorders of the placenta (5)
* •Miscarriage - 15% (40%!?) pregnancies!
* •Pre-eclampsia - 10% pregnancies!
* •Hydatidiform mole
* •Placental Insufficiency
* •Transfer of other substances - drugs, toxins, infections
217
What are some exampels of disorder of the amnion? (3)
* •Polyhydramnios
* •Oligohydramnios
* •Premature Rupture of Membranes
218
What is the role of progesterone in pregnancy? (4)
* •Decidualisation (CL)
* •Smooth muscle relaxation – uterine quiescence
* •Mineralocorticoid effect – cardiovascular changes
* •Breast development
219
What is the role of oestrogens in pregnancy? (4) Which estrogen is strongest? Where are they made?
* E3 \> E2 \> E1
* WHERE? Rely on androgens from fetus and maternal adrenals
* •Development of uterine hypertrophy
* •Metabolic changes (insulin resistance)
* •Cardiovascular changes
* •Breast development
220
REVIEW steroidogenesis - what is the precursor to testotsterone? What starts the whole process?
221
What are the roles of CRH and cortisol? When do they increase? Where are they produced?
* Placental
* Both increase from T2 onwards
* **Cortisol**
* Metabolic changes (insulin resistance)
* Fetal lung maturity
* **CRH**
* possibly involved in labour initiation (“placental biological clock”)
222
What are the roles of HPL and Prolactin? What is HPL structurally similar to?
* **•Human placental lactogen (HPL)**
* •Similar to GH
* •Metabolic changes – insulin resistance
* •Possibly some role in lactation
* **•Prolactin**
* •Increases throughout pregnancy
* •Breast development for lactation
223
What are the objectives of antenatal care? (3)
* **Promote and maintain** the physical, mental and social health of mother and baby by providing education on nutrition, personal hygiene and birthing process
* **Detect and manage** complications during pregnancy, whether medical, surgical or obstetric
* **Develop birth preparedness** and ‘complication readiness’
* **Help prepare mother to breastfeed** successfully, experience normal puerperium, and take good care of the child physically, psychologically and socially
224
Potential drawbacks on antenatal care (6)
* •‘Medicalisation’ of a normal pregnancy
* •Maternal anxiety
* •Unnecessary interventions
* •Doubtful benefit – many ‘age old’ practices
* •Cost – resources, social costs
* •Risk approach is not always an efficient or effective strategy for predicting complications
225
How many antenatal visits?
Low risk - as few as 6
Higher risk may be more than 14
Where depends on what care is needed
226
What is the main objective of the early antenatal ultrasound? When can it be performed? What issues does it help to prevent?
* Detect gestational age - crown rump length
* Between 10-13 weeks
* •Ensures consistency of gestational age assessments
* •Improves the performance of mid-trimester serum screening for Down’s syndrome
* Reduces the need for induction of labour after 41 weeks
227
What test can be used to measure gestational age after 14 weeks?
Pregnant women who present at or beyond 14 weeks’ gestation should be offered an ultrasound scan to estimate gestational age using head circumference or bi-parietal diameter
228
What exams should be done on the women during pregnancy? When and how often? Which exams are not necessary?
Maternal weight and height should be measured at the first antenatal appointment, and the woman’s BMI calculated (weight [kg]/height[m]2) - Repeated weighing during pregnancy should be confined to circumstances where clinical management is likely to be influenced.
Screen for anaemia - early and at 28 weeks
Routine breast examination during antenatal care is NOT recommended for the promotion of postnatal breastfeeding
Routine antenatal pelvic examination is NOT recommended
229
What blood screening should be offered in pregnancy?
Blood group and RhD status
If a pregnant woman is RhD-negative, her partner should be offered testing to determine whether the administration of anti-D prophylaxis is necessary
It is recommended that routine antenatal anti-D prophylaxis is offered to all non-sensitized pregnant women who are RhD negative
230
What is the purpose of the second routine ultrasound scan?
Pregnant women should be offered an ultrasound scan to screen for structural anomalies, ideally between 18 and 20 weeks’ gestation
231
Which infections are screened during pregnancy?
Rubella, HIV, Hep B, Syphilis
UTI check at every appointment
NO SCREENING for Hep C, Chlamydia and GBS
232
What are the tests needed to confirm pre-eclampsia?
Proteinuria and high BP
233
What dietary supplements should be given during pregnancy? For how long?
Folic acid (400mcg)
Vitamin D
Only the first 12 weeks ideally, and 3 months before
234
REVIEW schedule of prenatal visits
235
How do you determine the likely due date?
Last menstrual period - LMP – Add 7 days and 9 months (Naegle’s rule) - (The periods have to be 28 days – if not allowance should be given for irregular cycles, long cycles, lactation, use of contraceptives, early bleeding etc.)
236
How do you determine the age of the fetus during the second trimester?
Fetal biometry - head circumfrence, femur length, bipareital diameter (but has 2-3 week margin of error)
237
What causes maternal changes during pregnancy - general (3)
* »High levels of steroids
* »Mechanical displacement
* »Fetal requirements
238
Which hormones cause most of the maternal changesduring pregnancy? (4 types, 10 hormones)
* placental peptides
* hCG, hPL, GH
* maternal steroids
* placenta takes over ovarian (CL) production around wk 7
* placental and fetal steroids
* progesterone, oestradiol, oestriol
* Maternal and fetal pituitary hormones
* GH, thyroid hormones, prolactin, CRF
239
During which week does the placenta take over maternal steriod production?
Week 7
240
Outline the gain in weight during pregnancy
Recommended maximum weight gain?
* Fetus plus placenta 5 kg
* Fat and protein 4.5 kg
* Body Water (this is excluding that in other listed structures) 1.5 kg (intravascular, interstitial, intracellular)
* Breasts 1 kg
* Uterus 0.5- 1kg
* Ideally keep to less than 13kg: failure to gain or sudden change needs monitoring
241
Where is the majority of the fat and protein gained stored?
Anterior abdominal wall
242
What is the recommended increase in calorie consumption during pregnancy? What percent is for the fetus/uterus?
* »350 kcal/day mid gestation
* »250 kcal/day late gestation
* 75% fetus and uterus, 25% respiration(H&L)
243
When does the fetus need increased availability of glucose during pregnancy? Where does the fetus store some of the glucose?
2nd trimester, liver
244
What changes occur to glucose production in the mother during prgnancy? When?
* 1st Trimester
* Maternal reserves
* pancreatic b cells increase in number
* plasma insulin increases
* fasting serum glucose decreases (laid down as stores and used by muscle)
245
What changes occur to the fetal reserves of glucose during the 2nd trimester? What can go wrong?
* hPL causes insulin resistance ie less glucose into stores =increased availability in serum glucose (more crosses placenta)
* BUT can cause diabetes
246
What acts on RAAS system to increase water retention?
E2 and Progesterone
247
What causes water gain during pregnancy (4)? What is the average amount gained?
Sodium retention,
resetting of the osmostat,
decrease thirst threshold,
decrease in plasma oncotic pressure (albumin)
8.5L
248
Why and how does oxygen consumption increase during pregnancy?
249
What happens to maternal blood during pregnancy?
* Plasma volume increases (so do RBCs, but by less of a proportion so concentration of Hb falls)
* Increased efficiency of iron absoprtion from gut
* White cells go UP but immunocompromised
* Clotting factors increase so hypercoaguable (there is increased fibrinogen for placental separation but increased risk of thrombosis)
250
What are the CVS (HEART) changes the occur during pregnancy? (5)
* expanding uterus
* »pushes heart round
* »changes ECG and heart sounds
* increased cardiac output
* »increased heart rate and stroke volume
* »begins as early as 3 weeks to max 40% at 28 weeks
* »for maternal muscle and fetal supply
251
What are the CVS (VESSELS) changes the occur during pregnancy? (4)
Increased **cardiac output** and **vasodilation** by steroids= **Reduced peripheral resistance.**
Increased flow to :
* • uterus
* • placenta
* • muscle
* • kidney and
* • skin
**Neoangiogenesis**….including extra capillaries in skin (spider naevi) to assist in heat loss
252
Outline the changes to the GI tract during pregnancy?
* appetite and thirst
* reduced GIT motility (leading to constipation)
* relax lower oesophageal sphincter (leading to acid refleux, which is made worse by the large uterus)
253
How doees the urinary system change during pregnancy?
254
When do pregnant women have to pee more (which trimester)
First and Third, during second the uterus is lifted out of the pelvis
255
What are the changes to the uterus during pregnancy?
256
What are the changes to the cervix during pregnancy? (4)
* primary function is to retain the pregnancy
* increase in vascularity
* tissue softens from 8 weeks
* »changes in connective tissue
* »begins gradual preparation for expansion
* proliferation of glands
* »mucosal layer becomes half of mass
* »great increase in mucus production
* »protective..ie anti-infective
257
Describe the process of everything returning to normal post pregnancy
* Dramatic and rapid fall in steroids on delivery of the placenta
* Most endocrine-driven changes return to normal rapidly
* Uterine muscle rapidly looses oedema but contracts slowly: never returns to pre-pregnancy size
* Removal of steroids permits action of raised prolactin on breast
258
REVIEW the structure of chromosomes - how many chromosomes do humans have?
Histones are highly positively charged proteins that are attracted to the negative charge of DNA. Imagine this like coiling a garden hose up; in takes up less room to store than if you leave the garden hose out stretched. But it requires energy to coil that hose up and essentially that is what histones supply. They give the DNA a support to wrap around
A chromosome is an organized package of DNA found in the nucleus of the cell. Humans have 23 pairs of chromosomes--22 pairs of numbered chromosomes, called autosomes, and one pair of sex chromosomes, X and Y. Each parent contributes one chromosome to each pair so that offspring get half of their chromosomes from their mother and half from their father.
259
What do chromosomes usually exist as?
Chromatin (DNA wrapped around histones)
260
What is a nucleosome?
fundamental unit of DNA – eight histones and two turns of DNA
261
REVIEW structure of histone
262
What is euchromatin vs heterochromatin?
* **•Euchromatin**
* Extended state, dispersed through nucleus
* Allows gene expression
* **•Heterochormatin**
* Highly condensed, genes not expressed
Significance for staining
263
REVIEW what occurs to the chromome during s phase - how many chromosomes present?
264
What are the definitions of metacentric, submetacentric and acrocentric chromosomes? What is the clinical significance?
* •Metacentric
* •p & q arms even length
* •1-3, 16-18
* •Submetacentric
* •p arm shorter than q
* •4-12, 19-20, X
* •Acrocentric
* •Long q, small p
* •p contains no unique DNA
* •13-15, 21-22, Y
* TRISOMY MORE COMMON OF ACROCENTRIC
265
Define haploid, diploid, polyploid, aneuploid - what types of cells?
* •Haploid
* •Single copy of each chromosome (n=23) e.g. gamete
* •Diploid
* •Two copies of each chromosome (2n=46) e.g. somatic cell
* •Polyploid
* •Multiple complete sets of chromosomes e.g. triploidy (3n=69)
* •Aneuploid
* •Extra or missing chromosomes, not exact multiple of haploid number e.g. trisomy 21 (2n+1 = 47)
266
At what stage in the cell cycle are cells used for karyotyping?
Metaphase
267
What is the goal of MITOSIS? Describe the process
To form two identical cells, with 46 chromosomes
268
What is the goal of MEIOSIS? Describe the process
Meiosis is the formation of egg and sperm cells. In sexually reproducing organisms, body cells are diploid, meaning they contain two sets of chromosomes (one set from each parent). To maintain this state, the egg and sperm that unite during fertilization must be haploid, meaning they each contain a single set of chromosomes. During meiosis, diploid cells undergo DNA replication, followed by two rounds of cell division, producing four haploid sex cells.
STARTING CELL IS GERM CELL, END CELL IS SPERM OR EGG
269
REVIEW mitosis and meiosis - side by side
270
When does 'crossing over' occur? What are its other names?
Meiosis 1, Metaphase
chiasma formation, crossing over, recombination
271
What is being pulled apart in meiosis 1? What is being pulled apart in meiosis 2?
1: Homologues
2. Sister chromatids
272
What are the two types of chromosomal abnormalities that can occur? How can they be detected?
Numerical (traditional karyotyping, FISH, QF-PCR) or structural (traditional karyotyping, FISH)
273
Possibly autosomal aneuploidy conditions (3)
* Trisomy 13 - Patau Syndrome
* Trisomy 18 - Edward Syndrome
* Trisomy 21 - Down Syndrome
274
Possibly sex xhromosome aneuploidy conditions
* •47 XXY - Klinefelter
* •45 XO - Turner Syndrome
* •47 XYY
* •47 XXX – Triple X syndrome
275
Why do aneuploidies occur?
Non-disjunction during Meiosis 1 or 2
276
Describe G-banding - which enzyme is used? Which stain is used? What can it show? Significance of the bands?
* •Controlled digestion of chromosomes with **trypsin**
* •Stain with **Giemsa**, a DNA binding chemical dye
* Takes several days
* Need metaphase chromosomes
* Can detect aneuploidies, translocations & very large deletions but NOT small changes
* •Produces alternating light (GC rich) and dark (AT rich) bands
* •Banding pattern allows chromosome identification
* •2 different sorts: euchromatin & heterochromatin
* •Euchromatin = GC-rich; loosely packed; genes active
* •Heterochromatin = AT-rich; tightly packed; genes inactive
* •Stain differently
277
What is FISH testing? When is it used? How long does it take
Fluorescence in situ Hybridization: FISH
* •Requires probe specific to desired DNA sequence e.g. specific locus
* •Probe labelled with fluorescent dye
* •Probe hybridized to metaphase spread
* •Expose to UV to visualize fluorescence
* Often used in cancer diagnosis
* Takes several days
* Need to know what you are looking for! (in traditional kind)
278
279
What are the 4 areas of assessment of child development
Gross motor
Fine motor and vision
Communication and hearing
Social and interactive / play
280
REVIEW progression of gross motor skills (image 0-12 months)
281
What is normal gross motor progression for a 3month old? 6month old? 9 month? 12 month? 2 years?
* 4m- lifts head and shoulders, weight on forearms, can turn to sides
* 6m - arms extended, chest off couch,rolling front to back
* 9m - crawling position, roll from both ways
282
Describe a physical sign of DMD?
Gower sign
283
What are RED FLAGS for gross motor delay? examinations to rule things out?
Red flags
* Regression – neurological / neuro-degenerative
* Motor delay with visual/hearing and balance problems
* Other possibilities: Low muscle tone , severe Hypermobility of Joints, Hip , Nutritional Rickets, Hypothyroidism, systemic illness
* Poor motor coordination- Ataxia, neurological , muscular problems
* Autism- posturing, tip toe gait; repetitive climbing , spinning or body movement
* Atypical pattern – DMD , CP
Examine Hips, CNS-gait, muscle tone and reflexes
Check CPK (for DMD)TFT (for hypothyroid) and other test as indicated
284
What factor can affect fine motor development?
Visual impairment
285
When is abnormal to see hand preference BEFORE?
18 months
286
What is Developmental Co-ordination Disorder (DCD)?
Isolated difficulties in motor planning, balance and co-ordination
287
Describe the progression of fine motor skills? When should they transfer object between hands? Have a mature pincer grasp? Build a three block tower? Draw a cross?
288
When do babies spontaneously open hands? Regard their hands, play with feet?
3, 5, 5 months
289
When do children start casting? When can they draw a circle, cross, triangle?
1 year
3,4,5 years
290
Describe the progression of languages milestones - what are they doing at 3m, 6 months, 12 months? When do they ask questions? Tells stories?
291
What are some examples of atyplical speech and language development (6)
* Regression –, (transient or permanent?)
* \<3 years -commonly seen ? SCD; - Neurodegenerative disorders
* \>3 years ; Rare seizure Landau Kleffner syndrome
* Rett’s syndrome
* Echolalia – normal part of development but if it is persistent excessive - ?ASD
* Phonological disorder / Unclear speech – Check for ? High frequency HL / Glue ears? / cleft palate / bifid uvula
* Speech and motor difficulties – muscular problems / DCD
* No speech at 3 years – severe autism / hearing loss
* Selective mutism
292
Provide examples of social and adaptive milestones - what is normal at 3months, 6 moths, 12 months, 18 months, 4 years?
293
Examples of social behavious in a 6month old
* •Smiles at mirror image
* •Stretches arms to be lifted
* •Shows displeasure on removal of a toy
* •Fear of strangers
* •Object permanence
294
Examples of behaviours in a 9 month baby?
* •Plays peek a boo
* •Shows interest in picture books
* •Understands ‘no’
* •Anticipated actions in nursery rhymes
* •Repeats performance being laughed at
* •Waves bye-bye
* •Responds to word Eg “Where’s daddy?”
295
What 2 types of play are occurring by 2 years old? By 3-4 years? By 5?
* parallel and pretend play
* role-playing and interactive play
* Complex interactive games by 5
296
Overview - what are the developmental warning signs at each age?
* At any age – Parental concerns, discordant development, asymmetry, regression
* At 10 weeks – No social smile
* At 6 months – Persistent primitive reflexes , no interest in people, noise, hand preference
* At 8 months – Not sitting
* At 12 months – No pincer grasp
* At 18 months – Not walking, no words, drooling, mouthing
* At 2 years –No phrases, not interactive
* At 4 years – Unintelligible speech
297
Components of a developmental asessment history?
* Parental concerns
* Birth history
* Prenatal – AN scans, drugs, alcohol, maternal infections
* Perinatal – Prematurity, HIE, NICU admission, meningitis, sepsis, jaundice
* Past Medical History
* CNS infections, injuries, epilepsy, co-morbidity
* Developmental history
* Family/Social History
298
How common are developmental delays? What is a 'global' delay?
* Developmental difficulties occur in approximately 5–10% of the childhood population
* Specific/Global
* Global developmental delay - significant delay in two or more developmental domains
* Global delay prevalence - 1–3% of children \< 5 year
299
What does a GDD become after the age of 5yo? What are the three criteria of this diagnosis?
Intellectual disability
1. Deficits of intellectual functions (reasoning, planning, judgment, learning, etc.)
2. Deficits in adaptive functioning (not as independent / responsible as you ould expect for their age)
3. Onset during the developmental period
NOT DETERMINED BY IQ, but by levels of adaptive functioning
300
What are the assessments and investigations of GDD?
Assessment:
* Clinical history
* Family history
* Developmental history - Reports from nursery, speech therapist
* Developmental examination
* Full Physical examination including Dysmorphologic examination
* Neurologic examination
* Growth including head circumference
Investigations:
* Genetics – Array CGH/Fragile X
* Thyroid functions
* Creatinine kinase (all musclular dystrophies)
* Metabolic investigations (if indicated)
* MRI (if indicated)
301
What are the physical characteristics of Down's syndrome?
* Hypotonia
* Small nose and flat nasal bridge
* Small mouth with a tongue that may stick out
* Upward slanting palpebral fissures
* Epicanthl folds
* A flat back of the head
* Broad hands with short fingers
* Single palmar crease
* Below-average weight and height
302
Descrive QF-PCR - what is it good for finding?
Quantitative Floresence PCR uses microsatellites (varying lengths of CA dinucleotide repeats with specific ends) to locate how many chromosomes there are - used in trisomies 13, 18, 21 (and other aneuploidies)
QUICKER than other methods
BUT you need to know what you are looking for (to use the right microsattelite)
Total length of the microsatellie varies so you can see if peope are heterozygous or homocygous based on results
303
Describe the different causes / types of Down Syndrome (3)
Trisomy due to non-disjunction in meiosis (PICTURE) (95%)
Translocation - Robertsonian (4%) - generally translocation with chromosome 14 resulting in 2 and a bit chromosome 21
Mosiacism (1%) - mixed cell liknes, happens post-zygotically (forms a mosiac blastocyst), milder
304
Describe monsomic conditions - sex and sutosomal - are they common? Which conditions? How do they happen?
* •Autosomal are very very rare, found one case report from 1967
* •Relatively common sex chromosome monosomy = Turner’s
* •Full monosomy arise by non-disjunction in meiosis I or II
* •Mosaic arises by non-disjunction in mitosis
* •Partial monosomy (microdeletion syndromes) far more common – mechanism different (not non-disjunction)
* –One full copy of X chromosome, one missing a chunk!
305
Summary of numerical abnormalities - autosomal, sex-linked
How do they happen?
* •Types (all can be mosaic)
* –Autosomal
* •Trisomy 13, 18, 21
* –Sex chromosomes
* •XO, XXY, XXX, XYY
* •Mechanism
* –Nondisjunction
* –Robertsonian translocation – what’s this?
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What is a translocation? What are the two types? How common are they and what is the implication for offspring?
* •Two chromosomes sustain break and are incorrectly joined
* •Translocations may be:
* •**Reciprocal** (between two non-homologous chromosomes)
* •**Robertsonian** (between any two acrocentric chromosomes)
* •About 1 in 500 of us has a translocation
* •Carriers of balanced translocations generally ok BUT can produce unbalanced gametes
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What is a balanced vs unbalanced translocation?
* •Balanced = have the right amount of each chromosome just maybe not in the expected place!
* •Unbalanced = too much or too little of a particular chromosome
EXCEPTION to balanced being okay - WHEN THE NEW CHROMOSOME NOW HAS TWO PROTO-ONCOGENES. the Philadelphia chromosome arises due to a translocation between chromosomes 9 and 22. On chromosome 9 is a gene called ABL1 which is a proto-oncogene. When positioned correctly on chromosome 9, it is not harmful. On chromosome 22 is a gene called BCR (which stands for breakpoint cluster region). There is a relatively high frequency of translocation events between these two chromosomes which result in a new fusion gene being formed on the derivative chromosome which is mainly chromosome 22 plus the terminal chunk of chromosome 9 which contains ABL1. This fusion gene, BCR-ABL1, is oncogenic and is the cause of many cases of chronic myeloid leukaemia.
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Describe the possible outcomes of children of balanced translocation carriers (when partner has normal gametes)
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What is the chromosomal result of robertsonian translocation
45 rather than 46 because you have lost the small tops of two and the longer bottom bits have fused (losing top bit often okay, because this genetic material is superfluous)
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Describe the three types of chromsome shape - which are the acrocentric chromosomes? What is the significance of these? What is the significance of a 'centromere'?
311
Outline how a Robertsonian translocation may result in Trisomy 21 in thier children (so parent is balanced carrier)
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What are the possible outcomes of translocations? (3) Can you predict them?
* •Very difficult to predict
* –Only have approximate probability of producing possible gametes
* •Some unbalanced outcomes may lead to spontaneous abortion of conceptus so early that not seen as problem
* •Some unbalanced outcomes may lead to miscarriage later on and present clinically
* •Some may result in live-born baby with various problems
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Provide examples of other types of structural changes that can occur (4)
* The first two are deletions, either from the end of the chromosome or from within a chromosome
* If the end of the chromosome is lost then the only way the chromosome can be made stable is if a new telomere is added; without the telomere the cell will die
* Inversions and duplications are literally as they’re described:
* An inversion is where there are two breakpoints within the same chromosome and when these are repaired the middle section is “upside down”
* A duplication is where you get a region of the chromosome repeated – you’ll probably be familiar with this in terms of the globin gene family
* A ring chromosome is where you get two breaks in the same chromosome and then the non-homologous end joining mechanism (technical term for when broken ends of the same or two different chromosomes get stuck together) joins the two ends of the large chunk together, resulting in a ring.
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How common are chromosomal deletions? What are the two types? What is the result? What tests can you use to see them?
* 1:7000 live births
* Deletion may be terminal or interstitial
* Causes a region of monosomy
* Haploinsufficiency of some genes
* Monosomic region has phenotypic consequences
* Phenotype is specific for size and place on deletion
* Gross deletions seen on metaphase spread on G-banded karyotype
EXAMPLE: Di George syndrom (22q deletion)
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Describe what you would see on a FISH analysis of Cri-du-chat syndrome. How does FISH work?
5p-minus syndrome
(Left pic is G-banding, right is FISH)
YOU WOUD SEE NO FLUORESENCE ON ONE OF THE CHROMOSOMES
HOW FISH WORKS: A probe (a strand of DNA) is designed specifically to be complementary to part of the region deleted in 5p minus syndrome. The probe has a fluorophore attached which will glow under UV light. The probe will only anneal (bind to it’s complementary sequence) if that specific bit of sequence is present; otherwise it will be washed away. This shows the probe glowing yellow under UV on one copy of chromosome 5 but not on the other copy. And that is because that region simply isn’t there. So this shows that that region has been deleted.
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What tools should you use to visualise large structural abnormalities (translocations, inversions, rings, large deletions / duplications)
G-banding (metaphase spread) and FISH
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What is a microdeletion? What causes it? Three common examples
* Small deletions not seen on standard karyotype, use array comparative genomic hybridisation
* Unequal cross-over in meiosis I causes a gain or loss of a few genes
* Common deletion syndromes (typically developmentally delayed)
* Wolf-Hirschhorn, 4p16
* Williams, 7q11
* Di George, 22q11
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What test should you use to check for microdeletions? How does it work?
Array-CGH is how we can detect microdeletions and microduplications.
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Explain briefly how abnormal karyotypes may be detected using stained metaphase chromosomes, FISH and qfPCR
G-banding relies on differential staining of eu- and hetero-chromatin; FISH uses specific fluorescent probes; QFPCR is a quick molecular technique which amplifies specific chromosomal regions
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Outline how abnormal chromosome numbers or structures arise and state the karyotypic consequences
meiotic non-disjunction, mitotic non-disjunction, chromosomal breaks and incorrect repair, unequal crossing over in meiosis
321
Outline the clinical application of array CGH in the diagnosis of developmental delay and microdeletion syndromes
dosage-based analysis comparing patient with healthy control genome using fluorescent probes
322
Describe the structures / components of an early fertilised zygote (pre-cleavage)
323
How many polar bodies are in the fertilised zygote? When did these form?
324
Describe cell fate and give overview of how cells receive their fate. Consider what else can change cell fate
* By the progressive, sequential, restriction of cell fate
* A cell’s fate is determined by its gene expression
* Cell fate in embryos is specified by signals from surrounding cells
* Signals® receptors® transduction pathways® transcription factors® gene expression® switch in cell fate
* Long-term changes are fixed by epigenetic modification (but can be reversed!)
325
REVIEW restriction of cell fate - what does the inner cell mass develop into (2)
326
How many cell fate decisions are made pre-implantation?
In mammalian embryos, two cell fate decisions are taken before implantation.
Trophoectoderm, Inner cell mass, Primitive endoderm and epiblast
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Provide a simple overview of jounrey - ovulation, fertilisation and cleavage. What cell types are in the blastocyst?
* •At ovulation, a single (usually) oocyte is released
* –Guided by the fimbriated infundibulum into the ovarian tube
* •Fertilisation usually takes place in the ampulla region
* –Reductive/cleavage divisions (~16-24h) occur within the rigid, zona pellucida
* •Early blastomeres (cells) are totipotent (can give rise to ALL tissue) and the embryo can regulate (eg baby born from 5-cell embryo)
* –Blastomeres become progressively restricted in fate – pluripotent, multipotent etc
* •Morula (~12-16 cells) undergoes compaction and a cavity forms (blastocyst)
* •Blastocyst consists of TE and ICM
* –The blastocyst must hatch from the zona pellucida before implantation, TE forms trophoblast
328
What is the clincial significance of pre-implantation development? (4)
IVF
Pre-implantation diagnostics
Stem cell - research and therapeutic
Cloning
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What is the role of the zona peullcida in ectopic pregnancy?
It should prevent it from occurring as it provides a barrier to implantation pre-hatching (which should occur as zygote enters uterus. Early partial or full hatching may result in ectopic pregnancy
330
Describe the relationship between the epiblast, hypoblast, blastocoele and amniotic cavity during implantation
331
What does the blastocoele become? When? What is also developing at this time?
Yolk sac, day 14
Extraembryonic coelom around the outside (chorionic cavity)
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Describe the process of implantation - cell layers, differentiation of cell types, which cavities form
* •The syncytiotrophoblast surrounds the embryo
* –Invasion into uterine wall similar to metastasis
* –Trophoblast synthesises hCG (chorionic gonadotrophin)
* –Circulating hCG maintains the corpus luteum to secrete progesterone, maintain pregnancy
* •The ICM divides to generate epiblast (ectoderm) and hypoblast (extra-embryonic endoderm/primitive endoderm)
* –Two cavities are formed – amniotic and chorionic
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Once implantation has occurred what is the embryo ready to start?
Gastrulation
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What is imprinting?
Differential regulation of maternal/paternal genes
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What is the clinical significance of implantation? How many implant successfully? Where does it usually occur?
* Implantation usually in posterior uterine wall
* Morning-after pills (RU486) & IUDs interfere with implantation
* 70% of blastocysts implant
* –40% abort over week 2
* –15% abort over week 3
* •About 50% of spontaneously aborted embryos are chromosomally abnormal
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What is a hydaditiform mole?
•Expression of paternal genes only results in hydaditiform mole
–Contains trophoblast cells only, no embryo (but can be partial)
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Describe the early steps of gastrulation - what do the epi and hypoblast become? What transformation does the epiblast undergo?
* Primitive groove forms, then streak (thickening of epiblast/ectoderm) in mid line of embryonic disk
* Epiblast undergoes epithelial-mesenchymal transformation and cells migrate between epiblast/hypoblast to generate mesoderm and endoderm
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What is formed by the ecto, endo and mesoderm?
* Endoderm (inside)
* –Linings: epithelium of GI, urinary and respiratory tracts, epithelial parts of liver, pancreas, thyroid
* Ectoderm (outside)
* –Neurectoderm
* •Neural tube (CNS & spinal cord)
* •Neural crest
* –Surface ectoderm
* •Epidermis, hair, nails, internal ear, lens, enamel
* Mesoderm (middle)
* –Paraxial: somites – muscle, skeleton
* –Intermediate: urogenital
* –Lateral: Heart, spleen, blood
* –Head: skull, dentine
339
Describe different ways monozygotic twins can develop (4) - how common is each type? approx which day does the split occur?
340
Describe the process of neuralation - what is being formed? when does this occur?
* •The whole brain, spinal cord, cranial and spinal nerves all form from the neural tube
* •The cranial and spinal ganglia form from the neural crest (part of the neural tube)
* •This takes place at the end of week 3 and all of week 4
* –Often prior to detection of pregnancy
## Footnote
**This forms in the sequence: neural plate \> neural groove \> neural folds \> neural tube (and neural crest migration)**
341
REVIEW first steps in neurulation - what is the role of the notochord?
342
What day should the neural tube start to close? What covers the tube?
343
What is occurring at the same time as neuralation?
Gut formation, body folding ('silk purse' model)
344
What are the 3 types of error that can occur from improper neural tube closure?
* Anencephaly
* Craniorachischisis
* Spina bfida
345
Which closures are associated with each condition? Which days are these closures occuring?
346
What are the four variations of spina bfida?
* –Occulta (unfused vertebral arches)
* –Meningocoele – meninges protrude
* –Meningomyelocoele – meninges and nervous tissue protrude
* –Myeloschisis aperta – open spinal cord
347
What causes neural tube defects? How common are they? How can you test for them in pregnancy?
* CAUSE:
* Genetic - single or polygenic
* Environmental - drugs, geography?
* FOLATE, malnutrition
* Multifactorial likely
* Most common CNS malformation (between 0.5-2/1000 pregnancies)
* TEST: Leakage of Alpha Fetoprotein (AFP) associated with NTDs
* –Measure serum levels ~15 weeks
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Describe the closure of neural tube in respect to the notocord - what does it induce?
median hinge points
BETTER GENETIC UNDERSTANDING WOULD HELP US FIGURE OUT WHY THIS PROCESS SOMETIMES GOES WRONG
349
Outline the cell types, structures and organs developed from ECTODERM
350
Describe the process of convergence - extension: why does it happen? Which days?
A process of lengthening by narrowing, which requires cells to become polarized, in the plane of the cell layer
Lengthening of the neural plate is required for neural tube folding
351
How effective is folate in preventing NTds? What else does it help prevent? Why does it have these effects? One other supplement that may have this effect
* •Up to ~70% of NTDs can be prevented by folate
* •Only known intervention preventive for any congenital anomaly
* •Probably no adverse effects
* •Also reduces palate & heart defects
* •Folate is involved in one-carbon (1C) metabolism
* Human mutations of genes in this pathway lead to increased NTD risk
* •Other supplements?
* –Inositol shows promise
352
Describe somitogenesis - what is it? What layer does this process originate from?
Mesoderm
Skeleton, muscle and •relationships of bone to muscle to nerve to blood vessels along the trunk AND skin to nerve
353
Where does the somite originate from (which layer)? What are the four types of somite?
+ syndetome
354
What are the FOUR things that the epithelial somites differentiate into?
* –Sclerotome: vertebrae and ribs
* –Myotome: epimere, hypomere, limb muscle
* –Dermatome: dorsal dermis
* –Syndetome: tendons
355
Describe the origin of the vertebra, muscle, nerve relationship
& then with skin (dermatome on top and tendons between vertebra and muscle
356
REVIEW origins of the dermatome - what is an example of clinical significance (condition that presents along a dermatome)
Shingles
357
Define Teratogenesis - what is the most common type of anamoly? What is the most common cause? How many classes of known human teratogens? What is most potent? second?
* •The causes of congenital malformation
* –From teratos – Greek: “monster”
* •2-3% births have a structural anomaly
* –**Cardiovascular most common**
* –Functional and late onset disease - % unknown
* •Structural: ~**50% genetic,** ~10% environmental, ~40% unknown – polygenic and/or gene-environmental interactions
* •~20 classes of known human teratogen
* –Some receptor mediated
* –Of all toxicants, relatively few are teratogens
* Most potent: Thalidomide
* SECOND: Retinoids
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REVEIW: When is it most dangerous to be exposed to a teratogen? What defects are most common at each stage?
359
What are the 10 questions that make up the Abbreviated mental test score (AMTS) test? What is the purpose? and what is the significance of a high or low score?
1. How old are you?
2. WHat time is it (to nearest hour)?
REMEMBER ADDRESS - 42 West Street, have them repeat it
1. Who is that perosn (indicating to nurse or doctor)? What do they do?
2. What year is it?
3. What is the name of this place?
4. What is your date of birth?
5. What year did WW1 start?
6. Who is the present monarch?
7. Please count backwards from 20 to 1
8. Could you please tell me the address I told you early
