1
Q
Where are the various sites of metabolism within the body? (HINT: there’s 7)
A
- gut lumen
- gut wall
- plasma
- lungs
- kidneys
- nerves
- liver
2
Q
Drug metabolism mainly occurs in the liver in 2 phases, what are the 2 phases? Describe them.
A
Phase I Metabolism
- generally oxidation, reduction or hydrolysis (introduce/reveal reactive chemical group, “functionalisation”)
- products are often more reactive
Phase II Metabolism
- synthetic, conjugative reactions
- hydrophilic, inactive compounds usually generated
3
Q
What are the types of reactions which occur in (i) phase I (ii) phase II? List as many as you can.
A
(i) oxidation, reduction, hydrolysis, hydration, dethioacetylation, isomerisation
(ii) glucuronidation/glucosidation, sulfation, methylation, acetylation, amino acid conjugation, glutathione conjugation, fatty acid conjugation, condensation
4
Q
What is the mixed function oxidase system (CYP450s)? What does it consist of? What does it require?
A
Microsomal ER enzymes - liver, kidney, lung, intestine etc
Consists of :
- cytochrome P450, NAPDH-CYP450 reductase and a lipid
Requires: molecular oxygen and NADPH
5
Q
Many enzymes are capable of metabolising drugs and there is overlapping of substrate specificities, what is there potential for?
A
Competition and saturation
- drugs and endogenous compounds for same enzyme
- different enzymes for the same substrate
- enzyme can be saturated, conjugate depleted
6
Q
With regards to drug metabolism, what are there issues of?
A
Variation/induction/inhibition
- inter individual responses can vary
- substantial issue due to broad specificity of enzymes
7
Q
How are drugs eliminated? What types of drugs are excreted more easily?
A
- eliminated either unchanged or as metabolites
- hydrophilic drugs are eliminated more readily than lipophilic drugs
8
Q
What do the possible sources of excretion include?
A
- breath
- urine
- saliva
- perspiration
- faeces
- milk
- bile
- hair
9
Q
Explain biliary excretion.
A
Transfer of drugs from plasma to bile
- organic cation transporters (OCTs)
- organic anion transporters (OATs)
- P-glycoproteins (P-GP)
It is concentrated in bile then delivered to intestines
- hydrophilic drug conjugates
- hydrolysis of conjugate can occur: reabsorption of liberated drug or enterohepatic circulation
10
Q
What types of drugs does the glomerulus filter?
A
- filter drugs below 20kDa in molecular weight
- not filtered if drug bound to plasma albumin
11
Q
Describe tubular secretion/
A
OATs and OCTs
- OATs transport against ECG
- cleared even if bound to plasma albumin
12
Q
If the renal tubule is freely permeable, how much of the drug is reabsorbed?
A
99%
- lipophilic drugs excreted poorly
- polar drugs remain in lumen
13
Q
What is the effect of urinary pH on excretion of weak acids/bases?
A
- Weak acids more rapidly excreted if urine is alkaline
- Weak bases more rapidly excreted if urine is acidic
14
Q
How does ion trapping work?
A
- more ionised drug
- less able to be reabsorbed
- eliminated in urine
15
Q
What is zero order kinetics?
A
- few drugs
- rate of metabolism constant
- does not vary with amount of drug present
- enzyme saturation: alcohol dehydrogenase
16
Q
What is first order kinetics?
A
- most drugs
- a constant fraction metabolised/unit time
- increases proportionately to drug
- more drug, faster metabolism
17
Q
What is the eqn for the apparent volume of distribution of a drug?
A
Total amount drug in the body / blood plasma conc of drug
units = L or L/kg
18
Q
What is the clearance (CL) of a drug?
A
The sum of all routes of elimination
e.g. metabolism + excretion
units = L/h
19
Q
What doe t1/2 depend on? What is the eqn?
A
- depends on volume of distribution (Vd) and inversely on the clearance (CL) of drug from the body:
t1/2 = ln2 x Vd / CL
20
Q
What is the (i) Vd (ii) CL of aspirin?
A
(i) 10.5 L
(ii) 39 L/h
21
Q
What is the (i) Vd (ii) CL of salicylic acid?
A
(i) 11.9 L
ii) 3.6 L/h (dose dependent
22
Q
How does age affect metabolism?
A
- foetus: maternal protection
- children: low level of activity
- elderly: starts to decline
23
Q
How does disease affect metabolism?
A
- dependent on proper liver func: cirrhosis, hepatitis, cancer
- adequate essential amino acid supply: starvation, cancer
- other diseases/conditions: kidney disease, severe burns
24
Q
How does genetic variation affect metabolism?
A
- wild range of CYP phenotypes: rapid, slow, unusual metabolisers
- race: inherent generalisable variability
25
How does other medications affect the body's metabolism?
- induction of metabolic enzymes: reduced effectiveness of drugs
- inhibition of metabolic enzymes: dietary constituents or drugs
26
What is the differences in sexual response between mammals and humans? Why is this thought to be the case?
- all other mammals only mate when female ovulating and many signal their ovulation by oestrous behaviour 'heat'
- human ovulation is hidden and females are receptive to males throughout their menstrual cycle
- has been suggested humans do this as a way of strengthening pair bonding to support long development of human children
27
What are the 4 phases of the EPOR model?
1. EXCITEMENT sexual arousal - psychological and physical stimulation of erogenous zones. Tumesence and erection of penis and clitoris, engorgement of female tract
2. PLATEAU intensification of arousal
3. ORGASM series of involuntary muscular contractions in both sexes with intense pleasurable sensations
4. RESOLUTION detumescence and time during which re-arousal is impossible (may not be true of women)
28
What, approximately, is the length of the luteal phase?
14 days
29
How long are (i) sperm (ii) oocytes viable for?
(i) 24 - 72 hrs
(ii) 12 - 24 hrs
- for fertilisation coitus must be no more than 3 days before ovulation and no more than 1 day after
30
What must happen for pregnancy to occur?
Sperm introduction should be between 5 days before and one day after ovulation
- sperm are capable of fertilising an egg for approx 4-6 days
- ovulated egg remains viable for approx 24 - 48 hrs
31
When do the first, second and third trimesters occur? What is significant stages in each?
```
1st trimester weeks 1-12
- most miscarriages occur
2nd trimester weeks 13-28
- at 4 wks 50% survival rate for early prematurity
3rd trimester weeks 29-40
- parturition at about 40 wks from LMP
```
32
How likely are women likely to conceive?
Women under 35 in china and europe
- 50% pregnant after 2 cycles
- 85% pregnant after 6 months
- half remaining couple pregnant after 1 year, leaving approx 5% subfertile
33
How many pregnancies miscarry (a %)?
15-20%
34
What is spontaneous abortion?
pre-implantation and post-implantation failure
| - occurs frequently
35
Describe the (i) embryonic period (ii) foetal period.
(i) 8 weeks
- preimplantation embryo, implantation, differentiation and development of organ systems
- mother may not know pregnancy during this period and may not avoid harmful influences which may affect embryo development
(ii) 8-40 weeks
- differentiation continues, growth
36
How is the egg/oocyte transported during ovulation?
- egg extruded onto surface of ovary and smooth muscle of fimbrae cause them to pass over ovary while cilia beat in waves toward interior of duct
- cumulus cells aid transport from surface of the ovary and sticky cumulus cells cling to the ciliated surface of the fimbriae
- transported by a ciliary current (and perhaps peristalsis) to ampulla
37
Ejaculation deposits semen into vagina then movement into cervix, passage into cervical mucus is dependent on what?
Oestrogen-induced changes in mucus consistency
38
How is sperm moved through uterus and fallopian tubes?
Via its own propulsions and uterine contractions
39
How many sperm die from vagina to fallopian tubes? Why is this the case?
From several hundred million to 100-200 sperm
- vaginal environment acidic
- length and energy requirements of trip
Hence the large no. of sperm in ejaculate
40
What is the capacitation?
the action of the female tract secretions on sperm over several (6-8) hours
- essential for them to be capable of fertilisation
41
What is the causes of capacitation?
- change from wavelike beats of sperm tail to whip-like action to propel sperm forward
- sperm's plasma membrane altered so it's capable of fusing with surface membrane of egg (acrosomse reaction)
42
What happens during capacitation?
Destabilises the sperm surface membrane to enhance fusion with oocyte
- increase in Ca permeability so rise in intracellular Ca
- removal of membrane proteins (glycoprotein)
- change in surface charge
- depletion of cholesterol
43
What does sperm do during fertilisation?
1. sperm cell weaves past follicular cells and binds to zona pellucida
2. rise in Ca intracellularly in sperm triggers exocytosis of acrosome which contains hydrolytic enzymes
3. Hydrolytic enzymes contained in acrosomal cap are released. these enzymes locally dissolceolve zona pellucida. Whip-like action of the tail pushes sperm head towards oocyte membrane
4. With head of sperm lying sideways, microvilli on oocyte surround sperm head and the 2 membranes fuse. The contents of sperm enter oocytes and sperm membrane remains behind.
44
What happens next in fertilisation after the contents of the sperm enter the oocyte & the membrane remains behind?
1. rise in [Ca] inside oocyte triggers cortical reaction, where there's exocytosis of granules which previously lay immediately beneath plasma membrane. Enzymes released leads to changes in zona-pellucida proteins, so it hardens preventing entry of other sperm cells
2. rise [Ca] also induces completion of ooctes 2nd meiotic division and formation of 2nd polar body
3. Sperm head enlarges to become male pronucleus
45
What is an acrosome reaction? What is it induced by and what does it do?
Induced by sperm head contacting zona pellucida and binding to glycoproteins ZP2 and ZP3
- fusion of acrosome plasma membranes
- releases contents of acrosome and causes entry of more Ca
- sperm then digests a path through the zona pellucida (proteolytic enzymes)
46
What occurs as the male and female pronuclei fuse?
- sperm contributes its nuclear material and centrioles
- all other organelles are present in oocyte cytoplasm
- mDNA inherited exclusively via maternal route
47
Define (i) totipotent cells (ii) pluripotent cells (iii) multipotent cells.
(i) can form all cell types in a body, plus extra-embryonic or placental cells. Embryonic cells w/in first couple of cell divisions after fertilisation are the only cels which are totipotent
(ii) can give rise to all of the cell types that make up body; embryonic stem cells considered pluripotent
(iii) can develop into more than one cell type but are more limited than pluripotent cells, adult stem cells and cord blood stem cells considered multipotent
48
Describe the events which result in the conceptus/blastocyst entering the uterine cavity.
- plasma progesterone levels rise 3-4 days after fertilisation, smooth muscle relaxes and conceptus passes into uterus
- approx 4-5 days after fertilisation, cavities develop between cells
- for approx 3 days, conceptus/blastocyst lies free in uterine cavity supported by uterine secretions, receiving nutrients from it
49
What does the (i) trophoblast (ii) inner cell mass of a blastocyst give rise to?
(i) placenta
| (ii) embryo
50
What does the trophoblast differentiate into? Which layer invades the endometrium?
Inner cytotrophoblast and outer syncytiotrophoblast
| - fingers of syncytiotrophoblast invade endometrium
51
What are the results of metabolism?
1. pharmacological deactivation
2. pharmacological activation
3. types of pharmacological response
4. no change in pharmacological activity
5. change in drug uptake
6. change in drug distribution
52
How is it that the conceptus is 'held' in the fallopian tube?
Oestrogen maintains the contraction of smooth muscle near where fallopian tube enters wall of uterus
- conceptus undergoes no. mitotic cell divisions i.e. cleavage and morula formed ( divisions unusual as no cell growth before each division so conceptus reaching uterus is same size as original fertilised egg)
- cells = totipotent
53
In the earliest stages of pregnancy the anatomical link between mother and foetus develops through a series of phases. What are the 3 sequence of events?
1. Invasion - of conceptus to endometrium
2. Decidualisation - i.e. endometrial lining remodelling incl. secretory transformation of uterine glands, influx of specialised uterine natural killer cells, and vascular remodelling
3. Placentation - i.e. placenta formation
54
What is the (i) embryonic portion (ii) maternal portion of placenta supplied from?
(i) outermost layers of trophoblast cells i.e. chorion
| (ii) endometrium underlying chorion
55
Where do the chorionic villi extend from?
chorion to endonmetrium
56
The endometrium around villi is changed by what?
Enzymes and paracrine agents so each villi is surrounded by a pool/sinus of maternal blood
57
Describe the placental blood supply, ensuring to mention maternal & foetal blood.
Maternal Blood:
- enters placental sinuses/pools via uterine artery
- flows through sinuses
- exits via uterine veins
Foetus Blood
- flows into capillaries of chorionic villi via umbilical arteries and back to foetus via umbilical vein
Umbilical cord connects foetus to placenta
58
When do the following events occur; (i) fertilisation (ii) transport to uterus (iii) formation of blastocyst (iv) attachment?
(i) 24hrs post ovulation
(ii) 3-4 days
(iii) 4.5 days
(iv) 7-9 days
59
What happens to the blastocyst day 6/7?
Leaves zona pellucida and is bathed by uterine secretions for 2 days
- progesterone prepares supportive uterine environment increasing glandular tissue
- oestrodiol required to release glandular secretion
60
Attachment and Implantation
| includes complex interactions between trophoblast and maternal epithelial tissue, what does this cause?
- syncytiotrophoblast cells 'flow' into endometrium
- causing oedema, glycogen synthesis and increased vascularisation (decidualisation)
- pregnant endometrium is now termed the decidua
61
When does implantation occur? What does it involve?
Day 13
- syncytiotrophoblast cells erode through walls of large maternal capillaries which then bleed into spaces; primitive placental circulation
- nutrition still depends on uterine secretion and tissues
- breakthrough bleeding may occur
- growth in embryonic disc is slow and it remains v small
62
When is the placental side of circulation functional? As a result of this what is the first trimester embryo largely dependent on?
10-12 weeks
| - uterine tissues for nutrients and O2
63
Describe placental development.
- syncytiotrophoblast forms villi that project into blood filled spaces (chorionic villi). In core of villus is a fetal capillary loop which is dilated at the tip
- embryonic placental structure develops over several weeks with villi eventually becoming localised at embryonic pole and presenting a huge s.a for exchange of O2, nutrients and waste products
64
What is the syncytiotrophoblast bathed in?
maternal blood
65
Describe events that occur in the first trimester of pregnancy.
- limited embryonic growth
| - nutrition of embryo largely based on uterine secretion and tissues
66
What may be the reason for early pregnancy losses (1st trimester?
lack of appropriate hormonal support
| => luteal phase defect
67
How thick should the endometrium be for successful implantation?
At least 8mm thick
68
How are maternal sinusoids formed?
- trophoblastic lacunae appear w/in syncytiotrophoblast
| - maternal blood vessels near syncytiotrophoblast expand to form maternal sinusoids
69
What is a (i) primary villus (ii) secondary villus formed by?
(i) core of cytotrophoblast covered by multinucleated syncytiotrophoblast
(ii) inner core of extra-embryonic mesoderm, middle cytotrophoblast layer and an outer syncytiotrophoblast layer
70
What is the role/functions of hCG?
- in a non-fertile cycle the CL will fail after 10 days and menstruation will occur
- an invading embryo must prevent menstruation so the syncytiotrophoblast secreted hCG
- from day 6-7 after fertilisation hCG can be detected in maternal blood by immunoassay
- hCG mimics the action of LH and supports steroid synthesis of CL preventing menstruation and any further follicular development
- also stimulates leydig cells of male foetuses to produce testosterone (important for development of male duct system)
71
What are the placental functions in the (i) 1st month (ii) 2nd month (iii) 3rd month?
(i) villus formation
(ii) increasing surface area and circulation
(iii) growing, becoming increasingly efficient
72
What are the 4 functions of the placenta?
1. Foetal 'gut' supplying nutrients
2. Foetal 'lung' exchanging O2 and CO2
3. Foetal 'kidney' regulating fluid volumes and disposing of waste metabolites
4. Endocrine gland synthesises steroids and proteins which affect both maternal and foetal metabolism
73
What is the importance/need for progesterone in pregnancy? What is the substrate for its production?
- suppresses follicular growth and ovulation
- suppresses immune response
- maintenance of endometrium
- cholesterol from maternal circulation = substrate
74
When does the foetus become self sufficient? Why is this now the case?
After 4-5 weeks as the placental now secretes all steroid hormones required for pregnancy (CL not required after 5 weeks)
75
What is the main oestrogen in pregnancy?
oestriol
76
What secretes oestrogens in pregnancy?
foetus and placenta (feto-placental unit) cooperate to secrete oestrogens
77
What is the importance of oestrogen in pregnancy? (HINT there's 4 points)
1) stimulates continuous growth of uterine myometrium
2) stimulates growth (w progesterone) of ductal tissue of breast
3) along with relaxin, relaxes and softens maternal pelvic ligaments and symphysis pubic of pelvic bones allowing for expansion of uterus
4) stimulate LDL cholesterol uptake and activity of P450 enzymes which contribute to progesterone synthesis
78
Describe what occurs during nutrient exchange across the placenta.
- is rapid and increases as pregnancy advances
- water and electrolytes diffuse freely
- glucose passes via facilitated diffusion as foetus has little capacity for gluconeogenesis
- amino acids are actively transported for foetal growth
- lipids cross as free fatty acids
- vitamins
79
Describe what occurs during gas exchange across the placenta.
- simple diffusion of gases across membrane is close to efficiency of lungs
- conc. gradients influenced by blood flow rates
- quantity of O2 reaching foetus is flow limited
- foetal Hb has greater affinity for O2 than adult Hb
- towards end of pregnancy exchange capacity decreases and placenta is less able to meet demands of foetus
80
Where do 95-97% of ectopic pregnancies occur?
In ampulla/isthmus of tube with vast majority in ampulla
81
What can the symptoms of ectopic pregnancy be confused with? What is the risk associated with an ectopic pregnancy?
- symptoms can be confused with appendicitis
| - rupture of tube causes blood loss that may be life threatening to mother and fatal for the embryo
82
What is Genetic counselling?
process of helping people understand and adapt to the medial, psychological and familial implication of genetic contributions to disease
83
What does genetic counselling integrate?
- interpretation of family and medical histories to assess the chance of disease occurrence or recurrence
- education about inheritance, testing, management, prevention, resources and research
- counselling to promote informed choices and adaptation to the risk or condition.
84
What is the newborn screening programme for cystic fibrosis?
Based on heel-prick immuno-reactive trypsinogen (IRT) level
- raised IRT, test using CF mutation kit
- CF suspected if IRT raised and one pathogenic mutation found
- CF confirmed if 2 pathogenic mutations found
85
What is R117H? Describe its effects.
- the second mutation in 1.85% scottish CF pts but makes up 9% of CF mutation identified on postnatal screen
- majority of R117H compound heterozygotes don't present with CF in childhood
- the effects of R117H varies according to Intron 8 splice site efficiency
86
What is SMA (Werdnig- Hoffman Disease)?
Progressive muscle weakness from degeneration of anterior horn cells
- autosomal recessive
- 95% cases due to deletion of SMN1
- 1 in 50 pop carry mutation
87
Why with SMA do you not look directly for mutation?
Single cell - very low copy no. DNA
- problem w. contamination (FP result)
- allele drop out (FN result from failure to amplify mutation)
88
What is the average weight gain during pregnancy? What is the rough breakdown of where the weight comes from?
average 12.5kg
- 6kg uterus, foetus and breast
- 3kg fat reserves for lactation
- remainder is fluid
89
What are the various anatomical changes which occur to the mother during pregnancy?
- fist sized organ which begins to occupy most of pelvis by 13 weeks and palpable abdominally from 13 weeks
- compression of structures posterior abdo wall (IVC) especially when lying down
- changes centre of gravity, accentuated lumbar lordosis
90
What are the circulatory adaptations (blood volume and composition) which occur to the mother during pregnancy?
Physiological anaemia of pregnancy
- haematopoiesis is increased (up30%) but increase in plasma volume (up50%) means RCC, haematocrit and Hb conc are all reduced
- small increase in WBC
- unchanged platelet count but more reactive
- increase in clotting factors with thromboembolism risk
91
What changes occur to the mothers TPR during pregnancy?
- uteroplacental circulation is characterised by high volume, low resistance flow as uterine spiral arteries and arterioles lose capacity to vasoconstrictor
- pregnancy hormones reduce sensitivity to pressor agents such as angiotensin hence peripheral vasodilation (heat-intolerance)
92
What does reduced TPR trigger?
The renin-angiotensin- aldosterone system
| - increasing blood volume
93
What additional factors may favour vasodilation, maintaining normal (low) BP in the mother?
- oestrogen increases vascular endothelial growth factor (VEGF) and nitric oxide (NO) production in endothelial cells
- endothelial cells release prostacyclin (prostaglandin I2 or PGI2)
94
What changes occur to the mother's cardiac output throughout pregnancy?
- increases by 30-50% between weeks 6-28 (approx 6L) and increase in HR from 70 to 80/90 and increase in SV by approx 10%
- increased blood flow to uterus, breast and skin
- in late pregnancy CO sensitive to posture and can fall becuase of IVC obstruction by uterus so hypotension/fainting when lying flat
- by 6 weeks post partum CO returns to pre pregnancy condition
95
What changes occur to the mother's blood pressure throughout pregnancy?
although CO increases, BP normally falls in 2nd trimester
- systolic falls about 5-10 mmHg
- diastolic falls about 10-15 mmHg
96
How is BP measured on a pregnant woman? What is BP related to?
- measured semi-recumbent (NOT ling flat) using korotkoff phase 5 for diastolic
97
What is pre-eclampsia? What may it involve?
Placental problem involving an increase in BP, proteinuria and oedema
- may involve failure of 2nd wave of trophoblast invasion that normally impairs capacity of material spiral arterioles to constrict (12-16 weeks)
98
How many pregnancies does pre-eclampsia occur in? When can it begin?
- occurs in 2-8% pregnancies and is more common in 1st pregnancy
- can begin in approx week 20
99
What does an increase in vascular resistance to the placenta cause?
1) decreased blood to placenta
2) hypertension in mother
3) renal arteriolar endothelial damage causes oedema, glomerular damage and proteinuria (acute atherosis)
100
What can poor placental perfusion cause?
foetal growth restriction
101
What interventions are used for eclampsia?
1) magnesium sulphate
2) antihypertensives
3) rapid delivery
4) careful fluid balance
102
What are the symptoms of eclampsia? What is there risk of? What is the maternal mortality?
extreme hypertension (180/120)
- increased intracranial pressure, seizures, coma
- significant risk of cerebral haemorrhage
- mortality of mother = 8-36%
103
What happens to the respiratory system during pregnancy?
- progesterone increases sensitivity of central CO2 receptors
- more ventilation
- increase in tidal volume by about 40%
- ventilation rate unchanged
104
What happens to the renal system during pregnancy?
- kidneys deal with foetal urea so there is increased renal function
- increased GFR (by 20-50%) due to increased CO
- bladder compressed leading to frequent and urgent urination
- ureters are dilated whihc can predispose to infection
105
What happens to the total body water during pregnancy?
Increases by 6-8L
- ECF increases by 3L, split between plasma and ISF
- osmolarity falls by 10 mOsm/kg so decreased urea and creatinine
106
What happens to the mothers GI system during pregnancy?
Morning sickness, N/V especially in first 12-14 weeks
- parallels HCG levels and s worse in multiple pregnancy
Constipation
- pressure of uterus on rectum and lower colon results in decreased motility, progestogenic effect on smooth muscle
Gastric acid reflux, heartburn
- relaxation of LOS, pressure of uterus, worse lying down and an aspiration risk during endotracheal intubation
107
What are the weight gain requirements for pregnancy?
```
At term weight can is 7-14kg
- foetus = 3.5kg
- placenta and amniotic fluid = 1.5kg
- increased breast tissue = 0.5-1kg
- the rest is fat and ECF
Daily calorific requirement increases by approx 15% i.e. 200-300 kcal/day
```
108
What happens during early pregnancy?
- rate of growth of foetus relatively slow till 20weeks
- about 3kg fat laid down to provide energy source for final trimester when growth is v rapid
- maternal tissues more sensitive to insulin in early stages of pregnancy
- increased protein synthesis
109
When does the growth of the foetus peak?
between 30 - 36 weeks
110
What happens during later pregnancy?
- relative insulin resistance predisposing to 'high-normal' glucose levels
- increased lipolysis supplying mother with source of energy
- increase in circulating triglycerides stored in mammary tissue
- increased requirement for protein
111
What are the risk factors for gestational diabetes?
- race
- obesity
- family history
112
What can gestational diabetes be a predictor of? What is it associated with?
- predictor of future type 2 diabetes
| - associated with foetal macrosomia (increased insulin resistance; high glucose) and complications
113
What are the vitamin requirements during pregnancy?
- folic acid needed for neural tube fusion (pre-conception)
- veggies may need to increase B12 intake
- high levels of vitA may lead to foetal abnormalities
- vit D supplementation recommended
114
What minerals are required during pregnancy?
- calcium (calcification of skeleton)
- maternal gut absoprtion increases (vit D3)
- urinary loss decreases (PTH)
- increase in release of Ca from bone
- active transport across placenta
115
What is the importance of (i) zinc (ii) iron in pregnancy?
(i) important role in many metabolic processes: protein synthesis, nucleic acid synthesis, synthesis/activity of insulin, increased dietary need (especially in vegans)
(ii) globally, high incidence of maternal ion deficiency. If dietary iron low then may need supplements
Supplementation with normal ion stores is undesirable as may increase oxidative stress
116
What are the secretions from the (i) placenta (ii) mother during pregnancy?
(i) hCG has key role in maintaining pregnancy plus other placental proteins and steroids
(ii) increased growth hormone release
- decreased FSH and LH
- increased prolactin and parathyroid hormone
- pituitary increases in size (production of prolactin and ACTH and oxytocin)
- thyroid increases in size due to hCG (similar structure to TSH)
117
What changes can occur postnatally to the mother? (hint: there's 3 main points)
1) uterine involution complete by 6 weeks
2) amenorrhoea if breast feeding
- duration related to frequency and duration of suckling
- may be associated with hot flushes and vaginal dryness
3) systemic changes largely reversed by 6 weeks
- coagulation system changes may take longer
- glucose tolerance normalises v rapidly
118
What treatment is used for G551D mutation in CF?
Ivacaftor (Kalydeco) therapy
- artificially opens the channel
- 4 to 5% cases specific to this mutation
119
Describe preimplantation genetic diagnosis for SMA. What is hapylotyping?
- need lots of embryos, remove 1 cell day 5. Whole genome amplification
- look at inheritance of chromosome markers around site of disease associated mutation
- want to determine which chromosomes carry the mutations and from this which chromosomes have been inherited by embryo
- the closer the markers are they more likely they are to be inherited together
120
With SMA, why do you not look directly for a mutation?
- looking for gene deletion which is not there because it is deleted or because reaction didn't work => look at inheritance pattern near deletion- single cell = very low copy no. DNA
- problem with contamination (FP result)
- allele dropout: FN result form failure to amplify mutation
121
Why is Merkel Gruber unable to be tested directly for a mutation?
Due to sheer no. of genes and mutations
122
Define (i) estimated date of delivery (EDD) (ii) delivery at term?
(i) 40 weeks/280 days from FIRST DAY of LMP
* *actual foetal age is 14 days less than EDD
(ii) between 37 and 42 completed weeks
123
When is; (i) pre-term (ii) post-term ?
(i) before 37 completed weeks
| (ii) beyond 42 weeks
124
When is; (i) 1st trimester (ii) 2nd trimester (iii) 3rd trimester?
(i) up to 12 weeks
(ii) 12-27 weeks
(iii) 28 weeks to term
125
What are the ways that Gestational age are estimated?
1. from menstrual history - memory, cycle length, hormonal contraception
2. from clinical exam - size of uterus
3. symptoms - quickening
4. USS 1st trimester = gestation sac volume for v early gestation and crown-rump length. 2nd trimester = head circumference, biparietal diameter, abdo circumference and femur length
126
What is a late pregnancy U/S for?
GROWTH not dating
127
What is the pregnant state maintained by? (HINT there's 3 things)
1) uterine quiescence
- gap junction expression down regulated
- oxytocin receptors down regulated
- relaxin may play a role
2) anatomical arrangement of cervix
- collagen fibres predominate over smooth muscle
- glycosaminoglycan ground substance
3) Amnion and chorion membranes are intact
- low level of PG biosynthesis
128
How is labour initiated?
Trigger is unknown but there's increased oestrogen towards end of pregnancy which encourages uterine contraction
- increased PG production
- increased cytosol-free calcium needed for muscular contraction
- oxytocin (post pituitary) presenting part presses on pelvic floor
129
Describe cervical ripening and uterine contractions, which both occur during the initiation of labour.
CERVICAL RIPENING
- PG biosynthesis increases which increases water content of glycosaminoglycan matrix
- myometrial activity results in 'effacement' and thinning of cervix
- relaxin up-regulates matrix metalloproteinases
UTERINE CONTRACTIONS
- initially un-coordinated, non painful 'Braxton Hicks'
- progressively regular, frequent, co-ordinated and painful
130
How long is labour in (i) primiparous (ii) multiparous?
(i) 14 hrs
(ii) 8 hrs
- 1st stage takes up most of this time and 2nd stage about 1 hr
- 3rd stage = delivery of placenta
131
What happens during the first stage of labour?
Onset of regular contractions to fully dilated cervix
1. latent phase:
- onset of painful contractions at 5-10 min intervals
- cervical ripening and effacement
- cervix slowly dilating up to 3-4cm
2. active phase:
- from cervix 3-4cm dilated, more rapidly 0.5-1cm/hr
- progressive increase in frequency + strength of contractions
- cervical dilatation
- descent of the presenting part
- (rupture of the membranes - water break, usually at this point)
132
What happens during the second stage of labour?
Fully dilated cervix to birth
- cervix fully dilated (10cm)
- contractions stronger 2-5 mins
- presenting part descends
- urge to bear down
- 'Ferguson reflex' of perineal stretching
- delivery
133
What happens during the third stage of labour?
Expulsion of placenta and membranes
- separation due to forceful uterine contractions and reduces size of placental bed which reduces bleeding
- normally takes 5 mins
- can be manages expectantly (traditional/physiological) or actively (oxytocic drugs may be used to assist this process, coupled with physically pulling on umbilical cord.
134
What 5 factors influence uterine contractions?
1. Prostaglandins
2. Oxytocin
3. Relaxin
4. Stretch response
5. Positive feedback
135
Where are prostaglandins released from? What is their functions? (PGF2alpha and PGE2)
Paracrines released from uterine decidual cells
- stimulate uterine contractions
- soften, thin + dilate cervix
- potentiate contractions induced by oxytocin
- increase gap junction numbers
136
What is the function of oxytocin? Describe the difference in foetal and maternal oxytocin.
Triggers PLC cascade and release of intracellular Ca from smooth muscle SR (OT receptors on smooth muscle cells)
- stimulates PGF2-alpha production
- foetal oxytocin involved in onset of labour
- maternal is released in burst as a consequence of dilation of cervix (Ferguson reflex)
- constricts uterine blood vessels at site of placenta
137
What is relaxin produced by? What is its function?
Produced by CL, placenta and decidua
- contributes to uterine quiescence during pregnancy
- release increases immediately before labour as it softens and helps dilate cervix during labour
- affects collagen metabolism => softening ligaments as pregnant women vulnerable to ligamentous strain
Is not solely a pregnancy hormone - receptors in heart, smooth muscle + connective tissue
138
What is the mechanical stretch?
An increase in uterine contents to a critical level may stimulate uterine contractions via uterine smooth muscle stretch reflex
139
Describe the positive feedback loops which occur during labour.
- uterine contractions stimulate PG release which increases intensity of uterine contractions
- uterine contractions stretch cervix which stimulates oxytocin release (Ferguson reflex) + stimulates further uterine contractions
140
What is lightening? When does it tend to happen and in what pregnancies?
Engagement of head
2-4 weeks prior to delivery
- delivery in primiparous women but may not happen in multiparous women
141
With regards to the presentation during labour i.e. the part delivered first, what are the most common ways?
Cephalic 97%
Breech is buttocks first 3%
Shoulder 1%
142
What is external cephalic version (ECV)? What does it aim to do? What is its success rate? When can it be done?
The manipulation of foetus through abdomen from breech to cephalic presentation
- aim is to reduce electvue C section for breech
- success rate about 50% and more than 5% revert to breech if successful
From 36 weeks nulliparous or 37 weeks multiparous
143
How can you relax the uterus?
With tocolysis - salbutamol or terbutaline
144
What is intrapartum monitoring? What is monitored (i) maternally (ii) foetally?
(i) vital signs, increasing in frequency as labour progresses
- progress charted on 'partograph'
(ii) auscultation of foetal HR and pattern
- intermittent with Pinard stethoscope or hand held Doppler
- continuous electric monitoring with cardiotocography (CTG)
Inspection of the liquor once membranes are ruptured
145
What are the various things that a partograph can measure?
- foetal HR
- rate of cervix dilation
- descent of foetal head
- contraction characteristics
- if membranes ruptured, colour of amniotic fluid
- volume of maternal urine
- record of medications
- maternal vitals
146
What are the consequences of pre-term brith? (HINT there's 6)
- Resp distress
- hypothermia
- cerebral palsy (intraventricular haemorrhage)
- hypoglycaemia
- jaundice
- sepsis
147
During delivery, what ways does the foetus move/you move the foetus?
1. engagement of and flexion of head
2. internal rotation
3. delivery by extension of head - nose scrapes blanket
4. delivery of shoulders
148
What are the 3 layers of the body of the uterus?
1. Perimetrium (serosa) = single thin outer layer of epithelium, not evident clinically
2. Myometrium = thick middle layer of smooth muscle
3. Endometrium = inner layer with glands, blood vessels, lymphatics and epithelial cells
149
What do uterine contractions depend on?
gap junctions for phasic propagation of depolarisation
| - connexin 43
150
What are uterine contractions influenced by?
```
Hormonally influenced:
- menstrual cycle
- pregnancy
- labour
minimal influence of autonomic innervation on contractions under physiological conditions
```
151
Describe gap junctions isn (i) cardiac muscle (ii) vascular/intestinal smooth muscle (iii) uterine smooth muscle.
(i) constitutively expressed and arranged in intercalated discs. Depolarisation starts from SAN
(ii) constitutively expressed and not concentrated in specialised areas
(iii) inducible (esp. hormonally), fundal dominance during labour may arise form anatomical arrangement of expressed gap junctions
152
What is the innervation of the uterus?
- symp, p'symp and sensory
- innervation of vascular smooth muscle and myometrium
- symp outflow effect depends on receptor type: alpha adrenoreceptors = contraction and beta = relaxation
153
What is the ratio of sympathetic receptor types influenced by?
Hormonal status
154
What hormones are secreted from the posterior pituitary? What is their functions?
ADH/vasopressin - primarily acts on kidneys
Oxytocin
- both 9 amino acid peptides, 2 amino acids different
- both stimulate contraction of uterus
155
What is oxytocin receptor numbers and effect on uterine contraction influenced by?
sex hormone levels
156
What happens to various hormone levels at term?
- falling placental progesterone with sustained oestrogen levels
- stimulates PG synthesis
- oxytocin receptor expression
157
What happens at labour with regards to oxytocin?
- uterine smooth muscle sensitive prior to onset of labour
- stimulated increasingly regulated, co-ordinated contractions that travel from fundus to cervix (fundal dominance)
- uterus relaxes completely between contractions to allow blood to flow to foetus
158
What are uterine (i) stimulants (oxytocics) (ii) relaxants (tocolytics)?
(i) induce abortion
induce and accelerate labour
contract uterus after delivery to control PPH
(ii) (treat menstrual cramps/dysmenorrhoea)
prevent/treat preterm labour
Facilitate obstetric manoeuvres
Counteract (iatrogenic) uterine hyperstimulation
159
What are the current types of oxytocics?
1. Oxytocin
- IV infusion to induce/accelerate labour
- IV or IM injection after delivery to control PPH
2. Ergometrine
3. E + F series PGs
160
What is ergometrine used for in practice? What is its function?
- useful for bleeding related to early pregnancy complications e.g. miscarriage
- causes sustained powerful uterine contractions
- obsolete for PPH prophylaxis owing to stability, inadvisability in presence of HT, adverse effects of N/V
161
What is syntometrine?
combo of oxytocin and ergometrine for 3rd stage of labour
| - commonly in use until 1990s
162
What has significant PG synthesising capacity? What are PG relevance in pregnancy? What types are there?
- endometrium/decidua and myometrium
- membrane phospholipid substrate in late pregnancy
- PGF1a generated in large amounts. PGI2 and PGE2 occur naturally
163
What is the difference in function of F and E series PGs?
F more vasoconstrictor
E more vasodilator
- both act on cervical ripening and induce oxytocin receptors
164
Name the 4 PGs and what they are?
1. DINOPROSTONE
- equivalent to PGE2, naturally occurring
2. CARBOPROST
- synthetic analogue of PGF2a
3. GEMEPROST
- synthetic analogue of PGE1
4. MISOPROSTOL
- synthetic analogue of PGE1
165
Describe misoprostol. How is it stored? What is it used for? How can it be administered?
- room temp storgae
- treatment/prevention of peptic ulcers (initially)
- medical abortion, myometrium is sensitised bt mifepristone then misoprostol
- induction of labour
- control of PPH s2ndary to uterine atony (not as effective as IV/IM oxytocin)
- oral, vaginal, SL or rectal routes of administration
166
What are the various types of uterine relaxants (tocolytics)?
1. beta agonists - ritodrine, terbutaline, salbutamol
- increase cAMP levels in smooth muscle
- SE = tachycardia, HT, hyperglycaemia
2. Ca channel blockers - nifedipine (choice for preterm labour)
- Mg sulphate
- prevent intracellular Ca increase in smooth muscle
3. NSAIDs - indomethacin, inhibit PG biosynthesis
4. Oxytocin receptor antags - atosiban
5. Nitrates
- NO factors, nitroglycerine patch
167
What type of menstrual symptoms are NSAIDs effective for? Give examples.
- pain relief, unclear whetehr via uterine relaxation or central analgesic effect
- ibuprofen, naproxen, mefenamic acid
- may reduce blood loss by around 10% (but antifibrinolytics i.e. tranexamic acid are more effective)
168
What may play a role in dysmenorrhoea and menorrhagia?
Prostaglandins
| - imbalance of PGE vs PGF in endometrium
169
Who owns your body and parts of it when alive?
- limited property rights (we don't have ownership but 'a weaker package of limited property right')
- key issue of property is that you can transfer it to someone else. So we have a weak property right in that we can donate an organ, but we don't have a strong property right (cant sell it)
- ethical issues arise around ownership of bodies e.g. surrogacy, selling of organs
170
Who owns your body and its parts once you've died?
"There is no property in a corpse"
171
What is the Alder Hey organ scandal?
In late 1990s became apparent tissues had been stored without consent.
- parents had consented to post mortem but not to storage of tissues
- in Alder Hey hospital 1000s organs retained without consent
- nationally 105000 organs retained in hospital and medical schools in England
- Dr at centre of it all argued that "children are too precious to die w/out using every scrap of info which could help the next child"
172
What is the case of John Moore's spleen?
as diagnosed with hairy cell leukaemia
- had his spleen removed + returned to UCLA from Seattle several times to have blood and tissue samples taken
- meanwhile his Dr Golde patented a cell line derived from Moore's T-cells + products + was working in collab with pharma company so Golde made 15 million dollars
- moore found this all out and took to court 'he did not give informed consent and Golde had breached fiduciary duty
- decided spleen was not his property, Golde did not breach fiduciary duty and should have ensured Moore was fully informed
173
What is the Tissue Act (Scotland) 2006?
- requires authorisation for use of organs, tissues and samples from deceased
- does not regulate use of tissues from the living - NHS Scotland accreditation scheme (2011) now underHealthcare improvement Scotland
For DNA analysis: consent detailed in Human tissue act 2004 (Eng + Wales + N. Ireland) there's an offence known as "DNA theft"
174
What are the 2 main gene defects in familial breast cancer?
BRCA1 and BRCA2
175
In what families is the BRCA1 gene found?
- with breast and ovarian cancer
176
What is the BRCA1 gene defect?
Autosomal dominant
- increases lifetime risk to 50-80% i.e. not completely penetrant
- increases ovarian risk to 40-50%
177
How do you test for the BRCA1 gene defect?
SEQUENCING
- mutations occur throughout gene with over 650 different mutations identified
- most result in truncated protein
178
Why do defects in BRCA1 predispose to cancer?
Knudson 2 hit hypothesis
- both copies of tumour suppressor gene disrupted in tumour. May arise in both in both copies of gene in same cell by chance (rare + sporadic) or because patient has inherited one defective copy of gene already. In this situation only need one further mutation to occur by chance and tumour will arise
179
How many mutations of BRCA2 are there? What does it increase the risk of?
- more than 400 mutations
| - increases risk of prostate cancer in males and breast cancer in females
180
What are BRCA2 deficient cells sensitive to?
DNA damaging agents
181
What does BRCA1 do?
- binds to RAD51
| - involved in DNA damage response
182
How are DNA double strand breaks repaired?
HOMOLOGY DIRECTED REPAIR
- Double strand break recognised
- part of structure unwound to reveal single stranded section
- formation of d loop like structure where damaged DNA becomes intercalated with undamaged DNA of replicated chromosome
- giving template to repair DNA damage, then fill in gaps and restore wild type helix
183
What is BRCA2's involvement in DNA damage response?
It binds to and recruits Rad51 to site of DNA damage
- BRCA1 promotes nucleation of Rad51 filament
- BRCA2 stimulates Rad51 (mediated strand exchange and D-loop formation)
184
What factors should be considered in referral for genetic counselling?
- no. family members affected
- what generations
- age of onset
ethnic background
- breast cancer susceptibility genes have low penetrance
- polygenic disease?
185
What are the implications for treatment in a patient with a BRCA1/BRCA2 mutation?
Sensitivity to DNA damaging agents
| - via DNA double strand breaks or those occurring during replication fork stalling
186
What is synthetic lethality?
2 genetic mutations are independently compatible with life - but when combined and together, they cause mortality
187
What repairs single strand DNA breaks?
PARP (poly ADP-ribose polymerase)
188
What risk factors are associated with sporadic breast cancer? (HINT: there's 3)
1. Early menarche
2. Late menopause
3. First child after 30 years of age
189
Around what % of breast cancers are ER (oestrogen receptor) positive? How do you show it is ER positive?
60%
| - via immunostaining
190
Describe hormone therapy, using tamoxifen as an example of a drug which would be used? When is hormone therapy usually used? What is a common side effect?
Tamoxifen = prodrug
- antag of ER and prevents expression of genes which would otherwise be stimulated by oestrogen
- often used prophylactically after surgery for early stage breast cancer
- common SE = hot flushes
191
How does tamoxifen work?
- competes with oestrogen for receptors and prevents receptor from binding to target genes
- specific to ER cells and normal cells are, in theory, unaffected by it
192
Around what % of breast cancers are HER2/erbB2 (epidermal growth factor receptor 2) positive tumours?
20-30%
- get multiple copies of gene being amplified
- can be determined with a fluorescent probe to determine no copies of gene
193
What does HER2/erbB2 do?
- binds to growth factor, present on surface of cell (tyrosine kinase)
- once bound to growth factor it contributes to signal transduction to nucleus, gene activation = driving cell division
194
What is trastuzumab (herceptin)? What does it do?
- "humanised" monoclonal antibody to HER2
- binds to receptor directly and prevents signalling
- suppresses growth and angiogenesis
- cell mediated cytotoxicity
195
What are aneuploid tumours, as a result of defects in mitotic checkpoints, treated with?
Docetaxel (taxotere)
| - stabilises microtubules
196
What is mitotic catastrophe?
- aberrant, multipolar spindles
- chromosomes cannot segregate
- apoptosis
197
What are the risk factors for STIs?
1. young age
2. failure to use barrier contraceptives
3. non-regular sexual relationships
4. homosexuality
5. IV drug use
6. african origin
7. social deprivation
8. prostitution
9. poor access to advice and treatment of STIs
198
What are the determinants of risky sexual behaviour?
1. Individual factors - low self esteem, lack of skills, lack of knowledge of risks of unsafe sex
2. External influences - peer pressure, attitudes and prejudice of society
3. Service Provision - accessibility of sexual health services and/or lack of resources (condoms)
199
Where are genital warts found?
- shaft of penis (male)
| - vagina, vuvla, cervix (female)
200
What is the significance of genital warts? What is its incubation period?
- induces hyperplastic epithelial lesions
- types exhibit tissue/cell specificity
- incubation period of 1-6 months
201
What is HPV a precursor for?
- cervical carcinoma
- UG warts
- laryngeal/oropharyngeal papillomas
- common, flat and plantar warts
202
How is HPV treated?
- podophyllum
- cryo
- laser
- surgery
203
Describe the HPV vaccine.
Based on VLP1 - major capsid protein
- 2 vaccines available; cervarix (bivalent) and gardasil (quadrivalent)
- given to girls 12-13 to immunise before being sexually active and protection against MOST cases of cervical cancer
204
What investigations are done for diagnosing chlamydia? How is it treated?
- urine (NAATs)
- endocervical swab (cell culture)
- antigen detection or EIAs
- treat with azithromycin and tetracycline (doxycycline)
205
What are the (i) symptoms (ii) diagnosis (iii) treatment of thrush (candida albicans)?
(i) itchy vaginitis, may present as UTI
(ii) microscopy/culture
(iii) oral fluconazole and topical nystatin
206
What is trichomonas vaginalis? What does it do? What STI does it cause? What is its incubation period?
- anaerobic, single cell, flagellated protozoa whihc attaches to squamous epithelium to infect vagina and urethra
- causes trichomoniasis
- incubation = 4d - 3wk
207
What are the (i) symptoms (ii) diagnosis (iii) treatment of trichomoniasis?
(i) asymptomatic infection uncommon in women but common in men, yellow vaginal discharge
(ii) dark phase microscopy
(iii) metronidazole
208
What can neonate infection of genital herpes result in?
Disseminated infection often involving CNS
209
What are the symptoms that arise in a primary infection of genital herpes?
- febrile flu like prodrome (5-7 days)
- tingling neuropathic pain in genital area/buttocks/legs
- extensive bilateral crops of painful blisters/ulcers in genital area including vagina and cervix in women
- tender lymph nodes (inguinal)
- local oedema, dysuria, vaginal/urethral discharge
210
How is a primary infection of genital herpes treated?
Aciclovir
211
Describe what happens in a recurrence of genital herpes.
- following primary infection the virus becomes latent in local sensory ganglia
- periodic reactivation which can cause symptomatic lesions or asymptomatic, but still infectious, viral shedding
- episodes are usually shorter
- attacks become less frequent over time
212
What are the median recurrence rates after a symptomatic first episode of herpes with (i) HSV-2 (ii) HSV-1?
(i) 4 attacks in subsequent 12 months
| (ii) 1 attack in subsequent 12 months
213
How is HSV diagnosed?
- clinical appearance
- viral culture
- DNA detection using NAAT of swab from base of an ulcer/vesicle fluid
- serology to identify those with asymptomatic infection + distinguish between 2 types of HSV
- may take up to 12 weeks to become antibody positive after primary infection
214
What does neisseria gonorrhoeae infect in the human body?
- epithelial cells of mucous membrane of GU tract or rectum resulting in the development of localised infection w. pus
215
What are the symptoms and resultant complications of gonorrhoea?
- acute inflammation and discharge in male pts
- cervical discharge in female pts
- rectal infections in male homosexuals
- oral pharyngitis contracted by oral-genital contact
- disseminated infection = septic arthritis
216
What is ophthalmia neonatorum? How does it arise? What complication can occur?
- conjuctivitis contracted by newborns during delivery
- occurs because mother is infected with N. gonorrhoeae or C. trachomatis
- can cause blindness without any treatment
217
How is gonorrhoea diagnosed in the lab?
- light microscopy of gram stained genital specimens to look for gram -ve diplococci
- NAAT for use on urine
- PMN in urethral pus
218
What is the current treatment for gonorrhoea?
1. For confirmed, uncomplicated gonococcal infection (adult)
- ceftriaxone 250 mg IM
- cefixime 400mg oral
- ciprofloxacin 500mg oral
- increasing resistance to penicillin, tetracycline and ciprofloxacin but most strains respond to ceftriaxone
- doxycycline also given as many pts have concomitant chlamydial infection
219
What bacteria causes syphilis?
treponema pallidum
| - gram negative sprichete
220
What are the 3 stages of syphilis? Describe them.
1. PRIMARY: hard genital or oral ulcer (chancre) at site of infection after about 3 weeks
- asymptomatic for up to 24 weeks
2. SECONDARY: red maculopapular rash anywhere plus pale moist papules in UG region and mouth (condylomas)
- latent for 3 to 30 years
3. TERTIARY: degeneration of NS, aneurysms and granulomatous lesions in liver, skin and bones (gummas) in about 40% of pts
221
Describe congenital syphilis.
Placental transfer after 10-15 weeks of pregnancy
- infection can cause death or spontaneous abortion of foetus
- survivors will develop secondary syphilis symptoms
222
How is syphilis diagnosed?
- from lesions or infected lymoh nodes in early syphilis
- dark field microscopy
- DFA (direct fluorescent antibody) test
- NAAT
- EIA: can be for IgM for early infection or IgG which becomes +ve at 5 weeks or BOTH
223
What bacteria causes chancroid?
haemophilus ducreyi
| - gram -ve bacterium
224
For chancroid, what are the (i) symptoms (ii) diagnosis (iii) treatment?
(i) painful genital ulcers
(ii) microscopy/culture
(ii) macrolide e.g. erythromycin or ceftriaxone
MD3002
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