1
Q
Name, and explain, the 4 methods used for abortions.
A
- Medical
- Recommended by RCOG for pregnancies up to 13 weeks
- First pill = Mifepristone (prevents implantation of early embryo)
- Second pill = Mifoprostol, taken 2 days later (breaks down uterine lining)
- First pill administered in hospital/clinic, second possibly at home. The longer the pregnancy, the more risk for complications. - Vacuum aspiration/suction (From 7 to 15 weeks)
- Can be done under local or general anaesthetic
- Pill is given to soften cervix, and gentle vacuum is used - Surgical D&E (15 weeks onwards)
- Performed under general anaesthetic
- Cervix is dilated, fetus and tissue removed with forceps/suction - Late Abortions (20 weeks onwards)
- Either medical or surgical
- Experience may be similar to vaginal delivery
- Increased risk of complications, may require overnight stay in hospital
2
Q
Outline the historical development of abortions.
A
1861 Offences Against the Person Act
- Abortion illegal under any circumstance
- Woman performing abortion on self = felony
- Person assisting in abortion = misdemeanour
1929 Infant Life Preservation Act
- Abortion not an offence to save the life of the mother
1967AbortionAct
- Abortion legalized under certain circumstances
3
Q
What is the present legislation of termination of pregnancy?
A
Abortion permitted when:
- 24 weeks and under, if continuing is a greater risk to
woman’s physical or mental health or existing children
- Beyond 24 weeks, when necessary to prevent permanent injury
- Beyond 24 weeks, when continuing prevents risk to life of woman
- Beyond 24 weeks, when there is substantial risk of child being born with serious handicap
- Two doctors must agree abortion is indicated
- Females
4
Q
Discuss the different approaches to determining the moral status of the embryo
A
- Characterised by rationality/capacity for relationships
- Just by virtue of being a member of Homosapiens
- Linked to viability: once viable,should be protected the same as newborn
- Argument from potential: embryos are potential persons, and should have moral status of persons
- Personhood is a gradual process: increasing moral status from fertilisation until birth
NOTE: Whilst you are entitled to your view, not entitled to influence patient care based on view. - Regardless of your beliefs, certain requirements must be met: —— Continuity of care(referrals)
—— Non-judgmental and compassionate care
—— Provision of care within laws and regulations(in both refusal and provision)
5
Q
Identify and discuss the particular ethical difficulties surrounding start of life in the areas of selective feticide, fathers’ rights & the obligations of a pregnant woman to the foetus. (HINT: there’s 4)
A
- What is a serious handicap?
- Feticide
- Feticide recommended for abortions 22 weeks and
beyond
- Injection given to kill the fetus before extraction/induction proceeds
- Aim = prevent newborn suffering and pain, & prevent maternal distress
- Might be preferable in cases of abnormalities inconsistent with life (same outcome, prevention of suffering)
- Ethically questionable practice in regards to non-fatal abnormalities (cleft palette, Down’s Syndrome, etc.) - Potential father’s rights
- Differs once embryo is implanted; during pregnancy, father generally as no rights in regards to abortion or other courses of action
4.Obligations of woman to foetus
- At what point does autonomy of a woman end, and
rights of a fetus begin?
- Health guidelines encourage maternal choice and involvement in birth and throughout pregnancy
- Women cannot demand a certain method (C-section over vaginal birth)
6
Q
What implications did the case of St George’s Healthcare NHS Trust vs S has had on medical practice?
A
It was determined that dispensation was wrongly granted
- Capacity is not automatically effected due to pregnancy, pregnant women retain capacity to consent all else considered
- Foetus had no legal right to life
- Forced treatment for mental disorders under Mental Health Act don’t include physical treatments outside the scope of the mental disorder
- Takeaway: a woman cannot be forced to agree to treatment or procedure (if she retains capacity to consent) even if thinking process is “bizarre and irrational”
7
Q
Identify the different categories of euthanasia (by choice and by action).
A
- Euthanasia: X intentionally kills Y, or permits Y’s death, for Y’s benefit
- Active euthanasia: X performs an action which itself results in Y’s death
- Passive euthanasia: X allows Y to die. X withholds life prolonging treatment or withdraws life-prolonging treatment
- Voluntary euthanasia: Euthanasia when Y competently requests death himself
- Non-voluntary euthanasia: Euthanasia when Y is not competent to express a preference
- Involuntary euthanasia: Death is against Y’s competent wishes, although X permits or imposes death for Y’s benefit
8
Q
What is the link between pyramid pain killing and the doctrine of double effect? Explain.
A
This is where increasing doses of painkiller is given, to alleviate pain, but with the possibility of causing death.
This involves looking at the distinction between intending death, and foreseeing death.
9
Q
What is the availability and regulation of euthanasia in the Netherlands, Switzerland & Oregon (in the US)?
A
- NETHERLANDS
Euthanasia is allowed if:
- Patient incurably ill
- Patient experiencing unbearable suffering
- Patient requested his/her life be terminated
- Termination is performed by the patient’s own doctor
Three points to note:
- Advance directives are allowed
- Children > 12 can request euthanasia
- Euthanasia of severely disabled newborns allowed - SWITZERLAND
- Legally condoned
- Assisting someone to commit suicide is illegal ONLY if the motive is selfish; if motive unselfish, then NOT illegal
- Two organisations which help people to die = EXIT & Dignitas
~300 suicides are assisted by right-to-die organisations in Switzerland - OREGON
Physician-assisted suicide is legal in Oregon, not euthanasia (note: euthanasia = illegal in US, PAS varies from state-to-state)
- Death with Dignity Act 1994 only applies toresidents of Oregon
10
Q
What is palliative care? Outline the values of the hospice movement.
A
- Palliative care = multidisciplinary approach to specialised medical care for people with serious illnesses. Focuses on providing patients with relief from the symptoms, pain, physical stress, and mental stress of a serious illness.
The focus of care in the hospice (palliative care) is based on a holistic view of the person:
– Physical
– Emotional
– Psychological (Spiritual)
– Social
Often there is also a focus on pain management
11
Q
What are the different arrangements surrounding organ donation: opt in & opt out?
A
UK currently operates an opt-in system
Reasons why potential donors don’t become actual donors include:-
- Tests for brain stem death not carried out
- Refusal by relatives
- Medical contraindication to donation
- Relatives not asked about donation
- Heart stopped beating before brainstem death complete
- Organs offered but not retrieved (BMAreport,citedH,S&H,2008)
Do not allow directed/conditional donation
What factors determine who gets the organs? Compatibility, age, proximity to centre
12
Q
Name, and describe, the various enzymes involved in the process of ubiquitination.
A
E1 enzyme: only have 2 types of it. Is the ubiquitin activating enzyme
E2 enzyme: ubiquitin conjugating enzyme
E3 ubiquitin ligase enzyme: allows for the transfer of ubiquitin. It is a combination of E2 and E3 that recognise the substrate allowing Ub to transfer onto the substrate
13
Q
Once the substrate has been ubiquitinated, how is it degraded?
A
It is degraded through a proteasome
- found in the cytoplasm of cells
- has a CP (core particle) and a cap of an RP (regulatory particle)
- the recognition result sin unfolding of the substrate, which is then directed through the CP
- in the CP is where the substrate is cleaved into its component amino acids
- the AA are discharged through the bottom of the proteasome
14
Q
What are the various checkpoints per cycle to reduce/prevent DNA damage?
A
At the G1 stage: - damaged DNA - unfavourable EC environment At the S and G2 stage: - damaged/incompletely regulated DNA At the M phase - chromosome improperly attached to the mitotic spindle
15
Q
What is the importance of the R point?
A
it is where the cell has to decide whether it will grow or not grow (i.e. quiescence)
If non-proliferating: then p16 is active, and the Rb is active
If proliferatin: p16 is absent/inactive, and the Rb is inactive (and phosphorylated)
16
Q
Describe the process of DNA replication, and the mechanisms involved to ensure that it only occurs once per cycle.
A
The pre replicative complex within the G1 phase consnists of ORC (origin recognition complex), cdc6 and other proteins
S-cdk triggers the S phase which results in the splitting of the ORC from the other proteins of the pre-RC and from cdc6, which is phosphorylated and degraded. The degradation of cdc 6 means there is not enough cdc6 to restart the process of replication again.
The free ORC then allows for the assembly of the replication fork and then the completion of DNA replication
17
Q
What are the various stages of mitosis? Give a VERY rough overview.
A
Prophase
Prometaphase (these two stages are where the chromosomes condense)
Metaphase (chromosomes line up along equator)
Anaphase (chromosomes begin to be separated to either poles of cell)
Telophase (separation complete)
Cytokinesis (2 daughter cells begin to move apart)
18
Q
What are the various phases of the cell cycle? What is the function of each stage?
A
- G1 phase: checks the cellular environment is right for DNA replication
- S phase: DNA replication
- G2 phase: make sure that everything is in order
- M phase: mitosis (nuclear division) & cytokinesis (cytoplasmic division)
19
Q
What are the various enzymes involved in the phosphorylation/dephosphorylation of cdk’s?
A
- Inhibitory kinase = wee1
- Activating kinase = Cdk
- Activating protein phosphorylase = Cdc25
20
Q
What proteins are used to condense DNA?
A
Condensins
21
Q
How is the spindle formed? How to the chromosomes attach to the spindles?
A
- centrosome is replicated early in the cycle (G1)
- as the cell moves into the M phase there’s a massive polymerisation of microtubules, which eventually form the spindle
- the chromosomes attach o the newly formed spindles through the protein complex, known as a kinetochore, which binds to the centromere & joins it onto microtubules
22
Q
Describe the breakdown of the nuclear envelope.
A
The key target = nuclear lamins
- cyclical process
- phosphorylated lamins move WITH chromosomes so that when they arrive at their daughter cell, they can regeerate a nuclear envelope
23
Q
What important check has to be done at metaphase?
A
- mitosis can’t proceed until chromosomes are properly attached and under tension
- spindle checkpoint: monitors the number of connections of chromosome to the spindle & the orientation of said connections (to make sure that chromosomes are tensioned properly and => ready to move across
24
Q
What happens at Anaphase? What defects can occur at anaphase? Give an example of a condition that can arise from said defect.
A
- the inhibitory signal in anaphase is lost and the chromosomes separate out
the cohesion complex is what holds the sister chromatids together and prevents them from moving apart too quickly - defects in this cohesion can cause disease:
e.g. Roberts syndrome: cohesions are not held so tightly together
25
What are the various molecules involved in the process of metaphase -> anaphase?
Inhibitory protein = securin, which is ubiquitinated and degraded.
Separase is activated by active APC (anaphase promoting complex). Separase controls the cleavage of the cohesion complex
26
What can defects at the spindle checkpoint cause?
Aneuploidy (cancer, wrong no. chromosomes)
27
What happens in cytokinesis?
The remaining microtubules form a central spindle
Nuclear envelope is formed
Contractile ring of actin & myosin filaments forming a cleavage furrow between the 2 cells
28
Explain necrosis, and the various types that there is.
```
It is a lack of blood supply. Is pathological and generally affects a solid mass of tissue. It evokes an inflammatory response.
The 6 types are:
1. Coagulative = most common
2. Colliquative = the brain
3. Caseous = tuberculosis
4. Gangrene = putrefaction
5. Fibrinoid = arterioles of malignant hypertension
6. Fat = follow from trauma/pancreatitis
```
29
What are the key pathways that lead to apoptosis?
Affects single cells not tissues
1. Nuclear condensation
2. Cell fragmentation
- DNA fragmentation: p53 = inducible transcription factor that is induced by dna damage and forms a tetramere.Tells cells to: stop growing, repair, apoptosis
3. Phagocytosis
The recognition by macrophages & non professional phagocytes
- clearance of apoptotic cells requires the reorganisation of phosphatidylserine
30
How is apoptosis triggered?
EXTRINSICLY:
- receptors e.g. TNF family, Fas CD59 (caspases activation)
- T cells e.g. viral infection, transplant rejection
INTRINSICLY
- stress
- dna damage & p53
mitochondrial damage = proteins leak out, these are the proteins that can cause apoptosis
- note: this can be opposed, and the release of cytochrome C from mitochondria is the key step
31
What are caspases?
IAP: can stop signal getting to cytosol to activate caspases ( at the level of the mitochondrion)
this can result in resistance of death completely
Caspases are the cascade that break down proteins, DNA, fragments of the cell into bodies
32
What happens when apoptosis goes wrong?
autoimmune disease
cancer
neurodegeneration
33
Define (i) anoikis and (ii) pyroptosis.
(i) death after losing contact with the basement membrane/ extracellular matrix. Its morphology = apoptosis
NOTE: a key feature of metastasis is to overcome anoikis
(ii)"fever falling"
-microbial trigger e.g. salmonella
- pattern recognition receptors (NOD & TOL like)
- has similar features to BOTH a&n: caspase 1 activation (not caspase 3) nuclear fragmentation BUT NOT cytoplasmic blebbing, pro inflammatory
34
What is the importance of balance between pro an anti apoptotic factors; especially the Bcl2 family?
They control apoptosis
Bcl2 family: 2 of them can stop apoptosis. They are an anti-death signal.
Bax = pro death signal
it becomes a trial of strength (i.e. die or stay alive?)
Abnormal (i.e. overexpression) of Bcl2 can cause cancer
35
What are the 5 main classes of cholesterol? What do these classes vary in?
1. HDL
2. IDL
3. LDL
4. VLDL
5. Chylomicron
They vary in:
- core lipids
- apoproteins
- size
-density
36
How is cholesterol transported?
Chylomicrons transport TG & cholesterol from the GI to tissues
- they are split by lipoprotein lipase to release FFA (free fatty acids)
- FFA's are taken up by muscle & adipose
Chylomicron remnants are taken up by the liver
- the TGs are removed from VLDL, leaving LDL w. a high cholesterol (taken up by cells/liver)
HDL absorbs cholesterol from cell breakdown and transfers it to VLDL and LDL
37
What is hyperlipidaemia?
An increase in the plasma concentration
38
What is a common feature of atherosclerosis What can this lead to?
Increase in the plasma lipids (particularly cholesterol)
May lead to ischaemic heart disease, MI & cerebral vascular accidents
NOTE: increased risk of AS & CHD are associated with a high plasma conc of total AND LDL cholesterol
39
List the values for (i) Average cholesterol in UK (ii) Ideal (iii) mildly high (iv) moderately high (v) very high
(i) 5.7 mmol/L
(ii) less than 5mmol/L
(iii) 5 - 6.4 mmol/L
(iv) 6.5 - 7.8 mmol/L
(v) greater than 7.8 mmol/L
40
What are the drugs used to lower blood cholesterol levels? (HINT: there's 4 types)
1. Reduce cholesterol absorption/sequester bile acids in intestine
= colestyramine
2. Inhibit transport protein for cholesterol in the brush border of enterocytes in duodenum
= ezetimibe
3. Alter the levels of plasma lipoproteins
= fenofibrate, bezafibrate, gemfibrozil (& nicotinic acid)
4. Inhibit cholesterol synthesis
= simvastatin, pravastatin, atorvastatin, rosuvastatin
41
What 3 sources is cholesterol derived from?
1. De novo synthesis in liver
2. Uptake from circulating LDLs
3. Uptake from chylomicron remnants
42
What is the MoA for (i) cholestyramine (ii) niacin ?
(i) basic anion exchange resin
- sequester bile acids, preventing enterohepatic recirculation
- decreased absorption of exogenous cholesterol
- increased metabolism of endogenous cholesterol into bile acids
- increased LDL receptor numbers in liver, resulting in removal of LDLs from the blood
These plus statins can lower blood cholesterol by 50%
(ii) vitamin with lipid lowering properties
- decreased VLDL production leads to decreased LDL
- activated lipoprotein lipase
43
For Fibrates, (i) what is the MoA (ii) what are their clinical uses ?
(i) activators of lipoprotein lipase
- decrease plasma TGs, and, (to a lesser extent) cholesterol
- particularly decreased elevated concentrations of VLDL
- the main action = stimulation of lipoprotein lipase which decreases the TG content of VLDL
- clearance of LDL by the liver is also stimulated
- increased HDL production & reverse cholesterol transport
(ii) mixed dyslipidaemia - raised serum TG as well as cholesterol
Patients with low LDL and high risk atheromatous disease - type 2 diabetes
Combined w. other lipid lowering drugs in patients with severe treatment resistant hyperlipidaemia
44
For statins, (i) what is the MoA (mentioning the mevalonate pathway and protein prenylation) (ii) what are their clinical uses?
(i) Are HMG - CoA reductase inhibitors
`HMG - CoA = major rate limiting step in cholesterol synthesis
- converts HMG-CoA to mevalonic acid (MVA)
Simvastatin, pravastatin, atorvastatin & rosuvastatin are all long lasting HMG - CoA reductase inhibitors
Mevalonate pathway:
one half is cholesterol synthesis
one hald is protein prenylation (=addition of lipid tails to small GTPase signalling molecules, ensures they are localised correctly)
(ii) secondary prevention of MI & stroke in those who have atherosclerotic diseases
Primary prevention of arterial disease in patients w. high serum cholesterol
Atorvastatin lowers serum cholesterol in familial hypercholesterolaemia
45
What are the side effects of each of these lipid lowering drugs?
STATINS: myositis, angio-oedema, GI disturbances, insomnia, rash
FIBRATES: myositis, GI disturbances
NICOTINIC ACID: flushing, palpitations, GI disturbances
COLESTYRAMINE: GI symptoms (nausea, abdominal bloating, constipation, diarrhoea)
46
Define the terms HLA and MHC. Briefly outline their relevance to tissue transplantation.
```
HLA = human leukocyte antigen
MHC = major histocompatibility complex
```
47
What is thymic education?
- small double lymphocytes initially express low levels of TcR
- most of the TcR's don't recognise your own MHC => T cells die because of a lack of "positive selection"
- those left, go on to mature and express high levels of TcR. They also become single positive cells (either CD4 or CD8)
- during this, the cells also undergo 'negative selection' to eliminate T cells that see own MHC with high affinity (i.e. could become autoreactive T cells)
48
Describe the structure of a TcR molecule.
- almost like an immunoglobulin, but not quite
- has 2 polypeptide chains, membrane bound, each with a V and C domain
- binding site is v.similar to that of an Ab
- undergo chromosomal rearrangement (similar to Ab genes)
49
Describe, and state the differences between, the class I and class II MHC molecules.
CLASS I:
- 2 chains (heavy & small beta2 microglobulin)
- US forms groove: 8-10 aa peptides sit
- expressed on almost every cell in body (not RBC, and low levels neurally)
- recognised by CD8 T cells
CLASS II:
- 2 chains (alpha & beta - both membrane bound)
- US groove: over 20 aa peptides sit
- expression more limited to specialised antigen presenting cells & immune cells (macrophages, DC, B&T cels)
- recognised by CD4 T cells
50
What environments do (i) Class I and (ii) Class II pick up peptides from?
(i) picks up peptides mostly derived from the internal contents of the cell i.e. cytoplasm & nucleus
meets peptides in the endoplasmic reticulum
(ii) picks up peptides mostly derived from the external contents of the cell
meets peptides in endosomes
51
Explain the relevance of MHC molecules to autoimmunity, giving examples.
Ankylosing spondylitis = HLA-B27
Multiple sclerosis = HLA-DR2
Type 1 IDDM = HLA-DR3/DR4
Rheumatoid arthritis = HLA-DR4
52
Why is MHC disparity a major factor in graft rejection?
Because own T cells are educated to see your own MHC molecules, anyone else's are just different enough to cause a response
=> MHC matching is crucial
- even after a full match, you can still have enough different peptides to trigger a slow graft rejection
=> immunosuppression is still required
53
What are superantigens?
some bacteria & viruses produce proteins that interfere with the interaction of TcR & MHC, stimulating large numbers of T cells
54
How are B and T cells are activated?
They are activated by cytokines, which are released by cells in response to an activating stimulus.
55
What is a chemokine? What are the two main groups of chemokines?
A class of cytokine with chemoattractant properties
(Interleukins = cytokines released by leukocytes)
2 Main Groups:
(1) CC - which bind to CCR 1 to 9
e.g. IL-8
(2) CXC - bind to CXCR 1 to 5
e.g. IL-2, IL-4,
56
What 2 types of cell do CD4 T cells differentiate to?
(1) Th1 cell - macrophage activation, B cell activation & production of opsonising Ab (e.g. IgG1)
IN GENERAL: produces cell mediated immunity
(2)Th2 cell - general activation of B cells to make Ab
IN GENERAL: produce Ab responses
57
Describe dendritic cells and their function.
- professional antigen presenting cells that sit at the interface between the innate & adaptive immune response
- found in most surface epithelia (highly phagocytic)
- upon stimulation, they cease phagocytosis and migrate to lymph nodes - where they activate T cells (and influence B cells)
- DC express PRR (pattern recognition receptors) = members of the toll like receptor family (TLR)
...several PMN cells also express PRR, hence linking to innate immunity.
58
"TLR on DC" Explain this statement, and give examples.
Is something that you wouldn't normally have in circulation
=> the presence of them is a danger signal to the immune response
TLR 1 & 2 : lipopeptides
TLR 4 : lipopolysaccharide, heat shock protection
59
What are the various interleukons, interferons, and TNF's that you need to know? (give their function also)
```
IL-8 = chemotactic facotr, recruits neutrophils & T cells to the site of infection
IL-2 = activates T cells, involved in proliferation
IL-4 = activated B cells, switches them to produce IgE (=> important in allergy)
IFN-gamma = activates strong cell mediated responses (e.g. CTL)
TNF-alpha = activated vascular endothelium and increases vascular permeability
IL-12 = differentiated CD4 helper T cells into Th1 cells, also activates NK cells
```
60
What does meiosis produce? What does it involve?
produces haploid cells (gametes)
- one round of DNA replication and 2 divisions
=> the outcome has only half the amount of genetic material
61
What is the difference between meiosis and mitosis when chromosomes line up at the metaphase plate?
in meiosis = homologous chromosomes are paired
| in mitosis = homologous chromosomes line up independently
62
What features of meiosis contribute to genetic diversity? (HINT: there's 2)
(1) independent assortment of maternal and paternal homologs during meiosis I
(2) crossing over during meiotic prophase I (recombination, chiasma formed - holiday junction)
NOTE: control of meiosis is mediated by many of the same molecules as mitosis
63
Distinguish between meiosis in the male and female
Males = spermatogenesis
- continuous cycle of sperm production
Females = oogenesis
- discontinuous cycle
- Meiosis I starts during foetal stage development, not complete till 1st ovulation
- Polar body is formed => losing genetic info
- doesn't undergo meiosis II till fertilised
64
Discuss potential reasons for meiotic errors and explain the consequences. What do the fertilisation of these errors result in?
1. NON-DISJUNCTION (MI error):
- one daughter cell ends up with both copies of the duplicated chromosome, leaving the other cell with nothing
In chromosome 21: 3 copies = downs syndrome and 1 copy = not viable
2. In MII
- same sort of issue, but KEY difference = the aneuploid chromosome contains chromosomes that are BOTH parental (i.e. identical)
- fertilisation of these errors results in the formation of a trisomic zygote
After MI error = uniparental heterodisomy
After MII error = uniparental isodisomy
65
How are cohesion complexes degraded?
The division is staggered in order to prolong the time that the cohesion complexes are at the centromere
During metaphase I -> anaphase I: cohesion complexes are degraded, but those at the centromere are kept until Meiosis II - when they are degraded.
66
What are the changes in the distribution of active bone marrow with age?
At birth, most of the marrow in our bodies is red marrow
| - yellow marrow increases with age
67
Describe, and explain, the production of erythrocytes.
Erythrocytes are produced by erythropoiesis
- where an erythroblast proliferates (6-7 divisions) and matures into a smaller functional cell that can be released into the bloodstream (reticulocytes)
- as this happens, the nucleus is also expelled
68
What is the role of erythropoietin in erythropoiesis?
The role of erythropoietin is to control red blood cell production by regulating the differentiation and proliferation of erythroid progenitor cells in the bone marrow.
It is produced primarily in the kidney, erythropoietin circulates in the plasma and acts on target cells in the bone marrow.
69
What are the changes in erythropoiesis occurring (i) at altitude, (ii) after hypertransfusion, (iii) in chronic renal failure and (iv) patients with some kidney tumours?
(i) EPO increases => red cell mass increases
(ii) EPO decreases => switching off of RBC production
(iii) EPO loss => anaemia
(iv) EPO excess => polycythaemia (too many RBCs)
70
How can stem cells and progenitor cells can be assayed in vitro?
NO CLUE
