BMS3031 Theme VI Flashcards
1
Q
Define chronic disease
A
- Prolonged in duration
- Does not often resolve spontaneously
- Is rarely cured completely
2
Q
Examples of chronic disease
A
- Cardiovascular diseases (heart attacks, stroke)
- Cancers
- Chronic respiratory disease (COPD, asthma)
- Chronic kidney disease (CKD)
- Diabetes
3
Q
Features of chronic diseases
A
- Complex causality - multiple factors involved
- Long development period - during which there may be no symptoms
- Prolonged course of illness, perhaps leading to other health complications
4
Q
How many deaths (percentage) are due to non-communicable diseases?
A
60%
5
Q
Risk factors for chronic diseases
A
- Ageing
- Societal factors: poverty, affluence, living conditions, food (availability and quality), access to healthcare
- Globalisation of unhealthy lifestyles
- Modifiable behavourial risk factors
- Metabolic/Physiological risk factors
- Suboptimal fetal/neonatal development
6
Q
Examples of modifiable behavourial risk factors
A
- Tobacco
- Physical inactivity
- Alcohol
7
Q
Examples of metabolic/physiological risk factors
A
- Raised blood pressure
- Overweight/Obesity
- Hyperglycaemia
- Hyperlipidaemia
8
Q
Define the Barker Hypothesis
A
The Barker hypothesis proposed that adverse nutrition in early life, including prenatally as measured by birth weight, increased susceptibility to the metabolic syndrome which includes obesity, diabetes, insulin insensitivity, hypertension, and hyperlipidemia and complications that include coronary heart disease and stroke
9
Q
Link between birth weight and disease
A
There is now considerable evidence linking both low and high birth weight with increased risk of disease in adult life
10
Q
Link between birth weight and blood pressure
A
Low birth weight is associated with elevated blood pressure
11
Q
The Dutch Hunger Winter
A
December 1944 - April 1945
Rations cut to 200-400 calories a day
By 50 years of age:
Early gestation had: atherogenic plasma lipid profile, central obesity, increased risk of coronary heart disease
Late gestation had: impaired glucose tolerance
12
Q
What are the three pairs of excretory organs
A
- Pronephroi
- Mesonephroi
- Metanephroi –> permanent kidney
13
Q
Metanephric Development
A
- Ureteric bud (UB) makes contact with the metanephric mesenchyme (MM) at around day 32 and branches
- First nephrons appear in week 9
- Fetal kidney begins to produce urine around 10 weeks gestation
- Nephrogenesis ceases at approx. 36 weeks of gestation
- No new nephrons after brith
14
Q
Does nephrogenesis continue in premature babies?
A
It does continue however it does so at a slower rate and they usually finish with a lower number of nephrons than normal
15
Q
What signals induce branching morphogenesis?
A
Metanephric mesenchyme signals
16
Q
What signals induce nephrogenesis?
A
Branch tip (ureteric epithelial) signals
17
Q
Nephron Development Stages
A
- Mesenchymal cell condensation
- Epithelial vesicle
- Comma-shaped body
- S-shaped body
- Capillary loop stage glomerulus
- Maturing glomerulus
18
Q
Metanephroi are derived from which two sources?
A
- Ureteric bud
2. Metanephric mesenchyme
19
Q
What does the ureteric bud give rise to?
A
- Collecting ducts
- Calyces
- Pelvis
- Ureter
20
Q
What does the metaneprhic mesenchyme give rise to?
A
- Nephron: glomerulus, proximal convoluted tubule, loop of henle, distal convoluted tubule
- Interstitium
21
Q
Define Chronic Kidney Disease
A
CKD is defined as kidney damage for >3 months with/without decreased GFR, or GFR <60ml/min/1.73m2 for >3 months with/without kidney damage
22
Q
What percentage of the world are affect by CKD?
A
10%
23
Q
What are the main causes of CKD?
A
Diabetes
High Blood Pressure
24
Q
What is CKD the major cause of?
A
Hypertension
25
What is CKD a major risk multiplier of?
CVD
26
Who is CKD most prevalent in?
Disadvantaged populations in industrialised nations
27
Is there a cure for CKD?
No
28
What is the function of most treatments for CKD?
To slow the rate of decline of kidney function or to replace various kidney functions
29
In 2015, how much did the US Medicare spend on kidney dialysis?
$34 billion
30
In 2010 how many people died from lack of access to dialysis and transplantation in low income countries?
2.3-7.1 Million People
31
Define the Brenner Hypothesis
The Brenner Hypothesis states that individuals with a congenital reduction in nephron number have a much greater likelihood of developing adult hypertension and subsequent renal failure.
32
Brenner Hypothesis Steps
1. Low nephron number
2. Decreased filtration surface area
3. Decreased filtered load
4. Increase in sodium and fluid retention
5. Increase in extracellular fluid volume
6. Increased arterial pressure
7. Increased glomerular capillary pressure
8. Increased SNGFR
9. Glomerular hypertrophy
10. Glomerulosclerosis
1. Low nephron number
33
Low protein diet in rats - Sex Differences
Females: no difference observed
Males: reduced nephron number, larger glomeruli, increased MAP, reduced renal renin content and tissue Ang II
34
How long does it take to count the total number of glomeruli using a disector/fractionator
6 hours for a rat
| 10 hours for a human
35
What was the Keller study?
Study on 20 white accident victims to estimate their total nephron count
10 hypertensives
10 normotensives
His study agreed with the Brenner Hypothesis
36
What was the link between Indigenous Australians with a history of hypertension and the number of glomerulil?
In Indigenous Australians with a history of hypertension they are 250,000 fewer glomeruli than those without a history
37
Why do we estimate glomerular number and size?
- Obtain a measure of functional nephron/glomerular mass
- Enable more accurate estimation of SNGFR
- Estimate function nephron mass in patients newly-diagnosed with CKD
- Determine the effectiveness of therapy in patients with CKD
- Estimate nephron number in children born small or premature and identify those to monitor closely
38
What is epigenetics?
The process of development from a single cell at conception through to birth and beyond
The molecular mechanisms that control gene activity that enable this process to occur
39
Do epigenetic mechanisms work together?
yes
40
Where to epigenetic mechanisms act?
They act at DNA regions that regulate genes to facilitate 3D actions
41
At what level can epigenetic mechanisms act?
Level of gene, gene clusters, chromosomes and genomes
42
Are epigenetic mechanisms reversible?
Yes
43
What are epigenetic mechanisms influenced by?
Genetics, environment, and developmental noise
44
What disease are epigenetic mechanisms involved in?
- Cancer development
| - Human chronic diseases
45
What is the role of epigenetic mechanisms?
Change gene activity without changing DNA sequence
| Perpetuate levels of gene activity when cells divide
46
Example of epigenetic mechanism acting at gene level
Acting at gene promoter
| DNA methyl transferase - methylated promoter causing silencing of gene
47
Example of epigenetic mechanism acting at gene cluster level
Prader Willi and Angelman Syndrome
48
Example of epigenetic mechanism acting at chromosome level
X inactivation
49
Example of epigenetic mechanism acting at genomelevel
Erythroblast enucleation
50
Epigenetic changes are reversible through the 4 R's. What are they?
1. Recruiters
2. wRiters
3. Readers
4. eRasers
51
What is the role of Recruiters?
Recruiters are sequence-specific factors that bind to DNA
| Eg. transcription factors and non-coding RNA
52
What is the role of wRiters?
wRiters are epigenetic modifiers that are recruited to the DNA by Recruiters, where they "write" or "re-write" the epigenetic marks
53
What is the role of Readers?
Readers are complexes of proteins that bind ("read") the epigenetic wRiters on the DNA
54
What is the role of eRasers?
eRasers remove wRiters from the DNA after Readers have completed their job
55
Examples of Recruiters
Transcription factors
| Long non-coding RNAs
56
Examples of wRiters
Methyl/Acetyl transferases
57
Examples of re-wRiters
Methyl, Acetyl
58
Examples of Readers
Chromodomain proteins
59
Examples of eRasers
Histone deacetylases (HDACs)
60
Example of how epigenetic mechanisms are affect by genes
CpG islands, cause DNA methylation and gene silencing
61
Example of how epigenetic mechanisms are affect by environment
Being exposed to royal jelly causes a bee to become a queen bee, by being larger and living longer
62
Example of how epigenetic mechanisms are affect by developmental noise
Drugs are their effect on babies in gestation
63
Epigenetic mechanisms and cancer
- Genome-wide loss of DNA methylation
| - Gain of DNA methylation: silencing of tumour suppressor genes
64
How has understanding epigenetic mechanisms helped with cancer?
- We now have commercial biomarkers or prediction, diagnosis and prognosis
- Clinical trials of epigenetic therapies
65
What is the prevalence of fetal alcohol spectrum disorder?
2-5% of children, >30% in juvenile detention
66
What are the symptoms of fetal alcohol spectrum disorder?
```
Facial abnomalities
Short height
Low weight
Poor coordination
Behavioural problems
Learning difficulties
```
67
What causes 95% of celebral palsy?
Damage to the brain that occurred during pregnancy or birth
68
What percentage of children with cerebral palsy were born with low birth weight?
>40%
69
What percentage of babies in Australia are born pre-term (<37 weeks)
8.7%
70
What percentage of babies born preterm in the <34 weeks period receive a complete course of antenatal glucocorticoids
70%
71
What is the effect of antenatal glucocorticoids in pre-term babies?
- Decreases perinatal mortality by 50%
- Decreases the incidence of respiratory distress syndrome by 40%
- Also has a range of effects of the CVS and brain
72
What is cerebral palsy?
- It is the most common physical disability of childhood
- Occurs as a result of a lesion within the brain during brain development
- The injury is non-progressive
- Predominantly, the lesion affects the white matter of the brain - termed periventricular leukomalacia
73
What are 4 causes of brain injury in development?
1. Intrauterine growth restriction (FGR)
2. Intrauterine infection
3. Birth asphyxia
4. Preterm birth
74
Brain Development Stages
1. Formation of neural tube
2. Cell generation
3. Migration
4. Formation of specific populations
5. Cell lineage
6. Neuronal Differentiation
7. Axonal Growth - the growth cone
8. Axonal Guidance
9. Synaptogenesis
10. Myelination
75
Are there any antenatal interventions that can ensure the fetus remains in utero for longer?
Tocolytic therapy
76
Do tocolytics improve neonatal outcome?
They do not improve neonatal outcome on their own, but they are effective at delaying labour for 48 hours, which can provide time to give a course of glucocorticoids to mature the lungs.
77
Examples of tocolytics
- Prostaglandin inhibitors
- Magnesium sulfate
- Calcium channel blockers
78
Risk factors for cerebral palsy
- Viral infections
- Chorioamnionitis
- Intrauterine infection
79
Why does infection during pregnancy lead to brain injury during development?
Infection produces a strong fetoplacental inflammatory response and increase pro-inflammatory cytokines which can access the fetal brain.
80
Possible therapies for infection during pregnancy to prevent brain injury
- Antibiotics
- Anti-inflammatory drugs
- Stem cells
81
Define Intrauterine/Fetal Growth Restriction
FGR describes a fetus that fails to grow appropriatelyin utero, most often due to poor placental function
82
How is FGR diagnosed?
It is diagnosed with an estimated fetal weight below the 10th percentile, together with abnormal placental Doppler (blood flow)
83
What can FGR cause?
```
Structural deficits:
Reduced:
-head circumference
-total and grey matter volume
-hippocampal and cerebellar volume
-total number of cells
-myelin content
-connectivity
-Thinning cortex with altered gyrification
-Delayed myelination
Functional deficits:
-reduced gross and fine motor skills
-reduced visuomotor skills
-clumsiness
-cerebral palsy
-Reduced IQ/executive function
-Reduced verbal IQ
-poor memory
-attention and interaction
-hyperactivity
-mood and irritability
-anxiety
```
84
What was the affect of sildenafil citrate (Viagra) for FGR?
In sheep, antenatal sildenafil treatment adversely affected FGR and control fetuses:
- induced hypoxia, and worsened hypoxia in FGR
- caused a pronounced cardiovascular response
- it removed the brain sparing action
85
Affects on the brain from FGR
- Low myelination
| - High levels of oxidative stress
86
What was the affect of melatonin on FGR?
1. Improved placental blood flow
2. Decreased oxidative stress
3. Did not prolong pregnancy
4. Reduced the incidence of brain haemorrhage
5. Improved cardiovascular outcomes
87
What was the affect of glucocorticoids on FGR?
```
Good
1. Fetal lung cell maturation
Bad
1. Hypertension
2. Increased vascular resistance
3. Mild hypoxaemia
4. Growth restriction
5. Decreased brain weight
6. Altered brain development
```
88
Should glucocorticoids be used on both preterm babies and FGR babies?
It has been suggested that glucocorticoids should be used sparingly in pregnancy, as it so far seems okay in the brain of control babies but it certainly has a higher negative impact on FGR babies
FGR babies also naturally have higher levels of steroids due to the higher amount of stress they are under
89
Define perinatal asphyxia
It is described as a severe and prolonged lack of oxygen immediately before or during birth
90
Causes of perinatal asphyxia
- Inadequate uterine relaxation
- Cord compression
- Placental abruption
91
What is the resultant brain injury called that is caused by perinatal asphyxia?
Hypoxic Ischemic Encephalopathy (HIE)
92
What is the incidence of HIE?
2/1000 births
93
Current best treatment option for HIE caused by perinatal asphyxia?
HYPOTHERMIA
| If begun soon after birth significantly reduces death and disability in infants with HIE
94
Possible treatments for HIE
- HYPOTHERMIA
- Anti-oxidants
- Stem cells
95
When was the first ultrasound?
1956
96
What can you detect about pregnancy with an ultrasound?
- Pregnancy location
- Accurate dating
- Chorionicity (number of embryos)
- Fetal biometry
- Fetal anatomy
- Fetal Wellbeing
- Umbilical artery
- Middle cerebral artery
- Ductus Venosus
97
What procedures can be done guided by ultrasound?
- Chorionic Villi Sampling
| - Amniocentesis
98
When was the first MRI for pregnancy?
1983
99
Compare ultrasound and MRI for assessing the fetal brain
MRI potentially offers superior benefit in further assessing ultrasound detected abnormalities in the fetal brain. Such as ventriculomegaly
100
Define fetoscopy
It is an endoscopic procedure during pregnancy to allow surgical access to the fetus, the amniotic cavity, the umbilical cord, and the fetal side of the placenta.
101
When is a fetoscopy used?
- Monochorionic twins for twin-twin transfusion syndrome
- Tracheal occlusion for congenital diaphragmatic hernia
- Surgery for spina bifida
- Myelomeningocoele
102
How can the mother's circulation be used to determine information about the fetus?
Can look for fetal biomarkers released into maternal blood such as RNA and DNA
103
Benefits of analysing the mother's blood for fetus biomarkers?
It is non-invasive
104
Steps involved in analysing the mother's blood for fetal biomarkers
1. Maternal blood sample
2. Extract RNA in the lab
3. RNA-seq or microarray
4. Bioinformatic discovery
5. PCR - validation
6. New test for FGR or stillbirth
105
Why should in utero fetal therapies be researched?
It may enable treatment to be commenced during fetal development, a time when certain diseases can begin to exert pathology.
May provide the potential for disease cure or significant improvements in quality of life
106
What fetal conditions have maternally administered drugs for fetal therapy?
- Fetal tachyarrhymias
- Fetal lung and brain maturity
- Congenital adrenal hyperplasia
- Hypothyroidism
107
What maternally administered drugs for fetal therapy are currently in trial?
- Melatonin
| - Creatine
108
What is the theory behind in utero stem cell therapy?
Promise of normal cell integration to prevent disease development
109
Have haematopoietic stem cells been successful at all?
They have been successful in severe combined immunodeficiency
110
Have mesenchymal stem cells been successful at all?
They have shown promise in osteogenesis imperfecta
111
Have stem cells in general been successful at all in utero
Overall, the results up to date have been disappointing
112
What does fetal gene therapy provide promise for?
- Cystic fibrosis
- Duchenne muscular dystrophy
- Haemophilia
- Spinal muscular atrophy
- Thalassaemia
- Urea cycle defects
- Immunodeficiencies
113
When was fetal gene editing developed?
2012
114
How does fetal gene editing work?
Gene editing is done using CRISPR/Cas9, which enables the modification of the genetic sequence in its native genomic location
115
How can infertility be treated?
Using assisted reproductive technologies (ART)
116
Steps involved in ART
1. The woman is given hormone treatments to stimulate egg production
2. Multiple eggs are taken from the woman's ovaries
3. In the lab, the eggs are mixed with the man's sperm cells in a culture dish to become fertilised
4. The fertilised eggs, or embryos, are placed in an incubator for about 48 hours
5. Embryos are implanted in the woman's uterus or frozen for future implanting
117
How many ART babies are there worldwide?
9 million
118
How successful is ART/IVF?
<40%
119
When do fertility rates begin to drop?
Well before menopause, on average around 36 years old
120
What happens at around 36 years old to cause a drop in fertility?
Primordial follicles decrease drastically
| Primordial follicles are formed during foetal life and remain in an arrested state for forty years
121
What percentage of women are >35 in IVF programs?
>65%
122
Compare the number of pregnancies in women >35yo in 1970 vs 2012
In 1970 5%
| In 2012 30%
123
What happens to oocyte quality over time?
The quality decreases, beginning around 36yo
124
What is the association between a woman's age and risk of aneuploidy?
As the maternal age increases so too does the risk of aneuploidy
125
Why are oocytes so susceptible to replication errors?
Because they go through meiosis in two stages, when meiosis II occurs the oocyte may be quite old and the spindles may be disrupted
126
How is aneuploidy generated?
It can occur in either stage of meiosis
Meiosis I is more prone to chromosomal errors such as non-disjunction
Meiosis II is more prone to premature chromatid separation
127
How do chromosomal errors arise in meiosis I?
-Merotelic attachment
-Premature separation into univalents
-Bivalent rotation
These can result in:
-Lagging chromosome
-Premature separation of sister chromatids
128
What is merotelic attachment?
It is where two microtubules from opposite poles attach to the same kinetochore, causing the chromosome to lag
129
Association between lagging chromosomes and maternal age?
Lagging chromosomes increase with increasing maternal age
130
What does cohesin loss cause?
Segregation errors
131
What is the role of cohesin?
Cohesin (Rec8) holds chromosomes together and is decreased in old age
132
What is the role of mitochondrial ATP?
It maintains the mitotic spindle
133
What does oligomycin do?
It blocks ATP synthase
134
What triggers the oocyte to embryo transition?
Calcium oscillations
135
What stimulates mitochondrial ATP production?
Fertilisation
136
Association between calcium and mitochondrial ATP
Calcium mediated activation of mitochondria matches ATP supply and demand
137
Association between oocytes and mitochondria
If mitochondria are reduced in number and/or activity, the meiotic spindle will be interrupted and the oocyte is likely to produce an aneuploidy
138
What is the effect of mitochondria targeted antioxidants?
They can reverse ageing associated spindle defects
