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BMS3031 > BMS3031 Theme VI > Flashcards

BMS3031 Theme VI Flashcards

1
Q

Define chronic disease

A
  • Prolonged in duration
  • Does not often resolve spontaneously
  • Is rarely cured completely
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2
Q

Examples of chronic disease

A
  • Cardiovascular diseases (heart attacks, stroke)
  • Cancers
  • Chronic respiratory disease (COPD, asthma)
  • Chronic kidney disease (CKD)
  • Diabetes
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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
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4
Q

How many deaths (percentage) are due to non-communicable diseases?

A

60%

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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
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6
Q

Examples of modifiable behavourial risk factors

A
  • Tobacco
  • Physical inactivity
  • Alcohol
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7
Q

Examples of metabolic/physiological risk factors

A
  • Raised blood pressure
  • Overweight/Obesity
  • Hyperglycaemia
  • Hyperlipidaemia
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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

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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

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10
Q

Link between birth weight and blood pressure

A

Low birth weight is associated with elevated blood pressure

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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

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12
Q

What are the three pairs of excretory organs

A
  • Pronephroi
  • Mesonephroi
  • Metanephroi –> permanent kidney
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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
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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

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15
Q

What signals induce branching morphogenesis?

A

Metanephric mesenchyme signals

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16
Q

What signals induce nephrogenesis?

A

Branch tip (ureteric epithelial) signals

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17
Q

Nephron Development Stages

A
  • Mesenchymal cell condensation
  • Epithelial vesicle
  • Comma-shaped body
  • S-shaped body
  • Capillary loop stage glomerulus
  • Maturing glomerulus
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18
Q

Metanephroi are derived from which two sources?

A
  1. Ureteric bud

2. Metanephric mesenchyme

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19
Q

What does the ureteric bud give rise to?

A
  • Collecting ducts
  • Calyces
  • Pelvis
  • Ureter
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20
Q

What does the metaneprhic mesenchyme give rise to?

A
  • Nephron: glomerulus, proximal convoluted tubule, loop of henle, distal convoluted tubule
  • Interstitium
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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

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22
Q

What percentage of the world are affect by CKD?

A

10%

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23
Q

What are the main causes of CKD?

A

Diabetes

High Blood Pressure

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24
Q

What is CKD the major cause of?

A

Hypertension

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25
Q

What is CKD a major risk multiplier of?

A

CVD

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26
Q

Who is CKD most prevalent in?

A

Disadvantaged populations in industrialised nations

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27
Q

Is there a cure for CKD?

A

No

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28
Q

What is the function of most treatments for CKD?

A

To slow the rate of decline of kidney function or to replace various kidney functions

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29
Q

In 2015, how much did the US Medicare spend on kidney dialysis?

A

$34 billion

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30
Q

In 2010 how many people died from lack of access to dialysis and transplantation in low income countries?

A

2.3-7.1 Million People

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31
Q

Define the Brenner Hypothesis

A

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.

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32
Q

Brenner Hypothesis Steps

A
  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
  11. Low nephron number
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33
Q

Low protein diet in rats - Sex Differences

A

Females: no difference observed
Males: reduced nephron number, larger glomeruli, increased MAP, reduced renal renin content and tissue Ang II

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34
Q

How long does it take to count the total number of glomeruli using a disector/fractionator

A

6 hours for a rat

10 hours for a human

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35
Q

What was the Keller study?

A

Study on 20 white accident victims to estimate their total nephron count
10 hypertensives
10 normotensives
His study agreed with the Brenner Hypothesis

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36
Q

What was the link between Indigenous Australians with a history of hypertension and the number of glomerulil?

A

In Indigenous Australians with a history of hypertension they are 250,000 fewer glomeruli than those without a history

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37
Q

Why do we estimate glomerular number and size?

A
  • 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
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38
Q

What is epigenetics?

A

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

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39
Q

Do epigenetic mechanisms work together?

A

yes

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40
Q

Where to epigenetic mechanisms act?

A

They act at DNA regions that regulate genes to facilitate 3D actions

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41
Q

At what level can epigenetic mechanisms act?

A

Level of gene, gene clusters, chromosomes and genomes

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42
Q

Are epigenetic mechanisms reversible?

A

Yes

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43
Q

What are epigenetic mechanisms influenced by?

A

Genetics, environment, and developmental noise

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44
Q

What disease are epigenetic mechanisms involved in?

A
  • Cancer development

- Human chronic diseases

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45
Q

What is the role of epigenetic mechanisms?

A

Change gene activity without changing DNA sequence

Perpetuate levels of gene activity when cells divide

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46
Q

Example of epigenetic mechanism acting at gene level

A

Acting at gene promoter

DNA methyl transferase - methylated promoter causing silencing of gene

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47
Q

Example of epigenetic mechanism acting at gene cluster level

A

Prader Willi and Angelman Syndrome

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48
Q

Example of epigenetic mechanism acting at chromosome level

A

X inactivation

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49
Q

Example of epigenetic mechanism acting at genomelevel

A

Erythroblast enucleation

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50
Q

Epigenetic changes are reversible through the 4 R’s. What are they?

A
  1. Recruiters
  2. wRiters
  3. Readers
  4. eRasers
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51
Q

What is the role of Recruiters?

A

Recruiters are sequence-specific factors that bind to DNA

Eg. transcription factors and non-coding RNA

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52
Q

What is the role of wRiters?

A

wRiters are epigenetic modifiers that are recruited to the DNA by Recruiters, where they “write” or “re-write” the epigenetic marks

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53
Q

What is the role of Readers?

A

Readers are complexes of proteins that bind (“read”) the epigenetic wRiters on the DNA

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54
Q

What is the role of eRasers?

A

eRasers remove wRiters from the DNA after Readers have completed their job

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55
Q

Examples of Recruiters

A

Transcription factors

Long non-coding RNAs

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56
Q

Examples of wRiters

A

Methyl/Acetyl transferases

57
Q

Examples of re-wRiters

A

Methyl, Acetyl

58
Q

Examples of Readers

A

Chromodomain proteins

59
Q

Examples of eRasers

A

Histone deacetylases (HDACs)

60
Q

Example of how epigenetic mechanisms are affect by genes

A

CpG islands, cause DNA methylation and gene silencing

61
Q

Example of how epigenetic mechanisms are affect by environment

A

Being exposed to royal jelly causes a bee to become a queen bee, by being larger and living longer

62
Q

Example of how epigenetic mechanisms are affect by developmental noise

A

Drugs are their effect on babies in gestation

63
Q

Epigenetic mechanisms and cancer

A
  • Genome-wide loss of DNA methylation

- Gain of DNA methylation: silencing of tumour suppressor genes

64
Q

How has understanding epigenetic mechanisms helped with cancer?

A
  • We now have commercial biomarkers or prediction, diagnosis and prognosis
  • Clinical trials of epigenetic therapies
65
Q

What is the prevalence of fetal alcohol spectrum disorder?

A

2-5% of children, >30% in juvenile detention

66
Q

What are the symptoms of fetal alcohol spectrum disorder?

A 
Facial abnomalities
Short height
Low weight
Poor coordination
Behavioural problems
Learning difficulties
67
Q

What causes 95% of celebral palsy?

A

Damage to the brain that occurred during pregnancy or birth

68
Q

What percentage of children with cerebral palsy were born with low birth weight?

A

> 40%

69
Q

What percentage of babies in Australia are born pre-term (<37 weeks)

A

8.7%

70
Q

What percentage of babies born preterm in the <34 weeks period receive a complete course of antenatal glucocorticoids

A

70%

71
Q

What is the effect of antenatal glucocorticoids in pre-term babies?

A
  • 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
Q

What is cerebral palsy?

A
  • 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
Q

What are 4 causes of brain injury in development?

A
  1. Intrauterine growth restriction (FGR)
  2. Intrauterine infection
  3. Birth asphyxia
  4. Preterm birth
74
Q

Brain Development Stages

A
  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
Q

Are there any antenatal interventions that can ensure the fetus remains in utero for longer?

A

Tocolytic therapy

76
Q

Do tocolytics improve neonatal outcome?

A

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
Q

Examples of tocolytics

A
  • Prostaglandin inhibitors
  • Magnesium sulfate
  • Calcium channel blockers
78
Q

Risk factors for cerebral palsy

A
  • Viral infections
  • Chorioamnionitis
  • Intrauterine infection
79
Q

Why does infection during pregnancy lead to brain injury during development?

A

Infection produces a strong fetoplacental inflammatory response and increase pro-inflammatory cytokines which can access the fetal brain.

80
Q

Possible therapies for infection during pregnancy to prevent brain injury

A
  • Antibiotics
  • Anti-inflammatory drugs
  • Stem cells
81
Q

Define Intrauterine/Fetal Growth Restriction

A

FGR describes a fetus that fails to grow appropriatelyin utero, most often due to poor placental function

82
Q

How is FGR diagnosed?

A

It is diagnosed with an estimated fetal weight below the 10th percentile, together with abnormal placental Doppler (blood flow)

83
Q

What can FGR cause?

A 
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
Q

What was the affect of sildenafil citrate (Viagra) for FGR?

A

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
Q

Affects on the brain from FGR

A
  • Low myelination

- High levels of oxidative stress

86
Q

What was the affect of melatonin on FGR?

A
  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
Q

What was the affect of glucocorticoids on FGR?

A 
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
Q

Should glucocorticoids be used on both preterm babies and FGR babies?

A

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
Q

Define perinatal asphyxia

A

It is described as a severe and prolonged lack of oxygen immediately before or during birth

90
Q

Causes of perinatal asphyxia

A
  • Inadequate uterine relaxation
  • Cord compression
  • Placental abruption
91
Q

What is the resultant brain injury called that is caused by perinatal asphyxia?

A

Hypoxic Ischemic Encephalopathy (HIE)

92
Q

What is the incidence of HIE?

A

2/1000 births

93
Q

Current best treatment option for HIE caused by perinatal asphyxia?

A

HYPOTHERMIA

If begun soon after birth significantly reduces death and disability in infants with HIE

94
Q

Possible treatments for HIE

A
  • HYPOTHERMIA
  • Anti-oxidants
  • Stem cells
95
Q

When was the first ultrasound?

A

1956

96
Q

What can you detect about pregnancy with an ultrasound?

A
  • Pregnancy location
  • Accurate dating
  • Chorionicity (number of embryos)
  • Fetal biometry
  • Fetal anatomy
  • Fetal Wellbeing
  • Umbilical artery
  • Middle cerebral artery
  • Ductus Venosus
97
Q

What procedures can be done guided by ultrasound?

A
  • Chorionic Villi Sampling

- Amniocentesis

98
Q

When was the first MRI for pregnancy?

A

1983

99
Q

Compare ultrasound and MRI for assessing the fetal brain

A

MRI potentially offers superior benefit in further assessing ultrasound detected abnormalities in the fetal brain. Such as ventriculomegaly

100
Q

Define fetoscopy

A

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
Q

When is a fetoscopy used?

A
  • Monochorionic twins for twin-twin transfusion syndrome
  • Tracheal occlusion for congenital diaphragmatic hernia
  • Surgery for spina bifida
  • Myelomeningocoele
102
Q

How can the mother’s circulation be used to determine information about the fetus?

A

Can look for fetal biomarkers released into maternal blood such as RNA and DNA

103
Q

Benefits of analysing the mother’s blood for fetus biomarkers?

A

It is non-invasive

104
Q

Steps involved in analysing the mother’s blood for fetal biomarkers

A
  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
Q

Why should in utero fetal therapies be researched?

A

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
Q

What fetal conditions have maternally administered drugs for fetal therapy?

A
  • Fetal tachyarrhymias
  • Fetal lung and brain maturity
  • Congenital adrenal hyperplasia
  • Hypothyroidism
107
Q

What maternally administered drugs for fetal therapy are currently in trial?

A
  • Melatonin

- Creatine

108
Q

What is the theory behind in utero stem cell therapy?

A

Promise of normal cell integration to prevent disease development

109
Q

Have haematopoietic stem cells been successful at all?

A

They have been successful in severe combined immunodeficiency

110
Q

Have mesenchymal stem cells been successful at all?

A

They have shown promise in osteogenesis imperfecta

111
Q

Have stem cells in general been successful at all in utero

A

Overall, the results up to date have been disappointing

112
Q

What does fetal gene therapy provide promise for?

A
  • Cystic fibrosis
  • Duchenne muscular dystrophy
  • Haemophilia
  • Spinal muscular atrophy
  • Thalassaemia
  • Urea cycle defects
  • Immunodeficiencies
113
Q

When was fetal gene editing developed?

A

2012

114
Q

How does fetal gene editing work?

A

Gene editing is done using CRISPR/Cas9, which enables the modification of the genetic sequence in its native genomic location

115
Q

How can infertility be treated?

A

Using assisted reproductive technologies (ART)

116
Q

Steps involved in ART

A
  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
Q

How many ART babies are there worldwide?

A

9 million

118
Q

How successful is ART/IVF?

A

<40%

119
Q

When do fertility rates begin to drop?

A

Well before menopause, on average around 36 years old

120
Q

What happens at around 36 years old to cause a drop in fertility?

A

Primordial follicles decrease drastically

Primordial follicles are formed during foetal life and remain in an arrested state for forty years

121
Q

What percentage of women are >35 in IVF programs?

A

> 65%

122
Q

Compare the number of pregnancies in women >35yo in 1970 vs 2012

A

In 1970 5%

In 2012 30%

123
Q

What happens to oocyte quality over time?

A

The quality decreases, beginning around 36yo

124
Q

What is the association between a woman’s age and risk of aneuploidy?

A

As the maternal age increases so too does the risk of aneuploidy

125
Q

Why are oocytes so susceptible to replication errors?

A

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
Q

How is aneuploidy generated?

A

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
Q

How do chromosomal errors arise in meiosis I?

A

-Merotelic attachment
-Premature separation into univalents
-Bivalent rotation
These can result in:
-Lagging chromosome
-Premature separation of sister chromatids

128
Q

What is merotelic attachment?

A

It is where two microtubules from opposite poles attach to the same kinetochore, causing the chromosome to lag

129
Q

Association between lagging chromosomes and maternal age?

A

Lagging chromosomes increase with increasing maternal age

130
Q

What does cohesin loss cause?

A

Segregation errors

131
Q

What is the role of cohesin?

A

Cohesin (Rec8) holds chromosomes together and is decreased in old age

132
Q

What is the role of mitochondrial ATP?

A

It maintains the mitotic spindle

133
Q

What does oligomycin do?

A

It blocks ATP synthase

134
Q

What triggers the oocyte to embryo transition?

A

Calcium oscillations

135
Q

What stimulates mitochondrial ATP production?

A

Fertilisation

136
Q

Association between calcium and mitochondrial ATP

A

Calcium mediated activation of mitochondria matches ATP supply and demand

137
Q

Association between oocytes and mitochondria

A

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
Q

What is the effect of mitochondria targeted antioxidants?

A

They can reverse ageing associated spindle defects

BMS3031 (1 decks)

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