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Medicine YEAR 1 > Phase 1 - Week 4 (Imaging and Cancer), Phase 2 - Week 5 (Cell Cycle, Achondroplasia) > Flashcards

Phase 1 - Week 4 (Imaging and Cancer), Phase 2 - Week 5 (Cell Cycle, Achondroplasia) Flashcards

1
Q

Tumour

A

Formed by excessive, uncontrolled proliferation of cells as a result of an irreversible genetic change which is passed from one tumour cell to its progeny

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2
Q

Neoplasia

A

New growth

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3
Q

Hyperplasia

A

Increase in size of organ due to cell proliferation e.g. uterus in pregnancy

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4
Q

Hypertrophy

A

Increase in size of organ due to increase in size of constituent cells e.g. left ventricle of heart in hypertension

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5
Q

Dysplasia

A

Disordered epithelial cell growth, characterised by loss of architectural orientation and development of cellular atypia

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6
Q

Metaplasia

A

Change from one type of differentiated tissue to another - can be precursor of dysplasia/cancer

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7
Q

Benign

A

Stay localised at their site of origin

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8
Q

Malignant

A

Able to spread and invade different sites - often fatal

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9
Q

Cancer

A

An abnormal growth of cells which proliferate in an uncontrolled way

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10
Q

Teratoma

A

A tumour that contains elements of all three germ cell layers - ectoderm, endoderm and mesoderm. Composed of tissues foreign to area.

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11
Q

List the types of teratoma

A
  1. Mature cystic teratoma - show wide range of tissues found in adult
  2. Immature teratoma - composed of immature tissues similar to developing embryo
  3. Monodermal teratoma - composed of tissue derived from one germ cell layer
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12
Q

How to teratomas arise?

A

When germ cells differentiate along embryonic lines

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13
Q

Define the cell cycle

A

The series of events that take place in a cell leading to its division and duplication of its DNA to produce two daughter cells

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14
Q

List the stages of the cell cycle

A
  1. Interphase =
    - G1
    - S
    - G2
  2. M Phase
    - Metaphase
    - Cytokinesis
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15
Q

Events of G1

A
  • 1st growth phase
  • Cell grows in size and replicates organelles
  • Monitors external environment
  • Mitogen dependent e.g. growth factors
  • Prepares to undergo DNA synthesis
  • Checkpoints - restriction point, DNA damage G1 checkpoint
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16
Q

Events of the S phase

A
  • Synthesis of a complete copy of the DNA in the nucleus

- Centrosome is also duplicated

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17
Q

Events of G2

A
  • 2nd growth phase
  • Cell grows in size more
  • Makes proteins, duplicates organelles
  • Reorganises contents in preparation for mitosis
  • Duplicated chromosomes checked for damage (G2 checkpoint)
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18
Q

Events of the M phase

A
  • Mitosis - divison of the nucleus

- Cytokinesis - divison of the cytoplasm to produce two daughter cells

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19
Q

List the stages of mitosis

A
  1. Prophase
  2. Metaphase
  3. Anaphase
  4. Telophase
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20
Q

Prophase

A
  • Chromosomes coil up
  • Centrioles move to poles
  • Fibres move from polar centrioles forming spindle
  • Nucleolus disappears
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21
Q

Metaphase

A
  • Chromosomes align at metaphase plate
  • Nuclear envelope breaks down (MPF phosphorylates lamins)
  • Spindle checkpoint - checks all chromosomes are at metaphase plate w/ kinetochores attached to microtubules
  • Microtubules not attached attach to microtubules opposite, stabilising spindle
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22
Q

Anaphase

A
  • Proteins holding sister chromatids together break down

- Separate chromosomes pulled to opposite ends of cell - motor proteins

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23
Q

Telophase

A
  • Mitotic spindle breaks down
  • Two nuclei form
  • Nuclear membranes reform
  • Chromosomes decondense
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24
Q

Cytokinesis

A
  • Division of the cytoplasm to form two new cells
  • Overlaps with final stages of mitosis (starts anaphase/telophase)
  • Contractile - pinching of cell by band of actin filaments. Pinch crease called cleavage furrow
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25
Q

List the checkpoints of the cell cycle and when they occur

A
  1. Restriction point - late G1
  2. G1 DNA damage checkpoint - end of G1
  3. G2 DNA damage checkpoint - end of G2
  4. Metaphase checkpoint - metaphase of mitosis
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26
Q

What does the restriction point check for?

A

Checks for cell size, nutrients and growth factors

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27
Q

Describe the restriction point

A
  • Point of no return - once passed cell is committed to division
  • Mitogen dependent - requires presence of GFs, no longer required after restriction
  • Dependent on accumulation of cyclin D - allows phosphorylation of Retinoblastoma (Rb)
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28
Q

Describe the pathway which takes place if a cell is capable of passing the restriction point

A
  1. Accumulation of GFs
  2. Triggers pathway e.g. RAS
  3. Cyclin D binds to CDK 4/6
  4. Forms cyclin D - CDK 4/6 complex
  5. Phosphorylates Rb
  6. Rb cannot bind to E2F/DP1 (transcription factors)
  7. E2F/DP1 free to cause gene transcription + translation of proteins (e.g. enzymes needed for DNA replication in S phase)
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29
Q

Cyclin

A

Proteins, concentration of which rises and falls throughout cycle, forms complexes w/ CDK

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30
Q

Which cyclin is involved in the restriction point?

A

Cyclin D

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31
Q

Which cyclin is involved in the G1/S checkpoint?

A

Cyclin E/A

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32
Q

Which cyclin is involved in the G2/M checkpoint?

A

Cyclin B

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33
Q

CDK

A

Cyclin dependent kinase. Cyclin must bind to CDK to activate it, allowing it to phosphorylate target proteins.

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34
Q

What is recognised at DNA damage checkpoints?

A

Damage to DNA due to chemical mutagens, radiation, errors in replication etc.

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35
Q

What is the result of damage to DNA at DNA damage checkpoints?

A

p53 activation

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36
Q

p53

A
  • Tetrameric transcription factor (4 molecules in active p53)
  • Inhibits cell cycle progression - low level results in p21 expression, high levels trigger apoptosis
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37
Q

Describe the process which takes place at the G1/S checkpoint if there is DNA damage

A
  • p53 activation
  • p53 activates p21 - Cyclin dependent kinase inhibitor (CKI)
  • Cell cycle halted - cell goes into G0
  • Production of enzymes that repair DNA is stimulated
  • If DNA is repaired cell returns to cell cycle
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38
Q

Describe the process which takes place at the G1/S checkpoint if there is no DNA damage

A

CDK 2-cyclin E/A complex is formed, cell cycle progresses

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39
Q

Describe the process which takes place at the G2/M checkpoint if there is DNA damage

A
  • p53 activation
  • Cell cycle halted
  • Production of enzymes to repair DNA
  • If DNA cannot be repaired, apoptosis is triggered
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40
Q

Describe the process which takes place at the G2/M checkpoint if there is no DNA damage

A

Progression to M phase dependent on CDK 1-cyclin B complex

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41
Q

Maturation promoting factor (MPF)

A
  • CDK 1-cyclin B complex
  • Levels rise during G2
  • Phosphorylates condensins/histones - chromosome condensation
  • Phosphorylates lamins in nuclear membrane - allows it to dissolve for mitosis
  • Triggers formation of mitotic spindle
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42
Q

List the functions of tumour suppressor genes and the proteins they code for

A
  1. Repression of genes needed for progression of cell cycle - inhibit cell division
  2. Coupling the cell cycle to DNA damage - if damage can be repaired cell cycle can continue
  3. If damage cannot be repaired apoptosis is triggered
  4. Some involved in cell adhesion to block loss of contact inhibition + inhibit metastasis
  5. DNA repair proteins
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43
Q

Describe the function of retinoblastoma

A

Blocks transcription factors - E2F/DP1 to halt cell cycle

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44
Q

What is the effect of mutation in Rb or p53?

A

Loss of function, uncontrolled cell cycle, abnormal growth, tumours

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45
Q

Proto-oncogenes

A
  • Normal cellular genes
  • Code for proteins for normal cell division
  • Mutations cause them to become oncogenic
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46
Q

Oncogenes

A
  • Cause uncontrolled cell division
  • Only produced as the result of specific activating mutations
  • Activation of oncogenes allows cells to bypass need for extracellular signals
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47
Q

What do oncogenes code for?

A
  1. Hyperactive version of the protein
  2. Normal protein product but -
    - Abnormal quantities
    - Wrong time
    - Wrong cell type
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48
Q

What is production of a hyperactive protein by oncogenes caused by?

A
  • Point mutation e.g. KI-RAS
  • Deletion
  • Chromosomal rearrangement
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49
Q

What is production of a normal protein, but the wrong time/place/amount by oncogenes caused by?

A
  • Gene amplification

- Chromosomal rearrangement - gene downstream of strong promoter

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50
Q

Explain the basic principles of X-Rays

A
  • IONISING
  • Transmit electromagnetic X-Ray waves through a patient
  • Projected through body onto detector
  • An image is formed for the rays which are detected vs those absorbed/scattered in the patient and not absorbed
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51
Q

What are X-Rays used for?

A
  • Osteoarthritis
  • Pneumonia
  • Bone tumours
  • Fractures
  • Congenital skeletal anomalies
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52
Q

Explain the basic principles of CT scans

A
  • IONISING
  • Computerised tomography
  • Uses X-Rays w/ computer algorithms
  • X-Ray tube opposite detector in ring-shaped apparatus rotates around patient - produces computer generated cross sectional image
  • Can use radiocontrast agents to see anatomy better
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53
Q

What are CT scans used for?

A

Emergency situations:

  • Cerebral haemorrhage
  • Pulmonary embolism
  • Aortic dissection
  • Appendicitis
  • Diverticulitis
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54
Q

Explain the basic principles of MRI scans

A
  • NOT IONISING
  • Strong magnetic field aligns hydrogen ions in body tissues
  • Radio signal disturbs the axis of rotation of the nuclei
  • Observe radio signal generated as nuclei return to baseline states
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55
Q

What are MRI scans used for?

A

Soft tissue:
- Imaging brain, spine and musculoskeletal system

Not suitable for those w/ claustrophobia, pacemakers, cochlear implants etc.

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56
Q

List the ways in which tumours can be classified

A
  1. By biological behaviour - benign vs. malignant

2. By cell of origin - differentiation or histogenesis

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57
Q

Explain the naming of benign epithelial tumours and give examples

A

End in -oma

  • Covering epithelia e.g. skin = papilloma
  • Glandular epithelia (lining tubes or hollow organs e.g. stomach) = adenoma
  • Epithelia forming solid organs e.g. liver, kidneys = adenoma
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58
Q

Explain the naming of malignant epithelial tumours and give examples

A

End in -carcinoma

  • Covering epithelia e.g. skin = carcinoma, typically squamous
  • Glandular epithelia (lining tubes or hollow organs e.g. stomach) = adenocarcinoma
  • Epithelia forming solid organs e.g. liver, kidney = carcinoma e.g. hepatocellular or renal carcinoma
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59
Q

Explain the naming of benign connective tumours and give examples

A

End in -oma

  • Muscle - smooth skeletal = Leimyoma
  • Bone forming = Osteoma
  • Cartilage = Chondroma
  • Fibrous = Fibroma
  • BVs = Angioma
  • Adipose = Lipoma
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60
Q

Explain the naming of malignant connective tumours and give examples

A

End in -sarcoma

  • Muscle - smooth skeletal = Leiomyosarcoma
  • Bone forming = Osteosarcoma
  • Cartilage = Chondrosarcoma
  • Fibrous - Fibrosarcoma
  • BVs = Angiosarcoma
  • Adipose = Liposarcoma
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61
Q 
What names are given to: 
a) Lymphoid 
b) Haematopoietic
c) Primitive nerve cell
d) Melanocyte
e) Mesothelium 
f) Germ cell
Tumours
A

a) Malignant - lymphoma (Hodgkin or non-Hodgkin types)
b) Malignant - leukaemia
c) Malignant - Neuroblastoma, retinoblastoma etc.
d) Benign - Pigmented naevi (moles), Malignant - malignant melanoma
e) Malignant - malignant mesothelioma
f) Benign - teratoma, malignant - teratoma, seminoma

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62
Q

Compare the growth pattern of benign and malignant tumours

A 
Benign = expansion, remains localised
Malignant = infiltrate locally, spread to distant sites (metastasise)
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63
Q

Compare the growth rate of benign and malignant tumours

A 
Benign = generally slow
Malignant = faster
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64
Q

Compare mitoses of benign and malignant tumours

A 
Benign = few, normal
Malignant = numerous, including atypical forms
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65
Q

Compare the nuclei of benign and malignant tumours

A 
Benign = small, regular, uniform
Malignant = large, pleomorphic (w/ increased DNA content)
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66
Q

Compare the histology of benign and malignant tumours

A 
Benign = resembles tissue of origin
Malignant = may differ from tissue of origin (less well differentiated)
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67
Q

Compare the clinical effects of benign and malignant tumours

A 
Benign = local pressure effects, hormone secretion 
Malignant = local pressure effects + destruction, distant metastases, inappropriate hormone secretion
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68
Q

Compare the treatment of benign and malignant tumours

A 
Benign = local excision 
Malignant = local excision and radiotherapy and/or chemotherapy
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69
Q

List the routes by which tumour cells can metastasise

A
  1. Local invasion
  2. Lymphatic spread
  3. Blood spread
  4. Transloclomic spread
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70
Q

Describe lymphatic spread of tumours

A
  • Common mode of spread of carcinoma e.g. breast, colon, lung
  • Travel to draining lymph nodes e.g. from breast cancer to axillary lymph nodes
  • Thereby to thoracic duct + systemic blood circulation
  • Also for melanoma but rare in sarcoma
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71
Q

Describe blood spread of tumours

A
  • Common mode of spread of sarcomas
  • Also some carcinomas e.g. kidney, colorectum, prostate
  • Site of metastasis relates to primary origin
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72
Q

Describe transloclomic spread of tumours

A
  • Across the peritoneum
  • Ovary
  • Stomach
  • Malignant mesothelioma
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73
Q

List the three developmental stages of life before birth and give their timings

A

Week 1 - Preimplantation stage
Weeks 2-8 - Embryonic stage (organ development)
Weeks 9-38 - Foetal stage (growth and development)

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74
Q

Describe the events of day 0 and day 1 of development

A

Day 0 = zygote formed

Day 1 = cleavage

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75
Q

Describe the process of cleavage

A
  • Mitotic divisions of the fertilised oocyte
  • Overall size remains the same - allows passage down narrowest part of uterine tube (isthmus)
  • Surrounded by tough glycoprotein coat - zona pellucide - to prevent immature implantation
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76
Q

Describe the event which occurs after cleavage

A

Morula Formation

  • Day 4 after fertilisation, cells maximise contact with each other
  • Form cluster of cells held together by tight junctions
  • Enters the uterus
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77
Q

Describe blastocyst formation

A
  • First signs of cellular differentiation - inner cell mass which will form embryo + extraembryonic tissues and outer cells which form trophoblasts which will form the placenta
  • As embryo enters uterine cavity, fluid enters via zona pellucida into spaces of the inner cell mass
  • Fluid filled blastocyst cavity forms
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78
Q

Describe the process of blastocyst hatching

A
  • Blastocyst starts to run out of nutrients, needs to implant
  • ICM cells undergo proliferation + fluid builds up in cavity, eventually blastocyst hatches from zona to facilitate implantation
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79
Q

Describe the process of implantation

A

Week 2 - days 7-12

  • Interaction between implanting embryo and endometrium
  • Trophoblast cells implant first - differentiate into cytotrophoblast and syncytiotrophoblast cells
  • Abnormal implantation can occur - ectopoc sites include uterine tubes, external surface of uterus, ovary, bowel, GI tract, mesentery, peritoneal wall
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80
Q

Gastrulation

A

A process of cell division and migration resulting in the formation of the 3 germ layers

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81
Q

When does gastrulation occur?

A

Week 3

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82
Q

Describe gastrulation

A
  • Trilaminar embryo formed from bilaminar epiblast
  • 3 important structures - primitve streak, notochord, neural tube
  • Once cells have invaginated, some displace the hypoblast creating the endoderm
  • Others lie between the eipblasts and newly created endoderm to from the mesoderm
  • The remaining cells in the epiblast then form the ectoderm
83
Q

Derivatives of the ectoderm

A
  • Epidermis of skin + derivatives
  • Epithelial lining of mouth + anus
  • Cornea and lens of eye
  • Nervous system
  • Sensory receptors in epidermis
  • Adrenal medulla
  • Tooth enamel
  • Epithelium of pineal and pituitary glands
84
Q

Derivatives of the mesoderm

A
  • Notochord
  • Skeletal system
  • Muscular system
  • Muscular layer of stomach and intestine
  • Excretory system
  • Circulatory and lymphatic systems
  • Reproductive system (except germ cells)
  • Dermis of skin
  • Lining of body cavity
  • Adrenal cortex
85
Q

Derivatives of the endoderm

A
  • Epithelial lining of digestive tract
  • Epithelial lining of respiratory system
  • Lining of urethra, urinary bladder and reproductive system
  • Liver
  • Pancreas
  • Thymus
  • Thyroid and parathyroid glands
86
Q

Potency

A

Describes a cell’s ability to differentiate into other cell types

87
Q

Describe the changes which occur in week 4 gestation

A
  • Changes in body form - embryo ‘rolls up’ from a flat disc into a closed cylinder along its long axis, growth of the embryo makes the embryo fold laterally, head and tail ends curl under the fast growth of the neural tube
  • Embryo resembles a human form
88
Q

Describe the key events of weeks 1-2 of gestation

A

Pre-Implantation:

Fertilisation, cleavage, compaction, blastocyst formation

89
Q

Describe the key events of week 2 of gestation

A

Implantation:

Bilaminar germ disc

90
Q

Describe the key events of week 3 of gestation

A

Gastrulation:

Trilaminar embryo, notochord, neural tube

91
Q

Describe the key events of weeks 4-8 of gestation

A

Embryonic period:

Closure of neural tube, body folds, heart begins to pump, organs develop

92
Q

Describe the key events of weeks 5-7 of gestation

A

Septation of the heart, chambers form

93
Q

Describe the key events of weeks 5-10 of gestation

A

Physiological umbilical hernia of migut, out in week 5, back by week 10

94
Q

Describe the key events of week 6 of gestation

A

Minor and major calyces of kidney appear, clavicle begins to ossify

95
Q

Describe the key events of week 7 of gestation

A

First signs of sex differentiation

96
Q

Describe the key events of week 8 of gestation

A

All major organ systems in place, limbs distinct

97
Q

When is the foetal period?

A

Week 9 - full term

98
Q

Describe the key events of week 12 of gestation

A

Kidney produces dilute urine

99
Q

Describe the key events of weeks 17-25

A

Lung development, respiratory bronchioles

100
Q

Describe the key events of week 25-birth

A
  • CNS development proceeds

- Terminal sac stage of lung development

101
Q

List the reasons why cell signalling is important

A
  1. To coordinate development e.g. morphogens

2. To maintain normal physiological functions e.g. blood glucose level control

102
Q

Give examples of diseases caused by abnormal signalling

A
  1. Diabetes - lack of sufficient insulin production/reduced responsiveness to insulin in target cells
  2. Cancer - e.g. pancreatic cancer, hyperactive K-Ras pathway
103
Q

List the types of signalling classified by range of action

A
  1. Endocrine
  2. Paracrine
  3. Juxtacrine
  4. Autocrine
104
Q

Endocrine signalling

A
  • Signal (hormone) secreted from one cell type (gland)

- Travels long-distance to target cells in other tissues/organs (via blood)

105
Q

Juxtacrine signalling

A
  1. Cell-to-cell signalling via cell surface proteins e.g. T cell activation
  2. Extracellular matrix-to-cell signalling: control cell adhesion, migration, shape, proliferation, differentiation
  3. Gap junction signalling
106
Q

Paracrine signalling

A

Between nearby cells, bu diffusion. E.g. skin wound healing - GFs targeting cells in skin

107
Q

Autocrine signalling

A

Coordinates decisions by groups of identical cells - e.g. activated T cells produce IL-2 and receptors of IL-2, causing proliferation and differentiated of activated T cells

108
Q

List the ways in which types of signalling can be classified

A
  1. By range of action

2. By type of signal

109
Q

List the types of signalling classified by types of signal

A
  1. Electrical - ions
  2. Chemical
    - Neurotransmitters
    - Hormones
    - Growth factors
110
Q

List the main classes of human hormones

A
  • Amino acid derivatives
  • Peptides/proteins
  • Steroids
111
Q

Growth factors

A
  • Natural extracellular signalling substance that promotes cell growth/proliferation
  • May be endocrine (hormones), paracrine or autocrine
  • Usually proteins
112
Q

Cytokines

A

Immune or haematopoietic growth factors which may have positive or negative effects on growth

113
Q

Neurotransmitters mechanism of action

A
  • Transmit nerve impulse from one cell to another, across synapse
  • Released from vesicles in pre-synaptic cell
  • Bind to receptors in post-synaptic cell
  • Removed by re-uptake of enzyme degradation
114
Q

List the main classes of neurotransmitters

A
  1. Amino-acids e.g. glutamate
  2. Catecholamines e.g. noradrenaline
  3. Acetyl Choline
  4. Peptides e.g. endorphins
115
Q

Describe movement of hydrophobic chemical signals

A

Can diffuse through the plasma membrane directily

116
Q

Give an example of hydrophobic cell signalling and describe the mechanism of action

A
  • Bind directly to intracellular receptor proteins
  • Hormone-receptor complex acts as transcription factor
  • Complex binds to DNA and directly alters gene expression
117
Q

Describe movement of hydrophilic chemical signals

A
  • Must use a cell surface receptor to enter the cell e.g. protein/peptide hormones
  • Signal is amplified then transduced, from the receptor to the molecule within the cell that will produce a response
118
Q

How are chemical signals amplified prior to transduction?

A

Two main methods:

  1. Second messengers
  2. Enzyme cascade
119
Q

List the ways in which responder molecules can illicit a response from the cell

A
  • Altered gene transcription
  • Altered translation
  • Altered post-translational modification - enzyme activation/inhibition or structural proteins
120
Q

List the main types of cell surface receptors

A
  • Ion-channel-linked receptors
  • Enzyme-linked receptors - Receptor tyrosine kinases (RTKs)
  • G-protein-linked receptors
121
Q

Explain the basic mechanism of action of enzyme-linked cell-surface receptors

A
  • Receptors are enzymes, or recruit and activate other enzymes
  • Receptor kinase activity is activated by ligand binding (by dimerization/conformational change)
122
Q

Explain reversible protein phosphorylation

A
  • Protein kinases = enzymes that add a phosphate group to proteins
  • Phosphorylation can alter target protein activity, localisation, binding partners, turnover etc.
  • Reversible - phosphate can be removed by protein phosphatases
123
Q

Describe the mechanism of action of receptor tyrosine kinases

A
  • Phosphorylated receptor acts as docking site for intracellular signalling proteins e.g Grb2
  • Downstream signalling activated e.g. Grb2 binds Sos activating Ras (a G-protein)
  • Ras activates MAP kinase cascade - amplification and transmission
  • Final target = altered gene transcription or protein activity e.g. EGF promotes cell growth
124
Q

What is the role of receptor tyrosine kinases in cancer?

A
  • Signalling through RTKs often too high in cancer, causes excessive growth/proliferation
  • RTK activation by over expression or mutation
  • Mutation of downstream signalling molecules
  • Treat by blocking receptor downstream
125
Q

Ossification/osteogenesis

A

Process of bone development

126
Q

List the osteogenic pathways

A
  1. Intramembranous ossification - most cranial bones, clavicle etc.
  2. Endochondral ossification - long bones, bones at base of skull
127
Q

List the main stages of endochondral bone growth

A
  1. Hypertrophication = chondrocyte cells grow
  2. Calcification = hardening of hyaline cartilage matrix
  3. Cavitation = Chondrocytes die and leave cavities in bone
  4. Periosteal bud invasion = nutrient delivered to bone via BVs, nerves also enter
  5. Epiphyseal ossification = bone ends develop secondary ossification centres
128
Q

Describe the hypertrophication stage of endochondral bone growth

A
  1. 6-8 weeks after conception, some mesenchymal cells differentiate into chondrocytes that form the cartilaginous skeletal precursor of the bones
  2. Perichondrium appears soon after
  3. More matrix produced, chondrocytes grow in size
129
Q

Describe the calcification and cavitation stages of endochondral bone growth

A

Matrix calcifies, nutrients can’t reach the chondrocytes - results in death and disintegration of the surrounding cartilage

130
Q

Describe the periosteal bud invasion stage of endochondral bone growth

A
  1. BVs invade the spaces, enlarging the cavities and bringing osteogenic cells (will mature to osteoblasts) - spaces eventually become medullary cavity
  2. Capillaries penetrate cartilage as it grows, initiating transformation of the perichondrium into bone-producing periosteum
131
Q

Describe the epiphyseal ossification stage of endochondral bone growth

A
  1. Once the foetal skeleton is fully formed, cartilage is only on articular surfaces of joints and between the diaphysis and epiphyseal plate - responsible for longitudinal growth of bones
  2. After birth, same sequence of events occurs in epiphyseal regions, at the secondary ossification centres
132
Q

List the transcription factors involved with endochondral bone growth

A
  1. Sox-9
    - major regulator of chondrogenesis
    - regulates several cartilage-specific genes during endochondral ossification, including collagen type II, IV, XI and aggrecan
  2. PTHrP (parathyroid hormone-related peptides)
    - delays differentiation of chondrocytes in the zone of hypertrophy
  3. Insulin-like growth factor 1 (IGF-1)
133
Q

FGFR3

A

Fibroblasts growth factor receptor 3, coded for by FGFR3 gene

134
Q

Describe the structure of FGFR3

A

Have an extracellular domain of FGFRs and induce the phosphorylation of tyrosine residues in the intracellular domain of FGFRs

135
Q

Describe the function of FGFR3s

A
  • Play essential role in bone development and maintenance of adult bone homeostasis
  • Regulation of proliferation, differentiation and apoptosis of chondrocytes via downstream signalling pathways e.g. Ras-MAP kinase
136
Q

Describe the mechanism of action of FGFs/FGFR3s

A
  • FGFs bind to extracellular domain of FGFRs and cause changes to the intracellular domain, activating FGFRs
  • FGFs induce dimerisation, kinase activation and transphosphorylation of tyrosine residues of FGFRs to activate them
  • Activated FGFRs recruit target proteins by phosphorylation leading to activation of intracellular downstream signalling pathways, such as mitogen-activated protein kinase (Ras/MAPK)
137
Q

When/where is FGFR3 expressed?

A
  • First expressed in chondrocytes, differentiated initially for the core of the mesenchyme condensation
  • Expressed in reserve and proliferating chondrocytes as the epiphyseal growth plate is formed
  • Also expressed in mature osteoblasts and osteocytes and during calvarial bone development in sutural osteogenic fronts at the late stages
138
Q

What effect does FGFR3 have on chondrocytes?

A
  • FGFR3 signalling inhibits chondrocyte proliferation through STAT1 signalling by inducing the expression of cell cycle suppressor genes such the CDK inhibitor p21
  • FGFR3 inhibits chondrocyte differentiation through the ERK/MAPK pathway
  • Important regulator of osteogenesis - activated FGFR3 leads to decreased bone mass by regulating osteoclast/osteoblast activity
139
Q

Describe the MAPK/ERK pathway

A
  1. Extracellular mitogen binds to the membrane receptor
  2. Ras (a small GTPase) swaps its GDP for a GTP
  3. Ras can now activate Raf (MAP3K)
  4. Raf activates MAP2K
  5. MAP2K activates MAPK
  6. MAPK activates a transcription factor e.g. Myc
140
Q

What type of genetic condition is Achondroplasia?

A

Single-gene, autosomal dominant disorder

141
Q

Which gene is affected in Achondroplasia?

A

FGFR3

142
Q

If both parents have achondroplasia, what are the chances that their offspring will:

a) Have achondroplasia
b) Be of average stature
c) Have homozygous (lethal) achondroplasia

A

a) 50%
b) 25%
c) 25%

143
Q

Where do new gene mutations for achondroplasia arise from?

A

They are exclusively inherited from the father and occur during spermatogenesis. It is theorised that oogenesis has a regulatory mechanism that prevents the mutation from being passed on in females.

144
Q

Autosomal dominant inheritance

A
  • One copy of the mutant allele is sufficient to cause the disease
  • An affected individual possesses one copy of the mutant allele and one copy of a normal allele
145
Q

Describe the mutation which causes the defect in the FGFR3 gene

A
  • Point mutation causes substitution of glycine for arginine (Gly380Arg) in the transmembrane region of the receptor
  • The Gly380Arg pathogenic variant resulting in achondroplasia causes constitutive activation of FGFR3, which through its inhibition of chondrocyte proliferation + differentiation, is a negative regulator of bone growth
  • Results in excess inhibitory signalling in growth plate chondrocytes, principally through the MAPK pathway
146
Q

Describe the mechanisms through which mutations to genes can arise

A
  1. Spontaneous
  2. Error-prone replication bypass of naturally occurring DNA damage
  3. Errors introduced during DNA repair
  4. Induced mutations caused by mutagens
147
Q

Mutagen

A

An agent, such as radiation or a chemical substance, which causes genetic mutation

148
Q

List examples of mutagens and explain how they cause mutations

A
  1. Chemicals - deaminate bases (resemble different nucleotides and confuse the DNA replication machinery), cause insertion/deletion of base pairs. E.g. nitrous acid
  2. Radiation - ionising radiation e.g. X-rays break DNA sequences leading to chromosome rearrangement. Lower-energy radiation e.g. UV rays can damage DNA cross-linking two bases together
  3. Metals e.g. arsenic, nickel affect DNA repair processes
  4. Biological agents - virus DNA inserted into the genome + disrupts genetic function. Bacteria - cause inflammation during which oxidative species are produced, causing DNA damage + reducing efficiency of DNA repair systems
149
Q

Define achondroplasia

A

Most common form of disproportionate short-limb dwarfism, mutation in fibroblast growth factor receptor 3 causes abnormal endochondral bone growth. Periosteal and intramembranous ossification is normal.

150
Q

Explain the causes of achondroplasia

A
  • Hereditary - autosomal dominant single gene disorder (children of parents w/ achondroplasia)
  • Random mutation e.g. caused by environmental mutagens (children of parents of normal stature)
  • May be associated with advanced paternal age, >36 y/o
151
Q

Describe the characteristics/symptoms of a person with achondroplasia

A
  • Short stature
  • Average sized trunk
  • Frontal and parietal bossing (protruding forehead)
  • Small nasal bridge
  • Macroencephaly
  • ‘Button’ nose
  • Trident hands with short fingers
  • Infants have thoracolumbar kyphosis
  • Flexed position of elbows
  • Bowing of lower limbs
  • Normal IQ
  • ‘Champagne glass pelvis’
  • Dental overcrowding
152
Q

What is the average height for males/females with achondroplasia?

A

Average male = 131cm

Average female = 124cm

153
Q

List the medical complications associated with achondroplasia

A
  • Weight control problems
  • Dental problems due to overcrowding
  • Neurological complications due to cervicomedullary compression
  • Obstructive and restrictive respiratory complications (e.g. pneumonia, apnea)
  • Cardiovascular complications
  • Decreased life expectancy
154
Q

List the treatments used in achondroplasia

A
  • No cure - potential for growth factors to increase bone growth
  • Bone lengthening through metaphyseal corticotomy
  • Surgery to correct spinal deformities and protect the spinal cord
  • Osteotomy
  • Human growth hormone
  • Nutritional counselling
  • Dental treatment
  • Tonsillectomy/adenoidectomy
155
Q

Discuss the advantages and disadvantages of bone lengthening in the treatment of achondroplasia

A
  • Increases leg length to a limited degree
  • Traumatic + painful surgical procedure
  • Complications common
  • Disadvantages outweigh potential reward - not recommended
156
Q

List the types of surgery which may be required to correct spinal deformities in achondroplasia

A
  • Spinal fusion = connects separate vertebrae

- Laminectomy = opens spinal canal to relieve pressure on compressed spinal cord from spinal stenosis

157
Q

Describe how osteotomy is used in the treatment of achondroplasia

A
  • Used to correctly severely bowed legs
  • Bones of leg are cut and allowed to heal in the anatomically correct position
  • Increases mobility
158
Q

Describe how human growth hormone is used in the treatment of achondroplasia

A
  • Increases bone growth rate in first year of treatment
  • May not increase adult height
  • Therapy started at young age (1-6 years)
159
Q

Why is nutritional counselling recommended in those with achondroplasia?

A
  • Obesity in achondroplasia usually begins in early life

- Lifelong problem

160
Q

Why is tonsillectomy/adenoidectomy sometimes necessary in those with achondroplasia?

A

Treatment of sleep apnoea syndrome - common in those with achondroplasia

161
Q

Describe the steps involved in the antenatal screening of achondroplasia

A
  1. History
  2. Ultrasound scan
  3. Chorionic villus sampling/amniocentesis
162
Q

Describe the history taken to determine risk of achondroplasia (homozygous or heterozygous) in foetuses

A
  • Family history of achondroplasia? - chance of homozygous (lethal) achondroplasia
  • Paternal age - risk factor
163
Q

Describe how achondroplasia can be diagnosed through the use of an ultrasound scan

A
  • Done as part of first trimester screening for foetal abnormality or as part of anomaly screening program (18-20)
  • Short femurs, frontal bossing, over-rounded metaphyseal-epiphyseal interface at long bone ends while connecting to diaphysis (collar hoop), short pedicles of vertebrae etc. all indicators of achondroplasia
  • Long bone below third percentile for gestational age but normal head size and abdominal circumference
164
Q

Explain how chorionic villus sampling/amniocentesis are used in the diagnosis of achondroplasia

A
  • Needed only to confirm diagnosis
  • Only offered in pregnancies with high risk of achondroplasia
  • Detects FGFR3 gene
165
Q

Explain the affect of homozygous achondroplasia

A

Infants with homozygous achondroplasia are either stillborn or die shortly after birth - termination?

166
Q

Describe how mothers with achondroplasia must be treated when giving birth

A

If a mother has achondroplasia a caesarean section must be performed due to their small pelvis. May develop respiratory compromise in 3rd trimester.

167
Q

Where are the muscles of the axial skeleton, body wall and limbs derived from?

A

Somites. Most muscles are derived from the mesoderm.

168
Q

What is the lateral somatic frontier?

A
  • Border between each somite and the lateral plane mesoderm
  • Separates two mesodermal domains - primaxial domain and abaxial domain
  • Also defines the border between dermis derived from the dermatome and the dermis derived from the lateral plate mesoderm in the body wall
169
Q

Primaxial domain

A

Region around neural tube, somite derived mesoderm

170
Q

Abaxial domain

A

Parietal layer of lateral plate mesoderm and some migratory somitic cells

171
Q

What is the significance of the divide between the primaxial and abaxial domains

A

Signals controlling development come from different sources -

  • Primaxial - signals from neural tube and notochord
  • Abaxial - signals from lateral plate mesoderm
172
Q

Describe the innervation of epaxial muscles

A

Epaxial muscles (true back muscles) are innervated by dorsal primary rami

173
Q

Describe innervation of hypaxial muscles

A

Hypaxial (limb and body wall) muscles are innervated by ventral primary rami

174
Q

Briefly describe limb development in foetuses

A
  • Limbs develop from small buds of undifferentiated mesoderm cells, which are covered by ectoderm
  • Limb buds become visible by end of week 4
  • Upper limb buds appear first as ridges from ventrolateral body wall
  • Lower limb as small bulges
  • Limb morphgenesis = week 4-8
  • Lower limbs initially lag behind but catch up by end of developmental period
175
Q

Where do limbs arise from?

A

The lateral mesoderm and overlying ectoderm

176
Q

What is the role of HOX genes in limb development?

A

Regulate positioning of the limbs along the craniocaudal axis - mis-expression alters limb position

177
Q

How are upper limbs differentiated from lower limbs during lib developmet?

A

T-Box family transcription factors:

  • TBX-5 expressed in upper limbs
  • TBX-4 and PITX1 in lower limbs
178
Q

When does limb rotation occur in foetuses?

A

During week 7 - lower limbs are 1-2 days behind upper limbs

179
Q

Describe rotation of the upper limbs

A

Upper limb rotates 90 degrees laterally:

- Extensor muscles lie on the lateral and posterior side (thumb laterally, elbows pointing back)

180
Q

Describe rotation of the lower limbs

A

Lower limb rotates 90 degrees medially:

- Extensor muscles lie on anterior surface (big toe medially, knees face forward)

181
Q

Anomaly

A

Something that deviates from the normal or expected

182
Q

Congenital

A

A disease of physical anomaly present from birth

183
Q

Teratogen

A

An agent of factor which causes malformation of an embryo

184
Q

List the causes/types of congenital anomalies

A
  • Failure of formation
  • Failure of differentiation
  • Duplication
  • Overgrowth
  • Undergrowth
  • Constriction band syndromes
  • Generalised anomalies and syndromes
185
Q

Amelia

A

Absence of an entire limb

186
Q

Acheria/apodia

A

Absence of hands/feet

187
Q

Phocomelia

A

Absence or shortening of proximal limb segments

188
Q

Hemimelia

A

Absence of preaxial or postaxial parts of limb

189
Q

Meromelia

A

General term for absence of part of a limb

190
Q

Ectrodactyly

A

Absence of any number of digits

191
Q

Polydactyly

A

Excessive number of digits

192
Q

Syndactyly

A

Presence of interdigital webbing

193
Q

Brachydactyly

A

Shortened digits

194
Q

Split hand or foot

A

Absence of central components of hand or foot

195
Q

Give examples of congenital anomalies caused by failure of formation

A

Amelia, meromelia, phocomelia

196
Q

Give examples of genetic anomalies caused by failure of differentiation

A

Sirenomelia - fusion of limbs

197
Q

Give examples of congenital anomalies caused by overgrowth and undergrowth

A

Overgrowth = hemihypertrophy - one limb larger than the other
Undergrowth - micromelia

198
Q

Describe the pathogenesis of Marfan’s syndrome

A
  • Autosomal dominant
  • Disorder of connective tissue
  • Mutation in the FBN1 gene
199
Q

Describe the presentation of Marfan’s syndrome

A
  • Tall stature
  • Long, thin digits and limbs
  • Hyperextensible joints
  • Arched palate
  • Eye problems
  • Chest, heart and lung problems
200
Q

Developmental dysplasia of the hip

A
  • Poorly developed acetabulum and head of femur in utero
  • Dislocation commonly occurs after birth
  • Can be complications - avascular necrosis of the femoral head
  • Causes asymmetry of skin folds on hip and shortened affected limb
  • Treatment = pavlik harness/surgery if detected late
201
Q

List the risk factors for congenital anomalies

A

Intrinsic

  • Chromosomal abnormalities
  • Inherited
  • Sporadic mutations

Extrinsic

  • Teratogens e.g. thalidomide
  • Nutrient deficiency e.g. folate
  • Infections e.g. VACTERL
  • Failed termination
  • Removal of IUD
202
Q

List examples of teratogens

A
  • Thalidomide
  • Warfarin
  • Phenytoin
  • Valproic acid
  • Alcohol
  • Cocaine
203
Q

Which period of development is most sensitive for teratogen-induced limb defects?

A

Weeks 4 + 5

Medicine YEAR 1 (18 decks)

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