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Introductory Clinical Sciences Flashcards

1
Q

What are the two types of autopsy?

A

Hospital Autopsy

Medico-legal Autopsy

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2
Q

What are the three ‘types’ of death?

A

Presumed natural
Presumed iatrogenic
Presumed unnatural

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3
Q

What are the five stages of the autopsy?

A 
History/Scene
External examination
Evisceration
Internal Examination
Reconstruction
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4
Q

What are the four questions aimed to be answered by an autopsy?

A

Who was the deceased?
When did they die?
Where did they die?
How did they come about their death?

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5
Q

Define inflammation.

A

A reaction to injury or infection involving cells such as neutrophils and macrophages.

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6
Q

What is pus formed of?

A

Dead neutrophils.

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7
Q

Which cells are first on the scene in acute inflammation?

A

Neutrophil polymorphs

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8
Q

Which are the second cells to appear in acute inflammation?

A

Macrophages

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9
Q

What is the usual outcome of acute inflammation?

A

Resolution

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10
Q

What is the usual outcome of chronic inflammation?

A

Repair

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11
Q

What is the role of fibroblasts in inflammation?

A

Form collagen in areas of chronic inflammation and repair.

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12
Q

Which cells are usually involved in chronic inflammation?

A

Lymphocytes and macrophages

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13
Q

What are five signs of acute inflammation?

A 
Redness (rubor)
Heat (calor)
Swelling (tumour)
Pain (Dolor)
Loss of function
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14
Q

What is a granuloma?

A

A collection of macrophages surrounded by lymphocytes (appear in chronic inflammation).

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15
Q

Give 3 medications that can be used to treat inflammation.

A

Aspirin
Ibuprofen
Steroids

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16
Q

What is a histiocyte?

A

A stationary phagocytic cell present in connective tissue.

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17
Q

Which cells usually appear in a bacterial infection?

A

Neutrophils

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18
Q

Which cells usually appear in a viral infection?

A

Lymphocytes

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19
Q

What are the three hallmarks of inflammation?

A

Increased blood supply
Increased vascular permeability
Increased leukocyte transendothelial migration (extravasation)

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20
Q

How does blood flow increase in inflammation?

A

Cytokines open pre-capillary sphincters to increase blood flow to a tissue.

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21
Q

Are neutrophils long or short-lived?

A

Short lived.

They usually die at the scene of inflammation.

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22
Q

Are macrophages long or short-lived?

A

Long lived

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23
Q

Describe resolution

A

Initiating factor is removed and the tissue is undamaged or able to become exactly the same as before.

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24
Q

Describe repair.

A

Initiating factor is still present and the tissue is damaged and unable to regenerate.

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25
What is a labile cell? | Give an example.
High regenerative ability High turnover Eg - Epithelium
26
What is a stable cell? | Give an example.
High regenerative ability Low turnover Eg - Hepatocytes
27
What is a permanent cell? | Give an example.
No regenerative ability | Eg - Neurones
28
Give an example of repair.
Liver cirrhosis Hepatocytes can usually regenerate after liver damage but after continuing damage (cirrhosis) repair has to occur instead.
29
Give an example of regeneration.
Lobar pneumonia Acute inflammation causes the alveoli to fill with neutrophils but the alveolar walls are still in tact so the pneumocytes regenerate.
30
What is granulation tissue?
Capillary loops and myofibroblasts which can contract to reduce the wound.
31
Describe how an abrasion resolves.
Abrasion removes epidermis and scab forms over the surface. Epidermis regrows from the adnexa, protected by the scab. Epidermis continues to grow and scab comes off.
32
Describe healing by first intention.
Edges of skin are held together (sutures). Gap fills with blood and fibrin joins skin weakly. Epidermis regrows and dermis fills with collagen.
33
Describe healing by second intention.
Unable to bring edges of the skin together. Capillaries and myofibroblasts form granulation tissue. Collagen produced and epithelium grows in from the edges. Granulation tissue contracts to reduce wound size.
34
How does repair occur?
Replacement of damaged tissue by fibrous tissue. | Collagen produced by fibroblasts.
35
What is gliosis?
Fibrosis in the brain
36
Name some cells that regenerate.
``` Hepatocytes Blood cells Osteocytes Pneumocytes Gut epithelium Skin epithelium ```
37
Name some cells that don't regenerate.
Myocardial cells Neurones Nephrons
38
Why doesn't blood clot under normal conditions?
Endothelial cells are non-sticky (due to NO and glycocalyx coating) Cells flow in the centre of the vessels (laminar flow)
39
Briefly describe the steps in thrombus formation.
``` Damage to endothelium Exposed collagen Platelets stick Red blood cells trapped Thrombus formation Fibrin deposition ```
40
Define thrombus.
Solid mass of blood constituents formed within an intact vascular system during life.
41
What is Virchow's triad?
3 elements that increase the risk of thrombus formation.
42
What are the three elements of Virchow's triad?
Change in vessel wall Change in blood flow Change in blood constituents
43
What are two risk factors for arterial thrombosis?
Smoking | Atherosclerosis
44
Why does venous thrombosis occur?
Slower blood flow (stasis) occurs so cells touch the sides of the vein.
45
How can venous thrombosis be prevented using medication?
Low dose aspirin
46
What is an embolus?
Mass of material in the vascular system able to become lodged within a vessel and block it.
47
What are three things that can act as emboli?
A bit of thrombus Gas Talcum powder (IV drug users)
48
Where does an embolus get stuck if it enters the venous system?
Pulmonary arteries
49
Where does an embolus get stuck if it enters the arterial system?
Anywhere downstream of the point of entry
50
What are three inhibitors of thrombosis?
Protein S/Protein C Anti-thrombin III Tissue factor pathway inhibitor
51
Define ischaemia.
Reduction in blood flow to a tissue without any other implications.
52
Describe the consequences for the tissue in ischaemia.
Cells furthest from the blood supply become 'unhappy' but don't necessarily die.
53
Define infarction.
Reduction in blood flow to a tissue that is so reduced that it cannot even support mere maintenance of cells so they die.
54
What are the consequences of infarction?
Necrosis and inflammatory response.
55
Name some organs with a dual artery supply.
Lungs (pulmonary and bronchial arteries) Liver (portal vein and hepatic arteries) Brain (circle of Willis)
56
Describe reperfusion injury.
Calcium ions build up in the cell (transport mechanisms have been disrupted). This triggers oxygen-dependent free radical systems. Macrophages and neutrophils also bring free radicals to the area. This causes tissue damage associated with infarction.
57
Define atheroma.
Degeneration of the walls of the arteries caused by accumulated fatty deposits and scar tissue, and leading to restriction of the circulation.
58
Where does atherosclerosis occur?
Exclusively in high pressure arteries. | Not in pulmonary arteries, and usually at a bifurcation
59
What's in an atherosclerotic plaque?
Fibrous tissue Lipids (cholesterol) Lymphocytes
60
What are four risk factors for atherosclerosis?
Smoking Hyperlipidaemia Hypertension Diabetes
61
Describe the endothelial damage theory of atherosclerosis formation.
Endothelial cells are delicate. | They get damaged and platelet aggregation begins plaque formation.
62
How does smoking cause endothelial damage?
Free radicals Nicotine Carbon monoxide
63
How does hypertension cause endothelial damage?
Shearing forces on endothelial cells
64
How does diabetes cause endothelial damage?
Superoxide ions | Glycosylation products
65
How does hyperlipidaemia cause endothelial damage?
Direct damage to endothelial cells
66
Describe how platelet aggregation leads to atherosclerosis.
Thrombus forms with red blood cells and fibrin. Thrombus heals to leave a plaque. Plaques have capillaries so they can bleed (size increases). Incremental damage causes atherosclerosis.
67
What medication can be used to prevent atherosclerosis?
Aspirin
68
What are some complications of atherosclerosis?
``` Cerebral infarction Carotid atheroma Myocardial infarction Aortic aneurysm Peripheral vascular disease Gangrene ```
69
Define apoptosis
Programmed cell death
70
Name a protein which detects DNA damage.
p53
71
What happens in apoptosis?
``` Cell shrinks Membrane blebs Nucleus degenerates Proteins break down cellular components Cell breaks into small pieces Adjacent cells remove pieces ```
72
Which enzymes are involved in apoptosis?
Caspases
73
Which proteins in a cell can regulate enzymes involved in apoptosis?
BcL2
74
Which ligand and receptor induces apoptosis in a cell?
FAS ligand/FAS receptor
75
What are four ways that apoptosis is involved in normal development?
Removal of webbed fingers. Closure of spinal cord to prevent spina bifida. Prevents cleft palate. Prevents ventricular septal defects.
76
How is apoptosis involved in normal function?
Regeneration of gut epithelium
77
How can apoptosis cause disease?
Lack of apoptosis in cancer | Too much apoptosis in HIV
78
Define necrosis.
The traumatic death of many cells in a tissue.
79
Give five clinical examples of when necrosis occurs.
``` Toxic spider venom Frostbite Cerebral infarction Avascular necrosis of bone Pancreatitis ```
80
What is coagulative necrosis?
Dead tissue preserved and appears sticky. | Typically caused by ischaemia.
81
What is liquefactive necrosis?
Tissue transformed into viscous mass. | Associated with bacterial/fungal infections.
82
What is caseous necrosis?
Tissue maintains 'cheese-like' appearance. | Associated with TB.
83
Describe the mechanism of necrosis.
Energy failure. Impairment or cessation of ion homeostasis. Lysosomes leak lytic enzymes.
84
What are some inhibitors of apoptosis?
Growth factors Extracellular matrix Sex steroids Some viral proteins
85
What are some inducers of apoptosis?
``` Growth factor withdrawal Free radicals Loss of extracellular matrix attachment DNA damage Glucocorticoids Ionising radiation Some viruses Ligand binding at 'death receptors' ```
86
What is the intrinsic pathway of apoptosis stimulation?
Stimuli alter relative levels of members of the BcL-2 family.
87
What is the extrinsic pathway of apoptosis stimulation?
Ligand binding on 'death receptors' (eg - TNFR1 and FAS)
88
What are homeobox genes?
Genes which code for proteins that bind to DNA (transcription factors) to regulate development.
89
What does 'congenital' mean?
Present at birth. | May or may not be inherited.
90
What does 'inherited' mean?
Caused by an inherited genetic abnormality.
91
What does 'acquired' mean?
Caused by non-genetic environmental factors. | May be congenital.
92
Which protein is produced in excess in trisomy 21?
beta amyloid protein (encoded by gene on chromosome 21). | This accumulates in the brain.
93
What is the principal of Mendelian Inheritance?
Single gene alterations are inherited.
94
Define 'polygenic inheritance'.
A characteristic is controlled by more than one gene.
95
Which protein is produced in excess in Huntington's disease?
Huntingtin. | This accumulates in the brain.
96
What is the likely diagnosis if someone is in proportion but very small?
Growth hormone deficiency
97
What is the likely diagnosis if someone is very tall?
Growth hormone excess from pituitary adenoma.
98
What is acromegaly?
A growth hormone excess after puberty. | These people have very large hands and feet.
99
Which mutation can cause achondraplasia?
Mutation in the fibroblast growth factor receptor 3 gene.
100
What is trisomy 18?
Edwards' syndrome
101
What is trisomy 13?
Patau's syndrome
102
Define hypertrophy.
Increase in size of a tissue caused by an increase in size of the constituent cells.
103
Give an example of hypertrophy.
Body builders' muscles
104
Define hyperplasia.
Increase in size of a tissue caused by an increase in number of the constituent cells.
105
Give some examples of hyperplasia.
Benign prostatic hyperplasia Endometrial hyperplasia Endothelial hyperplasia Neuronal hyperplasia
106
Give an example of when hypertrophy and hyperplasia occur together?
Myometrium in pregnancy
107
How is apoptosis involved in hyperplasia?
It is decreased
108
Define atrophy.
Decrease in size of a tissue caused by a decrease in number of the constituent cells or a decrease in their size.
109
Give an example of atrophy.
Loss of brain tissue in Alzheimer's dementia. | Muscle atrophy.
110
Define metaplasia.
Change in differentiation of a cell from one fully-differentiated type to a different fully-differentiated type.
111
What is metaplasia a response to?
An altered cellular environment.
112
Give an example of metaplasia.
Ciliated columnar epithelium to squamous epithelium in the bronchi of a smoker.
113
Define dysplasia.
An imprecise term for the morphological changes seen in cells in the progression to becoming cancer. It results in an abnormal architecture and arrangement.
114
Define angiogenesis.
New blood vessels grow into damaged, ischaemic, or necrotic tissues.
115
Define vasculogenesis.
Blood vessel proliferation that occurs in the developing embryo/foetus.
116
What is a telomere?
A repetitive nucleotide sequence at the end of each chromosome.
117
What happens to telomeres when DNA replication occurs?
They get shorter.
118
What is the Hayflick limit?
The number of times a cell population is able to divide.
119
What is progeria?
Accelerated aging, caused by dysfunction of prelamin A in the nuclear membrane.
120
Give 10 ways that cells wear out.
``` Cross-linking/mutations of DNA Loss of calcium influx controls Loss of DNA repair mechanisms Free radical generation Telomere shortening Cross-linking of proteins Damage to mitochondrial DNA Peroxidation of membranes Time-dependent activation of ageing and death genes Accumulation of toxic by-products of metabolism ```
121
Describe dermal elastosis.
Wrinkles caused by UVB cross-linking collagen
122
What causes osteoporosis?
Lack of oestrogen causes increased bone resorption and decreased bone formation.
123
What causes cataracts?
UVB light causes protein cross-linking.
124
What 3 things cause senile/Alzheimer's dementia?
Neuronal loss Neurofibrillary tangles beta amyloid plaques
125
Define sarcopaenia.
Degenerative loss of skeletal muscle mass, quality, and strength, due to decreased growth hormone, decreased testosterone, and increased catabolic cytokines.
126
What causes deafness?
Loss of hair cells in the cochlea.
127
Which type of cancer never spreads?
Basal cell carcinoma of the skin
128
Which type of treatment is required for high grade lymphoma?
Chemotherapy
129
Where is the first site that carcinomas usually spread to?
Local lymph nodes
130
Which cancers commonly spread to bone?
``` Breast Prostate Lung Thyroid Kidney ```
131
Why is extra treatment sometimes still required after a tumour is completely excised?
Micro metastases could still be present
132
What is adjuvant therapy?
Extra treatment for a tumour given after surgical excision.
133
If a tumour is oestrogen receptor positive what type of treatment can be given?
Anti-oestrogen therapy
134
If a tumour has a mutation in the HER2 gene what type of treatment can be given?
Herceptin
135
Define carcinogenesis.
The transformation of normal cells to neoplastic cells through permanent genetic alterations or mutations.
136
How does carcinogenesis differ from oncogenesis?
Carcinogenesis applies to malignant neoplasms only, whereas oncogenesis applies to both benign and malignant neoplasms.
137
What are carcinogens?
Agents known or suspected to cause tumours.
138
What is the difference between 'carcinogenic' and 'oncogenic'?
``` Carcinogenic = cancer causing Oncogenic = tumour causing ```
139
Where do carcinogens act?
On DNA
140
How much cancer risk is environmental and how much is inherited?
85% environmental | 15% inherited
141
What are the problems with identifying carcinogens?
Latent interval may be decades Complexity of environment Ethical constraints
142
What are the four types of evidence for carcinogens?
Experimental Direct Epidemiological Occupational/behavioural risks
143
Give some examples of experimental evidence of carcinogens.
Cell/tissue cultures Mutagenicity testing in bacterial cultures Incidence of tumours in lab animals
144
Give some examples of direct evidence of carcinogens.
Thorotrast (angiosarcoma in liver) | Chernobyl (thyroid cancer)
145
Give some examples of epidemiological evidence of carcinogens.
``` Hepatocellular carcinoma (increased in areas with HepB/C and mycotoxins. Oesophageal carcinoma (related to diet). ```
146
Give some examples of occupational/behavioural evidence of carcinogens.
Increased scrotal cancer in chimney sweeps. Lung cancer in smokers. Bladder cancer in alanine dye & rubber industries.
147
Describe the three steps of carcinogenesis.
Initiation - a carcinogen induces genetic alterations. Promotion - stimulation of clonal proliferation of the transformed cell. Progression - invasion and metastatic behaviour.
148
What are three genetic mechanisms of carcinogenesis?
Telomerase expression Tumour suppressor gene inactivation Oncogene activation
149
Describe Knudson's Hypothesis.
Cancer is the result of multiple accumulated mutations to a cell's DNA.
150
What are the classes of carcinogens?
``` Chemical Viral Ionising/Non-ionising radiation Hormones/parasites/mycotoxins Miscellaneous ```
151
Describe how chemical carcinogens work.
Most require metabolic conversion from pro- to active forms. | Enzyme required may be ubiquitous or confined to certain organs.
152
What cancers does UV light (non-ionising radiation) cause?
Basal cell carcinoma Melanoma Squamous cell carcinoma
153
Which condition can further increase cancer risk after exposure to UV light?
Xeroderma pigmentosum
154
What cancers can ionising radiation increase the risk of?
``` Skin cancer (radiographers) Lung cancer (uranium miners) Thyroid cancer (Ukranian children) ```
155
Give some examples of how hormones can act as carcinogens.
Oestrogen increases mammary/endometrial cancer. | Anabolic steroids increase hepatocellular carcinoma.
156
Give an example of how mycotoxins act as carcinogens.
Aflatoxin B1 increases hepatocellular carcinoma.
157
Give some examples of how parasites act as carcinogens.
Chlonorchis sinensis increases cholangiocarcinoma. | Shistosoma increases bladder cancer.
158
Give some examples of miscellaneous carcinogens.
Asbestos | Metals
159
Give three diseases that asbestos causes.
Asbestosis Mesothelioma Lung cancer
160
What are some host factors that can alter the risk of cancer in an individual?
``` Race Diet Constitutional factors Premalignant lesions Transplacental exposure ```
161
Define 'lesion'.
A region in an organ/tissue which has suffered damage. | A localised abnormality.
162
Give four types of chemicals which are carcinogens.
Polycyclic aromatic hydrocarbons Aromatic amines Nitrosamines Alkylating agents
163
Define tumour and give some examples.
Any abnormal swelling. | Neoplasm, inflammation, hypertrophy, hyperplasia
164
Define neoplasm.
A lesion resulting from the autonomous or relatively autonomous abnormal growth of cells which persists after the initiating stimulus has been removed.
165
Give four characteristics of neoplasia.
Autonomous Abnormal Persistent New growth
166
What percentage of the population are affected by neoplasia?
25%
167
What percentage of deaths is neoplasia responsible for?
20%
168
What is the most common type of cancer in men and women?
Prostate (men) | Breast (women)
169
What is the most common cause of cancer death in men and women?
Lung (both men and women)
170
Give an example of a borderline tumour.
Some ovarian lesions are classified as borderline.
171
What are the two components of a neoplasm?
Neoplastic cells and stroma.
172
Describe a neoplastic cell.
Usually monoclonal cells derived from nucleated cells. | Growth pattern and synthetic activity related to parent cell.
173
What is the role of the stroma of a neoplasm, and what does it usually contain?
Connective tissue framework. Mechanical support. Nutrition. Keeps neoplastic cells alive. It usually contains fibroblasts and blood vessels.
174
How large can tumours grow before they need their own blood supply?
2mm
175
Why is central necrosis often seen in large, rapidly-growing tumours?
The tumour outgrows its blood supply.
176
Why can't angiogenesis currently be used as a target for cancer therapy?
It is essential for normal processes (menstruation and regeneration/repair).
177
What is the purpose of tumour classification?
Determine appropriate treatment. | Provide prognostic information.
178
What does the behavioural classification of tumours encompass?
Benign or malignant (or borderline)
179
What does the histogenetic classification of tumours encompass?
Cell of origin
180
Define pleomorphic.
Altered shape/size
181
What is the difference between exophytic and endophytic?
``` Exophytic = grows into lumen Endophytic = grows into tissue ```
182
``` Describe benign tumours. Include: - Localisation/invasiveness - Growth rate - Mitotic activity - Resemblance to normal tissue - Borders/capsules - Nuclear morphometry - Necrosis - Ulceration - Growth on mucosal surfaces ```
- Localised/non-invasive - Slow growth rate - Low mitotic activity - Close resemblance to normal tissue - Circumscribed/encapsulated - Nuclear morphometry often normal - Necrosis rare - Ulceration rare - Growth on mucosal surfaces often exophytic
183
``` Describe malignant tumours. Include: - Localisation/invasiveness - Growth rate - Mitotic activity - Resemblance to normal tissue - Borders/capsules - Nuclear morphometry - Necrosis - Ulceration - Growth on mucosal surfaces ```
- Invasive/metastases - Rapid growth rate - High mitotic activity - Variable resemblance to normal tissue - Poorly defined/irregular border - Hyperchromatic/pleomorphic nuclei - Necrosis common - Ulceration common - Growth on mucosal surfaces often endophytic
184
What are the consequences of benign neoplasms?
- Pressure on adjacent structures - Anxiety - Obstruct flow - Production of hormones - Transformation to malignant neoplasm
185
What are the consequences of malignant neoplasms?
- Destruction of adjacent tissue - Hormone production - Metastases - Paraneoplastic effects - Blood loss from ulcers - Anxiety and pain - Obstruction of flow
186
Define histogenesis.
The specific cell of origin of a tumour.
187
A tumour formed from well-differentiated cells is ________ grade tumour.
Low
188
Where can neoplasms arise from?
Epithelial cells Connective tissues Lymphoid/haemopoietic organs
189
What is a tumour called if the cells are so poorly differentiated that the cell-type of origin is unknown?
Anaplastic
190
What would a benign neoplasm from secretory epithelium be called?
Adenoma
191
What would a benign neoplasm from non-secretory epithelium be called?
Papilloma
192
What would a malignant neoplasm from secretory epithelium be called?
Adenocarcinoma
193
What would a malignant neoplasm from epithelium be called?
Carcinoma
194
What is the suffix for a benign neoplasm of connective tissue?
-oma
195
What is the suffix for a malignant neoplasm of connective tissue?
-sarcoma
196
Give three examples of malignant tumours which don't end in carcinoma/sarcoma.
Melanoma (melanocytes) Mesothelioma (mesothelial cells) Lymphoma (lymphoid cells)
197
What is the proper name for fibroids?
Leiomyoma
198
What is the cell of origin of Burkitt's lymphoma?
B cells
199
Where is Ewing's sarcoma found?
Bones
200
What is another name for Grawitz tumour?
Renal cell carcinoma
201
Where does Kaposi's sarcoma manifest and what is it caused by?
In skin/mouth. | Caused by herpes 8 virus.
202
Name 6 -omas or -sarcomas and their cells of origin.
``` Lipoma/Liposarcoma (adipose tissue) Chondroma/Chondrosarcoma (cartilage) Osteoma/Osteosarcoma (bone) Angioma/Angiosarcoma (vascular) Rhabdomyoma/Rhabdomyosarcoma (striated muscle) Leiomyoma/Leiomyosarcoma (smooth muscle) ```
203
What are two conditions that contribute to 'cancer cell' growth?
More cell division. | Less apoptosis.
204
What is the name for a carcinoma which is contained within a basement membrane?
Carcinoma in situ
205
When is a carcinoma classed as invasive?
When it has breached the basement membrane.
206
What is a mico-invasive carcinoma?
A carcinoma which has not invaded very far. | There is low risk of further spreading.
207
What causes invasion?
Reduced cellular cohesion. Production of proteolytic enzymes. Abnormal cell motility.
208
What are the six steps of metastasis?
1. Invasion of basement membrane 2. Invasion of extracellular matrix 3. Intravasation 4. Evasion of host immune defense 5. Extravasation 6. Growth and angiogenesis
209
What are the two factors that allow invasion of the basement membrane and extracellular matrix?
Proteases and cell motility
210
Which enzymes allow invasion of the basement membrane and extracellular matrix?
Matrix metalloproteinases Collagenase Cathepsin D Urokinase-type plasminogen activator
211
What factors contribute to cell motility?
Tumour cell derived motility factors. | Breakdown products of extracellular matrix.
212
What contributes to intravasation?
Collagenases and cell motility
213
How do neoplastic cells evade the host immune defense?
- Aggregation with platelets - Shedding of surface antigens - Adhesion to other tumour cells
214
What contributes to extravasation?
Adhesion receptors (on inside of vessels). Collagenases. Cell motility.
215
How do tumour cells divide at the new site of metastasis?
Autocrine growth factors
216
Name two angiogenesis promoters.
- Vascular endothelial growth factor | - Basic fibroblast growth factor
217
Name three angiogenesis inhibitors.
Angiostatin Endostatin Vasculostatin
218
Which cancers usually spread to the lungs?
Sarcomas, any common cancers
219
How do tumours spread to the lungs?
``` Enter lymph/venous channels. Empties into thoracic duct/vena cava. Enters right side of the heart. Enters pulmonary arteries. Invades lungs then enters pulmonary veins and left side of heart. ```
220
Which cancers usually spread to the liver?
Colon Stomach Pancreas Carcinoid tumours of the intestine
221
How do tumours spread to the liver?
Venous drainage to liver via hepatic portal vein. | Metastases form in liver.
222
How do tumours spread to bone?
Some tumour cells may recognise adhesion receptors in blood vessels in bone so that's where they exit the blood stream.
223
Is the primary tumour or the metastases more likey to kill a patient?
Metastases
224
How could the p53 protein be involved in cancer?
It detects DNA damage but it could be mutated in cancer.
225
What is telomerase and how could it be involved in cancer?
Enzyme present in germ cells and stem cells which prevents telomeric shortening. It could be present in neoplastic cells.
226
Give three symptoms of conventional chemotherapy.
Myelosuppression Hair loss Diarrhoea
227
Which types of tumours is conventional chemotherapy good for?
Fast dividing tumours
228
Give the names of four drugs used for conventional chemotherapy.
Vinblastine Etoposide Ifosamide Cisplatin
229
What is the concept of targeted chemotherapy?
It exploits some difference between cancer cells and normal cells to target drugs to cancer cells. It is more effective and has less side effects.
230
Name three drugs that have been developed for targeted chemotherapy.
Cetuximab Herceptin Gleevec
231
How do tumour cells evade the immune checkpoint?
Programmed cell death protein 1 is expressed on the surface of self-cells to downregulate the immune system. Some tumour cells produce lots of this protein.
232
Describe the TNM system of tumour classification.
``` T = size or local anatomical extent N = lymph node status M = metastases ```
233
What is the role of neutrophils in the innate immune system?
Phagocytosis
234
What receptors do neutrophils have?
Complement receptors | Fc receptors
235
What is the role of monocytes & macrophages in the immune response?
Phagocytosis and antigen presentation.
236
What receptors do monocytes & macrophages have?
Complement receptors Fc receptors Pattern-recognition receptors
237
Which cells are the first line of non-self recognition?
Macrophages
238
Which types of infections are eosinophils involved with?
Parasitic infections and allergy.
239
What receptors do eosinophils have?
Fc receptors with a strong affinity for IgE.
240
How are basophils involved in the immune response?
Involved in immunity to parasitic infections and allergy.
241
Which molecule is expressed as the T cell co-receptor?
CD3
242
Which receptor do Th cells express?
CD4
243
Which receptor do cytotoxic t cells express?
CD8
244
Which receptor do Treg cells express?
CD25
245
What is the name of the transcription factor in Treg cells which is vital to their proper function?
FOXP3
246
How do B cells act as antigen presenting cells?
B cells can recognise soluble antigens using their receptors, internalise them, and then present them on MHCII proteins.
247
What is the role of Natural Killer cells?
Recognise and kill virus infected cells and tumour cells by apoptosis.
248
What is the role of dendritic cells?
Process antigens and present them to T lymphocytes.
249
Name the 'professional' antigen presenting cells.
Monocytes/macrophages B lymphocytes Dendritic cells
250
What is the role of Fc receptors?
Recognise the Fc region of antibodies
251
What is the role of complement receptors?
Recognise pathogens coated in C3b from complement
252
What is the role of Toll-like receptors?
Recognise pathogen-associated molecular patterns expressed by microbes.
253
What is the role of mannose receptors?
C-type lectin that recognises carbohydrates
254
What is the role of scavenger receptors?
Bind to various ligands including bacterial cell wall components.
255
What are the soluble factors involved in the immune response?
Complement factors Antibodies Cytokines Chemokines
256
What are complement factors?
A group of 20 serum proteins that circulate in an inactive form.
257
What are the three complement activation pathways?
Classical Alternative Lectin
258
What is the classical pathway of complement activation?
Antibody bound to microbe
259
What is the alternative pathway of complement activation?
Complement bound to microbe
260
What is the lectin pathway of complement activation?
Mannose binding lectin bound to carbohydrates on a microbe.
261
What are the three ways complement contributes to the immune response?
- Lyse microbes directly - Increase chemotaxis to attract leukocytes - Opsonisation
262
Which component of complement is involved in lysing microbes?
Membrane attack complex
263
Which components of complement are involved in increasing leukocyte chemotaxis?
C3a and C5a
264
Which component of complement is involved in opsonisation?
C3b
265
In what three states can antibodies exist?
Soluble Bound to B lymphocytes Secreted
266
What are the 2 sections of an antibody?
``` Fab region (where antigen binds) Fc region (constant region) ```
267
What are the five classes of antibody?
``` IgG IgM IgA IgD IgE ```
268
Which antibody prevents tumour cells expressing the programmed cell death protein 1 checkpoint?
Nivolumab
269
Define immunosurveillance.
The process by which cells of the immune system look for and recognise foreign antigens.
270
What are the three stages of cancer immunoediting?
Elimination Equilibrium Escape
271
Describe the elimination stage of cancer immunoediting.
The immune system eliminates the tumour cells that it can.
272
Describe the equilibrium stage of cancer immunoediting.
The tumour cells which evaded elimination are selected to grow and replicate.
273
Describe the escape stage of cancer immunoediting.
Tumour cells grow and expand and have now escaped the immune system.
274
What are tumour specific antigens?
Antigens which are only found on tumour cells.
275
What are tumour associated antigens?
Antigens which are overexpressed on cancer cells.
276
Which types of cells can tumour cells promote to help them evade the immune system?
Tregs | Myeloid-derived suppressor cells
277
Name two methods of active immunotherapy.
Vaccination (using tumour antigens or killed tumour cells). | Augmentation of host immunity to tumours with cytokines and co-stimulators.
278
Name two methods of passive immunotherapy.
Adoptive cellular therapy. | Anti-tumour antibodies.
279
Describe adoptive cellular immunotherapy.
- Extract sample of tumour-infiltrating lymphocytes from tumour biopsy. - Stimulate the cells to grow ex-vivo. - Inject cells back into patient.
280
Which antibodies can active complement?
IgG | IgM
281
Which is the most abundant antibody in serum?
IgG
282
Which antibody can cross the placenta?
IgG
283
Which antibodies are involved in the primary and secondary immune responses?
Primary - IgM | Secondary - IgG
284
Which antibodies are expressed as B cell receptors?
IgM (in its monomer form) | IgD
285
Which antibodies require the J chain?
IgM | IgA
286
Which antibody is secreted as a dimer?
IgA
287
Which antibody has a secretory component?
IgA
288
Which antibody is usually found bound to basophils and mast cells?
IgE
289
What is released upon binding of an IgE antibody?
Histamine
290
Which antibody is associated with allergic response and parasitic infections?
IgE
291
What is the term used to describe the process of plasma cells changing from producing one class of antibody to another?
Class/isotype switching
292
Which immunoglobulin type (IgG or IgM) has the higher affinity?
IgG
293
Which cells are the primary secretors of cytokines?
Th1 Th2 Macrophages
294
What is the role of interferons (IFNs)?
Induce a state of antiviral resistance in uninfected cells and limit spread of viral infection.
295
Which cells secrete IFNa and IFNb?
Virus infected cells
296
Which cells secrete IFNy?
Activated Th1 cells
297
What is the role of interleukins (ILs)?
Can cause cells to divide, differentiate, and secrete factors.
298
Name a pro-inflammatory interleukin.
IL1
299
Name an anti-inflammatory interleukin.
IL-10
300
What is the role of colony stimulating factors?
Involved in directing division and differentiation on bone marrow pre-cursors of lymphocytes.
301
What is the role of tumour necrosis factors?
Pro-inflammatory (mediate inflammation and cytotoxic reactions).
302
Which interleukin is especially involved in regulating the differentiation of T cells?
IL-2
303
What is the role of chemokines?
To direct the movement of leukocytes from blood to tissues or lymph organs.
304
Name four types of chemokine.
CXCL CCL CX3CL XCL
305
What are five hallmarks of innate immunity?
- Primitive (spread across species) - Integrates with adaptive response - Does not depend on immune recognition by lymphocytes - Does not have long-lasting memory - Unlearned/instinctive response
306
What are the three components of the innate immune response?
``` Physical/chemical barriers Phagocytic cells (neutrophils & macrophages) Serum proteins (complement & acute phase proteins) ```
307
What physical barriers are part of the innate immune system?
- Bronchi (mucus, cilia) - Commensals in mouth - Lysozyme in tears (and other secretions) - Skin (physical barrier, fatty acids, commensals) - Low pH and commensals of vagina - Flushing of urinary tract - Gut (rapid pH change, acid, commensals) - Rapid passage of air over nasal turbinates
308
What mucous membranes contribute to the innate immune system?
``` Saliva Tears Mucus secretions/entrapment Cilia (beating removes microbes) Commensal colonies ```
309
What physiological barriers are part of the innate immune response?
- Temperature (fever inhibits growth) - pH - Gastric acidity - Oxygen (aerobes/anaerobes) - Inflammation
310
Which cells sense microbes in blood?
Monocytes | Neutrophils
311
Which cells sense microbes in tissues?
Macrophages | Dendritic cells
312
What are four pathogen-associated molecular patters that can be recognised by PRRs?
- Gram +ve/-ve - Double-stranded RNA - CpG oligodeoxynucleotides - Lipopolysaccharides
313
What are three types of secreted/circulating PRR? | Give examples.
- Antimicrobial peptides secreted in lining fluids (defensins, cathelicidin) - Lectins & collectins (mannose binding lectin, surfactant proteins A and D) - Pentraxins (proteins like CRP with some microbial actions)
314
Name four types of extracellular cell-associated PRR.
- Toll-like receptors - Dectin-1 - Mannose receptor - Scavenger receptor
315
Which TLR recognises lipopolysaccharides?
TLR-4
316
Which TLR recognises viral RNA?
TLR-3
317
Which TLR recognises bacterial DNA?
TLR-9
318
Name two types of intracellular PRR.
Nod-like receptors | Rig-I-like receptors
319
Name three types of NLR.
NOD1 NOD2 NLRP3
320
What do NLRs detect?
Intracellular microbial pathogens | Eg - peptidoglycan, muramyl dipeptide
321
What do RLRs detect?
Intracellular double stranded viral RNA/DNA.
322
How do RLRs work when activated?
Activate interferon production to stimulate antiviral response.
323
Name three RLRs.
RIG-I MDA5 LGP2
324
Give four ways that PRRs are involved in homeostasis.
- Neutrophil numbers are dependent on TLR-4 - Induction of endotoxin tolerance in newborn gut - Maturation of normal immune system - Maintaining balance with commensal organisms
325
In addition to Pathogen-associated molecular patterns, what else can TLRs recognise?
Molecules that signal cell damage.
326
What is one feature usually associated with damage-associated molecules?
Hydrophobicity
327
Name some molecules that can be seen as damage molecules.
- Fibrinogen - Hyaluronic acid - Tenascin C - HMGB1 protein - mRNA - Heat shock protein - Uric acid
328
Why are many hydrophobic molecules associated with cell damage?
They are usually contained inside cells so when cells are damaged they are released and available to TLRs.
329
What are heat shock proteins?
Proteins produced by cells in response to stress. | They protect proteins from stress and excess heat.
330
How are PRRs involved in adaptive immunity?
Activation of PRRs drives cytokine production by APCs to increase likelihood of T cell activation.
331
How are PRRs used in vaccination?
TLR-4 agonists are used as adjuvants to simulate TLR-4 to enhance the immune system.
332
Give three ways the PRRs are involved in disease.
- Recognition of host molecules leads to autoimmune disease - Potential failure to recognise pathogens - Increased inflammatory response
333
Which transcription factors can be activated by TLRs?
NF-kB | IRF3
334
What is the final outcome of TLR activation?
Interferon production and regulation of the immune response.
335
Which transcription factor pathway does TLR-4 activate?
NF-kB
336
What is primary immunodeficiency?
Part of the immune system is missing or functions improperly due to a genetic fault.
337
What is secondary immunodeficiency?
Synthesis of key immune components is suppressed (due to bone marrow infiltration/virus).
338
How does antibody deficiency usually present?
Recurrent bacterial infections of the respiratory tract.
339
How does defects in cellular immunity usually present?
Invasive and disseminated viral, fungal, and opportunistic bacterial infections involving any organ.
340
What are the main cells that carry out phagocytosis?
Neutrophils | Macrophages
341
What are the six steps of phagocytosis?
1. Microbe binding 2. Engulfment 3. Phagosome 4. Phagolysosome 5. Secretion of waste 6. Antigen presentation (MHCII)
342
Which receptors do phagocytes have which can bind pathogens for phagocytosis?
Fc receptors Complement receptors Mannose receptors
343
Name the two mechanisms of killing in phagocytosis.
Oxygen dependent | Oxygen independent
344
What is the respiratory burst?
Phagocyte oxygen consumption increases in phagocytosis so more ROIs produced which are used to kill pathogens.
345
Which enzyme is used to produce reactive oxygen species?
Superoxide dismutase
346
Give three ROS and link them.
O2 (superoxide) -> H2O2 (hydrogen peroxide) -> .OH (free radical)
347
How does the production of NO help phagocytosis?
Causes vasodilation and extravasation, and is also a direct antimicrobial.
348
What are three elements of the oxygen independent phagocyte killing pathway?
Enzymes (defensins and lysozyme) PH TNF (Tumour necrosis factor)
349
Where are dendritic cells found?
In tissues which are in contact with the external environment, eg - skin.
350
What is an acute phase protein?
A protein whose serum concentration will increase or decrease in response to inflammation.
351
Name an acute phase protein.
C Reactive Protein
352
What is the ultimate aim of complement activation?
Cleavage of C3
353
Which complement factor cleaves C5?
C3b
354
What are the four essential characteristics of adaptive immunity?
Specificity Diversity Memory Self/non-self recognition
355
What are four features of adaptive immunity?
Response specific to antigen Memory to specific antigen Quicker response Requires lymphocytes
356
Which cells and which microbes are involved in cell mediated immunity?
T cells | Intracellular microbes
357
Which cells and which microbes are involved in humoural immunity?
B cells | Extracellular microbes
358
What is primary lymphoid tissue? | Give examples.
Tissue where lymphocytes are formed and mature. | Eg - thymus and bone marrow
359
What is secondary lymphoid tissue? | Give examples.
Tissue where lymphocytes are activated. | Eg - spleen, lymph nodes, MALT
360
What is a major histocompatibility complex?
Glycoprotein which displays antigen on cell surface.
361
Which genes encode major histocompatibility complexes?
Human Leukocyte Antigen (HLA) genes
362
Describe MHC Class I. - Which cells is it on? - Which antigens does it display? - Which cells respond to it? - What is the outcome of displaying the antigen?
- Displayed on all nucleated cells - Presents intracellular antigens - Tc (CD8+) cells respond - Outcome is killing of infected cell
363
Describe MHC Class II. - Which cells is it on? - Which antigens does it display? - Which cells respond to it? - What is the outcome of displaying the antigen?
- Displayed on APCs - Presents extracellular antigens - Th (CD4+) cells respond - Outcome is helping B cells
364
What is the difference between antigen recognition by T cells and B cells?
B cells can recognise soluble antigens whereas T cells can only recognise antigens in association with MHC.
365
What autocrine molecule is secreted by T cells in order to activate the cell?
IL-2
366
Which receptor on naive T cells as a co-stimulatory molecule in T cell activation?
CD28
367
Which receptor acts as a co-stimulatory molecule on helper T cells?
CD4
368
Which receptor acts as a co-stimulatory molecule on cytotoxic T cells?
CD8
369
What are the four outcomes of T cell activation?
- Division - Differentiation - Effector functions - Memory
370
What are the roles of a Tc (CD8+) cell?
- Binds to MHCI - Forms proteolytic granules - Releases perforins/granulysin - Induces apoptosis
371
What are the roles of a Th1 (CD4+) cell?
- Binds to MHCII - Go to secondary lymphoid tissue and undergo clonal expansion - Recognises antigen on infected cells - Secretes INFy to stop virus spread - Induce apoptosis
372
What are the roles of a Th2 (CD4+) cell?
- Bind to B cells displaying antigen on MHCII | - Release cytokines to cause B cell clonal expansion
373
Which is the main cytokine that determines whether a Th cell will become Th1 or Th2?
Il-12 | High levels of Il-12 activate Th1, low levels activate Th2
374
Which types of cells can B cells differentiate to form?
Plasma cells | Memory cells
375
Where do B cells divide and differentiate?
Lymph nodes
376
What are the three functions of antibodies?
- Neutralise toxin by binding to it - Increase opsonisation for phagocytosis - Activate complement
377
Define autoimmunity.
Immune response against a self antigen
378
Define autoimmune disease.
Tissue damage or disturbed function resulting from an autoimmune response.
379
What is an organ-specific autoimmune disease?
Autoimmune diseases which affect a single organ.
380
What is a non-organ-specific autoimmune disease?
An autoimmune disease which affects multiple organs.
381
What are the two types of selection which occur in central (thymic) tolerance?
Positive selection | Negative selection
382
What is positive T cell selection?
T cells that bind to self antigens associated with MHC in the thymus with low affinity are allowed to mature.
383
What is negative T cell selection?
T cells that don’t recognise self MHC or bind with high affinity in the thymus undergo apoptosis.
384
How can central (thymic) T cell tolerance fail?
It can fail if self-peptides are not expressed in high enough concentrations in the thymus.
385
What are three methods of peripheral tolerance?
- Immunological ignorance - Anergy - Tregs
386
Describe immunological ignorance in relation to peripheral T cell tolerance.
Some self-antigens hide from the immune system. This can be due to: - Being in an avascular organ (vitreous humour) - A limited number of MHC molecules - Apoptosis keeping self-antigens contained
387
Describe anergy.
If the CD28 co-stimulator molecule on a T cell is not activated by the APC the T cell will become unresponsive.
388
Describe how Tregs contribute to peripheral tolerance.
They may suppress T cells if they recognise the same antigen.
389
What are four ways that treatments for autoimmune diseases can target the self-reactive lymphocyte?
- Inhibition of lymphocyte function - Reinduction of anergy - Removal of co-stimulation - Induction of inhibitory T cells
390
How can tissue damage caused by an autoimmune disease be treated?
Anti-inflammatory drugs (eg - corticosteroids)
391
Define passive immunisation.
Transfer of preformed antibodies
392
Describe the two types of passive immunity.
Natural (transfer of maternal antibodies) | Artificial (Treatment with human IgG or immune serum)
393
Give four uses of passive immunisation.
- Anti-toxins - Prophylaxis to prevent infection after exposure - Anti-venins - Given to patients with agammaglobulinaemias and immune-compromised patients
394
Define active immunisation.
Manipulating the immune system to generate a persistent protective response against pathogens by safely mimicking natural infections and establishing immunological memory.
395
What are the six steps of active immunisation?
1. Engage innate immune system 2. Elicit danger signals (PAMPs) 3. Engage TLR receptors 4. Activate APCs 5. Engage adaptive immune system 6. Generate memory T and B cells
396
What is somatic hypermutation?
Genes in B cells coding for the antigen binding sites on antibodies undergo rapid mutations during the immune response to create more specific and unique receptors.
397
How do T and B cell receptors achieve their huge range of diversity?
The genes coding for the antigen receptors are inherited as fragments. The fragments are joined together to form a complete antigen receptor gene only in individual lymphocytes as they develop.
398
What are the two vaccine designs that are currently used?
Whole organism | Subunit
399
What is a live attenuated vaccine?
The pathogen is still alive but the virulence has been reduced. This sets up a transient infection and engages a full immune response.
400
Give two examples of live attenuated pathogen vaccines.
Tuberculosis (BCG) | Polio Sabin
401
Describe whole inactivated pathogen vaccines.
Inactivation of the pathogen usually by chemical treatment (eg - formaldehyde). No risk of infection so immune response can be weak. Wide range of antigens present.
402
Give two examples of whole inactivated pathogen vaccines.
Salk polio, Hepatitis A
403
What are the three major types of subunit vaccine.
Inactivated exotoxins Capsular polysaccharides Recombinant microbial agents
404
What is the aim of a synthetic peptide vaccine?
To produce a peptide that includes immunodominant B cell epitopes and can stimulate memory T cell development. *Still being developed
405
What is the aim of a DNA vaccine?
To transiently express genes from pathogens in host cells to generate an immune response similar to natural infection leading to memory T and B cells. * Still being developed
406
What are recombinant vector vaccines?
Genes for pathogenic antigens are introduced into a non-pathogenic microorganism. *Still being developed
407
What is an adjuvant in relation to vaccines?
Any substance added to a vaccine to stimulate the immune system.
408
Give four examples of vaccine adjuvants.
- Aluminium salts form precipitates and increase opsonised phagocytosis - Chemicals cause irritation and inflammation - Toxoids and killed organisms send out danger signals - TLR agonists activate TLR receptors
409
Give some examples of medical non-adherence.
- Not taking prescribed medication - Taking a different dose than prescribed - Taking medication more/less often than prescribed - Stopping the medicine without finishing the course - Modifying treatment to accommodate other activities - Continuing with behaviours against medical advice
410
What are some unintentional/practical reasons for non-adherence?
- Difficulty understanding instructions - Problems using treatment - Inability to pay - Forgetting
411
What are some intentional/motivational reasons for non-adherence?
- Patients’ beliefs about their health/condition - Beliefs about treatments - Personal preferences
412
What are four impacts of good doctor-patient communication?
- Better health outcomes - Better adherence to therapies - Higher patient and clinician satisfaction - Decrease in malpractice risk
413
What are three patient barriers to concordance?
- Do patients want to engage in discussion with their doctor? - The patient may worry more - Patients may want the doctor to tell them what to do (especially in complex cases)
414
What are three health professional barriers to concordance?
- Relevant communication skills - Time/resources/organisational constraints - Challenging (patient voice V evidence)
415
Define adherence.
The extent to which the patient’s actions match agreed recommendations.
416
What are four ethical considerations when discussing patient adherence?
- Mental capacity - Decision may be detrimental to a patient’s wellbeing - Potential threat to the health of others - Wishes of parent/child
417
What does the Public Health Act 2010 allow?
Detention and isolation of an infectious individual.
418
What does section 1 of the Children Act 1989 say?
The child’s welfare shall be the Court’s paramount consideration.
419
What is a physiochemical drug interaction?
The way two drugs interact with each other.
420
What can a physiochemical drug interaction cause?
Adsorption Precipitation Chelation Neutralisation
421
Give an example of a physiochemical drug interaction.
Paracetamol adsorbs to activated charcoal so activated charcoal can be given in a paracetamol overdose.
422
What are the three ‘types’ of drug interaction?
- Physiochemical - Pharmacodynamic - Pharmacokinetic
423
Define pharmacodynamic.
The effects of a drug on the body.
424
What are the four types of pharmacodynamic drug interaction?
- Summation - Synergism - Antagonism - Potentiation
425
What is a summative pharmacodynamic reaction?
The effect of two drugs added together.
426
What is a synergistic pharmacodynamic interaction?
The effect of the drugs being given together is greater than the sum of the effects of both drugs individually.
427
What is an antagonistic pharmacodynamic interaction?
Two drugs oppose each other.
428
Give an example of a synergistic pharmacodynamic interaction.
Giving morphine and paracetamol together amplifies their effect.
429
Give an example of an antagonistic pharmacodynamic interaction.
Morphine and Naloxone (an opioid reversal drug)
430
What is potentiation, in terms of pharmacodynamic interactions?
One drug makes the other more powerful, but it doesn’t work the other way round.
431
Give an example of potentiation, in terms of pharmacodynamic interactions.
Probenecid makes penicillin more powerful.
432
What are some common drug interactions involving warfarin?
- Highly protein-bound (giving another highly protein-bound drug at the same time increases effect) - Metabolised by CYP450 (enzyme inducers/inhibitors alter effects)
433
What are four drugs that cause acute kidney injury, and why shouldn’t they be given together?
- NSAIDs - ACE inhibitors - Gentamicin - Furosemide NSAIDs and ACEi have synergistic effects, and so do gentamicin and furosemide.
434
Define druggability.
The ability of a protein target to bind small molecules with high affinity.
435
What are the four common drug targets?
Receptors Ion Channels Transporters Enzymes
436
What is a receptor?
A component of a cell that interacts with a specific ligand and initiates a change of biochemical events leading to the ligands observed effects.
437
What are the four types of receptor?
- Ligand-gated ion channel - G protein coupled receptor - Kinase-linked receptor - Nuclear receptor
438
How does a ligand-gated ion channel work?
A ligand binds and causes a conformational change which opens the ion channel.
439
How do GDP and GTP affect G protein coupled receptors?
They are switched off when bound to GDP and switched on when bound to GTP.
440
Which enzymes are commonly bound to G protein coupled receptors and which second messengers do they produce?
- Phospholipase C, which produces DAG/IP3 | - Adenylyl cyclase, which produces cyclic AMP
441
Which enzyme is usually present in kinase-linked receptors?
Tyrosine kinase
442
How to kinase-linked receptors work?
- Ligand binds and receptors dimerise - Receptors phosphorylate each other (usually tyrosine is phosphorylated) - Intracellular proteins bind to phosphorylated receptor to become phosphorylated
443
Which type of ligand usually binds to kinase-linked receptors?
Growth factors
444
How do nuclear receptors work?
Steroid hormones bind to cause conformational change. | Receptor binds to DNA to modify gene transcription.
445
Define ligand.
A molecule that binds to another (usually larger) molecule.
446
Define agonist.
A compound that binds to a receptor and activates it.
447
Define antagonist.
A compound that reduces the effect of an agonist.
448
What is potency?
A measure of drug activity expressed in terms of the amount required to produce an effect of given intensity.
449
What is EC50?
The concentration of a drug that gives half the maximal response.
450
What is efficacy (Emax)?
The maximum response achievable from a dose of a drug. | It describes how well a ligand activates the receptor.
451
What is intrinsic activity (IA)?
The ability of a drug-receptor complex to produce a maximum functional response. (Emax of partial agonist / Emax of full agonist)
452
What is the role of an antagonist?
To not activate the receptor and reverse the effects of agonists.
453
Describe competitive antagonism.
The agonist and antagonist compete for binding sites, and increasing the concentration of the antagonist decreases the agonist activity.
454
Describe non-competitive antagonism.
The antagonist binds to an allosteric on the receptor to prevent activation. This reduces Emax of the agonist.
455
Define affinity.
How well a ligand binds to the receptor.
456
What is an irreversible antagonist?
An antagonist which inactivates receptors and reduces the number of receptors present.
457
What is the receptor reserve?
Holds for a full agonist in a given tissue (spare receptors with a maximal response).
458
Define signal transduction.
The transmission of a signal from the exterior to the interior of a cell.
459
Define signal amplification.
The increase of a signal related to the amount of activation.
460
What is an inverse agonist?
A compound which downregulates a response. | It shows the opposite response to an agonist.
461
What is tolerance, in relation to pharmacology?
The reduction in a drug’s effect over time due to continuously, repeatedly, high concentrations.
462
What can desensitization be caused by?
- Uncoupling - Internalisation - Degradation
463
How should the terms specificity and selectivity be used when describing the actions of drugs and receptors.
No compound is ever truly specific, so selective is a better term to describe activity.
464
What is an irreversible enzyme inhibitor?
A substance which reacts with the enzyme and changes it chemically. Eg - via a covalent bond
465
What is a reversible enzyme inhibitor?
A substance which binds non-covalently to an enzyme, enzyme-substrate complex, or both.
466
Name an enzyme which is used as a drug.
Streptokinase (a clot buster)
467
What is the role of HMG-CoA inhibitors?
They block the rate-limiting step in the cholesterol pathway to act as a lipid-lowering medication.
468
What is the role of ACE inhibitors?
Reduce angiotensin II production to lower blood pressure.
469
How can enzymes be used in Parkinson’s Disease?
- Enzymes can be used to block L-DOPA breakdown in the periphery so it can cross the blood brain barrier. - They can also be used to block L-DOPA and Dopamine breakdown in the CNS so more dopamine is available.
470
Apart from enzymes, what other types of drugs can be used in Parkinson’s disease?
Central dopamine agonists
471
How does furosemide work?
Blocks NKCC cotransporter in the Loop of Henle to reduce hypertension and oedema.
472
Name a drug that blocks the Epithelial sodium channel (ENaC) to prevent reabsorption of sodium in the collecting duct.
Amiloride
473
Name an angioselective drug which blocks Ca channels in smooth muscle and cardiac muscle cells to cause vasodilation and reduce peripheral vascular resistance (and therefore blood pressure).
Amlodipine
474
How does lidocaine act as a local anaesthetic?
Blocks voltage-gated sodium channels to block the transmission of an action potential.
475
As well as use an anaesthetic, how else is lidocaine used?
For heart arrhythmia
476
Repaglinide, nateglinide, and sulfonylurea block metabolic potassium channels. How can they be used as drugs?
Block potassium channels in beta cells in pancreas to stimulate insulin release in type 2 diabetes.
477
Which neurotransmitter can open receptor-mediated chloride channels on neurones to hyperpolarise the cell?
GABA
478
Name a type of drug that can be used to increase the permeability of chloride channels in the brain to hyperpolarise neurones and therefore provide more action potential inhibition.
Barbiturates
479
How does digoxin lengthen the cardiac action potential and what conditions is it used for?
Inhibits Na/K ATPase in myocardium, which increases intracellular calcium. Used for atrial fibrilliation, atrial flutter, and heart failure.
480
Describe how omeprazole works.
Proton pump inhibitor which inhibits K/H ATPase in stomach to inhibit gastric acid secretion. It is metabolised at an acidic pH.
481
Name three types of drugs which are irreversible inhibitors.
- Organophosphates - Omeprazole - Aspirin
482
What is a pharmacokinetic drug interaction?
What the body does to a drug.
483
What is bioavailability (F)?
The proportion of a drug which enters the circulation so is able to have an effect.
484
What is the bioavailability for an IV drug?
100%
485
How do you work out the bioavailability for an oral drug?
Area under concentration-time curve for oral drug / AUC for IV drug
486
What are three factors which affect the rate of absorption of a drug?
- Gut motility - Acidity - Physiochemical effects
487
How does gut motility affect drug absorption?
Pain and certain drugs can cause slower peristalsis, so drugs taken orally will be less effective.
488
How does acidity affect drug absorption.
Drugs exist in equilibrium between ionised and unionised forms. A change in acidity alters the equilibrium. Unionised drugs are lipid soluble (can cross cell membrane) but ionised drug are water soluble (can’t cross cell membrane).
489
What is the pKa of a drug?
The pH at which half of the substance is ionised and half is unionised.
490
What are the three possible ‘destinations’ for a drug in the body?
- Bound to protein (usually albumin) - In random tissues - At the effect site
491
How does protein binding act as a depot for a drug?
Protein binding can be reversible or irreversible. | In irreversible protein binding the protein can release more of the drug as the plasma concentration falls.
492
What is the effect of giving two highly protein-bound drugs at the same time?
They will compete for binding sites, so less of each drug is protein-bound and the clinical effect will increase.
493
Define drug metabolism.
The transformation of the drug molecule into a different molecule.
494
How are most drugs metabolised?
CYP450 enzymes in the liver.
495
What are some inducers of CYP450 enzymes?
Phenytoin | Smoking
496
What are some inhibitors of CYP450 enzymes?
Metronidazole | Grapefruit juice
497
What two processes make up drug elimination?
Metabolism and Excretion
498
Define drug elimination.
The removal of a drugs activity from the body.
499
What are the three forms that drugs can be excreted as?
Fluids Solids Gases
500
Which types of drugs are excreted as fluids?
Low molecular weight
501
Which types of drugs are excreted as solids?
High molecular weight
502
Which types of drugs are excreted as gases?
Volatiles
503
How can excretion be accelerated in a drug overdose? | How would it be different if the drug was acidic?
``` Forced diuresis (fluid overload + diuretics). If it is an acidic drug (eg-aspirin), giving bicarbonate of soda causes a forced alkaline diuresis to get rid of the acidity. ```
504
What are the three factors that determine urinary excretion of a drug and how are they related to each other?
Urine excretion = glomerular filtration + tubular secretion - reabsorption
505
Define drug absorption.
The process of transfer from the site of administration into the general or systemic circulation.
506
What are the four ways that drugs can cross cell membranes?
- Passive diffusion - Pores/channels - Carrier mediated transport - Pinocytosis
507
What is the rate of passive diffusion dependent on?
- Concentration gradient - Area - Permeability - Thickness
508
What family of carriers are involved in active transport?
ATP-binding cassette (ABC)
509
What is the role of P-gp ATP-binding cassette?
Removes drugs from the cell cytoplasm to the extracellular environment. (Also known as multi drug resistance (MDR1))
510
Name a drug that inhibits P-gp so increases the concentration of a drug in the cell cytoplasm.
Verapamil
511
What family of carriers is involved in facilitated transport?
Solute carrier (SLC) superfamily
512
Describe pinocytosis.
Form of carrier mediated entry into the cytoplasm, usually involved in the uptake of endogenous macromolecules. Drugs can be taken up into a liposome for pinocytosis.
513
What two features of the small intestine aid in rapid and complete absorption of drugs taken orally?
Large surface area | High blood flow
514
How does the drug structure affect absorption?
- Needs to be lipid soluble - Highly polarised drugs tend to only be partially absorbed - Some drugs are unstable at low pH or in the presence of digestive enzymes
515
How does drug formulation affect absorption?
The capsule/tablet must dissolve.
516
What is it called when a capsule is specially formulated to dissolve slowly?
Modified release
517
What is it called when a capsule or tablet has an acid-resistant coat?
Enteric coating
518
What four barriers do drugs have to pass to reach the circulation?
Intestinal lumen Intestinal wall Liver Lungs
519
What aspects of the intestinal lumen provide a barrier to drugs?
Digestive enzymes | Colonic bacteria
520
What aspects of the intestinal wall provide a barrier to drugs?
``` Monoamine oxidases Efflux transporters (P-gp) ```
521
What is first pass metabolism?
The liver is the main site of drug metabolism, so some drugs that are absorbed from the small intestine undergo metabolism before they are able to enter the circulation.
522
How can first pass metabolism be avoided?
Give the drug via mouth (sublingually) or by rectum, as these areas are not drained to the liver.
523
What types of drugs can be given transcutaneously?
Lipid-soluble (limited rate & extent of absorption) Potent Non-irritant
524
When can transcutaneous be an effective way of drug administration?
For slow and continuous absorption using transdermal patches.
525
When are intradermal and subcutaneous administration methods used for drug delivery?
For local effect or deliberately limited rate of absorption.
526
How can the rate of absorption of a drug injected intramuscularly be increased?
Increasing blood flow to muscle | Increasing water solubility
527
What is a depot injection?
A drug injected IM in a lipophilic formulation for slow release.
528
What are the advantages of intranasal drug administration?
- Low levels of drug metabolising enzymes - Good surface area - Can be used for local or systemic effects
529
What are the advantages and disadvantages of inhalational administration of a drug?
ADVANTAGES: - Large surface area and blood flow DISADVANTAGES: - Limited by risks of toxicity to alveoli and restricted to volatile drugs
530
Define drug distribution.
The process by which the drug is transferred reversibly from the general circulation to the tissues as the blood concentration increases, and then returns from tissues to blood when blood concentration falls.
531
Describe the drug distribution in IV administration.
High plasma concentration initially. Drug delivered to well-perfused tissues. Drug then enters less well-perfused tissues. Blood concentration falls. Drug diffuses from well-perfused tissues to blood. Concentration in well-perfused tissues falls.
532
Do lipid-soluble or water-soluble drugs diffuse easily into the brain?
Lipid-soluble
533
How are drugs removed from the brain?
- Efflux transporters - Diffusion into plasma - Active transport in choroid plexus - Elimination in CSF
534
Do lipid-soluble or water-soluble drugs easily cross the placenta?
Lipid-soluble
535
How does the blood flow to the placenta affect the equilibrium with the foetus?
The placental blood flow is relatively low, so there is slow equilibrium with the foetus.
536
How does drug elimination occur in the foetus?
Foetal liver has low levels of drug metabolising enzymes so relies on maternal elimination.
537
How does metabolism alter the solubility of drugs?
Lipid-soluble drugs are converted to water-soluble drugs.
538
What are the two phases of drug metabolism?
Phase 1 | Phase 2
539
What is phase 1 of drug metabolism?
Transformation of the drug to a more polar metabolite by unmasking or adding a functional group.
540
What is the most common phase 1 metabolism reaction?
Oxidations, carried out by CYP450 enzymes.
541
Where are CYP450 enzymes found?
In the smooth endoplasmic reticulum in liver tissue.
542
Apart from oxidation, what are two other phase 1 metabolism reactions?
Reduction | Hydrolysis
543
What type of reaction occurs in phase 2 metabolism?
Conjugation
544
What is the purpose of drug conjugation?
To make the drug more polar (water-soluble) so it can be excreted by the kidneys.
545
What is rapid sequence induction?
Anaesthetising patients while applying cricoid pressure, followed by rapid intubation. This is used for patients as risk of aspirating their stomach contents when carrying out emergency surgery.
546
Describe first order kinetics.
The decline of a drugs plasma concentration is exponential - a constant fraction of the drug is eliminated per unit of time.
547
In first order kinetics, how is the change in concentration over time related to the concentration of the drug?
The change in concentration is related to the current concentration.
548
Describe zero order kinetics.
The rate of removal of a drug is constant and unaffected by an increase in concentration. This happens when an enzyme system that removes a drug becomes saturated.
549
What is the elimination rate constant?
The rate at which a drug is removed from the system. | It is given the letter K.
550
What is the formula for half life (how is it related to the rate constant)?
T1/2 = 0.693/K
551
Define half life.
The time taken for a concentration to reduce by one half.
552
What does water-soluble drug distribution depend on?
Rate of passage across membranes.
553
What does lipid-soluble drug distribution depend on?
Blood flow to tissues that accumulate the drug.
554
What is meant by the ‘volume of distribution’?
The volume of fluid into which the drug has been distributed in the body. It is given the symbol Vd.
555
What is the formula for volume of distribution?
Vd = total amount of drug in body (dose) / plasma concentration
556
What does a low Vd suggest?
The drug is confined to the circulatory volume.
557
What does a high Vd suggest?
The drug may be distributed in the total body water.
558
Define clearance (CL).
The volume of blood or plasma cleared of a drug per unit time.
559
How does Vd affect rate of elimination?
A high Vd means the drug has a lower plasma concentration so rate of elimination is slower.
560
Write an equation linking K, CL, and Vd.
K = CL/Vd
561
Write an equation for T1/2 using CL and Vd.
T1/2 = (0.693 x Vd) / CL
562
What is the equation for clearance of an IV drug?
CL = dose / area under conc-time curve
563
What is the equation for clearance for an oral drug?
CL = (dose x bioavailability) / area under conc-time curve
564
What is Css?
The concentration of a drug in the plasma when steady state has been reached.
565
Why are repeated drug doses used?
To maintain a constant drug concentration in the blood and at the site of action for therapeutic effect.
566
What is steady state?
The situation when the rate of elimination of a drug equals the rate of infusion (for IV drugs).
567
How long does a drug typically take to reach steady state?
4-5 half lives
568
What properties of a drug mean it will take a long time to reach steady state?
Slow elimination or high Vd
569
What is the equation for steady state for an IV infusion?
Css = rate of infusion / CL
570
How does rate of absorption affect the profile of the concentration-time graph for oral drugs?
Rapid absorption = exaggerated peaks | Slow absorption = Flatter peaks
571
Give an equation for Css for an oral drug.
Css = (dose x bioavailability) / (CL x time between doses)
572
How can plasma Css be altered with an oral drug?
By changing either dose or interval.
573
What is a loading dose and why is it used?
A high initial dose which is used to ‘load’ the system and shortens the time to steady state. It is used if a drug has a long half-like so will take a long time to reach steady state.
574
Give an equation to work out a loading dose.
Loading dose = Css x Vd
575
What is the current legislation surrounding opioid pharmacology?
Misuse of Drugs Act 1971
576
What is the bioavailability of oral morphine?
50%
577
What happens to the oral morphine that isn’t absorbed into the circulation?
It undergoes first pass metabolism in the liver.
578
What are the routes of administration for opioids?
- Oral - Parenteral (SC, IM, IV) - Epidural/CSF - Transdermal patches (for lipid soluble drugs)
579
What are the relative potencies for diamorphine, morphine, and pethidine?
``` Diamorphine 5mg = Morphine 10mg = Pethidine 100mg ```
580
What is dihydrocodeine?
A synthetic opioid which is about 1.5x more potent than codeine.
581
What is oxycodone?
A synthetic opioid which is about 1.5x as potent as morphine.
582
How do opioids work?
They inhibit the release of pain transmitters at the spinal cord and midbrain and modulate pain perception in higher centres (modulate emotional perception of pain). They provide descending inhibition of pain.
583
Name four opioid receptors.
µ - MOP Delta - DOP Kappa - KOP Nociceptin opioid-like receptor - NOP
584
Where else in the body (apart from the CNS) are opioid receptors present?
Gut and respiratory system
585
Why are opioid receptors in the respiratory system of clinical significance?
Opioids cause respiratory depression.
586
Agonists for which opioid receptor cause depression instead of euphoria?
Kapps (KOP)
587
All opioid drugs used at present are agonists for which receptor?
µ receptor
588
What are the two ‘types’ of opioid dependence?
Physical | Psychological
589
Why do opioids cause side effects?
There are receptors outside the pain system but opioids must usually by given systemically.
590
What are some side effects of opioids?
- Addiction - Respiratory depression - Sedation - Nausea/vomiting - Constipation - Itching - Immune suppression - Endocrine effects
591
Describe how genetic differences lead to the different effects of codeine.
Codeine is a prodrug and needs to be metabolised by CYP450 enzymes. Genetic differences in the CYP2D6 enzyme alter the effects of codeine.
592
How is morphine contra-indicated in patients with renal failure?
Morphine is metabolised to morphine-6-glucuronide which is more potent and renally excreted. In renal failure this builds up and causes respiratory depression.
593
What drugs does tramadol interact with and why?
Tramadol is a weak opioid agonist which also works as a serotonin and norepinephrine reuptake inhibitor. It interacts with SSRIs, tricyclic antidepressants, and monoamine oxidase inhibitors.
594
What are the two naturally occurring opioids?
Morphine | Codeine (weak)
595
Name three drugs which are simple chemical modifications of opioids.
- Diamorphine - Oxycodone - Dihydrocodeine
596
Name four synthetic opioids.
- Pethidine - Fentanyl - Alfentanil - Remifentanil
597
Name a synthetic partial opioid agonist.
Buprenorphine
598
Name an opioid antagonist.
Naloxone
599
The autonomic nervous system conveys all outputs from the CNS to the body, except for ______________.
Skeletal muscular control
600
What is the enteric nervous system involved in?
Gut function
601
Describe the relative lengths of the parasympathetic pre and post ganglionic nerve fibres.
Long pre-ganglionic | Short post-ganglionic
602
Describe the relative lengths of the sympathetic pre and post ganglionic nerve fibres.
Short pre-ganglionic | Long post-ganglionic
603
Describe the outflow of the parasympathetic nervous system.
Cranial nerves III, VII, IX, and X | Sacral outflow
604
Describe the neurotransmitter and receptor present in parasympathetic ganglia.
``` Neurotransmitter = ACh Receptor = Nicotinic ```
605
Describe the neurotransmitter and receptor present at the effector-organ of the parasympathetic nervous system.
``` Neurotransmitter = ACh Receptor = Muscarinic ```
606
Describe the neurotransmitter and receptor present in sympathetic ganglia.
``` Neurotransmitter = ACh Receptor = Nicotinic ```
607
Describe sympathetic outflow.
From T1 - L2/3 of the spinal cord
608
Describe the neurotransmitter and receptor present at the sympathetic effector-organ.
``` Neurotransmitter = Noradrenaline Receptor = Adrenergic ```
609
Describe the neurotransmitter and receptor present on skeletal muscle.
``` Neurotransmitter = ACh Receptor = Nicotinic ```
610
Describe sympathetic innervation of sweat glands.
ACh is released to act on muscarinic receptors.
611
Name two NANCs (non-adrenergic, non cholinergic autonomic transmitter) that are used in the parasympathetic nervous system.
Nitric oxide | Vasoactive intestinal peptide
612
Name two NANCs (non-adrenergic, non cholinergic autonomic transmitter) that are used in the sympathetic nervous system.
ATP | Neuropeptide Y
613
Which division of the autonomic nervous system will nicotine stimulate?
Both
614
Give an example of a muscarinic agonist and its use.
Pilocarpine - Stimulates salivation by activating PNS and contracts iris in smooth muscle to treat glaucoma. - It is not that therapeutically useful.
615
What is a side effect of muscarinic agonists?
Slowing of the heart
616
Name two muscarinic antagonists and their uses.
Atropine - Used for bradycardia, hypotension, to reverse beta blockers, and in cardiac arrest Hyoscine - Used in palliative care to antagonise parasympathetic driven secretions
617
How can cholinergic pharmacology be used to treat bronchoconstriction?
Use drugs which block the M3 receptor. | These can be short-acting muscarinic antagonists or long-acting muscarinic antagonists.
618
How are drugs used to treat bronchoconstriction adapted to avoid cardiac side effects?
Drug delivery mechanisms (inhalers) | Receptor selectivity
619
Give some other uses of anticholinergics.
- Treat overactive bladder - Open pupil to allow eye examination - Treat IBS - Anti-emetic actions
620
When can acetylcholinesterase inhibitors be useful?
Dementia | Myaesthenia gravis
621
Name three drugs that can inhibit ACh release to muscles.
Botox Pancuronium (muscle relaxant in surgery) Suxamethonium (muscle relaxant in surgery)
622
What are some side effects of anticholinergics?
- Worsen memory - Confusion - Constipation - Dry mouth - Blurred vision - Worsening of glaucoma
623
Why do anti-cholinergic drugs worsen memory?
ACh signalling is involved in memory.
624
Name two irreversible acetylcholinesterase inhibitors and give some symptoms associated with them.
Organophosphate insecticides Nerve gases Symptoms include: muscle paralysis, twitching, salivation, confusion.
625
What is adrenaline and where is it released from?
Hormone released from the adrenal medulla.
626
How is dopamine related to adrenaline and noradrenaline?
Dopamine is the precursor to adrenaline and noradrenaline.
627
What are the effects and side effects of alpha 1 agonists?
Vasoconstriction | - Can be used to treat septic shock but will raise blood pressure and cardiac work
628
What can alpha blockers be used for?
Blocking alpha 1 can lower blood pressure.
629
What do beta 1 agonists cause?
Increased heart rate
630
What do beta 2 agonists cause?
Bronchodilation and delay of premature labour
631
What can beta 3 agonists be used to treat?
Overactive bladder
632
What are the side effects of beta agonists?
Tachycardia | Altered glucose metabolism in liver
633
What is propanolol?
Beta 1 and 2 blocker which slows heart rate and reduces tremor. May cause wheeze.
634
Why could atenolol theoretically be used in people with asthma?
It is beta 1 selective so has its main effects on the heart.
635
What are the general effects of beta blockers?
Lower blood pressure Reduce cardiac work Treat arrhythmias
636
Give six uses of beta blockers.
- Angina - Prevent MI - Hypertension - Anxiety - Arrhythmias - Heart failure
637
Give six side effects of beta blockers.
- Tiredness - Cold extremities - Bronchoconstriction - Bradycardia - Hypoglycaemia - Cardiac depression
638
What is methyldopa?
Blocks NAd synthesis, and used as a last resort antihypertensive.
639
How do monoamine oxidase inhibitors affect the sympathetic nervous system?
Prevent NAd breakdown.
640
What are monoamine oxidases?
Enzymes which breakdown monoamine neurotransmitters.
641
How can adrenergic/cholinergic pharmacology be used to control COPD?
M3 antagonist | B2 agonist
642
How can adrenergic/cholinergic pharmacology be used to control prostatic hypertrophy?
Alpha agonist
643
How can adrenergic/cholinergic pharmacology be used to control bladder instability?
B3 agonist
644
How can adrenergic/cholinergic pharmacology be used to control angina and atrial fibrillation?
Beta 1 blocker
645
How can adrenergic/cholinergic pharmacology be used to control septic shock?
Give noradrenaline/adrenaline
646
How can adrenergic/cholinergic pharmacology be used to control asthma?
Beta agonists
647
How can adrenergic/cholinergic pharmacology be used to treat anaphylaxis?
Adrenaline
648
How can adrenergic/cholinergic pharmacology be used to treat a cardiac arrest?
Atropine for bradycardia
649
What can be used as an antagonist at nicotinic receptors?
Curare
650
What can be used as an antagonist at muscarinic receptors?
Atropine
651
What type of receptor are nicotinic receptors?
Ion channels
652
What type of receptor are muscarinic receptors?
G protein coupled receptors
653
Where are M1 receptors found?
CNS
654
Where are M2 receptors found?
Heart
655
Where are M3 receptors found?
Smooth muscle (bronchi, blood vessels, glands)
656
Where are M4 and M5 receptors found?
Mainly in CNS
657
What type of receptors are histamine receptors?
G protein coupled receptors
658
What are H1 receptors involved in?
Allergic conditions
659
What are H2 receptors involved in?
Gastric acid secretion
660
Where are H3 receptors found?
CNS
661
What are H4 receptors involved in?
Immune system and inflammatory conditions
662
What are alpha1 adrenoreceptors involved in?
Smooth muscle contraction
663
What are alpha2 adrenoreceptors involved in?
Smooth muscle contraction and relaxation
664
Where are beta1 adrenoreceptors found?
Heart
665
Where are beta2 adrenoreceptors found?
Lungs
666
Where are beta3 adrenoreceptors found?
Bladder
667
What type of receptors are adrenoreceptors?
G protein coupled receptors.
668
How does the G protein of beta adrenoreceptors work?
It is a Gs protein which raises the levels of cAMP.
669
Define allergy.
An abnormal response to harmless foreign material.
670
Define atopy.
A tendency to develop allergies.
671
What are four components of the pathogenesis of allergy?
- IgE - Genetic factors - Cells - Mediators
672
Apart from IgE, what other classes of antibody can be involved in allergy?
IgG and IgA
673
What cells are involved in allergy?
- Mast cells - Eosinophils - Lymphocytes - Dendritic cells - Epithelial cells - Smooth muscle - Fibroblasts
674
Name four mediators involved in allergy.
- Cytokines - Chemokines - Lipids - Small molecules
675
Where are most IgE molecules found in the body?
Bound to cells.
676
What is the high affinity IgE receptor called?
FceR1
677
How does IgE cause signalling in immune cells?
Via receptor clustering and cross-linking in the presence of an allergen.
678
Which immune cells express the FceR1 receptor?
Mast cells Basophils Eosinophils
679
What is the low affinity IgE receptor called?
FceRII or CD23
680
Which cells express the low affinity IgE receptor?
Other immune cells.
681
What is the role of the FceRII receptor?
- Regulates IgE synthesis - Triggers cytokine release by monocytes - Aids in antigen presentation by cells
682
Where are mast cells found?
In most tissues, but especially those in contact with the external environment.
683
What is the marker for mast cells?
CD117 (c-kit protein)
684
What is the c-kit protein?
A receptor for stem cell factor.
685
What are some immediate secretions from mast cells?
Histamine Cytokines Proteases Proteoglycans
686
What is the main outcome of mast cell chemotactic factors?
Eosinophil attraction and activation
687
What secretions are released within minutes of mast cell activation?
Leukotrienes Prostaglandin D2 Platelet activating factor
688
What secretions are released within hours of mast cell activation?
Cytokines
689
How do mast cell cytokines affect lymphocytes?
They promote a Th2 response and lead to B cell class switching (IgE production).
690
What are three types of mast cell activator? | Give examples.
Indirect - allergens, bacterial/viral antigens Enterobacteria - phagocytosis of bacteria in gut Direct - cold, aspirin, tartrazine, preservatives, NO2, latex, proteases
691
Which type of mast cell activation works via IgE?
Indirect
692
What are the hallmarks of the immune response against parasites?
Th2 cytokines and IgE, which bind to parasites.
693
In a parasitic infection, which cells are recruited after mast cell activation?
Eosinophils Macrophages Neutrophils
694
What do eosinophils form which can fight parasitic infections?
ROS | Proteases
695
Describe the hygiene hypothesis.
The relative absence of infections in western society has lead to an imbalance in the Th1/Th2 pathways, leading to more allergies.
696
How are neurones involved in allergy?
Coughing, sneezing, etc
697
How are epithelial cells involved in allergy?
Compromised barrier function
698
How are fibroblasts and smooth muscle cells involved in allergy?
Fibrosis
699
What are the required features of an allergen?
- Particulate delivery of antigens (have to be large) - Weak PAMPs for weak immune response (to evade evolution) - Nasal / skin delivery (oral delivery desensitises) - Low doses (high doses desensitise)
700
Describe the positive feedback loop of mast cell activation.
Th2 activates mast cells, B cells, and eosinophils, and then mast cell activation leads to more Th2 cells.
701
What is the ABCDE of anaphylaxis?
``` Airway Breathing Circulation Disability Exposure ```
702
Which cells are activated in anaphylaxis?
Mast cells or basophils
703
Which two serum concentrations will be elevated in anaphylaxis?
Histamine | Tryptase
704
What are the cardiovascular signs of anaphylaxis?
Vasodilation Increased vascular permeability Lowered blood pressure
705
What are the respiratory signs of anaphylaxis?
Bronchial smooth muscle contraction | Mucus
706
What are the skin-associated signs of anaphylaxis?
Rash | Swelling
707
What are the gastrointestinal signs of anaphylaxis which develop slowly?
GI pain | Vomiting
708
Describe asthma.
An inflammatory disease of the bronchi, commonly triggered by allergens.
709
Which cells commonly influx into the lungs in asthma?
Eosinophils
710
What is the long term treatment for asthma?
Immune suppression with corticosteroids
711
What are the seven approaches to allergy treatment?
- Avoid allergens - Desensitisation - Preventing IgE production - Anti-IgE therapy - Anti-cytokine antibodies - Mast cell activation inhibition - Mast cell product inhibition -
712
Describe allergy desensitisation.
Increasing doses of antigen (immunotherapy). | However this is very dangerous.
713
How can IgE production be prevented?
- Delivery of antigens with cholera toxin (strong Th1 response) - Suppressive cytokines - Blockade of cytokines using antagonists - Anti CD23 antibodies
714
How does anti-IgE therapy work?
Using anti-IgE antibodies
715
How can mast cell activation be inhibited?
- Mast cell stabilisers - Beta 2 agonists - Glucocorticoids - Calcium channel blockers - Signalling inhibitors
716
How can mast cell products be inhibited?
- H1 receptor antagonists - Leukotriene antagonists - Tryptase inhibitors - Protease-activated receptor (PAR) 2 antagonists
717
Name seven allergic diseases.
- Anaphylaxis - Allergic asthma - Allergic rhinitis (hayfever) - Atopic dermatitis - Allergic conjunctivitis - Oral allergy syndrome - Food allergy
718
Describe the events that occur immediately on exposure to an allergen.
- Antigen recognised by APC - Differentiation of Th2 cells - Th2 cells stimulate IgE release from B cells - IgE binds to mast cells - Allergen cross-links IgE on mast cells - Mast cell activation
719
What are two issues associated with the process of drug development?
It is long and costly.
720
Define drug development.
The process of bringing a new pharmaceutical drug to the market.
721
What is stage 1 of drug development?
Drug discovery
722
What is stage 2 of drug development?
Pre-clinical development
723
What is stage 3 of drug development?
Clinical development
724
What are the 5 phases of clinical drug development?
``` 0 - Effect on body I - Safety in humans II - Effectiveness at treating diseases III - Larger scale safety and effectiveness IV - Long term safety ```
725
Give four examples of drugs which come from plants.
- Digoxin from foxglove - Morphine from poppy - Atropine from deadly nightshade - Vincristine from periwinkle
726
What are most drug names derived from?
The drugs chemical structure
727
Are most drugs high or low molecular weight organic compounds?
Low molecular weight
728
Name three anaesthetics and one antiseptic drug produced by organic chemistry.
Anaesthetics: - Phenol - Chloroform - Isoflurane Antiseptic: - Chlorhexidine
729
Name three inorganic elements that are used in drugs.
- Platinum in anti-cancer agents - Bismuth in antacids - Gold in arthritis
730
Describe the concept of ‘magic bullets’.
Drugs that target specific pathways without harming the host - drugs have to bind to act.
731
What is the formula of a sulphonamide group?
R - S (=O)2 - NH2
732
What is the advantage of a drug having a sulphonamide group?
It is unreactive and rigid so gives the compound stability.
733
Give three drugs that were developed from bacteria/mould/fungi.
Penicillin Streptomycin Erythromycin
734
How can drugs be developed from bacteria?
Bacteria produce antimicrobials against other bacteria to eliminate competition.
735
What is a stereoisomer drug?
Drugs which have the same molecular formula and sequence of bonded atoms, but differ in the three dimensional orientations of their atoms in space. They can have different biological activities.
736
What is immunotherapy?
The passive transfer of serum/antibodies from immune individuals.
737
What is the suffix for a murine monoclonal antibody?
Omab
738
What is the suffix for a chimeric monoclonal antibody?
Ximab
739
What is the suffix for a humanised monoclonal antibody?
Zumab
740
What is the suffix for a human monoclonal antibody?
Umab
741
What is the role of TNFa?
- Released by macrophages - Stimulates acute phase proteins - Mediates endotoxin poisoning - Septic shock - Chronic inflammation
742
What are the 3 approaches to TNFa neutralisation?
- Chimeric antibody (infliximab) - Fusion protein (etanercept) - Human antibody (adalimumab)
743
What is the ultimate aim of TNFa neutralisation?
Inhibit lymphocyte proliferation
744
Which two proteins are fused to form the fusion protein to neutralise TNFa?
``` TNFII receptor (binds to TNFa) Fc portion of IgG antibody ```
745
What are some considerations to think about regarding immunotherapy?
- Immunoglobulins are not filtered by the kidney - FcRn receptor absorbs IgG into cells to avoid metabolism but mouse antibodies aren’t substrates so have a shorter half-life
746
Give three drugs that can be obtained from animal sources.
Insulin Thyroxine Steroids
747
What is the role of calcineurin?
Binds to promotor for IL-2 to block T cell activation.
748
What does methotrexate do?
Inhibits DNA synthesis
749
What does azathioprine do?
Alters DNA structure to end the chain.
750
What does cyclophosphamide do?
Irreversibly cross-links DNA to stimulate cell apoptosis.
751
What are protein kinase inhibitors and where are they used?
Block kinase enzymes in cells (tyrosine kinase). | They are used in cancer treatment.
752
What is the general concept of gene therapy?
Uses genes to treat or prevent disease by inserting genes into a patient’s cells.
753
What are three approaches to gene therapy?
- Replacing a mutated gene with a healthy gene - Inactivating or ‘knocking out’ a mutated gene - Introducing a new gene to help fight disease
754
What is high-throughput screening (HTS)?
A method used in drug discovery - computers analyse specific pathways and screen a library of molecules to look for drugs.
755
What is meant by rational drug design?
The process of finding new medications based on the knowledge of a biological target.
756
What is an adverse drug reaction?
An unwanted or harmful reaction following administration of a drug or combination of drugs under normal conditions of use and is suspected to be related to the drug.
757
What is a side effect?
An unintended effect of a drug related to its pharmacological properties and can include unexpected benefits of treatment.
758
What are the three classifications of adverse drug reaction relating to dose?
- Side effects (drug taken in its therapeutic range) - Toxic effects (more than the therapeutic range is taken) - Hypersusceptibility effects (the drug is used in low doses but the patient is more susceptible)
759
What are the DoTS factors relating to adverse drug reactions?
- Dose related (toxic, collateral, or hypersusceptibility) - Timing (drug infused too fast) - Patient susceptibility
760
Give an example of a drug that can cause an adverse effect if given too fast.
Frusemide causes hearing loss/tinnitus if given too fast.
761
Name the six types of adverse drug reaction given by the Rawlins Thompson classification.
- Type A (augmented physiological) - Type B (bizarre) - Type C (continuous) - Type D (delayed) - Type E (end of treatment) - Type F (failure of therapy)
762
Describe type A adverse drug reactions and give an example.
Predictable, dose-dependent, and common. An extension of the primary effect or a secondary effect. Eg - morphine and constipation
763
Describe a type B adverse drug reaction and give an example.
Not predictable or dose dependent. Can be idiosyncracy or allergy/hypersensitivity. Eg - anaphylaxis and penicillin
764
What is an idiosyncratic adverse drug reaction?
An inherant abnormal response to a drug. | Can be due to enzyme deficiency or receptor abnormality.
765
Describe a type C adverse drug reaction and give an example.
The consequences of chronic use of a drug. | Eg - osteoporosis and steroids
766
Describe a type D adverse drug reaction and give an example.
Occurs due to teratogenesis and carcinogenesis. | Eg - thalidomide, malignancies after immunosuppression
767
Describe a type E adverse drug reaction and give an example.
Occurs after abrupt withdrawal of a drug. | Eg - opiate withdrawal syndrome, seizures after withdrawal of an anti-epileptic drug
768
Describe a type F adverse drug reaction and give an example.
When a drug stops working, may be due to another drug. | Eg - enzyme inducers stop the oral contraceptive pill from working
769
What are some patient risk factors for adverse drug reactions?
- Gender (F>M) - Elderly - Neonates - Polypharmacy - Genetic predisposition - Hypersensitivity / allergies - Hepatic / renal impairment - Adherence problems
770
What are some characteristics of drugs that increase the likelihood of an adverse drug reaction?
- Steep dose-response curve - Low therapeutic index - Commonly causes ADRs
771
What are seven causes of adverse drug reactions?
- Pharmaceutical variation - Receptor abnormality - Abnormal biological system unmasked by drug - Abnormalities in drug metabolism - Immunological - Drug-drug interactions - Multifactorial
772
Why does an allergic response not occur on first exposure to an allergen.
The first dose stimulates Th2 response and IgE production by B cells. IgE binds to mast cells. Second dose then cross links IgE to produce a response.
773
When should an adverse drug reaction be suspected?
- Symptoms soon after a new drug is started - Symptoms after dose increase - Symptoms disappear when drug is stopped - Symptoms reappear when drug is restarted
774
What are the six most common drugs to have adverse drug reactions?
- Antibiotics - Anti-neoplastics - Cardiovascular drugs - Hypoglycaemics - NSAIDs - CNS drugs
775
What are the six most common systems to be affected by adverse drug reactions?
- GI - Renal - Haemorrhagic - Metabolic - Endocrine - Dermatologic
776
What are the six most common symptoms of adverse drug reactions?
- Confusion - Nausea - Balance problems - Diarrhoea - Constipation - Hypotension
777
Who is responsible for approving medicines and devices for use and monitoring their safety?
Medicines and Healthcare products Regulatory Agency (MHRA)
778
What is the yellow card scheme?
An adverse drug reaction reporting scheme which collects suspected adverse drug reactions.
779
What does it mean if a drug has a black triangle next to it?
It is undergoing additional monitoring.
780
Who can report on a yellow card?
- Doctors - Dentists - Coroners - Pharmacists - Nurses - Midwives - Health visitors - Radiographers - Optometrists - Patients
781
What are the four critical pieces of information to include on a yellow card?
- Suspected drug - Suspected reaction - Patient details - Reporter details
782
What is a type 1 hypersensitivity reaction?
IgE mediated allergy/anaphylaxis.
783
What are the classic features of anaphylaxis?
- Onset within minutes - Vasodilation - Increased vascular permeability - Bronchoconstriction - Urticaria (rash) - Angio-oedema
784
What is a type 2 hypersensitivity reaction?
IgG bound to antigen to activate complement
785
What is a type 3 hypersensitivity reaction?
Antigen and antibody form immune complexes and activate complement. Small blood vessels get damaged/blocked and leukocytes cause inflammation.
786
What is a type 4 hypersensitivity reaction?
Antigen specific receptors develop on T lymphocytes and subsequent exposure leads to a reaction.
787
Describe non-immune anaphylaxis.
Direct mast cell degranulation produces clinically identical features to anaphylaxis. No prior exposure required.
788
What are the seven main symptoms of anaphylaxis?
- Immediate rapid onset - Rash - Swelling of lips, face, oedema - Central cyanosis - Wheeze, shortness of breath - Hypotension - Cardiac arrest
789
What are the seven steps of the management of anaphylaxis?
- Stop drug/exposure - IM adrenaline - High flow oxygen - IV fluids - IV antihistamine - IV hydrocortisone - IV adrenaline (anaphylactic shock)
790
How does adrenaline treat anaphylaxis?
- Vasoconstriction (raises blood pressure) - Activates beta 1 receptors (positive inotropic and chronotropic effects) - Reduces oedema - Bronchodilation (beta 2 adrenoreceptors) - Reduces further release of inflammatory mediators
791
What are the six critical criteria for a drug allergy?
- Does not correlate with pharmacological properties of the drug - No linear correlation with dose - Reaction similar to those produced by other allergens - Induction period of primary exposure - Disappearance on cessation / reappears on re-exposure - Occurs in a minority of patients on the drug
792
What are the medicine risk factors for hypersensitivity?
Protein or polysaccharide based macromolecule
793
What are the host factor risk factors for hypersensitivity?
Females > males | Immunosuppression
794
What are the genetic risk factors for hypersensitivity?
Certain HLA groups
795
Define ‘pathogen’.
An organism that causes or is capable of causing disease.
796
Define ‘commensal’.
An organism which colonises the host but causes no disease in normal circumstances.
797
What is an opportunist pathogen?
A microbe that only causes disease if host defences are compromised.
798
Define ‘virulence/pathogenicity’.
The degree to which a given organism is pathogenic.
799
What is asymptomatic carriage?
When a pathogen is carried harmlessly at a tissue site where it causes no disease.
800
What is a virulence factor?
Any product or strategy that contributes to pathogenicity/virulence.
801
What name is given to a round-shaped bacterium?
Coccus
802
What name is given to a rod-shaped bacterium?
Bacillus
803
What is it called when two round-shaped bacteria are associated?
Diplococcus
804
Name two group morphologies that can apply to cocci.
Chain of cocci | Cluster of cocci
805
What is a curved rod-shaped bacterium called?
Vibrio
806
What is a spiral-shaped rod bacterium called?
Spirochaete
807
Describe the genetic material in a bacterium.
A chromosome of circular double stranded DNA.
808
What are pili?
Filamentous, hair-like projections on bacteria that are used for attachment.
809
What is the role of a bacterial capsule?
It protects the bacterium from the immune system and can also act as an antigen.
810
Describe a plasmid.
Autonomously replicating circle of DNA which can transfer genes between bacteria.
811
What are three genes that are contained in plasmids?
- Transfer promotion genes - Plasmid maintenance genes - Antibiotic/virulence determinant genes
812
What mutations can cause genetic variation in bacteria?
- Base substitution - Deletion - Insertion
813
Give three ways that gene transfer can cause genetic variation in bacteria.
- Transformation (picking up naked DNA) - Transduction via phage (a bacterial virus) - Conjugation (bacterial sex) via sex pilus (which transfers DNA/plasmids)
814
What is the primary stain used in the gram stain?
Crystal violet
815
What substance is added to crystal violet in the gram stain to help fix it to the cell wall?
Iodide
816
What is used to decolourise the sample in the gram stain?
Ethanol/acetone
817
What is the counterstain in the gram stain?
Safranin
818
What colour does gram positive bacteria stain with the gram stain and why?
Purple, because the crystal violet-iodide complexes get trapped in the peptidoglycan cell wall.
819
What colour does gram negative bacteria stain with the gram stain and why?
Pink, because the decolouriser washes away the outer lipids and lipopolysaccharide membrane (including the crystal violet).
820
What reaction takes place in the catalase test?
2H2O2 -> 2H2O + O2 (this uses the catalase enzyme)
821
Out of staphylococci and streptococci, which one is catalase positive and which is catalase negative?
Staphylococci are positive | Streptococci are negative
822
What is the theory behind the coagulase test?
Coagulase enzyme produced by bacteria activates prothrombin to convert fibrinogen to fibrin.
823
How can the coagulase test be used to distinguish between different species of Staphylococcus?
Staphylococcus aureus is coagulase positive, but other Staphylococci are coagulase negative.
824
What is the advantage of forming a fibrin clot around bacteria?
It may protect them from phagocytosis.
825
What is haemolysis?
The ability of bacteria to break down red blood cells (in blood agar) by expressing haemolysin.
826
What is a-haemolysis?
Partial haemolysis which occurs when H2O2 is released and reacts with haemoglobin.
827
Describe the appearance of the blood agar if a bacterium is a-haemolysis.
It appears green.
828
What is b-haemolysis?
Complete lysis due to the bacteria releasing haemolysins O and S.
829
Describe the appearance of the blood agar when the bacteria are b-haemolysis.
There is a clear area around the bacteria.
830
What is y-haemolysis?
No haemolysis
831
What feature of a bacterium indicates motility?
The flagellum
832
What is the purpose of the oxidase test?
It tests if a microorganism contains cytochrome oxidase/indophenol oxidase.
833
What indicator is used in the oxidase test and what is its role?
TMPD, which acts as an artificial electron donor.
834
What colour does the indicator in the oxidase test turn in the oxidised state (indicating the bacterium can use oxygen as the terminal electron acceptor)?
Blue/maroon
835
What three substances are present in MacConkey agar?
- Bile salts - Lactose - pH indicator
836
Describe the outer layers in a gram positive bacteria.
Cytoplasmic membrane and thick peptidoglycan cell wall.
837
What links the membrane with the cell wall in gram positive bacteria?
Lipoteichoic acid
838
What is a bacterial cell wall made from?
Peptidoglycan
839
Describe the layers in a gram negative bacterial cell wall.
Cytoplasmic membrane, thin peptidoglycan cell wall, lipoprotein molecules, outer membrane, lipopolysaccharide endotoxin.
840
Describe the three components of the lipopolysaccharide layer in a gram negative cell wall.
Lipid A closest to the cell O antigen in the middle Terminal sugars facing the exterior
841
What are the three main antigens present in a gram negative bacterium?
- K antigens from the exopolysaccharide capsule - H antigens from the flagella - O antigens from the lipopolysaccharide
842
Which bacterial antigens give rise to the serotype?
H antigen
843
Which bacterial antigens give rise to the serogroup?
O antigens
844
What is a bacterial capsule made from?
Polysaccharide
845
What four things determine a bacterium’s action in its environment?
- Temperature - pH - Water/desiccation - Light
846
What are the three phases of bacterial growth?
- Lag phase - Exponential (log) phase - Stationary phase
847
What is a toxoid?
A toxin treated (usually with formaldehyde) so that it loses its toxicity but retains its antigenicity.
848
What is an exotoxin?
A secreted protein of a gram positive or gram negative bacterium.
849
What is an endotoxin?
Component of the outer membrane of gram negative bacteria.
850
What is an endotoxin made from?
Lipopolysaccharide
851
What is a zoonosis?
A disease which can be transmitted from animals to humans.
852
Describe the microbiology of a mycobacterium. | Include respiration, spores, motility, and shape
Aerobic Non-spore forming Non-motile Bacillus
853
Describe the layers surrounding a mycobacterium.
Cell membrane Peptidoglycan Cell wall
854
What is the cell wall of a mycobacterium composed of?
High molecular weight lipids (mycolic acids and lipoarabinomannan)
855
Are mycobacteria gram positive or gram negative?
They don’t stain with the gram stain.
856
Are mycobacteria slow or fast growing?
Slow growing
857
What is another name for mycobacteria?
Acid-fast bacilli (AFB)
858
What stains can be used to identify acid-fast bacilli?
Ziehl-Neelsen stain | Also fluorochrome stains
859
Describe the Ziehl-Neelsen stain.
- Carbol fushin - Acid/alcohol (AFB are resistant to de-staining) - Methylene blue
860
Give three ways that mycobacteria can be cultured.
``` Solid culture (can take about 6 weeks) Liquid culture (takes 1-3 weeks) PCR (rapid identification of TB) ```
861
What happens when a mycobacterium is ingested by a macrophage?
- The mycobacterium adapts to the intracellular environment so can survive in the macrophage - The macrophage presents antigens to T cells
862
Describe the T cell response to mycobacteria.
- CD4 cells generate IFNy to activate intracellular killing by macrophage - Th1 cells stimulated by IL-12
863
Why does a granuloma form in response to a mycobacterial infection?
To try and contain the mycobacteria (as they can survive inside macrophages)
864
What cells are contained in a granuloma formed as a result of mycobacteria?
- The bacterial cells - Macrophages (epithelioid macrophages, multinucleate giant cells) - CD4 and CD8 T cells - B cells - Dendritic cells - Fibroblasts
865
What are the positive effects of the T cell response to mycobacteria?
- Macrophage killing of bacteria - Infection is contained - A tissue granuloma forms
866
What are the negative effects of the T cell response to mycobacteria?
Hypersensitivity reactions (skin/eye lesions, joint swelling)
867
What test can be used to observe the T cell response to TB?
Tuberculin (mantoux) test
868
What are Koch’s four postulates that make up the germ theory?
- Bacteria should be found in all people with disease - Bacteria should be isolated from the infected lesions in people with the disease - A pure culture inoculated into a susceptible person should produce symptoms of the disease - The same bacteria should be isolated from the intentionally infected individual
869
Give an example of a virus which can cause different diseases.
Enteroviruses (can cause respiratory infections, rashes, etc)
870
Give an example of a disease which can be caused by two separate viruses.
Hepatitis A and B
871
Name four different presentations of a viral infection.
Acute Chronic Cancer Latent
872
Name two types of virus that cause cancer.
Hepatitis (B and C) | Human papilloma virus (HPV)
873
What are five basic properties of a virus.
- Grow only inside living cells - Possess only 1 type of nucleic acid (DNA or RNA) - No cell wall but have an outer protein coat - Inert outside host cells (but carry enzymes which can be used inside cells) - Protein receptors on cell surface allow attachment to host cells
874
Describe the structure of a virus.
Viral genome surrounded by capsid (protein coat). | Some have a lipid envelope with envelope proteins surrounding the capsid.
875
What are the six steps of viral replication?
1. Attachment 2. Cell entry 3. Interaction 4. Replication 5. Assembly 6. Release
876
Which part of the virus enters the host cell?
The core carrying nucleic acids and associated proteins.
877
Where does viral replication take place within the host cell?
May be in the cytoplasm, nucleus, or both.
878
Where does assembly of a virus take place within the host cell?
Nucleus, cytoplasm, or cell membrane
879
What are the two methods which release viruses from host cells? Give an example of each.
Lysis (rhinoviruses) | Leaking (exocytosis) over a period of time (HIV/influenza)
880
What are five mechanisms that viruses can use to cause disease?
- Direct destruction of cells - Modification of host cell structure or function - ‘Over-reactivity’ of host as a response to infection - Cell proliferation and immortalisation - Evasion of host defences
881
How do rotaviruses cause diarrhoea?
It atrophies villi in the small intestine and causes malabsorption. Sugars don’t get broken down, so water enters intestine to cause diarrhoea.
882
Give an example of a virus that causes cell proliferation and immortalisation.
HPV (causes warts and cervical cancer)
883
How do viruses evade the host defence at the cellular level?
Latency | Cell-cell spread (virus doesn’t enter blood)
884
How do viruses evade the host defence at the molecular level?
- Antigenic variability - Apoptosis prevention - Interferon downregulation - Interference with host cell antigen processing pathway
885
Give five ways that viruses can be diagnosed.
- Electron microscope - Cell culture - Antigen (viral protein) detection - Serology (IgM/IgG) - PCR
886
What are the five features of the hepatitis B chronic carrier ‘steady state’?
- Limited but sustained viral replication - Natural hepatocyte regeneration - Proliferation of hepatocytes (due to oncogenic nature of virus) - Hepatocyte destruction by CD8 T cells - No clinical symptoms
887
What is the role of the haemolysis test?
It distinguishes between different types of streptococci.
888
What bacteria can the oxidase test be used for?
Gram negative, lactose negative, bacilli
889
What is the optochin test used for?
To distinguish between a-haemolytic bacteria
890
What is Lancefield typing used for?
To distinguish between b-haemolytic bacteria.
891
Which type of streptococci are optochin resistant?
Viridans strep
892
What is the role of the bile salts on MacConkey agar?
To inhibit growth of gram positive bacteria.
893
What colour do lactose-fermenting colonies turn on MacConkey agar?
Red/Pink
894
What colour is Staphylococcus aureus on agar?
Cream/yellow/golden
895
What are the sterile sites of the body?
- Urinary tract - Lower respiratory tract - Blood - CSF - Pleural fluid - Peritoneal cavity - Joints
896
Which sites of the body should normally house commensals?
- Mouth - Large intestine - Skin - Urethra - Vagina
897
In which ways can agar plates be altered to encourage the growth of some bacteria and restrict the growth of others?
- Different atmospheres - Different temperatures - Different nutrients - Using selective media
898
What bacteria is XLD agar selective for? | What colour do they turn?
Selective for Salmonella and Shigella | They turn red
899
What is chocolate agar?
Blood agar in which the cells have been lysed by heating in order to release nutrients.
900
Give seven common viral infections.
- Respiratory viruses - Viruses causing rashes - Herpes group - Hepatitis group - Enteroviruses - Viruses causing diarrhoea - Human Immunodeficiency Virus
901
If you see clusters of gram positive cocci in a specimen what organisms are likely to be present?
Staphylococci
902
If you see clusters of gram positive cocci in a specimen that are coagulase positive, what bacteria is likely to be present?
Staphylococcus aureus
903
If you see clusters of gram positive cocci which are coagulase negative in a sample, what bacteria are likely to be present?
Staphylococcus epidermidis
904
If you see chains or pairs of gram positive cocci in a specimen, what organism is likely to be present?
Streptococci
905
If an optichin resistant, a-haemolytic streptococcus is identified, what bacteria is it likely to be?
Viridans strep
906
If an optochin-sensitive, a-haemolytic streptococcus is identified, what bacteria is it likely to be?
Streptococcus pneumoniae
907
If a b-haemolytic streptococcus is identified, how would you determine further what bacterium is present?
Lancefield grouping
908
If a b-haemolytic streptococcus which is Lancefield group A is identified, what bacterium is it likely to be?
Streptococcus pyogenes
909
If a b-haemolytic streptococcus which is Lancefield group B is identified, what bacterium is it likely to be?
Streptococcus agalactiae
910
What is meant by vertical disease transmission?
Passes from mother to infant
911
What is meant by horizontal disease transmission?
Passed between unconnected individuals
912
When are bacterial endotoxins released?
Upon death of the bacterium.
913
Name four enzymes that bacteria produce to aid their invasion of the body.
- Coagulase - Streptokinase - Collagenase - Hyaluronidase
914
What are the four factors which mediate the pathogenicity of bacteria?
- Pili and adhesions - Toxins - Enzymes - Host immune responses
915
Give the classification of mycobacteria. | Include shape, gram stain
Bacilli | Don’t stain with gram (stain with Ziehl/Neelsen)
916
Give the classification of Corynebacterium. | Shape, gram stain, aerobic/anaerobic
Bacilli Gram positive Aerobic
917
Give the classification of Listeria. | Shape, gram stain, aerobic/anaerobic
Bacilli Gram positive Aerobic
918
Give the classification of Clostridium. | Shape, gram stain, aerobic/anaerobic
Bacilli Gram positive Anaerobic
919
Give the classification of Escherichia. | Shape, gram stain, aerobic/anaerobic, lactose fermenting
Bacilli Gram negative Aerobic Lactose fermenting
920
Give the classification of Salmonella. | Shape, gram stain, aerobic/anaerobic, lactose fermenting
Bacilli Gram negative Aerobic Non-lactose fermenting
921
Give the classification of Shigella. | Shape, gram stain, aerobic/anaerobic, lactose fermenting
Bacilli Gram negative Aerobic Non-lactose fermenting
922
Give the classification of Vibrio. | Shape, gram stain, aerobic/anaerobic
Bacilli Gram negative Aerobic
923
Give the classification of Campylobacter. | Shape, gram stain, aerobic/anaerobic
Bacilli Gram negative Aerobic
924
Give the classification of Helicobacter. | Shape, gram stain, aerobic/anaerobic
Bacilli Gram negative Aerobic
925
Give the classification of Haemophilus. | Shape, gram stain, aerobic/anaerobic
Bacilli Gram negative Aerobic
926
Give the classification of Bordatella. | Shape, gram stain, aerobic/anaerobic
Bacilli Gram negative Aerobic
927
Give the classification of Legionella. | Shape, gram stain, aerobic/anaerobic
Bacilli Gram negative Aerobic
928
Give an example of a gram negative bacillus which is anaerobic.
Bacteroides
929
Give three examples of gram negative cocci.
Neisseria Moraxella Veillonella
930
Give two examples of gram positive, aerobic cocci.
Staphylococcus and Streptococcus
931
Give an example of gram positive, anaerobic cocci.
Peptostreptococcus
932
Give two examples of coagulase-negative Staphylococci.
Staph.epidermidis | Staph.saprophiticus
933
Give two examples of a-haemolytic streptococci.
S.viridans | S.pneumoniae
934
Give two examples of b-haemolytic streptococci.
S.pyogenes | S.agalactiae
935
Are fungi eukaryotic or prokaryotic?
Eukaryotic
936
Give two substances that are contained in a fungal cell wall.
Chitin | 1,3 - beta glucan
937
How do fungi ‘move’?
Through growth or spores
938
Can fungi make their own food?
No (they are heterotrophic)
939
What are the two forms that fungi can exist as?
Yeast or Mould
940
Are yeasts single-cellular or multi-cellular?
Single-cellular
941
How do yeasts divide?
By budding
942
How do moulds divide?
Spores
943
Describe the microscopic structure of moulds.
Multicellular hyphae
944
What are dimorphic fungi?
Fungi which can exist as yeast or mould depending on the circumstances.
945
What types of infections do dimorphic fungi commonly cause?
Acute pulmonary infections
946
What form are dimorphic fungi in when they are in the soil and in the lungs?
Mould in the soil | Yeast in the lungs
947
Give two reasons why few species of fungi cause human infection.
- Inability to grow at 37 degrees | - Innate/adaptive immune response
948
Describe the concept of selective toxicity in antimicrobials.
To achieve inhibitory levels of the agent at the site of infection without host cell toxicity. This relies upon identifying molecules with selective toxicity for organism targets.
949
Why is treatment selectivity harder for fungi than for bacteria?
Fungi are eukaryotic
950
What is the drawback of targeting fungal DNA/RNA/protein synthesis with antimicrobials?
The process is similar to mammalian cells.
951
What is the advantage of antimicrobials targeting the fungal cell wall?
It doesn’t exist in humans
952
What is the difference between the fungal cell wall and the human cell wall?
Fungal cell walls contain ergosterol instead of cholesterol.
953
How do allylamines such as terbinafine act as antifungals?
They target the ergosterol synthetic pathway
954
How do azoles act as antifungal treatments?
They target the ergosterol synthetic pathway.
955
How do polyenes act as antifungals?
They form pores in ergosterol-containing membranes.
956
How do echinocandins act as antifungals?
They inhibit 1,3-beta glucan synthase
957
Which blood test can detect Aspergillus cell wall antigen in invasive aspergillosis?
Serum galactomannan test
958
Why can 1,3-beta glucan be detected on a blood test in an invasive fungal infection?
It is released into the serum.
959
Give five examples of invasive fungal infections in immunocompromised hosts.
- Candida line infections - Invasive aspergillosis - Pneumocystis - Cryptococcosis - Mucormycosis
960
Why do viruses need rapid cell entry once in the body?
A free virus in the bloodstream is easily neutralised
961
Give five elements of the humoral immune response to viruses.
- IgA blocks binding to mucosal surfaces - IgG/IgA/IgM blocks fusion to host cell - IgG/IgM causes opsonisation - IgM agglutinates viral particles - Complement causes opsonisation and lysis
962
Give three components of the cell mediated immune response to viruses.
- IFN has antiviral action - CD8 T cells kill infected cells - NK/Macrophages activate antibody-dependent cellular cytotoxicity killing
963
Describe the antiviral action of IFN.
Induces antiviral protein DAI (double stranded RNA activated inhibitor of translation) on nearby cells.
964
What is antibody-dependent cellular cytotoxicity?
An effector cell of the immune system actively lyses a target cell whose membrane surface antigens have been bound by specific antibodies.
965
Give four ways that toxins can be classified.
- Tissue target - Molecular action - Biological effect - Contribution to disease process
966
Give nine ways that viruses evade the immune system.
- Block action of DAI - Binds complement - Cause immune suppression - Change coat antigen - Antigenic variation - Infection of lymphocyte - Cytokine imbalance - Inhibition of MHCI expression - Prevention of MHCI translocation to membrane
967
Define antigenic drift.
Spontaneous mutations occur gradually giving minor changes to antigens.
968
Which molecules on the surface of an influenza virus are changed by antigenic drift?
Haemagglutinin | Neuraminidase
969
Define antigenic shift.
A sudden emergence of a new subtype different to that of the preceding virus.
970
What are the two stages of the immune response against protozoa?
- Blood stage (humoral immunity) | - Tissue stage (cell mediated immunity)
971
What causes symptoms in a protozoan infection?
Excessive production of cytokines (TNF).
972
Why are antibodies that are produced against sporozoites in a protozoan infection relatively ineffective?
Sporozoites are only present in the blood for a short time.
973
Give three ways that protozoa evade the immune response.
- Surface antigen variation - Intracellular phase - Outer coat sloughing
974
Give three ways that pathogenic bacteria compete with host cells and colonising flora.
- By sequestering nutrients - By using novel metabolic pathways - By out-competing other microorganisms
975
Which system do bacteria use to alter gene expression in response to a change in the environment?
2 component sensor-kinase system
976
Which cells are involved in the immune response against low number/virulence bacteria?
Phagocytes
977
Which component of the immune response deals with extracellular bacteria?
Antibodies
978
Which type of immune response deals with intracellular bacteria?
Cellular response
979
What molecules help bacteria to bind to mucosal surfaces?
Adhesins
980
What is a biofilm?
When bacteria stick together on a surface by secreting an extracellular polymeric substance.
981
What is the advantage to the bacteria of forming a biofilm?
Helps protect against antimicrobials.
982
Give four elements of the immune response against bacteria.
- IgA blocks attachment to host cell - Antibodies and C3b opsonise and prevent proliferation - Complement causes cell lysis and prevents proliferation - Antibodies neutralise toxins
983
Give ten methods that bacteria use to evade the immune system.
- Protease lyses IgA - Pili - Antigenic variation - M protein (inhibits phagocytosis) - Elastase secretion inhibits C3a and C5a - Mycobacteria escape from phagolysosome - Adhesion molecules - Polysaccharide capsule - Coagulase - Block phagosome/lysosome fusion
984
What antibodies are produced in response to worms?
IgG and IgE
985
Which cytokine produced in a worm infection triggers eosinophil production?
IL5
986
Which cytokine produced in a worm infection stimulates mast cell growth?
IL3
987
What substance do eosinophils produce which is toxic to worms?
Eosinophil basic protein
988
Give two ways that worms evade the immune system.
- Decreased antigen expression by adult | - Host cell derived glycolipid/glycoprotein coat
989
How does using a host-derived coat help pathogens evade the immune system?
They will be covered in self-antigens so will not be recognised by the immune system.
990
Define infectivity.
The ability of a pathogen to become established in a host.
991
Define invasiveness.
The capacity of a pathogen to penetrate mucosal surfaces to reach normally sterile sites.
992
How do commensals help someone to avoid infection?
They use up all the nutrients so there are none left for the pathogens.
993
What is meant by the ‘microbiome’?
The totality of micro-organisms, their genetic elements, and their environmental interactions in an environment.
994
What is metagenomics?
Uses genetic approaches to describe the diversity of micro-organisms in an environment.
995
What is the role of haemagglutinin on influenza?
Facilitates attachment
996
How do viruses obtain their lipid bilayer?
From infected host cells.
997
Name an antimicrobial used to treat some protozoan infections.
Metrinidazole
998
Describe the microscopic structure of a protozoa.
Single eukaryotic cell with a nucleus
999
Name the five categories of protozoa.
``` Flagellates Amoebae Cilliates Microsporidia Sporozoa ```
1000
Name the five forms in the life cycle of a sporozoa.
- Sporozoite - Schizont - Merozoite - Trophozoite - Hypnozoite
1001
What is a sporozoite?
Motile and spore-like. | Typically the infective agent introduced into a host in a sporozoan infection.
1002
What is a schizont?
A protozoan cell that divides to form daughter cells.
1003
How do schizonts divide?
Schizogany
1004
What is a merozoite?
A small amoeboid sporozoan produced by schizogony that is capable of initiating a new sexual or asexual cycle of development.
1005
What is a trophozoite?
The growing stage in the life cycle of a sporozoa, when the protozoan is absorbing nutrients from the host.
1006
What is a hypnozoite?
A dormant form of a sporozoa.
1007
Why do viruses not usually need treatment in a healthy host?
They are usually self-limiting.
1008
In which groups if patients would you treat a viral infection?
Immunocompromised (elderly, HIV, transplant)
1009
Which cells does the influenza virus infect?
Epithelial cells
1010
What molecule on the surface of influenza viruses helps new viruses break out of cells?
Neuraminidase
1011
How does tamiflu work?
It is a neuraminidase inhibitor that stops new viruses leaving the host cell.
1012
Why is acyclovir sometime used in herpes?
To treat encephalitis which results from the herpes virus.
1013
What does the cytomegalovirus cause in immunocompromised patients?
Retinitis Pneumonitis Colitis
1014
What was an antibiotic defined as when they were first discovered?
Agents produced by microorganisms that kill or inhibit growth of other microorganisms in high dilution.
1015
What is an antimicrobial?
A semi-synthetic derivative of an antibiotic.
1016
Define ‘antibiotic’ as the term is used today.
Molecules that work by binding a target site on a bacteria.
1017
What is the crucial binding site on a bacterium?
A point of biochemical reaction crucial to bacterial survival.
1018
What are five categories of targets that antibiotics can work against?
- Cell wall synthesis - Cell membrane function - Folate synthesis (metabolism) - Nucleic acid synthesis - Protein synthesis
1019
What do beta-lactam antibiotics target?
Cell wall synthesis
1020
What types of bacteria are beta-lactams good for treating?
Gram positive
1021
How do beta-lactams function as antibiotics?
They binds to the transpeptidase active site on penicillin binding group enzyme and prevents cross-linking of peptidoglycan in cell wall. This causes cell lysis.
1022
Name two general mechanisms of antibiotic action.
Bacteriostatic | Bactericidal
1023
How do bacteriostatic antibiotics treat bacterial infection?
Prevent growth of bacteria
1024
What are the main targets of bacteriostatic antibiotics?
Protein synthesis DNA replication Metabolism
1025
How do bacteriostatic antibiotics affect toxins?
- Reduce exotoxin production | - Reduce endotoxin surge from gram negative bacteria
1026
What is the concentration called that must be used of a bacteriostatic antibiotic to inhibit bacterial growth?
Minimum inhibitory concentration
1027
How does a bactericidal antibiotic stop a bacterial infection?
Kills the bacteria
1028
What is the general target of a bactericidal antibiotic?
Cell wall synthesis
1029
In which three circumstances are bactericidal antibiotics useful?
- When there is poor tissue penetration - When the infection is difficult to treat - When you need to eradicate the infection quickly
1030
What is the concentration called of a bactericidal antibiotic that is used to kill the bacteria?
Minimum bactericidal concentration
1031
What is concentration-dependent killing in relation to antibiotics?
How high the concentration of a drug is above the minimum inhibitory concentration.
1032
What is time-dependent killing in relation to antibiotics?
The time that the serum concentration remains above the minimum inhibitory concentration.
1033
What are four mechanisms that bacteria can use to resist antibiotics?
- Change antibiotic target - Destroy antibiotic - Prevent antibiotic access - Remove antibiotic from bacteria
1034
What is the main feature of intrinsic antibiotic resistance?
The bacteria are naturally resistant, so all subpopulations of a species will be equally resistant.
1035
What is acquired antibacterial resistance?
A bacterium which was previously susceptible obtains the ability to resist the activity of a particular antibiotic. Only certain strains or subpopulations of a species will be resistant.
1036
Give two ways that acquired antibiotic resistance can arise.
Spontaneous gene mutation | Horizontal gene transfer
1037
Give three mechanisms of horizontal gene transfer between bacteria.
Conjugation Transduction Transformation
1038
What enzyme can bacteria produce to destroy the beta-lactam ring in penicillins?
Beta-lactamase
1039
Which genes are important in MRSA?
MecA
1040
How can enterococci become resistant to vancomycin?
Plasmid mediated acquisition of gene encoding altered amino acids for cell wall components.
1041
What medications can be given with penicillin to bacteria which produce beta-lactamase?
Beta-lactamase inhibitors
1042
How can bacteria become resistant to beta-lactams and beta-lactamase inhibitors?
Further mutations at the beta-lactamase active site causes extended-spectrum beta-lactamases.
1043
Why can carbapenems be used to treat bacteria which are resistant to beta-lactams?
They are highly resistant to degradation by beta-lactamases or cephalosporinases.
1044
Name two groups of bacteria that are resistant to carbapenems?
- Carbapenemase-producing enterobacteriaceae (CPE) | - Carbapenem-resistant enterobacteriaceae (CRE)
1045
Give two ways that bacteria cause damage directly.
- Kills cells | - Toxins
1046
Give three ways that bacteria cause damage indirectly.
- Inflammation - Antibodies - Diarrhoea (to get rid of bacteria)
1047
What are eight things to consider before prescribing antibiotics for a patient?
- Intolerance/allergy - Side effects - Age - Renal function - Liver function - Pregnancy/breast feeding - Drug interactions - Risk of Clostridium difficile
1048
What causes Clostridium difficile infection?
An interruption to the bacterial flora by recent use of antibiotics.
1049
What are the main symptoms of C.diff?
Diarrhoea and bowel infection
1050
What law governs healthcare-related infection and infection control?
The Health Act 2006
1051
How is infection different from colonisation?
Infection requires harm to be done to the individual.
1052
What are three possible routes of transmission of hospital-related infection?
- Patient A to Patient B via environment - Patient A to Patient B directly - Patient A to Patient B via staff
1053
How can someone who is at risk of passing a healthcare-related infection to another patient be identified?
- Risk factors - Screening - Clinical diagnosis - Lab diagnosis
1054
Give two groups of patients who are at risk of contracting healthcare-related carbapenemase producing Enterobacteriaceae.
- Recently received overseas medical treatment | - Recently been an inpatient in London or North West
1055
Give two ways that direct spread of infection between patients can be avoided.
- Isolation | - Ward design
1056
Give three ways that transmission of infection to patients via the environment can be avoided.
- Isolation - Cleaning - Ward design
1057
Give two ways that transmission of an infection between patients via staff can be avoided.
- Handwashing | - Barrier precautions
1058
Give six times when you should wash your hands.
- Before and after handling patients - After handling soiled items - After using the toilet - Before and after handling food - Before and after an aseptic procedure - After removing protective clothing (including gloves)
1059
What is an endogenous infection?
Infection of a patient by their own flora.
1060
Give two groups of patients in which endogenous infections are more likely.
- Patients with invasive devices | - Surgical patients
1061
Give five ways to prevent endogenous | Healthcare-associated infections.
- Good nutrition/hydration - Antisepsis and skin prep - Control underlying disease - Remove lines and catheters as soon as clinically possible - Reduce antibiotic pressure
1062
How many herpes viruses are there in total?
8
1063
How many types of viral hepatitis exist?
5
1064
Which two types of viral hepatitis are the most serious?
B and C
1065
Give two ways in which viruses used to be detected in a patient sample.
- Cell/tissue culture | - Electron microscopy
1066
Give a way in which viruses can be quickly and easily identified in a patient sample.
QPCR
1067
What does qPCR stand for?
Quantitative polymerase chain reaction
1068
What is serology (related to diagnosing infections)?
The study or detection of antibody responses in the serum.
1069
Which antibody present in an infection indicates a primary infection?
IgM
1070
Which swab is used to collect a sample to test for viruses?
Green viral swab
1071
Which swab is used to collect a patient sample to test for bacteria?
Black charcoal swab
1072
What technique can be used to detect antibodies in a serum sample?
ELISA
1073
Which bacterium produces streptolysin O?
Streptococcus pyogenes
1074
Why can the presence of IgG in a patient’s serum indicate that they have had a certain infection in the past?
IgG remains in the body for many years after an infection.
1075
What is one difficulty associated with doing qPCR to look for a virus in a patient sample?
You have to know which virus you’re looking for.
1076
Which antibodies will be produced in response to a latent virus which has become reactivated?
IgG
1077
What three markers can you look for when testing a blood sample for HIV, and which techniques would be used?
- HIV antigen (ELISA) - Antibodies (ELISA) - Viral RNA (PCR)
1078
What is confidentiality?
The right of an individual to have personal, identifiable medical information kept private. Such information should be available only to the physician of record and other healthcare and insurance personnel as necessary.
1079
What are the three guidance points the GMC provide about confidentiality and HIV?
- Allow disclosure to a known sexual partner if at risk (not on treatment) and unaware, if you cannot persuade index to do so - Disclosure is confidential (do not identify patient) - Must inform patient you are going to tell partner (unless it endangers contact)
1080
How many people are living with HIV globally?
36.9 million
1081
How many people are living with HIV in Africa?
25.7 million
1082
How many people are living with HIV in the UK?
101,600
1083
What are the three UNAID goals?
- 90% of people living with HIV being diagnosed - 90% of people diagnosed on antiretroviral treatment - 90% of people on ART being virally suppressed (by 2020)
1084
Give nine HIV prevention strategies.
- HIV testing (universal and partner) - STI testing and treatment - HAART - Post exposure prophylaxis (PEP) - Pre exposure prophylaxis (PrEP) - Screening of blood products - Needle exchange programs - Microbicides - Male circumcision
1085
Give five behavioural strategies to prevent HIV.
- Appropriate sex education - Reduce frequency of partner change - Avoid overlapping sexual partners - Reduce high risk sexual practices - Condom useage
1086
What does U=U mean in regard to HIV?
Undetectable = Untransmissable | It means that treatment to an undetectable viral load prevents the transmission of HIV.
1087
What must a patient’s CD4 count be before they get put on antiretroviral treatment?
People usually get put on treatment regardless of CD4 count.
1088
Give seven groups of people who are most at risk of HIV.
- Men who have sex with men - Injecting drug users - Heterosexual men - Migrant workers - Heterosexual women - Commercial sex workers - Truck drivers
1089
In which age group do the most new HIV infections occur in worldwide?
15-24
1090
Give the three stages of an epidemic and describe them.
- Nascent - <5% prevalence in all risk groups - Concentrated - >5% prevalence in one or more risk groups - Generalised - >5% prevalence in general population
1091
What are the three goals of HIV testing services?
- Provide a high quality service for identifying HIV - HIV treatment, care, and support - Prevent transmission
1092
Give seven problems with the delivery of ART in developing countries.
- Awareness - Cost/choice of drugs - Efficacy - Procurement/delivery - Adherence - Co-morbidities - Clinical services (staff, clinics, testing/monitoring facilities)
1093
What are four important features of the HIV virus that make it so hard to eradicate?
- Sexually transmitted (increased transmission when asymptomatic) - Latent (asymptomatic patients unaware of condition) - Attacks cells of immune system - Mutates every time it reproduces (resistance to immune system)
1094
Give the family and genus of the HIV virus.
``` Family = retroviridiae Genus = Lentivirus ```
1095
What are three primate lentiviruses?
- HIV-1 - HIV-2 - SIV (simian immunodeficiency virus)
1096
How did HIV-1 arise in humans?
From transmission of SIV from Chimpanzees to humans.
1097
Describe the genetic material in retroviruses.
RNA is copied into DNA by reverse transcription and incorporated into host genome.
1098
Give a common feature of all lentiviruses.
They are slow viruses with a long incubation period.
1099
What are the three groups of the HIV-1 virus?
- M (main) - O (outlying) - N (new)
1100
How many clades is the main group of HIV-1 viruses split into?
9
1101
Why are the different clades of the main group of the HIV-1 virus important?
The different clades predominate in different areas worldwide.
1102
What are the main receptors on the HIV virus and the host cell that interact?
Gp120 on virus | CD4 on host cell
1103
What does the HIV virus do as it buds from a host cell that allows it to evade the immune system?
It envelopes itself with part of the host cell membrane.
1104
What is the co-receptor that allows HIV to attach to host cells?
CCR5
1105
Name the nine steps of HIV replication.
1. Attachment 2. Entry 3. Uncoating 4. Reverse transcription 5. Genome integration 6. Transcription of viral RNA 7. mRNA splicing and translation 8. Assembly of new virions 9. Budding
1106
How does genomic instability occur in HIV viruses?
Reverse transcription is error prone so causes mutations.
1107
What is the role of viral reverse transcriptase?
Produce double stranded DNA from viral RNA
1108
What is the role of viral integrase?
Enzyme which incorporates viral DNA into host DNA
1109
What is the role of viral protease?
Enzyme which cleaves viral proteins before virion assembly.
1110
How many genes are encoded in the HIV genome?
Nine
1111
Why is alternate splicing essential when synthesising proteins from the HIV genome?
The genes overlap so alternate splicing is required to produce a range of proteins.
1112
Name the nine genes on the HIV genome.
``` Gag Pol Env Tat Rev Nef Vif Vpr Vpu ```
1113
Which five HIV genes are essential for infectivity?
``` Gag Pol Env Tat Rev ```
1114
What does the HIV Pol gene encode?
Enzymes (reverse transcriptase, integrase, protease)
1115
What does the HIV Env gene encode?
Envelope proteins
1116
What does the HIV Nef gene encode?
Factors which increase infectivity
1117
What does the HIV Tat gene encode?
Factors which contribute to viral replication (and it also enhances host transcription factors, eg NF-kB)
1118
What does the HIV Gag gene encode?
Structural proteins
1119
What does the HIV Rev gene do?
Binds to viral RNA and allows export from the nucleus.
1120
Which cells can be infected in HIV?
- CD4 T cells - Macrophages - Dendritic cells - Occasionally other cells
1121
Which cells are first infected by HIV?
Macrophages or dendritic cells
1122
How does HIV go from infecting APCs to T cells?
The virus escapes the phagolysosome and hijacks MHC presentation, so when the APC presents the antigen to the T cell the virus infects the T cell.
1123
Describe the humoral immune response to HIV.
Neutralising antibodies are poor/slow to develop.
1124
Why are antibodies against HIV such poor quality?
- gp120 is poorly immunogenic | - High genetic diversity means that by the time the antibody is made the antigen has changed
1125
Describe the CD8 T cell response to HIV.
- Initial early decline in virus | - Virus eventually escapes CD8 cells through mutations
1126
Describe the CD4 cell response to HIV.
Infection causes failure of CD4 cell proliferation
1127
Give three factors that could contribute to the effective immune response against HIV in long term non-progressors.
- CCR5 mutation - Vigorous CD8 response - HLA differences
1128
Give five methods of CD4 killing in HIV.
- Direct cytotoxicity of infected cells - Activation induced death - Decreased production - Redistribution - Bystander cell killing
1129
Give seven other immune consequences of HIV.
- Excessive activation of immune system - Decreased proliferation in response to antigens - Skewing of CD4 T cell receptor (involvement of memory cells) - CD8 enhanced activation - B cells show enhanced activation but decreased proliferation - Decreased NK, neutrophil, and macrophage function - Disturbed cytokine networks
1130
What is the result of enhanced B cell activation but decreased proliferation?
Increased non-specific but decreased specific antibodies.
1131
Name four sanctuary sites where HIV can reside.
- Genital tract - CNS - GI system - Bone marrow
1132
Name three specific cells where HIV can ‘hide’ to escape treatment.
- Macrophages - Microglia - Resting (memory) T cells
1133
Give four ways that circumcision could reduce transmission of HIV.
- Keratinisation of the inner aspect of remaining foreskin reduces penetration - Langerhans cells (targets for HIV) removed with foreskin - Ulcers which can facilitate transmission often occur on foreskin - Foreskin may suffer abrasions during sex which facilitates transmission
1134
Give four examples of beta-lactam antibiotics.
- Penicillin - Flucloxacillin - Amoxicillin - Meropenem
1135
What are cephalosporins?
Antibiotics with similar mechanisms to beta-lactams.
1136
What types of bacteria are cephalosporins used for?
Mainly for gram positives.
1137
What types of patients are cephalosporins useful for?
Patients with a penicillin allergy.
1138
What antibiotics could be used for gram positive bacteria with penicillin resistance?
Cephalosporins
1139
Give an example of a condition that cephalosporins can be used to treat.
Meningitis
1140
What do glycopeptide antibiotics target?
Cell wall synthesis
1141
Give two examples of glycopeptide antibiotics.
Vancomycin | Teichoplanin
1142
What type of bacteria are glycopeptide antibiotics used for?
Gram positive
1143
In what situations would glycopeptide antibiotics be used?
- MRSA | - Penicillin allergy
1144
Why can’t glycopeptide antibiotics be given via a rapid IV infusion?
It will cause side effects.
1145
What do macrolide antibiotics target?
Protein synthesis
1146
Give two examples of macrolide antibiotics.
- Clarithromycin | - Erythromycin
1147
What types of bacteria are macrolides useful for?
- Gram positive | - Atypical pneumonia pathogens
1148
In what situations would macrolide antibiotics be used?
- Penicillin allergy | - Severe pneumonia
1149
What do lincosamide antibiotics target?
Protein synthesis
1150
Give an example of a lincosamide antibiotic.
Clindamycin
1151
What types of bacteria can lincosamide antibiotics be used to treat?
- Gram positive - Group A Streptococci - Anaerobes
1152
Give two conditions that can be treated with lincosamide antibiotics.
- Cellulitis (if penicillin allergy) | - Necrotising fasciitis
1153
What is the effect of lincosamide antibiotics on toxins released by gram positive bacteria?
Turns them off
1154
What do tetracycline antibiotics target?
Protein synthesis
1155
Give an example of a tetracycline antibiotic.
Doxycycline
1156
What types of bacteria are tetracycline antibiotics used for?
Broad spectrum but mainly gram positive
1157
Give two conditions that can be treated using tetracycline antibiotics.
- Cellulitis (if penicillin allergy) | - Chest infections
1158
What do quinolone antibiotics target?
DNA synthesis
1159
Give an example of a quinolone antibiotic.
Ciprofloxacin
1160
What types of bacteria can quinolone antibiotics be used against?
Gram negative
1161
Give three conditions that can be treated using quinolone antibiotics.
- UTI - Gallbladder infections - Abdominal infections
1162
How do trimethoprim work as an antibiotic?
It is a folate antagonist.
1163
What types of bacteria is trimethoprim used for?
Broad spectrum but mainly gram negatives.
1164
Give a condition that trimethoprim can be used to treat.
UTI
1165
What type of bacteria can nitrofurantoin be used against?
Gram negatives
1166
Give a condition which nitrofurantoin can be used to treat.
UTI
1167
What are two complications of a Streptococcus infection?
- Rheumatic fever | - Glomerulonephritis
1168
Give three infections that Staphylococcus epidermidis causes.
- Opportunistic infections in debilitated patients - Prostheses - Catheters
1169
What infection can staphylococcus saprophyticus cause?
Acute cystitis
1170
What infections does Streptococcus agalactiae cause?
Neonatal infections (including meningitis)
1171
What group of viridans streptococci are the most virulent?
Milleri group
1172
What types of infections does Viridans Streptococcus cause?
Infections in the mouth
1173
Give a disease which is caused by Corynebacteria.
Diphtheria
1174
What bacterium is the main cause of cystitis?
Escherichia coli
1175
Give five methods of pathogenesis of Escherichia coli.
- Enterotoxigenic - Enterohaemorrhagic - Enteropathogenic - Enteroinvasive - Enteroaggregative
1176
What disease is caused by Shigella bacteria?
Shigellosis
1177
Which bacteria is responsible for salmonellosis in humans?
Salmonella enterica
1178
Give a disease caused by a vibrio bacterium.
Cholera
1179
Give an infection that is caused by Legionella pneumophila.
Legionnaire’s disease (a severe form of pneumonia)
1180
What disease does Bordetella pertussis cause?
Whooping cough
1181
Give the two species of bacteria belonging to the Neisseria genus.
- Neisseria meningitidis | - Neisseria gonorhoeae
1182
Give the genus of bacteria which is the most common cause of food poisoning.
Campylobacter
1183
Describe the two developmental phases of Chlamydiae bacteria.
- Elementary bodies - infectious | - Reticulate bodies - replicative, non-infectious
1184
Name a phylum of bacteria which are obligate intracellular parasites.
Chlamydiae
1185
What is a spirochaete?
Any spiral-shaped bacterium
1186
What is an endoflagellum in spirochaetes?
Flagellum located between peptidoglycan and outer membrane
1187
What is the pre-patent period, in relation to worms?
The interval between infection and the appearance of eggs in the stools.
1188
Give the three major categories of helminths.
- Nematodes (roundworms) - Cestodes (tapeworms) - Trematodes (flatworms, flukes)
1189
Which genus of fungi can cause opportunistic invasive infections in humans? (Eg - line infections)
Candida
1190
Is Candida a yeast or a mould?
Yeast
1191
Name a type of mould.
Aspergillus
1192
Name a condition caused by Aspergillus.
Invasive aspergillosis
1193
What are dermatophytes?
A collection of fungi which can metabolise and subsist on keratin.
1194
Name the fungus which causes Pneumocystis pneumonia.
Pneumocystis jirovecii
1195
What other condition may be indicated if a patient presents with pneumocystis pneumonia?
HIV
1196
Name the five major types of fungi.
- Yeast - Mould - Dimorphic - Dermatophytes - Pneumocystis
1197
Name three major types of protozoa.
- Flagellates - Amoebas - Sporozoa
1198
What type of microorganism is Giardia?
Flagellate protozoa
1199
Name a flagellate protozoa which causes dysuria and frothy yellow discharge.
Trichomonas vaginalis
1200
What type of microorganism is toxoplasma?
Sporozoa protozoa
1201
Give an alternative name for enterococcus.
Lancefield group D b-haemolytic (or non-haemolytic) streptococcus.
1202
Describe the appearance of shigella on XLD agar.
Red
1203
Describe the appearance of salmonella on XLD agar.
Red with black centres or yellow.
1204
How is salmonella classified further?
Using the Kauffman-White scheme which uses O and H antigens.
1205
What is an API strip?
An analytic profile index, which is a series of biochemical reactions carried out by pathogens which can be matched to a database.
1206
What antibiotics can be used for a C.diff infection?
Metrinidazole or vancomycin
1207
What antibiotics can be used for a campylobacter infection?
Clarythromycin
1208
Give three pathogens which can cause cholecystitis.
- Klebsiella - E.coli - Enterococcus
1209
Why do inflammatory cells stick to the endothelium when endothelial damage occurs?
The endothelium can no longer produce NO.
1210
Give the five possible consequences of an atherosclerotic plaque.
- Rupture - Erosion into vessel wall - Embolism - Haemorrhage - Occlusion of blood vessel
1211
What antibiotic would be used to treat MRSA?
Vancomycin
1212
Give three things essential to taking good blood cultures.
- Good volumes - Take from >1 site - Take on >1 occasion
1213
What other condition is a patient with Staphylococcus aureus bacteraemia at risk of?
Infective endocarditis
1214
What suspected infection would you use a CLED plate for?
UTI
1215
What colour do lactose-fermenting bacteria turn on CLED plate?
Yellow
1216
What colour do non-lactose-fermenting bacteria turn on CLED plate?
Blue
1217
What is the purpose of chocolate agar and what organisms does it grow?
Blood agar which has been heated to release nutrients. | It can be used to grow fastidious bacteria which wouldn’t otherwise grow on normal blood agar.
1218
What is the most likely source of Group B Streptococci in neonates?
Commensal in mother’s genital tract.
1219
Where is Listeria commonly found?
Refrigerated foods, eg. Lettuce, cheese
1220
Who is at risk of a Listeria infection?
Immunocompromised
1221
What is the normal CSF glucose level compared to serum glucose?
About 60%
1222
Describe and explain the CSF glucose measurements in bacterial and viral meningitis.
Bacterial has a low glucose and viral has a normal glucose because bacteria use to glucose for respiration and replication.

Phase2a (12 decks)

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