Intro to Clinical Sciences Phase2a

Which type of inflammation is primarily associated with neutrophils?

Acute inflammation

What is chronic inflammation?

Slow or sequel to acute, long term inflammation involving B&T lymphocytes (plasma cells) and macrophages

Which cell type lives for 1-3 days?

Neutrophil polymorphs

Which cell types are involved in inflammation?

Neutrophil polymorphs
Macrophages
Lymphocytes
Endothelial cells
Fibroblasts

What is the approximate life-span of a macrophage?

weeks-months

What are the 5 cardinal signs?

1. rubor (redness)
2. calor (heat)
3. tumor (swelling)
4. dolor (pain)
5. loss of function

What are the 3 stages of acute inflammation?

Change in vessel calibre (wider space for same no. cells)
Increased vascular permeability
Formation of fluid exudate

What is inflammation?

A local physiological response to tissue injury

What is margination?

Stage in neutrophil action where neutrophils move to the plasmatic zone near the endothelium due to loss of fluid

Define granuloma

Aggregate of epitheloid histiocytes

(small area of chronic inflammation characterised by a collection of macrophages in a histological horse shoe shape)

What is meant by the term 'pavementing' in neutrophil action?

Neutrophils adhere to the endothelium and "roll"

The term used to describe neutrophils moving through walls of venules and veins into the extravascular space is...

Emigration

What is diapedesis?

The migration of blood cells (R&W) into the extravascular space in inflammation

What are the possible outcomes of inflammation?

1) resolution - complete return to normal
2) suppuration - pus formation
3) organisation (repair) - necrosis, regrowth, scarring
4) progression - chronic inflammation

What are the benefits of acute inflammation?

- dilution of toxins to be carried away in lymphatics
- entry of antibodies
- useful for drug transport to site eg. antibiotics to bacteria
- fibrin formation
- delivery of nutrients and oxygen from increased fluid flow
- stimulation of immune response by fluid exudate entering lymphatics

What are the negatives of acute inflammation?

- digestion of normal tissues by enzymes
- swelling in bad areas eg. brain, epiglottis
- inappropriate responses eg. hypersensitivity reactions, autoimmune

What is shown?

Granuloma

What is the clinical significance of raised Angiotensin-Converting-Enzyme in the blood?

Granulomas secrete ACE Marker of other granulomatous diseases such as TB, parasitic infections (if eosinophil is raised), sarcoidosis, leprosy, syphilis, Crohn's disease

What is a caseating granuloma?

Cheese-like necrosis

found in TB, fungal infections

What are non-caseating granulomas?

Granulomas formed by inflammatory conditions (sarcoidosis, chron) or foreign objects

What happens in resolution of acute inflammation?

The initiating factor is removed, the tissue is either undamaged or can regenerate
eg. a bone after a break

What happens in the organisation of acute inflammation?

the initiating factor is still present
the tissue is damaged and unable to regenerate
the damaged tissue is replaced by fibrous tissue (mainly collagen) forming a scar

Name an example of a tissue and condition that cannot be resolved, only organised

heart after myocardial infarction
brain after cerebral infarction
spinal cord after trauma

What is the difference between exudate and transudate?

Exudate - high protein, increased vascular permeability, formed in inflammation
transudate - low protein, normal permeability, normal circumstances

Give 5 types of cell capable of regeneration

Hepatocytes
Osteocytes
Pneumocytes
Blood cells
Gut and skin epithelial cells

Why do blood clots not constantly form?

1) laminar flow (blood travels in the centre of arterial vessels)
2) endothelial cells are not sticky if healthy

Define thrombosis

The formation of a solid mass from blood constituents in an intact vessel

Define embolism

A blocked blood vessel caused by an embolus such as a clot or air bubble

What is ischaemia?

reduced blood flow to a tissue without other implications

What is infarction?

Ischaemic necrosis of tissue

What are the causes of thrombosis?

1. change in blood flow (stasis)
2. change in blood constituents (hyper coagulability)
3. change in the vessel wall (endothelial damage)

What is the most common cause of a venous thrombosis?

stasis

What is the most common cause of an arterial thrombosis?

Atheroma

What are the different types of embolism?

venous thromboembolism
pulmonary embolism
systemic embolism
infective emboli
fat embolism
gas embolism
amniotic embolism
tumour
foreign

What happens to a thrombus?

1. the body dissolves and clears it
2. organised into a scar by macrophages
3. capillaries grow into the thrombus and fuse later, vessel is recanalized
4. death
5. embolism

Explain primary plug formation in haemostasis

1. damaged endothelium exposes collagen to the inter vascular space
2. vasospasm: endothelin-1 release causes vasoconstriction
3. platelet adhesion: platelets glycoprotein 1b receptor bind to collagen via von-willebrand-factor
4. platelet activation: platelets release platelet dense granules with ADP, thromboxane, Clotting factors and activates other platelet.
5. aggregation: ADP dependent expression of glycoprotein IIb/IIIa, + ADP P2Y12 receptor activates glycoprotein IIb/IIa on platelets bind to fibrinogen creating crosslinks, platelets are aggregated

Intrinsic pathway of secondary plug in haemostasis

contact activation
XII -> XIIa
XI -> XIa
IX -> IXa + VIIIa
X -> Xa
common pathway

Extrinsic pathway of the secondary platelet plug

Secondary plug formation in hemostasis

Define congenital disease

Disease which is present at birth

Compare inherited and acquired disease

inherited - inherited genetic abnormality
acquired - caused by non-genetic environmental factors

An increase in the size of a tissue due to increase in the size of constituent cells is

hypertrophy

what is hyperplasia?

Increase in the size of a tissue due to increase in the number of the cells

What is metaplasia?

The change in differentiation of a cell from one fully-differentiated type to a different fully differentiated type

Give an example of normal metaplasia in the body

Change from respiratory epithelium in the trachea to simple squamous in the alveoli

pre-malignant cells changing morphology is known as

dysplasia

decrease in the size of an organ or tissue

atrophy

Give 3 physiological examples of hyperplasia

- bone marrow production of erythrocytes at high altitude
- breast tissue at pregnancy/puberty
- thyroid in puberty/pregnancy

Give an example of pathological hyperplasia

Grave's disease
Prostate with age and excess oestrogen

What are the pathological causes of hypertrophy?

- arterial walls in hypertension
- RV from pulmonary valve stenosis, hypertension or septal defects
- LV from aortic valve stenosis or systemic hypertension

Give an example of physiological hyperplasia and hypertrophy

uterine smooth muscle in puberty and pregnancy

When is atrophy considered normal?

- thymus in early adulthood
- fetus
- genitals, mandible, cerebrum, lymphoid tissues in the elderly

When is atrophy considered pathological?

- loss of blood supply
- loss of innervation
- pressure eg. pressure sores, tumours
- lack of nutrition
- lack of, or hormonal stimulation
- decreased function eg. fracture

The use of topical corticosteroids can cause what?

skin atrophy

What is the difference between apoptosis and necrosis?

Apoptosis: programmed cell death, non-inflammatory, sometimes pathological
Necrosis: traumatic unexpected cell death, inflammatory, always pathological

Explain the intrinsic pathway of apoptosis

BAX & BAK proteins promote apoptosis by signalling the mitochondria to release cytochrome C which activates caspases which cause cell death

Explain the extrinsic pathway of apoptosis

Fas-Ligand & Fas or TNF-a & TNF-R
activate initiator caspases
activates caspases
cell death

Which proteins inhibit apoptosis?

Bcl-2 and Bcl-xl

Explain the cytotoxic pathway of apoptosis

if a cytotoxic T cell binds to a membrane, it releases Granzyme B which allows perforin to enter the cell and activate caspases

Give an example of necrosis from ischaemia

fingers in frostbite
avascular necrosis in scaphoid fractures
pancreatitis
caseous necrosis in TB

What is atherosclerosis?

disease of the arteries in which fatty plaques develop on their inner walls

Risk factors for atherosclerosis

- increasing age
- smoking
- unhealthy high fat diet
- sedentary lifestyle
- obese/overweight
- excessive alcohol use
- hypertension
- hypercholesterolemia (family or self)
- diabetes
- family history
- south asian, African, african-caribbean descent

Treatments for atherosclerosis

statins
antihypertensives
low-dose aspirin (reduce platelet aggregation medicines)
anti-platelet
surgery

What does an atheromatous plaque look like when fully developed?

a lesion with a lipid core and fibrous cap covered by arterial endothelium

what are the clinical manifestations of atherosclerosis?

1. progressive lumen narrowing causing ischemia eg. angina
2. acute atherothrombotic occlusion eg. plaque rupture

What can detect DNA damage to trigger apoptosis?

p53 protein

Describe and explain the time course of atherosclerosis

birth - none
late teen/early 20s - fatty streaks
30s-50s established plaques
40s-80s complications of plaques

Why is there a limit on how many times a cell can divide?

Hayflick limit
At each cell division, the telomere region at the end of chromosomes shorten until its no longer possible to divide and replicate
cancer cells can produce telomerase enzymes thus maintain their telomere region and continue to divide

What factors can cause damage to a cell for it to die?

- DNA mutation
- cross linking of proteins
- loss of control of calcium influx
- mitochondrial damage
- loss of DNA repair mechanisms
- time dependent activation genes
- telomere shortening
- accumulation of toxins (from metabolism)
- free radicals

What are the effects of ageing in skin?

wrinkling (dermal elastosis) from UV-B

How does age affect the eyes?

cataracts from UV-B

What are the effects of ageing on bone?

Osteoporosis - loss of bone matrix in women after menopause

What are the effects of ageing on the brain?

Dementia

How does age affect muscle?

Sarcopaenia (loss of muscle)

How does age affect hearing?

Deafness
hair cells do not divide so will die if damaged and not be replaced

What are the causes of acute inflammation?

- microbial infections
- hypersensitivity reactions
- physical agents (trauma, temperature)
- chemicals
- bacterial toxins
- tissue necrosis

What is suppuration?

An outcome of acute inflammation. Pus is formed and leads to scarring

What are the causes of chronic inflammation?

Resistance of infective agent
Endogenous materials eg. necrotic tissue
Exogenous tissues eg. asbestos
Autoimmune conditions
granulomatous disease
transplant rejection

neoplasm

A lesion resulting from autonomous abnormal growth of cells

Tumour

any abnormal swelling in or on a part of the body

Cancer

uncontrolled proliferation of cells that arise from virtually any cell type in the body

Carcinogenesis

The transformation of normal cells to neoplastic cells through permanent genetic alterations or mutations

What is angiogenesis?

The growth of new blood vessels

Define exophytic

growth outwards from an epithelial surface (characteristic of benign tumours)

What is meant by endophytic?

Growth inwards from an epithelial surface (characteristic of malignant)

What is meant by the term histogenesis?

the specific cell or origin of a tumour

What is the difference between oncogenic and carcinogenic?

oncogenic: tumour/neoplasm causing agent
carcinogenic: malignant neoplasm causing agent

What do tumours secrete for angiogenesis?

Vascular endothelial growth factor (VEGF)

A grade 2 cancer is...

moderately differentiated
cells look abnormal and grow faster than normal

If the cancer has grown in size, but not spread, what numerical classification would it be?

3

What is TNM cancer staging?

T - size 1-4
N - lymph nodes 0-3
M - metastases 0 or 1

what are the features of a benign tumour?

- slow growing
- localised
- well defined capsule
- exophytic growth

what are the features of a malignant tumour?

- not contained
- cause angiogenesis
- cancerous
- rapid growth
- consists of different cell types
- endophytic
- ulceration

How is cancer graded?

1 well differentiated - cells resemble normal cells, not rapidly growing
2 moderately differentiated - look abnormal, grow faster than normal cells
3 poorly differentiated - look abnormal, grow/spreads aggressively

numerical classification of cancer

0 - cancer in situ no spread
1 - cancer is small hasn’t spread elsewhere
2 - cancer has grown, no spread
3 - cancer is larger and may have spread to surrounding tissues/lymph nodes

What 5 types of cancer can spread to bone?

Breast
Lung
Thyroid
Kidney
Prostate
(BLT KP)

How can benign tumours cause clinical issues?

pressure on structures
obstruction
hormone production
anxiety & stress

How do tumours spread?

1. hematogenous spread (blood)
2. lymphatic system
3. transcoelomic (into body cavities through peritoneal, pleural, pericardial, subarachnoid)

What are the exceptions to usual tumour nomenclature?

Hepatoma/hepatocellular carcinoma
Melanoma (malignant from melanocytes)
Mesothelioma (malignant of mesothelial cells)

malignant tumour of adipocytes

liposarcoma