Learnt in past papers Flashcards
Role of BUB
Is dissociated from chromatid to commence anaphase
Role of CENPE
Senses tension in chromatid
Role of CHKE1 and 2
Anticancer therapy arresting cell at G2
How can carcinoma prognosis and invasive ability be assessed
Degree of cell-cell adhesion
When to give platelet concentrations
haematology patients with bone marrow failure (if platelets <10 x 109/L)
Massive bleeding or acute DIC
If very low platelets and patient needs surgery
If for cardiac bypass and patient on anti-platelet drugs
When to not give platelet concentrations
Autoimmune thrombocytopenia
2 examples of reduced survival of platelets
Autoimmune thrombocytopenia
DIC
Presentation of beta thalassaemia
○ Profound anaemia thalassaemia
○ Failure to thrive
○ Malaise
○ Splenomegaly
All in first year of life
Treatment for beta thalasaemia major
Lifelong transfusion
iron chelating agent
Risks of life long infection
Viral infection in particular Hep C
Causes of liver cancer
Hep C. Chronic Hep. B Alcoholism Aflatoxin B1 (aspergillus flavus) Haemochromatosis Diabetes Obesity Drugs & Medication Steroids Oestrogens
Liver cancer pathophysiology
Hepatitis infection > becomes chronic if untreated > inflammation > cirrhosis > dysplastic lesions >clonal selection > hepatocellular carcinoma
Example of initial signalling protein
Grb2
How do cells go from benign to malignant
Disassembly of the cell-cell contact
Loss of polarity
Increased motility
Release of MMP to break down the extracellular matrix
Problems with metastases
Worse prognosis
Hard to resect
5 steps for investigating outbreak
Preliminary Investigation Case definition and identification Descriptive study Analytic study Control
Drugs given with transplant
Tacrolimus - inhibit t lymphocyte signal transduction (CNI inhibitor)
Cyclosporin - inhibit t lymphocyte signal transduction (CNI inhibitor)
Rapamycin - inhibit t lymphocyte signal transduction (mTOR inhibitors
Azathioprine - antiproliferative agent - purine synthesis inhibitor
Corticosteroids
Risks of immunosuppression
1) Increase risk of getting infection both conventional infections and opportunistic
2) Activation of dormant pathogen such as TB due to immunosuppression
3) Cardiovascular morbidity and mortality
4) Azathioprine - side effects include nausea, vomiting anaemia and Cyclosporin - side effects include convulsions, pancreatitis, kidney and liver dysfunction
5) Increase risk of malignancy
Blood film iron deficiency anaemia
Anisocytosis, Poikilocytosis, Hypochromasia, Pencil Shaped RBC
Drugs that cause iron deficiency anaemia
NSAIDS
Fluoroquinalone
Advantages and disadvantages of PCR, electron microscope, cell culturing and immunofluorescence
PCR; advantage; able to work out viral load. Also highly sensitive method (low rate of false negatives) used to detect specific sequences of nucleic acids. Disadvantage; prone to contamination
Electron microscope; able to visualise the viral structure disadvantage; expensive? Not highly specific?
Cell culture; able to see viral susceptibility to drugs ( useful for phenotypic antiretroviral susceptibility testing) disadvantage;slow and time-consuming
Immunofluorescence - useful for direct detection of viral antigens in clinical setting. used for typing and cell culture confirmation, rapid and inexpensive. Disadvantage - subjective and dependant on skill of technician and quality of sample
Advantages and disadvantages of molecular techniques and culture
Culture: advantage; figure out which antibiotic to use (test for antimicrobial resistance). Disadvantage; it takes about 24 hrs to grow the bacteria and another 24 hrs to do the susceptibility testing.
Molecular techniques: advantage; rapid and sensitive (low level of false negatives). Disadvantage; myriad of resistance genes.
Tacrolimus side effects
side effects include cardiac damage, nephrotoxicity, lung damage, increased chance of malignancy
Side effects rapamycin
Lung toxicitiy
Diabetes M
Side effects azothyoprine
nausea, vomiting anaemia
Side effects corticosteroids
Cushings
Side effects cyclosporin
side effects include convulsions, pancreatitis, kidney and liver dysfunction
How can proto-oncogene become oncogene
Amplification of gene
Point mutation
Insertion
Creation of fusion gene
Classes of proto-oncogenes
Cyclin D
C-myc
Ras/raf
EGFR
Why do you need 2 mutations for TSG
Even with 1 the other can still function
Features of thrombocytopenia
Superficial bleeding into skin, mucusoal membranes, spontaneous bleeding, epistaxis, easy bruising, petechiae
How are platelets formed
Granulation of megakaryocytes
Aspirin MOA
Irreversible COX 1 inhibitor - prevents thromboxane from being produced by platelets as platelets don’t have nuclei so can’t make more enzyme.
Uses of aspirin
Use as antithrombotic in arterial thrombosis, acute coronary syndrome -STEMI and NSTEMI, atrial fibrillation
Why give red blood cells rather than full bood
1) Avoid fluid overload (potential heart failure)
2) More efficient - less is wasted because patients may not need all the components
3) Some components degenerate quickly if stored as whole blood
● Putting blood in the fridge is NOT good for the coagulation factors
● The fridge is also not good for preserving platelets
Why are red blood cells stored at 4 degrees
Preserve them
Reduced infection
What are ESCAPE bacteria
Cause hospital acquired infections
3 things causing anaphylaxis
Food
Insect bite
Medicine
Describe f actin structure
Filamentous
Soluble chain of G actin monomers
What happens in anaphylaxis
Allergens stimulate anaphylaxis via IgE antibodies. Type 1: Immediate hypersensitivity
○ IgE antibody produced
○ Antigen cross-links IgE on the mast cells and basophils
○ This leads to degranulation of IgE sensitised mast cells and release of inflammatory mediators
Cardiovascular collapse, vomiting, diahorrea.
Respiratory effects are bronchospasm and laryngeal oedema - contraction of bronchial smooth muscle and constriction of the muscles around the throat and endothelial cells within the membranes of the blood vessels move apart so you get a lot of fluid moving into the tissues
Skin effects are vasodilation, erythema, urticaria and angioedema
How does fluoride oxalate work
Inhibits glycolysis preventing glucose uptake
Things looked for when grading a tumour
Abnormal growth pattern
Loss of uniformity
Deeply staining nuclei
Variation in shape/size
Things for when staging a tumour
Site of tumour
Size of tumour
Sites of metastases
Lymph node involvement
Sequence to carcinogenesis
There is damage or random mutation in the cells that affect cell proliferation pathways.
They become permanently switched on (oncogenes)and lose the ability to apoptose (tumour suppressor genes).
They proliferate uncontrollably, even without external stimulation, and often remain poorly differentiated.
They can also gain the ability to become invasive via loss of anchorage-dependence and can spread away from the primary cancer site.
4 common resp infections
Mycobaterium tuberculosis (Gram +ve) streptococcus pneumoniae (Gram +ve) Haemophilus influenzae (Gram -ve) Legionella pneumophila (Gram -ve)
2 types of cervical cancer
Squamous cell carcinoma
Adenocarcinoma
ESCAPE bacteria
Enterococcus faecium (+) Staphyloccocus aeureus (+) C. Difficile (+) Clostridium Difficile Acinetobacter baumannii (-) Pseudamonas aeruginosa (-) E. coli (-) Escherichia
Things done with stool sample
Naked eye examination Culture for bacteria on agar Microscopy to look for cysts Parasite staining Toxin detection Antigen detection (EIA) PCR Test for Salmonella: XLD (xylosine lysine deoxycholate) agar goes bright pink or red colour and bacteria produces hydrogen sulfide so forms black colonies on agar. Campylobacter: incubate sample at 42 degrees
Things included in report to doctor from microbiologist
Any abnormalities - Appearance, culture results, any sensitivity test results
Tests carried out and findings of each test
If there was an infection and if so the type of bacteria
How much infection there was (number of bacteria).
Early effect of chemotherapy
Nausea
Delayed effect of chemotherapy
Lethargy
Late effect of chemotherapy
Immunosuppression
Psycological effect of chemotherapy
Anticipatory vomitting
What is a gray
1j of energy per kg of tissue
2 examples of biotic anti cancer therapy
Cisplatin – adds a platinum group to guanine, causing DNA interlinks and intralinks. The DNA is unable to uncoil at replication and therefore undergoes apoptosis.
Bevazizumab - VEGF-R
Effects of GTPases and their effects on motility
Cdc42 promotes filopodia – polarised activity and actin polymerisation
Rac promotes lamellipodia – actin polymerisation and branching.
Rho promotes stress fibres – tension and contraction
Lammellipodia are thin like sheets of polymerised actin that are used to project the front of the cell forward.
Filopodia are finger like projections that also move forward and are used in combination of lamellopodia to extend the cell.
Stress fibres are contracted and are used to drag the cell forwards. They are anchored on focal points (ie points of anchorage at the front of the cell).
Difference in migration of normal and tumour cells
Tumour cells lose their anchorage dependent and cell-cell adhesion and are consequently able to migrate and invade uncontrollably.
When would take liver sample
To check for primary liver cancer
To investigate for cirrhosis
To check for liver infection
To detect presence of metastasis
Why give anaemics RBC not whole blood
Whole blood may cause fluid overload
Only need RBCs
There’s a shortage of blood, so why give clotting factors when they’re not needed.
Concept of universal donor
A universal donor has blood type O-.
This means they have no A or B antigens or Rh-D antigens so it can be given to any blood type as there are no antigens in the blood so it will not cause a haemolytic reaction in the recipient that may contain antibodies (anti-A or anti-B or anti-D)
Potential problems with this - there are hundreds of red cell antigens on membranes (C, c, E, e etc) and 12-15% of them are clinically significant but are not matched for when giving transfusions. Therefore, a patient on a prior transfusion may have developed an antibody to one or more of these antigens. This can lead to a delayed haemolytic reaction
Immunological occurences of asthma
Allergen presentation via dendritic cell to Th 2 cells.
These then cause degranulation of eosinophils by releasing IL-5
Th2 cells also release IL-4 and IL-13, which stimulate the production of IgE by plasma cells
The IgE then becomes mobilised onto the surface of mast cells
The antigens then cross-link with the IgE on the surface of the mast cells and cause degranulation
Degranulation causes histamine, cytokines, toxic proteins, leokotrienes and prostaglandins to be released.
These cause vascular leakage → airway oedema, mucus secretion and smooth muscle contraction arounf bronchi → bronchoconstriction
Clinical features of asthma
SOB
Mucous production leading to cough
Wheezing
Chest tightness
Features of thrombocytopaenic bleeding
Spontaneous bleeding
Nosebleeds
Prolonged bleeding
How can infection predispose to hypersensitivity/allergy
1) Molecular mimicry of other molecules
2) induction of co-stimulatory molecule or inappropriate MHC class II expression -> proinflammatory environment,
3) failure in regulation -> effects on regulatory T cells,
4) immune deviation -> shift in type of immune response eg Th1 to Th2
Why is suppression used in faecal testing
Many other flora bacteria in faeces
Features on blood film for megaloblastic anaemia
Macrocytosis Hyper-segmented Neutrophils Anisocytosis and poikilocytosis Low Hb, platelets and WCC Giant Metamyelocytes Howell Jolly bodies
When do you give DDAVP
Haemophilia
Type 1 vWb disease
Common cancers giving vertebral metastases
Breast, Prostate, Lung
Cytological features looked for in staging
Degree of differentiation, number of mitotic bodies, pleomorphism, integrity of cells, necrosis
Cancers leading to physiological functioning changes
Lung cancer - can secrete ACTH -> cushing’s
Thyroid cancer - secrete thyroxine -> thyrotoxicosis
Non enzyme substances looked for when doing lLFTs
Bilirubin
Albumin
How configuration of Hb helps oxygen delivery
A lower pH, as in metabolically active tissues, lowers the oxygen affinity of Hb and facilitates the downloading of O2 to tissues.
HbA can carry up to 4 oxygen molecules. This is referred to as different liganded states. The main function of Hb is the carriage of oxygen from the lungs to metabolically active tissues. To facilitate this, the Hb can exist in two spatial configurations.
Deoxy haemoglobin exists in a tight configuration and has a relatively low affinity for oxygen.
Oxygen molecules are taken up sequentially by the 4 haem groups.
At some point the partially liganded Hb molecule switches to a relaxed configuration which has a markedly higher affinity for oxygen.
Universal donor
O neg, no A, B or D antigens on RBC surface
Other uses of tamoxifen
Infertility
Gynaecomastia
Why is PSA elevated in blood in prostate cancer
PSA is normal part of seminal fluid, only released into serum upon damage to prostate, such as in prostate cancer, thus causing elevated levels PSA
3 genomic causes of androgen independence
Mutation allows the prostate to respond to anti-androgens and oestrogen.
Upregulation of androgen receptors in response to low levels of circulating androgen and other weak androgens or by co-stimulatory molecules.
Also decreased levels of co-repressors of the prostate.
G1 checks on cell
Assesses chromosome stability
ext environment
cell size
G2 checks on cell
cell size
ext environment
correct and complete DNA replication
Vaccinated bacterial infections
Hemophilus influenzae (Gram -) Neisseria meningitidis (Gram -) Streptococcus pneumoniae (Gram +) clostridium tetani corynebacterium diphtheriaea ←is this not clostridium diptheriae? Salmonella typhi Bacillus anthracis Bordetella pertussis
What causes high Hb and Hct
Polycythaemia
Advantage of diagnosing sickle cell at birth
Penicillin
● Should be started at 3 months of age to reduce the risk of life-threatening pneumococal infection
Vaccination
● Against the organisms that individuals with hyposplenism are susceptible to
Monitor Spleen Size
● Splenic sequestration is a potential cause of death in young people (repetitive vaso-occlusive damage from infarction from early life)
● Parents can be taught how to monitor spleen size
Prophylaxis against pneumococcal infection
● Risk of recurrent stroke in children with sickle cell anaemia is very high so they should keep having regular transfusions
Induction of HbF
HYDROXYUREA (Hydroxycarbamide)
● This is cytotoxic - it is a ribonucleotide reductase inhibitor
● It induces the production of red cells in the bone marrow that mainly contain HbF
● This means that, over time, there will be an increase in the number of red cells that are UNABLE to sickle
● It will also have other effects such as reducing the adhesion to the vascular endothelium
Reason for elevated Hb in sickle cell
Low affinity for oxygen so releases it to tissues meaning less EPO released
Free Hb from intravascular haemolysis
How can ALL cause hyperuricaemia. Is this clinically significant? How?
Hyperuricaemia esult of the release of cellular contents of dying cells into the bloodstream from breakdown of cells after cytotoxic therapy or from cancers with high cell turnover and tumor proliferation rates
result in nausea and vomiting, acute kidney failure, seizures, cardiac arrhythmia, death
Reason for bone pain in ALL
Increased pressure in bone marrow
Reason for anaemia in ALL
Reduced production of other cells
Reasons against prostate screening
PSA not only released by prostate cancer, elevated levels can be due to other reasons so this may cause undue anxiety while they wait for further, invasive, investigations
A raised PSA will cause further invasive tests to occur, and cause acute anxiety for patient. If cancer is detected will undergo treatment - has unpleasant side effects - decrease quality of life. However if leason was left alone may not have affected man in his lifetime.
Most probable cause of high lymphocytes and normal other cells
T cell hodgkins lymphoma
Causes of eosinophilia
Parasites
Autoimmune
Test for hodgkins lymphoma
TCR gene recombination
Test for B12 deficiency
Schilling
Romberg
Example of antigenic shift
Influenza
Example of antigenic drift
Rhinovirus
Why do blood samples sometimes show abnormally high potassium levels
Haemolysis of RBCs
What differentiates serum from plasma
Plasma contains clotting proteins, serum does not contain clotting proteins
Diagnosing viral infection
- Cell culture
- Electron microscopy
- Immunofluorescence (IF)
- Enzyme immuno assays (EIA)
- Viral genome detection and quantification – PCR
What observations on urine sample
Bedside examination with the naked eye: is the specimen clear, cloudy, haemorrhagic etc.
● Microscopy: the cell types that may be present include white blood cells (high
concentrations indicate infection), red blood cells, epithelial cells etc. Crystals and casts
may also be present.
● Culture on agar: urine should be sterile so any growth may suggest infection.
● Quantitative colony count: for significant bacteruria of >105 bacteria/mL.
● Antibiotic sensitivity testing: for any bacterial growth.
4 benefits of autopsy
- To determine the cause of death of a patient.
- To explain why treatment for the patient was unsuccessful.
- To show the spread of disease.
- To educate doctors regarding disease processes.
3 ways to generate commercial antibodies
- Antisera from immunised animals.
- Monoclonal antibodies.
- Genetically engineered antibodies.
When do you find smear cells
CLL
Use of thrombin clotting time
Detects abnormalities in the fibrinogen to fibrin conversion
Differentiating between primary and reactive lymphocytosis
- Immunophenotyping – test for light chain restriction.
2. Test for gene rearrangement using Southern Blot analysis.
Prophylactic measures for sickle cell
1 Folic acid 5mg / day To compensate for the short RBC lifespan, RBC
turnover may be increased, depleting stores of
folic acid.
2 Vaccination To protect against pneumococcal infection
(normally dealt with by the spleen; hyposplenism
is a feature of sickle cell anaemia).
3 Penicillin prophylaxis To prevent some of the infections caused by
hyposplenism
4 Monitoring spleen size To check for future splenic sequestration
Example of bacteria and their virulence factor
● Capsule - S.pneumoniae
● Endospores - clostridium, bacillus
● Biofilms - pseudomonas aeruginosa, staphylococcus epidermis
● Neurotoxins - tetanus, botulinum
● Enterotoxins - infectious diarrhoea (V. cholera, E. coli, C. Jejuni, etc …), food poisoning (S.
aureus, B. cereus)
● Pyrogenic exotoxins - S. Aureus, S. pyogenes
● Tissue invasive exotoxins - S. Aureus, S. pyogenes, C. perfringens
● Endotoxins - any gram negative bacteria
Resistance to vancomycin, methicillin, cephalosporins and carbapenems
Cephalosporins Inhibit peptidoglycan synthesis by inhibiting the activity of penicillin binding proteins Extended spectrum beta lactamase cleaves cephalosporins Carbapenems Inhibit peptidoglycan synthesis by inhibiting the activity of penicillin binding proteins Carbapenemase enzyme encoded on a transposon which cleaves carbapenem Methicillin Inhibit peptidoglycan synthesis by inhibiting the activity of penicillin binding proteins Expression of additional penicillin binding proteins such as PBP2A 13 Vancomycin Inhibit peptidoglycan synthesis by binding to a peptidoglycan precursor Multiple proteins synthesised by genes carried on a plasmid or transposon resulting in the synthesis of different peptidoglycan precursors
7 ways viruses can evade interferon system
- Hide the PAMP to avoid detection
- Interfere with host gene expression/protein synthesis no ISGs made
- Blocking interferon induction cascades
- Inhibiting interferon signalling
- Block the action of individual interferon induced antiviral enzymes specifically
- Activate SOCs genes
- Replication strategy insensitive to IFN, i.e. too quickly for IFN to work
How knowledge of evasion of interferon system can be used in future therapies
1) Vaccines: if we block the ability of viruses to control the interferon response they become
attenuated, and thus can be used in vaccinations.
2) Influenza therapy: interferon lambda receptors are only present on epithelial surfaces. Since this
is where influenza grows, interferon lambda could potentially be used as influenza therapy with
lesser systemic side effects than type 1 interferons, which bind to many cell types.
3) Cancer therapy: cancer cells are deficient in interferon so viruses are able to grow well in them.
Viruses could therefore be used to lyse cancer cells, without harming healthy cells.
Differences between protozoa and metazoa
Protozoa Metazoa
Single-celled Multicellular
Do not produce eosinophilia in the host Forms which invade the blood often cause
eosinophilia
Acute and chronic immunopathophysiology of asthma
Acute ● Mast cell activation and degranulation ● Release of preformed histamine and newly formed prostaglandin and leukotriene ● Features: o Vascular leakage o Mucosal oedema, mucous secretion and smooth muscle contraction leads to acute, reversible airway narrowing Chronic ● Th2 lymphocyte and eosinophil activation ● Features: o Inflammatory cellular infiltration o Tissue damage o Epithelial cell shedding o Sub-epithelial fibrosis o Smooth muscle hypertrophy o Mucus pluggin
Tissues transplanted and reasons for transplants
Failed organ / tissue Reason for failure
- Cornea
- Skin
- Kidney
- Liver
- Heart
- Lungs
- Pancreas
- Bone marrow
- Small bowel
- Degenerative disease, infections, trauma
- Burns, trauma, infection
- Diabetes, hypertension, glomerulonephritis, hereditary conditions
- Cirrhosis, acute liver failure
- Coronary artery/valve disease, cardiomyopathy, congenital defects
- COPD, interstitial fibrosis, cystic fibrosis, pulmonary hypertension
- Type I diabetes
- Tumours, hereditary diseases
- ‘Short gut’, Crohn’s, vascular disease etc
Define tolerance
Acquired inability to respond with an immune reaction to an antigen to which the organism usually
responds
Name and describe 3 tolerance mechanisms
- Anergy: an absence of costimulation for naïve T cells results in a refractive state so that cell
proliferation and factor production cannot proceed. - Ignorance of antigen: occurs in immunologically privileged sites where immune cells cannot
normally penetrate, such as the eye. - Suppression by regulatory T cells: autoreactive T cells are present but controlled by ‘regulatory’ T
cells to prevent them from responding to autoantigen.
Example of diseased caused by central tolerance issue
APCED
Example of disease casued by peripheral tolerance issue
IPEX
How can infection lead to issue with tolerance
- Molecular mimicry of self molecules
- Induction of co-stimulatory molecules
- Induction of inappropriate MHC II expression
- Failure of regulatory T cells
- Shift in the immune response from Th1 to Th2
- Tissue damage at immunologically privileged sites leading to ‘leakage’ of antigen
Genomic causes of oncogenes
● A mutation in the coding sequence (point mutation or deletion) leading to an aberrantly
active protein.
● Gene amplification leading to multiple gene copies and overproduction of the normal protein.
● Chromosomal translocation: an inappropriate piece of one chromosome is joined to another
chromosome e.g. a ‘strong enhancer’.
● Insertional mutagenesis: a virus inserts its genome into the host, which fuses to actively
transcribed gene leading to overproduction of a protein or the fusion protein itself is
overactive.
Angiogenesis in disease
Cancer ● Chronic inflammatory diseases ● Diabetic retinopathy ● Cardiovascular disease ● Psoriasis ● Vascular malformation
Angiogenesis physiological
Wound healing
Embryo
Menstrual cycle
