Exam Questions Flashcards
(9 cards)
Draw a flow diagram showing the cellular and molecular events that had occured when this patient’s skin became inflammed due to the sunburn.
Direct skin DNA damage by UV light in sunburn causes acute inflammation of the skin.
The inflammation is the body’s response to the tissue injury. Pro-inflammatory substances will be released from injured and necrotic cells that activate macrophages in the tissues and endothelial cells lining local blood vessel walls.
the activated endothelial cells produce inflammatory cytokines, prostaglandins and NO -> vasodilation and increased permeability of blood vessels in injured tissue
This leads to hyperaemia (an increase in blood flow to the damaged tissue) and flow of protein-rich fluid (exudation) out of vessels into damaged tissue -> oedema. This fluid exudate contains proteins key to the inflammatory response e.g. antibodies, fibrinogen (‘glue’ which seals damaged blood vessels and stabilises damaged tissues), proteins of the complement, kinin and plasmin cascades.
This flow of fluid out of the blood vessels -> increase in blood viscocity and slowing of blood flow -> stasis. As stasis develops, leukocytes are found at the edges of the blood flow (margination) allowing leukocytes (mostly neutrophils) to accumulate along the vascular epithelium. There is an increase in cell adhesion molecules on the endothelial cell lumenal surface e.g. selectin which slows the flow of neutrophils so they roll slowly along the endothelium. Integrin is a cell adhesion molecule expressed on neutrophils that bind to addressins on the endothelial cell surface causing the neutrophil to stop and adhere firmly to the endothelium. The neutrophils then move into the tissues = diapedesis by inserting extended cell processes into the junctions between epithelial cells and squeezing through the inter-endothelial junctions.
Neutrophil summary: rolling, integrin activation by chemokines, stable adhesion, migration through endothelium.
Once in the tissues, neutrophils are activated by chemokines, IL-1, TNF-alpha etc and this binds to TNF-a recpetor causing release of NFkb which activate and recruit neutrophils. These are signals released from damaged tissues, activated endothelial cells and other leukocytes. Neutrophils migrate to the site of injury via chemotaxis (from substances like bacterial products, components of the complement system, chemokines etc. In general, chemotactic factors bind to specific G-protein-coupled receptors on the surface of the leukocyte causing extension of filopodia toward the site of injury
Neutrophils then attack the cause of the inflammation, however those that are killed and undergo necrosis damage adjacent tissues. Dead neutrophils + tissue debris + bacteria -> pus which is seen in particularly bad sunburn.
Signs of inflammation: redness, swelling, heat, pain, loss of function
Define the following terms:
Somatic cell
Germ cell
Autosomal
Mutation
Polymorphism
Silent mutation
Missense mutation
Nonsense mutation
Frameshift mutation
Dominant
Recessive
Autosome
Gain-of-function mutation
Loss-of-function mutation
Dominant negative
Allelic heterogeneity
Locus heterogeneity
Non-disjunction
Translocation
somatic cell - all cells in the body that are non-gamete cells
germ cell - gamete cells i..e sperm and egg cells
autosomal = related to chormosomes that are not sex chromosomoes
mutation - alteratin, change or deletion in the sequence pf genomic DNA which can be passed onto offspring
polymorphisms - the existence of two or more variants (alleles and chromosomal variants) that are non-pathogenic, with the less common variant occuring at <1% frequency in the normal population
silent mutation - a single base change that does not result in an AA change
missense - a single base change that does result in an AA change.
nonsense - single base chnage that chnages an AA to a stop codon, meaning that the resulting protein may be truncated and thus cause a loss of normal activity
frameshift mutation - where insertions or deletiond of multiples of other than 3 cause a the reading frame of the DNA to be altered
dominant - vertical transmission of a gene in a heteozygous form, whereby the inheritance of a mutated allele results in the disorder
recessive - transmission of a gene in heterozygous form causes the individual to be a carier of that disorder. in the homozygous form, transmission of the mutant alleles results in the phenotype
autosome - non-sex chromosomes i.e. we have 22 autosomes in our genome
gain of function mutation - inheritance of an additional allele causes overexpression of the gene
loss of function mutation - where either a loss of an allele, or loss of a normal function of alleles results in reduced expression of the gene, hence lower protein product
dominant negative - loss of fucntion mutations in heterozygous form, where the mutant popylpetide reduces the acitivity of the wild-type protein
allelic heterogeneity - different mutations at the same locus of the same gene
locus heterogeneity - mutations at different gene loci cause the same or similar phenotypic manisfestations of the disorder
non-disjunction - failure for homologous chromosomes to segrate at meiosis or mitosis phases
translocation - where breaks in the arms of a chromosome and subsequent rearrangement of fragments at different chromosomal location, can cause overall loss, or gain in genetic material
What is the difference between a benign tumour and a malignant tumour?
Histopathological:
-Benign if hasn’t metastasised, Malignant if has.
-Benign if well differentiated, Malignant if undifferentiated (specific functional genes switched off, proliferative genes switched on, therefore high grade due to all proliferative genes switched on)
-Benign if expansile growth (pushes tissue out of the way, Malignant if rapid and invasive growth.
-Benign if non-fatal, malignant if has high risk of fatality.
Describe how experimental studies have identified two categories of cancer-causing agents that interact to produce skin cancers. How does sunlight act in these two capacities in the skin to produce epithelial tumours?
Cancer causing agents can be classified as Initiator carcinogens and Promoter Carcinogens. A carcinogen that is able to both promote and initate cancer is called a complete carcinogen. Common in skin cancer, a gene which is most notably effected is the p53 gene, which is a Tumour Supressor Gene.
An example of an Intiator carcinogen in the development of skin cancer is UVB rays from sunlight. UVB rays are not able to penetrate the skin as deeply compared to other rays such as UVA. UVB causes damage to DNA by causing DNA adducts to occur. This results in C to T transistions due to DNA repair machinary not working properly, thus resulting in a mutation.
An example of a Promoter Carcinogen in the development of skin cancer is UVA rays from sunlight. UVA ray are able to penetrate the skin much more deeply in comparison to UVB. It causes Reactive Oxygen Speices to be made which causes indirect damage to DNA.
Prenatal genetic screening vs Prenatal diagnostic testing:
Prenatal genetic screening: These tests only determine if the baby has an increased risk of having a particular disease or problem, an increased risk does not result in the baby definitely having the disease. These tests are non-invasive and are low-risk. Results tend to be found out faster. Screening tests include:
- Ultrasound scanning (can be diagnostic aswell) (8-10 weeks and 18 weeks)
- Non-invasive prenatal testing (NIPT)
- Maternal serum testing (15-17)
If positive screening tests, then lead to…..
Prenatal diagnostic testing: Determines if the baby definitely has or will develop a disease after birth. These are more invasive tests and carry some risks. If testing for genetic conditions within families, straight to diagnostic tests. If testing for chromosomal or other genetic abornmalities do screening tests first. Results take longer to come out. Diagnostic tests include:
- CVS testing (can be done at 11-12 weeks)
- Amniocentesis (done at 15-19 weeks)
- Fetoscopy + umbilical cord blood sampling (rarely done as it is performed too late in the pregancy for anything to be done.
- PGD where IVF has been used to conceive child
List the sorts of cells you would expect to find in this man’s spleen and summarise the functions of each of them.
The spleen is a secondary lymphoid organ, so most of the cells found in the spleen would be involved in the immune system.
- B lymphocytes: recognise extracellular pathogens and mark them with antibodies so that it can be phagocytosed or killed
- CD8 T cells: recognise antigens presented by own cells on MHC I receptors and have cytotoxic abilities which are activated when an antigen is recognised as non-self
- CD4 T cells: recognise antigens presented by antigen-presenting cells on MHC II receptors. Once an antigen is recognised they secrete cytokines which activat the immune system such as phagocytes, Killer cells, complement system and neutrophils
Antigen presenting Cells: they roam around the body, picking up anything present in ECM which could possibly be an antigen. They return to secondary lymphoid organs, such as the spleen, where they will present what they have picked up on their MHC II receptors to CD4 cells.
Other leukocytes may be found in the spleen such as neutrophils (inflammation), phagocytes such as macrophages (phagocytosis), killer cells (cytotoxic)
Describe the changes that occur inside a cell following cell injury, including the changes driven by reduced availability of ATP.
MEMBRANE DAMAGE:
LOSS of cellular contents, osmotic balanace,
Influx of fluids and ions,
Loss of proteins: enzymes. coenzymes & rNA
LYSOSOMAL MEMBRANES:
Leakage of enzymes causing digestion of cellular components - autolysis
MITOCHONDRIAL MEMBRANES
Formation of nonselective highconductance mebrane channels in inner mitochondrial membrane, removing the transmembrane potential needed for oxidative phosphorylation. As a consequence, leakage of cytochrome C into the cell primes the cell for apoptosis.
Loss of cytochrome C also decreases energy production and hinders oxidative phosphorylation
INCREASED CYTOSOLIC CALCIUM: destructive calcium-dependent enzymes in cytosol
ATPase: decreased ATP
Phospholipase: damage to lipid components of membranes
Protease: break down membrane and cytoskeletal proteins
Endonucleases:DNA and Chromatin damage
REACTIVE OXYGEN SPECIES DAMAGE
Lipid Peroxidation: break double bonds in unsaturated fatty acids in membranes
Enzyme Damage:via oxidation of amino acid residue side chains
Thiamine Reactions:Causing damage to nuclear and mitochondrial DNA
*molecules with which ROS react also converted to free radicals
REDUCED ATP: loss of energy dependent cellular functions
ENZYME ACTIVITY: reduced energy for enzymes involved in repair of damages DNA and proteins
ATP ION PUMPS: reduced activity of ATP driven ion pumps that control ionic and osmotic gradients of the cell and organelles
Na+ pump: causes influx of NA+ and water accumulation so the cell swells
Ca2+ pump: influx of Calcium into the cell, activating destructive calcium-dependent enzymes
PROTEIN SYNTHESIS: decreased protein synthesis as a result of decreased energy driving the process
mode of inheritance for each of the following disorders:
Marfan syndrome
Achondroplasia
Phenylketonuria
Down syndrome
Hereditary Haemochromatosis
Beta Thalassaemia
Marfan syndrome: AD
Achondroplasia: AD
Phenylketonuria: AR
Down syndrome: Sporadic
Hereditary Haemochromatosis: AR
Beta Thalassaemia: AR
Haemophilia A: X-linked recessive inheritance
Huntington’s disease: Autosomal dominant inheritance
Define the following terms:
Apoptosis
Necrosis
Cell injury
Hyperplasia
Metaplasia
Hypertrophy
Autophagy
Acute inflammation
Chronic inflammation
Granulation tissue
Organisation
Apoptosis: regulated cell death (suicide). Requires ATP. “clean”, no collateral damage. CytC from mito. Cell and contents shrink and appear darkly stained pink in H&E (anoikis, pyknosis), also see apoptotic bodies which are phagocytosed by macrophages.
Necrosis: uncontrolled, messy cell death. No ATP required. Causes collateral damage due to leakage of proteolytic enzymes –>inflammation. Pathogenic. See vacuolation due to lysozome bursting and autophagy. See membrane blebs, anucleated cells, pale cells.
Cell injury: Injurious stimulus e.g., hypoxia, ROS, radiation, pathogen, toxin causes cellular damage–>loss of function. May be repaired or lead to apoptosis signalling (and necrosis).
Hyperplasia: Increase in cell number due to increased functional need. May be via cell division or stem cells.
Metaplasia: Persistent injurious stimulus –>adaptation by changing into a more resistant adult cell type. Reversible. Stimulate stem cells to differentiate via different pathways.
Hypertrophy: Increase in cell size as a result of increased functional need.
Autophagy: cell shrinkeage as a result of reduced functional need, loss of innervation, reduced nutrient/O2. Signalling to proteolysis and ubiquitin-proteosome system
Acute inflammation: Immediate reaction to cell injury or pathogen. Involves cytokines (TNF-a, IL-1) which signal endothelial changes (vasodilation, expression of adherance molecules, engoregement, leakyness), recruitment of neutrophils, macrophages (margination, diapadesis, chemotaxis). These cause oedema, pain, redness, functional changes, heat. Systemic effects: pyrexia, leukocytosis, acute-phase proteins, endocrine changes.
Chronic inflammation: when injurious agent is not removed and acute inflammation not resolved. Recruit macrophages, lymphocytes. Fibroblasts are also activated and may attempt to repair (via fibrosis).
Granulation tissue: results from the “organisation” stage of repair. This tissue is rich in blood vessels and fibroblasts to aid tissue repair. These are activated by the macrophages’ secretion of VEGF and FGF.
Organisation: Macrophages release FGF and VEGF which stimulate fibroblasts and angiogenesis–>repair the tissue. Granulation tissue is formed.
