Sepsis PPQ Flashcards
- C-reactive protein (CRP) is an acute phase protein found in the blood. The levels of CRP rise in response to inflammation.
Which organ releases this protein?
Kidney Liver Pancreas Spleen Thymus Remainder of spare ribs
Liver
IL-6 stimulates hepatocytes in the liver to produce acute phase proteins (APP) including C-reactive protein (CRP). CRP binds to phosphoryl choline, which is found on the surface of many pathogens and is exposed after tissue damage. It activates complement and binds to phagocyte Fc receptors and therefore acts as an opsonin. Binding of CRP to Fc receptors triggers phagocytosis and stimulates the release of more cytokines.
CRP is used as a non-specific serum biomarker of acute inflammation (or flare-up on chronic inflammatry conditions) or infection.
- Erythrocyte sedimentation rate (ESR) is a measurement used as a marker of inflammation.
Which component of the blood rises during inflammation to cause an increase in this measurement?
A Fibrinogen
B Folate
C Heparin
D Thrombospondin
E Tissue factor pathway inhibitor
A Fibrinogen
IL-6 stimulates hepatocytes in the liver to produce acute phase proteins (APP) including C-reactive protein (CRP). CRP binds to phosphoryl choline, which is found on the surface of many pathogens and is exposed after tissue damage. It activates complement and binds to phagocyte Fc receptors and therefore acts as an opsonin. Binding of CRP to Fc receptors triggers phagocytosis and stimulates the release of more cytokines.
CRP is used as a non-specific serum biomarker of acute inflammation (or flare-up on chronic inflammatry conditions) or infection.
- A pharmaceutical company is interested in developing novel drugs for gastrointestinal ulcers. Peptic ulceration can occur due to inhibition of prostaglandin production.
NSAIDs (nonsteroidal antiinflammatory drugs) produce this effect by preventing breakdown of which precursor?
A Arachidonic acid
B Phosphatidylinositol (4,5) bisphosphate
C Phosphatidylinositol (3,4,5) trisphosphate
D Prostacyclin
E Thromboxane A2
A Arachidonic acid
Cyclooxygenase (COX) inhibitor drugs have been used as anti-inflammatory agents for many years. However, some of these drugs carry a risk of stroke or myocardial infarction, due to inappropriate blood clotting resulting from the non-specific inhibition of arachidonic acid metabolism.
- Cyclooxygenase (COX) inhibitor drugs have been used as anti-inflammatory agents for many years. However, some of these drugs carry a risk of stroke or myocardial infarction, due to inappropriate blood clotting resulting from the non-specific inhibition of arachidonic acid metabolism.
Which other enzyme in this pathway could be specifically inhibited to reduce the risk of clotting?
A Lipoxygenase
B Phospholipase C
C Prostacyclin synthase
D Prostaglandin E synthase
E Thromboxane synthase
E Thromboxane synthase Image from: cvphysiology.com "Arachidonic Acid Metabolites (Prostaglandins and Related Compounds)" | http://www.cvphysiology.com/Blood%20Flow/BF013 Phospholipase C not involved in this pathway. PLC enzyme breaks down membrane phospholipids as part of the G-alphag signalling cascade (IP3, DAG ------> Ca2+ (from ER or SR via IP3R), PKC). Intitiating enzyme which breaks down membrane phospholipids in the arachdonic acid pathway (biosynthetic pathway of the inflammatory mediators prostaglandins, leukotrienes, thromboxane and plateletactivating factor) is phospholipase A2 (PLA2). Arachidonate is converted to the cyclic endoperoxidase, prostaglandin H2 by cyclooxygenase (COX) enzymes. Thromboxane (TXA2) is a vasoconstrictor that promotes clot formation (thrombotic). It is formed from the cycloendoperoxide, prostaglandin H2 (PGH2) by thromboxane synthase. Note TXA2 acts on vascular smooth muscle via Gsignalling, which releases Ca2+ from the SR, via IP3R. Ca2+ binds to calmodulin and activates myosin light chain kinase, MLCK leading to smooth muscle contraction and vasoconstriction) Prostacyclin (PG12) is a vasodilator and inhibitor of platelet adhesion (anti-thrombotic). It is formed from the cycloendoperoxide, prostaglandin H2 (PGH2) by prostacyclin synthase. Prostaglandin E (PGE2) is a vasodilator and is synthesised from the cycloendoperoxide, prostaglandin H2 (PGH2) by the action of PGE synthase (also called isomerase). Note prostacylin and PGE2 signal to smooth muscle via a Gs coupled receptor: CAMP inhibits the myosin light chain kinase, MLCK and promotes smooth muscle relaxation - vasodilation).
- You are a researcher investigating the role of platelet-derived growth factor (PDGF) signalling in airway remodelling in asthma. PDGF signals for cell proliferation via binding to its receptor, leading to the activation of Janus kinase (JAK). Active JAK then phosphorylates Signal Transducer and Activator of Transcription (STAT) proteins enabling them to dimerise and translocate to the nucleus.
Which protein domain of STAT is required for recruitment to the receptor?
A GTPase domain
B Phosphatase domain
C Serine/threonine kinase domain
D SH2 domain
E Tyrosine kinase domain
D SH2 domain
- Many pharmacological agents act at receptors, which act to convert a chemical signal into a physiological response. Different classes of receptor exist, which utilise different mechanisms to convert the signal into a response.
Which of the following receptors is coupled to tyrosine kinase activity?
A Beta (β1) adrenergic receptor
B Erythropoietin (EPO) receptor
C Glucocorticoid receptor
D Muscarinic (M2) acetylcholine receptor
E Nicotinic acetylcholine receptor
B Erythropoietin (EPO) receptor
EPO receptor signals via JAK/STAT. Other JAK/STAT receptors inlcude cytokine receptors for the ligands IFN-gamma and IL6. Growth Hormone and prolactin are ligands that also signal via a receptor that is coupled to the JAK/STAT pathway.
Ligand (EPO or cytokine) binds to receptor causing receptor dimeration Dimerisation attracts cytosolic JAKs (tyrosine kinases) to the receptor monomers JAKs phosphorylate receptor on tyrosine residues STATs recruited to the receptor and bind the receptor phosphotyrosines via their SH2 domains STATs are phosphorylated by JAKs on single tyrosine Phosphorylated STATs dimerise and translocate to the nucleus and act as transcription factors.
- A 23 year old woman is rushed to hospital with suspected bacterial meningitis. One available diagnostic test for meningitis is culture of cerebrospinal fluid to look for the presence of bacteria.
What is the major limitation of this approach to the diagnosis of this condition?
A Cost of the test
B Risk of sample contamination
C Sensitivity of the test
D Specificity of the test
E Speed of the test
E Speed of the test
Consider the time course of the development of symptoms postinfection as detailed in the Lancet paper from the lecture. Non specific symptoms in the first 4-6 hours. Classic symptoms including haemorrhagic rash, neck stiffness, light aversion develop late (13-22 hours) and children may be close to death by 24 hours.
Basic cytological examination of the CSF can indicate presence of different classes of leukocyte and the glucose and protein concentration. Presumptive identification of disease causing bacterial species can be obtained reletively quickly with Gram staining of centrifuged CSF sediment.
Culture of the CSF requires around 48 hours to culture (grow) any bacteria that may be present. Can be used to test antibiotic senstivity of the bacteria. Important for undertstanding which bacteria are causing disease in the population.
- A 42 year old man develops severe sepsis following bowel perforation resulting from acute diverticulitis. His blood pressure falls rapidly, and he is at risk of multiple organ failure if prompt treatment is not administered. The pathogen responsible for this condition is confirmed as E. coli on laboratory analysis, a Gram negative bacterium usually found in the bowel.
Which immune cell receptor is involved in detecting the presence of this microorganism?
A B cell receptor
B Fc receptor
C Scavenger receptor
D T cell receptor
E Toll-like receptor
E Toll-like receptor
- Scavenger receptors present on cells recognise anionic polymers and acetylated low-density proteins. The CD14 scavenger receptor binds to lipopolysaccharide (LPS).
Which Toll-like receptor (TLR) does this then activate?
A TLR2
B TLR4
C TLR5
D TLR6
E TLR7
B TLR4
During an inflammatory response, activation of NFkappaB signalling leads to the transcription of a gene coding for an enzyme. This enzyme synthesises a molecule which causes vasodilatation,
10. A pathogenic bacterium enters the body. In response, the immune system upregulates pro-inflammatory cytokines in order to mount a defence against the organism.
Activation of which transcription factor is responsible for this increase?
A Gli
B Glucocorticoid receptor (GR)
C Hypoxia-inducible factor 1a (HIF-1a)
D Nuclear factor kappa B (NF-ᵬB)
E Signal Transducer and Activator of
Transcription-2 (STAT-2)D Nuclear factor kappa B (NF-ᵬB)
- During an inflammatory response, activation of NFkappaB signalling leads to the transcription of a gene coding for an enzyme. This enzyme synthesises a molecule which causes vasodilatation.
Which molecule is synthesised by this enzyme?
A Aldosterone
B Angiotensin II
C Antidiuretic hormone
D Endothelin I
E Nitric Oxide
E Nitric Oxide
INOS (inducible nitric oxide synthase) produces NO which is a ROS which is part of the oxidative burst used by phagocytes for bacterial
killing.
INOS is not constitutitive (always expressed) - it needs stimulation during inflammation (via NF Kappa B signalling, downstream of PAMPS from bacterial endotoxins binding to TLRs)
NO causes vascular smooth muscle relaxation (vasodilation or vasodilatation) by activating guanylate cyclase, which converts GTP to CGMP. CGMP activates a protein which activates the smooth muscle myosin light chain phosphatase, cGMP also inbits calcium entry into
the smooth muscle cell.
An interesting (and uplifting) point: sildenafil (viagra) is a PDE5 inhibitor. Phosphodiesterase (PDE5) is found in the corpus cavernosum of the penis and in vascular smooth muscle. It breaks down cGMP to GMP and therefore causes smooth muscle contraction. Inhibiting PDE5 enhances relaxation as it prevents this breakdown and therefore extends and enhances smooth muscle relaxation. This causes vasodilation (in blood vessels) and penile erection.
- Oxidative stress is defined as “an imbalance between oxidants and antioxidants in favour of the oxidants, potentially leading to damage” (Sies, 1991), and has been observed in numerous diseases as well as human ageing.
Which of the following catalyses the generation of the superoxide anion radical?
A Catalase
B Glutathione peroxidase
C Myeloperoxidase
D NADPH oxidase
E Thioredoxin
D NADPH oxidase
NADPH oxidase catalyses the production of superoxide anion (02) from molecular oxygen by transferring electrons from NADPH. This occurs in phagosomes. The superoxide anion is a radical that can spontaneously react with water to form hydrogen peroxide (H2O2)
Myeloperoxidase is a lysosomal enzyme which produces hypochlorous acid (HOCl) from hydrogen peroxide (H2O2) and a chloride anion (CI ). It contains haem and can give mucus its green colour when there is a bacterial infection present.
Glutathione peroxidase is a an antioxidant enzyme which catatlyses the conversion of hydrogen peroxide to water via several redox reactions.
Catalase: is another antioxidant enzyme which converts hydrogen peroxide to water and molecular oxygen 2 H2O2 → 2 H2O + O2
Thioredoxin is involved in redox signalling
- You are beginning your Professional Training Year research project in a microbiology laboratory, investigating the rise in antibiotic resistance in commensal bacteria in the general population. One of the first steps in your project is to culture and identify commensal bacterial in samples taken from the study participants.
From which part of the body would the greatest range of microorganisms be obtained?
A Blood
B Duodenum
C Hand
D Stomach
E Terminal ileum
E Terminal ileum
- You are carrying out a research project in an environmental microbiology laboratory, which involves profiling the bacteria present in samples of untreated water from streams across the South West region. As part of this study, you perform Gram staining on the samples and find purple/blue-stained spherical bacteria that are arranged in chains under the light microscope.
What type of microorganism is present in the sample?
A Gram negative cocci
B Gram negative diplococci
C Gram negative rods
D Gram positive rods
E Gram positive cocci
E Gram positive cocci
Bacterial Gram Staining & shape
spherical (cocci), rods (bacillus), curved (vibrio), and spirals (spirochetes)
Pink Gram -ve (thinner layer - counter stained by safranin) Purple Gram +ve (thick peptidoglycan layer in cell wall - retains crystal violet)
Examples:
MRSA (Methicillin-resistant Staphylococcus aureus): Gram positive cocci (bunch of grapes) E.coli: Gram negative rods
- Once severe sepsis is identified, antibiotics must be started rapidly to treat the underlying infection. Patients are often treated with broad-spectrum cephalosporin antibiotic, such as cefuroxime, until the causative organism and its specific antibiotic susceptibilities are defined.
What is the mechanism of action of cefuroxime?
A Binds to the 30S bacterial ribosome subunit
B Inhibits DNA gyrase
C Inhibits protein synthesis
D Inhibits bacterial cell wall synthesis
E Inhibits tetrahydrofolic acid synthesis
D Inhibits bacterial cell wall synthesis
Cephalosporins are beta-lactam antibiotics which inhibit bacterial cell wall peptidoglycan synthesis.
Aminoglycasides and tetracyclins inhibit bacterial protein synthesis by targeting the 30s ribosomal subunit
Macrolides and amphenicols also inhibit bacterial protein synthesis by binding the 50s ribosome
Fluoroquinolones (such as ciprofloxacin) inhibit bacterial DNA synthesis by inhibiting DNA gyrase
